2024 28 3 0 362

New drugs for Alzheimer’s disease: Aducanumab or Donanemab? 2 2 The main pathological features of Alzheimer’s disease (AD) include the cytotoxic extracellular accumulation of the amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles. The Aβ plaques are responsible for cholinergic dysfunction and dementia in AD patients. Immunoglobulin G (IgG) and Aβ form an immune complex that activates neuroglia, clearing Aβ from the brain. Various Aβ-based therapeutic strategies have been proposed to reduce Aβ production, inhibit Aβ aggregation, and increase Aβ clearance. New medicines, such as aducanumab and donanemab, which are human IgG1 monoclonal antibodies, reduce cognitive impairment in patients with AD by decreasing the amount of Aβ plaques. Despite the considerable advantages of these agents, some disadvantages have also been reported, including Aβ-related imaging abnormalities, anaphylaxis, high cost, and contradictory results. Moreover, donanemab has delivered contradictory outcomes in improving recognition and performance in AD. However, although not fully proven yet, fewer side effects are reported for donanemab compared to aducanumab. Therefore, this review aims to explore the research background, compare the mechanism of action, and understand the advantages and disadvantages of aducanumab and donanemab. As a result, these medicines with maximum effectiveness and safety, yet fewer side effects, could be developed for future treatment and references. 219 236 2023/05/16 1402/2/26 2024/04/6 1403/1/18 Mehran Joodaki Mehran Joodaki Department of physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Iran mehran.joodaki@resident.mui.ac.ir Mona Merati Shirazi Mona Merati Shirazi Biomedical engineering faculty, Biomechanics Department, Islamic Azad University, Science and Research branch, Tehran, Iran Iran merati.mona@gmail.com Nasrin Hosseini Nasrin Hosseini Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran Iran hosseini.n@iums.ac.ir Amyloid-beta Donanemab Aducanumab Alzheimer’s disease Monoclonal antibodies Abyadeh M, Gupta V, Gupta V, Chitranshi N, Wu Y, Amirkhani A, et al. Comparative analysis of aducanumab, zagotenemab and pioglitazone as targeted treatment strategies for Alzheimer’s disease. Aging and disease 2021; 12: 1964. https://doi.org/10.14336/AD.2021.0719##Aisen P S, Cummings J, Schneider L S. Symptomatic and nonamyloid/tau based pharmacologic treatment for Alzheimer disease. Cold spring harbor perspectives in medicine 2012; 2: a006395. https://doi.org/10.1101/cshperspect.a006395##Arndt J W, Qian F, Smith B A, Quan C, Kilambi K P, Bush M W, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Scientific reports 2018; 8: 1-16. https://doi.org/10.1038/s41598-018-24501-0##Ayton S. Brain volume loss due to donanemab. Eur J Neurol 2021; 28: e67-e68. https://doi.org/10.1111/ene.15007##Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiology of aging 2004; 25: 5-18. https://doi.org/10.1016/j.neurobiolaging.2003.03.001##Beshir S A, Aadithsoorya A, Parveen A, Goh S S L, Hussain N, Menon V B. Aducanumab therapy to treat Alzheimer’s disease: a narrative review. International journal of alzheimer’s disease 2022; 2022. https://doi.org/10.1155/2022/9343514##Bianchetti A, Trabucchi M. Clinical aspects of Alzheimer’s disease. Aging clinical and experimental research 2001; 13: 221-230. https://doi.org/10.1007/BF03351480##Buchman A S, Wilson R S, Bienias J L, Shah R C, Evans D A, Bennett D A. Change in body mass index and risk of incident Alzheimer disease. Neurology 2005; 65: 892-897. https://doi.org/10.1212/01.wnl.0000176061.33817.90##Budd Haeberlein S, Aisen P, Barkhof F, Chalkias S, Chen T, Cohen S, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. The Journal of prevention of alzheimer’s disease 2022a; 9: 197-210. https://doi.org/10.14283/jpad.2022.30##Cable J, Holtzman D M, Hyman B T, Tansey M G, Colonna M, Kellis M, et al. Alternatives to amyloid for Alzheimer’s disease therapies-a symposium report. 2020. https://doi.org/10.1111/nyas.14371##Chiao P, Bedell B J, Avants B, Zijdenbos A P, Grand’Maison M, O’Neill P, et al. Impact of reference and target region selection on amyloid PET SUV ratios in the phase 1b PRIME study of aducanumab. Journal of nuclear medicine 2019; 60: 100-106. https://doi.org/10.2967/jnumed.118.209130##Chiong W, Tolchin B D, Bonnie R J, Busl K M, Cruz-Flores S, Epstein L G, et al. Decisions with patients and families regarding aducanumab in Alzheimer disease, with recommendations for consent: AAN position statement. Neurology 2022; 98: 154-159. https://doi.org/10.1212/WNL.0000000000013053##Coerver K, Melissa M Y, D’Abreu A, Wasserman M, Nair K. Practical considerations in the administration of aducanumab for the neurologist. neurology: Clinical practice 2021. https://doi.org/10.1212/CPJ.0000000000001144##Costa T, Cauda F. A bayesian reanalysis of the phase III aducanumab (ADU) trial. J Alzheimers Dis: 2022;87(3):1009-1012. https://doi.org/10.3233/JAD-220132##Cummings J, Aisen P, Apostolova L, Atri A, Salloway S, Weiner M. Aducanumab: appropriate use recommendations. The journal of prevention of Alzheimer’s disease 2021a; 8: 398-410. https://doi.org/10.14283/jpad.2022.34##Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimer’s research & therapy 2021c; 13: 1-3. https://doi.org/10.1186/s13195-021-00838-z##Cummings J, Osse A M L, Cammann D, Powell J, Chen J. Anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. BioDrugs 2024; 38: 5-22. https://doi.org/10.1007/s40259-023-00633-2##Decourt B, Boumelhem F, Pope E D, Shi J, Mari Z, Sabbagh M N. Critical appraisal of amyloid lowering agents in AD. Current neurology and neuroscience reports 2021; 21: 1-10. https://doi.org/10.1007/s11910-021-01125-y##Eric L. Ross; Marc S. Weinberg; Steven E. Arnold. Cost-effectiveness of aducanumab and donanemab for early Alzheimer disease in the US. JAMA neurology 2022. https://doi.org/10.1001/jamaneurol.2022.0315##Farrer L A, Cupples L A, Haines J L, Hyman B, Kukull W A, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama 1997; 278: 1349-1356. https://doi.org/10.1001/jama.1997.03550160069041##Ferrero J, Williams L, Stella H, Leitermann K, Mikulskis A, O’Gorman J, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimer’s & Dementia: Translational research & clinical interventions 2016; 2: 169-176. https://doi.org/10.1016/j.trci.2016.06.002##Fleisher A S, Lowe S L, Liu P, Shcherbinin S, Li L, Chua L, et al. SSignificant And sustained florbetapir F18 uptake reduction in patients with symptomatic Alzheimer’s disease with Ly3002813, A Β-amyloid plaque-specific antibody. . Alzheimer’s & dementia 2018; 14: P239-P240. https://doi.org/10.1016/j.jalz.2018.06.2378##Frautschy S A, Yang F, Irrizarry M, Hyman B, Saido T, Hsiao K, et al. Microglial response to amyloid plaques in APPsw transgenic mice. The American journal of pathology 1998; 152: 307.##Frost C V, Zacharias M. From monomer to fibril: Abeta-amyloid binding to Aducanumab antibody studied by molecular dynamics simulation. Proteins 2020; 88: 1592-1606. https://doi.org/10.1002/prot.25978##Gamage K K, Kumar S. Aducanumab therapy ameliorates calcium overload in a mouse model of Alzheimer’s disease. Journal of neuroscience 2017; 37: 4430-4432. https://doi.org/10.1523/JNEUROSCI.0420-17.2017##Glymour M.M., Weuve J, Dufouil C, Mayeda E.R., Aduhelm, the newly approved medication for Alzheimer disease: what epidemiologists can learn and what epidemiology can offer. American Journal of Epidemiology 2022; 191(8): 1347-1351. https://doi.org/10.1093/aje/kwac063##Greig S L. Memantine ER/donepezil: a review in Alzheimer’s disease. CNS drugs 2015; 29: 963-970. https://doi.org/10.1007/s40263-015-0287-2##Gunawardena I P, Retinasamy T, Shaikh M F. Is Aducanumab for LMICs? Promises and challenges. Brain sciences 2021; 11: 1547. https://doi.org/10.3390/brainsci11111547##Hassan N A, Alshamari A K, Hassan A A, Elharrif M G, Alhajri A M, Sattam M, et al. Advances on therapeutic strategies for Alzheimer’s disease: from medicinal plant to nanotechnology. Molecules 2022; 27: 4839. https://doi.org/10.3390/molecules27154839##Hebert L, Bienias J, Aggarwal N, Wilson R, Bennett D, Shah R, et al. Change in risk of Alzheimer disease over time. Neurology 2010; 75: 786-791. https://doi.org/10.1212/WNL.0b013e3181f0754f##Hensley K. Neuroinflammation in Alzheimer’s disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. Journal of Alzheimer’s disease 2010; 21: 1-14. https://doi.org/10.3233/JAD-2010-1414##Hershey L A, Tarawneh R. Clinical efficacy, drug safety, and surrogate endpoints: has aducanumab met all of its expectations? Neurology 2021; 97: 517-518. https://doi.org/10.1212/WNL.0000000000012453##Huang Y. Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends in molecular medicine 2010; 16: 287-294. https://doi.org/10.1016/j.molmed.2010.04.004##Imbimbo B P, Ippati S, Watling M, Imbimbo C. Role of monomeric amyloid-β in cognitive performance in Alzheimer’s disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacological research 2023; 187: 106631. https://doi.org/10.1016/j.phrs.2022.106631##Irizarry M C, Sims J R, Lowe S L, Nakano M, Hawdon A, Willis B A, et al. Safety, pharmacokinetics (Pk), and florbetapir F-18 positron emission tomography (Pet) after multiple dose administration of Ly3002813, AΒ-amyloid plaque-specific antibody, in Alzheimer’s disease (Ad). Alzheimer’s & dementia 2016a; 12: 352-353. https://doi.org/10.1016/j.jalz.2016.06.665##Kastanenka K V, Bussiere T, Shakerdge N, Qian F, Weinreb P H, Rhodes K, et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. Journal of neuroscience 2016; 36: 12549-12558. https://doi.org/10.1523/JNEUROSCI.2080-16.2016##Kim D, Bae G H, Kim H Y, Jeon H, Kim K, Shin J, et al. Orally administered benzofuran derivative disaggregated Aβ plaques and oligomers in the brain of 5XFAD Alzheimer transgenic mouse. ACS chemical neuroscience 2020; 12: 99-108. https://doi.org/10.1021/acschemneuro.0c00606##Kim H, Jeong W, Kwon J, Kim Y, Park E-C, Jang S-I. Association between depression and the risk of Alzheimer’s disease using the Korean national health insurance service-elderly cohort. Scientific reports 2021; 11: 22591. https://doi.org/10.1038/s41598-021-02201-6##Knight E M, Kim S H, Kottwitz J C, Hatami A, Albay R, Suzuki A, et al. Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes. Neurology-neuroimmunology neuroinflammation 2016; 3. https://doi.org/10.1212/NXI.0000000000000237##Knopman D S, Jones D T, Greicius M D. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s & dementia 2021; 17: 696-701. https://doi.org/10.1002/alz.12213##Knopman D S, Perlmutter J S. Prescribing aducanumab in the face of meager efficacy and real risks. Neurology 2021; 97: 545-547. https://doi.org/10.1212/WNL.0000000000012452##Leinenga G, Koh W K, Götz J. A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease. Alzheimer’s research & therapy 2021; 13: 1-14. https://doi.org/10.1186/s13195-021-00809-4##Li J, Wu X, Tan X, Wang S, Qu R, Wu X, et al. The efficacy and safety of anti-Aβ agents for delaying cognitive decline in Alzheimer’s disease: a meta-analysis. Frontiers in aging neuroscience 2023; 15. https://doi.org/10.3389/fnagi.2023.1257973##Lin L, Hua F, Salinas C, Young C, Bussiere T, Apgar J F, et al. Quantitative systems pharmacology model for Alzheimer’s disease to predict effect of aducanumab on brain amyloid CPT: Pharmacometrics & systems pharmacology 2022. https://doi.org/10.1002/psp4.12759##Lowe S, Duggan Evans C, Shcherbinin S, Cheng Y-J, Willis B, Gueorguieva I, et al. Donanemab (LY3002813) phase 1b study in Alzheimer’s disease: rapid and sustained reduction of brain amyloid measured by florbetapir F18 imaging. The Journal of prevention of Alzheimer’s disease 2021a; 8: 414-424. https://doi.org/10.14283/jpad.2021.56##Lowe S L, Willis B A, Hawdon A, Natanegara F, Chua L, Foster J, et al. Donanemab (LY3002813) dose-escalation study in Alzheimer’s disease. Alzheimer’s & Dementia 2021b; 7: e12112. https://doi.org/10.1002/trc2.12112##Mintun M A, Lo A C, Duggan Evans C, Wessels A M, Ardayfio P A, Andersen S W, et al. Donanemab in early Alzheimer’s disease. New England Journal of Medicine 2021a; 384: 1691-1704. https://doi.org/10.1056/NEJMoa2100708##Mintun M A, Wessels A M, Sims J R. Donanemab in early Alzheimer’s disease. Reply. The new england journal of medicine 2021b; 385: 667-667. https://doi.org/10.1056/NEJMc2109455##Mo J J, Li J y, Yang Z, Liu Z, Feng J S. Efficacy and safety of anti-amyloid-β immunotherapy for Alzheimer’s disease: a systematic review and network meta-analysis. Annals of clinical and translational neurology 2017; 4: 931-942. https://doi.org/10.1002/acn3.469##Pais M, Martinez L, Ribeiro O, Loureiro J, Fernandez R, Valiengo L, et al. Early diagnosis and treatment of Alzheimer’s disease: new definitions and challenges. Brazilian journal of psychiatry 2020; 42: 431-441. https://doi.org/10.1590/1516-4446-2019-0735##Panza F, Lozupone M, Dibello V, Greco A, Daniele A, Seripa D, et al. Are antibodies directed against amyloid-β (Aβ) oligomers the last call for the Aβ hypothesis of Alzheimer’s disease? Immunotherapy 2019; 11: 3-6. https://doi.org/10.2217/imt-2018-0119##Panza F, Seripa D, Solfrizzi V, Imbimbo B P, Lozupone M, Leo A, et al. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients. Expert opinion on emerging drugs 2016; 21: 377-391. https://doi.org/10.1080/14728214.2016.1241232##Paul S, Planque S, Nishiyama Y. Immunological origin and functional properties of catalytic autoantibodies to amyloid β peptide. Journal of clinical immunology 2010; 30: 43-49. https://doi.org/10.1007/s10875-010-9414-5##Petch J, Bressington D. Aducanumab for Alzheimer’s disease: The never-ending story that nurses should know. Nursing open 2021; 8: 1524. https://doi.org/10.1002/nop2.878##Pritam Das M P M, Linda H. Younkin, Steven.G. Younkin, TTodd Eliot Golde. Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiology of aging 2001; 22: 721-727. https://doi.org/10.1016/S0197-4580(01)00245-7##Qiu C, Kivipelto M, Von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues in clinical neuroscience 2009; 11: 111. https://doi.org/10.31887/DCNS.2009.11.2/cqiu##Ramanan V K, Day G S. Anti-amyloid therapies for Alzheimer disease: Finally, good news for patients. Molecular neurodegeneration 2023; 18: 42. https://doi.org/10.1186/s13024-023-00637-0##Rashad A, Rasool A, Shaheryar M, Sarfraz A, Sarfraz Z, Robles-Velasco K, et al. Donanemab for Alzheimer’s disease: a systematic review of clinical trials. Healthcare 2022; 11: 32. https://doi.org/10.3390/healthcare11010032##Refolo L M, Pappolla M A, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiology of disease 2000; 7: 321-331. https://doi.org/10.1006/nbdi.2000.0366##Retinasamy T, Shaikh M F. Aducanumab for Alzheimer’s disease: an update. Neuroscience research notes 2021; 4: 17-20. https://doi.org/10.31117/neuroscirn.v4i2.81##Rostagno A, Cabrera E, Lashley T, Ghiso J. N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology. Translational neurodegeneration 2022; 11: 1-18. https://doi.org/10.1186/s40035-022-00303-3##Rubio-Perez J M, Morillas-Ruiz J M. A review: inflammatory process in Alzheimer’s disease, role of cytokines. The scientific world journal 2012; 2012. https://doi.org/10.1100/2012/756357##Ryman J T, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT: pharmacometrics & systems pharmacology 2017; 6: 576-588. https://doi.org/10.1002/psp4.12224##Sabbagh M N, Cummings J. Open Peer Commentary to “Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE Trials as reported by Biogen December 2019”. Alzheimer’s & dementia 2021; 17: 702. https://doi.org/10.1002/alz.12235##Sahni J K, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C. Neurotherapeutic applications of nanoparticles in Alzheimer’s disease. Journal of controlled release 2011; 152: 208-231. https://doi.org/10.1016/j.jconrel.2010.11.033##Sáiz-Vázquez O, Gracia-García P, Ubillos-Landa S, Puente-Martínez A, Casado-Yusta S, Olaya B, et al. Depression as a risk factor for Alzheimer’s disease: a systematic review of longitudinal meta-analyses. Journal of clinical medicine 2021; 10: 1809. https://doi.org/10.3390/jcm10091809##Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA neurology 2022; 79: 13-21. https://doi.org/10.1001/jamaneurol.2021.4161##Scearce-Levie K, Sanchez P E, Lewcock J W. Leveraging preclinical models for the development of Alzheimer disease therapeutics. Nature reviews drug discovery 2020; 19: 447-462. https://doi.org/10.1038/s41573-020-0065-9##Sevigny J, Chiao P, Bussière T, Weinreb P H, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537: 50-56. https://doi.org/10.1038/nature19323##Silva M V F, Loures C d M G, Alves L C V, de Souza L C, Borges K B G, Carvalho M d G. Alzheimer’s disease: risk factors and potentially protective measures. Journal of biomedical science 2019; 26: 1-11. https://doi.org/10.1186/s12929-019-0524-y##Sun B-L, Li W-W, Zhu C, Jin W-S, Zeng F, Liu Y-H, et al. Clinical research on Alzheimer’s disease: progress and perspectives. Neuroscience bulletin 2018; 34: 1111-1118. https://doi.org/10.1007/s12264-018-0249-z##Synnott P G, Whittington M D, Lin G A, Rind D M, Pearson S D. The effectiveness and value of aducanumab for Alzheimer’s disease: a summary from the institute for clinical and economic review’s California technology assessment forum. Journal of managed care & specialty pharmacy 2021; 27: 1613-1617. https://doi.org/10.18553/jmcp.2021.27.11.1613##Tabassum S, Misrani A, Yang L. Exploiting common aspects of obesity and Alzheimer’s disease. Frontiers in human neuroscience 2020; 14: 602360. https://doi.org/10.3389/fnhum.2020.602360##Tampi R R, Forester B P, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs in context 2021; 10. https://doi.org/10.7573/dic.2021-7-3##Thomas E, Wasunna-Smith B, Kuruvilla T. Aducanumab and disease modifying treatments for Alzheimer’s disease. Progress in neurology and psychiatry 2021; 25: 4-6. https://doi.org/10.1002/pnp.711##Tolar M, Abushakra S, Hey J A, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimer’s research & therapy 2020; 12: 1-10. https://doi.org/10.1186/s13195-020-00663-w##Tolar M, Hey J, Power A, Abushakra S. Neurotoxic soluble amyloid oligomers drive Alzheimer’s pathogenesis and represent a clinically validated target for slowing disease progression. International journal of molecular sciences 2021; 22: 6355. https://doi.org/10.3390/ijms22126355##Touchon J, Lachaine J, Beauchemin C, Granghaud A, Rive B, Bineau S. The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer’s disease to nursing homes: cost-effectiveness analysis in France. The european journal of health economics 2014; 15: 791-800. https://doi.org/10.1007/s10198-013-0523-y##van der Kant R, Goldstein L S, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nature reviews neuroscience 2020; 21: 21-35. https://doi.org/10.1038/s41583-019-0240-3##Van Eldik L J, Carrillo M C, Cole P E, Feuerbach D, Greenberg B D, Hendrix J A, et al. The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimer’s & dementia: 2016; 2: 99-109. https://doi.org/10.1016/j.trci.2016.05.001##Vaz M, Silvestre S. Alzheimer’s disease: recent treatment strategies. European journal of pharmacology 2020; 887: 173554. https://doi.org/10.1016/j.ejphar.2020.173554##Vellas B J. The Geriatrician, the primary care physician, aducanumab and the FDA decision: from frustration to new hope. The journal of nutrition, health & aging 2021; 25: 821-823. https://doi.org/10.1007/s12603-021-1657-8##Weller J, Budson A. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Research 2018; 7. https://doi.org/10.12688/f1000research.14506.1##Wessels A, Siemers E, Yu P, Andersen S, Holdridge K, Sims J, et al. A combined measure of cognition and function for clinical trials: The integrated Alzheimer’s Disease Rating Scale (iADRS). The journal of prevention of Alzheimer’s disease 2015; 2: 227. https://doi.org/10.14283/jpad.2015.82##Xu X, Li Y, Wang J, Cao Y, Feng C, Guo Y, et al. Family history of AD/Dementia, polygenic risk score for AD, and Parkinson’s disease. Movement Disorders Clinical Practice 2023; 10: 1787-1794. https://doi.org/10.1002/mdc3.13919##Yang P, Sun F. Aducanumab: The first targeted Alzheimer’s therapy. Drug discoveries & therapeutics 2021; 15: 166-168. https://doi.org/10.5582/ddt.2021.01061##Yiannopoulou K G, Anastasiou A I, Zachariou V, Pelidou S-H. Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicines 2019; 7: 97. https://doi.org/10.3390/biomedicines7040097##Yona Levites P D, Robert W Price, Marjorie J Rochette, Lisa A Kostura, Eileen M McGowan, Michael P Murphy, et al. Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. Journal of clinical investigation 2006; 116: 193-201. https://doi.org/10.1172/JCI25410##Zimmer J, Solomon P, Evans C D, Lu M, Sims J R, Brooks D A, et al. TRAILBLAZER-ALZ 2: A phase 3 study to assess safety and efficacy of donanemab in early symptomatic Alzheimer’s disease (P18-3.005). Journal 2022.## ##

Circadian rhythm and body health: A review of the literatur 2 2 Circadian rhythm is a biological clock that regulates various physiological and pathological processes in the body. It is believed that any disturbance in circadian rhythm leads to impairment in some physiological systems, such as the endocrine, reproductive, renal, and cardiovascular systems. Various internal and external factors can alter circadian homeostasis and metabolism in a tissue-specific manner, and any disruption in these temporal interactions can result in the development of some chronic disorders. Circadian rhythm plays a crucial role in the pathogenesis of diseases, including cardiovascular disease, neurodegenerative disease, mood disorders, sleep disorders, diabetes mellitus, metabolism disorders, and cancer. This review aims to provide a brief overview of the basic circadian processes and an overview of current and future research directions in circadian rhythm and its related treatments. 237 256 2023/05/162023/11/15 1402/8/24 2024/04/62024/04/2 1403/1/14 Shahrzad Sadat Eftekhar Vaghefi Shahrzad Sadat Eftekhar Vaghefi Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Reza Malekpour Afshar Reza Malekpour Afshar Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Fatemeh Shahsavari Fatemeh Shahsavari Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran Iran Fatemeh Mousavi Fatemeh Mousavi Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran Iran Seyed Hossein Eftekhar Vaghefi Seyed Hossein Eftekhar Vaghefi Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Seyyed Jafar Nosratabadi Seyyed Jafar Nosratabadi Department of Basic Sciences, Faculty of Medicine, Kerman Branch, Islamic Azad University, Kerman, Iran Iran Mohammad Khaksari Mohammad Khaksari Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran Iran Zahra Soltani Zahra Soltani Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran Iran Gholamreza Asadikaram Gholamreza Asadikaram Department of Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran Iran Manzoomeh Shamsi Meymandi Manzoomeh Shamsi Meymandi Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Alireza Raji Amir Hasani Alireza Raji Amir Hasani Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran Iran Mona Saheli Mona Saheli Department of Anatomical Sciences, Kerman University of Medical Sciences, Kerman, Iran Iran Masoumeh Baghalishahi Masoumeh Baghalishahi Department of Anatomical Sciences, Kerman University of Medical Sciences, Kerman, Iran Iran Maryam Fekri Soofi Abadi Maryam Fekri Soofi Abadi Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Mahnaz Mohammadizadeh Mahnaz Mohammadizadeh Pathology and stem cell Research center, Kerman University of Medical, Sciences, Kerman, Iran Iran Shahriar Dabiri Shahriar Dabiri Pathology and Stem Cell Research Center, Department of Pathology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran Iran dabiri12@yahoo.com Circadian rhythm Physiology Circadian Clock System Chronotherapy Circadian disruption Adamczak-Ratajczak A, Kupsz J, Owecki M, Zielonka D, Sowinska A, Checinska-Maciejewska Z, et al. Circadian rhythms of melatonin and cortisol in manifest Huntington’s disease and in acute cortical ischemic stroke. J Physiol Pharmacol 2017; 68: 539-546.##Agarwal R. Regulation of circadian blood pressure: from mice to astronauts. Curr Opin Nephrol Hypertens 2010; 19: 51-58. https://doi.org/10.1097/MNH.0b013e3283336ddb##Alston M, Cain S W, Rajaratnam S M W. Advances of melatonin-based therapies in the treatment of disturbed sleep and mood. Handb Exp Pharmacol 2019; 253: 305-319. https://doi.org/10.1007/164_2018_139##Alvord V M, Kantra E J, Pendergast J S. Estrogens and the circadian system. Semin Cell Dev Biol 2022; 126: 56-65. https://doi.org/10.1016/j.semcdb.2021.04.010##Ando H, Shahjahan M, Kitahashi T. Periodic regulation of expression of genes for kisspeptin, gonadotropin-inhibitory hormone and their receptors in the grass puffer: Implications in seasonal, daily and lunar rhythms of reproduction. Gen Comp Endocrinol 2018; 265: 149-153. https://doi.org/10.1016/j.ygcen.2018.04.006##Anna G, Kannan N N. Post-transcriptional modulators and mediators of the circadian clock. Chronobiol Int 2021; 38: 1244-1261. https://doi.org/10.1080/07420528.2021.1928159##Aoyama S, Shibata S. The role of circadian rhythms in muscular and osseous physiology and their regulation by nutrition and exercise. Front Neurosci 2017; 11: 63. https://doi.org/10.3389/fnins.2017.00063##Beauchamp M T, Lundgren J D. A systematic review of bright light therapy for eating disorders. The Primary Care Companion for CNS Disorders 2016; 18: 26718. https://doi.org/10.4088/PCC.16r02008##Begemann K, Neumann A M, Oster H. Regulation and function of extra-SCN circadian oscillators in the brain. Acta Physiol (Oxf) 2020; 229: e13446. https://doi.org/10.1111/apha.13446##Bekki H, Duffy T, Okubo N, Olmer M, Alvarez-Garcia O, Lamia K, et al. Suppression of circadian clock protein cryptochrome 2 promotes osteoarthritis. Osteoarthritis Cartilage 2020; 28: 966-976. https://doi.org/10.1016/j.joca.2020.04.004##Benz A, Meier M, Mankin M, Unternaehrer E, Pruessner J C. The duration of the cortisol awakening pulse exceeds sixty minutes in a meaningful pattern. Psychoneuroendocrinology 2019; 105: 187-194. https://doi.org/10.1016/j.psyneuen.2018.12.225##Bessi V, Balestrini J, Bagnoli S, Mazzeo S, Giacomucci G, Padiglioni S, et al. Influence of ApoE genotype and clock T3111C Interaction with cardiovascular risk factors on the progression to Alzheimer’s disease in subjective cognitive decline and mild cognitive impairment patients. J Pers Med 2020; 10. https://doi.org/10.3390/jpm10020045##Bhat B B, Mehta C H, Suresh A, Velagacherla V, Nayak U Y. Controlled Release technologies for chronotherapy: current status and future perspectives. Curr Pharm Des 2023; 29: 1069-1091. https://doi.org/10.2174/1381612829666230423144232##Boden M J, Varcoe T J, Kennaway D J. Circadian regulation of reproduction: from gamete to offspring. Prog Biophys Mol Biol 2013; 113: 387-397. https://doi.org/10.1016/j.pbiomolbio.2013.01.003##Boden M J, Varcoe T J, Voultsios A, Kennaway D J. Reproductive biology of female Bmal1 null mice. Reproduction 2010; 139: 1077-1090. https://doi.org/10.1530/REP-09-0523##Bonaconsa M, Malpeli G, Montaruli A, Carandente F, Grassi-Zucconi G, Bentivoglio M. Differential modulation of clock gene expression in the suprachiasmatic nucleus, liver and heart of aged mice. Exp Gerontol 2014; 55: 70-79. https://doi.org/10.1016/j.exger.2014.03.011##Borengasser S J, Kang P, Faske J, Gomez-Acevedo H, Blackburn M L, Badger T M, et al. High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS One 2014; 9: e84209. https://doi.org/10.1371/journal.pone.0084209 ##Brooks J F, 2nd, Behrendt C L, Ruhn K A, Lee S, Raj P, Takahashi J S, et al. The microbiota coordinates diurnal rhythms in innate immunity with the circadian clock. Cell 2021; 184: 4154-4167. https://doi.org/10.1016/j.cell.2021.07.001##Burke T M, Markwald R R, McHill A W, Chinoy E D, Snider J A, Bessman S C, et al. Effects of caffeine on the human circadian clock in vivo and in vitro. Sci Transl Med 2015; 7: 305ra146-305ra146. https://doi.org/10.1126/scitranslmed.aac5125##Buttgereit F, Smolen J S, Coogan A N, Cajochen C. Clocking in: chronobiology in rheumatoid arthritis. Nat Rev Rheumatol 2015; 11: 349-356. https://doi.org/10.1038/nrrheum.2015.31##Cai Z Y, Wen-Chyuan Chen K, Wen H J. Effects of a group-based step aerobics training on sleep quality and melatonin levels in sleep-impaired postmenopausal women. J Strength Cond Res 2014; 28: 2597-2603. https://doi.org/10.1519/JSC.0000000000000428##Cambras T, Castejón L, Díez-Noguera A. Social interaction and sex differences influence rat temperature circadian rhythm under LD cycles and constant light. Physiology & Behavior 2011; 103: 365-371. https://doi.org/10.1016/j.physbeh.2011.03.010##Cao X, Wang L, Selby C P, Lindsey-Boltz L A, Sancar A. Analysis of mammalian circadian clock protein complexes over a circadian cycle. J Biol Chem 2023; 299: 102929. https://doi.org/10.1016/j.jbc.2023.102929##Cardinali D P, Brown G M, Pandi-Perumal S R. Chapter 24 - Chronotherapy. In: Swaab DF, Kreier F, Lucassen PJ, Salehi A and Buijs RM, editors. Handbook of clinical neurology. Vol 179: Elsevier, 2021a: 357-370. https://doi.org/10.1016/B978-0-12-819975-6.00023-6##Cardinali D P, Brown G M, Pandi-Perumal S R. Chronotherapy. Handb Clin Neurol 2021b; 179: 357-370. https://doi.org/10.1016/B978-0-12-819975-6.00023-6##Chang Y G, Cohen S E, Phong C, Myers W K, Kim Y I, Tseng R, et al. Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. Science 2015; 349: 324-328. https://doi.org/10.1126/science.1260031##Chen C-Y, Logan R W, Ma T, Lewis D A, Tseng G C, Sibille E, et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proceedings of the National Academy of Sciences 2016; 113: 206-211. https://doi.org/10.1073/pnas.1508249112##Chen M, Zhang L, Liu X, Ma Z, Lv L. PER1 is a prognostic biomarker and correlated with immune infiltrates in ovarian cancer. Front Genet 2021; 12: 697471. https://doi.org/10.3389/fgene.2021.697471##Chu A, Zhu L, Blum I D, Mai O, Leliavski A, Fahrenkrug J, et al. Global but not gonadotrope-specific disruption of Bmal1 abolishes the luteinizing hormone surge without affecting ovulation. Endocrinology 2013; 154: 2924-2935. https://doi.org/10.1210/en.2013-1080##Cox S L, O’Siorain J R, Fagan L E, Curtis A M, Carroll R G. Intertwining roles of circadian and metabolic regulation of the innate immune response. Semin Immunopathol 2022; 44: 225-237. https://doi.org/10.1007/s00281-021-00905-5##Crislip G R, Masten S H, Gumz M L. Recent advances in understanding the circadian clock in renal physiology. Current Opinion in Physiology 2018; 5: 38-44. https://doi.org/10.1016/j.cophys.2018.06.002##Cruz-Sanabria F, Carmassi C, Bruno S, Bazzani A, Carli M, Scarselli M, et al. Melatonin as a chronobiotic with sleep-promoting properties. Curr Neuropharmacol 2023; 21: 951-987. https://doi.org/10.2174/1570159X20666220217152617##Culnan E, McCullough L M, Wyatt J K. Circadian rhythm sleep-wake phase disorders. Neurol Clin 2019; 37: 527-543. https://doi.org/10.1016/j.ncl.2019.04.003##D’Agostino A, Ferrara P, Terzoni S, Ostinelli E G, Carrara C, Prunas C, et al. Efficacy of Triple Chronotherapy in unipolar and bipolar depression: A systematic review of the available evidence. J Affect Disord 2020; 276: 297-304. https://doi.org/10.1016/j.jad.2020.07.026##Daneault V, Vandewalle G, Hébert M, Teikari P, Mure L S, Doyon J, et al. Does pupil constriction under blue and green monochromatic light exposure change with age? J Biol Rhythms 2012; 27: 257-264. https://doi.org/10.1177/0748730412441172##Dardente H. Melatonin-dependent timing of seasonal reproduction by the pars tuberalis: pivotal roles for long daylengths and thyroid hormones. J Neuroendocrinol 2012; 24: 249-266. https://doi.org/10.1111/j.1365-2826.2011.02250.x##de Bruijn R, Romero L M. The role of glucocorticoids in the vertebrate response to weather. Gen Comp Endocrinol 2018; 269: 11-32. https://doi.org/10.1016/j.ygcen.2018.07.007##De Bundel D, Gangarossa G, Biever A, Bonnefont X, Valjent E. Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice. Front Behav Neurosci 2013; 7: 152. https://doi.org/10.3389/fnbeh.2013.00152##de Jesus D S, Bargi-Souza P, Cruzat V, Yechoor V, Carpinelli A R, Peliciari-Garcia R A. BMAL1 modulates ROS generation and insulin secretion in pancreatic β-cells: An effect possibly mediated via NOX2. Mol Cell Endocrinol 2022; 555: 111725. https://doi.org/10.1016/j.mce.2022.111725##Deibel S H, Zelinski E L, Keeley R J, Kovalchuk O, McDonald R J. Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline. Oncotarget 2015; 6: 23181-23203. https://doi.org/10.18632/oncotarget.4036##Ding L, Liu J, Zhou L, Jia X, Li S, Zhang Q, et al. A high-fat diet disrupts the hepatic and adipose circadian rhythms and modulates the diurnal rhythm of gut microbiota-derived short-chain fatty acids in gestational mice. Front Nutr 2022; 9: 925390. https://doi.org/10.3389/fnut.2022.925390##Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, et al. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med 2010; 16: 67-74. https://doi.org/10.1038/nm.2061##Douma L G, Gumz M L. Circadian clock-mediated regulation of blood pressure. Free Radic Biol Med 2018; 119: 108-114. https://doi.org/10.1016/j.freeradbiomed.2017.11.024##Duffy J F, Zitting K M, Chinoy E D. Aging and circadian rhythms. Sleep Med Clin 2015; 10: 423-434. https://doi.org/10.1016/j.jsmc.2015.08.002##Dumbell R, Matveeva O, Oster H. Circadian clocks, stress, and immunity. Front Endocrinol (Lausanne) 2016; 7: 37. https://doi.org/10.3389/fendo.2016.00037##Dyar K A, Ciciliot S, Tagliazucchi G M, Pallafacchina G, Tothova J, Argentini C, et al. The calcineurin-NFAT pathway controls activity-dependent circadian gene expression in slow skeletal muscle. Mol Metab 2015; 4: 823-833. https://doi.org/10.1016/j.molmet.2015.09.004##Elkhatib Smidt S D, Ghorai A, Taylor S C, Gehringer B N, Dow H C, Langer A, et al. The relationship between autism spectrum and sleep-wake traits. Autism Res 2022; 15: 641-652. https://doi.org/10.1002/aur.2660##Engmann O. How Psychoactive Drugs and the circadian clock are enlightening one another. Adv Exp Med Biol 2021; 1344: 129-152. https://doi.org/10.1007/978-3-030-81147-1_8##Ertosun M G, Kocak G, Ozes O N. The regulation of circadian clock by tumor necrosis factor alpha. Cytokine Growth Factor Rev 2019; 46: 10-16. https://doi.org/10.1016/j.cytogfr.2019.04.001##Fang L, Yang Z, Zhou J, Tung J Y, Hsiao C D, Wang L, et al. Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer. Mol Cancer Ther 2015; 14: 1476-1487. https://doi.org/10.1158/1535-7163.MCT-15-0030##Farhud D, Aryan Z. Circadian rhythm, lifestyle and health: a narrative review. Iran J Public Health 2018; 47: 1068-1076.##Fernandes P, Pereira L M, Horta N A C, Cardoso T S R, Coimbra C C, Szawka R E, et al. Social interaction masking contributes to changes in the activity of the suprachiasmatic nucleus and impacts on circadian rhythms. Physiol Behav 2021; 237: 113420. https://doi.org/10.1016/j.physbeh.2021.113420##Firsov D, Bonny O. Circadian rhythms and the kidney. Nat Rev Nephrol 2018; 14: 626-635. https://doi.org/10.1038/s41581-018-0048-9##Firsov D, Tokonami N, Bonny O. Role of the renal circadian timing system in maintaining water and electrolytes homeostasis. Mol Cell Endocrinol 2012; 349: 51-55. https://doi.org/10.1016/j.mce.2011.06.037##Focke C M B, Iremonger K J. Rhythmicity matters: circadian and ultradian patterns of HPA axis activity. Mol Cell Endocrinol 2020; 501: 110652. https://doi.org/10.1016/j.mce.2019.110652##Foster R G, Peirson S N, Wulff K, Winnebeck E, Vetter C, Roenneberg T. Sleep and circadian rhythm disruption in social jetlag and mental illness. Prog Mol Biol Transl Sci 2013; 119: 325-346. https://doi.org/10.1016/B978-0-12-396971-2.00011-7##Freund P R, Watson J, Gilmour G S, Gaillard F, Sauvé Y. Differential changes in retina function with normal aging in humans. Doc Ophthalmol 2011; 122: 177-190. https://doi.org/10.1007/s10633-011-9273-2##Fukuda M, Wakamatsu-Yamanaka T, Mizuno M, Miura T, Tomonari T, Kato Y, et al. Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption. Am J Physiol Renal Physiol 2011; 301: 953-957. https://doi.org/10.1152/ajprenal.00167.2011##Fukumitsu K, Kuroda K O. Behavioral and histochemical characterization of sexually dimorphic responses to acute social isolation and reunion in mice. Neurosci Res 2023; 194: 36-43. https://doi.org/10.1016/j.neures.2023.04.001##Gamble K L, Berry R, Frank S J, Young M E. Circadian clock control of endocrine factors. Nat Rev Endocrinol 2014; 10: 466-475. https://doi.org/10.1038/nrendo.2014.78##Giles D A, Moreno-Fernandez M E, Stankiewicz T E, Graspeuntner S, Cappelletti M, Wu D, et al. Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat Med 2017; 23: 829-838. https://doi.org/10.1038/nm.4346##Gu C, Li J, Zhou J, Yang H, Rohling J. Network Structure of the master clock is important for its primary function. Front Physiol 2021; 12: 678391. https://doi.org/10.3389/fphys.2021.678391##Guan Y, Xu M, Zhang Z, Liu C, Zhou J, Lin F, et al. Maternal circadian disruption before pregnancy impairs the ovarian function of female offspring in mice. Sci Total Environ 2023; 864: 161161. https://doi.org/10.1016/j.scitotenv.2022.161161##Guichard K, Micoulaud-Franchi J A, Philip P, Taillard J. Sleep deprivation therapy to reset the circadian pacemaker in a non-24-hour sleep-wake disorder: a case report. J Clin Sleep Med 2021; 17: 1503-1506. https://doi.org/10.5664/jcsm.9294##Gul S, Aydin C, Ozcan O, Gurkan B, Surme S, Baris I, et al. The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm. J Biol Chem 2020; 295: 17187-17199. https://doi.org/10.1074/jbc.RA120.014333##Gumz M L. Molecular basis of circadian rhythmicity in renal physiology and pathophysiology. Exp Physiol 2016; 101: 1025-1029. https://doi.org/10.1113/EP085781##Guo F, Tang Q, Chen G, Sun J, Zhu J, Jia Y, et al. Aberrant expression and subcellular localization of PER2 promote the progression of oral squamous cell carcinoma. Biomed Res Int 2020; 2020: 8587458. https://doi.org/10.1155/2020/8587458##Han Y, Meng F, Venter J, Wu N, Wan Y, Standeford H, et al. miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J Hepatol 2016; 64: 1295-1304. https://doi.org/10.1016/j.jhep.2016.02.024##He M, Liu K, Cao J, Chen Q. An update on the role and potential mechanisms of clock genes regulating spermatogenesis: A systematic review of human and animal experimental studies. Rev Endocr Metab Disord 2023; 24: 585-610. https://doi.org/10.1007/s11154-022-09783-0## Healy K L, Morris A R, Liu A C. Circadian synchrony: sleep, nutrition, and physical activity. Front Netw Physiol 2021; 1. https://doi.org/10.3389/fnetp.2021.732243##Hinoura T, Mukai S, Kamoto T, Kuroda Y. PER3 polymorphisms and their association with prostate cancer risk in Japanese men. J Prev Med Hyg 2021; 62: 489-495.##Hirota T, Lee J W, St John P C, Sawa M, Iwaisako K, Noguchi T, et al. Identification of small molecule activators of cryptochrome. Science 2012; 337: 1094-1097. https://doi.org/10.1126/science.1223710##Hodges T E, Baumbach J L, McCormick C M. Predictors of social instability stress effects on social interaction and anxiety in adolescent male rats. Dev Psychobiol 2018; 60: 651-663. https://doi.org/10.1002/dev.21626##Holst S C, Landolt H P. Sleep-wake neurochemistry. Sleep Med Clin 2018; 13: 137-146. https://doi.org/10.1016/j.jsmc.2018.03.002##Honma S. The mammalian circadian system: a hierarchical multi-oscillator structure for generating circadian rhythm. J Physiol Sci 2018; 68: 207-219. https://doi.org/10.1007/s12576-018-0597-5##Hoogerwerf W A. Role of clock genes in gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol 2010; 299: 549-555. https://doi.org/10.1152/ajpgi.00147.2010##Hower I M, Harper S A, Buford T W. Circadian rhythms, exercise, and cardiovascular health. J Circadian Rhythms 2018; 16: 7. https://doi.org/10.5334/jcr.164##Huang J Q, Lu M, Ho C T. Health benefits of dietary chronobiotics: beyond resynchronizing internal clocks. Food Funct 2021; 12: 6136-6156. https://doi.org/10.1039/D1FO00661D##Huang X M, Chen W L, Yuan J P, Yang Y H, Mei Q H, Huang L X. Altered diurnal variation and localization of clock proteins in the remnant kidney of 5/6 nephrectomy rats. Nephrology (Carlton) 2013; 18: 555-562. https://doi.org/10.1111/nep.12111##Husse J, Leliavski A, Tsang A H, Oster H, Eichele G. The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock. Faseb j 2014; 28: 4950-4960. https://doi.org/10.1096/fj.14-256594##Ihara T, Nakamura Y, Mitsui T, Tsuchiya S, Kanda M, Kira S, et al. Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia. Sci Rep 2019; 9: 10069. https://doi.org/10.1038/s41598-019-46517-w##Izumo M, Pejchal M, Schook A C, Lange R P, Walisser J A, Sato T R, et al. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. eLife 2014; 3: e04617. https://doi.org/10.7554/eLife.04617##Jha P K, Bouâouda H, Kalsbeek A, Challet E. Distinct feedback actions of behavioural arousal to the master circadian clock in nocturnal and diurnal mammals. Neurosci Biobehav Rev 2021; 123: 48-60. https://doi.org/10.1016/j.neubiorev.2020.12.011##Jiang T T, Ji S, Yang G R, Chen L H. [Research advances in relationship between biological clock and cardiovascular diseases]. Sheng Li Xue Bao 2019; 71: 783-791.##Johnsa J D, Neville M W. Tasimelteon:A melatonin receptor agonist for non-24-hour sleep-wake disorder. Annals of Pharmacotherapy 2014; 48: 1636-1641. https://doi.org/10.1177/1060028014550476##Keijer J, Li M, Speakman J R. To best mimic human thermal conditions, mice should be housed slightly below thermoneutrality. Mol Metab 2019; 26: 4. https://doi.org/10.1016/j.molmet.2019.05.007##Kim Y Y, Jang H, Lee G, Jeon Y G, Sohn J H, Han J S, et al. Hepatic GSK3β-dependent CRY1 degradation contributes to diabetic hyperglycemia. Diabetes 2022; 71: 1373-1387. https://doi.org/10.2337/db21-0649##Kudagammna S T, Vidanapathirana G U. Chronobiology and chronotherapy of allergic diseases. Sri Lanka Journal of Child Health 2021; 50: 711-715. https://doi.org/10.4038/sljch.v50i4.9893##Kuo T T, Ladurner A G. Exploiting the circadian clock for improved cancer therapy: perspective from a cell biologist. Front Genet 2019; 10: 1210. https://doi.org/10.3389/fgene.2019.01210##Lan R, Jin B, Liu Y Z, Zhang K, Niu T, You Z. Genome and transcriptome profiling of FBXW family in human prostate cancer. Am J Clin Exp Urol 2020; 8: 116-128.##Lang C, Richardson C, Short M A, Gradisar M. Low-intensity scheduled morning exercise for adolescents with a late chronotype: a novel treatment to advance circadian phase? Sleep Adv 2022; 3: zpac021. https://doi.org/10.1093/sleepadvances/zpac021##Lee H, Noh J. Social exclusion intensifies anxiety-like behavior in adolescent rats. Behav Brain Res 2015; 284: 112-117. https://doi.org/10.1016/j.bbr.2015.02.006##Leembruggen A J L, Stamp L A, Bornstein J C, Hao M M. Circadian control of gastrointestinal motility. Adv Exp Med Biol 2022; 1383: 191-203. https://doi.org/10.1007/978-3-031-05843-1_18##Lewis P, Korf H W, Kuffer L, Groß J V, Erren T C. Exercise time cues (zeitgebers) for human circadian systems can foster health and improve performance: a systematic review. BMJ Open Sport Exerc Med 2018; 4: e000443. https://doi.org/10.1136/bmjsem-2018-000443##Li C, Xiao S, Hao J, Liao X, Li G. Cry1 deficiency leads to testicular dysfunction and altered expression of genes involved in cell communication, chromatin reorganization, spermatogenesis, and immune response in mouse testis. Mol Reprod Dev 2018; 85: 325-335. https://doi.org/10.1002/mrd.22968##Li H X, Fu X J, Yang K, Chen D, Tang H, Zhao Q. The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma. Oncotarget 2016; 7: 20574-20583. https://doi.org/10.18632/oncotarget.7827##Li J, Zhang L, Xiong J, Cheng X, Huang Y, Su Z, et al. Polyamines disrupt the KaiABC oscillator by inducing protein denaturation. Molecules 2019; 24. https://doi.org/10.3390/molecules24183351##Li T, Bai Y, Jiang Y, Jiang K, Tian Y, Gu J, et al. The potential impacts of circadian rhythm disturbances on male fertility. Front Endocrinol (Lausanne) 2022; 13: 1001316. https://doi.org/10.3389/fendo.2022.1001316##Li Y, Li J, Hou Y, Huang L, Bian Y, Song G, et al. Circadian clock gene clock is involved in the pathogenesis of preeclampsia through hypoxia. Life Sci 2020; 247: 117441. https://doi.org/10.1016/j.lfs.2020.117441##Lindskov F O, Iversen H K, West A S. Clinical outcomes of light therapy in hospitalized patients - A systematic review. Chronobiol Int 2022; 39: 299-310. https://doi.org/10.1080/07420528.2021.1993240##Liu C, Tang X, Gong Z, Zeng W, Hou Q, Lu R. Circadian rhythm sleep disorders: genetics, mechanisms, and adverse effects on health. Front Genet 2022; 13: 875342. https://doi.org/10.3389/fgene.2022.875342## Liu S, Cheng L, Liu Y, Zhan S, Wu Z, Zhang X. Relationship between dietary polyphenols and gut microbiota: new clues to improve cognitive disorders, Mood Disorders and Circadian Rhythms. Foods 2023; 12. https://doi.org/10.3390/foods12061309## Liu Y, Hao J, Yuan G, Wei M, Bu Y, Jin T, et al. PER1 as a tumor suppressor attenuated in the malignant phenotypes of breast cancer cells. Int J Gen Med 2021; 14: 7077-7087. https://doi.org/10.2147/IJGM.S328184## Liu Y, Johnson B P, Shen A L, Wallisser J A, Krentz K J, Moran S M, et al. Loss of BMAL1 in ovarian steroidogenic cells results in implantation failure in female mice. Proc Natl Acad Sci U S A 2014; 111: 14295-14300. https://doi.org/10.1073/pnas.1209249111##Lokshin M, LeSauter J, Silver R. Selective Distribution of Retinal Input to Mouse SCN Revealed in Analysis of Sagittal Sections. J Biol Rhythms 2015; 30: 251-257. https://doi.org/10.1177/0748730415584058##López-Olmeda J F. Nonphotic entrainment in fish. Comp Biochem Physiol A Mol Integr Physiol 2017; 203: 133-143. https://doi.org/10.1016/j.cbpa.2016.09.006##Luo W, Ma S, Yang Y, Wang C, Zhang D, Zhang Q, et al. TFEB regulates PER3 expression via glucose-dependent effects on CLOCK/BMAL1. Int J Biochem Cell Biol 2016; 78: 31-42. https://doi.org/10.1016/j.biocel.2016.06.020##Luo X, Yang X, Yang Y, Li H, Cui H, Cao X. The interrelationship between inflammatory cytokines and skeletal muscle decay from the viewpoint of circadian rhythms. Arch Physiol Biochem 2022; 128: 1559-1565.https://doi.org/10.1080/13813455.2020.1782435##Mander B A, Winer J R, Walker M P. Sleep and Human Aging. Neuron 2017; 94: 19-36. https://doi.org/10.1016/j.neuron.2017.02.004##Mao Y, Fu A, Hoffman A E, Jacobs D I, Jin M, Chen K, et al. The circadian gene CRY2 is associated with breast cancer aggressiveness possibly via epigenomic modifications. Tumour Biol 2015; 36: 3533-3539. https://doi.org/10.1007/s13277-014-2989-3##Martinez-Nicolas A, Madrid J A, García F J, Campos M, Moreno-Casbas M T, Almaida-Pagán P F, et al. Circadian monitoring as an aging predictor. Sci Rep 2018; 8: 15027.##https://doi.org/10.1038/s41598-018-33195-3##Mason I C, Qian J, Adler G K, Scheer F. Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes. Diabetologia 2020; 63: 462-472. https://doi.org/10.1007/s00125-019-05059-6##Masuda K, Katsuda Y, Niwa Y, Sakurai T, Hirano A. Analysis of circadian rhythm components in EEG/EMG data of aged mice. Front Neurosci 2023; 17: 1173537. https://doi.org/10.3389/fnins.2023.1173537##Mayeuf-Louchart A, Staels B, Duez H. Skeletal muscle functions around the clock. Diabetes Obes Metab 2015; 17 Suppl 1: 39-46. https://doi.org/10.1111/dom.12517##McKie G L, Medak K D, Knuth C M, Shamshoum H, Townsend L K, Peppler W T, et al. Housing temperature affects the acute and chronic metabolic adaptations to exercise in mice. J Physiol 2019; 597: 4581-4600. https://doi.org/10.1113/JP278221##Mehrzadi S, Pourhanifeh M H, Mirzaei A, Moradian F, Hosseinzadeh A. An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell Int 2021; 21: 188. https://doi.org/10.1186/s12935-021-01892-1##Meléndez-Fernández O H, Liu J A, Nelson R J. Circadian rhythms disrupted by light at night and mistimed food intake alter hormonal rhythms and metabolism. Int J Mol Sci 2023; 24. https://doi.org/10.3390/ijms24043392##Meneses-Santos D, Buonfiglio D D C, Peliciari-Garcia R A, Ramos-Lobo A M, Souza D D N, Carpinelli A R, et al. Chronic treatment with dexamethasone alters clock gene expression and melatonin synthesis in rat pineal gland at night. Nat Sci Sleep 2018; 10: 203-215. https://doi.org/10.2147/NSS.S158602##Míková H, Kuchtiak V, Svobodová I, Spišská V, Pačesová D, Balík A, et al. Circadian regulation of GluA2 mRNA processing in the rat suprachiasmatic nucleus and other brain structures. Mol Neurobiol 2021; 58: 439-449. https://doi.org/10.1007/s12035-020-02141-8##Miller B H, Takahashi J S. Central circadian control of female reproductive function. Front Endocrinol (Lausanne) 2013; 4: 195. https://doi.org/10.3389/fendo.2013.00195##Miller S, Aikawa Y, Sugiyama A, Nagai Y, Hara A, Oshima T, et al. An Isoform-selective modulator of cryptochrome 1 regulates circadian rhythms in mammals. Cell Chem Biol 2020; 27: 1192-1198.e5. https://doi.org/10.1016/j.chembiol.2020.05.008##Mohandas R, Douma L G, Scindia Y, Gumz M L. Circadian rhythms and renal pathophysiology. J Clin Invest 2022; 132. https://doi.org/10.1172/JCI148277##Mukherji A, Kobiita A, Damara M, Misra N, Meziane H, Champy M F, et al. Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome. Proc Natl Acad Sci U S A 2015; 112: 6691-6698. https://doi.org/10.1073/pnas.1519807112##Nakamoto I, Uiji S, Okata R, Endo H, Tohyama S, Nitta R, et al. Diurnal rhythms of urine volume and electrolyte excretion in healthy young men under differing intensities of daytime light exposure. Sci Rep 2021; 11: 13097. https://doi.org/10.1038/s41598-021-92595-0##Noda M, Iwamoto I, Tabata H, Yamagata T, Ito H, Nagata K I. Role of Per3, a circadian clock gene, in embryonic development of mouse cerebral cortex. Sci Rep 2019; 9: 5874. https://doi.org/10.1038/s41598-019-42390-9##Oh D J, Hong H O, Lee B A. The effects of strenuous exercises on resting heart rate, blood pressure, and maximal oxygen uptake. J Exerc Rehabil 2016; 12: 42-46. https://doi.org/10.12965/jer.150258##Olcese J M. Melatonin and Female Reproduction: An Expanding Universe. Front Endocrinol (Lausanne) 2020; 11: 85. https://doi.org/10.3389/fendo.2020.00085##Onishi K G, Maneval A C, Cable E C, Tuohy M C, Scasny A J, Sterina E, et al. Circadian and circannual timescales interact to generate seasonal changes in immune function. Brain Behav Immun 2020; 83: 33-43. https://doi.org/10.1016/j.bbi.2019.07.024##Ono M, Ando H, Daikoku T, Fujiwara T, Mieda M, Mizumoto Y, et al. The circadian clock, nutritional signals and reproduction: a close relationship. Int J Mol Sci 2023; 24: 1545. https://doi.org/10.3390/ijms24021545##Ota S M, Kong X, Hut R, Suchecki D, Meerlo P. The impact of stress and stress hormones on endogenous clocks and circadian rhythms. Front Neuroendocrinol 2021; 63: 100931. https://doi.org/10.1016/j.yfrne.2021.100931##Pan X, Taylor M J, Cohen E, Hanna N, Mota S. Circadian clock, time-restricted feeding and reproduction. Int J Mol Sci 2020; 21. https://doi.org/10.3390/ijms21030831##Patke A, Young M W, Axelrod S. Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol 2020; 21: 67-84. https://doi.org/10.1038/s41580-019-0179-2##Pendergast J S, Branecky K L, Yang W, Ellacott K L, Niswender K D, Yamazaki S. High-fat diet acutely affects circadian organisation and eating behavior. Eur J Neurosci 2013; 37: 1350-1356. https://doi.org/10.1111/ejn.12133##Peng F, Li X, Xiao F, Zhao R, Sun Z. Circadian clock, diurnal glucose metabolic rhythm, and dawn phenomenon. Trends Neurosci 2022; 45: 471-482. https://doi.org/10.1016/j.tins.2022.03.010##Peng L, Zhang K, Chen K. Period circadian clock 3 inhibits palmitic acid-induced oxidative stress and inflammatory factor secretion in podocytes. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021; 46: 1177-1186. ##Petković M, Henis M, Heese O, Relógio A. Chronotherapy in Glioblastoma: state of the art and future perspectives. EBioMedicine 2023; 89: 104470. https://doi.org/10.1016/j.ebiom.2023.104470##Piet R. Circadian and kisspeptin regulation of the preovulatory surge. Peptides 2023; 163: 170981. https://doi.org/10.1016/j.peptides.2023.170981##Pilorz V, Helfrich-Förster C, Oster H. The role of the circadian clock system in physiology. Pflugers Arch 2018; 470: 227-239. https://doi.org/10.1007/s00424-017-2103-y##Pizarro A, Hayer K, Lahens N F, Hogenesch J B. CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res 2013; 41: 1009-1013. https://doi.org/10.1093/nar/gks1161##Qian J, Scheer F. Circadian system and glucose metabolism: implications for physiology and disease. Trends Endocrinol Metab 2016; 27: 282-293. https://doi.org/10.1016/j.tem.2016.03.005##Ramkisoensing A, Meijer J H. Synchronization of biological clock neurons by light and peripheral feedback systems promotes circadian rhythms and health. Front Neurol 2015; 6: 128. https://doi.org/10.3389/fneur.2015.00128##Ramsay S, Zagorodnyuk V. Role of circadian rhythms and melatonin in bladder function in heath and diseases. Auton Neurosci 2023; 246: 103083. https://doi.org/10.1016/j.autneu.2023.103083##Raun S H, Henriquez-Olguín C, Karavaeva I, Ali M, Møller L L V, Kot W, et al. Housing temperature influences exercise training adaptations in mice. Nat Commun 2020; 11: 1560. https://doi.org/10.1038/s41467-020-15311-y##Reddy S, Reddy V, Sharma S. Physiology, circadian rhythm. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC., 2023.##Refinetti R. Circadian rhythmicity of body temperature and metabolism. Temperature (Austin) 2020; 7: 321-362. https://doi.org/10.1080/23328940.2020.1743605##Richards J, Gumz M L. Mechanism of the circadian clock in physiology. Am J Physiol Regul Integr Comp Physiol 2013; 304: 1053-1064. https://doi.org/10.1152/ajpregu.00066.2013##Rivas G B S, Teles-de-Freitas R, Pavan M G, Lima J B P, Peixoto A A, Bruno R V. Effects of light and temperature on daily activity and clock gene expression in two mosquito disease vectors. J Biol Rhythms 2018; 33: 272-288. https://doi.org/10.1177/0748730418772175##Rondanelli M, Faliva M A, Perna S, Antoniello N. Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res 2013; 25: 499-510. https://doi.org/10.1007/s40520-013-0118-6##Ruan W, Yuan X, Eltzschig H K. Circadian rhythm as a therapeutic target. Nat Rev Drug Discov 2021; 20: 287-307. https://doi.org/10.1038/s41573-020-00109-w##Ruben M D, Wu G, Smith D F, Schmidt R E, Francey L J, Lee Y Y, et al. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci Transl Med 2018; 10. https://doi.org/10.1126/scitranslmed.aat8806##Ruby C L, Verbanes N M, Palmer K N, Zisk C F, Bunion D J, Marinos L N. Caffeine Delays Light-entrained Activity and Potentiates Circadian Photic Phase-resetting in Mice. J Biol Rhythms 2018; 33: 523-534. https://doi.org/10.1177/0748730418789236##Russell G M, Kalafatakis K, Lightman S L. The importance of biological oscillators for hypothalamic-pituitary-adrenal activity and tissue glucocorticoid response: coordinating stress and neurobehavioural adaptation. J Neuroendocrinol 2015; 27: 378-388. https://doi.org/10.1111/jne.12247##Sahar S, Sassone-Corsi P. Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab 2012; 23: 1-8. https://doi.org/10.1016/j.tem.2011.10.005##Saidi O, Colin E, Rance M, Doré E, Pereira B, Duché P. Effect of morning versus evening exercise training on sleep, physical activity, fitness, fatigue and quality of life in overweight and obese adults. Chronobiol Int 2021; 38: 1537-1548. https://doi.org/10.1080/07420528.2021.1935988##Sargin D, Oliver D K, Lambe E K. Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels. Elife 2016; 5. https://doi.org/10.7554/eLife.21416##Scheer F, Hilton M F, Evoniuk H L, Shiels S A, Malhotra A, Sugarbaker R, et al. The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles. Proc Natl Acad Sci U S A 2021; 118. https://doi.org/10.1073/pnas.2018486118##Schibler U, Gotic I, Saini C, Gos P, Curie T, Emmenegger Y, et al. Clock-talk: interactions between central and peripheral circadian oscillators in mammals. Cold Spring Harb Symp Quant Biol 2015; 80: 223-232. https://doi.org/10.1101/sqb.2015.80.027490##Sciarra F, Franceschini E, Campolo F, Gianfrilli D, Pallotti F, Paoli D, et al. Disruption of circadian rhythms: a crucial factor in the etiology of infertility. Int J Mol Sci 2020; 21. https://doi.org/10.3390/ijms21113943##Scott M R, McClung C A. Circadian rhythms in mood disorders. Adv Exp Med Biol 2021; 1344: 153-168. https://doi.org/10.1007/978-3-030-81147-1_9##Sebti Y, Hebras A, Pourcet B, Staels B, Duez H. The circadian clock and obesity. Handb Exp Pharmacol 2022; 274: 29-56. https://doi.org/10.1007/164_2021_579##Segers A, Depoortere I. Circadian clocks in the digestive system. Nat Rev Gastroenterol Hepatol 2021; 18: 239-251. https://doi.org/10.1038/s41575-020-00401-5##Sellami M, Bragazzi N L, Slimani M, Hayes L, Jabbour G, De Giorgio A, et al. The effect of exercise on glucoregulatory hormones: a countermeasure to human aging: insights from a comprehensive review of the literature. Int J Environ Res Public Health 2019; 16. https://doi.org/10.3390/ijerph16101709##Shafi A A, McNair C M, McCann J J, Alshalalfa M, Shostak A, Severson T M, et al. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair. Nat Commun 2021; 12: 401. https://doi.org/10.1038/s41467-020-20513-5##Sherman H, Gutman R, Chapnik N, Meylan J, le Coutre J, Froy O. Caffeine alters circadian rhythms and expression of disease and metabolic markers. Int J Biochem Cell Biol 2011; 43: 829-838. https://doi.org/10.1016/j.biocel.2011.02.008##Shuboni-Mulligan D D, Young D L, Jr., De La Cruz Minyety J, Vera E, Munasinghe J, Gall A J, et al. Impact of age on the circadian visual system and the sleep-wake cycle in mus musculus. NPJ Aging Mech Dis 2021; 7: 10. https://doi.org/10.1038/s41514-021-00063-w##Silva C C, Domínguez R. Clock control of mammalian reproductive cycles: Looking beyond the pre-ovulatory surge of gonadotropins. Rev Endocr Metab Disord 2020; 21: 149-163. https://doi.org/10.1007/s11154-019-09525-9##Singh R, Singh R K, Masood T, Tripathi A K, Mahdi A A, Singh R K, et al. Circadian time structure of circulating plasma lipid peroxides, antioxidant enzymes and other small molecules in peptic ulcers. Clin Chim Acta 2015; 451: 222-226. https://doi.org/10.1016/j.cca.2015.09.033##Small L, Altıntaş A, Laker R C, Ehrlich A, Pattamaprapanont P, Villarroel J, et al. Contraction influences Per2 gene expression in skeletal muscle through a calcium-dependent pathway. J Physiol 2020; 598: 5739-5752. https://doi.org/10.1113/JP280428##Sokolowska E, Viitanen R, Misiewicz Z, Mennesson M, Saarnio S, Kulesskaya N, et al. The circadian gene Cryptochrome 2 influences stress-induced brain activity and depressive-like behavior in mice. Genes Brain Behav 2021; 20: e12708. https://doi.org/10.1111/gbb.12708##Solocinski K, Gumz M L. The circadian clock in the regulation of renal rhythms. J Biol Rhythms 2015; 30: 470-486. https://doi.org/10.1177/0748730415610879##Son G H, Chung S, Kim K. The adrenal peripheral clock: glucocorticoid and the circadian timing system. Front Neuroendocrinol 2011; 32: 451-465. https://doi.org/10.1016/j.yfrne.2011.07.003##Speed J S, Hyndman K A, Roth K, Heimlich J B, Kasztan M, Fox B M, et al. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 2018; 314: 89-98. https://doi.org/10.1152/ajprenal.00028.2017##Stow L R, Richards J, Cheng K Y, Lynch I J, Jeffers L A, Greenlee M M, et al. The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. Hypertension 2012; 59: 1151-1156. https://doi.org/10.1161/HYPERTENSIONAHA.112.190892##Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nat Rev Gastroenterol Hepatol 2016; 13: 217-226. https://doi.org/10.1038/nrgastro.2016.8##Tahara Y, Shiraishi T, Kikuchi Y, Haraguchi A, Kuriki D, Sasaki H, et al. Entrainment of the mouse circadian clock by sub-acute physical and psychological stress. Sci Rep 2015; 5: 11417. https://doi.org/10.1038/srep11417##Takeshima M, Shimizu T, Echizenya M, Ishikawa H, Kanbayashi T. Inpatient phase-advance therapy for delayed sleep-wake phase disorder: a retrospective study. Nat Sci Sleep 2018; 10: 327-333. https://doi.org/10.2147/NSS.S179264##Talpur H S, Chandio I B, Brohi R D, Worku T, Rehman Z, Bhattarai D, et al. Research progress on the role of melatonin and its receptors in animal reproduction: A comprehensive review. Reprod Domest Anim 2018; 53: 831-849. https://doi.org/10.1111/rda.13188##Tang Q, Cheng B, Xie M, Chen Y, Zhao J, Zhou X, et al. Circadian clock gene bmal1 inhibits tumorigenesis and increases paclitaxel sensitivity in tongue squamous cell carcinoma. Cancer Res 2017; 77: 532-544. https://doi.org/10.1158/0008-5472.CAN-16-1322##Tarquini R, Mazzoccoli G. Clock Genes, Metabolism, and Cardiovascular Risk. Heart Fail Clin 2017; 13: 645-655. https://doi.org/10.1016/j.hfc.2017.05.001##Tokuoka A, Itoh T Q, Hori S, Uryu O, Danbara Y, Nose M, et al. cryptochrome genes form an oscillatory loop independent of the per/tim loop in the circadian clockwork of the cricket Gryllus bimaculatus. Zoological Lett 2017; 3: 5. https://doi.org/10.1186/s40851-017-0066-7##Tong X, Zhang D, Charney N, Jin E, VanDommelen K, Stamper K, et al. DDB1-mediated CRY1 degradation promotes FOXO1-Driven gluconeogenesis in liver. Diabetes 2017; 66: 2571-2582. https://doi.org/10.2337/db16-1600##Tsang A H, Astiz M, Friedrichs M, Oster H. Endocrine regulation of circadian physiology. J Endocrinol 2016; 230: 1-11. https://doi.org/10.1530/JOE-16-0051##Tsang A H, Barclay J L, Oster H. Interactions between endocrine and circadian systems. J Mol Endocrinol 2014; 52: 1-16. https://doi.org/10.1530/JME-13-0118##Tse A C, Lee P H, Zhang J, Chan R C, Ho A W, Lai E W. Effects of exercise on sleep, melatonin level, and behavioral functioning in children with autism. Autism 2022; 26: 1712-1722. https://doi.org/10.1177/13623613211062952##Turek F W, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005; 308: 1043-1045. https://doi.org/10.1126/science.1108750##Uenoyama Y, Tsukamura H. KNDy neurones and GnRH/LH pulse generation: Current understanding and future aspects. J Neuroendocrinol 2023; 35: e13285. https://doi.org/10.1111/jne.13285##Walker W H, Walton J C, DeVries A C, Nelson R J. Circadian rhythm disruption and mental health. Translational Psychiatry 2020; 10: 28. https://doi.org/10.1038/s41398-020-0694-0##Wang F, Li C, Yongluo, Chen L. The Circadian gene clock plays an important role in cell apoptosis and the DNA damage response in vitro. Technol Cancer Res Treat 2016; 15: 480-486. https://doi.org/10.1177/1533034615585433##Wang J, Hou W T, Qin X M, Du G H, Gao X X. [Research progress of circadian rhythm]. Zhongguo Zhong Yao Za Zhi 2021; 46: 3240-3248.##Wang M, Jing Y, Hu L, Gao J, Ding L, Zhang J. Recent advances on the circadian gene PER2 and metabolic rhythm of lactation of mammary gland. Anim Nutr 2015a; 1: 257-261. https://doi.org/10.1016/j.aninu.2015.11.008##Wang Y, Xing T, Huang L, Song G, Sun X, Zhong L, et al. Period 1 and estrogen receptor-beta are downregulated in Chinese colon cancers. Int J Clin Exp Pathol 2015b; 8: 8178-8188.##Webb J. ECT-resistant bipolar depression treated with a single course of triple chronotherapy. Case Rep Psychiatry 2022; 2022: 9957190. https://doi.org/10.1155/2022/9957190##Xie Y, Tang Q, Chen G, Xie M, Yu S, Zhao J, et al. New insights into the circadian rhythm and its related diseases. Front Physiol 2019; 10: 682. https://doi.org/10.3389/fphys.2019.00682##Yang J, Zhang Z, Zhang Y, Zheng X, Lu Y, Tao D, et al. Clock interacts with RANBP9 and is involved in alternative splicing in spermatogenesis. Gene 2018; 642: 199-204. https://doi.org/10.1016/j.gene.2017.11.007##Ye L, Wu H, Xu W. Deletion of Bmal1 impairs pancreatic β-cell function via mitochondrial signaling pathway. Biomed Res Int 2020; 2020: 9803024. https://doi.org/10.1155/2020/9803024##Youn S, Choi B, Lee S, Kim C, Chung S. Time to Take Sleeping Pills and Subjective Satisfaction among Cancer Patients. Psychiatry Investig 2020; 17: 249-255. https://doi.org/10.30773/pi.2019.0216##Yu F, Liu Y, Zhang R, Zhu L, Zhang T, Shi Y. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochem Pharmacol 2022; 203: 115185. https://doi.org/10.1016/j.bcp.2022.115185##Yun S, Lee E J, Choe H K, Son G H, Kim K, Chung S. Programming effects of maternal stress on the circadian system of adult offspring. Exp Mol Med 2020; 52: 473-484. https://doi.org/10.1038/s12276-020-0398-9##Zhang J, Sun R, Jiang T, Yang G, Chen L. Circadian blood pressure rhythm in cardiovascular and renal health and disease. Biomolecules 2021; 11. https://doi.org/10.3390/biom11060868##Zhang S, Dai M, Wang X, Jiang S-H, Hu L-P, Zhang X-L, et al. Signalling entrains the peripheral circadian clock. Cellular Signalling 2020; 69: 109433. https://doi.org/10.1016/j.cellsig.2019.109433##Zhang W X, Chen S Y, Liu C. Regulation of reproduction by the circadian rhythms. Sheng Li Xue Bao 2016; 68: 799-808.##Zhang Y, Meng N, Bao H, Jiang Y, Yang N, Wu K, et al. Circadian gene PER1 senses progesterone signal during human endometrial decidualization. J Endocrinol 2019. https://doi.org/10.1530/JOE-19-0284##Zheng D, Ratiner K, Elinav E. Circadian influences of diet on the microbiome and immunity. Trends Immunol 2020; 41: 512-530. https://doi.org/10.1016/j.it.2020.04.005##Zhou J, Wang J, Zhang X, Tang Q. New Insights into cancer chronotherapies. Front Pharmacol 2021; 12: 741295. https://doi.org/10.3389/fphar.2021.741295##Zhou X, Yu R, Long Y, Zhao J, Yu S, Tang Q, et al. BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation. Cell Prolif 2018; 51: e12470. https://doi.org/10.1111/cpr.12470##Zietara A, Spires D R, Juffre A, Costello H M, Crislip G R, Douma L G, et al. Knockout of the circadian clock protein PER1 (Period1) exacerbates hypertension and increases kidney injury in dahl salt-sensitive rats. Hypertension 2022; 79: 2519-2529. https://doi.org/10.1161/HYPERTENSIONAHA.122.19316##Zuber A M, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, et al. Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci U S A 2009; 106: 16523-16528. https://doi.org/10.1073/pnas.0904890106## ##

An Evidence-Based Systematic Review: The Impact of Artificial Intelligence in Pharmacology and Health Research 2 2 Introduction: Artificial intelligence (AI) has gradually become a vital part of health care currently. AI and machine learning (ML) have made significant progress in recent years, particularly in terms of deep learning (DL) approaches in pharmacology. AI will have a significant impact on pharmacologists at all levels in the coming decade, including drug development and research, medical education, and clinical practice. AI is transforming health research, by boosting data analysis, providing diagnostic tools, predicting outcomes, and helping develop personalized treatments. AI affords early detection of diseases and creates virtual patient models to assess treatments. In this reverence, the objective of this systematic review is to evaluate the impact of AI in the field of Pharmacology and health research.  Methods: The review was performed by preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The studies published from 2009 to 2022 were identified using specific keywords through searches on PubMed, Google Scholar, Web of Science, Science Direct, and Cochrane review databases. The explorations retrieved 972 studies and on subsequent screening with the inclusion and exclusion criteria, 71 studies were included for this systematic review. Results: The collective results showed that AI plays a significant role in the fields of pharmacology, research, medical education, health care diagnostics, and clinical practice, with high accuracy and efficiency. Conclusion: AI has emerged as a powerful tool in pharmacology and healthcare, offering innovative solutions to longstanding challenges. It has revolutionized and digitally transformed the manual healthcare system into an automated version in many areas. 257 270 2023/05/162023/11/152023/06/25 1402/4/4 2024/04/62024/04/22024/02/19 1402/11/30 Anupama Gudadappanavar Anupama Gudadappanavar Department of Pharmacology, J N Medical College, KLE Academy of Higher Education and Research (KAHER), Belagavi, Karnataka, India India dranumg26@gmail.com Prashant Hombal Prashant Hombal Department of General Surgery, J N Medical College, KLE Academy of Higher Education and Research (KAHER), Belagavi, Karnataka, India India hombalp@yahoo.com Jyoti Benni Jyoti Benni Department of Pharmacology, J N Medical College, KLE Academy of Higher Education and Research (KAHER), Belagavi, Karnataka, India India benni_jyoti@yahoo.co.in Artificial Intelligence Machine Learning Deep Learning Pharmacology Health Research Abatemarco D, Perera S, Bao S H, Desai S, Assuncao B, Tetarenko N, et al. Training augmented intelligent capabilities for pharmacovigilance: applying deep-learning approaches to individual case safety report processing. Pharmaceut Med. 2018; 32(6): 391-401. https://doi.org/10.1007/s40290-018-0251-9##Aldahdooh J, Tanoli Z, Tang J. R-BERT-CNN: Drug-target interactions extraction from biomedical literature. arXiv preprint arXiv:2111.00611 2021.##Alimadadi A, Aryal S, Manandhar I, Munroe P B, Joe B, Cheng X. Artificial intelligence and machine learning to fight COVID-19. Physiol Genomics. 2020; 52(4): 200-202. https://doi.org/10.1152/physiolgenomics.00029.2020##Ampadu H H, Hoekman J, de Bruin M L, Pal S N, Olsson S, Sartori D, et al. Adverse drug reaction reporting in Africa and a comparison of individual case safety report characteristics between Africa and the rest of the world: analyses of spontaneous reports in VigiBase®. Drug safety 2016; 39: 335-345. https://doi.org/10.1007/s40264-015-0387-4##Arnold M H. Teasing out artificial intelligence in medicine: an ethical critique of artificial intelligence and machine learning in medicine. Journal of bioethical inquiry 2021; 18: 121-139. https://doi.org/10.1007/s11673-020-10080-1##Athreya A P, Iyer R, Wang L, Weinshilboum R M, Bobo W V. Integration of machine learning and pharmacogenomic biomarkers for predicting response to antidepressant treatment: can computational intelligence be used to augment clinical assessments? Pharmacogenomics. 2019; 20(14): 983-938. https://doi.org/10.2217/pgs-2019-0119##Bakkar N, Kovalik T, Lorenzini I, Spangler S, Lacoste A, Sponaugle K, et al. Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. Acta Neuropathol 2018; 135: 227-247. https://doi.org/10.1007/s00401-017-1785-8##Baron R J. Using artificial intelligence to make use of electronic health records less painful-fighting fire with fire. JAMA Netw Open. 2021; 4(7): e2118298. https://doi.org/10.1001/jamanetworkopen.2021.18298##Basile A O, Yahi A, Tatonetti N P. Artificial intelligence for drug toxicity and safety. Trends Pharmacol Sci. 2019; 40(9): 624-635. https://doi.org/10.1016/j.tips.2019.07.005##Benbya H, Davenport T H, Pachidi S. Artificial intelligence in organizations: current state and future opportunities. MIS Quarterly Executive, 2020. 19(4): 9-21. https://doi.org/10.2139/ssrn.3741983##Blais C, Jean S, Sirois C, Rochette L, Plante C, Larocque I, et al. Quebec integrated chronic disease surveillance system (QICDSS), an innovative approach. Chronic Dis Inj Can. 2014; 34(4): 226-235. https://doi.org/10.24095/hpcdp.34.4.06##Bosale S, Pujari V, Multani Z. Advantages and disadvantages of artificial intelligence. Aayushi International Interdisciplinary Research Journal. 2020, 9(1): 227-230.##Cabitza F, Rasoini R, Gensini G F. Unintended consequences of machine learning in medicine. JAMA. 2017; 318(6): 517-518. https://doi.org/10.1001/jama.2017.7797##Chan K S, Zary N. Applications and challenges of implementing artificial intelligence in medical education. Integrative Review JMIR Med Educ 2019; 5(1): e13930. https://doi.org/10.2196/13930##Chaudhari R, Fong L W, Tan Z, Huang B, Zhang S. An up-to-date overview of computational polypharmacology in modern drug discovery. Expert Opin Drug Discov. 2020; 15(9): 1025-1044. https://doi.org/10.1080/17460441.2020.1767063##Chen J, See K C. Artificial intelligence for COVID-19: rapid review. J Med Internet Res. 2020; 22(10): e21476. https://doi.org/10.2196/21476##Christopoulou F, Tran T T, Sahu S K, Miwa M, Ananiadou S. Adverse drug events and medication relation extraction in electronic health records with ensemble deep learning methods. J Am Med Inform Assoc. 2020; 27(1): 39-46. https://doi.org/10.1093/jamia/ocz101##Dandala B, Joopudi V, Devarakonda M. IBM Research System at MADE 2018: detecting adverse drug events from electronic health records. Journal 2018: 39-47. ##Dodziuk H. Applications of 3D printing in healthcare. Kardiochir Torakochirurgia Pol. 2016; 13(3): 283-293. https://doi.org/10.5114/kitp.2016.62625##D’Souza S, Prema K V, Balaji S. Machine learning models for drug-target interactions: current knowledge and future directions. Drug Discov Today. 2020; 25(4): 748-756. https://doi.org/10.1016/j.drudis.2020.03.003##Duke J, Faiola A, Kharrazi H. A novel visualization tool for evaluating medication side-effects in multi-drug regimens. Human-Computer Interaction 2009: 478-487. https://doi.org/10.1007/978-3-642-02583-9_52##Friedrichs M, Shoshi A. History and Future of KALIS: Towards computer-assisted decision making in prescriptive medicine. J Integr Bioinform. 2019; 16(3): 20190011. https://doi.org/10.1515/jib-2019-0011##Ganbaatar U, Liu C. CRISPR-based COVID-19 testing: toward next-generation point-of-care diagnostics. Frontiers in cellular and infection microbiology 2021; 11: 663949. https://doi.org/10.3389/fcimb.2021.663949##Gupta R, Srivastava D, Sahu M, Tiwari S, Ambasta R K, Kumar P. Artificial intelligence to deep learning: machine intelligence approach for drug discovery. Mol Divers. 2021; 25(3): 1315-1360. https://doi.org/10.1007/s11030-021-10217-3##Han E R, Yeo S, Kim M J, Lee Y H, Park K H, Roh H. Medical education trends for future physicians in the era of advanced technology and artificial intelligence: an integrative review. BMC medical education. 2019; 19(1): 1-5. https://doi.org/10.1186/s12909-019-1891-5##Hashimoto D A, Rosman G, Rus D, Meireles O R. Artificial intelligence in surgery: promises and perils. Ann Surg. 2018; 268(1): 70-76. https://doi.org/10.1097/SLA.0000000000002693##Hessler G, Baringhaus K H. Artificial intelligence in drug design. Molecules. 2018; 23(10): 2520. https://doi.org/10.3390/molecules23102520##Hu M, Ge X, Chen X, Mao W, Qian X, Yuan W E. Micro/nanorobot: a promising targeted drug delivery system. Pharmaceutics. 2020; 12(7): 665. https://doi.org/10.3390/pharmaceutics12070665##Jang I J. Artificial intelligence in drug development: clinical pharmacologist perspective. Transl Clin Pharmacol. 2019; 27(3): 87-88. https://doi.org/10.12793/tcp.2019.27.3.87##Jecker N S. Sociable robots for later life: Carebots, friendbots and sexbots. Sex robots: Social impact and the future of human relations 2021: 25-40. https://doi.org/10.1007/978-3-030-82280-4_2##Jiménez-Luna J, Grisoni F, Weskamp N, Schneider G. Artificial intelligence in drug discovery: recent advances and future perspectives. Expert Opin Drug Discov. 2021; 16(9): 949-959. https://doi.org/10.1080/17460441.2021.1909567##Kalinin A A, Higgins G A, Reamaroon N, Soroushmehr S, Allyn-Feuer A, Dinov I D, et al. Deep learning in pharmacogenomics: from gene regulation to patient stratification. Pharmacogenomics. 2018; 19(7): 629-650. https://doi.org/10.2217/pgs-2018-0008##Keskinbora K H. Medical ethics considerations on artificial intelligence. J Clin Neurosci. 2019; 64: 277-282. https://doi.org/10.1016/j.jocn.2019.03.001##Khanzode K C, Sarode R D. Advantages and disadvantages of artificial intelligence and machine learning: aliterature review. International Journal of Library & Information Science (IJLIS). 2020; 9(1):3.##Kompa B, Hakim J B, Palepu A, Kompa K G, Smith M, Bain P A, et al. Artificial intelligence based on machine learning in pharmacovigilance: a scoping review. Drug Safety. 2022; 45(5): 477-491. https://doi.org/10.1007/s40264-022-01176-1##Kornegay J G, Leone K A, Wallner C, Hansen M, Yarris L M. Development and implementation of an asynchronous emergency medicine residency curriculum using a web-based platform. Intern Emerg Med. 2016; 11(8): 1115-1120. https://doi.org/10.1007/s11739-016-1418-6##Lake F. Artificial intelligence in drug discovery: What is new, and what is next? Advances in clinical immunology, medical microbiology, COVID-19, and big data: Jenny Stanford Publishing, 2021: 539-545.##Lavan A H, O’Mahony D, Gallagher P, Fordham R, Flanagan E, Dahly D, et al. The effect of SENATOR (Software ENgine for the Assessment and optimisation of drug and non-drug Therapy in Older peRsons) on incident adverse drug reactions (ADRs) in an older hospital cohort - Trial Protocol. BMC Geriatr. 2019; 19(1): 40. https://doi.org/10.1186/s12877-019-1047-9##Lin E, Kuo P H, Liu Y L, Yu Y W, Yang A C, Tsai S J. Prediction of antidepressant treatment response and remission using an ensemble machine learning framework. Pharmaceuticals (Basel). 2020; 13(10): 305. https://doi.org/10.3390/ph13100305##Lociciro A, Guillon A, Bodet-Contentin L. A telepresence robot in the room of a COVID-19 patient can provide virtual family presence. Can J Anaesth. 2021; 68(11): 1705-1706. https://doi.org/10.1007/s12630-021-02039-6##Lysenko A, Sharma A, Boroevich KA, Tsunoda T. An integrative machine learning approach for prediction of toxicity-related drug safety. Life Sci Alliance. 2018; 1(6): e201800098. https://doi.org/10.26508/lsa.201800098##Mak K K and Pichika M R. Artificial intelligence in drug development: present status and future prospects, Drug Discovery Today, 2019, 24(3): 773-780. https://doi.org/10.1016/j.drudis.2018.11.014##Masters K. Artificial intelligence in medical education. Med Teach. 2019; 41(9): 976-980. https://doi.org/10.1080/0142159X.2019.1595557##McDonald E G, Wu P E, Rashidi B, Wilson M G, Bortolussi-Courval É, Atique A, et al. The medsafer study-electronic decision support for deprescribing in hospitalized older adults: a cluster randomized clinical trial. JAMA Intern Med. 2022; 182(3): 265-273. https://doi.org/10.1001/jamainternmed.2021.7429##Meenakshi K, Safa M, Karthick T, Sivaranjani N. A novel study of machine learning algorithms for classifying health care data. Research J Pharm and Tech. 2017; 10(5): 1429-1432. https://doi.org/10.5958/0974-360X.2017.00253.0##Mockute R, Desai S, Perera S, Assuncao B, Danysz K, Tetarenko N, et al. Artificial intelligence within pharmacovigilance: a means to identify cognitive services and the framework for their validation. Pharmaceut Med. 2019; 33(2): 109-120. https://doi.org/10.1007/s40290-019-00269-0##Müller-Staub M, de Graaf-Waar H, Paans W. An internationally consented standard for nursing process-clinical decision support systems in electronic health records. Comput Inform Nurs. 2016; 34(11): 493-502. https://doi.org/10.1097/CIN.0000000000000277##Kotni M, Kaur S, Prakash A, Medhi B. Artificial intelligence in pharmacovigilance: practical utility. Indian Journal of Pharmacology. 2019; 51(6): 373-376. https://doi.org/10.4103/ijp.IJP_814_19##Nelson G S. Bias in artificial intelligence. North Carolina medical journal 2019; 80: 220-222. https://doi.org/10.18043/ncm.80.4.220##Ngiam K Y, Khor I W. Big data and machine learning algorithms for health-care delivery. Lancet Oncol. 2019; 20(5): 262-273. https://doi.org/10.1016/S1470-2045(19)30149-4##Ong E, Cooke M F, Huffman A, Xiang Z, Wong M U, Wang H, et al. Vaxign2: The second generation of the first Web-based vaccine design program using reverse vaccinology and machine learning. Nucleic Acids Research. 2021;49(W1): 671-678. https://doi.org/10.1093/nar/gkab279##Palanica A, Docktor M J, Lieberman M, Fossat Y. The need for artificial intelligence in digital therapeutics. Digit Biomark. 2020; 4(1): 21-25. https://doi.org/10.1159/000506861##Paranjape K, Schinkel M, Nannan Panday R, Car J, Nanayakkara P. Introducing artificial intelligence training in medical education. JMIR Med Educ. 2019; 5(2): e16048. https://doi.org/10.2196/16048##Parikh R B, Teeple S, Navathe A S. Addressing bias in artificial intelligence in health care. JAMA. 2019; 322(24): 2377-2378. https://doi.org/10.1001/jama.2019.18058##Paul D, Sanap G, Shenoy S, Kalyane D, Kalia K, Tekade R K. Artificial intelligence in drug discovery and development. Drug Discov Today. 2021; 26(1): 80-93. https://doi.org/10.1016/j.drudis.2020.10.010##Rodrigues P P, Ferreira-Santos D, Silva A, Polónia J, Ribeiro-Vaz I. Causality assessment of adverse drug reaction reports using an expert-defined Bayesian network. Artif Intell Med. 2018; 91: 12-22. https://doi.org/10.1016/j.artmed.2018.07.005##Shakshuki E, Reid M. Multi-agent system applications in healthcare: current technology and future roadmap. Procedia Computer Science. 2015; 52: 252-261. https://doi.org/10.1016/j.procs.2015.05.071##Silva P, Jacobs D, Kriak J, Abu-Baker A, Udeani G, Neal G, et al. Implementation of pharmacogenomics and artificial intelligence tools for chronic disease management in primary care setting. J Pers Med. 2021; 11(6): 443. https://doi.org/10.3390/jpm11060443##Sirois C, Khoury R, Durand A, Deziel P L, Bukhtiyarova O, Chiu Y, et al. Exploring polypharmacy with artificial intelligence: data analysis protocol. BMC Med Inform Decis Mak. 2021; 21(1): 219. https://doi.org/10.1186/s12911-021-01583-x##Smith J, Stein V. SPORCalc: A development of a database analysis that provides putative metabolic enzyme reactions for ligand-based drug design. Comput Biol Chem. 2009; 33(2): 149-159. https://doi.org/10.1016/j.compbiolchem.2008.11.002##Souri EA, Laddach R, Karagiannis SN, Papageorgiou LG, Tsoka S. A computational approach to predict drug-target interactions using machine learning. BMC Bioinformatics. 2022 Apr 4;23(121).##Suhail M, Khan A, Rahim M A, Naeem A, Fahad M, Badshah S F, Jabar A, Janakiraman AK. Micro and nanorobot-based drug delivery: an overview. J Drug Target. 2022; 30(4): 349-358. https://doi.org/10.1080/1061186X.2021.1999962##Sun H, Scott D O. Structure-based drug metabolism predictions for drug design. Chem Biol Drug Des. 2010; 75(1): 3-17. https://doi.org/10.1111/j.1747-0285.2009.00899.x##Vamathevan J, Clark D, Czodrowski P, Dunham I, Ferran E, et al. Applications of machine learning in drug discovery and development. Nat Rev Drug Discov. 2019; 18(6): 463-477. https://doi.org/10.1038/s41573-019-0024-5##Vanhaelen Q, Lin YC, Zhavoronkov A. The advent of generative chemistry. ACS Med Chem Lett. 2020; 11(8): 1496-1505. https://doi.org/10.1021/acsmedchemlett.0c00088##Vermeer N S, Straus S M, Mantel-Teeuwisse A K, Domergue F, Egberts T C, Leufkens H G, et al. Traceability of biopharmaceuticals in spontaneous reporting systems: a cross-sectional study in the FDA Adverse Event Reporting System (FAERS) and Eudra Vigilance databases. Drug Saf. 2013; 36(8): 617-625. https://doi.org/10.1007/s40264-013-0073-3##Whirl-Carrillo M, McDonagh E M, Hebert J M, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012; 92(4): 414-417. https://doi.org/10.1038/clpt.2012.96##Wilfling D, Hinz A, Steinhäuser J. Big data analysis techniques to address polypharmacy in patients - a scoping review. BMC Fam Pract. 2020; 21(1): 180. https://doi.org/10.1186/s12875-020-01247-1##Wolbrink T A, Burns J P. Internet-based learning and applications for critical care medicine. J Intensive Care Med. 2012; 27(5): 322-332. https://doi.org/10.1177/0885066611429539##Yang X, Bian J, Gong Y, Hogan W R, Wu Y. MADEx: A system for detecting medications, adverse drug events, and their relations from clinical notes. Drug Saf. 2019; 42(1): 123-133. https://doi.org/10.1007/s40264-018-0761-0##Yew G C K. Trust in and ethical design of carebots: the case for ethics of care. Int J Soc Robot. 2021; 13(4): 629-645. https://doi.org/10.1007/s12369-020-00653-w##Zhang L, Tan J, Han D, Zhu H. From machine learning to deep learning: progress in machine intelligence for rational drug discovery. Drug Discov Today. 2017; 22(11): 1680-1685. https://doi.org/10.1016/j.drudis.2017.08.010##Zhao Z, Ma Y, Mushtaq A, Rajper A M A, Shehab M, Heybourne A, et al. Applications of robotics, artificial intelligence, and digital technologies during COVID-19: A Review. Disaster Med Public Health Prep. 2021: 1-11. https://doi.org/10.1017/dmp.2021.9##Zhou XY, Guo Y, Shen M, Yang G Z. Application of artificial intelligence in surgery. Front Med. 2020; 14(4): 417-430. https://doi.org/10.1007/s11684-020-0770-0## ##

Effects of long-term repeated treatment with artemisinin-based combination therapy on the reproductive potential of male mice 2 2 Introduction: In endemic malarial nations, repeated use of antimalarial drugs has increased due to resistance, misuse, and unrestricted availability, which could contribute to infertility rates. Therefore, we investigated the effects of long-term repeated treatment with two commonly prescribed artemisinin-based combination therapies, artemether/lumefantrine (A/L) and artesunate-amodiaquine (A/A), on reproductive potential in mice.  Methods: Sixty male mice were divided into three groups: control, A/L, and A/A treatment.  Mice underwent treatment for three consecutive days per week, and this regimen was repeated every two weeks for a total of six cycles. Sperm parameters were evaluated after the 1st, 2nd, 3rd, and 6th exposure cycles, after which treated male mice were paired with female mice for mating. Results: Sperm viability was significantly reduced by 21% (P<0.001) following the 6th exposure to A/L, whereas the 2nd, 3rd, and 6th exposures to A/A resulted in significant decreases in sperm viability of 26% (P<0.001), 12% (P<0.01), and 31% (P<0.001), respectively, compared to the control group. Treatment with A/A during the 3rd and 6th periods led to a significant decline (P<0.001) in sperm mass activity by 20% and 28%, respectively, compared to the control group. However, long-term therapeutic exposure to A/L or A/A did not affect testosterone levels, epididymal content, or the ability to impregnate female mice. Conclusion: Long-term treatment with A/L or A/A did not affect testosterone levels or epididymal content. However, a decrease in sperm viability was observed, even though the mice remained fertile. 271 281 2023/05/162023/11/152023/06/252023/06/13 1402/3/23 2024/04/62024/04/22024/02/192024/04/23 1403/2/4 David Audu David Audu Department of Pure and Applied Zoology, College of Biosciences, Federal University of Agri-culture Abeokuta, Ogun State, Nigeria Nigeria audud@funaab.edu.ng Idowu Olufunmilayo Ajoke Idowu Olufunmilayo Ajoke Department of Pure and Applied Zoology, College of Biosciences, Federal University of Agri-culture Abeokuta, Ogun State, Nigeria Nigeria Mshelbwala Fakilahyel Musa Mshelbwala Fakilahyel Musa Department of Veterinary Pathology, College of Veterinary Medicine, Federal University of Agriculture Abeokuta, Ogun State, Nigeria Nigeria Idowu Adewumi Babatunde Idowu Adewumi Babatunde Department of Pure and Applied Zoology, College of Biosciences, Federal University of Agri-culture Abeokuta, Ogun State, Nigeria Nigeria Infertility Artemisinin Sperm cells testosterone Abolaji A O, Eteng M U, Omonua O, Adenrele Y. Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats. Human & Experimental Toxicology 2012; 32: 206-215. https://doi.org/10.1177/0960327112464666##Agarwal A, Mulgund A, Hamada A, Chyatte M R. A unique view on male infertility around the globe. Reproductive Biology and Endocrinology 2015; 13: 37. https://doi.org/10.1186/s12958-015-0032-1##Ajayi N A, Ukwaja K N. Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases. Revista da sociedade Brasileira de medicina Tropical 2013; 46: 525-527. https://doi.org/10.1590/0037-8682-0098-2013##Ajogbasile F V, Oluniyi P E, Kayode A T, Akano K O, Adegboyega B B, Philip C, et al. Molecular profiling of the artemisinin resistance Kelch 13 gene in Plasmodium falciparum from Nigeria. PLoS One 2022; 17: e0264548. https://doi.org/10.1371/journal.pone.0264548##Alagbonsi A I, Salman T M, Sulaiman S O, Adedini K A, Kebu S. Possible mechanisms of the hypoglycaemic effect of artesunate: Gender implication. Metabolism Open 2021; 10: 100087. https://doi.org/10.1016/j.metop.2021.100087##Alghobary M, Mostafa T. Addiction and human male fertility: A systematic review and a critical appraisal. Andrology 2022; 10: 1073-1095. https://doi.org/10.1111/andr.13196##Anyanwu P E, Fulton J, Evans E, Paget T. Exploring the role of socioeconomic factors in the development and spread of anti-malarial drug resistance: a qualitative study. Malaria Journal 2017; 16: 203. https://doi.org/10.1186/s12936-017-1849-1##Aprioku J S. Early effects of concurrent administration of artesunate-amodiaquine and nifedipine on sperm parameters and sex hormones in guinea pigs: An experimental study. Int J Reprod Biomed 2018; 16: 629-636. https://doi.org/10.29252/ijrm.16.10.629##Aprioku J S, Mankwe A C. Study on testicular response to prolong artemisinin-based combination therapy treatments in guinea pigs. Andrologia 2018; 50: e12852. https://doi.org/10.1111/and.12852##Asadi N, Bahmani M, Kheradmand A, Rafieian-Kopaei M. The impact of oxidative stress on testicular function and the role of antioxidants in improving it: a review. J Clin Diagn Res 2017; 11: Ie01-ie05. https://doi.org/10.7860/JCDR/2017/23927.9886##Audu D, Patel V, Idowu O. Repeated treatment with antimalarial agents causes in vitro liver toxicity. Liver Res 2023;4(1):1-6. https://doi.org/10.17140/LROJ-4-113##Audu D, Petagine L, Idowu O A, Patel V B, Idowu A B. Biomarkers of the toxic effects of chemotherapeutic agents: a focus on antimalarials. In: Patel V B, Preedy V R and Rajendram R, editors. Biomarkers in toxicology. Cham: Springer International Publishing, 2023b: 1035-1061. https://doi.org/10.1007/978-3-031-07392-2_73##Baker D J. Semen analysis. Clinical Laboratory Science 2007; 20: 172.##Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nature Reviews Urology 2017; 14: 470-485. https://doi.org/10.1038/nrurol.2017.69##Bui A D, Sharma R, Henkel R, Agarwal A. Reactive oxygen species impact on sperm DNA and its role in male infertility. Andrologia 2018; 50: e13012. https://doi.org/10.1111/and.13012##Charan J, Kantharia N D. How to calculate sample size in animal studies? Journal of Pharmacology and Pharmacotherapeutics 2013; 4: 303-306. https://doi.org/10.4103/0976-500X.119726##Daikwo A O, Mohammed, U. Kawu , Rabiu, A. Magaji , Ejike, D. Eze effect of prolonged administration of artemether-lumefantrine on testicular biomarkers of oxidative stress: ameliorative effect of vitamin E. Basic Sciences of Medicine 2018; 7(1): 1-6.##Daikwo O A, Kawu, M. U. Evaluation of prolonged administration of artemether-lumefantrine on sperm indices and testicular testosterone concentration in adult male Wistar rats. Annals of Medical and Biomedical Sciences 2015; 1(2): 52-56.##Durairajanayagam D. Lifestyle causes of male infertility. Arab Journal of Urology 2018; 16: 10-20. https://doi.org/10.1016/j.aju.2017.12.004##Dutta S, Majzoub A, Agarwal A. Oxidative stress and sperm function: A systematic review on evaluation and management. Arab Journal of Urology 2019; 17: 87-97. https://doi.org/10.1080/2090598X.2019.1599624##Hanboonkunupakarn B, White N J. The threat of artemisinin resistant malaria in Southeast Asia. Travel Med Infect Dis 2016; 14: 548-550. https://doi.org/10.1016/j.tmaid.2016.11.016##Jafari H, Mirzaiinajmabadi K, Roudsari R L, Rakhshkhorshid M. The factors affecting male infertility: A systematic review. Int J Reprod Biomed 2021; 19: 681-688. https://doi.org/10.18502/ijrm.v19i8.9615##James E R, Carrell D T, Aston K I, Jenkins T G, Yeste M, Salas-Huetos A. The role of the epididymis and the contribution of epididymosomes to mammalian reproduction. International Journal of Molecular Sciences 2020; 21: 5377. https://doi.org/10.3390/ijms21155377##Johnson P D, Besselsen D G. Practical aspects of experimental design in animal research. ILAR Journal 2002; 43: 202-206. https://doi.org/10.1093/ilar.43.4.202##Kavishe R A, Koenderink J B, Alifrangis M. Oxidative stress in malaria and artemisinin combination therapy: Pros and Cons. The FEBS Journal 2017; 284: 2579-2591. https://doi.org/10.1111/febs.14097##Ko E Y, Sabanegh E S, Agarwal A. Male infertility testing: reactive oxygen species and antioxidant capacity. Fertility and Sterility 2014; 102: 1518-1527. https://doi.org/10.1016/j.fertnstert.2014.10.020##Koko V S, Warsame M, Vonhm B, Jeuronlon M K, Menard D, Ma L, et al. Artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers. Malaria Journal 2022; 21: 134. https://doi.org/10.1186/s12936-022-04140-7##Kumar N, Singh A K. Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci 2015; 8: 191-6. https://doi.org/10.4103/0974-1208.170370##Leisegang K, Dutta S. Do lifestyle practices impede male fertility? Andrologia 2021; 53: e13595. https://doi.org/10.1111/and.13595##Li X-Q, Björkman A, Andersson T B, Ridderström M, Masimirembwa C M. Amodiaquine clearance and its metabolism to N-Desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. Journal of Pharmacology and Experimental Therapeutics 2002; 300: 399. https://doi.org/10.1124/jpet.300.2.399##Mann U, Shiff B, Patel P. Reasons for worldwide decline in male fertility. Current Opinion in Urology 2020; 30. https://doi.org/10.1097/MOU.0000000000000745##Marchiani S, Tamburrino L, Muratori M, Baldi E. Epididymal sperm transport and fertilization. Endocrinology of the Testis and Male Reproduction 2017; 1: 457. https://doi.org/10.1007/978-3-319-44441-3_14##Mofio B M, John R, Attah O R, Adikpe A O, Usende I L. Chronic oral exposure to Artemether-lumenfantrine induced testicular and epidydimal damage, germ cell death and severe decrease sperm viability in BALB/c mice. Scientific African 2020; 8: e00454. https://doi.org/10.1016/j.sciaf.2020.e00454##Nassar G N, Leslie S W. Physiology, testosterone: StatPear is Publishing, Treasure Island (FL), 2023.##Nsanzabana C. Resistance to artemisinin combination therapies (ACTs): do not forget the partner drug! Tropical Medicine and Infectious Disease 2019; 4: 26. https://doi.org/10.3390/tropicalmed4010026##Nwokolo E, Ujuju C, Anyanti J, Isiguzo C, Udoye I, Bongos-Ikwue E, et al. Misuse of Artemisinin combination therapies by clients of medicine retailers suspected to have malaria without prior parasitological confirmation in Nigeria. International Journal of Health Policy and Management 2018; 7: 542-548. https://doi.org/10.15171/ijhpm.2017.122##Obianime A W, Aprioku J S. Comparative study of artesunate, ACTs and their combinants on the spermatic parameters of the male guinea pig. Niger J Physiol Sci 2009; 24: 1-6. https://doi.org/10.4314/njps.v24i1.46372##Okwakpam F N, Nwonodi M A, Obediah G, Azuonwu O O. Evaluation of chronic administration of the concomitant combination of artemether-lumefantrine and ciprofloxacin on reproductive hormones and prostate specific antigen of adult male Wistar rats. Biomed J. Sci. & Tech Res 2023; 48: 39770-39775. https://doi.org/10.26717/BJSTR.2023.48.007659##Olufemi M A, Oludare Gabriel O, Sheriff O, Oladele A A. Effects of Short Term Administration of Artemether-Lumefantrine on Testicular Functions and Antioxidant Defence in the Rat. Research Journal of Medicine and Medical Sciences 2009; 4: 165-170.##Omole M K, and O. T. Onademuren. A survey of antimalarial drug use practices among urban dwellers in Abeokuta, Nigeria. African Journal of Biomedical Research 2010; 13: 1-7.##Otuechere C A, Edewor G, Kale O E, Ekor M. Subacute Therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine combination preserves plasma cholesterol, renal antioxidant status, and organ weights in rats. Malaria Research and Treatment 2012; 2012: 257986. https://doi.org/10.1155/2012/257986##Patricio A, Cruz D F, Silva J V, Padrão A, Correia B R, Korrodi-Gregório L, et al. Relation between seminal quality and oxidative balance in sperm cells. Acta Urológica Portuguesa 2016; 33: 6-15. https://doi.org/10.1016/j.acup.2015.10.001##Pousibet-Puerto J, Salas-Coronas J, Sánchez-Crespo A, Molina-Arrebola M A, Soriano-Pérez M J, Giménez-López M J, et al. Impact of using artemisinin-based combination therapy (ACT) in the treatment of uncomplicated malaria from Plasmodium falciparum in a non-endemic zone. Malaria Journal 2016; 15: 339. https://doi.org/10.1186/s12936-016-1408-1##Raji Y, Akinsomisoye O S, Salman T M. Antispermatogenic activity of Morinda lucida extract in male rats. Asian Journal of Andrology 2005; 7: 405-410. https://doi.org/10.1111/j.1745-7262.2005.00051.x##Sabeti P, Pourmasumi S, Rahiminia T, Akyash F, Talebi A R. Etiologies of sperm oxidative stress. Int J Reprod Biomed 2016; 14: 231-40. https://doi.org/10.29252/ijrm.14.4.231##Samuel S A, Ayobami D, E Jane A. Comparative effects of commonly used Artemisinin-based combination therapies (ACTs) on reproductive parameters in male wistar rats. MOJ Bioequivalence & Bioavailability 2018; 5. https://doi.org/10.15406/mojbb.2018.05.00090##Sansone A, Di Dato C, de Angelis C, Menafra D, Pozza C, Pivonello R, et al. Smoke, alcohol and drug addiction and male fertility. Reproductive Biology and Endocrinology 2018; 16: 3. https://doi.org/10.1186/s12958-018-0320-7##Shibeshi W, Alemkere G, Mulu A, Engidawork E. Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis. BMC Infectious Diseases 2021; 21: 326. https://doi.org/10.1186/s12879-021-06018-6##Tavilani H, Doosti M, Saeidi H. Malondialdehyde levels in sperm and seminal plasma ofasthenozoospermic and its relationship with semen parameters. Clinica Chimica Acta 2005; 356: 199-203. https://doi.org/10.1016/j.cccn.2005.01.017##Uadia P O, Abiodun M. E. Male infertility in Nigeria: A neglected reproductive health issue requiring attention. Journal of Basic and Clinical Reproductive Sciences 2015; 4: 45-53. https://doi.org/10.4103/2278-960X.161042##Villaverde A I S B, Netherton J, Baker M A. From past to present: the link between reactive oxygen species in sperm and male infertility. Antioxidants 2019; 8: 616. https://doi.org/10.3390/antiox8120616##W.H.O. Fifth Edition: Examination and processing of human semen. 2010.##W.H.O. Infertility prevalence estimates, 1990-2021: World Health Organization, 2023.##W.H.O. WHO Guidelines for malaria World Health Organization 2021.##Wagner H, Cheng J W, Ko E Y. Role of reactive oxygen species in male infertility: An updated review of literature. Arab Journal of Urology 2018; 16: 35-43. https://doi.org/10.1016/j.aju.2017.11.001## ##

Omega-3 PUFAs counteracts high fructose diet-induced gonadal impairment via fortified antioxidant defense 2 2 Introduction: The consumption of fructose sweeteners as an alternative to high-calorie diets has been linked to various metabolic diseases due to increased oxidative stress. This study investigated changes in testicular and ovarian functions following Omega-3 polyunsaturated fatty acid supplementation (ω-3 PUFAs) in rats fed a High Fructose Diet (HFD). Methods: Forty Wistar rats were equally and randomly distributed into four groups. Each group was further subdivided by gender, with an equal number of animals in each sub-group. Group A assigned as control, while Groups B and C were administered HFD containing 10% and 20% v/v fructose solution, respectively. Group D rats were provided 20% v/v HFD and ω-3 PUFAs.  Results: After six weeks of consumption, HFD resulted in reduced semen quality and gonadal reproductive hormone levels, while increasing testicular and ovarian oxidative stress. ω-3 PUFAs improved semen quality, reproductive hormone concentrations, and antioxidant defense system. Conclusion: HFD impairs gonadal function, however, dietary supplementation with ω-3 PUFAs improves gonadal functions by enhancing the antioxidant defense mechanism. 282 294 2023/05/162023/11/152023/06/252023/06/132022/05/21 1401/2/31 2024/04/62024/04/22024/02/192024/04/232023/04/11 1402/1/22 Ehitare Ekhoye Ehitare Ekhoye Department of Physiology, College of Medical Sciences, Edo State University Uzairue, Nigeria Nigeria ekhoye.ehitare@edouniversity.edu.ng Ejime Agbonifo-Chijiokwu Ejime Agbonifo-Chijiokwu Department of Physiology, College of Health Sciences, Delta State University, Abraka, Nigeria Nigeria eagbonifo-chijiokwu@delsu.edu.ng Eze Nwangwa Eze Nwangwa Department of Physiology, College of Health Sciences, Delta State University, Abraka, Nigeria Nigeria eknwangwa@delsu.edu.ng High-fructose diet Infertility Omega-3 Ovary Oxidative stress Aebi H. Catalase in vitro. in: methods enzymol, Vol 105. 1984. https://doi.org/10.1016/S0076-6879(84)05016-3##Agarwal A, Aponte-Mellado A, Premkumar B J, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol 2012; 10: 49. https://doi.org/10.1186/1477-7827-10-49##Ahmed M, Ahamed R N, H Aladakatti R, G Ghodesawar M A. Effect of benzene extract of Ocimum sanctum leaves on cauda epididymal spermatozoa of rats. Iran J Reprod Med 2011; 9: 177-186.##Aitken R J, Gibb Z, Baker M A, Drevet J, Gharagozloo P. Causes and consequences of oxidative stress in spermatozoa. Reprod Fertil Dev 2016; 28: 1-10. https://doi.org/10.1071/RD15325##Al-chalabi A S, Rahim H A, Aklilu E. Histopathological changes associated with oxidative stress induced by electromagnetic waves in rats ‘ ovarian and uterine tissues. Asian J Pacific Reprod 2016; 5: 301-310. https://doi.org/10.1016/j.apjr.2016.06.008##Almaghrabi O A. Molecular and biochemical investigations on the effect of quercetin on oxidative stress induced by cisplatin in rat kidney. Saudi J Biol Sci 2015; 22(2): 227-231. https://doi.org/10.1016/j.sjbs.2014.12.008##Arafa H, Aly H, Abd-Ellah M, El-Refaey H. Hesperidin attenuates benzo [α] pyrene-induced testicular toxicity in rats via regulation of oxidant/antioxidant balance. Toxicol Ind Health 2009; 25: 417-427. https://doi.org/10.1177/0748233709106624##Asadi N, Bahmani M, Kheradmand A, Rafieian-Kopaei M. The Impact of oxidative stress on testicular function and the role of antioxidants in improving it: a review. J Clin Diagn Res 2017; 11: IE01-5. https://doi.org/10.7860/JCDR/2017/23927.9886##Aydos O S, Yükselten Y, Kaplan F, Sunguroğlu A, Aydos K. Analysis of the correlation between sperm DNA integrity and conventional semen parameters in infertile men. Turkish J Urol 2015; 41: 191-197. https://doi.org/10.5152/tud.2015.98475##Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab 2005; 2: 1-14. https://doi.org/10.1186/1743-7075-2-5##Chandramohan R, Pari L. Protective effect of umbelliferone on high-fructose diet-induced insulin resistance and oxidative stress in rats. Biomed Aging Pathol 2014; 4: 23-28. https://doi.org/10.1016/j.biomag.2013.12.003##Cooray A, Kim J H, Chae M R, Lee S, Lee K P. Perspectives on potential fatty acid modulations of motility associated human sperm ion channels. Int J Mol Sci 2022; 23(7): 3718. https://doi.org/10.3390/ijms23073718##Datta K, Sinha S, Chattopadhyay P. Reactive oxygen species in health and disease. Natl Med J India 2000; 13: 304-310.##DeChristopher L R, Uribarri J, Tucker K L. Intake of high fructose corn syrup sweetened soft drinks is associated with prevalent chronic bronchitis in U.S. Adults, ages 20-55 y. Nutr J 2015; 14: 107. https://doi.org/10.1186/s12937-015-0097-x##Devine P J, Perreault S D, Luderer U. Roles of reactive oxygen species and antioxidants in ovarian toxicity. Biol Reprod 2012; 86: 27. https://doi.org/10.1095/biolreprod.111.095224##Dobrakowski M, Kaletka Z, Machoń-Grecka A, Kasperczyk S, Horak S, Birkner E, et al. The role of oxidative stress, selected metals, and parameters of the immune system in male fertility. Oxid Med Cell Longev 2018; 2018: 6249536. https://doi.org/10.1155/2018/6249536##Farombi E O, Adedara I A, Oyenihi A B, Ekakitie E, Kehinde S. Hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kolaseed. J Ethnopharmacol 2013; 146: 536-542. https://doi.org/10.1016/j.jep.2013.01.018##Gómez-Crisóstomo N P, de la Cruz Arias D, Camacho Liévano J U, de la Cruz-Hernández E N, Martínez-Abundis E. Chronic consumption of refined but not brown sugar induces Hypertriglyceridemia and fat accumulation in rat liver. Acad J Sci Res 2017; 5: 451-459.##Gunzel-Apel A, Urhausen C, Wolf K, Einspanier A, Oei C, Piechotta M. Serum progesterone in pregnant bitches supplemented with progestin because of expected or suspected luteal insufficiency. Reprod Domest Anim 2012; 47: 55-60. https://doi.org/10.1111/rda.12029##Jarukamjorn K, Jearapong N, Pimson C, Chatuphonprasert W. A High-fat, high-fructose diet induces antioxidant imbalance and increases the risk and progression of nonalcoholic fatty liver disease in mice. Scientifica (Cairo) 2016; 2016: 5029414. https://doi.org/10.1155/2016/5029414##Kamaraj S, Anandakumar P, Jagan S, Ramakrishnan G, Devaki T. Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice. Fundam Clin Pharmacol 2011; 25: 91-98. https://doi.org/10.1111/j.1472-8206.2010.00812.x##Karuppanapandian T, Moon J, Kim C, Kim W. Reactive oxygen species in plants : their generation , signal transduction , and scavenging mechanisms mechanisms. Aust J Crop Sci 2011; 5: 709-725.##Kokacya M H, Inanir S, Copoglu U S, Dokuyucu R, Erbas O. The antipsychotic effects of omega-3 fatty acids in rats. Am J Med Sci 2015; 350: 212-217. https://doi.org/10.1097/MAJ.0000000000000531##Leong C T, D’Souza U J, Iqbal M, Mustapha Z A. Lipid peroxidation and decline in antioxidant status as one of the toxicity measures of diazinon in the testis. Redox report 2013; 18: 155-164. https://doi.org/10.1179/1351000213Y.0000000054##Lian H Y, Gao Y, Jiao G Z, Sun M J, Wu X F, Wang T Y, et al. Antioxidant supplementation overcomes the deleterious effects of maternal restraint stress-induced oxidative stress on mouse oocytes. Reproduction 2013; 146: 559-568. https://doi.org/10.1530/REP-13-0268##Liu SJ. (2007). Inhibition of L-type Ca2+ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes. Am J Physiol Cell Physiol 2007; 293(5): 1594-1604. https://doi.org/10.1152/ajpcell.00284.2007##Marik P E, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol 2009; 32: 365-372. https://doi.org/10.1002/clc.20604##Martins A D, Agarwal A. Oxidation reduction potential: a new biomarker of male infertility. Panminerva Med. 2019; 61: 108-117. https://doi.org/10.23736/S0031-0808.18.03529-2##Matsuda F, Inoue N, Manabe N, Ohkura S. Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells. J Reprod Dev 2012; 58: 44-50. https://doi.org/10.1262/jrd.2011-012##McGlory C, Calder P C, Nunes E A. The influence of omega-3 fatty acids on skeletal muscle protein turnover in health, disuse, and disease. Front Nutr 2019; 6: 1-13. https://doi.org/10.3389/fnut.2019.00144##McLean A C, Valenzuela N, Fai S, Bennett S A. Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp 2012: e4389. https://doi.org/10.3791/4389##Meital L T, Windsor M T, Perissiou M, Schulze K, Magee R, Kuballa A et al. Omega-3 fatty acids decrease oxidative stress and inflammation in macrophages from patients with small abdominal aortic aneurysm. Sci Rep 2019; 9: 12978. https://doi.org/10.1038/s41598-019-49362-z##Menkveld R, Holleboom C A , Rhemrev J P. Measurement and significance of sperm morphology. Asian J Androl 2011; 13: 59-68. https://doi.org/10.1038/aja.2010.67##Mohd Mutalip S S, Ab-Rahim S, Rajikin M H. Vitamin E as an antioxidant in female reproductive health. Antioxidants (Basel, Switzerland) 2018; 7. https://doi.org/10.3390/antiox7020022##Mupfiga C, Fisher D, Kruger T, Henkel R. The relationship between seminal leukocytes, oxidative status in the ejaculate, and apoptotic markers in human spermatozoa. Syst Biol Reprod Med. 2013; 59: 304-311. https://doi.org/10.3109/19396368.2013.821540##Naeimi R A, Talebpour Amiri F, Khalatbary A R, Ghasemi A, Zargari M, Ghesemi M et al., Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. Reprod Toxicol. 2017; 72: 115-121. https://doi.org/10.1016/j.reprotox.2017.06.052##Nyakudya T T, Mukwevho E, Erlwanger K H. The protective effect of neonatal oral administration of oleanolic acid against the subsequent development of fructose-induced metabolic dysfunction in male and female rats. Nutr Metab (Lond) 2018; 15: 82. https://doi.org/10.1186/s12986-018-0314-7##Olutope A M, Solomon S A, Ayantayo A K. Ameliorative and protective effect of omega 3 - fatty acid on testicular lipid concentration in ethanol- induced Wistar rats. Am J Biochem 2014; 4: 25-28.##Paglia D E, Valentine W N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70: 158-169.##Pereira R M, Botezelli J D, da Cruz Rodrigues K C, Mekary R A, Cintra D E, et al. Fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism. Nutrients 2017; 9. https://doi.org/10.3390/nu9040405##Placer Z A, Cushman L L, Johnson B C. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 1966; 16: 359-364. https://doi.org/10.1016/0003-2697(66)90167-9##Pradeep K, Ko K C, Choi M H, Kang J A, Chung Y J, Park S H. Protective effect of hesperidin, a citrus flavanoglycone, against γ-radiation-induced tissue damage in Sprague-Dawley rats. J Med Food 2012; 15: 419-427. https://doi.org/10.1089/jmf.2011.1737##Rajendar B, Bharavi K, Rao G, Kishore P, Kumar P R, Kumar C S, et al. Protective effect of an aphrodisiac herb Tribulus terrestris Linn on cadmium-induced testicular damage. Indian J Pharmacol 2011; 43: 568-573. https://doi.org/10.4103/0253-7613.84974##Robeck T R, Gill C, Doescher B M, Sweeney J, De Laender P, Van Elk C E et al. Altrenogest and progesterone therapy during pregnancy in bottlenose dolphins (Tursiops truncatus) with progesterone insufficiency. J Zoo Wildl Med Off Publ Am Assoc Zoo Vet 2012; 43: 296-308. https://doi.org/10.1638/2011-0166.1##de Roos B, Duthie G G. Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress. Mol Nutr Food Res 2015; 59: 1229-1248. https://doi.org/10.1002/mnfr.201400568##Rossi B V, Abusief M, Missmer S A. Modifiable Risk Factors and Infertility: What are the Connections? Am J Lifestyle Med 2014; 10: 220-231. https://doi.org/10.1177/1559827614558020##Sahoo D K, Roy A, Chattopadhyay S, Chainy G B N. Effect of T3 treatment on glutathione redox pool and its metabolizing enzymes in mitochondrial and post-mitochondrial fractions of adult rat testes. Indian J Exp Biol 2007; 45: 338-346.##Salem N J, Litman B, Kim H Y, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001; 36: 945-959. https://doi.org/10.1007/s11745-001-0805-6##Sarabia L, Maurer I, Bustos-Obregón E. Melatonin prevents damage elicited by the organophosphorous pesticide diazinon on mouse sperm DNA. Ecotoxicol Environ Saf 2009; 72: 663-668. https://doi.org/10.1016/j.ecoenv.2008.04.023##Showell M G, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev 2014: CD007411. https://doi.org/10.1002/14651858.CD007411.pub3##Softic S, Cohen D E, Kahn C R. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci 2016; 61: 1282-1293. https://doi.org/10.1007/s10620-016-4054-0##Soliman M, Mahmoud B, Kefafy M, Yassien R, El-Roghy E. Effect of antidepressant drug (fluoxetine) on the testes of adult male albino rats and the possible protective role of omega-3. Menoufia Med J 2017; 30: 1135-1142. https://doi.org/10.4103/mmj.mmj_521_17##Spahis S, Borys J M, Levy E. Metabolic syndrome as a multifaceted risk factor for oxidative stress. Antioxid Redox Signal 2017; 26: 445-461. https://doi.org/10.1089/ars.2016.6756##Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D et al. The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer 2009; 45: 2077-86. https://doi.org/10.1016/j.ejca.2009.04.026##Srividhya S, Anuradha C V. Metformin improves liver antioxidant potential in rats fed a high-fructose diet. Asia Pac J Clin Nutr 2002; 11: 319-22. https://doi.org/10.1046/j.1440-6047.2002.00306.x##Stoffel W, Schmidt-Soltau I, Binczek E, Thomas A, Thevis M, Wegner I. Dietary ω3-and ω6-Polyunsaturated fatty acids reconstitute fertility of Juvenile and adult Fads2-Deficient mice. Mol Metab 2020; 36: 100974. https://doi.org/10.1016/j.molmet.2020.100974##Sun Y, Oberley L W, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34: 497-500. https://doi.org/10.1093/clinchem/34.3.497##Tan B L, Norhaizan M E, Huynh K, Heshu S R, Yeap S K, Hazilawati H et al. Water extract of brewers’ rice induces apoptosis in human colorectal cancer cells via activation of caspase-3 and caspase-8 and downregulates the Wnt/β-catenin downstream signaling pathway in brewers’ rice-treated rats with azoxymethane-induced colon car. BMC Complement Altern Med 2015; 15: 205. https://doi.org/10.1186/s12906-015-0730-4##Tchernof A, Després J-P. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93: 359-404. https://doi.org/10.1152/physrev.00033.2011##Thusgaard M, Christensen J H, Mørn B, Andersen T S, Vige R, Arildsen H et al. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41: 760-766. https://doi.org/10.1080/00365540903168056##Tkachenko O Y, Shayakhmetova G M, Matvienko A V, Kovalenko V M. Reproductive disorders in male rats induced by high-fructose consumption from juvenile age to puberty. Arh Hig Rada Toksikol 2020; 71: 78-86. https://doi.org/10.2478/aiht-2020-71-3303##Toop C R, Gentili S. Fructose beverage consumption induces a metabolic syndrome phenotype in the rat: a systematic review and meta-analysis. Nutrients 2016; 8. https://doi.org/10.3390/nu8090577##Turner T T, Lysiak J J. Oxidative stress: a common factor in testicular dysfunction. J Androl 2008; 29: 488-498. https://doi.org/10.2164/jandrol.108.005132##Vijaya Bharathi B, Jaya Prakash G, Krishna K, Ravi Krishna C, Sivanarayana T, Madan K, et al. Protective effect of alpha glucosyl hesperidin (G-hesperidin) on chronic vanadium induced testicular toxicity and sperm nuclear DNA damage in male Sprague Dawley rats. Andrologia 2015; 47: 568-578. https://doi.org/10.1111/and.12304##Wakefield S L, Lane M, Schulz S J, Hebart M L, Thompson J G, Mitchell M. Maternal supply of omega-3 polyunsaturated fatty acids alter mechanisms involved in oocyte and early embryo development in the mouse. Am J Physiol Endocrinol Metab 2008; 294: 425-434. https://doi.org/10.1152/ajpendo.00409.2007##Wang YX, Wang P, Feng W, Liu C, Yang P, Chen YJ, et al. Relationships between seminal plasma metals/metalloids and semen quality, sperm apoptosis and DNA integrity. Environ Pollut 2017; 224: 224-34. https://doi.org/10.1016/j.envpol.2017.01.083##Weylandt K H, Serini S, Chen Y Q, Su H M, Lim K, Cittadini A et al. Omega-3 polyunsaturated fatty acids: the way forward in times of mixed evidence. Biomed Res Int 2015; 2015: 143109. https://doi.org/10.1155/2015/143109##Zalata A, Christophe A B, Depuydt C.E., Schoonjans F, Comhaire FH. The fatty acid composition of phospholipids of spermatozoa from infertile patients. Mol Hum Reprod 1998; 4: 111-118. https://doi.org/10.1093/molehr/4.2.111## ##

Effects of dietary nitrate or nitrite supplementation on inhibitory avoidance task and pentylenetetrazole-induced clonic seizure threshold in mice 2 2 Introduction: The nitrate-nitrite-nitric oxide (NO) is considered a possible alternative pathway for NO production. Consequently, this research aimed to assess how adding dietary nitrate or nitrite affects the inhibitory avoidance task, the threshold for clonic seizures induced by pentylenetetrazole (PTZ), and levels of nitric oxide metabolites (NOx) in mice. Methods: In this research, 40 male NMRI mice were used, with 8 mice in each of the five groups including control and four experimental groups (given 50 or 100 mg/l nitrate or nitrite in drinking water for 21 days). The mice’s memory retention was assessed through the step-down passive avoidance test, while their locomotor activity was measured using the open-field apparatus. The seizure threshold was determined by administering PTZ through intravenous infusion. Additionally, the levels of NOx in the brain tissue were quantified using the Griess method. Results: Supplementation with either nitrate or nitrite at a concentration of 100 mg/L resulted in a significant increase in the step-down passive avoidance latency compared to the control group (P<0.01). Only nitrate at a concentration of 100 mg/L significantly increased the threshold for PTZ-induced clonic seizures (P<0.001). The levels of NOx were significantly elevated in all groups that received nitrate or nitrite at concentrations of 50 and 100 mg/L (P<0.05). Conclusion: We conclude that the nitrate-nitrite-NO pathway is partly involved in the memory-improving effects of nitrate or nitrite and the increase of PTZ-induced clonic seizure threshold following nitrate supplementation.  295 303 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/2 1402/6/11 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/27 1402/12/8 shima davoudi shima davoudi Student Research Center, Kashan University of Medical Sciences, Kashan, Iran Iran shimadavoudi7@gmail.com abolfazl ardjmand abolfazl ardjmand Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran Iran ardjmand_ab@kaums.ac.ir azhdar heydari azhdar heydari Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran Iran heydariazh@kaums.ac.ir Nitric oxide Nitrite Pentylenetetrazole Memory step-down passive avoidance Andrabi S M, Sharma N S, Karan A, Shahriar S S, Cordon B, Ma B, et al. Nitric oxide: physiological functions, delivery, and biomedical applications. Advanced Science 2023; 10: 2303259. https://doi.org/10.1002/advs.202303259##Bailey D M, Rasmussen P, Evans K A, Bohm A M, Zaar M, Nielsen H B, et al. Hypoxia compounds exercise-induced free radical formation in humans; partitioning contributions from the cerebral and femoral circulation. Free Radic Biol Med 2018; 124: 104-113. https://doi.org/10.1016/j.freeradbiomed.2018.05.090##Bedale W, Sindelar J J, Milkowski AL. Dietary nitrate and nitrite: Benefits, risks, and evolving perceptions. Meat Sci 2016; 120: 85-92. https://doi.org/10.1016/j.meatsci.2016.03.009##Bernabeu R, de Stein M L, Fin C, Izquierdo I, Medina J H. Role of hippocampal NO in the acquisition and consolidation of inhibitory avoidance learning. Neuroreport 1995; 6: 1498-1500. https://doi.org/10.1097/00001756-199507310-00008##Bryan N S, Rassaf T, Maloney R E, Rodriguez C M, Saijo F, Rodriguez J R, et al. Cellular targets and mechanisms of nitrous (yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A 2004; 101: 4308-4313. https://doi.org/10.1073/pnas.0306706101##Bryan N S, Ivy J L. Inorganic nitrite and nitrate: evidence to support consideration as dietary nutrients. Nutr Res 2015; 35: 643-654. https://doi.org/10.1016/j.nutres.2015.06.001##Carlstrom M, Persson A E G, Larsson E, Hezel M, Scheffer P G, Teerlink T, et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res 2011; 89: 574-585. https://doi.org/10.1093/cvr/cvq366##Chen Y, Cui Z, Wang L, Liu H, Fan W, Deng J, et al. The impairment of learning and memory and synaptic loss in mouse after chronic nitrite exposure. Environ Toxicol 2016; 31: 1720-1730. https://doi.org/10.1002/tox.22174##Dawson T M, Dawson V L. Nitric oxide signaling in neurodegeneration and cell death. Adv Pharmacol 2018; 82: 57-83. https://doi.org/10.1016/bs.apha.2017.09.003##DeMartino A W, Kim-Shapiro D B, Patel R P, Gladwin M T. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol 2019; 176(2): 228-245. https://doi.org/10.1111/bph.14484##Devi P U, Manocha A, Vohora D. Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers. Expert Opin Pharmacother 2008; 9: 3169-3177. https://doi.org/10.1517/14656560802568230##Dos Reis E A, de Oliveira L S, Lamers M L, Netto C A, Wyse A T de S. Arginine administration inhibits hippocampal Na(+),K(+)-ATPase activity and impairs retention of an inhibitory avoidance task in rats. Brain Res 2002; 951: 151-157. https://doi.org/10.1016/S0006-8993(02)03077-9##Esmaili Z, Heydari A. Effect of acute caffeine administration on PTZ-induced seizure threshold in mice: Involvement of adenosine receptors and NO-cGMP signaling pathway. Epilepsy Res 2019; 149: 1-8. https://doi.org/10.1016/j.eplepsyres.2018.10.013##Fukaya R, Miyano R, Hirai H, Sakaba T. Mechanistic insights into cAMP-mediated presynaptic potentiation at hippocampal mossy fiber synapses. Front Cell Neurosci 2023; 17: 1237589. https://doi.org/10.3389/fncel.2023.1237589##Glebov-McCloud A G P, Saide W S, Gaine M E, Strack S. Protein Kinase A in neurological disorders. J Neurodev Disord. 2024; 16(1): 9. https://doi.org/10.1186/s11689-024-09525-0##Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi F, Cogliano V. Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol 2006; 7: 628-629. https://doi.org/10.1016/S1470-2045(06)70789-6 ##Guimaraes D, Portella R, Kamga-Pride C, Tanus-Santos J E, Shiva S. nitrite differently activates cGMP versus cAMP. Free Radical Biology and Medicine 2017; 112: 164-165. https://doi.org/10.1016/j.freeradbiomed.2017.10.255##Guimaraes D A, Dos Passos M A, Rizzi E, Pinheiro L C, Amaral J H, Gerlach R F, et al. Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy. Free Radical Biology and Medicine 2018; 120: 25-32. https://doi.org/10.1016/j.freeradbiomed.2018.03.006##Harooni H E, Naghdi N, Sepehri H, Rohani A H. The role of hippocampal nitric oxide (NO) on learning and immediate, short- and long-term memory retrieval in inhibitory avoidance task in male adult rats. Behav Brain Res 2009; 201: 166-172. https://doi.org/10.1016/j.bbr.2009.02.011##Heydari A, Davoudi S. The effect of sertraline and 8-OH-DPAT on the PTZ_induced seizure threshold: Role of the nitrergic system. Seizure 2017; 45. https://doi.org/10.1016/j.seizure.2016.12.005##Hu Z-H, Fan L-L, Hu Y-M. Effect of sodium nitrite on phosphorylation of cytoskeletal proteins and spatial learning and memory in rats. Sheng li xue bao:[Acta Physiologica Sinica] 2015; 67: 479-486.##Larsen F J, Schiffer T A, Borniquel S, Sahlin K, Ekblom B, Lundberg J O, et al. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab 2011; 13:149-159. https://doi.org/10.1016/j.cmet.2011.01.004##Lefferts W K, Hughes W E, White C N, Brutsaert T D, Heffernan K S. Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia. Appl Physiol Nutr Metab 2016; 41: 133-141. https://doi.org/10.1139/apnm-2015-0400##Lundberg J O, Gladwin M T, Ahluwalia A, Benjamin N, Bryan N S, Butler A, et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 2009; 5: 865-869. https://doi.org/10.1038/nchembio.260##Nasehi M, Morteza-Zadeh P, Khakpai F, Zarrindast M-R. Additive effect of harmane and muscimol for memory consolidation impairment in inhibitory avoidance task. Neuroscience 2016; 339: 287-295. https://doi.org/10.1016/j.neuroscience.2016.10.007##Paul V, Ekambaram P. Involvement of nitric oxide in learning & memory processes. Indian J Med Res 2011; 133:471-478.##Paul V, Reddy L, Ekambaram P. A reversal by L-arginine and sodium nitroprusside of ageing-induced memory impairment in rats by increasing nitric oxide concentration in the hippocampus. Indian J Physiol Pharmacol 2005; 49: 179-186.##Pigott B M, Garthwaite J. Nitric oxide is required for L-type Ca(2+) channel-dependent long-term potentiation in the hippocampus. Front Synaptic Neurosci. 2016; 8:17. https://doi.org/10.3389/fnsyn.2016.00017##Piknova B, Kocharyan A, Schechter AN, Silva AC. The role of nitrite in neurovascular coupling. Brain Res 2011; 1407: 62-68. https://doi.org/10.1016/j.brainres.2011.06.045##Qin L, Wang S. Protective roles of inorganic nitrate in health and diseases. Curr Med 2022; 1, 4. https://doi.org/10.1007/s44194-022-00002-1##Reddy P L, Rajasekaran K, Paul V. Evidence for an involvement of nitric oxide in memory of shock avoidance task in rats. Indian J Physiol Pharmacol 2002; 46: 119-122.##Richardson RJ, Petrou S, Bryson A. Established and emerging GABAA receptor pharmacotherapy for epilepsy. Front Pharmacol. 2024; 15: 1341472. https://doi.org/10.3389/fphar.2024.1341472##Roberts L D, Ashmore T, McNally B D, Murfitt S A, Fernandez B O, Feelisch M, et al. Inorganic nitrate mimics exercise-stimulated muscular fiber-type switching and myokine and gamma-aminobutyric acid release. Diabetes 2017; 66:674-688. https://doi.org/10.2337/db16-0843##Siervo M, Lara J, Ogbonmwan I, Mathers J C. Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr 2013; 143: 818-826. https://doi.org/10.3945/jn.112.170233##Tiso M, Schechter A N. Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions. PloS One 2015; 10: e0119712. https://doi.org/10.1371/journal.pone.0119712##Wightman E L, Haskell-Ramsay C F, Thompson K G, Blackwell J R, Winyard P G, Forster J, et al. Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation. Physiol Behav 2015; 149:149-158. https://doi.org/10.1016/j.physbeh.2015.05.035##Xu X-X, Shi R-X, Fu Y, Wang J-L, Tong X, Zhang S-Q, et al. Neuronal nitric oxide synthase/reactive oxygen species pathway is involved in apoptosis and pyroptosis in epilepsy. Neural Regen Res 2023; 18(6): 1277-1285. https://doi.org/10.4103/1673-5374.357906##Zandieh A, Maleki F, Hajimirzabeigi A, Zandieh B, Khalilzadeh O, Dehpour A R. Anticonvulsant effect of celecoxib on pentylenetetrazole-induced convulsion: Modulation by NO pathway. Acta Neurobiol Exp (Wars) 2010; 70: 390-397. https://doi.org/10.55782/ane-2010-1811## ##

Hypoxia-Induced Impairment of Glucose Homeostasis: Sympathovagal Imbalance and the Potential Therapeutic Role of L/N type Calcium Channel Blocker Cilnidipine 2 2 Introduction: Frequent occurrence of diabetes mellitus type 2 (T2DM) in patients with respiratory disease suggests a role of underlying chronic hypoxia (CH) in its pathogenesis. The present study aimed to delineate the link between CH, sympathovagal balance, and glucose homeostasis (GH) as well as to explore the role of L/N type calcium channel blocker, cilnidipine in alleviating CH-induced pathophysiology in experimental animals. Methods: Wister rats were divided into four groups: group I: control, (normoxia, 21%O2); group II: chronic hypoxia (CH) (10%O2, 90%N2); group III: normoxia+cilnidipine (cil, 2mg/kg/day); group IV: CH+Cil (10%O2, 90%N2 + cil, 2mg/kg/day). Sympathovagal balance was assessed by heart rate variability (HRV) analysis. Glucose homeostasis was evaluated by fasting plasma glucose (FPG), fasting plasma insulin, oral glucose tolerance test (OGTT), HOMA-IR, and HOMA-β. The fasting lipid profile was also assessed.   Results: CH increased LF (nu), LF/HF, and decreased HF (nu). Additionally, CH increased FPG and HOMA-IR which were positively correlated with LF/HF and induced an atherogenic lipid profile. OGTT revealed normal 2h post-challenge glucose levels. In the cilnidipine-treated CH exposed group, LF (nu), HF (nu), and LF/HF were lower compared CH and glucose homeostasis parameters were comparable to control.  Conclusion: CH, by enhancing sympathetic activity, disturbs glucose homeostasis, leading to isolated impaired fasting glycemia (i-IFG), a prediabetic state. Cilnidipine improved glucose homeostasis in CH-exposed experimental animals by ameliorating sympathetic hyperactivity with complementary effects on lipid profile, suggesting its utility as an adjunctive therapy against CH-induced T2DM. 304 313 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/22023/01/28 1401/11/8 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/272024/02/27 1402/12/8 Shrilaxmi Bagali Shrilaxmi Bagali Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India India shrilaxmi.bagali@bldedu.ac.in Pallavi Kanthe Pallavi Kanthe Dr Kiran C Patel Medical College Hospital and Research Institute, Bharuch, Gujarat, India India pallavi.kanthe@bldedu.ac.in R Chandramouli Reddy R Chandramouli Reddy Department of Biochemistry, Shri B. M. Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India India rcm.reddy@bldedu.ac.in Gouher Banu Shaikh Gouher Banu Shaikh Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India India gouher.banu@bldedu.ac.in Sumangala Patil Sumangala Patil Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India India sumangala.patil@bldedu.ac.in Kusal Das Kusal Das Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India India kusaldas@bldedu.ac.in Cilnidipine HOMA IR Hypoxia Glucose Tolerance Test Prediabetes Abu Eid S, Hackl M T, Kaplanian M, Winter M P, Kaltenecker D, Moriggl R, et al. Life under hypoxia lowers blood glucose independently of effects on appetite and body weight in mice. Front Endocrinol (Lausanne) 2018; 9: 490. https://doi.org/10.3389/fendo.2018.00490##Bagali S, Nerune S M, Reddy R C, Yendigeri S M, Patil B S, Naikwadi A A, et al. Low oxygen microenvironment and cardiovascular remodeling: Role of dual L/N type Ca2+ channel blocker. Indian J Pharmacol 2020; 52(5): 383-391. https://doi.org/10.4103/ijp.IJP_136_20##Bowe J E, Franklin Z J, Hauge-Evans A C, King A J, Persaud S J, Jones P M. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models. J Endocrinol 2014; 222(3): G13-25. https://doi.org/10.1530/JOE-14-0182##Cavaillès A, Brinchault-Rabin G, Dixmier A, Goupil F, Gut-Gobert C, Marchand-Adam S, et al. Comorbidities of COPD. Eur Respir Rev 2013; 22(130): 454-745. https://doi.org/10.1183/09059180.00008612##Cazzola M, Bettoncelli G, Sessa E, Cricelli C, Biscione G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80(2): 112-119. https://doi.org/10.1159/000281880##Das K K, Jargar J G, Saha S, Yendigeri S M, Singh S B. α-tocopherol supplementation prevents lead acetate and hypoxia-induced hepatic dysfunction. Indian J Pharmacol 2015; 47(3): 285-291. https://doi.org/10.4103/0253-7613.157126##Das K K, Nemagouda S R, Patil S G, Saha S. Possible hypoxia signaling induced alteration of glucose homeostasis in rats exposed to chronic intermittent hypoxia - role of antioxidant (vitamin C) and Ca2+ channel blocker (cilnidipine). Current Signal Transduction Therapy 2016; 11(1): 49-55. https://doi.org/10.2174/1574362411666160517131248##Faerch K, Borch-Johnsen K, Holst J J, Vaag A. Pathophysiology and aetiology of impaired fasting glycaemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes? Diabetologia 2009; 52(9): 1714-1723. https://doi.org/10.1007/s00125-009-1443-3##Fenik V B, Singletary T, Branconi J L, Davies R O, Kubin L. Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic-intermittent hypoxia: effects of the duration of exposure and losartan. Front Neurol 2012; 3: 51. https://doi.org/10.3389/fneur.2012.00051##Friedewald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18(6): 499-502. https://doi.org/10.1093/clinchem/18.6.499##Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe K B, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci 2020; 21(17): 6275. https://doi.org/10.3390/ijms21176275##Gläser S, Krüger S, Merkel M, Bramlage P, Herth F J. Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature. Respiration 2015; 89(3): 253-264. https://doi.org/10.1159/000369863##Gutch M, Kumar S, Razi S M, Gupta K K, Gupta A. Assessment of insulin sensitivity/resistance. Indian J Endocrinol Metab 2015; 19(1): 160-164. https://doi.org/10.4103/2230-8210.146874##Hainsworth R, Drinkhill M J, Rivera-Chira M. The autonomic nervous system at high altitude. Clin Auton Res 2007; 17(1): 131-139. https://doi.org/10.1007/s10286-006-0395-7##Herman J P, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 2016; 6(2): 603-621. https://doi.org/10.1002/cphy.c150015##Hinds J A, Sanchez E R. The Role of the hypothalamus-pituitary-adrenal (HPA) axis in test-induced anxiety: assessments, physiological responses, and molecular details. Stresses 2022; 2(1): 146-155. https://doi.org/10.3390/stresses2010011##Khalili D, Khayamzadeh M, Kohansal K, Ahanchi N S, Hasheminia M, Hadaegh F, et al. Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes? BMC Endocr Disord 2023; 23(1): 39. https://doi.org/10.1186/s12902-023-01291-9##Lee C T, Mao I C, Lin C H, Lin S H, Hsieh M C. Chronic obstructive pulmonary disease: a risk factor for type 2 diabetes: a nationwide population-based study. Eur J Clin Invest 2013; 43(11): 1113-1119. https://doi.org/10.1111/eci.12147##Lewis P, Sheehan D, Soares R, Varela Coelho A, O’Halloran K D. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle. Front Physiol 2015; 6: 122. https://doi.org/10.3389/fphys.2015.00122##Mahishale V, Mahishale A, Patil B, Sindhuri A, Eti A. Screening for diabetes mellitus in patients with chronic obstructive pulmonary disease in tertiary care hospital in India. Niger Med J 2015; 56(2): 122-125. https://doi.org/10.4103/0300-1652.150699##Messina G, De Luca V, Viggiano A, Ascione A, Iannaccone T, Chieffi S, et al. Autonomic nervous system in the control of energy balance and body weight: personal contributions. Neurol Res Int 2013; 2013: 639280. https://doi.org/10.1155/2013/639280##Nair A B, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016; 7(2): 27-31. https://doi.org/10.4103/0976-0105.177703##Nonogaki K. New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 2000; 43(5): 533-549. https://doi.org/10.1007/s001250051341##Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga F A. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol 2018; 17(1): 122. https://doi.org/10.1186/s12933-018-0762-4##Parhofer K G. Interaction between glucose and lipid metabolism: More than diabetic dyslipidemia. Diabetes Metab J 2015; 39(5): 353-362. https://doi.org/10.4093/dmj.2015.39.5.353##Polak J, Shimoda L A, Drager L F, Undem C, McHugh H, Polotsky V Y, et al. Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep 2013; 36(10): 1483-1490. https://doi.org/10.5665/sleep.3040##Ramirez T A, Jourdan-Le Saux C, Joy A, Zhang J, Dai Q, et al. Chronic and intermittent hypoxia differentially regulate left ventricular inflammatory and extracellular matrix responses. Hypertens Res 2012; 35(8): 811-818. https://doi.org/10.1038/hr.2012.32##Reddy R C, Devaranavadagi B, Yendigeri S M, Bagali S, Kulkarni R V, Das K K. Effect of L-ascorbic acid on nickel-induced alteration of cardiovascular pathophysiology in wistar rats. Biol Trace Elem Res 2020; 195(1): 178-186. https://doi.org/10.1007/s12011-019-01829-w##Rogliani P, Calzetta L, Segreti A, Barrile A, Cazzola M. Diabetes mellitus among outpatients with COPD attending a university hospital. Acta Diabetologica 2014; 51(6), 933-940. https://doi.org/10.1007/s00592-014-0584-0##Rogliani P, Lucà G, Lauro D. Chronic obstructive pulmonary disease and diabetes. COPD Res Pract 2015; 1, 3. https://doi.org/10.1186/s40749-015-0005-y##Safari S, Amini M, Aminorroaya A, Feizi A. Patterns of changes in serum lipid profiles in prediabetic subjects: results from a 16-year prospective cohort study among first-degree relatives of type 2 diabetic patients. Lipids Health Dis 2020; 19(1): 193. https://doi.org/10.1186/s12944-020-01371-y##Shaffer F, Ginsberg J P. An overview of heart rate variability metrics and norms. Front Public Health 2017; 5: 258. https://doi.org/10.3389/fpubh.2017.00258##Takahara A, Koganei H, Takeda T, Iwata S. Antisympathetic and hemodynamic property of a dual L/N-type Ca (2+) channel blocker cilnidipine in rats. Eur J Pharmacol 2002; 434 (1-2): 43-47. https://doi.org/10.1016/S0014-2999(01)01521-7##Takahara A. Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release. Cardiovasc Ther 2009; 27(2): 124-139. https://doi.org/10.1111/j.1755-5922.2009.00079.x##Thorp A A, Schlaich M P. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res 2015; 2015: 341583. https://doi.org/10.1155/2015/341583##Xie A, Skatrud J B, Puleo D S, Morgan B J. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol (1985) 2001; 91(4): 1555-1562. https://doi.org/10.1152/jappl.2001.91.4.1555##Yang H. Sympathovagal imbalance in type 2 diabetes-Role of brainstem thyrotropin releasing hormone. Type 2013; 2: 115-141. https://doi.org/10.5772/56541##Yoon H, Jeon D J, Park C E, You H S, Moon A E. Relationship between homeostasis model assessment of insulin resistance and beta cell function and serum 25-hydroxyvitamin D in non-diabetic Korean adults. J Clin Biochem Nutr 2016; 59(2): 139-144. https://doi.org/10.3164/jcbn.15-143## ##

Effect of RND-efflux pumps inhibitor on the synergy of different antibiotics combinations against carbapenem-resistant Pseudomonas aeruginosa 2 2 Introduction: The high-level antimicrobial resistance, particularly carbapenem resistance, in Pseudomonas aeruginosa is a global health challenge. The combination of antibiotics and synergy effects is beneficial in control of drug-resistant P. aeruginosa. The synergic interaction of antimicrobial agents is af-fected by the mechanisms of antimicrobial resistance. The aim of the current study was to evaluate the effect of efflux pump inhibition on the synergy of antibiotics against carbapenem-resistant P. aeruginosa. Methods: The antibiotics’ minimum inhibitory concentration (MIC) was determined by the microbroth dilu-tion method. The synergy effect of antibiotics was determined using the checkerboard assay with-out and with Resistance-Nodulation- Division (RND) efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PAβN). Results: The highest levels of synergistic effects were found between cefepime/tobramycin and meropenem/tobramycin combinations in 35.3% of isolates. After adding PAβN, the most frequent synergistic effects were observed between the meropenem/ciprofloxacin and cefepime/ciprofloxacin combinations, found in 64.7% of isolates. The adding PAβN led to an increase in the synergy of all combinations except tobramycin/colistin. The highest effect of PAβN on the synergy effects of antibiotics combination was observed in meropenem/ciprofloxacin, cefepime/ciprofloxacin, and ciprofloxacin/colistin (an increase of 41.2%).  Conclusion: RND efflux pump inhibition has a noticeable effect on the results of synergy tests of some antimi-crobial agent combinations. Given the drug- and strain-dependent effects of PAβN on synergy re-sults, the effects of efflux pump inhibitors should be studied on different combinations of drugs and a large population of bacterial strains.  314 323 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/22023/01/282023/07/13 1402/4/22 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/272024/02/272024/01/31 1402/11/11 Mahsa Vahdatipur Dizaj Mahsa Vahdatipur Dizaj Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran vahdati_elect90@yahoo.com Reza Ghotaslou Reza Ghotaslou Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran rzgottaslo@yahoo.com Mina Yekani Mina Yekani Department of Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran Iran mina_yekani71@yahoo.com Seyyed Reza Moaddab Seyyed Reza Moaddab Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran srmoaddab@gmail.com Behrooz Naghili Behrooz Naghili Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran naghili_b@yahoo.com Edris Nabizadeh Edris Nabizadeh Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran nabizadeh.edris@gmail.com Mohammad Yousef Memar Mohammad Yousef Memar Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran y.memar@yahoo.com Synergy Efflux pumps inhibitors Pseudomonas aeruginosa Balke B, Hogardt M, Schmoldt S, Hoy L, Weissbrodt H, Häussler S. Evaluation of the E test for the assessment of synergy of antibiotic combinations against multiresistant Pseudomonas aeruginosa isolates from cystic fibrosis patients. European Journal of Clinical Microbiology and Infectious Diseases 2006; 25: 25-30. https://doi.org/10.1007/s10096-005-0076-9##Bayat M, Nahand J S, Farsad-Akhatr N, Memar M Y. Bile effects on the Pseudomonas aeruginosa pathogenesis in cystic fibrosis patients with gastroesophageal reflux. Heliyon 2023. https://doi.org/10.1016/j.heliyon.2023.e22111##Britt N S, Ritchie D J, Kollef M H, Burnham C-A D, Durkin M J, Hampton N B, et al. Importance of site of infection and antibiotic selection in the treatment of carbapenem-resistant Pseudomonas aeruginosa sepsis. Antimicrobial agents and chemotherapy 2018; 62: e02400-17. https://doi.org/10.1128/AAC.02400-17##Campana S, Taccetti G, Farina S, Ravenni N, Martino M D. Antimicrobial susceptibility mand synergistic activity of meropenem against Gram-negative non-fermentative bacteria isolated from cystic fibrosis patients. Journal of chemotherapy 2003; 15: 551-554. https://doi.org/10.1179/joc.2003.15.6.551##Ghorbani H, Memar M Y, Sefidan F Y, Yekani M, Ghotaslou R. In vitro synergy of antibiotic combinations against planktonic and biofilm Pseudomonas aeruginosa. GMS hygiene and infection control 2017; 12. ##Ghotaslou R, Yekani M, Memar M Y. The role of efflux pumps in Bacteroides fragilis resistance to antibiotics. Microbiological research 2018; 210: 1-5. https://doi.org/10.1016/j.micres.2018.02.007##Japoni A, Alborzi A, Kalani M, Nasiri J, Hayati M, Farshad S. Susceptibility patterns and cross-resistance of antibiotics against Pseudomonas aeruginosa isolated from burn patients in the South of Iran. Burns 2006; 32: 343-347. https://doi.org/10.1016/j.burns.2005.10.017##Khalili Y, Memar M Y, Farajnia S, Adibkia K, Kafil H S, Ghotaslou R. Molecular epidemiology and carbapenem resistance of Pseudomonas aeruginosa isolated from patients with burns. Journal of Wound Care 2021; 30: 135-141. https://doi.org/10.12968/jowc.2021.30.2.135##Khalili Y, Yekani M, Goli H R, Memar M Y. Characterization of carbapenem-resistant but cephalosporin-susceptible Pseudomonas aeruginosa. Acta microbiologica et immunologica Hungarica 2019; 66: 529-540. https://doi.org/10.1556/030.66.2019.036##Khuntayaporn P, Montakantikul P, Santanirand P, Kiratisin P, Chomnawang M T. Molecular investigation of carbapenem resistance among multidrug-resistant Pseudomonas aeruginosa isolated clinically in Thailand. Microbiology and immunology 2013; 57: 170-178. https://doi.org/10.1111/1348-0421.12021##Leite G C, Oliveira M S, Perdigao-Neto L V, Rocha C K D, Guimaraes T, Rizek C, et al. Antimicrobial combinations against pan-resistant Acinetobacter baumannii isolates with different resistance mechanisms. PloS one 2016; 11: e0151270. https://doi.org/10.1371/journal.pone.0151270##Li X-Z, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clinical microbiology reviews 2015; 28: 337-418. https://doi.org/10.1128/CMR.00117-14##Lomovskaya O, Warren M S, Lee A, Galazzo J, Fronko R, Lee M, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrobial agents and chemotherapy 2001; 45: 105-116. https://doi.org/10.1128/AAC.45.1.105-116.2001##Memar M Y, Adibkia K, Farajnia S, Kafil H S, Khalili Y, Azargun R, et al. In-vitro effect of imipenem, fosfomycin, colistin, and gentamicin combination against carbapenem-resistant and biofilm-forming Pseudomonas aeruginosa isolated from burn patients. Iranian Journal of Pharmaceutical Research: IJPR 2021; 20: 286.##Memar M Y, Pormehrali R, Alizadeh N, Ghotaslou R, Bannazadeh B H. Colistin, an option for treatment of multiple drug resistant Pseudomonas aeruginosa. 2016.##Mirakhur A, Gallagher M, Ledson M, Hart C, Walshaw M. Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis. Journal of Cystic Fibrosis 2003; 2: 19-24. https://doi.org/10.1016/S1569-1993(02)00143-1##Mobaraki S, Aghazadeh M, Barhaghi M H S, Memar M Y, Goli H R, Gholizadeh P, et al. Prevalence of integrons 1, 2, 3 associated with antibiotic resistance in Pseudomonas aeruginosa isolates from Northwest of Iran. BioMedicine 2018; 8. https://doi.org/10.1051/bmdcn/2018080102##Montero M M, Ochoa S D, López-Causapé C, VanScoy B, Luque S, Sorlí L, et al. Colistin plus meropenem combination is synergistic in vitro against extensively drug-resistant Pseudomonas aeruginosa, including high-risk clones. Journal of Global Antimicrobial Resistance 2019; 18: 37-44. https://doi.org/10.1016/j.jgar.2019.04.012##Pan Y-p, Xu Y-h, Wang Z-x, Fang Y-p, Shen J-l. Overexpression of MexAB-OprM efflux pump in carbapenem-resistant Pseudomonas aeruginosa. Archives of microbiology 2016; 198: 565-571. https://doi.org/10.1007/s00203-016-1215-7##Rampioni G, Pillai C R, Longo F, Bondì R, Baldelli V, Messina M, et al. Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence. Scientific reports 2017; 7: 1-14. https://doi.org/10.1038/s41598-017-11892-9##Saderi H, Owlia P. Detection of multidrug resistant (MDR) and extremely drug resistant (XDR) P. aeruginosa isolated from patients in Tehran, Iran. Iranian journal of pathology 2015; 10: 265.##Tschudin-Sutter S, Fosse N, Frei R, Widmer A F. Combination therapy for treatment of Pseudomonas aeruginosa bloodstream infections. PLoS One 2018; 13: e0203295. https://doi.org/10.1371/journal.pone.0203295##Uechi K, Tada T, Shimada K, Kuwahara-Arai K, Arakaki M, Tome T, et al. A modified carbapenem inactivation method, CIMTris, for carbapenemase production in Acinetobacter and Pseudomonas species. Journal of Clinical Microbiology 2017; 55: 3405-3410. https://doi.org/10.1128/JCM.00893-17##Ugwuanyi F C, Ajayi A, Ojo D A, Adeleye A I, Smith S I. Evaluation of efflux pump activity and biofilm formation in multidrug resistant clinical isolates of Pseudomonas aeruginosa isolated from a Federal Medical Center in Nigeria. Annals of Clinical Microbiology and Antimicrobials 2021; 20: 1-7. https://doi.org/10.1186/s12941-021-00417-y##Wang Y, Venter H, Ma S. Efflux pump inhibitors: a novel approach to combat efflux-mediated drug resistance in bacteria. Current drug targets 2016; 17: 702-719. https://doi.org/10.2174/1389450116666151001103948##Weinstein M, Patel J, Bobenchik A, Campeau S, Cullen S, Galas M, et al. M100 Performance Standards for Antimicrobial Susceptibility Testing A CLSI supplement for global application. Performance standards for antimicrobial susceptibility testing performance standards for antimicrobial susceptibility testing 2020.##Wikler M. Methods for dilution antimicrobial susceptibility test s for bacteria that grow aerobically: approved standard, CLSI (NCCLS), 26 (2006) M7-A7. Citation: NK Soliman 2019.##Yekani M, Azargun R, Sharifi S, Nabizadeh E, Nahand J S, Ansari N K, et al. Collateral sensitivity: An evolutionary trade-off between antibiotic resistance mechanisms, attractive for dealing with drug-resistance crisis. Health Science Reports 2023; 6: e1418. https://doi.org/10.1002/hsr2.1418##Yoneda K, Chikumi H, Murata T, Gotoh N, Yamamoto H, Fujiwara H, et al. Measurement of Pseudomonas aeruginosa multidrug efflux pumps by quantitative real-time polymerase chain reaction. FEMS microbiology letters 2005; 243: 125-131. https://doi.org/10.1016/j.femsle.2004.11.048## ##

Alteration of melatonin receptor expression associated with melatonin-mediated amelioration of oxidative stress in the spleen of hyperthyroid mice 2 2 Introduction: Excessive synthesis of thyroid hormone in hyperthyroidism is related to the imbalance of oxidative status in living organisms. Melatonin mediates its effects either directly through scavenging free radicals or indirectly through the activation of melatonin receptors (MT1 and MT2). The present study investigated the involvement of melatonin receptors in the melatonin-mediated attenuation of hyperthyroidism-induced oxidative stress in the spleen of laboratory mice. Methods: The hyperthyroidism was induced by L-thyroxine (0.6µg/g B. wt.) supplementation. The experimental mice were supplemented with melatonin (25 µg/100g B. wt.) subcutaneously. Oxidative stress, melatonin receptor expression in the spleen tissues, and circulatory levels of thyroid hormone were determined.  Results: L-thyroxine treatment caused a significant increase in serum T3 and T4 levels. Melatonin supplementation caused a significant decrease in serum T3 and T4 levels in L-thyroxine-treated mice. L-thyroxine treatment increased MDA levels and suppressed catalase and SOD enzyme activities. Melatonin treatment caused suppression of MDA levels and an increase in SOD and catalase activities. L-thyroxine treatment caused significant suppression in MT1 receptor expression and a significant increase in MT2 receptor expression. Melatonin supplementation significantly induced the MT2 receptor protein expression in the spleen tissues of experimental mice. Conclusion: This study suggests that alterations in MT2 melatonin receptor expression may be associated with melatonin-mediated attenuation of oxidative stress in the spleen tissues of hyperthyroid mice. 324 337 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/22023/01/282023/07/132023/12/1 1402/9/10 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/272024/02/272024/01/312024/04/2 1403/1/14 Shiv Singh Shiv Singh Tripura University India shivssingh@tripurauniv.ac.in Subhrata Sarma Subhrata Sarma Molecular Endocrinology Laboratory, Department of Zoology, Tripura University, Suryamaninagar, Tripura (West)- 799022, India India subhrata84sarma@gmail.com Anubhuti Kashyap Anubhuti Kashyap Molecular Endocrinology Laboratory, Department of Zoology, Tripura University, Suryamaninagar, Tripura (West)- 799022, India India anu95kashyap@gmail.com Arjita Chakrabarti Arjita Chakrabarti Molecular Endocrinology Laboratory, Department of Zoology, Tripura University, Suryamaninagar, Tripura (West)- 799022, India India arjitachakrabarti95@gmail.com Hyperthyroidism oxidative stress melatonin MT1 MT2 receptors Acharjee S, Singh S S. In-vivo thermal stress induces melatonin receptors and heat shock protein expression in the spleen of mice in a time and temperature dependent manner. J Stress Physiol Biochem 2023; 19(3): 125-142.##Ahmad R, Gupta S, Haldar C. Age dependent expression of melatonin membrane receptor (MT1, MT2) and its role in regulation of nitrosative stress in tropical rodent Funambulus pennanti. Free Radic Res 2012; 46(2): 194-203. https://doi.org/10.3109/10715762.2011.647690. ##Asayama K, Kato K. Oxidative muscular injury and its relevance to hyperthyroidism. Free Radic Biol Med 1990; 8: 293-303. https://doi.org/10.1016/0891-5849(90)90077-V##Brix T H, Kyvik KO, Hegedus L. What is the evidence of genetic factors in the etiology of Graves’ disease? A brief review. Thyroid 1998; 8: 627–634. https://doi.org/10.1089/thy.1998.8.627##Catala M D, Quay W B, Timiras P S. Effects of thyroid hormone on light/dark melatonin synthesis and release by young and maturing rat pineal glands in vitro. Int J Dev Neurosci 1988; 6(3): 285-288. https://doi.org/10.1016/0736-5748(88)90008-1##Chainy G B, Sahoo D K. Hormones and oxidative stress: an overview. Free Redic Res 2020; 54(1): 1-26. https://doi.org/10.1080/10715762.2019.1702656##Chattopadhyay S, Sahoo D K, Subudhi U, Chainy G B N. Differential expression profiles of antioxidant enzymes and glutathione redox status in hyperthyroid rats: A temporal analysis. Comp Biochem Physiol Part C 2007; 146: 383-391. https://doi.org/10.1016/j.cbpc.2007.04.010##Costilla M, Macri Delbono R, Klecha A, Cremaschi G A, Barreiro Arcos M L. Oxidative stress produced by hyperthyroidism status induces the antioxidant enzyme transcription through the activation of the Nrf-2 factor in lymphoid tissues of Balb/c mice. Oxid Med Cell Longev 2019; 2019. https://doi.org/10.1155/2019/7471890##Das K, Samanta L, Chainy G B. A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Indian J Biochem Biophys 2000; 37: 201–204.##Dhabhar F S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014; 58: 193-210. https://doi.org/10.1007/s12026-014-8517-0##El-Sokkary G H, Omar H M, Hassanein A F, Cuzzocrea S, Reiter R J. Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni. Free Radic Biol Med 2002; 32(4): 319-332. https://doi.org/10.1016/S0891-5849(01)00753-5##Ghosh G, De K, Maity S, Bandyopadhyay D, Bhattacharya S, Reiter R J, et al. Melatonin protects against oxidative damage and restores expression of GLUT4 gene in the hyperthyroid rat heart. J Pineal Res 2007; 42(1): 71–82. https://doi.org/10.1111/j.1600-079X.2006.00386.x##Ghosh H, Rai S, Manzar Md D, Pandi-Perumal S R, Brown G M, Reiter R J, Cardinali D P. Differential expression and interaction of melatonin and thyroid hormone receptors with estrogen receptor α improve ovarian functions in letrozole-induced rat polycystic ovary syndrome. Life Sci 2022; 295:120086. https://doi.org/10.1016/j.lfs.2021.120086##Giavarotti S K A, Rodrigues L, Rodrigues T, Junqueira V B, Videla L A. Liver microsomal parameters related to oxidative stress and antioxidant systems in hyperthyroid rats subjected to acute lindane treatment. Free Radic Res 1998; 29(1): 35-42. https://doi.org/10.1080/10715769800300051##Grisanti L A, Perez D M, Porter J E. Modulation of immune cell function by α1-adrenergic receptor activation. Curr Opin Solid ST M 2011; 67:113-138. https://doi.org/10.1016/B978-0-12-384921-2.00006-9##Guerrero A, Pamplona R, Portero-Otin M, Barja G, LopezTorres M. Effect of thyroid status on lipid composition and peroxidation in the mouse liver. Free Radic Biol Med 1999; 26: 73-80. https://doi.org/10.1016/S0891-5849(98)00173-7##Guria S, Bose M, Mondal J, Majumder N. Alteration of cytomorphology of mice peritoneal macrophages, spleen cell and histological analysis of liver and pancreas under eltroxin induced condition: A preliminary study of “Thyroid Diabetes”. GJLSBR 2015; 2395:115X.##Hadwan M H. New method for assessment of serum catalase activity. Indian J Sci Technol 2016; 9(4): 1-5. https://doi.org/10.17485/ijst/2016/v9i4/80499 ##Ilardo M, dos Santos M C F, Beverborg N G, Ranjan M, Said M A, Veweij N, Harst P V D, Meer P V D, Leibold E A. An erythropoietin-independent mechanism of erythrocytic precursor proliferation underlies hypoxia tolerance in sea nomads. Front Physiol 2021; 12: 760851. https://doi.org/10.3389/fphys.2021.760851##Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell B 2005; 37: 2478–2503. https://doi.org/10.1016/j.biocel.2005.05.013##Laskar P, Singh S S. Melatonin modulates thyroid hormones and splenocytes proliferation through mediation of its MT1 and MT2 receptors in hyperthyroid mice. Proc Zool Soc 2018; 71: 186-193. https://doi.org/10.1007/s12595-017-0244-9##Leo S D, Lee S Y, Braverman LE. Hyperthyroidism. Lancet 2016; 2016388 (10047): 906-918. https://doi.org/10.1016/S0140-6736(16)00278-6##Mogulkoc R, Baltaci A K, Oztekin E, Aydin L, Sivrikaya A. Melatonin prevents oxidant damage in various tissues of rats with hyperthyroidism. Life Sci 2006; 79(3): 311-315. https://doi.org/10.1016/j.lfs.2006.01.009##Mullur R, Liu Y Y, Brent G A. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94(2): 355–382. https://doi.org/10.1152/physrev.00030.2013##Niedowicz D M, Wang W X, Price D A, Nelson P T. Modulating thyroid hormone levels in adult mice: impact on behavior and compensatory brain changes. J Thyroid Res 2021; 2021. https://doi.org/10.1155/2021/9960188##Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-358. https://doi.org/10.1016/0003-2697(79)90738-3##Pereira B, Rosa L F, Safi D A, Bechara E J H, Curi R. Control of superoxide dismutase, catalase and glutathione peroxidase activities in rat lymphoid organs by thyroid hormones. J Endocrinol 1994; 140(1): 73–77.##Petrulea M, Muresan A, Duncea I. Oxidative stress and antioxidant status in hypo-and hyperthyroidism. Antioxidant enzyme 2012; 8:197-236. https://doi.org/10.5772/51018##Ramadan H M, Taha N A, Ahmed H H. Melatonin enhances antioxidant defenses but could not ameliorate the reproductive disorders in induced hyperthyroidism model in male rats. Environ Sci Pollut Res Int 2021; 28:4790-4804. https://doi.org/10.1007/s11356-020-10682-7##Rastogi S, Haldar C. Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti. Food Chem Toxicol 2018; 120: 243-252. https://doi.org/10.1016/j.fct.2018.06.062##Reiter R J, Carneiro R C, Oh C S. Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res 1997; 29(8): 363-372. https://doi.org/10.1055/s-2007-979057##Robinson M V, Obut T A, Melnikova E V, Trufakin V A. Parameters of cellular and humoral immunity in experimental hyperthyroidism and its correction. Bull Exp Biol Med 2014; 156(4): 473-476.##Rodriguez C, Mayo J C, Sainz R M, Antolín I, Herrera F, Martín V, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36(1): 1-9. https://doi.org/10.1046/j.1600-079X.2003.00092.x##Sawant B U, Nadkarni G D, Thakare U R, Joseph L J, Rajan M G. Changes in lipid peroxidation and free radical scavengers in kidney of hypothyroid and hyperthyroid rats. Indian J Exp Biol 2003; 41(1): 1334-1337.##Sewerynek E, Wiktorska J, Lewinski A. Effects of melatonin on the oxidative stress induced by thyrotoxicosis in rats. Neuro Endocrinol lett 1999; 20: 157-161.##Shinohara R, Mano T, Nagasaka A, Hayashi R, Uchimura K, Nakano I, et al. Lipid peroxidation levels in rat cardiac muscle are affected by age and thyroid status. J Endocrinol 2000; 164(1): 97.##Singh S S, Deb A, Sutradhar S. Melatonin modulates melatonin MT2 receptor expression in splenic tissue and humoral immune response in mice. Biol Rhythm Res 2017; 48(3): 425-435. https://doi.org/10.1080/09291016.2016.1268330##Singh S S, Laskar P, Acharjee S. Age-and sex-dependent effect of exogenous melatonin on expression pattern of melatonin receptor (MT1 and MT2) proteins in spleen of mice. Biol Rhythm Res 2015; 46(3): 403-415. https://doi.org/10.1080/09291016.2015.1020198##Sinha A K. Colorimetric assay of catalase. Anal Biochem 1972; 47(2): 389-394. https://doi.org/10.1016/0003-2697(72)90132-7##Sutradhar S, Deb A, Singh S S. Melatonin attenuates diabetes-induced oxidative stress in spleen and suppression of splenocyte proliferation in laboratory mice. Arch Physiol Biochem 2022; 128(5): 1401-1412. https://doi.org/10.1080/13813455.2020.1773506##Taleux N, Guigas B, Dubouchaud H, Moreno M, Weitzel JM, Goglia F, et al. High expression of thyroid hormone receptors and mitochondrial glycerol-3-phosphate dehydrogenase in the liver is linked to enhanced fatty acid oxidation in Lou/C, a rat strain resistant to obesity. J Biol Chem 2008; 284: 4308–4316. https://doi.org/10.1074/jbc.M806187200##Treeck O, Haldar C, Ortmann O. Antiestrogens modulate MT1 melatonin receptor expression in breast and ovarian cancer cell lines. Oncol Rep 2006; 15(1): 231-235. https://doi.org/10.3892/or.15.1.231##Watanabe K, Iwatani Y, Hidaka Y, Watanabe M, Amino N. Long-term effects of thyroid hormone on lymphocyte subsets in spleens and thymuses of mice. J Endocrinol 1995; 42(5): 661-668. https://doi.org/10.1507/endocrj.42.661##Wiersinga W M, Poppe K G, Effraimidis G. Hyperthyroidism: aetiology, pathogenesis, diagnosis, management, complications, and prognosis. Lancet Diabetes Endocrinol 2023; 11(4): 282-298. https://doi.org/10.1016/S2213-8587(23)00005-0##Zhang M, Jiang W, Lu G, Wang R, Lv ZLi D. Insight into mouse models of hyperthyroidism. Front Endocrinol 2022b; 13: 929750. https://doi.org/10.3389/fendo.2022.929750##Zhang X, Zhang L, Xia K, Dai J, Huang J, Wang Y, et al. Effects of dietary selenium on immune function of spleen in mice. J Funct Foods 2022a; 89: 104914. https://doi.org/10.1016/j.jff.2021.104914## ##

Comparing the Analgesic and Anti-Ulcer Properties of Green Tea Aqueous Extract with Licofelone 2 2 Introduction: Green tea possesses gastroprotective effects via different mechanisms including lipoxygenase inhibition. We compared its protective effects with licofelone (as a potent lipoxygenase inhibitor) on reducing the incidence of gastric ulcers caused by indomethacin. Methods: 48 rats received an aqueous extract of green tea (GTAE; 50, 100, and 200 mg/kg), licofelone (30 mg/kg), zileuton (100 mg/kg), or 0.18% Tween 80 in the presence of indomethacin (100 mg/kg). Two groups received only GTAE (200 mg/kg) or indomethacin (100 mg/kg). The gastric ulcer index and Malondialdehyde (MDA) in gastric tissues were evaluated. To investigate the analgesic effect in acute and chronic phases, 24 rats received GTAE (200 mg/kg), licofelone (30 mg/kg), indomethacin (30 mg/kg), or 0.18% Tween 80 in the presence of formalin (2.5%). The behavior of rats was monitored for 30 minutes (minutes 0 to 5 and 25 to 30) for licking and biting feet and tails. Results: Indomethacin (100 mg/kg) produced clear macroscopic lesions compared to the control group. GTAE (100 and 200 mg/kg), licofelone, and Zileuton showed a significant decrease in wound score compared to indomethacin. GTAE (100 mg/kg and 200), licofelone, and zileuton displayed a significant decrease in the MDA content of gastric tissue compared to the indomethacin group. Notably, GTAE exerted greater benefits than licofelone. Besides, GTAE (200 mg/kg) showed a significant decrease observed in both acute and chronic stages of pain compared to licofelone (30 mg/kg). Conclusion: GTAE (200 mg/kg) possesses anti-ulcer and analgesic effects similar to licofelone. The exact mechanism is probably via inhibition of lipoxygenase (LOX) and antioxidant effects. 338 350 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/22023/01/282023/07/132023/12/12023/12/4 1402/9/13 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/272024/02/272024/01/312024/04/22024/04/2 1403/1/14 habibeh mashayekhi-sardoo habibeh mashayekhi-sardoo Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran Iran mashayekhih951@mums.ac.ir Atieh Vasegh Atieh Vasegh Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Iran VaseghA931@mums.ac.ir BiBi Marjan Razavi BiBi Marjan Razavi Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Iran RazaviMr@mums.ac.ir Mohsen Imenshahidi Mohsen Imenshahidi Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Iran imenm@mums.ac.ir Green tea Lipoxygenase Indomethacin Gastric or peptic ulcer Analgesic Aal-Aaboda M, Al-Juhaishi A M R, Khalil A M, Abdulkareem N G. Gastroprotective effect of zafirlukast against indomethacin induced gastric ulcer in rats via PGE2 and anti-inflammatory pathways. Iranian Journal of Basic Medical Sciences 2023; 26: 799.##Abbasifard M, Heidari M, Kamiab Z, Kaeidi A, Kahnooji M, Khajehsharifi G, et al. Comparison of gastric-ulcerogenecity effect of methanolic extract of capparis spinosa and indomethacin in rat. Jundishapur Journal of Natural Pharmaceutical Products 2021: 16. https://doi.org/10.5812/jjnpp.93823IF: 1.0 Q4##Ali K A, Maity A, Roy S D, Pramanik S D, Das P P, Shaharyar M A. Insight into the mechanism of steroidal and non-steroidal anti-inflammatory drugs. How Synthetic Drugs Work: Elsevier, 2023: 61-94. https://doi.org/10.1016/B978-0-323-99855-0.00004-X##Amirtha V, Anju C, Kumar S R. Preparation of Camellia sinensis (Green Tea) and acacia nilotica (babul) herbal formulation and its anti-inflammatory activity. Pharmacognosy Research 2023; 15. https://doi.org/10.5530/pres.15.2.027IF: 0.7 Q4##Andrade G K C, Ortega M J M, Sarmiento E F M, Minchala J P O, Maldonado C G J, Rosales E I C, et al. Gastrointestinal bleeding, description, etiology, epidemiology, classification, clinical presentation, treatment and prognosis. EPRA International Journal of Multidisciplinary Research (IJMR) 2024; 10: 534-539. https://doi.org/10.36713/epra15654##Begg M, Tarhuni M, M N F, Gonzalez N A, Sanivarapu R R, Osman U, et al. Comparing the safety and efficacy of proton pump inhibitors and histamine-2 receptor antagonists in the management of patients with peptic ulcer disease: a systematic review. Cureus 2023; 15: e44341. https://doi.org/10.7759/cureus.44341##Chan W C, Millwood I Y, Kartsonaki C, Du H, Guo Y, Chen Y, et al. Spicy food consumption and risk of gastrointestinal-tract cancers: findings from the China Kadoorie Biobank. Int J Epidemiol 2021; 50: 199-211. https://doi.org/10.1093/ije/dyaa275##Choi J H, Chai Y M, Joo G J, Rhee I K, Lee I S, Kim K R, et al. Effects of green tea catechin on polymorphonuclear leukocyte 5’-lipoxygenase activity, leukotriene B4 synthesis, and renal damage in diabetic rats. Ann Nutr Metab 2004; 48: 151-155. https://doi.org/10.1159/000078378IF: 3.2 Q2##Choi J H, Chang H W, Rhee S J. Effect of green tea catechin on arachidonic acid cascade in chronic cadmium-poisoned rats. Asia Pac J Clin Nutr 2002; 11: 292-7. https://doi.org/10.1046/j.1440-6047.2002.00305.x##Chu K O, Chan S O, Pang C P, Wang C C. Pro-oxidative and antioxidative controls and signaling modification of polyphenolic phytochemicals: contribution to health promotion and disease prevention? J Agric Food Chem 2014; 62: 4026-4038. https://doi.org/10.1021/jf500080z##Coppock R W, Dziwenka M. Chapter 46 - Green tea extract. In: Gupta RC, editor. Nutraceuticals. Boston: Academic Press, 2016: 633-652. https://doi.org/10.1016/B978-0-12-802147-7.00046-2##Cseh E K, Veres G, Körtési T, Polyák H, Nánási N, Tajti J, et al. Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund’s adjuvant model of orofacial pain. J Headache Pain 2020; 21: 35. https://doi.org/10.1186/s10194-020-01105-6##El-Ashmawy N E, Khedr E G, El-Bahrawy H A, Selim H M. Nebivolol prevents indomethacin-induced gastric ulcer in rats. J Immunotoxicol 2016; 13: 580-589. https://doi.org/10.3109/1547691X.2016.1142488##Elvina E, Kusnoto J, Halim H, Roeslan B. Chewing Gum, Acetaminophen, and green tea effect in reducing pain after orthodontic appliance placement. Scientific Dental Journal 2018; 2: 53. https://doi.org/10.26912/sdj.v2i2.2530##Etemadi Sh M, Haghighat A, Fattahi B, Tajmiri G, Alizargar J. Evaluation of the effect of green tea extract on postoperative pain management following surgical removal of impacted mandibular third molar. Dent Res J (Isfahan) 2023; 20: 17. https://doi.org/10.4103/1735-3327.369619##Fahmi A, Syukur S, Chaidir Z, Melia S. Applications and implications from epigallo catechin gallate (egcg) in green tea. Journal of Midwifery and Nursing 2024; 6: 22-29.##Fallah Huseini H, Kianbakht S, Rajabian T. Effects of Aloe vera, Camellia sinensis, Hibiscus sabdariffa and Sophora alopecuroides in rat model of indomethacin-induced gastric ulcer. Journal of Medicinal Plants 2015; 14: 58-65.##Fernandes D C, Martins B P, Silva G P d, Fonseca E N d, Santos S V M, Velozo L S M, et al. Echinodorus macrophyllus fraction with a high level of flavonoid inhibits peripheral and central mechanisms of nociception. Journal of Traditional and Complementary Medicine 2022; 12: 123-130. https://doi.org/10.1016/j.jtcme.2021.07.001##Gandhi M N, Challa S R, Prasanth P, Gandhi T R. Role of leukotrienes in NSAID induced gastric ulceration and inflammation in wistar rats. Asian Pacific Journal of Tropical Disease 2012; 2: 215-219. https://doi.org/10.1016/S2222-1808(12)60049-8##Ghorbanoghli S, Hashemi S, Amirkhanloo S, Rezaei Shahmirzadi A, Hadian A, Nazemi N, et al. Clinical properties of green tea: focus on blood lipid profiles, analgesia, periodontal status. Journal of Research in Medical and Dental Science 2019; 7: 32-43.##Hajhashemi V, Khodarahmi G, Asadi P, Rajabi H. Evaluation of the antinociceptive effects of a selection of triazine derivatives in mice. Korean J Pain 2022; 35: 440-446. https://doi.org/10.3344/kjp.2022.35.4.440##Hawkey C, Avery A, Coupland C A C, Crooks C, Dumbleton J, Hobbs F D R, et al. Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial. The Lancet 2022; 400: 1597-1606. https://doi.org/10.1016/S0140-6736(22)01843-8##Honcharuk L, Piddubna A, Andrushchak M, Panchuk V, Skakun A. Stress and peptic ulcer of the stomach and duodenum. Journal 2023: 53-55.##Katary M, Salahuddin A. Gastroprotective effect of vanillin on indomethacin-induced gastric ulcer in rats: protective pathways and anti-secretory mechanism. Clin Exp Pharmacol 2017; 7.##Kim H-S, Quon M J, Kim J-a. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox biology 2014; 2: 187-195. https://doi.org/10.1016/j.redox.2013.12.022##Kuipers E J. PPIs for prevention and treatment of peptic ulcer. The Lancet Gastroenterology & Hepatology 2018; 3: 214-215. https://doi.org/10.1016/S2468-1253(18)30047-5##Lan H, Wang H, Chen C, Hu W, Ai C, Chen L, Teng H. Flavonoids and gastrointestinal health: Single molecule for multiple roles. Critical Reviews in Food Science and Nutrition 2023: 1-19. https://doi.org/10.1080/10408398.2023.2230501IF: 7.3 Q1##Lanas Á, Carrera-Lasfuentes P, Arguedas Y, García S, Bujanda L, Calvet X, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015; 13: 906-912. https://doi.org/10.1016/j.cgh.2014.11.007##Liu D, Jing X, Cao S, Liu X, Tan X, Jiang H, et al. Impact of drinking Chinese green tea on postoperative short outcomes for gastric cancer: a randomized controlled trial. Eur J Clin Nutr 2021; 75: 1568-1577. https://doi.org/10.1038/s41430-021-00868-8##Liu R, Zhu N, Hao Y, Liu X, Kang J, Mao R, et al. The protective effect of walnut oligopeptides against indomethacin-induced gastric ulcer in rats. Nutrients 2023a; 15: 1675. https://doi.org/10.3390/nu15071675##Liu Y, Xiao Z, Ye K, Xu L, Zhang Y. Smoking, alcohol consumption, diabetes, body mass index, and peptic ulcer risk: A two-sample Mendelian randomization study. Frontiers in Genetics 2023b; 13: 992080. https://doi.org/10.3389/fgene.2022.992080##Mahdian Dehkordi F, Kaboutari J, Zendehdel M, Javdani M. The antinociceptive effect of artemisinin on the inflammatory pain and role of GABAergic and opioidergic systems. Korean J Pain 2019; 32: 160-167. https://doi.org/10.3344/kjp.2019.32.3.160##Maity S, Chaudhuri T, Vedasiromoni J, Ganguly D. Cytoprotection mediated antiulcer effect of tea root extract. Indian Journal of Pharmacology 2003; 35: 213-219.##Majka J, Brzozowski T. Exploring the gastroprotective, ulcer healing and chemopreventive properties of nitric oxide-releasing nonsteroidal anti-inflammatory drugs. Nitric Oxide: From Research to Therapeutics: Springer, 2023: 377-390. https://doi.org/10.1007/978-3-031-24778-1_18##Malfertheiner P, Camargo M C, El-Omar E, Liou J-M, Peek R, Schulz C, et al. Helicobacter pylori infection. Nature Reviews Disease Primers 2023; 9: 19. https://doi.org/10.1038/s41572-023-00431-8##Mashayekhi-Sardoo H, Razavi B M, Ekhtiari M, Kheradmand N, Imenshahidi M. Gastroprotective effects of both aqueous and ethanolic extracts of Lemon verbena leaves against indomethacin-induced gastric ulcer in rats. Iran J Basic Med Sci 2020; 23: 1639-1646.##Matsuo N, Yamada K, Yamashita K, Shoji K, Mori M, Sugano M. Inhibitory effect of tea polyphenols on histamine and leukotriene B4 release from rat peritoneal exudate cells. In Vitro Cell Dev Biol Anim 1996; 32: 340-344. https://doi.org/10.1007/BF02722960##Medeiros P, Dos Santos I R, Medeiros A C, da Silva J A, Ferreira S H, de Freitas R L, Coimbra N C. Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury. Braz J Med Biol Res 2020; 53: e9255. https://doi.org/10.1590/1414-431x20209255##Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86: 271-278. https://doi.org/10.1016/0003-2697(78)90342-1##Mota M A, Landim J S, Targino T S, Silva S F, Silva S L, Pereira M R. Evaluation of the anti-inflammatory and analgesic effects of green tea (Camellia sinensis) in mice. Acta Cir Bras 2015; 30: 242-246. https://doi.org/10.1590/S0102-865020150040000002##Movaghari Pour A, Khazaeli P, Kamyab N, Pourzamani M, Moeinzadeh F, Sheikh Fathollahi M. Effect of green tea mucoadhesive paste on recurrent aphthous stomatitis treatment. Journal of Mashhad Dental School 2020; 44: 279-288.##Nikoui V, Mehrzadi S, Khan M I, Aman W, Ostadhadi S, Dehpour A R. Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, reverses endotoxin-induced impaired atrial chronotropic responsiveness to cholinergic stimulation in rats. European Journal of Pharmacology 2020; 887: 173569. https://doi.org/10.1016/j.ejphar.2020.173569##Ogar F O, Ibubeleye V T, Uahomo P O, Kofii N B. Evaluation of the effects of green tea (Camellia sinensis) on markers of liver function and liver histology in wistar rats. Journal of Complementary and Alternative Medical Research 2023; 24: 23-34. https://doi.org/10.9734/jocamr/2023/v24i1490##Omar M, Adnan N, Kumolosasi E, Azmi N, Damanhuri N, Buang F. Green tea (Camellia sinensis) extract reduces peptic ulcer induced by helicobacter pylori in sprague dawley rats. Sains Malaysiana 2020; 49: 2793-2800. https://doi.org/10.17576/jsm-2020-4911-18##Oz H S. Chronic Inflammatory Diseases and Green Tea Polyphenols. Nutrients 2017; 9: 1-14. https://doi.org/10.3390/nu9060561##Ozleyen A, Yilmaz Y B, Donmez S, Atalay H N, Antika G, Tumer T B. Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention. Journal of Cancer Research and Clinical Oncology 2023; 149: 2095-2113. https://doi.org/10.1007/s00432-022-04187-8##Panchal N K, Sabina E P. Non-steroidal anti-inflammatory drugs (NSAIDs): A current insight into its molecular mechanism eliciting organ toxicities. Food and Chemical Toxicology 2023: 113598. https://doi.org/10.1016/j.fct.2022.113598##Pineda-Peña E A, Chávez-Piña A E. Gaseous mediators (H2S, NO and CO) a new approach in gastrointestinal protection. Mexican Journal of Medical Research ICSA 2023. https://doi.org/10.29057/mjmr.v11i21.9436##Rainsford K D. The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiinflammatory drugs in mice. Agents Actions 1987; 21: 316-319. https://doi.org/10.1007/BF01966502##Rakshit S, Jana S, Dassarma B, Sarkar B, Samanta S. Protective role of green tea extract against cold-restraint stress induced gastric ulcerogenesis in albino rats. J Pharm Chem Biol Sci 2018; 6: 218-227.##Scarpignato C, Hunt R H. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 2010; 39: 433-464. https://doi.org/10.1016/j.gtc.2010.08.010##Shahraki F N, Momtaz S, Baeeri M, Khayatan D, Lashgari N-A, Roudsari N M, et al. Licofelone Attenuates acetic acid-induced colitis in rats through suppression of the inflammatory mediators. Inflammation 2023: 1-16. https://doi.org/10.21203/rs.3.rs-1665485/v1##Singh N, Kulkarni G, Kumar Y. Montelukast sodium formulation containing green tea extract to reduce the oxidative stress in guinea pig model of chronic allergic asthma. Recent Patents on Drug Delivery & Formulation 2018; 13. https://doi.org/10.2174/1872211313666181211123903##Singh V P, Patil C S, Kulkarni S K. Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation. Indian J Exp Biol 2005; 43: 247-253.##Tsai T C, Brooks D C. Evaluation of Peptic Ulcer Disease. In: Grams J, Perry KA and Tavakkoli A, editors. The SAGES Manual of Foregut Surgery. Cham: Springer International Publishing, 2019: 635-642. https://doi.org/10.1007/978-3-319-96122-4_53##Turan M I, Bilen H, Demiryilmaz I, Özgeriş F, Baykal H, Turkoglu M, Suleyman H. Effects of Hypericum perforatum and Hippophae rhamnoides extracts on indomethacin-induced gastric oxidative stress in rats. Biomedical Research (India) 2013; 24: 314-319.##Xie X, Ren K, Zhou Z, Dang C, Zhang H. The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study. BMC Gastroenterology 2022; 22: 58. https://doi.org/10.1186/s12876-022-02130-2##Al-Mahdi Z K A, Ewadh R M, Hindi N K K. Health benefits of aqueous extract of black and green tea leaves. Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health 2020.##Żuchnik O, Szydłowska J, Gładysz K, Kwiatkowski P, Szydłowski M, Kłos A, et al. Consumption of green tea - potential health benefits. Journal of Education, Health and Sport 2022; 13: 229-234. https://doi.org/10.12775/JEHS.2023.13.01.034## ##

Chrysin’s potential in ameliorating the toxic effects of Cyclophosphamide on mouse oocytes and embryos 2 2 Introduction: The study investigates the protective effects of chrysin (CR) on the quality of oocytes and embryos in rats undergoing in vitro fertilization after treatment with cyclophosphamide (CPH).  Methods: In this study, female NMRI mice were divided into five groups: I. control group, II. sham group, III. CPH group (receiving 120 mg/kg.wk of CPH intraperitoneally (IP), IV and V: CR groups receiving 5 and 10 mg/kg. day CR for four weeks. For oocyte induction, ten units of pregnant mare serum gonadotropin were injected IP after the last injection. All mice were then sacrificed by aspiration of their oocytes for further experiments. The growth of embryos was investigated using mature oocytes in vitro. Results: CR significantly increased the number of 2 cells and 4 cells after 24 and 48 hours compared to the CPH group. Groups treated with CR showed a significant increase in the expression level of the BMP-15 and GDF-9 genes in a dose-dependent manner compared to the CPH group. Conclusion: In mice, CR reduced oxidative damage and oocyte cytokine levels in ovarian tissue after CPH-induced degeneration. 351 362 2023/05/162023/11/152023/06/252023/06/132022/05/212023/09/22023/01/282023/07/132023/12/12023/12/42023/03/18 1401/12/27 2024/04/62024/04/22024/02/192024/04/232023/04/112024/02/272024/02/272024/01/312024/04/22024/04/22024/02/27 1402/12/8 Sima Etebari Sima Etebari Department of Physiology, Sabzevar University of Medical Sciences, Sabzevar, Iran Iran simetebari@Yahoo.com Mojdeh Gholami Mojdeh Gholami Department of Biology, Shahid Chamran University of Ahvaz, Ahvaz, Iran Iran mojdeh.gh1374166@gmail.com Mohsen Asouri Mohsen Asouri Department of Paramedicine, Amol School of Paramedicine, Mazandaran University of Medical Sciences, Sari, Iran Iran Mehrab Nasirikenari Mehrab Nasirikenari North Research Center, Pasteur Institute of Iran, Amol, Iran Iran Yahya Babaki Yahya Babaki North Research Center, Pasteur Institute of Iran, Amol, Iran Iran Mohammad Reza Momtaz Mohammad Reza Momtaz North Research Center, Pasteur Institute of Iran, Amol, Iran Iran Ali Asghar Ahmadi Ali Asghar Ahmadi North Research Center, Pasteur Institute of Iran, Amol, Iran Iran ahmadi.pasteur@gmail.com Chrysin Cyclophosphamide Oocyte quality Oocyte collection Athira V R, Shivanandappa T, Yajurvedi H N. Cyclophosphamide, a cancer chemotherapy drug-induced early onset of reproductive senescence and alterations in reproductive performance and their prevention in mice. Drug and Chemical Toxicology. 2022; 45(2): 760-766. https://doi.org/10.1080/01480545.2020.1774773##Athira V R, Saranya M K, Shivanandappa T, Yajurvedi H N. Multiple dose treatment reduces cyclophosphamide-induced ovarian follicular loss in mice. Birth Defects Research. 2020; 112(1): 71-80. https://doi.org/10.1002/bdr2.1603##Agarwal A, Saleh R A, Bedaiwy M A. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertility and sterility. 2003; 79(4): 829-843. https://doi.org/10.1016/S0015-0282(02)04948-8##Aktas C, Kanter M, Kocak Z. Antiapoptotic and proliferative activity of curcumin on ovarian follicles in mice exposed to whole body ionizing radiation. Toxicology and industrial health. 2012; 28(9): 852-863. https://doi.org/10.1177/0748233711425080##Amini E, Baharara J, Nikdel N, Salek Abdollahi F. Cytotoxic and pro-apoptotic effects of honey bee venom and chrysin on human ovarian cancer cells. Asia Pacific Journal of Medical Toxicology. 2015; 4(2): 68-73.##Ahmad H I, Ahmad M J, Adeel M M, Asif A R, Du X. Positive selection drives the evolution of endocrine regulatory bone morphogenetic protein system in mammals. Oncotarget. 2018; 9(26): 18435. https://doi.org/10.18632/oncotarget.24240##Brechbuhl H M, Kachadourian R, Min E, Chan D, Day B J. Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: the role of glutathione. Toxicology and applied pharmacology. 2012; 258(1): 1-9. https://doi.org/10.1016/j.taap.2011.08.004##Bargi R, Asgharzadeh F, Beheshti F, Hosseini M, Farzadnia M, Khazaei M. Thymoquinone protects the rat kidneys against renal fibrosis. Research in pharmaceutical sciences. 2017; 12(6): 479. https://doi.org/10.4103/1735-5362.217428##Boots C E, Jungheim E S. Inflammation and human ovarian follicular dynamics. Journal 2015; 33: 270-275. https://doi.org/10.1055/s-0035-1554928##Chen Y, Zhao Y, Miao C, Yang L, Wang R, Chen B, et al. Quercetin alleviates cyclophosphamide-induced premature ovarian insufficiency in mice by reducing mitochondrial oxidative stress and pyroptosis in granulosa cells. Journal of Ovarian Research 2022; 15(1): 138. https://doi.org/10.1186/s13048-022-01080-3##Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: what’s the matter? International journal of molecular sciences 2016; 17(6): 836. https://doi.org/10.3390/ijms17060836 ##Demir EA, Mentese A, Demir S, Küçük H, Türkmen N, Aliyazicioğlu Y. Evaluation of therapeutic effect of chrysin against 5-fluorouracil-induced ovarian damage in rats. Farabi Tıp Dergisi. 2023; 2(1): 1-7. https://doi.org/10.59518/farabimedj.1221397##Guigon CJ, Mazaud S, Forest MG, Brailly-Tabard S, Coudouel N, Magre S. Unaltered development of the initial follicular waves and normal pubertal onset in female rats after neonatal deletion of the follicular reserve. Endocrinology 2003; 144(8): 3651-3662. https://doi.org/10.1210/en.2003-0072 ##Helsby N A, Yong M, van Kan M, de Zoysa J R, Burns K E. The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. British journal of clinical pharmacology. 2019: 85(9): 1925-1934. https://doi.org/10.1111/bcp.14031##Hou J, Lei Z, Cui L, Hou Y, Yang L, An R, et al. Polystyrene microplastics lead to pyroptosis and apoptosis of ovarian granulosa cells via NLRP3/Caspase-1 signaling pathway in rats. Ecotoxicology and Environmental Safety 2021; 212: 112012. https://doi.org/10.1016/j.ecoenv.2021.112012##Jessmon P, Boulanger T, Zhou W, Patwardhan P. Epidemiology and treatment patterns of epithelial ovarian cancer. Expert review of anticancer therapy 2017; 17(5): 427-437. https://doi.org/10.1080/14737140.2017.1299575##Jiao Y, Jiang T, Lin Q, Guo J, Bei C, Cong P, et al. Molecular characterization of the follicular development of BMP15-edited pigs. Reproduction 2023; 166: 247-261. https://doi.org/10.1530/REP-23-0034##Jang H, Hong K, Choi Y. Melatonin and fertoprotective adjuvants: prevention against premature ovarian failure during chemotherapy. International journal of molecular sciences 2017; 18(6): 1221. https://doi.org/10.3390/ijms18061221##Kovanci E, Schutt A K. Premature ovarian failure: clinical presentation and treatment. Obstetrics and Gynecology Clinics 2015; 42(1): 153-161. https://doi.org/10.1016/j.ogc.2014.10.004 ##Khoo BY, Chua SL, Balaram P. Apoptotic effects of chrysin in human cancer cell lines. International journal of molecular sciences 2010; 11(5): 2188-2199. https://doi.org/10.3390/ijms11052188##Koike M, Kanda A, Kido K, Goto K, Kumasako Y, Nagaki M, et al. Effects of cyclophosphamide administration on the in vitro fertilization of mice. Reproductive Medicine and Biology 2018; 17: 262-267. https://doi.org/10.1002/rmb2.12099##Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reproductive biomedicine online 2014; 29(6): 684-691. https://doi.org/10.1016/j.rbmo.2014.08.009##Lin J, Li X-l, Song H, Li Q, Wang M-y, Qiu X-m, et al. A general description for Chinese medicine in treating premature ovarian failure. Chinese journal of integrative medicine 2017; 23: 91-97. https://doi.org/10.1007/s11655-016-2642-7 ##Li X, Li X, Deng L. Chrysin reduces inflammation and oxidative stress and improves ovarian function in D-gal-induced premature ovarian failure. Bioengineered 2022; 13(4): 8291-8301. https://doi.org/10.1080/21655979.2021.2005991##Mantawy E M, Said R S, Abdel-Aziz A K. Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: emphasis on TGF-β/MAPKs signaling pathway. Biomedicine & Pharmacotherapy 2019; 109: 293-303. https://doi.org/10.1016/j.biopha.2018.10.092##Mentese A, Alemdar N T, Livaoglu A, Ayazoglu Demir E, Aliyazicioglu Y, Demir S. Suppression of cisplatin-induced ovarian injury in rats by chrysin: an experimental study. Journal of Obstetrics and Gynaecology 2022; 42(8): 3584-3590. https://doi.org/10.1080/01443615.2022.2130201##Melekoglu R, Ciftci O, Eraslan S, Alan S, Basak N. The protective effects of glycyrrhetinic acid and chrysin against ischemia-reperfusion injury in rat ovaries. BioMed research international 2018; 2018: 5421308. https://doi.org/10.1155/2018/5421308##Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Human reproduction update. 2001; 7(6): 535-543. https://doi.org/10.1093/humupd/7.6.535##Özatik F Y, Özatik O, Tekşen Y, Koçak H, Arı N S, Ünel Ç Ç. Dose-Dependent Effect of Hydrogen Sulfide in Cyclophosphamide-Induced Hepatotoxicity in Rats. The Turkish Journal of Gastroenterology 2023; 34: 626. https://doi.org/10.5152/tjg.2023.22040##Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. The Lancet Global Health 2016; 4(9): 609-616. https://doi.org/10.1016/S2214-109X(16)30143-7 ##Siegel R L, Miller K D, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018; 68: 7-30. https://doi.org/10.3322/caac.21442##Shahbaz M, Naeem H, Imran M, Ul Hassan H, Alsagaby S A, Al Abdulmonem W, et al. Chrysin a promising anticancer agent: Recent perspectives. International Journal of Food Properties 2023; 26: 2294-2337. https://doi.org/10.1080/10942912.2023.2246678##Sanfins A, Rodrigues P, Albertini D F. GDF-9 and BMP-15 direct the follicle symphony. Journal of assisted reproduction and genetics. 2018; 35: 1741-1750. https://doi.org/10.1007/s10815-018-1268-4##Shao J J, Zhang A P, Qin W, Zheng L, Zhu Y F, Chen X. AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells. Biochemical and Biophysical Research Communications 2012; 423(3): 448-453.https://doi.org/10.1016/j.bbrc.2012.05.123##Samarghandian S, Afshari J T, Davoodi S. Chrysin reduces proliferation and induces apoptosis in the human prostate cancer cell line pc-3. Clinics 2011; 66(6): 1073-1079.https://doi.org/10.1590/S1807-59322011000600026##Salimi A, Shabani M, Mohammadi H, Sudi V. Intraperitoneal pretreatment of ellagic acid and chrysin alleviate ifosfamide-induced neurotoxicity, but betanin induces death in male wistar rats. Human & Experimental Toxicology 2023; 42: 09603271221147883. https://doi.org/10.1177/09603271221147883##Temel Y, Çağlayan C, Ahmed BM, Kandemir F M, Çiftci M. The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: biochemical evaluation of some enzyme activities in vivo and in vitro. Naunyn-Schmiedeberg’s Archives of Pharmacology 2021; 394: 645-654. https://doi.org/10.1007/s00210-020-01987-y##Taslimi P, Kandemir F M, Demir Y, İleritürk M, Temel Y, Caglayan C, et al. The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide-induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. Journal of biochemical and molecular toxicology 2019; 33: e22313. https://doi.org/10.1002/jbt.22313##Yuksel A, Bildik G, Senbabaoglu F, Akin N, Arvas M, Unal F, et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Human reproduction 2015; 30: 2926-2935.https://doi.org/10.1093/humrep/dev256 ##Wu N L, Fang J Y, Chen M, Wu C J, Huang C C, Hung C F. Chrysin protects epidermal keratinocytes from UVA-and UVB-induced damage. Journal of agricultural and food chemistry 2011; 59(15): 8391-8400. https://doi.org/10.1021/jf200931t##Wei J H, Yuan X Y, Zhang J M, Wei J Q. Caspase activity and oxidative stress of granulosa cells are associated with the viability and developmental potential of vitrified immature oocytes. European Journal of Obstetrics & Gynecology and Reproductive Biology 2016; 198: 22-26. https://doi.org/10.1016/j.ejogrb.2015.12.010## ##