2024 28 2 0 218

Prevention of glycerol-induced acute kidney injury by isoflurane inhalation in male rats 2 2 Introduction: Acute kidney injury (AKI) is a severe complication of rhabdomyolysis (RM), where skeletal muscle injury leads to the release of cell contents into the bloodstream, ultimately obstructing renal tubules. This results in renal dysfunction due to increased oxidative stress, inflammation, and apoptosis. Glycerol (10 mL/kg) injection is one of the most common methods to induce experimental AKI; but 10 mL/kg dosage seems to be harmful to rats because we have observed some side effects. This study was designed to evaluate the effects of isoflurane pretreatment in the glycerol model of acute kidney injury, but at first we tried to find a better dosage of glycerol to induce AKI less harmful. Methods: 28 male Wistar rats were used in our investigation. We first studied to find the most effective dosage of glycerol for AKI induction in three groups (5, 6.25, and 10 mL/kg), and accordingly 6.25 mL/kg was selected. Secondly, we investigated isoflurane (1.5%, 20 minutes) pretreatment effects on glycerol-induced AKI by estimating blood urea nitrogen (BUN), creatinine (Cr), Bax/Bcl-2 proteins ratio (Bcl-2-associated X/B-cell lymphoma 2), malondialdehyde (MDA), superoxide dismutase (SOD), and histological changes in renal tissues. Results: The results showed that isoflurane pretreatment suppressed oxidative stress and apoptosis, and therefore was able to improve renal function. Conclusion: Isoflurane pretreatment might be protective against rhabdomyolysis-induced AKI because of its anti-oxidant and anti-apoptotic activities. 91 98 2023/05/6 1402/2/16 2023/09/25 1402/7/3 Negin Givechian Negin Givechian Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran ngngivechian.74@gmail.com Ghorbangol Ashabi Ghorbangol Ashabi Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran gh-ashabi@tums.ac.ir Mehri Kadkhodaee Mehri Kadkhodaee Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran kadkhodm@tums.ac.ir Behjat Seifi Behjat Seifi Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran b-seifi@tums.ac.ir Arash Abdi Arash Abdi Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran a-abdi@razi.tums.ac.ir Farzaneh Kianian Farzaneh Kianian Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran kianian.f1989@gmail.com Tina Kianfar Tina Kianfar Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Iran tina.kiyanfar1376@gmail.com Glycerol Blood Urea Nitrogen Creatinine Isoflurane Kidney Abd-Ellatif R N, Hegab I I, Atef M M, Sadek M T, Hafez Y M. Diacerein protects against glycerol-induced acute kidney injury: modulating oxidative stress, inflammation, apoptosis and necroptosis. Chemico-Biological Interactions 2019; 306: 47-53. https://doi.org/10.1016/j.cbi.2019.04.008##Al Asmari A K, Al Sadoon K T, Obaid A A, Yesunayagam D, Tariq M. Protective effect of quinacrine against glycerol-induced acute kidney injury in rats. BMC Nephrology 2017; 18: 1-10. https://doi.org/10.1186/s12882-017-0450-8##Bradford M M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 1976; 72: 248-254. https://doi.org/10.1016/0003-2697(76)90527-3##Cabral B M I, Edding S N, Portocarrero J P, Lerma E V. Rhabdomyolysis. Disease-a-Month 2020; 66: 101015. https://doi.org/10.1016/j.disamonth.2020.101015##Englert J A, Macias A A, Amador-Munoz D, Pinilla Vera M, Isabelle C, Guan J, et al. Isoflurane ameliorates acute lung injury by preserving epithelial tight junction integrity. Anesthesiology 2015; 123: 377-388. https://doi.org/10.1097/ALN.0000000000000742##Esterbauer H, Cheeseman K H. [42] Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods in Enzymology. Vol 186: Elsevier, 1990: 407-421. https://doi.org/10.1016/0076-6879(90)86134-H##Gonsalez S R, Cortes A L, da Silva R C, Lowe J, Prieto M C, da Silva Lara L. Acute kidney injury overview: from basic findings to new prevention and therapy strategies. Pharmacology & Therapeutics 2019; 200: 1-12. https://doi.org/10.1016/j.pharmthera.2019.04.001##Goyal A, Daneshpajouhnejad P, Hashmi M F, Bashir K, John B K. Acute Kidney Injury (Nursing). Journal 2022. ##Hashiguchi H, Morooka H, Miyoshi H, Matsumoto M, Koji T, Sumikawa K. Isoflurane protects renal function against ischemia and reperfusion through inhibition of protein kinases, JNK and ERK. Anesthesia & Analgesia 2005; 101: 1584-1589. https://doi.org/10.1213/01.ANE.0000184044.51749.B8##Kim J H, Lee S S, Jung M H, Yeo H D, Kim H-J, Yang J I, et al. N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins. Nephrology Dialysis Transplantation 2010; 25: 1435-1443. https://doi.org/10.1093/ndt/gfp659##Li X, Wang J, Zhang H, Zhang Q. Renoprotective effect of low-molecular-weight sulfated polysaccharide from the seaweed Laminaria japonica on glycerol-induced acute kidney injury in rats. International Journal of Biological Macromolecules 2017; 95: 132-137. https://doi.org/10.1016/j.ijbiomac.2016.11.051##Liang Y, Li Z, Mo N, Li M, Zhuang Z, Wang J, et al. Isoflurane preconditioning ameliorates renal ischemia-reperfusion injury through antiinflammatory and antiapoptotic actions in rats. Biological and Pharmaceutical Bulletin 2014; 37: 1599-1605. https://doi.org/10.1248/bpb.b14-00211##Liu J, Yang S, Zhang X, Liu G, Yue X. Isoflurane reduces oxygen-glucose deprivation-induced oxidative, inflammatory, and apoptotic responses in H9c2 cardiomyocytes. American Journal of Translational Research 2016; 8: 2597. ##Mahdy M A. Glycerol-induced injury as a new model of muscle regeneration. Cell and Tissue Research 2018; 374: 233-241. https://doi.org/10.1007/s00441-018-2846-6##Mahdy M A, Warita K, Hosaka Y Z. Glycerol induces early fibrosis in regenerating rat skeletal muscle. Journal of Veterinary Medical Science 2018; 80: 1646-1649. https://doi.org/10.1292/jvms.18-0328##Mercado M G, Smith D K, Guard E L. Acute kidney injury: diagnosis and management. American Family Physician 2019; 100: 687-694. ##Michelsen J, Cordtz J, Liboriussen L, Behzadi M T, Ibsen M, Damholt M B, et al. Prevention of rhabdomyolysis-induced acute kidney injury-a DASAIM/DSIT clinical practice guideline. Acta Anaesthesiologica Scandinavica 2019; 63: 576-586. https://doi.org/10.1111/aas.13308 ##Mohsenin V. Practical approach to detection and management of acute kidney injury in critically ill patient. Journal of Intensive Care 2017; 5: 1-8. https://doi.org/10.1186/s40560-017-0251-y ##Niimura M, Takagi N, Takagi K, Mizutani R, Ishihara N, Matsumoto K, et al. Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. Journal of Cerebral Blood Flow & Metabolism 2006; 26: 1354-1365. https://doi.org/10.1038/sj.jcbfm.9600287## Panizo N, Rubio-Navarro A, Amaro-Villalobos J M, Egido J, Moreno J A. Molecular mechanisms and novel therapeutic approaches to rhabdomyolysis-induced acute kidney injury. Kidney and Blood Pressure Research 2015; 40: 520-532. https://doi.org/10.1159/000368528##Press A, Butans M, Haider T, Weber C, Neugebauer S, Kiehntopf M, et al. Fast simultaneous assessment of renal and liver function using polymethine dyes in animal models of chronic and acute organ injury. Scientific Reports 2017; 7: 15397. https://doi.org/10.1038/s41598-017-14987-5##Qin Z, Lv E, Zhan L, Xing X, Jiang J, Zhang M. Intravenous pretreatment with emulsified isoflurane preconditioning protects kidneys against ischemia/reperfusion injury in rats. BMC Anesthesiology 2014; 14: 1-8. https://doi.org/10.1186/1471-2253-14-28##Rao Z, Pan X, Zhang H, Sun J, Li J, Lu T, et al. Isoflurane preconditioning alleviated murine liver ischemia and reperfusion injury by restoring AMPK/mTOR-mediated autophagy. Anesthesia & Analgesia 2017; 125: 1355-1363. https://doi.org/10.1213/ANE.0000000000002385##Sharawy M H, Abdelrahman R S, El-Kashef D H. Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. Life Sciences 2018; 208: 79-86. https://doi.org/10.1016/j.lfs.2018.07.019##Taguchi K, Ogaki S, Nagasaki T, Yanagisawa H, Nishida K, Maeda H, et al. Carbon monoxide rescues the developmental lethality of experimental rat models of rhabdomyolysis-induced acute kidney injury. Journal of Pharmacology and Experimental Therapeutics 2020; 372: 355-365. https://doi.org/10.1124/jpet.119.262485##Wen X, Peng Z, Kellum J A. Pathogenesis of acute kidney injury: effects of remote tissue damage on the kidney. Controversies in Acute Kidney Injury 2011; 174: 129-137. https://doi.org/10.1159/000329382##Wu J, Pan X, Fu H, Zheng Y, Dai Y, Yin Y, et al. Effect of curcumin on glycerol-induced acute kidney injury in rats. Scientific Reports 2017; 7: 10114. https://doi.org/10.1038/s41598-017-10693-4##Zhang S, Zhang Y. Isoflurane reduces endotoxin-induced oxidative, inflammatory, and apoptotic responses in H9c2 cardiomyocytes. European Review for Medical and Pharmacological Sciences 2018; 22: 3976-87. ##Zuk A, Bonventre J V. Acute kidney injury. Annual Review of Medicine 2016; 67: 293-307. https://doi.org/10.1146/annurev-med-050214-013407## ##

Antioxidant and anti-inflammatory effects of Cinnamomum species and their bioactive compounds: An updated review of the molecular mechanisms 2 2 Introduction: The genus Cinnamomum (cinnamon) is one of the well-known aromatic spices throughout the world with numerous medicinal applications. Several beneficial pharmacological properties of cinnamon have been evaluated, including antioxidant, antiinflammatory, anti-diabetic, anticancer, cardiovascular-disease-lowering, and neurological disorder-improving effects. This review critically evaluates studies regarding the molecular mechanisms underlying the antioxidant and anti-inflammatory properties of cinnamon species. Methods: Using three online literature databases (PubMed, Scopus, Science Direct), we identified studies describing the antioxidant and anti-inflammatory properties of cinnamon species. A literature search was carried out using a combination of keywords such as (“Cinnamomum,”) AND (“antioxidant” OR “anti-inflammatory”) or other related words. In this review, we evaluated new findings regarding the molecular mechanisms of antioxidant and anti-inflammatory effects of Cinnamomum species published from 2005 until December 2022. A total of 38 papers were selected to describe the antioxidant and anti-inflammatory properties of cinnamon species. Results: Cinnamon species possess antioxidant effects by reducing ROS, MDA, and NO levels, and depleting GSH, decreasing MPO activity, and enhancing the growth of SOD and CAT. Additionally, the suppression of caspase-3 and caspase-9 activity and the upregulation of bcl-2 expression determine the anti-apoptotic effects of cinnamon. Their anti-inflammatory effects are mainly related to the reduction of TNF-α, IL-1β, IL-6, IL-18, IL-10, iNOS, MCP-1, and COX-2, and the inhibition of NF-κB, ERK1/2, p38, and JNK activation. Conclusion: This review highlighted the antioxidant and anti-inflammatory effects of genus cinnamon and can provide a suitable basis for further pharmacologic surveys and efficient clinical research on cinnamon to obtain new evidence on its benefits for human health. 99 116 2023/05/62023/10/2 1402/7/10 2023/09/252024/01/17 1402/10/27 Farzaneh Davoudi Farzaneh Davoudi Department of Cell and Molecular Biology, Kosar University of Bojnord, Bojnord, Iran Iran farzanehdavoudi597@gmail.com Elham Ramazani Elham Ramazani Department of Biology, Faculty of Science, Yazd University, Yazd, Iran Iran el.ramazani@yazd.ac.ir Cinnamon Antioxidant Anti-inflammatory Anderson R A. Chromium and polyphenols from cinnamon improve insulin sensitivity: plenary lecture. Proceedings of the Nutrition Society 2008; 67: 48-53. https://doi.org/10.1017/S0029665108006010##Aneja K R, Joshi R, Sharma C. Antimicrobial activity of Dalchini (Cinnamomum zeylanicum bark) extracts on some dental caries pathogens. Journal of Pharmacy Research 2009; 2: 1387-1390.##Aspland A M, Douagi I, Filby A, Jellison E R, Martinez L, Shinko D, et al. Biosafety during a pandemic: shared resource laboratories rise to the challenge. Cytometry Part A 2021; 99: 68-80. https://doi.org/10.1002/cyto.a.24280##Atsamo A D, Lontsie Songmene A, Metchi Donfack M F, Ngouateu O B, Nguelefack TB, Dimo T. Aqueous Extract from Cinnamomum zeylanicum (Lauraceae) Stem Bark Ameliorates Gentamicin-Induced Nephrotoxicity in Rats by Modulating Oxidative Stress and Inflammatory Markers. Evidence-based Complementary and Alternative Medicine 2021; 2021: 1-12. https://doi.org/10.1155/2021/5543889##Azab K S, Mostafa A-H A, Ali E M, Abdel-Aziz M A. Cinnamon extract ameliorates ionizing radiation-induced cellular injury in rats. Ecotoxicology and Environmental Safety 2011; 74: 2324-2329. https://doi.org/10.1016/j.ecoenv.2011.06.016##Bendavit G, Aboulkassim T, Hilmi K, Shah S, Batist G. Nrf2 transcription factor can directly regulate mTOR: linking cytoprotective gene expression to a major metabolic regulator that generates redox activity. Journal of Biological Chemistry 2016; 291: 25476254-25476288. https://doi.org/10.1074/jbc.M116.760249##Berlin D A, Gulick R M, Martinez F J. Severe covid-19. The New England Journal of Medicine 2020; 383: 2451-2460. https://doi.org/10.1056/NEJMcp2009575##Borzoei A, Rafraf M, Niromanesh S, Farzadi L, Narimani F, Doostan F. Effects of cinnamon supplementation on antioxidant status and serum lipids in women with polycystic ovary syndrome. Journal of Traditional and Complementary Medicine 2018; 8: 128-133. https://doi.org/10.1016/j.jtcme.2017.04.008##Chan K W, Khong N M H, Iqbal S, Ch’Ng SE, Younas U, Babji A S. Cinnamon bark deodorised aqueous extract as potential natural antioxidant in meat emulsion system: a comparative study with synthetic and natural food antioxidants. Journal of Food Science and Technology 2014; 51: 3269-3276. https://doi.org/10.1007/s13197-012-0818-5##Chen P, Ruan A, Zhou J, Huang L, Zhang X, Ma Y, et al. Cinnamic aldehyde inhibits lipopolysaccharide-induced chondrocyte inflammation and reduces cartilage degeneration by blocking the nuclear factor-kappa B signaling pathway. Frontiers in Pharmacology 2020;11: 1-9 .https://doi.org/10.3389/fphar.2020.00949##Chen J, Tang C, Zhou Y, Zhang R, Ye S, Zhao Z, et al. Anti-inflammatory property of the essential oil from cinnamomum camphora (Linn.) presl leaves and the evaluation of its underlying mechanism by using metabolomics analysis. Molecules 2020; 25:1-13. https://doi.org/10.3390/molecules25204796 ##Csikós E, Cseko K, Ashraf AR, Kemény Á, Kereskai L, Kocsis B, et al. Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) rendle essential oils in the endotoxin-induced acute airway inflammation mouse model. Molecules 2020; 25: 3553-3566. https://doi.org/10.3390/molecules25153553##Das J, Ghosh J, Manna P, Sil PC. Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology 2010; 269: 24-34. https://doi.org/10.1016/j.tox.2010.01.003##Dassanayake M, Larsen K. A revised handbook to the Flora of Ceylon. Nordic Journal of Botany. 1996; 16: 660. https://doi.org/10.1111/j.1756-1051.1996.tb00284.x##Davari M, Hashemi R, Mirmiran P, Hedayati M, Sahranavard S, Bahreini S, et al. Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB and Sirtuin-1 (SIRT1) in type 2 diabetes: A randomized, double blind, and controlled clinical trial. Nutrition Journal 2020; 19: 1-8. https://doi.org/10.1186/s12937-019-0518-3##Ekor M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Frontiers in Pharmacology 2014; 4: 177-186. https://doi.org/10.3389/fphar.2013.00177##Elshafie M M, Nawar I A, Algamal M A, Ahmad S M. Evaluation of the biological effects for adding cinnamon volatile oil and TBHQ as antioxidant on rats’ lipid profiles. Asian Journal of Plant Sciences 2012; 11: 100-108. https://doi.org/10.3923/ajps.2012.100.108##El-ezz A, Maher A, Sallam N, El-Brairy A, Kenawy S. Trans-cinnamaldehyde modulates hippocampal Nrf2 factor and inhibits amyloid beta aggregation in LPS-induced neuroinflammation mouse model. Neurochemical Research 2018; 43: 2333-2342. https://doi.org/10.1007/s11064-018-2656-y##Ervina M, Nawu Y, Esar S. Comparison of in vitro antioxidant activity of infusion, extract and fractions of Indonesian Cinnamon (Cinnamomum burmannii) bark. International Food Research Journal 2016; 23: 1346-1350.##Flohé L, Brigelius-Flohé R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radical Biology and Medicine 1997; 22: 1115-1126. https://doi.org/10.1016/S0891-5849(96)00501-1##Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell 2002; 109: 81-96. https://doi.org/10.1016/S0092-8674(02)00703-1##Gilgun-sherki Y, Melamed E, Offen D. Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 2001; 40: 959-975. https://doi.org/10.1016/S0028-3908(01)00019-3##Giuliani C, Bucci I, Napolitano G. The role of the transcription factor Nuclear Factor-kappa B in thyroid autoimmunity and cancer. Frontiers in Endocrinology 2018; 9: 471-478. https://doi.org/10.3389/fendo.2018.00471##Gunawardena D, Karunaweera N, Lee S, Van Der Kooy F, Harman DG, Raju R, et al. Anti-inflammatory activity of cinnamon (C. zeylanicum and C. cassia) extracts - Identification of E-cinnamaldehyde and o-methoxy cinnamaldehyde as the most potent bioactive compounds. Food & Function 2015; 6: 910-919. https://doi.org/10.1039/C4FO00680A##Gupta C, Garg A P, Prakash D, Goyal S, Gupta S. Comparative study of cinnamon oil and clove oil on some oral microbiota. Acta Biomedica 2011; 82: 197-199.##Haidari F, Mohammadshahi M, Abiri B, Zarei M, Fathi M. Cinnamon extract supplementation improves inflammation and oxidative stress induced by acrylamide: An experimental animal study. Avicenna Journal of Phytomedicine 2020; 10: 243-252.##Han X, Parker T L. Antiinflammatory activity of cinnamon (Cinnamomum zeylanicum) bark essential oil in a human skin disease model. Phytotherapy Research 2017; 31: 1034-1038. https://doi.org/10.1002/ptr.5822##Hao X, Sun W, Ke C, Wang F, Xue Y, Luo Z, et al. Anti-inflammatory activities of leaf oil from Cinnamomum subavenium in vitro and in vivo. BioMed Research International 2019; 2019. https://doi.org/10.1155/2019/1823149##Heneka M T, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimer’s Research & Therapy 2020; 12: 1-3. https://doi.org/10.1186/s13195-020-00640-3##Hong J-W, Yang G-E, Kim YB, Eom S H, Lew J-H, Kang H. Anti-inflammatory activity of cinnamon water extract in vivo and in vitro LPS-induced models. BMC Complementary Medicine and Therapies 2012; 12: 1-8. https://doi.org/10.1186/1472-6882-12-237##Hsueh W A, Law R E. Cardiovascular risk continuum: implications of insulin resistance and diabetes. American Journal of Medicine 1998; 105: 4-14. https://doi.org/10.1016/S0002-9343(98)00205-8##Huang B, Yuan H D, Kim D Y, Quan H Y, Chung S H. Cinnamaldehyde prevents adipocyte differentiation and adipogenesis via regulation of peroxisome proliferator-activated receptor-γ (PPARγ) and AMP-activated protein kinase (AMPK) pathways. Journal of Agricultural and Food Chemistry 2011; 59: 3666-3673. https://doi.org/10.1021/jf104814t##Hussain Z, Khan J A, Arshad A, Asif P, Rashid H, Arshad M I. Protective effects of Cinnamomum zeylanicum L. (Darchini) in acetaminophen-induced oxidative stress, hepatotoxicity and nephrotoxicity in mouse model. Biomedicine & Pharmacotherapy 2019; 109: 2285-2292. https://doi.org/10.1016/j.biopha.2018.11.123##Hussain S, Ashafaq M, Alshahrani S, Siddiqui R, Ahmed R A, Khuwaja G, et al. Cinnamon oil against acetaminophen-induced acute liver toxicity by attenuating inflammation, oxidative stress and apoptosis. Toxicology Reports 2020; 7: 1296-1304. https://doi.org/10.1016/j.toxrep.2020.09.008##Jayaprakasha G K, Jagan Mohan Rao L, Sakariah K K. Volatile constituents from Cinnamomum zeylanicum fruit stalks and their antioxidant activities. Journal of Agricultural and Food Chemistry 2003; 51: 4344-4348. https://doi.org/10.1021/jf034169i##Jayaprakasha G K, Ohnishi-Kameyama M, Ono H, Yoshida M, Rao L J. Phenolic constituents in the fruits of Cinnamomum zeylanicum and their antioxidant activity. Journal of Agricultural and Food Chemistry 2006; 54: 1672-1679. https://doi.org/10.1021/jf052736r ##Jazet Dongmo PM, Tatsadjieu LN, Tchoumbougnang F, Sameza ML, Dongnio BN, Amvam Zollo PH, et al. Chemical composition, antiradical and antifungal activities of essential oil of the leaves of cinnamomum zeylanicum blume from Cameroon. Natural Product Communications 2007; 2: 1287-1290. https://doi.org/10.1177/1934578X0700201219##Jindarat S, Muangnoi C, Changsiriporn D, Platong A, Thanamontra B, Chiewchanwit D, Vongvanvatana V, Rongrungsri N, Krittasilp K, Kaewkong N, Kantawan S. Efficacy and safety of cinnamon stomachic mixture for patients with functional dyspepsia. Siriraj Medical Journal 2006; 58: 1103-1106. ##Kallel I, Hadrich B, Gargouri B, Chaabane A, Lassoued S, Gdoura R, et al. Optimization of cinnamon (Cinnamomum zeylanicum Blume) essential oil extraction: evaluation of antioxidant and antiproliferative effects. Evidence-Based Complementary and Alternative Medicine 2019; 2019. https://doi.org/10.1155/2019/6498347##Kany S, Vollrath J T, Relja B. Cytokines in inflammatory disease. International Journal of Molecular Sciences 2019; 20: 6008-39. https://doi.org/10.3390/ijms20236008##Kim M S, Kim J Y. Cinnamon subcritical water extract attenuates intestinal inflammation and enhances intestinal tight junction in a Caco-2 and RAW264. 7 co-culture model. Food C Function 2019; 10: 4350-4360. https://doi.org/10.1039/C9FO00302A##Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harbor Perspectives in Biology 2009; 1: a001651. https://doi.org/10.1101/cshperspect.a001651##Lee S K, Hong C-H, Huh S-K, Kim S-S, Oh O-J, Min H-Y, et al. Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) activity in mouse macrophage cells. Journal of Environmental Pathology, Toxicology and Oncology 2002; 21: 141-148. https://doi.org/10.1615/JEnvironPatholToxicolOncol.v21.i2.70##Lee H-S, Kim B-S, Kim M-K. Suppression effect of Cinnamomum cassia bark-derived component on nitric oxide synthase. Journal of Agricultural and Food Chemistry 2002; 50: 7700-7703. https://doi.org/10.1021/jf020751f##Lee H J, Hyun E-A, Yoon W J, Kim B H, Rhee M H, Kang H K, et al. In vitro anti-inflammatory and anti-oxidative effects of Cinnamomum camphora extractsJournal of Ethnopharmacology 2006; 103: 208-216. https://doi.org/10.1016/j.jep.2005.08.009##Li W, Zhi W, Zhao J, Li W, Zang L, Liu F, et al. Cinnamaldehyde attenuates atherosclerosis: Via targeting the IκB/NF-κB signaling pathway in high fat diet-induced ApoE-/- mice. Food & Function 2019; 10: 4001-4009. https://doi.org/10.1039/C9FO00396G##Lin C-T, Chen C-J, Lin T-Y, Tung JC, Wang S-Y. Anti-inflammation activity of fruit essential oil from Cinnamomum insularimontanum Hayata. Bioresource Technology 2008; 99: 8783-8787. https://doi.org/10.1016/j.biortech.2008.04.041##Mahmoodnia L, Aghadavod E, Rafieian-Kopaei M. Ameliorative impact of cinnamon against high blood pressure; an updated review. Journal of Renal Injury Prevention 2017; 6: 171-176. https://doi.org/10.15171/jrip.2017.33##Mathew S, Abraham T E. In vitro antioxidant activity and scavenging effects of Cinnamomum verum leaf extract assayed by different methodologies. Food and Chemical Toxicology 2006; 44: 198-206. https://doi.org/10.1016/j.fct.2005.06.013##Miguel M G. Antioxidant and anti-inflammatory activities of essential oils: a short review. Molecules 2010; 15: 9252-9287. https://doi.org/10.3390/molecules15129252##Mitrani R D, Dabas N, Goldberger J J. COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm 2020; 17: 1984-1990. https://doi.org/10.1016/j.hrthm.2020.06.026##Noori S, Azmat M, Mahboob T. Study on antioxidant effects of cinnamon and garlic extract in liver, kidney and heart tissue of rat. Bioscience Research 2012; 9: 17-22.##Pelaia C, Tinello C, Vatrella A, De Sarro G, Pelaia G. Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications. Therapeutic Advances in Respiratory Disease 2020; 14: 1-9. https://doi.org/10.1177/1753466620933508##Penckofer S, Schwertz D, Florczak K. Oxidative stress and cardiovascular disease in type 2 diabetes: the role of antioxidants and pro-oxidants. Journal of Cardiovascular Nursing 2002; 16: 68-85. https://doi.org/10.1097/00005082-200201000-00007##Peng X, Cheng K W, Ma J, Chen B, Ho C T, Lo C, et al. Cinnamon bark proanthocyanidins as reactive carbonyl scavengers to prevent the formation of advanced glycation endproducts. Journal of Agricultural and Food Chemistry 2008; 56: 1907-1911. https://doi.org/10.1021/jf073065v##Petrocelli G, Farabegoli F, Valerii M C, Giovannini C, Sardo A, Spisni E. Molecules present in plant essential oils for prevention and treatment of colorectal cancer (Crc). Molecules 2021; 26: 1-12. https://doi.org/10.3390/molecules26040885 ##Ping H, Zhang G, Ren G. Antidiabetic effects of cinnamon oil in diabetic KK-Ay mice. Food and Chemical Toxicology 2010; 48: 2344-2349. https://doi.org/10.1016/j.fct.2010.05.069##Plata-Rueda A, Campos J M, da Silva Rolim G, Martínez L C, Dos Santos M H, Fernandes FL, et al. Terpenoid constituents of cinnamon and clove essential oils cause toxic effects and behavior repellency response on granary weevil, Sitophilus granarius. Ecotoxicology and Environmental Safety. 2018; 156: 263-270. https://doi.org/10.1016/j.ecoenv.2018.03.033##Prakash B, Singh P, Yadav S, Singh S C, Dubey N K. Safety profile assessment and efficacy of chemically characterized Cinnamomum glaucescens essential oil against storage fungi, insect, aflatoxin secretion and as antioxidant. Food and Chemical Toxicology 2013; 53: 160-167. https://doi.org/10.1016/j.fct.2012.11.044##Ramazani E, YazdFazeli M, Emami S A, Mohtashami L, Javadi B, Asili J, et al. Protective effects of Cinnamomum verum, Cinnamomum cassia and cinnamaldehyde against 6-OHDA-induced apoptosis in PC12 cells. Molecular Biology Reports 2020; 47: 2437-2445. https://doi.org/10.1007/s11033-020-05284-y##Ramazani E, Emami S A, Tayarani-Najaran N, Sahebkar A, Tayarani-Najaran Z. Antiviral plants in view of avicenna’s the canon of medicine and modern medicine against common cold. Natural Products and Human Diseases: Pharmacology, Molecular Targets, and Therapeutic Benefits. 2021: 99-121. https://doi.org/10.1007/978-3-030-73234-9_7##Ranasinghe P, Pigera S, Premakumara G, Galappaththy P, Constantine GR, Katulanda P. Medicinal properties of ‘true’cinnamon (Cinnamomum zeylanicum): a systematic review. BMC Complementary Medicine and Therapies 2013; 13: 1-10. https://doi.org/10.1186/1472-6882-13-275##Roussel A-M, Hininger I, Benaraba R, Ziegenfuss T N, Anderson R A. Antioxidant effects of a cinnamon extract in people with impaired fasting glucose that are overweight or obese. Journal of the American College of Nutrition 2009; 28: 16-21. https://doi.org/10.1080/07315724.2009.10719756##Sahib A S. Anti-diabetic and antioxidant effect of cinnamon in poorly controlled type-2 diabetic Iraqi patients: A randomized, placebo-controlled clinical trial. Journal of Intercultural Ethnopharmacology 2016; 5: 108-113. https://doi.org/10.5455/jice.20160217044511##Salamatian M, Mohammadi V, Abtahi Froushani S M. Ameliorative effects of aqueous cinnamon extract on ulcerative colitis in rats. Physiology and Pharmacology 2019; 23: 140-149.##Schink A, Naumoska K, Kitanovski Z, Kampf C J, Fröhlich-Nowoisky J, Thines E, et al. Anti-inflammatory effects of cinnamon extract and identification of active compounds influencing the TLR2 and TLR4 signaling pathways. Food & Function 2018; 9: 5950-5964. https://doi.org/10.1039/C8FO01286E##Seyed Ahmadi S G, Farahpour M R, Hamishehkar H. Topical application of Cinnamon verum essential oil accelerates infected wound healing process by increasing tissue antioxidant capacity and keratin biosynthesis. Kaohsiung Journal of Medical Sciences 2019; 35: 686-694. https://doi.org/10.1002/kjm2.12120##Shalaby M A, Saifan H Y. Some pharmacological effects of cinnamon and ginger herbs in obese diabetic rats. Journal of Intercultural Ethnopharmacology 2014; 3: 144-149. https://doi.org/10.5455/jice.20140818050741##Sharma P, Jha A B, Dubey R S, Pessarakli M. Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. Journal of Botany 2012; 2012: 217037. https://doi.org/10.1155/2012/217037##Somade O T, Ajayi B O, Adeyi O E, Aina B O, David B O, Sodiya I D. Activation of NF-kB mediates up-regulation of cerebellar and hypothalamic pro-inflammatory chemokines (RANTES and MCP-1) and cytokines (TNF-α, IL-1β, IL-6) in acute edible camphor administration. Scientific African 2019; 5: e00114. https://doi.org/10.1016/j.sciaf.2019.e00114##Taghizadeh M, Hamedifard Z, Jafarnejad S. Effect of garlic supplementation on serum C-reactive protein level: A systematic review and meta-analysis of randomized controlled trials. Phytotherapy Research 2019; 33: 243-252. https://doi.org/10.1002/ptr.6225##Tanaka S, Yoon YH, Fukui H, Tabata M, Akira T, Okano K, et al. Antiulcerogenic compounds isolated from Chinese cinnamon Planta Medica 1989; 55: 245-248. https://doi.org/10.1055/s-2006-961994##Taneja MK. Modified Bhramari Pranayama in Covid 19 Infection. Indian Journal of Otolaryngology 2020; 72: 395-397. https://doi.org/10.1007/s12070-020-01883-0##Tulunay M, Aypak C, Yikilkan H, Gorpelioglu S. Herbal medicine use among patients with chronic diseases. Journal of Intercultural Ethnopharmacology 2015; 4: 217-220. https://doi.org/10.5455/jice.20150623090040##Tung Y-T, Chua M-T, Wang S-Y, Chang S-T. Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresource Technology 2008; 99: 3908-3913. https://doi.org/10.1016/j.biortech.2007.07.050##Tuzcu Z, Orhan C, Sahin N, Juturu V, Sahin K. Cinnamon polyphenol extract inhibits hyperlipidemia and inflammation by modulation of transcription factors in high-fat diet-fed rats. Oxidative Medicine and Cellular Longevity 2017; 2017. https://doi.org/10.1155/2017/1583098##Udayaprakash N K, Ranjithkumar M, Deepa S, Sripriya N, Al-Arfaj AA, Bhuvaneswari S. Antioxidant, free radical scavenging and GC-MS composition of Cinnamomum iners Reinw. ex Blume. Industrial Crops and Products 2015; 69: 175-179 .https://doi.org/10.1016/j.indcrop.2015.02.018##Vallianou N, Tsang C, Taghizadeh M, Davoodvandi A, Jafarnejad S. Effect of cinnamon (Cinnamomum Zeylanicum) supplementation on serum C-reactive protein concentrations: A meta-analysis and systematic review. Complementary Therapies in Medicine 2019; 42: 271-278. https://doi.org/10.1016/j.ctim.2018.12.005##Vetal S, Bodhankar S L, Mohan V, Thakurdesai P A. Anti-inflammatory and anti-arthritic activity of type-A procyanidine polyphenols from bark of Cinnamomum zeylanicum in rats. Food Science and Human Wellness 2013; 2: 59-67. https://doi.org/10.1016/j.fshw.2013.03.003##Wang S-Y, Chen P-F, Chang S-T. Antifungal activities of essential oils and their constituents from indigenous cinnamon (Cinnamomum osmophloeum) leaves against wood decay fungi. Bioresource Technology 2005; 96: 813-818. https://doi.org/10.1016/j.biortech.2004.07.010##Wang F, Pu C, Zhou P, Wang P, Liang D, Wang Q, et al. Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2. Cellular Physiology and Biochemistry 2015; 36: 315-324. https://doi.org/10.1159/000374074##Weiss S R, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiology and Molecular Biology Reviews 2005; 69: 635-664. https://doi.org/10.1128/MMBR.69.4.635-664.2005##Wondrak G T, Villeneuve N F, Lamore S D, Bause A S, Jiang T, Zhang D D. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules 2010; 15: 3338-3355. https://doi.org/10.3390/molecules15053338##Wong Y C, Ahmad-Mudzaqqir M Y, Wan-Nurdiyana W A. Extraction of essential oil from cinnamon (Cinnamomum zeylanicum). Oriental Journal of Chemistry 2014; 30: 37-47. https://doi.org/10.13005/ojc/300105##Woolbright B L, Jaeschke H. Mechanisms of inflammatory liver injury and drug-induced hepatotoxicity. Current Pharmacology Reports 2018; 4: 346-357. https://doi.org/10.1007/s40495-018-0147-0##Wu C-T, Deng J-S, Huang W-C, Shieh P-C, Chung M-I, Huang G-J. Salvianolic acid C against acetaminophen-induced acute liver injury by attenuating inflammation, oxidative stress, and apoptosis through inhibition of the Keap1/Nrf2/HO-1 signaling. Oxidative Medicine and Cellular Longevity 2019; 2019. https://doi.org/10.1155/2019/9056845##Yakhchali M, Taghipour Z, Mirabzadeh Ardakani M, Alizadeh Vaghasloo M, Vazirian M, Sadrai S. Cinnamon and its possible impact on COVID-19: The viewpoint of traditional and conventional medicine. Biomedicine & Pharmacotherapy 2021; 143: 112221-112231. https://doi.org/10.1016/j.biopha.2021.112221##Youn H S, Lee J K, Choi Y J, Saitoh S I, Miyake K, Hwang D H, et al. Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biomedicine & Pharmacotherapy 2008; 75: 494-502. https://doi.org/10.1016/j.bcp.2007.08.033##Yu H-S, Lee S-Y, Jang C-G. Involvement of 5-HT1A and GABAA receptors in the anxiolytic-like effects of Cinnamomum cassia in mice. Pharmacology Biochemistry and Behavior 2007; 87: 164-170. https://doi.org/10.1016/j.pbb.2007.04.013##Yu T, Lee S, Yang W S, Jang H-J, Lee Y J, Kim T W, et al. The ability of an ethanol extract of Cinnamomum cassia to inhibit Src and spleen tyrosine kinase activity contributes to its anti-inflammatory action. Journal of Ethnopharmacology 2012; 139: 566-573. https://doi.org/10.1016/j.jep.2011.11.051##Zhuang M, Jiang H, Suzuki Y, Li X, Xiao P, Tanaka T, et al. Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antiviral Research 2009; 82: 73-81. https://doi.org/10.1016/j.antiviral.2009.02.001##Zu Y, Yu H, Liang L, Fu Y, Efferth T, Liu X, et al. Activities of ten essential oils towards Propionibacterium acnes and PC-3, A-549 and MCF-7 cancer cells. Molecules 2010; 15: 3200-3210. https://doi.org/10.3390/molecules15053200## ##

The effect of Neuropeptide Y Y2 receptor blockade on memory impairment and autophagy in a rat model of Alzheimer’s disease 2 2 Introduction: While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. Some studies suggest that NPY may also play a role in autophagy. In our investigation, we aimed to explore whether NPY and its Y2 receptor inhibitor could influence memory modulation or affect Beclin-1 expression in a rat model of Alzheimer’s disease (AD). NPY may also have a role in autophagy, according to some studies. Methods: Intracerebroventricular (i.c.v) injections of amyloid-beta (Aβ1-42, 2µg/µl/ side) were used to establish an animal model of AD. NPY (10 ng/µl, 10 µl, i.c.v) was administered 30 minutes before the retrieval. Y2 antagonist BIIE-0246 was injected 15 minutes before NPY administration in the targeted groups. BIIE-0246 was used at three different concentrations (20 nM, 200 nM, and 2 µM). Passive avoidance memory and novel object recognition were both evaluated. Subsequently, Beclin-1 protein expression in the hippocampus was determined using western blot analysis. Results: It was found that NPY administration improved passive avoidance and cognitive memory in animals treated with Aβ. Injecting BIIE-0246 before NPY did not reverse the improving effect of NPY on passive avoidance and Novel Object Recognition memories. Furthermore, compared to sham-operated animals, Aβ treatment significantly reduced the hippocampal expression of Beclin-1 protein (P≤0.05), and neither NPY nor NPY Y2 receptor inhibitors affected Beclin-1. Conclusion: In Aβ-induced memory impairment, it is thought that NPY can improve both aversive and cognitive memory. Blocking NPY Y2 receptors with BIIE-0246 did not alter NPY’s memory-enhancing effect 117 127 2023/05/62023/10/22022/12/10 1401/9/19 2023/09/252024/01/172023/11/21 1402/8/30 Esfandiar Esfaniari Esfandiar Esfaniari Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Iran esfaniari.esfandiar19971997@gmail.com Ali Hosseinkhani Ali Hosseinkhani Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Iran alihosseinkhany@gmail.com Samira Rashtiani Samira Rashtiani Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Iran sa.rashtiani67@gmail.com Kambiz Rohampour Kambiz Rohampour Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Iran rohampour@gmail.com Adele Jafari Adele Jafari Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Iran jafari.adele@gmail.com Neuropeptide Y Neuropeptide Y2 receptor Memory Alzheimer’s disease Akanmu M A, Ukponmwan O E, Katayama Y, Honda K. Neuropeptide-Y Y2-receptor agonist, PYY3-36 promotes non-rapid eye movement sleep in rat. Neuroscience Research 2006; 54: 165-170. https://doi.org/10.1016/j.neures.2005.11.006##Ashourpour F, Jafari A, Babaei P. Co-treatment of AMPA endocytosis inhibitor and GluN2B antagonist facilitate consolidation and retrieval of memory impaired by β amyloid peptide. International Journal of Neuroscience 2020: 1-10. https://doi.org/10.1080/00207454.2020.1837800##Aveleira C A, Botelho M, Carmo-Silva S, Pascoal J F, Ferreira-Marques M, Nóbrega C, et al. Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proceedings of the National Academy of Sciences (PNAS) 2015; 112: 1642-1651. https://doi.org/10.1073/pnas.1416609112##Bertocchi I, Mele P, Ferrero G, Oberto A, Carulli D, Eva C. NPY-Y1 receptor signaling controls spatial learning and perineuronal net expression. Neuropharmacology 2021; 184: 108425. https://doi.org/10.1016/j.neuropharm.2020.108425##Borbély E, Scheich B, Helyes Z. Neuropeptides in learning and memory. Neuropeptides 2013; 47: 439-450. https://doi.org/10.1016/j.npep.2013.10.012##Borroto-Escuela D O, Fores R, Pita M, Barbancho M A, Zamorano-Gonzalez P, Casares N G, et al. Intranasal delivery of galanin 2 and neuropeptide Y1 agonists enhanced spatial memory performance and neuronal precursor cells proliferation in the dorsal hippocampus in rats. Frontiers in Pharmacology 2022; 13: 820210. https://doi.org/10.3389/fphar.2022.820210##Botelho M, Cavadas C. Neuropeptide Y: An anti-aging player? Trends in Neurosciences 2015; 38: 701-711. https://doi.org/10.1016/j.tins.2015.08.012##Brothers S P, Saldanha S A, Spicer T P, Cameron M, Mercer B A, Chase P, et al. Selective and brain penetrant neuropeptide Y Y2 receptor antagonists discovered by whole-cell high-throughput screening. Molecular Pharmacology 2010; 77: 46-57. https://doi.org/10.1124/mol.109.058677##Cai H, Cong W N, Ji S, Rothman S, Maudsley S, Martin B. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Current Alzheimer Research 2012; 9: 5-17. https://doi.org/10.2174/156720512799015064##Cannizzaro C, Tel B C, Rose S, Zeng B Y, Jenner P. Increased neuropeptide Y mRNA expression in striatum in Parkinson’s disease. Brain Research Molecular Brain Research 2003; 110: 169-176. https://doi.org/10.1016/S0169-328X(02)00555-7##Carrillo-Mora P, Luna R, Colín-Barenque L. Amyloid beta: multiple mechanisms of toxicity and only some protective effects? Oxidative Medicine and Cellular Longevity 2014; 2014. https://doi.org/10.1155/2014/795375##Croce N, Ciotti M T, Gelfo F, Cortelli S, Federici G, Caltagirone C, et al. Neuropeptide Y protects rat cortical neurons against β-amyloid toxicity and re-establishes synthesis and release of nerve growth factor. ACS Chemical Neuroscience 2012; 3: 312-318. https://doi.org/10.1021/cn200127e##Croce N, Dinallo V, Ricci V, Federici G, Caltagirone C, Bernardini S, et al. Neuroprotective effect of neuropeptide Y against β-amyloid 25-35 toxicity in SH-SY5Y neuroblastoma cells is associated with increased neurotrophin production. Neurodegenerative Diseases 2011; 8: 300-309. https://doi.org/10.1159/000323468##Decressac M, Barker R A. Neuropeptide Y and its role in CNS disease and repair. Experimental Neurology 2012; 238: 265-272. https://doi.org/10.1016/j.expneurol.2012.09.004##Domin H. Neuropeptide Y Y2 and Y5 receptors as potential targets for neuroprotective and antidepressant therapies: Evidence from preclinical studies. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2021; 111: 110349. https://doi.org/10.1016/j.pnpbp.2021.110349##dos Santos V V, Santos D B, Lach G, Rodrigues A L, Farina M, De Lima T C, et al. Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ(1-40)) administration in mice. Behavioural Brain Research 2013; 244: 107-115. https://doi.org/10.1016/j.bbr.2013.01.039##Doze V A, Papay R S, Goldenstein B L, Gupta M K, Collette K M, Nelson B W, et al. Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Molecular Pharmacology 2011; 80: 747-758. https://doi.org/10.1124/mol.111.073734##Duarte-Neves J, de Almeida L P, Cavadas C. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiology of Disease 2016a; 95: 210-224. https://doi.org/10.1016/j.nbd.2016.07.022##Fatoba O, Kloster E, Reick C, Saft C, Gold R, Epplen J T, et al. Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington’s disease. Experimental Neurology 2018; 302: 112-128. https://doi.org/10.1016/j.expneurol.2018.01.001##Fendt M, Bürki H, Imobersteg S, Lingenhöhl K, McAllister K H, Orain D, et al. Fear-reducing effects of intra-amygdala neuropeptide Y infusion in animal models of conditioned fear: an NPY Y1 receptor independent effect. Psychopharmacology (Berl) 2009; 206: 291-301. https://doi.org/10.1007/s00213-009-1610-8##Goswami P, Afjal M A, Akhter J, Mangla A, Khan J, Parvez S, et al. Involvement of endoplasmic reticulum stress in amyloid β. Brain Research Bulletin 2020; 165: 108-117. https://doi.org/10.1016/j.brainresbull.2020.09.022##Gøtzsche C R, Woldbye D P. The role of NPY in learning and memory. Neuropeptides 2016; 55: 79-89. https://doi.org/10.1016/j.npep.2015.09.010##Gupta S, Gautam M, Prasoon P, Kumar R, Ray S B, Kaler Jhajhria S. Involvement of neuropeptide Y in post-incisional nociception in rats. Annals of Neurosciences 2018; 25: 268-276. https://doi.org/10.1159/000495130##Hörmer B A, Verma D, Gasser E, Wieselthaler-Hölzl A, Herzog H, Tasan R O. Hippocampal NPY Y2 receptors modulate memory depending on emotional valence and time. Neuropharmacology 2018; 143: 20-28. https://doi.org/10.1016/j.neuropharm.2018.09.018##Ishida H, Shirayama Y, Iwata M, Katayama S, Yamamoto A, Kawahara R, et al. Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor. Hippocampus 2007; 17: 271-280. https://doi.org/10.1002/hipo.20264##Jaeger P A, Wyss-Coray T. Beclin 1 complex in autophagy and Alzheimer disease. Archives of Neurology 2010; 67: 1181-1184. https://doi.org/10.1001/archneurol.2010.258##Karl T, Chesworth R, Duffy L, Herzog H. Schizophrenia-relevant behaviours in a genetic mouse model for Y2 deficiency. Behavioural Brain Research 2010; 207: 434-440. https://doi.org/10.1016/j.bbr.2009.10.029 ##Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880-884. https://doi.org/10.1038/nature04723 ##Komatsu M, Wang Q J, Holstein G R, Friedrich V L, Iwata J, Kominami E, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proceedings of the National Academy of Sciences (PNAS) 2007; 104: 144891448-144891494. https://doi.org/10.1073/pnas.0701311104##Kornhuber J, Zoicas I. Neuropeptide Y prolongs non-social memory in a brain region- and receptor-specific way in male mice. Neuropharmacology 2020; 175: 108199. https://doi.org/10.1016/j.neuropharm.2020.108199 ##Letra L, Santana I. The influence of adipose tissue on brain development, cognition, and risk of neurodegenerative disorders. Advances in Neurobiology 2017; 19: 151-161. https://doi.org/10.1007/978-3-319-63260-5_6 ##Martel J C, Fournier A, St-Pierre S, Dumont Y, Forest M, Quirion R. Comparative structural requirements of brain neuropeptide Y binding sites and vas deferens neuropeptide Y receptors. Molecular Pharmacology 1990; 38: 494-502. ##Mazrooie R, Rohampour K, Zamani M, Hosseinmardi N, Zeraati M. Intracerebroventricular administration of adiponectin attenuates streptozotocin-induced memory impairment in rats. Physiology International 2017; 104: 150-157. https://doi.org/10.1556/2060.104.2017.1.4 ##Méndez-Couz M, Manahan-Vaughan D, Silva A P, González-Pardo H, Arias J L, Conejo N M. Metaplastic contribution of neuropeptide Y receptors to spatial memory acquisition. Behavioural Brain Research 2021; 396: 112864. https://doi.org/10.1016/j.bbr.2020.112864 ##Michel M C, Beck-Sickinger A, Cox H, Doods H N, Herzog H, Larhammar D, et al. XVI. International union of pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacological Reviews 1998; 50: 143-150.##Minthon L, Edvinsson L, Gustafson L. Correlation between clinical characteristics and cerebrospinal fluid neuropeptide Y levels in dementia of the Alzheimer type and frontotemporal dementia. Alzheimer Disease & Associated Disorders 1996; 10: 197-203. https://doi.org/10.1097/00002093-199601040-00005 ##Mittapalli G K, Roberts E. Ligands of the neuropeptide Y Y2 receptor. Bioorganic & Medicinal Chemistry Letters 2014; 24: 430-441. https://doi.org/10.1016/j.bmcl.2013.11.061 ##Nilsson C L, Brinkmalm A, Minthon L, Blennow K, Ekman R. Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. Peptides 2001; 22: 2105-2112. https://doi.org/10.1016/S0196-9781(01)00571-X ##Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition: Elsevier, 2006.##Perez D M. α1-adrenergic receptors in neurotransmission, synaptic plasticity, and cognition. Frontiers in Pharmacology 2020; 11: 581098. https://doi.org/10.3389/fphar.2020.581098##Persaud S J, Bewick G A. Peptide YY: more than just an appetite regulator. Diabetologia 2014; 57: 1762-1769 .https://doi.org/10.1007/s00125-014-3292-y##Pickens C L, Adams-Deutsch T, Nair S G, Navarre B M, Heilig M, Shaham Y. Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear. Neuroscience 2009; 164: 1398-1406. https://doi.org/10.1016/j.neuroscience.2009.09.079##Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger P A, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. Journal of Clinical Investigation 2008; 118: 2190-2199. https://doi.org/10.1172/JCI33585##Rangani R J, Upadhya M A, Nakhate K T, Kokare D M, Subhedar N K. Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer’s disease. Peptides 2012; 33: 317-328. https://doi.org/10.1016/j.peptides.2012.01.004##Rashtiani S, Goudarzi I, Jafari A, Rohampour K. Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin. Neuroscience Letters 2021a; 749: 135721. https://doi.org/10.1016/j.neulet.2021.135721##Rashtiani S, Goudarzi I, Jafari A, Rohampour K. Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin. Neuroscience Letters 2021b; 749: 135721. https://doi.org/10.1016/j.neulet.2021.135721##Rohn T T, Wirawan E, Brown R J, Harris J R, Masliah E, Vandenabeele P. Depletion of beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiology of Disease 2011; 43: 68-78. https://doi.org/10.1016/j.nbd.2010.11.003##Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Medical Principles and Practice 2015; 24: 1-10. https://doi.org/10.1159/000369101##Shende P, Desai D. Physiological and therapeutic roles of neuropeptide Y on biological functions. Advances in Experimental Medicine and Biology 2020; 1237: 37-47. https://doi.org/10.1007/5584_2019_427##Silva A P, Pinheiro P S, Carvalho A P, Carvalho C M, Jakobsen B, Zimmer J, et al. Activation of neuropeptide Y receptors is neuroprotective against excitotoxicity in organotypic hippocampal slice cultures. FASEB journal 2003; 17: 1118-1120. https://doi.org/10.1096/fj.02-0885fje##Śmiałowska M, Domin H, Zięba B, Koźniewska E, Michalik R, Piotrowski P, et al. Neuroprotective effects of neuropeptide Y-Y2 and Y5 receptor agonists in vitro and in vivo. Neuropeptides 2009; 43: 235-249. https://doi.org/10.1016/j.npep.2009.02.002##Smiałowska M, Wierońska J M, Szewczyk B. Neuroprotective effect of NPY on kainate neurotoxicity in the hippocampus. Polish journal of pharmacology 2003; 55: 979-986.##Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E, et al. Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. Journal of Biological Chemistry 2016; 291: 1905-1920. https://doi.org/10.1074/jbc.M115.678185##Stanić D, Mulder J, Watanabe M, Hökfelt T. Characterization of NPY Y2 receptor protein expression in the mouse brain. II. Coexistence with NPY, the Y1 receptor, and other neurotransmitter-related molecules. Journal of Comparative Neurology 2011; 519: 1219-1257. https://doi.org/10.1002/cne.22608##van Wamelen D J, Aziz N A, Anink J J, Roos R A, Swaab D F. Neuropeptide alterations in the infundibular nucleus of Huntington’s disease patients. Journal of Neuroendocrinology 2013; 25: 198-205. https://doi.org/10.1111/j.1365-2826.2012.02379.x##Verma D, Tasan R O, Herzog H, Sperk G. NPY controls fear conditioning and fear extinction by combined action on Y1 and Y2 receptors. British Journal of Pharmacology 2012; 166: 1461-1473. https://doi.org/10.1111/j.1476-5381.2012.01872.x##Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Molecular Cell 2008; 30: 678-688. https://doi.org/10.1016/j.molcel.2008.06.001##Xapelli S, Silva A P, Ferreira R, Malva J O. Neuropeptide Y can rescue neurons from cell death following the application of an excitotoxic insult with kainate in rat organotypic hippocampal slice cultures. Peptides 2007; 28: 288-294. https://doi.org/10.1016/j.peptides.2006.09.031##Xu H D, Qin Z H. Beclin 1, Bcl-2 and autophagy. Advances in Experimental Medicine and Biology 2019; 1206: 109-126. https://doi.org/10.1007/978-981-15-0602-4_5##Zhang L, Bijker M S, Herzog H. The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. Pharmacology & Therapeutics 2011; 131: 91-113. https://doi.org/10.1016/j.pharmthera.2011.03.011## ##

Insulin and toll-like receptor 4 interaction in the rat model of Parkinson’s disease induced by lipopolysaccharide 2 2 Introduction: Toll-like receptor (TLR) 4 is involved in neuroinflammatory processes in peripheral tissues and central nervous system. Pro-inflammatory cytokines production, due to over activation of TLR4, interfere with insulin signaling elements lead to insulin resistance. Regarding the critical roles of TLR4 and insulin in the pathogenesis of Parkinson’s disease (PD), in the present study the TLR4/insulin receptor interaction was assessed in a neuroinflammation model of PD. Methods: LPS was injected into the right striatum of male Wistar rats (20µg/rat). Insulin (2.5IU/ day), insulin receptor antagonist (S961; 6.5nM/kg), or TLR4 antibody (Resatorvid (TAK242); 0.01µg/rat) were administered intracerebroventricularly (ICV) for 14 days. Insulin and TAK242 were also simultaneously injected in a distinct group. Behavioral assessments were performed using rotarod, apomorphine-induced rotation, and cylinder tests. The levels of α-synuclein, TLR4, and elements of the insulin signaling pathway were measured in the striatum. Results: LPS impaired motor performance of the animals and increased the levels of α-synuclein and TLR4. Furthermore, it reduced mRNA levels of IRS1 and IRS2 and enhanced GSK3β mRNA and protein levels, indicating the development of insulin resistance. Treatment with insulin and TAK 242 improved motor deficits, restored insulin signaling pathway, and reduced α-synuclein and TLR4 levels. Conclusion: The findings indicate that LPS impaired motor function, at least in part, via α-synuclein and TLR4 overexpression, leading to insulin resistance. Suppression of TLR4 and activation of insulin receptors attenuated motor deficits, suggesting that TLR4 and insulin receptors are promising therapeutic targets for PD modification. 128 140 2023/05/62023/10/22022/12/102023/10/4 1402/7/12 2023/09/252024/01/172023/11/212023/12/18 1402/9/27 Fatemeh Hemmati Fatemeh Hemmati Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran lhemmati7@gmail.com Neda Valian Neda Valian Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran mn.valian281@yahoo.com Abolhassan Ahmadiani Abolhassan Ahmadiani Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran aahmadiani@yahoo.com Zahurin Mohamed Zahurin Mohamed Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia Malaysia zahurin@ummc.edu.my Raymond Azman Ali Raymond Azman Ali Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia Malaysia raymond@ppukm.ukm.my Norlinah Mohamed Ibrahim Norlinah Mohamed Ibrahim Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia Malaysia norlinah@ppukm.ukm.edu.my Seyed Farshad Hosseini Shirazi Seyed Farshad Hosseini Shirazi Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran farshadshirazisbmu7@gmail.com Parkinson’s disease Insulin Lipopolysaccharide TLR4 TAK242 Akhtar A, Sah S P. Insulin signaling pathway and related molecules: role in neurodegeneration and Alzheimer’s disease. Neurochemistry international 2020; 135: 104707. https://doi.org/10.1016/j.neuint.2020.104707##Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: a new target for disease modification? Progress in neurobiology 2016; 145: 98-120. https://doi.org/10.1016/j.pneurobio.2016.10.001##Balakumar M, Saravanan N, Prabhu D, Regin B, Reddy G B, Mohan V, et al. Benefits of early glycemic control by insulin on sensory neuropathy and cataract in diabetic rats. 2013.##Banks W A, Owen J B, Erickson M A. Insulin in the brain: there and back again. Pharmacology & Therapeutics 2012; 136: 82-93. https://doi.org/10.1016/j.pharmthera.2012.07.006##Bellini M J, Hereñú C B, Goya R G, Garcia-Segura L M. Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide. Journal of Neuroinflammation 2011; 8: 1-13. https://doi.org/10.1186/1742-2094-8-21##Bendor J T, Logan T P, Edwards R H. The function of α-synuclein. Neuron 2013; 79: 1044-1066. https://doi.org/10.1016/j.neuron.2013.09.004##Bowman C C, Rasley A, Tranguch S L, Marriott I. Cultured astrocytes express toll-like receptors for bacterial products. Glia 2003; 43: 281-291. https://doi.org/10.1002/glia.10256##Chinta S J, Mallajosyula J K, Rane A, Andersen J K. Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neuroscience Letters 2010; 486: 235-239. https://doi.org/10.1016/j.neulet.2010.09.061##Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PloS One 2013; 8: e55375. https://doi.org/10.1371/journal.pone.0055375##Copps K, White M. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012; 55: 2565-2582. https://doi.org/10.1007/s00125-012-2644-8##da Conceição F S, Ngo-Abdalla S, Houzel J-C, Rehen S K. Murine model for Parkinson’s disease: from 6-OH dopamine lesion to behavioral test. JoVE (Journal of Visualized Experiments) 2010: e1376. https://doi.org/10.3791/1376##Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker R A, et al. Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson’s disease. International Journal of Neuropsychopharmacology 2015; 18. https://doi.org/10.1093/ijnp/pyu103##Duka T, Duka V, Joyce J N, Sidhu A. α-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models. The FASEB Journal 2009; 23: 2820-2830. https://doi.org/10.1096/fj.08-120410##Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, et al. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 2013; 61: 349-360. https://doi.org/10.1002/glia.22437##Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Molecular Neurobiology 2013; 47: 145-171. https://doi.org/10.1007/s12035-012-8339-9##Gorecki A M, Anyaegbu C C, Anderton R S. TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut. Translational Neurodegeneration 2021; 10: 1-19. https://doi.org/10.1186/s40035-021-00271-0##Heidari A, Yazdanpanah N, Rezaei N. The role of Toll-like receptors and neuroinflammation in Parkinson’s disease. Journal of Neuroinflammation 2022; 19: 1-21. https://doi.org/10.1186/s12974-022-02496-w##Heras-Sandoval D, Pérez-Rojas J M, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cellular Signalling 2014; 26: 2694-2701. https://doi.org/10.1016/j.cellsig.2014.08.019##Huang N-Q, Jin H, Zhou S-y, Shi J-s, Jin F. TLR4 is a link between diabetes and Alzheimer’s disease. Behavioural Brain Research 2017; 316: 234-244. https://doi.org/10.1016/j.bbr.2016.08.047##Hughes C D, Choi M L, Ryten M, Hopkins L, Drews A, Botía J A, et al. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis. Acta Neuropathologica 2019; 137: 103-120. https://doi.org/10.1007/s00401-018-1919-7##Hunter R L, Dragicevic N, Seifert K, Choi D Y, Liu M, Kim H C, et al. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. Journal of Neurochemistry 2007; 100: 1375-1386. https://doi.org/10.1111/j.1471-4159.2006.04327.x##Iravanpour F, Dargahi L, Rezaei M, Haghani M, Heidari R, Valian N, et al. Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6-OHDA model of Parkinson’s disease. CNS Neuroscience & Therapeutics 2021; 27: 308-319. https://doi.org/10.1111/cns.13609##Kam T-I, Hinkle J T, Dawson T M, Dawson V L. Microglia and astrocyte dysfunction in parkinson’s disease. Neurobiology of Disease 2020; 144: 105028. https://doi.org/10.1016/j.nbd.2020.105028##Kim B, Feldman E L. Insulin resistance in the nervous system. Trends in Endocrinology & Metabolism 2012; 23: 133-141. https://doi.org/10.1016/j.tem.2011.12.004##Kim J J, Sears D D. TLR4 and insulin resistance. Gastroenterology Research and Practice 2010; 2010. https://doi.org/10.1155/2010/212563##Kim Y S, Joh T H. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Experimental & Molecular Medicine 2006; 38: 333-347. https://doi.org/10.1038/emm.2006.40##Knudsen L, Hansen B F, Jensen P, Pedersen T Å, Vestergaard K, Schäffer L, et al. Agonism and antagonism at the insulin receptor. PloS One 2012; 7: e51972. https://doi.org/10.1371/journal.pone.0051972##La Vitola P, Balducci C, Baroni M, Artioli L, Santamaria G, Castiglioni M, et al. Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson’s models. Neuropathology and Applied Neurobiology 2021; 47: 43-60. https://doi.org/10.1111/nan.12644##Li D W, Liu Z Q, Chen W, Yao M, Li G R. Association of glycogen synthase kinase‑3β with Parkinson’s disease. Molecular Medicine Reports 2014; 9: 2043-2050. https://doi.org/10.3892/mmr.2014.2080##Li N, Zhang X, Dong H, Zhang S, Sun J, Qian Y. Lithium ameliorates LPS-induced astrocytes activation partly via inhibition of toll-like receptor 4 expression. Cellular Physiology and Biochemistry 2016; 38: 714-725. https://doi.org/10.1159/000443028##Liu M, Bing G. Lipopolysaccharide animal models for Parkinson’s disease. Parkinson’s Disease 2011; 2011. https://doi.org/10.4061/2011/327089##Lv Y-Q, Yuan L, Sun Y, Dou H-W, Su J-H, Hou Z-P, et al. Long-term hyperglycemia induces α-synuclein aggregation and dopaminergic neuronal loss in parkinson’s disease mouse model. Translational Neurodegeneration 2021; 11:14. https://doi.org/10.21203/rs.3.rs-961629/v1##Ma L, Wang J, Li Y. Insulin resistance and cognitive dysfunction. Clinica Chimica Acta 2015; 444: 18-23. https://doi.org/10.1016/j.cca.2015.01.027##Maciejczyk M, Żebrowska E, Chabowski A. Insulin resistance and oxidative stress in the brain: what’s new? International Journal of Molecular Sciences 2019; 20: 874. https://doi.org/10.3390/ijms20040874##Martinez P A. Evaluation of Biogenic Aldehydes as Therapeutic Targets in Parkinson’S Disease. Current Opinion in Toxicology 2019.##Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T. Interleukin (IL)-1β, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neuroscience Letters 1996; 211: 13-16. https://doi.org/10.1016/0304-3940(96)12706-3##Mollenhauer B, Zimmermann J, Sixel-Döring F, Focke N K, Wicke T, Ebentheuer J, et al. Baseline predictors for progression 4 years after Parkinson’s disease diagnosis in the De Novo Parkinson Cohort (DeNoPa). Movement Disorders 2019; 34: 67-77. https://doi.org/10.1002/mds.27492##Moon H C, Won S Y, Kim E G, Kim H K, Cho C B, Park Y S. Effect of optogenetic modulation on entopeduncular input affects thalamic discharge and behavior in an AAV2-α-synuclein-induced hemiparkinson rat model. Neuroscience Letters 2018; 662: 129-135. https://doi.org/10.1016/j.neulet.2017.10.019##Morris J, Bomhoff G, Gorres B, Davis V, Kim J, Lee P-P, et al. Insulin resistance impairs nigrostriatal dopamine function. Experimental Neurology 2011; 231: 171-180. https://doi.org/10.1016/j.expneurol.2011.06.005##Niu H, Wang Q, Zhao W, Liu J, Wang D, Muhammad B, et al. IL-1β/IL-1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha-Synuclein pathology in the olfactory bulb, substantia nigra and striatum. Brain Pathology 2020; 30: 1102-1118. https://doi.org/10.1111/bpa.12886##Oliynyk Z, Marynchenko A, Rudyk M, Dovbynchuk T, Dzyubenko N, Tolstanova G. Functional changes in peripheral phagocytes in rats with LPS-induced Parkinson’s Disease. Mugla Journal of Science and Technology 2021; 7: 73-78. https://doi.org/10.22531/muglajsci.957174##Ou R, Wei Q, Hou Y, Zhang L, Liu K, Lin J, et al. Effect of diabetes control status on the progression of Parkinson’s disease: A prospective study. Annals of Clinical and Translational Neurology 2021; 8: 887-897. https://doi.org/10.1002/acn3.51343##Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N, Niccolini F, et al. Diabetes mellitus and Parkinson disease. Neurology 2018; 90: 1654-1662. https://doi.org/10.1212/WNL.0000000000005475##Perez-Pardo P, Dodiya H B, Engen P A, Forsyth C B, Huschens A M, Shaikh M, et al. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 2019; 68: 829-843. https://doi.org/10.1136/gutjnl-2018-316844##Pignalosa F C, Desiderio A, Mirra P, Nigro C, Perruolo G, Ulianich L, et al. Diabetes and cognitive impairment: a role for glucotoxicity and dopaminergic dysfunction. International Journal of Molecular Sciences 2021; 22: 12366. https://doi.org/10.3390/ijms222212366##Qin X-Y, Zhang S-P, Cao C, Loh Y P, Cheng Y. Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis. JAMA Neurology 2016; 73: 1316-1324. https://doi.org/10.1001/jamaneurol.2016.2742##Ramalingam M, Kim S-J. Protective effects of activated signaling pathways by insulin on C6 glial cell model of MPP+-induced Parkinson’s disease. Journal of Receptors and Signal Transduction 2017; 37: 100-107. https://doi.org/10.3109/10799893.2016.1171342##Rannikko E H, Weber S S, Kahle P J. Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neuroscience 2015; 16: 1-11. https://doi.org/10.1186/s12868-015-0192-0##Sandyk R. The relationship between diabetes mellitus and Parkinson’s disease. International Journal of Neuroscience 1993; 69: 125-130. https://doi.org/10.3109/00207459309003322##Sarkar S, Davies J E, Huang Z, Tunnacliffe A, Rubinsztein D C. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. Journal of Biological Chemistry 2007; 282: 5641-5652. https://doi.org/10.1074/jbc.M609532200##Sharma S, Taliyan R. High fat diet feeding induced insulin resistance exacerbates 6-OHDA mediated neurotoxicity and behavioral abnormalities in rats. Behavioural Brain Research 2018; 351: 17-23. https://doi.org/10.1016/j.bbr.2018.05.025##Shukuri M, Uchino M, Sakamaki T, Onoe S, Hosoi R, Todoroki K, et al. Ex vivo imaging and analysis of ROS generation correlated with microglial activation in rat model with acute neuroinflammation induced by intrastriatal injection of LPS. Biochemical and Biophysical Research Communications 2021; 584: 101-106. https://doi.org/10.1016/j.bbrc.2021.11.008##Song J, Kim J. Degeneration of dopaminergic neurons due to metabolic alterations and Parkinson’s disease. Frontiers in Aging Neuroscience 2016; 8: 65. https://doi.org/10.3389/fnagi.2016.00065##Speed N, Saunders C, Davis A R, Owens W A, Matthies H J, Saadat S, et al. Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding. PloS One 2011; 6: e25169. https://doi.org/10.1371/journal.pone.0025169##Suzuki Y, Hattori K, Hamanaka J, Murase T, Egashira Y, Mishiro K, et al. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Scientific Reports 2012; 2: 896. https://doi.org/10.1038/srep00896##Tain L S, Mortiboys H, Tao R N, Ziviani E, Bandmann O, Whitworth A J. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience 2009; 12: 1129-1135. https://doi.org/10.1038/nn.2372##Tufekci K U, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinson’s Disease 2011; 2011. https://doi.org/10.4061/2011/487450##Vargas A M, Rivera-Rodriguez D E, Martinez L R. Methamphetamine alters the TLR4 signaling pathway, NF-κB activation, and pro-inflammatory cytokine production in LPS-challenged NR-9460 microglia-like cells. Molecular Immunology 2020; 121: 159-166. https://doi.org/10.1016/j.molimm.2020.03.013##Vijiaratnam N, Girges C, Auld G, Chau M, Maclagan K, King A, et al. Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson’s disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The ‘Exenatide-PD3’study. BMJ Open 2021; 11: e047993. https://doi.org/10.1136/bmjopen-2020-047993##Vikram A, Jena G. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats. Biochemical and Biophysical Research Communications 2010; 398: 260-265. https://doi.org/10.1016/j.bbrc.2010.06.070##Yang Y-W, Hsieh T-F, Li C-I, Liu C-S, Lin W-Y, Chiang J-H, et al. Increased risk of Parkinson disease with diabetes mellitus in a population-based study. Medicine 2017; 96. https://doi.org/10.1097/MD.0000000000005921## ##

Combined metformin and insulin therapy improves neurocognitive dysfunction in type 2 diabetic rat model via anti-inflammatory and antioxidant mechanisms 2 2 Introduction: Improper glycemic control is associated with diabetic cognitive dysfunction. Several studies have confirmed the neuroprotective effects of metformin and insulin. This study aimed to investigate the effects of metformin and/or insulin therapy on neurocognitive functions in a type 2 diabetes mellitus (T2DM) rat model. Methods: Fifty adult male Wistar rats were used in this study and had free access to water and a normal chow diet. After an acclimatization period, 10 rats were kept on a normal chow diet and considered as the control group. T2DM was induced in the other 40 rats by a high-fat diet and low-dose streptozotocin method. Then, diabetic rats were randomly allocated into 4 equal groups: Non-treated diabetic group; Metformin-treated diabetic group (treated with metformin 250 mg/kg/day for 6 weeks); Insulin-treated diabetic group (treated with NPH insulin 40 U/kg for 6 weeks); and Metformin and insulin-treated diabetic group. Neurocognitive functions were assessed by footprint assay, Y-maze, open field test, and Morris water maze. Glycaemic profile, serum levels of amyloid A, interleukin-18, and nuclear factor-kappa B were analyzed. Brain malondialdehyde and total antioxidant capacity were measured. A histopathological examination of the frontal lobe was performed. Results: Treatment with metformin and/or insulin significantly improved the impaired neurocognitive dysfunction, brain oxidative stress, changes in biochemical parameters, and the associated histopathological changes in the frontal cortex of diabetic rats. The combined therapy showed a better effect than either monotherapy alone. Conclusion: Metformin and insulin therapy may be valuable for the prevention of neurocognitive dysfunction in T2DM. 141 156 2023/05/62023/10/22022/12/102023/10/42023/09/7 1402/6/16 2023/09/252024/01/172023/11/212023/12/182024/01/17 1402/10/27 Heba Rady Salem Heba Rady Salem Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Egypt heba.saelm.12@med.menofia.edu.eg Gergess S. Hanna Gergess S. Hanna Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Egypt hannagergess77@gmail.com Mohammed H. Hassan Mohammed H. Hassan Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Egypt drhanafy56@gmail.com Safaa El-kotb Safaa El-kotb Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Egypt Safaa_kotb48@yahoo.com Samar Rashad Samar Rashad Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Egypt drsamarrashad90@gmail.com Rania Ibrahim Yassien Rania Ibrahim Yassien Histology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt Egypt raniayassien@yahoo.com Mahmoud Selim Mahmoud Selim Internal Medicine Department, Faculty of Medicine, Tanta University, Egypt Egypt Mahmoud.saleem@med.tanta.edu.eg Ghada Samir Amer Ghada Samir Amer Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt Egypt ghada.amer@med.menofia.edu.eg Diabetes mellitus Memory Metformin NF-kB Oxidative stress Alzamily A A, Obaid K M, Al-Azzawi B. Metformin may ameliorate inflammatory events of IL-18 in some inflammatory conditions. Immunity 2021; 3: 4. https://doi.org/10.31482/mmsl.2021.039##Bădescu S, Tătaru C, Kobylinska L, Georgescu E, Zahiu D, Zăgrean A, et al. Effects of caffeine on locomotor activity in streptozotocin-induced diabetic rats. Journal of medicine and life 2016; 9: 275.##Baker C, Retzik-Stahr C, Singh V, Plomondon R, Anderson V, Rasouli N. Should metformin remain the first-line therapy for treatment of type 2 diabetes? Therapeutic Advances in Endocrinology and Metabolism 2021; 12: 2042018820980225. https://doi.org/10.1177/2042018820980225##Baptista M G, Ferreira C G, Albuquerque Y M, D’assunção C G, Alves R C, Wanderley-Teixeira V, et al. Histomorphometric and immunohistochemical evaluation of the frontal cerebral cortex in diabetic rats after treatment with melatonin. Pesquisa Veterinária Brasileira 2021; 40: 1077-1087. https://doi.org/10.1590/1678-5150-pvb-6421##Biessels G J, Whitmer R A. Cognitive dysfunction in diabetes: how to implement emerging guidelines. Diabetologia 2020; 63: 3-9. https://doi.org/10.1007/s00125-019-04977-9##Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain, Behavior, and Immunity 2008; 22: 487-492. https://doi.org/10.1016/j.bbi.2007.10.001##Bracchi-Ricard V, Brambilla R, Levenson J, Hu W H, Bramwell A, Sweatt J D, et al. Astroglial nuclear factor-κB regulates learning and memory and synaptic plasticity in female mice. Journal of Neurochemistry 2008; 104: 611-623. https://doi.org/10.1111/j.1471-4159.2007.04993.x##Brooks S P, Trueman R C, Dunnett S B. Assessment of motor coordination and balance in mice using the rotarod, elevated bridge, and footprint tests. Current Protocols in Mouse Biology 2012; 2: 37-53. https://doi.org/10.1002/9780470942390.mo110165##Chao P-C, Li Y, Chang C-H, Shieh J P, Cheng J-T, Cheng K-C. Investigation of insulin resistance in the popularly used four rat models of type-2 diabetes. Biomedicine & Pharmacotherapy 2018; 101: 155-161. https://doi.org/10.1016/j.biopha.2018.02.084##Chavoshinezhad S, Kouchesfahani H M, Ahmadiani A, Dargahi L. Interferon beta ameliorates cognitive dysfunction in a rat model of Alzheimer’s disease: Modulation of hippocampal neurogenesis and apoptosis as underlying mechanism. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2019; 94: 109661. https://doi.org/10.1016/j.pnpbp.2019.109661##Chen H, Sullivan G, Yue L Q, Katz A, Quon M J. QUICKI is a useful index of insulin sensitivity in subjects with hypertension. American Journal of Physiology-Endocrinology and Metabolism 2003; 284: E804-E812. https://doi.org/10.1152/ajpendo.00330.2002##Chen Q, Xie D, Yao Q, Yang L. Effect of metformin on locomotor function recovery in rat spinal cord injury model: a meta-analysis. Oxidative Medicine and Cellular Longevity 2021; 2021. https://doi.org/10.1155/2021/1948003##Correia S, Carvalho C, Santos M S, Proença T, Nunes E, Duarte A I, et al. Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med Chem 2008; 4: 358-64. https://doi.org/10.2174/157340608784872299##Cui Y, Tang T Y, Lu C Q, Ju S. Insulin resistance and cognitive impairment: evidence from neuroimaging. Journal of Magnetic Resonance Imaging 2022; 56: 1621-1649. https://doi.org/10.1002/jmri.28358##Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, et al. Insulin inhibits intranuclear nuclear factor κB and stimulates IκB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? The Journal of Clinical Endocrinology & Metabolism 2001; 86: 3257-3265. https://doi.org/10.1210/jcem.86.7.7623##Dong X, Kong L, Huang L, Su Y, Li X, Yang L, et al. Ginsenoside Rg1 treatment protects against cognitive dysfunction via inhibiting PLC-CN-NFAT1 signaling in T2DM mice. Journal of Ginseng Research 2023; 47: 458-468. https://doi.org/10.1016/j.jgr.2022.12.006##Ertas B, Hazar-Yavuz A N, Topal F, Keles-Kaya R, Karakus Ö, Ozcan G S, et al. Rosa canina L. improves learning and memory-associated cognitive impairment by regulating glucose levels and reducing hippocampal insulin resistance in high-fat diet/streptozotocin-induced diabetic rats. Journal of Ethnopharmacology 2023: 116541. https://doi.org/10.1016/j.jep.2023.116541##Evans M C, Rizwan M Z, Anderson G M. Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice. Endocrinology 2014; 155: 4368-4379. https://doi.org/10.1210/en.2014-1412##Fischer C P, Perstrup L B, Berntsen A, Eskildsen P, Pedersen B K. Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. Clinical Immunology 2005; 117: 152-160. https://doi.org/10.1016/j.clim.2005.07.008##Furman B L. Streptozotocin-induced diabetic models in mice and rats. Current protocols in pharmacology 2015; 70: 5.47. 1-5.47. 20. https://doi.org/10.1002/0471141755.ph0547s70##Ghasemi A, Jeddi S. Streptozotocin as a tool for induction of rat models of diabetes: A practical guide. EXCLI journal 2023; 22: 274.##Gould T D, Dao D, Kovacsics C. Mood and anxiety related phenotypes in mice: characterization using behavioral tests. Vol 2: Springer, 2009. https://doi.org/10.1007/978-1-60761-303-9##Grover B, Auberger C, Sarangarajan R, Cacini W. Functional impairment of renal organic cation transport in experimental diabetes. Pharmacology & Toxicology 2002; 90: 181-186. https://doi.org/10.1034/j.1600-0773.2002.900402.x##Gupta M, Pandey S, Rumman M, Singh B, Mahdi A A. Molecular mechanisms underlying hyperglycemia associated cognitive decline. IBRO Neuroscience Reports 2023; 14: 57-63. https://doi.org/10.1016/j.ibneur.2022.12.006##Henderson A D, Johnson A W, Ridge S T, Egbert J S, Curtis K P, Berry L J, et al. Diabetic gait is not just slow gait: gait compensations in diabetic neuropathy. Journal of Diabetes Research 2019; 2019. https://doi.org/10.1155/2019/4512501##Herman R, Kravos N A, Jensterle M, Janež A, Dolžan V. Metformin and insulin resistance: a review of the underlying mechanisms behind changes in GLUT4-mediated glucose transport. International Journal of Molecular Sciences 2022; 23: 1264. https://doi.org/10.3390/ijms23031264##Hurlock E C, Bose M, Pierce G, Joho R H. Rescue of motor coordination by Purkinje cell-targeted restoration of Kv3. 3 channels in Kcnc3-null mice requires Kcnc1. Journal of Neuroscience 2009; 29: 15735-15744. https://doi.org/10.1523/JNEUROSCI.4048-09.2009##Jang S, Jang W Y, Choi M, Lee J, Kwon W, Yi J, et al. Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition. Transgenic Research 2019; 28: 499-508. https://doi.org/10.1007/s11248-019-00166-x##Janthakhin Y, Kingtong S, Aphibanthammakit C, Juntapremjit S. Metformin mitigates memory impairment of diabetic mice through modulation of plasma pro-inflammatory cytokines and Aβ1-42 levels. Chiang Mai University Journal of Natural Sciences 2023; 22: e2023001. https://doi.org/10.12982/NLSC.2023.001##Karvani M, Simos P, Stavrakaki S, Kapoukranidou D. Neurocognitive impairment in type 2 diabetes mellitus. Hormones 2019; 18: 523-534. https://doi.org/10.1007/s42000-019-00128-2##Ke Y, Bu S, Ma H, Gao L, Cai Y, Zhang Y, et al. Preventive and therapeutic effects of astaxanthin on depressive-like behaviors in high-fat diet and streptozotocin-treated rats. Frontiers in Pharmacology 2020; 10: 1621. https://doi.org/10.3389/fphar.2019.01621##Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. The Lancet Neurology 2020; 19: 758-766. https://doi.org/10.1016/S1474-4422(20)30231-3##Kermer P, Liman J, Weishaupt J H, Bähr M. Neuronal apoptosis in neurodegenerative diseases: from basic research to clinical application. Neurodegenerative Diseases 2004; 1: 9-19. https://doi.org/10.1159/000076665##Koekkoek P S, Kappelle L J, van den Berg E, Rutten G E, Biessels G J. Cognitive function in patients with diabetes mellitus: guidance for daily care. The Lancet Neurology 2015; 14: 329-340. https://doi.org/10.1016/S1474-4422(14)70249-2##Kremer M, Becker L J, Barrot M, Yalcin I. How to study anxiety and depression in rodent models of chronic pain? European Journal of Neuroscience 2021; 53: 236-270. https://doi.org/10.1111/ejn.14686##Kumar Datusalia A, Sunder Sharma S. NF-κB inhibition resolves cognitive deficits in experimental type 2 diabetes mellitus through CREB and glutamate/GABA neurotransmitters pathway. Current Neurovascular Research 2016; 13: 22-32. https://doi.org/10.2174/1567202612666151030104810##Łabuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacological Reports 2010; 62: 956-965. https://doi.org/10.1016/S1734-1140(10)70357-1##Leo A, Citraro R, Tallarico M, Iannone M, Fedosova E, Nesci V, et al. Cognitive impairment in the WAG/Rij rat absence model is secondary to absence seizures and depressive-like behavior. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2019; 94: 109652. https://doi.org/10.1016/j.pnpbp.2019.109652##Lin Y, Gong Z, Ma C, Wang Z, Wang K. Relationship between glycemic control and cognitive impairment: A systematic review and meta-analysis. Frontiers in Aging Neuroscience 2023; 15. https://doi.org/10.3389/fnagi.2023.1126183##Liu S, Zheng M, Li Y, He L, Chen T. The protective effect of Geniposide on diabetic cognitive impairment through BTK/TLR4/NF-κB pathway. Psychopharmacology 2020; 237: 465-477. https://doi.org/10.1007/s00213-019-05379-w##Luo A, Xie Z, Wang Y, Wang X, Li S, Yan J, et al. Type 2 diabetes mellitus-associated cognitive dysfunction: advances in potential mechanisms and therapies. Neuroscience & Biobehavioral Reviews 2022: 104642. https://doi.org/10.1016/j.neubiorev.2022.104642##Madhu L N, Kodali M, Shetty A K. Promise of metformin for preventing age-related cognitive dysfunction. Neural Regeneration Research 2022; 17: 503. https://doi.org/10.4103/1673-5374.320971##Magliano D J, Chen L, Islam R M, Carstensen B, Gregg E W, Pavkov M E, et al. Trends in the incidence of diagnosed diabetes: a multicountry analysis of aggregate data from 22 million diagnoses in high-income and middle-income settings. The lancet Diabetes & endocrinology 2021; 9: 203-211. https://doi.org/10.1016/S2213-8587(20)30402-2##Martínez-Tellez R, de Jesús Gómez-Villalobos M, Flores G. Alteration in dendritic morphology of cortical neurons in rats with diabetes mellitus induced by streptozotocin. Brain Research 2005; 1048: 108-115. https://doi.org/10.1016/j.brainres.2005.04.048##Matthews D R, Hosker J P, Rudenski A S, Naylor B, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419. https://doi.org/10.1007/BF00280883##Mehta B K, Nerkar D, Banerjee S. Characterization of peripheral neuropathy in rat model of type 2 diabetes. Indian Journal of Pharmaceutical Education and Research 2017; 51: 92-101. https://doi.org/10.5530/ijper.51.1.13##Muriach M, Flores-Bellver M, Romero F J, Barcia J M. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxidative medicine and cellular longevity 2014; 2014. https://doi.org/10.1155/2014/102158##Neurath M, Becker C, Barbulescu K. Role of NF-κB in immune and inflammatory responses in the gut. Gut 1998; 43: 856-860. https://doi.org/10.1136/gut.43.6.856##Nijboer C H, Heijnen C J, Groenendaal F, Van Bel F, Kavelaars A. Alternate pathways preserve tumor necrosis factor-α production after nuclear factor-κB inhibition in neonatal cerebral hypoxia-ischemia. Stroke 2009; 40: 3362-3368. https://doi.org/10.1161/STROKEAHA.109.560250##Ola M S, Aleisa A M, Al-Rejaie S S, Abuohashish H M, Parmar M Y, Alhomida A S, et al. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurological sciences 2014; 35: 1003-1008. https://doi.org/10.1007/s10072-014-1628-5##Papachristoforou E, Lambadiari V, Maratou E, Makrilakis K. Association of glycemic indices (hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress and diabetic complications. Journal of Diabetes Research 2020; 2020. https://doi.org/10.1155/2020/7489795##Paylor R, Spencer C M, Yuva-Paylor L A, Pieke-Dahl S. The use of behavioral test batteries, II: effect of test interval. Physiology & Behavior 2006; 87: 95-102. https://doi.org/10.1016/j.physbeh.2005.09.002##Piatkowska-Chmiel I, Herbet M, Gawronska-Grzywacz M, Ostrowska-Lesko M, Dudka J. The role of molecular and inflammatory indicators in the assessment of cognitive dysfunction in a mouse model of diabetes. International Journal of Molecular Sciences 2021; 22: 3878. https://doi.org/10.3390/ijms22083878##Qian C, Zhu C, Yu W, Jiang X, Zhang F. High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells. PLoS One 2015; 10: e0136390. https://doi.org/10.1371/journal.pone.0136390##Ren H, Shao Y, Wu C, Ma X, Lv C, Wang Q. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Molecular and Cellular Endocrinology 2020; 500: 110628. https://doi.org/10.1016/j.mce.2019.110628##Rosyadi I, Wahono A T U, Ramadhona E, Hijrati Y N. Acute phase protein serum amyloid a (SAA) profile in diabetic Wistar rats induced streptozotocin. AIP Conference Proceedings 2019; 2099: 020019. https://doi.org/10.1063/1.5098424##Sanna R S, Muthangi S, B.K C S, Devi S A. Grape seed proanthocyanidin extract and insulin prevents cognitive decline in type 1 diabetic rat by impacting Bcl-2 and Bax in the prefrontal cortex. Metabolic Brain Disease 2019; 34: 103-117. https://doi.org/10.1007/s11011-018-0320-5##Scarabino D, Peconi M, Broggio E, Gambina G, Maggi E, Armeli F, et al. Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer’s disease. Experimental Gerontology 2020; 136: 110945. https://doi.org/10.1016/j.exger.2020.110945##Skovsø S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. Journal of Diabetes Investigation 2014; 5: 349-358. https://doi.org/10.1111/jdi.12235##Song Y, Ding W, Bei Y, Xiao Y, Tong H-D, Wang L-B, et al. Insulin is a potential antioxidant for diabetes-associated cognitive decline via regulating Nrf2 dependent antioxidant enzymes. Biomedicine & Pharmacotherapy 2018; 104: 474-484. https://doi.org/10.1016/j.biopha.2018.04.097##Srinivasan K, Viswanad B, Asrat L, Kaul C, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacological Research 2005; 52: 313-320. https://doi.org/10.1016/j.phrs.2005.05.004##Stuss D T, Knight R T. Principles of frontal lobe function: Oxford University Press, 2013. https://doi.org/10.1093/med/9780199837755.001.0001##Suryavanshi S V, Kulkarni Y A. NF-κβ: a potential target in the management of vascular complications of diabetes. Frontiers in Pharmacology 2017; 8: 798. https://doi.org/10.3389/fphar.2017.00798##Suvarna K S, Layton C, Bancroft J D. Bancroft’s theory and practice of histological techniques E-Book: Elsevier Health Sciences, 2018.##Wang F, Guan M, Wei L, Yan H. IL‑18 promotes the secretion of matrix metalloproteinases in human periodontal ligament fibroblasts by activating NF‑κB signaling. Molecular Medicine Reports 2019; 19: 703-710. https://doi.org/10.3892/mmr.2018.9697##Wickramasinghe A S D, Attanayake A P, Kalansuriya P. Biochemical characterization of high fat diet fed and low dose streptozotocin induced diabetic Wistar rat model. Journal of Pharmacological and Toxicological Methods 2022; 113: 107144. https://doi.org/10.1016/j.vascn.2021.107144##Wium-Andersen I, Rungby J, Jørgensen M, Sandbæk A, Osler M, Wium-Andersen M. Risk of dementia and cognitive dysfunction in individuals with diabetes or elevated blood glucose. Epidemiology and Psychiatric Sciences 2020; 29: e43. https://doi.org/10.1017/S2045796019000374##Zhang W, Zhao L, Zhang J, Li P, Lv Z. Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia. Bioengineered 2021; 12: 10982-10993. https://doi.org/10.1080/21655979.2021.2004978##Zhao W Q, Chen H, Quon M J, Alkon D L. Insulin and the insulin receptor in experimental models of learning and memory. European Journal of Pharmacology 2004; 490: 71-81. https://doi.org/10.1016/j.ejphar.2004.02.045##Zheng B, Su B, Price G, Tzoulaki I, Ahmadi-Abhari S, Middleton L. Glycemic control, diabetic complications, and risk of dementia in patients with diabetes: results from a large UK cohort study. Diabetes Care 2021; 44: 1556-1563. https://doi.org/10.2337/dc20-2850## ##

Impact of two-month sodium citrate supplementation along with moderate-intensity continuous training on PGC-1α and Nrf2 expression in diabetic rats 2 2 Introduction: Sports activity increases PGC1α and Nrf2, the regulatory factors of mitochondrial biogenesis. This paper aims to study the impact of two-month sodium citrate supplementation with Moderate-Intensity Continuous Training (MICT) on PGC-1α and Nrf2 expression in diabetic rats. Methods: Forty-five three-month-old male Wistar rats were haphazardly assigned to one of five equal groups (N=9): (1) healthy; (2) diabetic; (3) diabetes + exercise (DE); (4) diabetes+ supplementation (DS); and (5) diabetic + exercise + supplementation (DSE), matched according to their weights. After induction, exercises began on a treadmill for 8 weeks, five days a week. The MICT protocol ran at 70% of their maximum speed for 36 minutes. The rats supplemented with sodium-citrate- at 15 mmol/L in drinking water for two months. PGC-1α and Nrf2 expression were measured through Western blotting in the soleus muscle. Data were analyzed using univariate analysis of variance (ANOVA) and the Tukey post-hoc test. Cohen’s D effect size (ES) was calculated to compare the groups. Results: The results showed that induction of diabetes significantly reduced the expression of PGC-1α (P< 0.001; ES=1.36) and Nrf2 (P<0.088; ES=0.24), while exercise increased PGC-1α expression (P<0.001; ES=0.68). Sodium citrate supplementation, either alone or in combination with MICT activity, did not show a clear advantage for Nrf2 expression. Conclusion: MICT activity and sodium citrate supplementation, by increasing PGC-1α expression, can be considered therapeutic strategies for diabetic patients. However, to increase Nrf2 expression, further studies with different exercise intensities and doses of sodium citrate supplementation are needed. 157 168 2023/05/62023/10/22022/12/102023/10/42023/09/72023/06/22 1402/4/1 2023/09/252024/01/172023/11/212023/12/182024/01/172023/12/18 1402/9/27 Maghsoud Nabilpour Maghsoud Nabilpour Department of Sports Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Ardabil, Iran Iran nabilpour@yahoo.com Farnaz Seifi-Skishahr Farnaz Seifi-Skishahr Department of Sports Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Ardabil, Iran Iran f.seify@yahoo.com Ameneh PourRahim Ameneh PourRahim Department of Sports Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Ardabil, Iran Iran amenehpoorrahim@yahoo.com Hadi Nobari Hadi Nobari Faculty of Sport Sciences, University of Extremadura, Cáceres, Spain Spain hadi.nobari1@gmail.com Diabetic mellitus exercise gene expression KEAP1 protein PPARGC1A protein. Bengal E, Aviram S, Hayek T. p38 MAPK in glucose metabolism of skeletal muscle: Beneficial or harmful? International Journal of Molecular Sciences 2020; 21: 6480. https://doi.org/10.3390/ijms21186480##Chavanelle V, Boisseau N, Otero Y F, Combaret L, Dardevet D, Montaurier C, et al. Effects of high-intensity interval training and moderate-intensity continuous training on glycaemic control and skeletal muscle mitochondrial function in db/db mice. Scientific Reports 2017; 7: 204. https://doi.org/10.1038/s41598-017-00276-8##Chen X, Ji Y, Liu R, Zhu X, Wang K, Yang X, et al. Mitochondrial dysfunction: roles in skeletal muscle atrophy. Journal of Translational Medicine 2023; 21: 503. https://doi.org/10.1186/s12967-023-04369-z##Chen Y, Zhang J, Li P, Liu C, Li L. N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway. Molecular Medicine Reports 2021; 23: 1-1. https://doi.org/10.3892/mmr.2020.11666##Cho N H, Shaw J E, Karuranga S, Huang Y, da Rocha Fernandes J D, Ohlrogge A W, et al. IDF diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Research and Clinical Practice 2018; 138: 271-281. https://doi.org/10.1016/j.diabres.2018.02.023##Corona J C, Duchen M R. PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochemical Research 2015; 40: 308-316. https://doi.org/10.1007/s11064-014-1377-0##Cunha V C R, Aoki M S, Zourdos M C, Gomes R V, Barbosa W P, Massa M, et al. Sodium citrate supplementation enhances tennis skill performance: A crossover, placebo-controlled, double blind study. Journal of the International Society of Sports Nutrition 2019; 16: 32. https://doi.org/10.1186/s12970-019-0297-4##Deng X, Lin N, Fu J, Xu L, Luo H, Jin Y, et al. The Nrf2/PGC1α pathway regulates antioxidant and proteasomal activity to alter cisplatin sensitivity in ovarian cancer. Oxidative Medicine and Cellular Longevity 2020; 2020: 4830418-4830418. https://doi.org/10.1155/2020/4830418##Dinkova-Kostova A T, Abramov A Y. The emerging role of Nrf2 in mitochondrial function. Free Radical Biology and Medicine 2015a; 88: 179-188. https://doi.org/10.1016/j.freeradbiomed.2015.04.036##Gounder S S, Kannan S, Devadoss D, Miller C J, Whitehead K S, Odelberg S J, et al. Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training. PLoS One 2012. https://doi.org/10.1371/annotation/8690bb36-3c5d-48a6-b3be-39a2b50896e1##Granata C, Oliveira R S, Little J P, Renner K, Bishop D J. Sprint-interval but not continuous exercise increases PGC-1α protein content and p53 phosphorylation in nuclear fractions of human skeletal muscle. Scientific Reports 2017; 7: 44227. https://doi.org/10.1038/srep44227##Halling J F, Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications. Applied Physiology, Nutrition, and Metabolism 2020; 45: 927-936. https://doi.org/10.1139/apnm-2020-0005##Handschin C, Rhee J, Lin J, Tarr P T, Spiegelman B M. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proceedings of the National Academy of Sciences 2003; 100: 7111-7116. https://doi.org/10.1073/pnas.1232352100##Heiat F, Ghanbarzadeh M, Ranjbar R, Shojaeifard M. Continuous swimming training arises a remarkable effect on some longevity biomarkers in rat skeletal muscles. Annals of Applied Sport Science 2020; 8.##Holmström K M, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land J M, et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open 2013; 2: 761-770. https://doi.org/10.1242/bio.20134853##Hood D A. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Applied Physiology, Nutrition, and Metabolism 2009; 34: 465-472. https://doi.org/10.1139/H09-045##Kim B. Western blot techniques. Molecular profiling: Methods and Protocols 2017: 133-139. https://doi.org/10.1007/978-1-4939-6990-6_9##Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation 2006; 46: 113-140. https://doi.org/10.1016/j.advenzreg.2006.01.007##Konopka A R, Suer M K, Wolff C A, Harber M P. Markers of human skeletal muscle mitochondrial biogenesis and quality control: effects of age and aerobic exercise training. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 2014; 69: 371-378. https://doi.org/10.1093/gerona/glt107##Kramer H F, Witczak C A, Fujii N, Jessen N, Taylor E B, Arnolds D E, et al. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 2006; 55: 2067-2076. https://doi.org/10.2337/db06-0150##Lancha Junior A H, Painelli Vde S, Saunders B, Artioli G G. Nutritional strategies to modulate intracellular and extracellular buffering capacity during high-intensity exercise. Sports Medicine 2015; 45 Suppl 1: 71-81. https://doi.org/10.1007/s40279-015-0397-5##Lira V A, Benton C R, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. American Journal of Physiology-Endocrinology and Metabolism 2010; 299: 145-161. https://doi.org/10.1152/ajpendo.00755.2009##McGee S L, Hargreaves M. Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 2004; 53: 1208-1214. https://doi.org/10.2337/diabetes.53.5.1208##McGinley C, Bishop D J. Rest interval duration does not influence adaptations in acid/base transport proteins following 10 wk of sprint-interval training in active women. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2017; 312: 702-717. https://doi.org/10.1152/ajpregu.00459.2016##Mootha V K, Lindgren C M, Eriksson K-F, Subramanian A, Sihag S, Lehar J, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 2003; 34: 267-273. https://doi.org/10.1038/ng1180##Mora S, Pessin J E. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. Journal of Biological Chemistry 2000; 275: 16323-16328. https://doi.org/10.1074/jbc.M910259199##Narasimhan M, Hong J, Atieno N, Muthusamy V R, Davidson C J, Abu-Rmaileh N, et al. Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells. Free Radical Biology and Medicine 2014; 71: 402-414. https://doi.org/10.1016/j.freeradbiomed.2014.02.023##Neufer P D. The bioenergetics of exercise. Cold Spring Harbor perspectives in medicine 2018; 8. https://doi.org/10.1101/cshperspect.a029678##Nielsen O B, Ørtenblad N, Lamb G D, Stephenson D G. Excitability of the T-tubular system in rat skeletal muscle: roles of K+ and Na+ gradients and Na+-K+ pump activity. Journal of Physiology 2004a; 557: 133-146. https://doi.org/10.1113/jphysiol.2003.059014##Ou Y, Hou W, Li S, Zhu X, Lin Y, Han J, et al. Sodium citrate inhibits endoplasmic reticulum stress in rats with adenine-induced chronic renal failure. American Journal of Nephrology 2015; 42: 14-21. https://doi.org/10.1159/000437235##Park S, Kim B, Kang S. Interaction effect of PGC-1α rs10517030 variants and energy intake in the risk of type 2 diabetes in middle-aged adults. European Journal of Clinical Nutrition 2017; 71: 1442-1448. https://doi.org/10.1038/ejcn.2017.68##Parry-Billings M, MacLaren D P. The effect of sodium bicarbonate and sodium citrate ingestion on anaerobic power during intermittent exercise. European Journal of Applied Physiology 1986; 55: 524-529. https://doi.org/10.1007/BF00421648##Pilegaard H, Saltin B, Neufer P D. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. Journal of Physiology 2003; 546: 851-858.https://doi.org/10.1113/jphysiol.2002.034850##Rabah H M, Mohamed D A, Mariah R A, Abd El-Khalik S R, Khattab H A, AbuoHashish N A, et al. Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment of letrozole-induced polycystic ovarian syndrome: targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue. Redox Report 2023; 28: 2160569. https://doi.org/10.1080/13510002.2022.2160569##Raciti G A, Iadicicco C, Ulianich L, Vind B F, Gaster M, Andreozzi F, et al. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010; 53: 955-965. https://doi.org/10.1007/s00125-010-1676-1 ##Ramachandran B, Yu G, Gulick T. Nuclear respiratory factor 1 controls myocyte enhancer factor 2A transcription to provide a mechanism for coordinate expression of respiratory chain subunits. Journal of Biological Chemistry 2008; 283: 11935-11946. https://doi.org/10.1074/jbc.M707389200##Requena B, Zabala M, Padial P, Feriche B. Sodium bicarbonate and sodium citrate: ergogenic aids? The Journal of Strength & Conditioning Research 2005; 19: 213-224. https://doi.org/10.1519/00124278-200502000-00036##Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega Á L, Pérez S. PGC-1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxidative Medicine and Cellular Longevity 2020; 2020. https://doi.org/10.1155/2020/1452696##Ruhee R T, Suzuki K. The integrative role of sulforaphane in preventing inflammation, oxidative stress and fatigue: A review of a potential protective phytochemical. Antioxidants (Basel) 2020; 9. https://doi.org/10.3390/antiox9060521##Sergi D, Naumovski N, Heilbronn L K, Abeywardena M, O’Callaghan N, Lionetti L, et al. Mitochondrial (Dys)function and Insulin resistance: From pathophysiological molecular mechanisms to the impact of diet. Frontiers in Physiology 2019; 10: 532. https://doi.org/10.3389/fphys.2019.00532##Sundberg C W, Fitts R H. Bioenergetic basis of skeletal muscle fatigue. Current Opinion in Physiology 2019; 10: 118-127. https://doi.org/10.1016/j.cophys.2019.05.004##Suwa M, Nakano H, Radák Z, Kumagai S. A comparison of chronic AICAR treatment-induced metabolic adaptations in red and white muscles of rats. The Journal of Physiological Sciences 2014; 65: 121-130. https://doi.org/10.1007/s12576-014-0349-0##Taylor E B, Lamb J D, Hurst R W, Chesser D G, Ellingson W J, Greenwood L J, et al. Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: Effects of time and intensity. American Journal of Physiology-Endocrinology and Metabolism 2005; 289: 960-968. https://doi.org/10.1152/ajpendo.00237.2005##Urwin C S, Snow R J, Condo D, Snipe R, Wadley G D, Carr A J. Factors influencing blood alkalosis and other physiological responses, gastrointestinal symptoms, and exercise performance following sodium citrate supplementation: A review. International Journal of Sport Nutrition and Exercise Metabolism 2021; 31: 168-186. https://doi.org/10.1123/ijsnem.2020-0192##Urwin C S, Snow R J, Orellana L, Condo D, Wadley G D, Carr A J. Sodium citrate ingestion protocol impacts induced alkalosis, gastrointestinal symptoms, and palatability. Physiological Reports 2019; 7: 14216. https://doi.org/10.14814/phy2.14216##Wu H, Deng X, Shi Y, Su Y, Wei J, Duan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. Journal of Endocrinology 2016; 229: 99-115. https://doi.org/10.1530/JOE-16-0021##Yavari A, Javadi M, Mirmiran P, Bahadoran Z. Exercise-induced oxidative stress and dietary antioxidants. Asian Journal of Sports Medicine 2015; 6: 24898. https://doi.org/10.5812/asjsm.24898##Zaccardi F, Webb D R, Yates T, Davies M J. Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. Postgraduate Medical Journal 2016; 92: 63-69. https://doi.org/10.1136/postgradmedj-2015-133281##Zhang M, Lv X-Y, Li J, Xu Z-G, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Journal of Diabetes Research 2008; 2008. https://doi.org/10.1155/2008/704045## ##

The evaluation of synergistic effects of combination therapy with sulfasalazine and angiotensin-converting enzyme inhibitor in the treatment of experimental colitis in mice 2 2 Introduction: Intestinal colitis, also known as ulcerative colitis, is an inflammatory bowel disease characterized by long-term inflammation and ulcers in the gastrointestinal tract. It has been suggested that the mucosal expression of angiotensin II (AT-II) is increased in colitis. This study aimed to examine the potential therapeutic effects of combination therapy with Enalapril, an angiotensin-converting enzyme inhibitor, and sulfasalazine (SSZ) in a murine colitis model. Methods: Male C57BL/6 mice were divided into five groups: control group (distilled water), dextran sulphate sodium (DSS) group (colitis group) (1% DSS), SSZ group (positive control group) with 100 mg/kg/day, Enalapril alone group with 4 mg/kg/day, and Enalapril (4 mg/kg/day) + SSZ (100 mg/kg/day) group. Results: There was a significant reduction in the disease activity index among the mice receiving the combination of Enalapril and SSZ compared to the colitis group. Enalapril and SSZ treatment was associated with a lower reduction in colon length, decreased colon weight, spleen weight, and spleen-to-body weight in mice with colitis. Following DSS administration, Enalapril and SSZ also significantly decreased MDA levels, an oxidant marker, and increased total thiol, SOD, and CAT levels, as antioxidants. Additionally, mucosal damage, crypt loss, pathological changes, and inflammation scores decreased after treatment with Enalapril and SSZ in comparison with the colitis group. The combination of Enalapril and SSZ reduced colon collagen content and caused a decrease in fibrosis compared to the colitis group. Conclusion: The results of this study indicated that Enalapril alone and in combination with SSZ decreased inflammation and clinical symptoms of colitis induced by DSS. 169 179 2023/05/62023/10/22022/12/102023/10/42023/09/72023/06/222023/02/2 1401/11/13 2023/09/252024/01/172023/11/212023/12/182024/01/172023/12/182023/12/18 1402/9/27 Asma Mostafapour Asma Mostafapour Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran Iran MostafapourA@mums.ac.ir Fereshteh Asgharzadeh Fereshteh Asgharzadeh Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran asgharzadehf4001@mums.ac.ir Seyedeh Elnaz Nazari Seyedeh Elnaz Nazari Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Nazarie971@mums.ac.ir Moein Eskandari Moein Eskandari Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran EskandariM981@mums.ac.ir Niloufar Naghibzadeh Niloufar Naghibzadeh Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Naghibzadehn971@mums.ac.ir Javad baharara Javad baharara Department of Biology & Research Center for Animal Development Applied Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran Iran bahararaj961@gmail.com Amir Avan Amir Avan Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Iran Avana@mums.ac.ir Seyed Mahdi Hassanian Seyed Mahdi Hassanian Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran HasanianMehrM@mums.ac.ir Majid Khazaei Majid Khazaei Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran khazaeimaj@gmail.com Colitis Angiotensin-converting Enzyme inhibitor Enalapril Inflammation Alican I, Şener G, Yüksel M, Gedik N, Ercan F, Jahovic N. The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats. Regulatory Peptides 2005; 130:67-74. https://doi.org/10.1016/j.regpep.2005.03.009##Amidon S, Brown J E, Dave V S. Colon-targeted oral drug delivery systems: design trends and approaches. Aaps Pharmscitech 2015; 16: 731-741. https://doi.org/10.1208/s12249-015-0350-9##Asgharzadeh F, Yaghoubi A, Nazari S E, Hashemzadeh A, Hasanian S M, Avan A, et al. The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. EXCLI Journal 2021; 20: 236.##Beniwal-Patel P, Shaker R. Gastrointestinal and liver disorders in women’s health: A point of care clinical guide: Springer, 2019. https://doi.org/10.1007/978-3-030-25626-5##Bordoni L, Fedeli D, Nasuti C, Maggi F, Papa F, Wabitsch M, et al. Antioxidant and anti-inflammatory properties of Nigella sativa oil in human pre-adipocytes. Antioxidants 2019; 8: 51. https://doi.org/10.3390/antiox8020051##Chassaing B, Aitken J D, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Current Protocols in Immunology 2014; 104: 15.25. 1-15.25. 14. https://doi.org/10.1002/0471142735.im1525s104##Feagan B G, MacDonald J K. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2012. https://doi.org/10.1002/14651858.CD000543.pub3##Flynn S, Eisenstein S. Inflammatory bowel disease presentation and diagnosis. Surgical Clinics of North America 2019; 99: 1051-62. https://doi.org/10.1016/j.suc.2019.08.001##Garg M, Royce S G, Tikellis C, Shallue C, Batu D, Velkoska E, et al. Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target? Gut 2020; 69: 841-851. https://doi.org/10.1136/gutjnl-2019-318512##Ghafouri Z, Seyyedian S, Nikbakht J, Kouhsari E, Bayat S, Zargar H, et al. Effect of Sodium Cromoglycate on acetic acid-induced ulcerative colitis in mice. Korean Journal of Gastroenterology 2020; 75: 39-45. https://doi.org/10.4166/kjg.2020.75.1.39##Haendeler J, Ishida M, Hunyady L, Berk B C. The third cytoplasmic loop of the angiotensin ii type 1 receptor exerts differential effects on extracellular signal-regulated kinase (ERK1/ERK2) and apoptosis via Ras-and Rap1-dependent pathways. Circulation Research 2000; 86: 729-736. https://doi.org/10.1161/01.RES.86.7.729##Hamer H M, Jonkers D M, Vanhoutvin S A, Troost F J, Rijkers G, de Bruïne A, et al. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clinical Nutrition 2010; 29: 738-744. https://doi.org/10.1016/j.clnu.2010.04.002##Hamza S M, Dyck J R. Systemic and renal oxidative stress in the pathogenesis of hypertension: modulation of long-term control of arterial blood pressure by resveratrol. Frontiers in Physiology 2014; 5: 292. https://doi.org/10.3389/fphys.2014.00292##Hashemzehi M, Naghibzadeh N, Asgharzadeh F, Mostafapour A, Hassanian S M, Ferns G A, et al. The therapeutic potential of losartan in lung metastasis of colorectal cancer. EXCLI Journal 2020; 19: 927.##Heidari M, Hashemi S M, Baghaei K, Zali M R Z M. Comparative effects of different doses of dextran sodium sulfate on the induction of chronic colitis in C57BL/6 mice. Research in Medicine 2020; 44: 346-351.##Husain K, Edu Suarez A I, Hernandez W, Ferder L. Effect of paricalcitol and enalapril on renal inflammation/oxidative stress in atherosclerosis. World Journal of Biological Chemistry 2015; 6: 240. https://doi.org/10.4331/wjbc.v6.i3.240##Kumar S D, Mutlu E A. What do I do with my medications if I become Pregnant? Safety of IBD medications during pregnancy. Inflammatory Bowel Disease: Springer, 2015: 171-187. https://doi.org/10.1007/978-3-319-14072-8_23##Lee C, Chun J, Hwang S W, Kang S J, Im J P, Kim J S. Enalapril inhibits nuclear factor-κB signaling in intestinal epithelial cells and peritoneal macrophages and attenuates experimental colitis in mice. Life Sciences 2014; 95: 29-39. https://doi.org/10.1016/j.lfs.2013.11.005##Lee S Y, Hur S J. Effect of treatment with peptide extract from beef myofibrillar protein on oxidative stress in the brains of spontaneously hypertensive rats. Foods 2019; 8: 455. https://doi.org/10.3390/foods8100455##Moum B. Which are the 5-ASA compound side effects and how is it possible to avoid them? Inflammatory bowel diseases 2008; 14: S212-S213. https://doi.org/10.1002/ibd.20712##Nikfar S, Rahimi R, Rezaie A, Abdollahi M. A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Digestive Diseases and Sciences 2009; 54: 1157-1170. https://doi.org/10.1007/s10620-008-0481-x##Perše M, Cerar A. Dextran sodium sulphate colitis mouse model: traps and tricks. Journal of Biomedicine and Biotechnology 2012; 2012. https://doi.org/10.1155/2012/718617##Rieder F, Bettenworth D, Ma C, Parker C E, Williamson L A, Nelson S A, et al. An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn’s disease. Alimentary pharmacology & therapeutics 2018; 48: 347-357. https://doi.org/10.1111/apt.14853##Shi Y, Liu T, He L, Dougherty U, Chen L, Adhikari S, et al. Activation of the renin-angiotensin system promotes colitis development. Scientific Reports 2016; 6: 1-11. https://doi.org/10.1038/srep27552##Spencer A U, Yang H, Haxhija E Q, Wildhaber B E, Greenson J K, Teitelbaum D H. Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition. Digestive Diseases and Sciences 2007; 52: 1060-1070. https://doi.org/10.1007/s10620-006-9124-2##Sueyoshi R, Ignatoski K M W, Daignault S, Okawada M, Teitelbaum D H. Angiotensin converting enzyme-inhibitor reduces colitis severity in an IL-10 knockout model. Digestive Diseases and Sciences 2013; 58: 3165-3177. https://doi.org/10.1007/s10620-013-2825-4##Sutherland L R, MacDonald J K. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2006. https://doi.org/10.1002/14651858.CD000544.pub2##Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, et al. Angiotensin II and tumor necrosis factor-α synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-κB, p38, and reactive oxygen species. American Journal of Physiology-Heart and Circulatory Physiology 2008; 294: H2879-H2888. https://doi.org/10.1152/ajpheart.91406.2007##Walker A M, Szneke P, Bianchi L A, Field L G, Sutherland L R, Dreyer N A. 5-Aminosalicylates, sulfasalazine, steroid use, and complications in patients with ulcerative colitis. American Journal of Gastroenterology (Springer Nature) 1997; 92.##Wang L-X, Ideishi M, Yahiro E, Urata H, Arakawa K, Saku K. Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. Hypertension Research 2001; 24: 179-187. https://doi.org/10.1291/hypres.24.179##Wengrower D, Zannineli G, Pappo O, Latella G, Sestieri M, Villanova A, et al. Prevention of fibrosis in experimental colitis by captopril: The role of TGF-β1. Inflammatory Bowel Diseases 2004; 10: 536-545. https://doi.org/10.1097/00054725-200409000-00007## ##

Comparing the efficacy of sulfasalazine and an aqueous extract of tarragon in an experimental model of ulcerative colitis 2 2 Introduction: The anti-inflammatory and immunomodulatory properties of tarragon have been noted. Here, we examined the effects of an aqueous extract of the tarragon plant in a rat model of ulcerative colitis. Methods: Ulcerative colitis was induced in Wistar rats using a 2 ml acetic acid (4%) intrarectal enema. Experimental groups received sulfasalazine (2 mg/kg) or tarragon aqueous extract (100 mg/kg) orally for ten consecutive days. After ten days, the animals were euthanized and evaluated for disease activity index (DAI), production of inflammatory and pro-inflammatory mediators in the intestinal tissue. Results: Both the tarragon aqueous extract and sulfasalazine treatments were effective in reducing the disease severity index in experimental ulcerative colitis. Malondialdehyde intensity, nitric oxide level, and myeloperoxidase activity regressed in the colon of animals treated with the tarragon aqueous extract more than in the group treated with sulfasalazine. However, sulfasalazine significantly reduced TNF-α and IL-1 levels compared to the tarragon aqueous extract. There was no statistical difference in IL-6 and PGE2 reduction between the two groups. Conclusion: These findings suggested that the aqueous extract of tarragon may be applied as a natural resource to control ulcerative colitis. 180 189 2023/05/62023/10/22022/12/102023/10/42023/09/72023/06/222023/02/22023/07/7 1402/4/16 2023/09/252024/01/172023/11/212023/12/182024/01/172023/12/182023/12/182023/10/18 1402/7/26 Milad Qaderi Milad Qaderi Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran Iran st_mi.ghderi@urmia.ac.ir Ahmad Enferadi Qazanabad Ahmad Enferadi Qazanabad Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran Iran a.enferadi@urmia.ac.ir Peyman Khademi Peyman Khademi Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iranp. Iran khademi@urmia.ac.ir Parvin Mahdavi Parvin Mahdavi Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran Iran parvin.mahdaviiiii73@gmail.com Seyyed Meysam Abtahi Froushani Seyyed Meysam Abtahi Froushani Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran Iran sm.abtahi@urmia.ac.ir Ulcerative colitis Sulfasalazine Tarragon aqueous extract Wistar rat Abtahi Froushani S M, Mashouri S. The beneficial effects of hypiran in ameliorating rat model of ulcerative colitis. Zahedan Journal of Research in Medical Sciences 2018; 20. https://doi.org/10.5812/zjrms.58919##Abtahi Froushani S M, Zarei L, Ghaleh H E G, Motlagh B M. Estragole and methyl-eugenol-free extract of Artemisia dracunculus possesses immunomodulatory effects. Avicenna Journal of Phytomedicine 2016; 6: 526.##Aglarova A, Zilfikarov I, Severtseva O. Biological characteristics and useful properties of tarragon (Artemisia dracunculus L.). Pharmaceutical Chemistry Journal 2008; 42: 81-86. https://doi.org/10.1007/s11094-008-0064-3##Al-Rejaie S S, Abuohashish H M, Al-Enazi M M, Al-Assaf A H, Parmar M Y, Ahmed M M. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World Journal of Gastroenterology 2013a; 19: 5633. https://doi.org/10.3748/wjg.v19.i34.5633##Al-Rejaie S S, Aleisa A M, Sayed-Ahmed M M, Al-Shabanah O A, Abuohashish H M, Ahmed M M, et al. Protective effect of rutin on the antioxidant genes expression in hypercholestrolemic male Westar rat. BMC Complementary and Alternative Medicine 2013b; 13: 136. https://doi.org/10.1186/1472-6882-13-136##D’haens G. Systematic review: second-generation vs. conventional corticosteroids for induction of remission in ulcerative colitis. Alimentary Pharmacology Therapeutics 2016; 44: 1018-1029. https://doi.org/10.1111/apt.13803##de Carvalho L R, de Brito T V, Junior J S d C, Júnior G J D, de Aguiar Magalhãres D, Sousa S G, et al. Epiisopiloturine, an imidazole alkaloid, reverses inflammation and lipid peroxidation parameters in the Crohn disease model induced by trinitrobenzenosulfonic acid in Wistar rats. Biomedicine Pharmacotherapy 2018; 102: 278-285. https://doi.org/10.1016/j.biopha.2018.03.090##de Ridder L, Turner D, Wilson D C, Koletzko S, Martin-de-Carpi J, Fagerberg U L, et al. Malignancy and mortality in pediatric patients with inflammatory bowel disease: a multinational study from the porto pediatric IBD group. Inflammatory Bowel Diseases 2014; 20: 291-300. https://doi.org/10.1097/01.MIB.0000439066.69340.3c##De Vincenzi M, Silano M, Maialetti F, Scazzocchio B. Constituents of aromatic plants: II. Estragole. Fitoterapia 2000; 71: 725-729. https://doi.org/10.1016/S0367-326X(00)00153-2##Dubska L, Literak I, Kocianova E, Taragelova V, Sychra O. Differential role of passerine birds in distribution of Borrelia spirochetes, based on data from ticks collected from birds during the postbreeding migration period in Central Europe. Applied and Environmental Microbiology 2009; 75: 596-602. https://doi.org/10.1128/AEM.01674-08##Ekiert H, Świątkowska J, Knut E, Klin P, Rzepiela A, Tomczyk M, et al. Artemisia dracunculus (Tarragon): A review of its traditional uses, Phytochemistry and Pharmacology. Frontiers in Pharmacology 2021; 12. https://doi.org/10.3389/fphar.2021.653993##Esmaeilnejad B, Abtahi Froushani S, Tehrani A, Esmaeili Gouvarchin Ghaleh H, Moshrefzadeh F. Effect of Fasciola hepatica on acetic acid induced ulcerative colitis in rat model. Journal of Fasa University of Medical Sciences 2018; 8: 1136-1145.##Gupta M, Mishra V, Gulati M, Kapoor B, Kaur A, Gupta R, et al. Natural compounds as safe therapeutic options for ulcerative colitis. Inflammopharmacology 2022; 30: 397-434. https://doi.org/10.1007/s10787-022-00931-1##Hauso Ø, Martinsen T C, Waldum H. 5-Aminosalicylic acid, a specific drug for ulcerative colitis. Scandinavian Journal of Gastroenterology 2015; 50: 933-941. https://doi.org/10.3109/00365521.2015.1018937##Hindryckx P, Jairath V, D’haens G. Acute severe ulcerative colitis: from pathophysiology to clinical management. Nature Reviews Gastroenterology Hepatology 2016; 13: 654-664. https://doi.org/10.1038/nrgastro.2016.116##Kordali S, Kotan R, Mavi A, Cakir A, Ala A, Yildirim A. Determination of the chemical composition and antioxidant activity of the essential oil of Artemisia dracunculus and of the antifungal and antibacterial activities of Turkish Artemisia absinthium, A. dracunculus, Artemisia santonicum, and Artemisia spicigera essential oils. Journal of agricultural food chemistry 2005; 53: 9452-9458. https://doi.org/10.1021/jf0516538##Landgren A M, Landgren O, Gridley G, Dores G M, Linet M S, Morton L M. Autoimmune disease and subsequent risk of developing alimentary tract cancers among 4.5 million US male veterans. Cancer 2011; 117: 1163-1171. https://doi.org/10.1002/cncr.25524##Liu B, Li S, Sui X, Guo L, Liu X, Li H, et al. Root extract of Polygonum cuspidatum Siebold & Zucc. ameliorates DSS-induced ulcerative colitis by affecting NF-kappaB signaling pathway in a mouse model via synergistic effects of polydatin, resveratrol, and emodin. Frontiers in Pharmacology 2018; 9: 347. https://doi.org/10.3389/fphar.2018.00347##Low D, Nguyen D D, Mizoguchi E. Animal models of ulcerative colitis and their application in drug research. Drug Design, Development Therapy 2013: 1341-1357. https://doi.org/10.2147/DDDT.S40107##Majdan M, Kiss A K, Hałasa R, Granica S, Osińska E, Czerwińska M E. Inhibition of neutrophil functions and antibacterial effects of tarragon (Artemisia dracunculus L.) infusion-phytochemical characterization. Frontiers in Pharmacology 2020; 11: 947.##Mashhouri S, Abtahi Froushani S M, Tehrani A A. Non-Adherent Bone marrow-derived mesenchymal stem cells ameliorate clinical manifestations and inflammation in an experimental model of ulcerative colitis in rats. Iranian Journal of Medical Sciences 2020; 45: 341.##Menichini F, Conforti F, Rigano D, Formisano C, Piozzi F, Senatore F. Phytochemical composition, anti-inflammatory and antitumour activities of four Teucrium essential oils from Greece. Food Chemistry 2009; 115: 679-686. https://doi.org/10.1016/j.foodchem.2008.12.067##Nageeb A, Al-Tawashi A, Mohammad Emwas A-H, Abdel-Halim Al-Talla Z, Al-Rifai N. Comparison of Artemisia annua bioactivities between traditional medicine and chemical extracts. Current Bioactive Compounds 2013; 9: 324-332. https://doi.org/10.2174/157340720904140404151439##Obolskiy D, Pischel I, Feistel B, Glotov N, Heinrich M. Artemisia dracunculus L.(tarragon): a critical review of its traditional use, chemical composition, pharmacology, and safety. Journal of Agricultural Food Chemistry 2011; 59: 11367-11384. https://doi.org/10.1021/jf202277w##Orsonneau J, Douet P, Massoubre C, Lustenberger P, Bernard S. An improved pyrogallol red-molybdate method for determining total urinary protein. Clinical chemistry 1989; 35: 2233-2236. https://doi.org/10.1093/clinchem/35.11.2233##Osanloo M, Firooziyan S, Abdollahi A, Hatami S, Nematollahi A, Elahi N, et al. Nanoemulsion and nanogel containing Artemisia dracunculus essential oil; larvicidal effect and antibacterial activity. BMC Research Notes 2022; 15: 276. https://doi.org/10.1186/s13104-022-06135-8##Salamatian M, Mohammadi V, Abtahi Froushani S M. Ameliorative effects of aqueous cinnamon extract on ulcerative colitis in rats. Physiology Pharmacology 2019; 23: 140-149.##Saraiva R A, Araruna M K, Oliveira R C, Menezes K D, Leite G O, Kerntopf M R, et al. Topical anti-inflammatory effect of Caryocar coriaceum Wittm. (Caryocaraceae) fruit pulp fixed oil on mice ear edema induced by different irritant agents. Journal of Ethnopharmacology 2011; 136: 504-510. https://doi.org/10.1016/j.jep.2010.07.002##Sayyah M, Nadjafnia L, Kamalinejad M. Anticonvulsant activity and chemical composition of Artemisia dracunculus L. essential oil. Journal of Ethnopharmacology 2004; 94: 283-287. https://doi.org/10.1016/j.jep.2004.05.021##Schepetkin I A, Özek G, Özek T, Kirpotina L N, Khlebnikov A I, Klein R A, et al. Neutrophil immunomodulatory activity of farnesene, a component of Artemisia dracunculus essential oils. Pharmaceuticals 2022; 15: 642. https://doi.org/10.3390/ph15050642##Shahid M, Raish M, Ahmad A, Bin Jardan Y A, Ansari M A, Ahad A, et al. Sinapic acid ameliorates acetic acid-induced ulcerative colitis in rats by suppressing inflammation, oxidative stress, and apoptosis. Molecules 2022; 27. https://doi.org/10.3390/molecules27134139##Shahrivari S, Alizadeh S, Ghassemi-Golezani K, Aryakia E. A comprehensive study on essential oil compositions, antioxidant, anticholinesterase and antityrosinase activities of three Iranian Artemisia species. Scientific Reports 2022; 12: 7234. https://doi.org/10.1038/s41598-022-11375-6##Shahriyary L, Yazdanparast R. Inhibition of blood platelet adhesion, aggregation and secretion by Artemisia dracunculus leaves extracts. Journal of Ethnopharmacology 2007; 114: 194-198. https://doi.org/10.1016/j.jep.2007.07.029##Shibrya E E, Rashed R R, Abd El Fattah M A, El-Ghazaly M A, Kenawy S A. Apigenin and exposure to low dose gamma radiation ameliorate acetic acid-induced ulcerative colitis in rats. Dose-Response 2023; 21: 15593258231155787. https://doi.org/10.1177/15593258231155787##Visavadiya N P, Soni B, Dalwadi N, nutrition. Evaluation of antioxidant and anti-atherogenic properties of Glycyrrhiza glabra root using in vitro models. International Journal of Food Sciences 2009; 60: 135-149. https://doi.org/10.1080/09637480902877998##Wang Y, Parker C E, Feagan B G, MacDonald J K. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2016. https://doi.org/10.1002/14651858.CD000544.pub4##Weinoehrl S, Feistel B, Pischel I, Kopp B, Butterweck V. Comparative evaluation of two different Artemisia dracunculus L. cultivars for blood sugar lowering effects in rats. hytotherapy Research 2012; 26: 625-629. https://doi.org/10.1002/ptr.3605## ##

The role of the AT1 receptor antagonist on renal hemodynamic responses to angiotensin 1-7 in acute sympathectomized male and female rats 2 2 Introduction: The sympathetic nervous system and the renin-angiotensin system (RAS) are the most pivotal vasoactive systems in regulating renal hemodynamics. The main objective of this study was to determine the role of the angiotensin II (Ang II) type 1 receptor (AT1R) antagonist on renal hemodynamic responses to Ang 1-7 infusion in innervated and denervated male and female rats. Methods: Male and female Wistar rats underwent unilateral nephrectomy. Four weeks later, they were divided into two groups: innervated and acutely denervated groups. Subsequently, the anesthetized and catheterized rats in both groups were treated with saline as a vehicle and losartan infusion. Mean arterial pressure (MAP), renal blood flow (RBF), renal perfusion pressure (RPP), and renal vascular resistance (RVR) responses to Ang 1-7 (100, 300, and 1000 ng kg−1 min−1 ) were then measured at controlled RPP. Results: Basal MAP, RPP, RBF, and RVR did not show significant differences between the intact and denervated groups. Losartan significantly decreased MAP, RPP, and RVR in both innervated and denervated male and female rats (P<0.001), while RBF increased only in innervated and denervated female rats (P<0.004). However, following Ang 1-7 administration, the RBF response to Ang 1-7 infusion differed significantly between intact and denervated male rats treated with losartan (P<0.04). This response was not observed in female rats. Conclusion: These data suggest a synergistic effect of losartan and Ang 1-7 on increased RBF in the presence of renal sympathetic nerves in male rats. 190 205 2023/05/62023/10/22022/12/102023/10/42023/09/72023/06/222023/02/22023/07/72023/02/22 1401/12/3 2023/09/252024/01/172023/11/212023/12/182024/01/172023/12/182023/12/182023/10/182023/12/18 1402/9/27 Fatemeh Kharazmi Fatemeh Kharazmi Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran fa.kharazmi@gmail.com Ail-Asghar Pourshanazari Ail-Asghar Pourshanazari Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran Iran aapoursha@gmail.com Mehdi Nematbakhsh Mehdi Nematbakhsh Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran nematbakhsh@med.mui.ac.ir Angiotensin 1-7 Sympathectomy Losartan Renal blood flow Abdulla M, Sattar M, Abdullah N, Hazim A, Anand Swarup K, Rathore H, et al. Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats. Autonomic and Autacoid Pharmacology 2008a; 28: 95-101. https://doi.org/10.1111/j.1474-8673.2008.00422.x##Abdulla M, Sattar M, Salman I, Abdullah N, Ameer O, Khan M A, et al. Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats. Autonomic and Autacoid Pharmacology 2008b; 28: 87-94. https://doi.org/10.1111/j.1474-8673.2008.00421.x##Abdulla M H, Sattar M, Khan M A, Abdullah N A, Johns E. Influence of sympathetic and AT1-receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive rats. Acta Physiologica 2009; 195: 397-404. https://doi.org/10.1111/j.1748-1716.2008.01895.x##Abildgaard U, Holstein-rathlou N H, Leyssac P P. Effect of renal nerve activity on tubular sodium and water reabsorption in dog kidneys as determined by the lithium clearance method. Acta Physiologica Scandinavica 1986; 126: 251-257. https://doi.org/10.1111/j.1748-1716.1986.tb07812.x##Abu-Amarah I, Ajikobi D O, Bachelard H, Cupples W A, Salevsky F C. Responses of mesenteric and renal blood flow dynamics to acute denervation in anesthetized rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 1998; 275: R1543-R1552. https://doi.org/10.1152/ajpregu.1998.275.5.R1543##Ajayi A F, Akhigbe R E. Staging of the estrous cycle and induction of estrus in experimental rodents: an update. Fertility Research and Practice 2020; 6: 1-15. https://doi.org/10.1186/s40738-020-00074-3##Almeida A, Frábregas B, Madureira M, Santos R, Campagnole-Santos M, Santos R. Angiotensin-(1-7) potentiates the coronary vasodilatatory effect of bradykinin in the isolated rat heart. Brazilian Journal of Medical and Biological Research 2000; 33: 709-713. https://doi.org/10.1590/S0100-879X2000000600012##Armando I. Jezova M, Juorio AV, Terrón JA, Falcón-Neri A, Semino-Mora C, Imboden H, and Saavedra JM. Estrogen upregulates renal angiotensin II AT. American Journal of Physiology. Renal Physiology 2002; 2. https://doi.org/10.1152/ajprenal.00145.2002##Azadbakht M K, Nematbakhsh M. Angiotensin 1-7 administration alters baroreflex sensitivity and renal function in sympathectomized rats. Journal of Nephropathology 2017; 7: 79-82. https://doi.org/10.15171/jnp.2018.19##Barry E F, O’Neill J, Abdulla M H, Johns E J. The renal excretory responses to acute renal interstitial angiotensin (1-7) infusion in anaesthetised spontaneously hypertensive rats. Clinical and Experimental Pharmacology and Physiology 2021; 48: 1674-1684. https://doi.org/10.1111/1440-1681.13570##Bello-Reuss E, Colindres R, Pastoriza-Munoz E, Mueller R, Gottschalk C. Effects of acute unilateral renal denervation in the rat. The Journal of Clinical Investigation 1975; 56: 208-217. https://doi.org/10.1172/JCI108069##Bohlender J M, Nussberger J, Birkhäuser F, Grouzmann E, Thalmann G N, Imboden H. Resetting of renal tissular renin-angiotensin and bradykinin-kallikrein systems after unilateral kidney denervation in rats. Histochemistry and Cell Biology 2017; 147: 585-593. https://doi.org/10.1007/s00418-017-1543-y##Braga A N G, da Silva Lemos M, Da Silva J R, Fontes W R P, Augusto Souza Dos Santos R. Effects of angiotensins on day-night fluctuations and stress-induced changes in blood pressure. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2002; 282: 1663-1671. https://doi.org/10.1152/ajpregu.00583.2001##Bürgelová M, Kramer H J, Teplan V, Veličková G, Vítko Š, Heller J, et al. Intrarenal infusion of angiotensin-(1-7) modulates renal functional responses to exogenous angiotensin II in the rat. Kidney and Blood Pressure Research 2002; 25: 202-210. https://doi.org/10.1159/000066340##Cai X-N, Wang C-Y, Cai Y, Peng F. Effects of renal denervation on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats. Chinese Journal of Traumatology 2018; 21: 293-300. https://doi.org/10.1016/j.cjtee.2018.09.001##Caplea A, Seachrist D, Daneshvar H, Dunphy G, Ely D. Noradrenergic content and turnover rate in kidney and heart shows gender and strain differences. Journal of Applied Physiology 2002; 92: 567-571. https://doi.org/10.1152/japplphysiol.00557.2001##Carey R M. The intrarenal renin-angiotensin system in hypertension. Advances in Chronic Kidney Disease 2015; 22: 204-210. https://doi.org/10.1053/j.ackd.2014.11.004##Carey R M, Siragy H M. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocrine Reviews 2003; 24: 261-271. https://doi.org/10.1210/er.2003-0001##Chappell M C, Modrall J G, Diz D I, Ferrario C M. Novel aspects of the renal renin-angiotensin system: angiotensin-(1-7), ACE2 and blood pressure regulation. Contributions to Nephrology 2004; 143: 77-89. https://doi.org/10.1159/000078713##Collister J P, Hendel M D. The role of Ang (1-7) in mediating the chronic hypotensive effects of losartan in normal rats. Journal of the Renin-Angiotensin-Aldosterone System 2003; 4: 176-179. https://doi.org/10.3317/jraas.2003.028##Crackower M A, Sarao R, Oudit G Y, Yagil C, Kozieradzki I, Scanga S E, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002; 417: 822-828. https://doi.org/10.1038/nature00786##De Moura R S, Resende A, Emiliano A, Tano T, Mendes-Ribeiro A, Correia M, et al. The role of bradykinin, AT2 and angiotensin 1-7 receptors in the EDRF-dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat. British Journal of Pharmacology 2004; 141: 860-866. https://doi.org/10.1038/sj.bjp.0705669##Dibona G F. Peripheral and central interactions between the renin-angiotensin system and the renal sympathetic nerves in control of renal function. Annals of the New York Academy of Sciences 2001; 940: 395-406. https://doi.org/10.1111/j.1749-6632.2001.tb03693.x##DiBona G F, Rios L L. Renal nerves in compensatory renal response to contralateral renal denervation. American Journal of Physiology-Renal Physiology 1980; 238: F26-F30. https://doi.org/10.1152/ajprenal.1980.238.1.F26##Dibona G F, Sawin L L. Effect of renal denervation on dynamic autoregulation of renal blood flow. American Journal of Physiology-Renal Physiology 2004; 286: F1209-F1218. https://doi.org/10.1152/ajprenal.00010.2004##Dilauro M, Burns K D. Angiotensin-(1-7) and its effects in the kidney. The Scientific World Journal 2009; 9: 522-535. https://doi.org/10.1100/tsw.2009.70##e Silva A S, Pinheiro S V, Pereira R M, Ferreira A J, Santos R A. The therapeutic potential of angiotensin-(1-7) as a novel renin-angiotensin system mediator. Mini Reviews in Medicinal Chemistry 2006; 6: 603. https://doi.org/10.2174/138955706776876203##Fernandes L, Fortes Z B, Nigro D, Tostes R C, Santos R A, Catelli de Carvalho M H. Potentiation of bradykinin by angiotensin-(1-7) on arterioles of spontaneously hypertensive rats studied in vivo. Hypertension 2001; 37: 703-709. https://doi.org/10.1161/01.HYP.37.2.703##Ferrario C, Chappell M. What’s new in the renin-angiotensin system? Cellular and Molecular Life Sciences CMLS 2004; 61: 2720-2727. https://doi.org/10.1007/s00018-004-4243-4##Fountain J H, Kaur J, Lappin S L. Physiology, renin angiotensin system. Stat Pearls [Internet]: Stat Pearls Publishing, 2023.##Gorelik G, Carbini L, Scicli A. Angiotensin 1-7 induces bradykinin-mediated relaxation in porcine coronary artery. Journal of Pharmacology and Experimental Therapeutics 1998; 286: 403-410.##Grady H C, Bullivant E. Renal blood flow varies during normal activity in conscious unrestrained rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 1992; 262: R926-R932. https://doi.org/10.1152/ajpregu.1992.262.5.R926##Handa R, Johns E J. Interaction of the renin-angiotensin system and the renal nerves in the regulation of rat kidney function. The Journal of Physiology 1985; 369: 311-321. https://doi.org/10.1113/jphysiol.1985.sp015903##Handa R K. Binding and signaling of angiotensin-(1-7) in bovine kidney epithelial cells involves the AT4 receptor. Peptides 2000; 21: 729-736. https://doi.org/10.1016/S0196-9781(00)00188-1##Handa R K, Ferrario C M, Strandhoy J W. Renal actions of angiotensin-(1-7): in vivo and in vitro studies. American Journal of Physiology-Renal Physiology 1996; 270: F141-F147. https://doi.org/10.1152/ajprenal.1996.270.1.F141##Heller J, Kramer H, Malý J, Červenka L, Horáček V. Effect of intrarenal infusion of angiotensin-(1-7) in the dog. Kidney and Blood Pressure Research 2000; 23: 89-94. https://doi.org/10.1159/000025959##Hilgers K F, Mann J F. ACE inhibitors versus AT1 receptor antagonists in patients with chronic renal disease. Journal of the American Society of Nephrology 2002; 13: 1100-1108. https://doi.org/10.1681/ASN.V1341100##Iyer S N, Chappell M C, Averill D B, Diz D I, Ferrario C M. Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan. Hypertension 1998; 31: 699-705. https://doi.org/10.1161/01.HYP.31.2.699##Joyner M J, Barnes J N, Hart E C, Wallin B G, Charkoudian N. Neural control of the circulation: how sex and age differences interact in humans. Comprehensive Physiology 2015; 5: 193. https://doi.org/10.1002/cphy.c140005##Just A, Wittmann U, Ehmke H, Kirchheim H R. Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback. The Journal of Physiology 1998; 506: 275-290. https://doi.org/10.1111/j.1469-7793.1998.275bx.x##Kacem K, Sercombe R. Differing influence of sympathectomy on smooth muscle cells and fibroblasts in cerebral and peripheral muscular arteries. Autonomic Neuroscience 2006; 124: 38-48. https://doi.org/10.1016/j.autneu.2005.11.003##Kassab K, Soni R, Kassier A, Fischell T A. The potential role of renal denervation in the management of heart failure. Journal of Clinical Medicine 2022; 11: 4147. https://doi.org/10.3390/jcm11144147##Katsurada K, Shinohara K, Aoki J, Nanto S, Kario K. Renal denervation: basic and clinical evidence. Hypertension Research 2022; 45: 198-209. https://doi.org/10.1038/s41440-021-00827-7##Kazi A. Renal functional & haemodynamic changes following acute unilateral renal denervation in Sprague Dawley rats. Indian Journal of Medical Research 2010; 131: 76-82. ##Khan S A, Sattar M A, Rathore H A, Abdulla M H, Ud Din Ahmad F, Ahmad A, et al. Renal denervation restores the baroreflex control of renal sympathetic nerve activity and heart rate in Wistar-Kyoto rats with cisplatin-induced renal failure. Acta Physiologica 2014; 210: 690-700. https://doi.org/10.1111/apha.12237##Kobori H, Nangaku M, Navar L G, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacological Reviews 2007; 59: 251-287. https://doi.org/10.1124/pr.59.3.3##Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin-aldosterone system. Fundamental & Clinical Pharmacology 2010; 24: 687-698. https://doi.org/10.1111/j.1472-8206.2010.00854.x##Kopp U C, DiBona G F. Neural control of renal function. Reflex Control of the Circulation: CRC Press, 2020: 493-528. https://doi.org/10.1201/9780367813338-17##Kuczeriszka M, Kompanowska-Jezierska E, Sadowski J, Prieto M C, Navar L G. Modulating role of Ang1-7 in control of blood pressure and renal function in AngII-infused hypertensive rats. American Journal of Hypertension 2018; 31: 504-511. https://doi.org/10.1093/ajh/hpy006##Liao W, Wu J. The ACE2/Ang (1-7)/MasR axis as an emerging target for antihypertensive peptides. Critical Reviews in Food Science and Nutrition 2021; 61: 2572-2586. https://doi.org/10.1080/10408398.2020.1781049##Liu L, Barajas L. The rat renal nerves during development. Anatomy and Embryology 1993; 188: 345-361. https://doi.org/10.1007/BF00185944##Lovick T A, Zangrossi Jr H. Effect of estrous cycle on behavior of females in rodent tests of anxiety. Frontiers in Psychiatry 2021; 12: 711065. https://doi.org/10.3389/fpsyt.2021.711065##Luippold G, Beilharz M, Mühlbauer B. Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrology Dialysis Transplantation 2004; 19: 342-347. https://doi.org/10.1093/ndt/gfg584##Magaldi A J, Cesar K R, de Araújo M, Simões e Silva A C, Santos R A. Angiotensin-(1-7) stimulates water transport in rat inner medullary collecting duct: evidence for involvement of vasopressin V2 receptors. Pflügers Archiv 2003; 447: 223-230. https://doi.org/10.1007/s00424-003-1173-1##MALPAS S, EVANS R. Do different levels and patterns of sympathetic activation all provoke renal vasoconstriction? Journal of the Autonomic Nervous System 1998; 69: 72-82. https://doi.org/10.1016/S0165-1838(98)00010-1##Malpas S C, Evans R G, Head G A, Lukoshkova E V. Contribution of renal nerves to renal blood flow variability during hemorrhage. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 1998; 274: R1283-R1294. https://doi.org/10.1152/ajpregu.1998.274.5.R1283##Medina D, Mehay D, Arnold A C. Sex differences in cardiovascular actions of the renin-angiotensin system. Clinical Autonomic Research 2020; 30: 393-408. https://doi.org/10.1007/s10286-020-00720-2##Messerli F H, Bangalore S. Renal denervation for resistant hypertension. New England Journal of Medicine 2014; 370: 1454-7. https://doi.org/10.1056/NEJMe1402388##Moon J-Y. ACE2 and angiotensin-(1-7) in hypertensive renal disease. Electrolytes & Blood Pressure 2011; 9: 41-44. https://doi.org/10.5049/EBP.2011.9.2.41##Navar L, Inscho E, Majid S, Imig J, Harrison-Bernard L, Mitchell K. Paracrine regulation of the renal microcirculation. Physiological Reviews 1996; 76: 425-536. https://doi.org/10.1152/physrev.1996.76.2.425##Nematbakhsh M, Mansouri A. Renal vascular response to angiotensin 1-7 in rats: the role of Mas receptor. Research in Pharmaceutical Sciences 2018; 13: 177. https://doi.org/10.4103/1735-5362.223803##Nematbakhsh M, Safari T. Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats. General Physiology and Biophysics 2014; 33: 365-372. https://doi.org/10.4149/gpb_2014008##Neves L A, Averill D B, Chappell M C, Aschner J L, Walkup M P, Brosnihan K B, et al. Characterization of angiotensin-(1-7) receptor subtype in mesenteric arteries. Peptides 2003; 24: 455-462. https://doi.org/10.1016/S0196-9781(03)00062-7##Neves L A, Averill D B, Ferrario C M, Aschner J L, Brosnihan K B. Vascular responses to angiotensin-(1-7) during the estrous cycle. Endocrine 2004; 24: 161-165. https://doi.org/10.1385/ENDO:24:2:161##O’Neill J, Corbett A, Johns E J. Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1-7) administration in anesthetized rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2013; 304: R260-R266. https://doi.org/10.1152/ajpregu.00583.2011##O’Neill J, Healy V, Johns E J. Intrarenal Mas and AT1 receptors play a role in mediating the excretory actions of renal interstitial angiotensin-(1-7) infusion in anaesthetized rats. Experimental Physiology 2017; 102: 1700-1715. https://doi.org/10.1113/EP086513##Osborn J L, Francisco L L, DiBona G F. Effect of renal nerve stimulation on renal blood flow autoregulation and antinatriuresis during reductions in renal perfusion pressure. Proceedings of the Society for Experimental Biology and Medicine 1981; 168: 77-81. https://doi.org/10.3181/00379727-168-41238##Oudit G Y, Kassiri Z, Patel M P, Chappell M, Butany J, Backx P H, et al. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovascular Research 2007; 75: 29-39. https://doi.org/10.1016/j.cardiores.2007.04.007##Pinheiro S V B, Simões e Silva A C. Angiotensin converting enzyme 2, Angiotensin-(1-7), and receptor MAS axis in the kidney. International Journal of Hypertension 2012; 2012. https://doi.org/10.1155/2012/414128##Potthoff S A, Fähling M, Clasen T, Mende S, Ishak B, Suvorava T, et al. Angiotensin-(1-7) modulates renal vascular resistance through inhibition of p38 mitogen-activated protein kinase in apolipoprotein E-deficient mice. Hypertension 2014; 63: 265-272. https://doi.org/10.1161/HYPERTENSIONAHA.113.02289##Povlsen A L, Grimm D, Wehland M, Infanger M, Krüger M. The vasoactive Mas receptor in essential hypertension. Journal of Clinical Medicine 2020; 9: 267. https://doi.org/10.3390/jcm9010267##Ren Y, Garvin J L, Carretero O A. Vasodilator action of angiotensin-(1-7) on isolated rabbit afferent arterioles. Hypertension 2002; 39: 799-802. https://doi.org/10.1161/hy0302.104673##Rudd M A, Grippo R S, Arendshorst W J. Acute renal denervation produces a diuresis and natriuresis in young SHR but not WKY rats. American Journal of Physiology-Renal Physiology 1986; 251: F655-F661. https://doi.org/10.1152/ajprenal.1986.251.4.F655##Saberi S, Dehghani A, Nematbakhsh M. Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats. Research in Pharmaceutical Sciences 2016; 11: 65. https://doi.org/10.1155/2015/801053##Sadowski J, Kurkus J, Gellert R. Denervated and intact kidney responses to saline load in awake and anesthetized dogs. American Journal of Physiology-Renal Physiology 1979; 237: F262-F267. https://doi.org/10.1152/ajprenal.1979.237.4.F262##Safari T, Shahraki M R, Miri S, Bakhshani N M, Niazi A A, Komeili G R, et al. The effect of angiotensin 1-7 and losartan on renal ischemic/reperfusion injury in male rats. Research in Pharmaceutical Sciences 2019; 14: 441. https://doi.org/10.4103/1735-5362.268205##Sampson A K, Moritz K M, Denton K M. Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats. Gender Medicine 2012; 9: 21-32. https://doi.org/10.1016/j.genm.2011.12.003##Sampson A K, Widdop R E, Denton K M. Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats. Clinical and Experimental Pharmacology and Physiology 2008; 35: 391-395. https://doi.org/10.1111/j.1440-1681.2008.04884.x##Sandberg K, Umans J G, Work G t G C C. Recommendations concerning the new US National Institutes of Health initiative to balance the sex of cells and animals in preclinical research. The FASEB Journal 2015; 29: 1646-1652. https://doi.org/10.1096/fj.14-269548##Santos R, Ferreira A J, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. Journal of Endocrinology 2013; 216: R1-R17. https://doi.org/10.1530/JOE-12-0341##Santos R A. Angiotensin-(1-7). Hypertension 2014; 63: 1138-1147. https://doi.org/10.1161/HYPERTENSIONAHA.113.01274##Santos R A, e Silva A C S, Maric C, Silva D M, Machado R P, de Buhr I, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences 2003; 100: 8258-8263. https://doi.org/10.1073/pnas.1432869100##Scalise F, Sole A, Singh G, Sorropago A, Sorropago G, Ballabeni C, et al. Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis. Journal of Hypertension 2020; 38: 936-942. https://doi.org/10.1097/HJH.0000000000002358##Schlaich M P, Hering D, Sobotka P A, Krum H, Esler M D. Renal denervation in human hypertension: mechanisms, current findings, and future prospects. Current Hypertension Reports 2012; 14: 247-253. https://doi.org/10.1007/s11906-012-0264-9##Simões e Silva A, Silveira K, Ferreira A, Teixeira M. ACE2, angiotensin-(1-7) and M as receptor axis in inflammation and fibrosis. British Journal of Pharmacology 2013; 169: 477-492. https://doi.org/10.1111/bph.12159##Siragy H M, Inagami T, Ichiki T, Carey R M. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proceedings of the National Academy of Sciences 1999; 96: 6506-6510. https://doi.org/10.1073/pnas.96.11.6506##Sobrino A, Vallejo S, Novella S, Lázaro-Franco M, Mompeón A, Bueno-Betí C, et al. Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation. Biochemical Pharmacology 2017; 129: 67-72. https://doi.org/10.1016/j.bcp.2017.01.012## Souza Á P, Sobrinho D B, Almeida J F, Alves G M, Macedo L M, Porto J E, et al. Angiotensin II type 1 receptor blockade restores angiotensin-(1-7)-induced coronary vasodilation in hypertrophic rat hearts. Clinical Science 2013; 125: 449-459. https://doi.org/10.1042/CS20120519##Stegbauer J, Oberhauser V, Vonend O, Rump L C. Angiotensin-(1-7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats. Cardiovascular Research 2004; 61: 352-359. https://doi.org/10.1016/j.cardiores.2003.11.017##Stegbauer J, Vonend O, Oberhauser V, Rump L C. Effects of angiotensin-(1-7) and other bioactive components of the renin-angiotensin system on vascular resistance and noradrenaline release in rat kidney. Journal of Hypertension 2003; 21: 1391-1399. https://doi.org/10.1097/00004872-200307000-00030##Sullivan J C. Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2008; 294: R1220-R1226. https://doi.org/10.1152/ajpregu.00864.2007##Sun H-J, Li P, Chen W-W, Xiong X-Q, Han Y. Angiotensin II and angiotensin-(1-7) in paraventricular nucleus modulate cardiac sympathetic afferent reflex in renovascular hypertensive rats. PLoS One 2012; 7: e52557. https://doi.org/10.1371/journal.pone.0052557##Takabatake T, Ushiogi Y, Ohta K, Hattori N. Attenuation of enhanced tubuloglomerular feedback activity in SHR by renal denervation. American Journal of Physiology-Renal Physiology 1990; 258: F980-F985. https://doi.org/10.1152/ajprenal.1990.258.4.F980##Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. The Journal of Clinical Investigation 1999; 104: 925-935. https://doi.org/10.1172/JCI7886##Ueda S, Masumori-Maemoto S, Wada A, Ishii M, Brosnihan K B, Umemura S. Angiotensin (1-7) potentiates bradykinin-induced vasodilatation in man. Journal of Hypertension 2001; 19. https://doi.org/10.1097/00004872-200111000-00010##Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. The American Journal of Cardiology 2002; 89: 3-9. https://doi.org/10.1016/S0002-9149(01)02321-9##Urushihara M, Kagami S. Role of the intrarenal renin-angiotensin system in the progression of renal disease. Pediatric Nephrology 2017; 32: 1471-1479. https://doi.org/10.1007/s00467-016-3449-7##Vallon V, Heyne N, Richter K, Khosla M C, Fechter K. [7-D-ALA]-angiotensin 1-7 blocks renal actions of angiotensin 1-7 in the anesthetized rat. Journal of Cardiovascular Pharmacology 1998; 32: 164-167. https://doi.org/10.1097/00005344-199807000-00025##van der Wouden E A, Ochodnický P, van Dokkum R P, Roks A J, Deelman L E, de Zeeuw D, et al. The role of angiotensin (1-7) in renal vasculature of the rat. Journal of Hypertension 2006; 24: 1971-1978. https://doi.org/10.1097/01.hjh.0000244945.42169.c0##Veiga A C, Milanez M I, Campos R R, Bergamaschi C T, Nishi E E. The involvement of renal afferents in the maintenance of cardiorenal diseases. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2021; 320: R88-R93. https://doi.org/10.1152/ajpregu.00225.2020##Velez J C Q, Ryan K J, Harbeson C E, Bland A M, Budisavljevic M N, Arthur J M, et al. Angiotensin I is largely converted to angiotensin (1-7) and angiotensin (2-10) by isolated rat glomeruli. Hypertension 2009; 53: 790-797. https://doi.org/10.1161/HYPERTENSIONAHA.109.128819##Xue B, Johnson A, Hay M. Sex differences in angiotensin II-induced hypertension. Brazilian Journal of Medical and Biological Research 2007; 40: 727-734. https://doi.org/10.1590/S0100-879X2007000500018##Yousif M H, Benter I F, Diz D I, Chappell M C. Angiotensin-(1-7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity. Peptides 2017; 90: 10-16. https://doi.org/10.1016/j.peptides.2017.02.001##Zalups R K. Autometallographic localization of inorganic mercury in the kidneys of rats: Effect of unilateral nephrectomy and compensatory renal growth. Experimental and Molecular Pathology 1991; 54: 10-21. https://doi.org/10.1016/0014-4800(91)90039-Z##Zhang Z, Chen L, Zhong J, Gao P, Oudit G Y. ACE2/Ang-(1-7) signaling and vascular remodeling. Science China Life Sciences 2014; 57: 802-808. https://doi.org/10.1007/s11427-014-4693-3## ##

High concentration of nitric oxide impaired proliferation of bone marrow mesenchymal stem cells due to cell cycle arrest at G1 stage 2 2 Introduction: Although exogenous nitric oxide (NO) is used as medicine, in the previous we showed its inhibitory effect on the proliferation ability of rat bone marrow mesenchymal stem cells (BMSCs). In the present investigation, the inhibitory role of exogenous NO on BMSCs cell cycle was studied. Methods: BMSCs after the third passage were treated for one hour every 48 hours with 100μM of sodium nitroprusside as an NO donor. Then, after 5,10,15, and 20 days of treatment, the viability, proliferation, and cell cycle of the BMSCs was investigated. In addition, the expression of the Raf1, CDK2, CDK4, P53, and GAPDH genes was studied. Results: Cell treatment caused a significant reduction in viability and proliferation at 5,10,15, and 20 days. Also, the treatment caused cell cycle arrest at G1 after 20 days. In addition, it was found that the CDK2 and CDK4 expression were down-regulated whereas the P53 expression was up-regulated, but the expression of Raf1 as well as GAPDH remained the same. Conclusion: This study showed that prolonged treatment with a NO donor arrest the BMSCs cell cycle due to overexpression of P53, which inhibits the expression of Cdk2 and Cdk4. 206 218 2023/05/62023/10/22022/12/102023/10/42023/09/72023/06/222023/02/22023/07/72023/02/222022/12/22 1401/10/1 2023/09/252024/01/172023/11/212023/12/182024/01/172023/12/182023/12/182023/10/182023/12/182023/10/21 1402/7/29 Mahsa Maleklou Mahsa Maleklou Department of Biology, Faculty of Science, Arak University, Arak 384817758, Iran Iran mozhgan_b14194@yahoo.com Mohammad Husein Abnosi Mohammad Husein Abnosi Department of Biology, Faculty of Science, Arak University, Arak 384817758, Iran Iran m-abnosi@araku.ac.ir Cell cycle Nitric oxide Mesenchymal stem cells cyclin-dependent kinases Cell proliferation Abnosi M H, Masoomi S. Para-nonylphenol toxicity induces oxidative stress and arrests the cell cycle in mesenchymal stem cells of bone marrow. Iranian Journal of Toxicology 2019;13 (3): 1-8. http://dx.doi.org/10.32598/IJT.13.3.496.2##Abnosi M H, Masoomi S. p-Nonylphenol impairment of osteogenic differentiation of mesenchymal stem cells was found to be due to oxidative stress and down-regulation of RUNX2 and BMP. Endocrine, Metabolic & Immune Disorders - Drug Targets. 2020; 20: 1336-1346. https://doi.org/10.2174/1871530320666200505114058##Abnosi M H, Pari S. Exogenous nitric oxide induced early mineralization in rat bone marrow mesenchymal stem cells via activation of alkaline phosphatase. Iranian Biomedical Journal. 2019; 23 (2): 142-152. https://doi.org/10.29252/.23.2.142##Abnosi M H, Sargolzaei I D J, Maleklou M. Exogenous nitric oxide up-regulates the runx2 via bmp7 overexpression to increase the osteoblast matrix production in vitro. Avicenna Journal of Medical Biochemistry 2022; 10(1): 58-64. ##Abnosi M H, Yari S. The toxic effect of gallic acid on biochemical factors, viability and proliferation of rat bone marrow mesenchymal stem cells was compensated. by boric acid. Journal of Trace Elements in Medicine and Biology. 2018; 48: 246-253. https://doi.org/10.1016/j.jtemb.2018.04.016##Fok H, Jiang B, Clapp B, Chowienczyk P. Regulation of vascular tone and pulse wave velocity in human muscular conduit arteries: selective effects of nitric oxide donors to dilate muscular arteries relative to resistance vessels. Hypertension. 2012; 60(5): 1220-5. https://doi.org/10.1161/hypertensionaha.112.198788##Chu L, Jiang Y, Hao H, Xia Y, Xu J, Liu Z, et al. Nitric oxide enhances Oct-4 expression in bone marrow stem cells and promotes endothelial differentiation. European Journal of Pharmacology 2008; 591(1-3): 59-65. https://doi.org/10.1016/j.ejphar.2008.06.066##Coller H A, Sang L, Roberts J M. A new description of cellular quiescence. PLOS Biology 2006; 4: e83. https://doi.org/10.1371/journal.pbio.0040083 ##Darzynkiewicz Z, Juan G. DNA content measurement for DNA ploidy and cell cycle analysis. Current Protocols in Cytometry 1997; 00(1): 7.5.1–7.5.24. https://doi.org/10.1002/0471142956.cy0705s00##Ding L, Cao G, Lin W, Chen H, Xiong X, Ao H, Yu M, Lin J, Cui. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. International Molecular Science. 2020; 21(6): 1960. https://doi.org/10.3390/ijms21061960 ##Dong P, Maddali M V, Srimani J K, Thelt F, Nevins J R, Mathey-Prevot B, You L. Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. Nature Communications 2014; 5:4750. https://doi.org/10.1038/ncomms5750##Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death & Differentiation 2022; 29: 946–960. https://doi.org/10.1038/s41418-022-00988-z##García-Aranda M I, Gonzalez-Padilla J E, Gómez-Castro C Z, Gómez-Gómez Y M, Rosales- Hernández M C, et al. Anti-inflammatory effect and inhibition of nitric oxide production by targeting COXs and iNOS enzymes with the 1,2-diphenylbenzimidazole pharmacophore. Bioorganic & Medicinal Chemistry. 2020; 28(9): 115427. https://doi.org/10.1016/j.bmc.2020.115427 ##Hill BG, Dranka BP, Bailey S M, Lancaster J R Jr, Darley-Usmar V M. What part of NO don’t you understand? Some answers to the cardinal questions in nitric oxide biology. Journal of Biological Chemistry 2010; 285(26): 19699-19704. https://doi.org/10.1074/jbc.r110.101618##Hinrichsen R Hansen, A H, Haunsø S, Busk P K. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy. Cell Proliferation 2008; 41(5): 813-829. https://doi.org/10.1111/j.1365-2184.2008.00549.x##Hottinger D G, Beebe D S, Kozhimannil T, Prielipp R C, Belani K G. Sodium nitroprusside in 2014: A clinical concepts review. Journal of Anaesthesiology Clinical Pharmacology 2014; 30(4): 462-71. https://doi.org/10.4103/0970-9185.142799 ##Hume S, Dianov GL, Ramadan K. A unified model for the G1/S cell cycle transition. Nucleic Acids Research 2020; 48(22): 12483–12501. https://doi.org/10.1093/nar/gkaa1002##Mohammadi A, Abnosi M H, Pakyari R. Low concentration of sodium nitroprusside promotes mesenchymal stem cell viability and proliferation through elevation of metabolic activity. Avicenna Journal of Medical Biochemistry. 2017;5(1):9-16. http://dx.doi.org/10.15171/ajmb.2017.02##Oleson B J, Corbett J A. Dual role of nitric oxide in regulating the response of β cells to DNA damage. Antioxidants & Redox Signaling 2018; 29(14):1432-1445. https://doi.org/10.1089/ars.2017.7351##Pack L R, Daigh L H, Chung M, Meyer T. Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2. Nature Communications 2021; 12: 3356. https://doi.org/10.1038/s41467-021-23612-z##Pari S, Abnosi M H, Pakyari R. Sodium nitroprusside changed the metabolism of mesenchymal stem cells to an anaerobic state while viability and proliferation remained intact. Cell Journal (Yakhteh). 2017; 19(1): 146-158. https://doi.org/10.22074/cellj.2016.4875##Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts A I, Zhao R C, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 7;2(2):141-50. https://doi.org/10.1016/j.stem.2007.11.014. ##Takagi K, Isobe Y, Yasukawa K, Okouchi E, Suketa Y. Nitric oxide blocks the cell cycle of mouse macrophage-like cells in the early G2+ M phase. FEBS Letters 1994; 340(3): 159-162. https://doi.org/10.1016/0014-5793(94)80128-2##Thomas D D, Ridnour L A, Isenberg J S, et al. The chemical biology of nitric oxide: implications in cellular signaling. Free Radical Biology and Medicine 2008; 45:18-31. https://doi.org/10.1016/j.freeradbiomed.2008.03.020##Vermeulen K, Van Bockstaele D R, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferation 2003; 36(3):131-149. https://doi.org/10.1046/j.1365-2184.2003.00266.x##Villalobo A. Nitric oxide and cell proliferation. The FEBS Journal 2006; 273(11): 2329-2344. https://doi.org/10.1111/j.1742-4658.2006.05250.x##Wimalawansa S J. Nitric oxide: novel therapy for osteoporosis. Expert Opinion on Pharmacotherapy 2008; 9(17): 3025-3044. https://doi.org/10.1517/14656560802197162##Wood J, Garthwaite J. Models of the diffusional spread of nitric oxide: implications for neural nitric oxide signaling and its pharmacological properties. Neuropharmacology 1994; 33(11): 1235-1244. https://doi.org/10.1016/0028-3908(94)90022-1##Zhou Z, Hossain M S, Liu D. Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration. Stem Cell Research & Therapy 2021; 12(1):74. https://doi.org/10.1186/s13287-021-02149-4## ##