2021 25 2 0 188

Potential therapeutic effects of some flavonoids oncoronavirus disease 2019 2 2 Editorial Article 99 101 2021/01/31 1399/11/12 2021/04/10 1400/1/21 Mohammad Reza Khazdair Mohammad Reza Khazdair Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran Iran M.khazdair@yahoo.com - Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Reyburn HT, et al. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromolecul 2020; 164: 1693-703. https://doi.org/10.1016/j.ijbiomac.2020.07.235##Colunga Biancatelli RM, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 2020; 11: 1451. https://doi.org/10.3389/fimmu.2020.01451##Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Eng J Med 2020; 382: 1708-20. https://doi.org/10.1056/NEJMoa2002032 ##Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-80. https://doi.org/10.1016/j.cell.2020.02.052 ##Huang YF, Bai C, He F, Xie Y, Zhou H. Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19). Pharmacol Res 2020. https://doi.org/10.1016/j.phrs.2020.104939 ##Jimilihan S. Study on the active components in the adjuvant treatment of novel coronavirus pneumonia (COVID-19) with Jinhua Qinggan Granules based on network pharmacology and molecular docking. J Chine Med Material 2020: 1-10. ##Khazdair M, Alavinezhad A, Boskabady MH. Carvacrol ameliorates haematological parameters, oxidant/antioxidant biomarkers and pulmonary function tests in patients with sulphur mustard-induced lung disorders: A randomized double-blind clinical trial. J Clin Pharm Therap 2018; 43: 664-74. https://doi.org/10.1111/jcpt.12684 ##Khazdair MR, Anaeigoudari A, Kianmehr M. Anti-asthmatic effects of Portulaca oleracea and its constituents, a review. J Pharmacopunct 2019; 22: 122. ##Khazdair MR, Boskabady MH. The effect of carvacrol on inflammatory mediators and respiratory symptoms in veterans exposed to sulfur mustard, a randomized, placebo-controlled trial. Resp Med 2019; 150: 21-9. https://doi.org/10.1016/j.rmed.2019.01.020 ##Kianmehr M, Khazdair MR. Possible therapeutic effects of Crocus sativus stigma and its petal flavonoid, kaempferol, on respiratory disorders. Pharm Biol 2020; 58: 1140-9. https://doi.org/10.1080/13880209.2020.1844762 ##Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, et al. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68: 36-42. https://doi.org/10.1016/j.antiviral.2005.07.002 ##Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, et al. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med 2014; 80: 177. https://doi.org/10.1055/s-0033-1360277 ##Vijayakumar BG, Ramesh D, Joji A, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020: 173448. https://doi.org/10.1016/j.ejphar.2020.173448 ##Wang L. Study on the network pharmacology and preliminary evidence of Lianhua Qingwen in the treatment of novel coronavirus (2019-nCoV). J Chin Med Material 2020; 3: 772-8. ##Williamson G, Kerimi A. Testing of natural products in clinical trials targeting the SARS-CoV-2 (Covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction. Biochem Pharmacol 2020: 114123.https://doi.org/10.1016/j.bcp.2020.114123 ##Yarmolinsky L, Huleihel M, Zaccai M, Ben-Shabat S. Potent antiviral flavone glycosides from Ficus benjamina leaves. Fitoterapia 2012; 83: 362-7. https://doi.org/10.1016/j.fitote.2011.11.014 ##Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, et al. Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways. Biomed Pharmacother 2017; 89: 660-72. https://doi.org/10.1016/j.biopha.2017.02.081## ##

Complements C3 and C4 in serum and stimulatedsaliva of patients suffer oral erosive lichen planus 2 2 Introduction: The objective of this study was to compare the level of complements C3 and C4 in serum, and stimulated saliva between oral lichen planus (OLP) and healthy individuals. Methods: A case-control study was performed on 31 healthy and 31 who suffer the erosive type of OLP. Serum and saliva level of C3 and C4 were measured by immunoturbidimetry method. Results: C3 and C4 were expressed at a lower level in serum and saliva of OLP patients compared to control groups. Serum C3 and C4 levels did not correlate with their saliva levels. The receiver operating characteristic analysis showed significantly diagnostic abilities for serum and saliva C3 and C4 to discrimination of OLP patients from controls (cutoff [mg/dl] for C3 were 83 in serum and 3.45 in saliva and for C4 were 9.5 in serum and 0.9 in saliva). Conclusion: Serum and salivary levels of total C3 and C4 were lower in patients with OLP than in healthy controls. Therefore, they may able to discriminate OLP from healthy. 102 107 2021/01/312020/06/29 1399/4/9 2021/04/102020/11/10 1399/8/20 Mohammad-Hossein Mirzaii-Dizgah Mohammad-Hossein Mirzaii-Dizgah Student Research Committee, School of Dentistry, Aja University of Medical Sciences, Tehran, Iran Iran Bita Rohani Bita Rohani Department of Oral Medicine, School of Dentistry, Aja University of Medical Sciences, Tehran, Iran Iran Iraj Mirzaii-Dizgah Iraj Mirzaii-Dizgah Department of Physiology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran Iran emirzaii@alumnus.tums.ac.ir Complement C3 Complement C4 Oral lichen planus Saliva Serum. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology Saunders. Elsevier, Philadelphia. 2007.##Afshar-Kharghan V. The role of the complement system in cancer. J Clin Invest 2017; 127: 780-9. https://doi.org/10.1172/JCI90962##Agha-Hosseini F, Imanpour M, Mirzaii-Dizgah I, Moosavi MS. Mucin 5B in saliva and serum of patients with oral lichen planus. Sci Rep 2017; 7: 1-6. https://doi.org/10.1038/s41598-017-12157-1##Agha-Hosseini F, Mirzaii-Dizgah I, Mirjalili N. Relationship of unstimulated saliva cortisol level with severity of oral dryness feeling in menopausal women. Aust Dent J 2011a; 56: 171-4. https://doi.org/10.1111/j.1834-7819.2011.01320.x##Agha-Hosseini F, Mirzaii-Dizgah I, Mirjalili N. Relationship of stimulated whole saliva cortisol level with the severity of a feeling of dry mouth in menopausal women. Gerodontology 2012; 29: 43-7. https://doi.org/10.1111/j.1741-2358.2010.00403.x##Agha-Hosseini F, Mirzaii-Dizgah I, Mohebbian M, Sarookani MR. Vascular endothelial growth factor in serum and saliva of oral lichen planus and oral squamous cell carcinoma patients. J Kerman Univ Medical Sci 2018; 25: 27-33.##Agha-Hosseini F, Mirzaii-Dizgah I, Moosavi MS. Relationship of lumbar spine bone mineral density and oral dryness feeling in menopause. Menopause 2011b; 18: 625-8. https://doi.org/10.1097/gme.0b013e31820285b2##Agha-Hosseini F, Mohebbian M, Sarookani MR, Harirchi I, Mirzaii-Dizgah I. Comparative evaluation of EGF in oral lichen planus and oral squamous cell carcinoma. Acta Med Iran 2015; 53: 471-5.##Andoh A, Fujiyama Y, Kimura T, Uchihara H, Sakumoto H, Okabe H, Bamba T. Molecular characterization of complement components (C3, C4, and factor B) in human saliva. J Clin Immunol 1997; 17: 404-7. https://doi.org/10.1023/A:1027320425291##Buajeeb W, Okuma N, Thanakun S, Laothumthut T. Direct immunofluorescence in oral lichen planus. J Clin Diagn Res 2015; 9: ZC34. https://doi.org/10.7860/JCDR/2015/13510.6312##Cheng YS, Gould A, Kurago Z, Fantasia J, Muller S. Diagnosis of oral lichen planus: a position paper of the American Academy of oral and maxillofacial pathology. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 122: 332-54. https://doi.org/10.1016/j.oooo.2016.05.004##Chiang CP, Chang JY, Wang YP, Wu YH, Lu SY, Sun A. Oral lichen planus - Differential diagnoses, serum autoantibodies, hematinic deficiencies, and management. J Formos Med Assoc 2018; 117: 756-65.##https://doi.org/10.1016/j.jfma.2018.01.021##de la Faille-Kuyper Eb, De la Faille HB. An immunofluorescence study of lichen planus. Br J Dermatol 1974; 90: 365-71. https://doi.org/10.1111/j.1365-2133.1974.tb06420.x##Gandolfo S, Carrozzo M, Carbone M, Broccoletti R, Cascio G. Humoral immunological parameters in Italian patients with oral lichen planus. Bull Group Int Rech Sci Stomatol Odontol 1994; 37: 71-7.##Gupta S, Jawanda MK. Oral lichen planus: an update on etiology, pathogenesis, clinical presentation, diagnosis and management. Indian J Dermatol 2015; 60: 222 https://doi.org/10.4103/0019-5154.156315##Huang Y, Zhou S, Cai Y. Expression of interleukin-12 and interleukin-27 proteins and immune status in serum of patients with oral lichen planus. Hua Xi Kou Qiang Yi Xue Za Zhi 2016; 34: 140-4.##Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, et al. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 2005; 437: 505-11. https://doi.org/10.1038/nature04005##Kaczor-Urbanowicz KE, Martin Carreras-Presas C, Aro K, Tu M, Garcia-Godoy F, Wong DT. Saliva diagnostics - current views and directions. Exp Biol Med 2017; 242: 459-72. https://doi.org/10.1177/1535370216681550##Lawrence HP. Salivary markers of systemic disease: noninvasive diagnosis of disease and monitoring of general health. J Can Dent Assoc 2002; 68: 170-5.##Li C, Tang X, Zheng X, Ge S, Wen H, Lin X, et al. Global prevalence and incidence estimates of oral lichen planus: a systematic review and meta-analysis. JAMA Dermatol 2020; 156: 172-81. https://doi.org/10.1001/jamadermatol.2019.3797##Lintner KE, Wu YL, Yang Y, Spencer CH, Hauptmann G, Hebert LA, et al. Early components of the complement classical activation pathway in human systemic autoimmune diseases. Front Immunol 2016; 7: 36. https://doi.org/10.3389/fimmu.2016.00036##Luo L, Shu M, Li S, Cai Y. Expression of soluble programmed death-1, soluble programmed death ligand 1 proteins and immune status in patients with oral lichen planus. Zhonghua Kou Qiang Yi Xue Za Zhi 2015; 50: 585-9.##Mirzaii-Dizgah MR, Mirzaii-Dizgah MH, Mirzaii-Dizgah I. Reduction of saliva and serum 25-hydroxycholecalciferol in multiple sclerosis. J Kerman Univ Medical Sci 2020; 27(2):106-12. https://doi.org/10.22062/JKMU.2020.90613##Mirzaii-Dizgah I, Agha-Hosseini F. Stimulated and unstimulated saliva progesterone in menopausal women with oral dryness feeling. Clin Oral Investig. 2011 Dec;15(6):859-62. https://doi.org/10.1007/s00784-010-0449-z.##Mirzaii-Dizgah I, Riahi E. Salivary high-sensitivity cardiac troponin T levels in patients with acute myocardial infarction. Oral Dis 2013; 19: 180-4. https://doi.org/10.1111/j.1601-0825.2012.01968.x##Mirzaii-Dizgah MH, Mirzaii-Dizgah MR, Mirzaii-Dizgah I. Serum and saliva total tau protein as a marker for relapsing-remitting multiple sclerosis. Med Hypotheses 2020b; 135: 109476. https://doi.org/10.1016/j.mehy.2019.109476##Mittal N, Shankari GM, Palaskar S. Role of angiogenesis in the pathogenesis of oral lichen planus. J Oral Maxillofac Pathol 2012; 16: 45. https://doi.org/10.4103/0973-029X.92972##Mollaoglu N. Oral lichen planus: a review. Br J Oral Maxillofac Surg 2000; 38: 370-7. https://doi.org/10.1054/bjom.2000.0335##Mominzadeh M, Mirzaii-Dizgah I, Mirzaii-Dizgah MR, Mirzaii-Dizgah MH. Stimulated saliva aminotransaminase alteration after experiencing acute hypoxia training. Air Med J 2014; 33: 157-60. https://doi.org/10.1016/j.amj.2014.03.004##Popovska M, Minovska A, Radojkova-Nikolovska V, Muratovska I, Kapuševska B, Aleksova P, et al. Salivary humoral changes in oral lichen planus in bullous lichen planus. Acta Stomatologica Naissi 2015; 31: 1493-503. https://doi.org/10.5937/asn1572493P##Rodríguez-Núñez I, Blanco-Carrión A, García AG, Rey JG. Peripheral T-cell subsets in patients with reticular and atrophic-erosive oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91: 180-8. https://doi.org/10.1067/moe.2001.110415##Sklavounou AD, Laskaris G, Angelopoulos AP. Serum immunoglobulins and complement (C’3) in oral lichen planus. Oral Surg Oral Med Oral Pathol 1983; 55: 47-51. https://doi.org/10.1016/0030-4220(83)90304-3##Sun A, Wu YC, Liang LC, Kwan HW. Serum immunoglobulins, complements and circulating immune complexes in oral lichen planus. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1986; 19: 46-51.##Talungchit S, Buajeeb W, Lerdtripop C, Surarit R, Chairatvit K, Roytrakul S, et al. Putative salivary protein biomarkers for the diagnosis of oral lichen planus: a case-control study. BMC Oral Health 2018; 18: 1-4. https://doi.org/10.1186/s12903-018-0504-8##Trouw LA, Pickering MC, Blom AM. The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol 2017; 13: 538-47. https://doi.org/10.1038/nrrheum.2017.125##van der Meij EH, van der Waal I. Lack of clinicopathologic correlation in the diagnosis of oral lichen planus based on the presently available diagnostic criteria and suggestions for modifications. J Oral Pathol Med 2003; 32: 507-12. https://doi.org/10.1034/j.1600-0714.2003.00125.x##Van der Waal I. Oral lichen planus and oral lichenoid lesions; A critical appraisal with emphasis on the diagnostic aspects. Med Oral Patol Oral Cir Bucal 2009; 14: 310-4.## ##

A study of metabolic syndrome in chronic obstructive pulmonary disease patients attending out-patient department of a medical college 2 2 Introduction: Metabolic syndrome (MetS) occurs as co-morbidity in chronic obstructive pulmonary disease (COPD) and requires evaluation. Methods: MetS was studied in 336 patients of COPD (NCP-ATP III guidelines). TNF-α, IL-6 and C reactive protein were analysed. Patients were divided into metabolic (n=89) and non-MetS (n=247) groups and further divided into mild to very severe COPD category as per Global Initiative for Chronic Obstructive Lung Disease. Results: The 89 patients (26.49%) had MetS. Waist hip ratio (WHR) was more in 80.89% (72/89). Triglycerides and HDL derangements were found in 63 and 75 patients. Fasting blood glucose, systolic and diastolic blood pressure criterion were met by 58 (65.17 %), 20 (22.47%) and 32 (35.95%) patients respectively. In non-MetS group, the derangement in above parameters were found in 41, 53, 109, 47, 43 and 46 patients respectively. Compared to MetS group, significant difference was found in WHR, lipid profile and blood pressure. Significant difference was found in waist circumference, triglycerides, HDL, fasting blood glucose and diastolic blood pressure between COPD groups with and without MetS. Moderate COPD patients had highest MetS. Difference in results as per severity of disease was found to be non-significant. Inflammatory markers between COPD groups with and without MetS were non-significant with levels more in latter group. Within COPD group (as per severity of disease) with MetS their levels were significantly raised. Conclusion: MetS occurs as co-morbidity in COPD and requires evaluation which will help in better management and prevent cardio metabolic complications. 108 115 2021/01/312020/06/292020/02/12 1398/11/23 2021/04/102020/11/102020/11/10 1399/8/20 Shah Mohammad Abbas Waseem Shah Mohammad Abbas Waseem Department of Physiology, JNMC, Aligarh Muslim University, Aligarh , India India abbas14waseem5@gmail.com Najmul Islam Najmul Islam Department of Physiology, JNMC, Aligarh Muslim University, Aligarh , India India COPD Metabolic syndrome Inflammation Lipid profile Blood pressure Blood glucose. Acharyya A, Shahjahan MD, Mesbah FB, Dey SK, Ali L. Association of metabolic syndrome with chronic obstructive pulmonary disease in an Indian population. Lung India 2016; 33:385-90. https://doi.org/10.4103/0970-2113.184871##Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med 2014; 35: 71-86. https://doi.org/10.1016/j.ccm.2013.10.004##Bianco A, Mazzarella G, Turchiarelli V, Nigro E, Corbi G, Scudiero O, et al. Adiponectin: an attractive marker for metabolic disorders in Chronic Obstructive Pulmonary Disease (COPD). Nutrients 2013; 5: 4115-25. https://doi.org/10.3390/nu5104115##Boyer L, Bastuji-Garin S, Chouaid C, Housset B, Le Corvoisier P, Derumeaux G, et al. Are systemic manifestations ascribable to COPD in smokers? a structural equation modeling approach. Sci Rep 2018; 5: 1-8. https://doi.org/10.1038/s41598-018-26766-x##Castro AM, Macedo-De la Concha LE, Pantoja-Meléndez CA. Low-grade inflammation and its relation to obesity and chronic degenerative diseases. Rev Med Hosp Gen (Mex) 2017; 80:101-5. https://doi.org/10.1016/j.hgmx.2016.06.011##Cebron Lipovec N, Beijers RJ, van den Borst B, Doehner W, Lainscak M, Schols AM. The prevalence of metabolic syndrome in chronic obstructive pulmonary disease: a systematic review. Chronic Obstr Pulm Dis 2016; 13: 399-406. https://doi.org/10.3109/15412555.2016.1140732##Chakraborty SN, Roy SK, Rahaman MA. Epidemiological predictors of metabolic syndrome in urban West Bengal, India. J Family Med Prim Care 2015; 4: 535-8. https://doi.org/10.4103/2249-4863.174279##Choudhary PR and Jani RD. Study of pulmonary functions in patients with metabolic syndrome. Physiol Pharmacol 2016; 20: 90-97.##Dedinska I, Laca L, Miklusica J, Palkoci B, Sadlonova J, Galajda P, et al. Is smoking a risk factor for metabolic syndrome? Diabetol Klin 2014; 3: 136-43.##Despres JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008; 28: 1039-49. https://doi.org/10.1161/ATVBAHA.107.159228##Doehner W, Haeusler KG, Endres M, Anker SD, MacNee W, Lainscak M. Neurological and endocrinological disorders: orphans in chronic obstructive pulmonary disease. Respir Med 2011; 105: S12-9. https://doi.org/10.1016/S0954-6111(11)70005-1##Gupta KK, Singh J, Gupta P, Patel ML, Kumar V, Chaudhary SC. Uncovering metabolic syndrome among chronic obstructive pulmonary disease patients in a Tertiary Care Hospital, India. J Clin Diagn Res  2017; 11: 08-11. https://doi.org/10.7860/JCDR/2017/26488.9829##Houssaini A, Breau M, Kanny Kebe SA, Marcos E, Lipskaia L, Rideau D, et al. mTOR pathway activation drives lung cell senescence and emphysema. J Clin Invest Insight 2018; 3. https://doi.org/10.1172/jci.insight.93203##Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech 2009; 2: 231-7. https://doi.org/10.1242/dmm.001180##James BD, Jones AV, Trethewey RE and Evans RA. Obesity and metabolic syndrome in COPD: is exercise the answer? Chronic Respir Dis 2018; 15: 173-81. https://doi.org/10.1177/1479972317736294##Jaswal S, Saini V, Kaur J, Gupta S, Kaur H, Garg K. Association of adiponectin with lung function impairment and disease severity in chronic obstructive pulmonary disease. Int J App Basic Med Res 2018; 8: 14. https://doi.org/10.4103/ijabmr.IJABMR_65_17##Kane S, Bajpai S, Biswas TK. A clinical study of COPD in elderly with special reference to HRCT chest and PFT. Int Arch Integrated Med 2018; 5: 99-104.##Kolovou GD, Kolovou V and Mavrogeni S. Cigarette smoking/cessation and metabolic syndrome. Clin Lipidol 2016; 11: 6-14.##Lazovic B, Stajic Z, Mazic S and Đelic M. Prevalence of metabolic syndrome in patients suffered from chronic obstructive pulmonary disease. Timok Medical Gazettes 2012; 37.##Mantoo S, Khan UH, Mohamad Akbar Shah, Qadri SM, Mir AW, Shah ZA, et al. Systemic inflammatory markers as predictor of severity of chronic obstructive pulmonary disease (COPD) a case - control study. Int J Contemp Med Res 2017; 4: 241-245.##Mirrakhimov AE. Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony. Cardiovasc Diabetol 2012; 11: 1-26. https://doi.org/10.1186/1475-2840-11-132##Mohanan PP. Metabolic syndrome in the Indian population: public health implications. Hypertens J 2016; 2: 1-6. https://doi.org/10.5005/jp-journals-10043-0021##Naik D, Joshi A, Paul TV, Thomas N. Chronic obstructive pulmonary disease and the metabolic syndrome: consequences of a dual threat. Indian J Endocrinol Metab 2014; 18: 608.##Pasdar Y, Nazari LH, Rezaei M, Barzegar A, Darbandi M Niazi P. Which factors predict metabolic syndrome? A cross sectional study in Kermanshah, Iran. Ann Trop Med Public Health 2017; 10: 993. https://doi.org/10.4103/ATMPH.ATMPH_308_17##Pasha MM, Salimath S, Rao MK. Metabolic syndrome in chronic obstructive pulmonary disease. Int J Adv Med 2018; 5: 597-603. https://doi.org/10.18203/2349-3933.ijam20182109##Rafie S, Moitra S, Brashier BB. Association between the serum metabolic profile and lung function in chronic obstructive pulmonary disease. Turk Thorac J 2018; 19: 13. https://doi.org/10.5152/TurkThoracJ.2017.17043##Ragulan R, Viswambhar V, Krishnaveni R, Meenakshi Narasimhan, Aruna Shanmuganathan, Nisha Ganga, et al. Evaluation of platelet indices among patients with exacerbation of COPD in a tertiary care center in South India. IAIM 2017; 4: 161-166.##Siafakas NM, Tzortzaki EG. Few smokers develop COPD. Why? Respir Med 2002; 96: 615-24. https://doi.org/10.1053/rmed.2002.1318##Singh A, Shenoy S, Sandhu JS. Prevalence of metabolic syndrome and its risk factors among urban Sikh population of Amritsar. J Postgrad Med Edu Res 2015; 49: 18. https://doi.org/10.5005/jp-journals-10028-1137##Sun K, Liu J and Ning G. Active smoking and risk of metabolic syndrome: a meta analysis of prospective studies. Plos One 2012; 7: e47791. https://doi.org/10.1371/journal.pone.0047791##Terzikhan N, Verhamme KM, Hofman A, Stricker BH, Brusselle GG, Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study. Eur J Epidemiol 2016; 31: 785-92. https://doi.org/10.1007/s10654-016-0132-z##Thakur S, Raina S, Thakur S, Negi PC, Verma BS. Prevalence of metabolic syndrome among newly diagnosed hypertensive patients in the hills of Himachal Pradesh, India. Indian J Endocrinol Metab 2013; 17: 723. https://doi.org/10.4103/2230-8210.113768##Verma AK, Singh S, Gupta P and Tripathi AK. Role of vitamin D in the management of chronic obstructive pulmonary disease: an option or necessity. J Med Dent Sci 2015; 4: 11063-9. https://doi.org/10.14260/jemds/2015/1593##Vitezova A, Zillikens MC, Van Herpt TT, Sijbrands EJ, Hofman A, Uitterlinden AG, et al. Vitamin D status and metabolic syndrome in the elderly: the Rotterdam Study. Eur J Endocrinol 2015; 172: 327-5. https://doi.org/10.1530/EJE-14-0580##Waseem SM, Hossain M, Rizvi SA, Zuber Ahmad NI. Oxidative stress and lipid profile in COPD patients: beneficial role of exercise and scope for improvement. Biomed Res 2013; 24: 135-8.##Waseem SM, Hossain MM, Rizvi S, Islam N, Ahmad Z. Comparative study of oxidant antioxidants and inflammatory markers between obese and non-obese newly diagnosed COPD patients. Indian J Physiol Pharmacol 2015; 59: 341-5.##Waseem SMA, Hossain MM, Islam N and Ahmad Z. Comparative Study of pulmonary functions and oxidative stress in smokers and non-smokers. Indian J Physiol Pharmacol 2012; 56: 345-352.##Waseem SM, Srivastava VK, Bano R, Singh S, Dhunagana H. Anemia as co-morbidity in COPD: comparative study of oxidant anti-oxidant imbalance in anemic and non anemic COPD patients. Int J Contemp Med Res 2017; 4: 1223-7.## ##

Extra ordinary high blood lead levels in Mashhad,Iran: a one-year study in a referral center 2 2 Introduction: Lead is a heavy metal with vast usage in the industry. Lead toxicity affects any organ in the body. It causes various clinical presentations, which leads to diagnostic complexity. Regarding recent increased observation of cases with lead toxicity in our center, we aimed to evaluate the frequencies of lead toxicity in patients referred to Imam-Reza Hospital’s laboratory and find a possible relationship between the blood lead level (BLL) and hematological and biochemical tests. Methods: From 2016 to 2017, the patients referred to Imam-Reza hospital’s laboratory to detect BLL enrolled in the study. Among them, 254 adult cases with BLLs≥10 μg/dl were selected. Complete blood counts and peripheral blood smear were done. Other lab data were extracted from hospital files. Results: The mean BLL of 1649 participants was 59.11±116.25 μg/dl, ranging from 0 to 1580. Sixty nine percent of them had lead toxicity. Eighty-one percent (n=1341) of patients were males and 18.7% (n=308) were females. In 254 selected cases, the mean BLL was 138.17±189.98 μg/dl. There were significant inverse correlations between BLL and red blood cell counts, hemoglobin, mean cell hemoglobin, total iron-binding capacity, target shape and basophilic stippling, as well as positive correlations between BLL and white blood cell counts, red cell distribution width, neutrophil counts and iron. Conclusion: Lead toxicity seems to be more frequent than it is expected. Patients with unexplained anemia with increased iron and decreased total iron-binding capacity are better to be evaluated for BLL. 116 124 2021/01/312020/06/292020/02/122020/04/26 1399/2/7 2021/04/102020/11/102020/11/102020/11/10 1399/8/20 Samaneh Boroumand-Noughabi Samaneh Boroumand-Noughabi Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Mohammad Reza Keramati Mohammad Reza Keramati Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Keramatimr@mums.ac.ir Zahra Sadrzadeh Sadrzadeh Zahra Sadrzadeh Sadrzadeh Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Zohreh Asadi Zohreh Asadi Central Laboratory, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran Iran Shirin Taraz Jamshidi Shirin Taraz Jamshidi Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Lead toxicity Opium Hematological tests Biochemical tests Blood Lead Level. Ab Latif Wani AA, Usmani JA. Lead toxicity: a review. Interdiscip Toxicol 2015; 8: 55-64. https://doi.org/10.1515/intox-2015-0009##Abbasi MM, Ansari M, Shahesmaeili A, Qaraie A. Lead serum levels in opium-dependent individuals. Addict Health 2009; 1: 106.##Ahmadinejad M, Ahmadipour M, Divsalar K. Blood lead level in opiate addicts hospitalized in the intensive care unit of a trauma referral center in Kerman, Iran. Addict Health 2019; 11: 11-17.##Alasia DD, Emem-Chioma PC, Wokoma FS. Association of lead exposure, serum uric acid and parameters of renal function in Nigerian lead-exposed workers. Int J Occup Environ Med (The IJOEM) 2010; 1.##Alinejad S, Aaseth J, Abdollahi M, Hassanian-Moghaddam H, Mehrpour O. Clinical aspects of opium adulterated with lead in Iran: a review. Basic Clin Pharmacol Toxicol 2018; 122: 56-64. https://doi.org/10.1111/bcpt.12855##Amiri M, Amini R. A comparison of blood-lead level (BLL) in opium-dependant addicts with healthy control group using the graphite furnace/atomic absorption spectroscopy (GF-AAS) followed by chemometric analysis. Iran Red Crescent Med J 2012; 14: 488-91.##Balali-Mood M, Shademanfar S, Moghadam JR, Afshari R, Ghassemi MN, Nemati HA, et al. Occupational lead poisoning in workers of traditional tile factories in Mashhad, Northeast of Iran. Int J Occup Environ Med (The IJOEM) 2010; 1.##Beigmohammadi MT, Aghdashi M, Najafi A, Mojtahedzadeh M, Karvandian K. Quadriplegia due to lead-contaminated opium--case report. Middle East J Anaesthesiol 2008; 19: 1411-6.##Bhagwat VR, Patil AJ, Patil JA, Sontakke AV. Occupational lead exposure and liver functions in battery manufacture workers around Kolhapur (Maharashtra). Al Ameen J Med Sci 2008; 1: 2-9.##Buser MC, Ingber SZ, Raines N, Fowler DA, Scinicariello F. Urinary and blood cadmium and lead and kidney function: NHANES 2007-2012. Int J Hyg Environ Health 2016; 219: 261-7. https://doi.org/10.1016/j.ijheh.2016.01.005##Carvalho FM, Silvanyneto AM, Barbosa AC, Cotrim CR, Tavares TM. Erythrocyte protoporphyrin versus blood lead: relationship with iron status among children exposed to gross environmental pollution. Environ Res 1995; 71: 11-5. https://doi.org/10.1006/enrs.1995.1061##Dadpour B, Afshari R, Mousavi SR, Kianoush S, Keramati MR, Moradi VA, et al. Clinical and laboratory findings of lead hepatotoxicity in the workers of a car battery manufacturing factory. Iranian Journal of Toxicology 2016; 10: 1-6.##Deldar K, Nazemi E, Mood MB, Emami SA, MohammadPour AH, Tafaghodi M, et al. Effect of Coriandrum sativum L. extract on lead excretion in 3-7 year old children. J Birjand Univ Med Sci 2008; 15: 11-19.##Domeneh BH, Tavakoli N, Jafari N. Blood lead level in opium dependents and its association with anemia: a cross-sectional study from the capital of Iran. J Res Med Sci 2014; 19: 939-43.##Dongre NN, Suryakar A, Patil AJ, Rathi D. Occupational lead exposure in automobile workers in North Karnataka (India): effect on liver and kidney functions. Al Ameen J Med Sci 2010; 3: 284-92.##Fakoor M, Akhgari M, Shafaroodi H. Lead poisoning in opium-addicted subjects, its correlation with pyrimidine 5′-nucleotidase activity and liver function tests. Int J Prev Med 2019; 10. https://doi.org/10.4103/ijpvm.IJPVM_490_18##Farhat ASH, Parizadeh SMJ, Balali M, Khademi GR. The serum lead level of children in emergency ward. Med J Mashad Univ Med Sci 2006; 48: 405-8.##Farzin L, Amiri M, Shams H, Ahmadi Faghih MA, Moassesi ME. Blood levels of lead, cadmium, and mercury in residents of Tehran. Biol Trace Elem Res 2008; 123: 14-26. https://doi.org/10.1007/s12011-008-8106-y##Fatemi R, Jafarzadeh F, Moosavi S, Afshar Amin F. Acute lead poisoning in an opium user: a case report. Gastroenterol Hepatol From Bed Bench 2008; 1: 139-42.##Froutan H, Kashefi ZA, Kalani M, Andrabi Y. Lead toxicity: a probable cause of abdominal pain in drug abusers. Med j Islam Repub Iran 2011; 25: 16-20.##Gerhardsson L, Chettle DR, Englyst V, Nordberg GF, Nyhlin H, Scott MC, et al. Kidney effects in long term exposed lead smelter workers. Occup Environ Med 1992; 49: 186-92. https://doi.org/10.1136/oem.49.3.186##Ghane T, Zamani N, Hassanian-Moghaddam H, Beyrami A, Noroozi A. Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016-2017. Bull World Health Organ 2018; 96: 165-72. https://doi.org/10.2471/BLT.17.196287##Gidlow DA. Lead toxicity. Occup Med 2015; 65: 345-56. https://doi.org/10.1093/occmed/kqv018##Halmo L, Nappe TM. Lead Toxicity. Treasure Island (FL): StatPearls Publishing 2021.##Hassanian-Moghaddam H, Zamani N, Hamidi F, Farnaghi F, Gachkar L. Blood lead levels in pregnant women referring to midwifery clinic in a referral center in Tehran. J Res Med Sci 2018; 23: 88. https://doi.org/10.4103/jrms.JRMS_72_18##Hayatbakhsh MM, Oghabian Z, Conlon E, Nakhaee S, Amirabadizadeh AR, Zahedi MJ, et al. Lead poisoning among opium users in Iran: an emerging health hazard. Subst Abuse Treat Prev Policy 2017; 12: 1-8. https://doi.org/10.1186/s13011-017-0127-0##Jalili M, Azizkhani R. Lead toxicity resulting from chronic ingestion of opium. West J Emerg Med 2009; 10: 244-6.##Karrari P, Mehrpour O, Abdollahi M. A systematic review on status of lead pollution and toxicity in Iran; Guidance for preventive measures. DARU J Pharm Sci 2012; 20: 1-7. https://doi.org/10.1186/1560-8115-20-2##Keramati MR, Sadeghian MH, Mahdi M. Correlation between iron deficiency and lead intoxication in the workers of a car battery plant. Int J Hematol Oncol Stem Cell Res 2010; 30: 169-74.##Kianoush S, Balali-Mood M, Mousavi SR, Shakeri MT, Dadpour B, Moradi V, et al. Clinical, toxicological, biochemical, and hematologic parameters in lead exposed workers of a car battery industry. Iran J Med Sci 2013; 38: 30.##Kim HS, Lee SS, Hwangbo Y, Ahn KD, Lee BK. Cross-sectional study of blood lead effects on iron status in Korean lead workers. Nutrition 2003; 19: 571-6. https://doi.org/10.1016/S0899-9007(03)00035-2##Kshirsagar M, Patil J, Patil A, Ghanwat G, Sontakke A, Ayachit RK. Biochemical effects of lead exposure and toxicity on battery manufacturing workers of Western Maharashtra (India): with respect to liver and kidney function tests. Al Ameen J Med Sci 2015; 8: 107-14.##Kuhlmann WD. Romanowsky-Giemsa staining. MVZ für Laboratoriumsmedizin Koblenz-Mittelrhein Viktoriastrasse 2018; 39: 56068.##Leikin S, Eng G. Erythrokinetic studies of the anemia of lead poisoning. Pediatrics 1963; 31: 996-1002.##Lilis R, Eisinger J, Blumberg W, Fischbein A, Selikoff IJ. Hemoglobin, serum iron, and zinc protoporphyrin in lead-exposed workers. Environ Health Perspect 1978; 25: 97-102. https://doi.org/10.1289/ehp.782597##Mansoori M, Shah Farhat A, Mohammadzadeh A. The evaluation of the effect of maternal blood lead concentration on the incidence of delivery of low birth weight neonates. J Kurdistan Uni Med Sci 2009; 14: 41-46.##Masoodi M, Zali MR, Ehsani-Ardakani M, Mohammad-Alizadeh AH, Aiassofi K, Aghazadeh R, et al. Abdominal pain due to lead-contaminated opium: a new source of inorganic lead poisoning in Iran. Arch Iran Med 2006; 9: 72-75.##McPherson RA. Henry’s clinical diagnosis and management by laboratory methods: First South Asia Edition_e-Book: Elsevier India, 2017.##Meybodi FA, Eslick GD, Sasani S, Abdolhoseyni M, Sazegar S, Ebrahimi F. Oral opium: an unusual cause of lead poisoning. Singapore Med J 2012; 53: 395-7.##Moharari RS, Khajavi MR, Panahkhahi M, Mojtahedzadeh M, Najafi A. Loss of consciousness secondary to lead poisoning--case reports. Middle East J Anaesthesiol 2009; 20: 453-5.##Nakhaee S, Amirabadizadeh A, Brent J, Mehrpour O. Impact of chronic lead exposure on liver and kidney function and haematologic parameters. Basic Clin Pharmacol Toxicol 2019; 124: 621-28. https://doi.org/10.1111/bcpt.13179##Palmer L, Briggs C, McFadden S, Zini G, Burthem J, Rozenberg G, et al. ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. Int J Lab Hematol 2015; 37: 287-303. https://doi.org/10.1111/ijlh.12327##Patil AJ, Bhagwat VR, Patil JA, Dongre NN, Ambekar JG, Das KK. Biochemical aspects of lead exposure in silver jewelry workers in western Maharastra (India). J Basic Clin Physiol Pharmacol 2006; 17: 213-30. https://doi.org/10.1515/JBCPP.2006.17.4.213##Salman-Roghani H, Foroozan A. Lead poisoning, report of an interesting case. Govaresh J 2009; 14: 39-45.##Soltaninejad K, Flückiger A, Shadnia S. Opium addiction and lead poisoning. J Subst Use 2011; 16: 208-12. https://doi.org/10.3109/14659891.2010.545860##Soltaninejad K, Shadnia S. Lead poisoning in opium abuser in Iran: a systematic review. Int J Prev Med 2018; 9. https://doi.org/10.4103/ijpvm.IJPVM_22_17##Verheij J, Voortman J, van Nieuwkerk CM, Jarbandhan SV, Mulder CJ, Bloemena E. Hepatic morphopathologic findings of lead poisoning in a drug addict: a case report. J Gastrointestin Liver Dis 2009; 18: 225-7.##Wang VS, Lee MT, Chiou JY, Guu C-F, Wu CC, Wu TN, et al. Relationship between blood lead levels and renal function in lead battery workers. Int Arch Occup Environ Health 2002; 75: 569-75. https://doi.org/10.1007/s00420-002-0362-0##Wibowo AA, Del Castilho P, Herber R, Zielhuis R. Blood lead and serum iron levels in non-occupationally exposed males and females. Int Arch Occup Environ Health 1977; 39: 113-20. https://doi.org/10.1007/BF00380891## ##

The effect of vitamin D therapy on glycemic control and biochemical indices in type 2 diabetic patients: a randomized, clinical trial study 2 2 Introduction: The aim of the present study was to evaluate the effect of vitamin D on glycemic control and biochemical indices in type 2 diabetes. Methods: This randomized double blind placebo-controlled clinical trial was conducted on 80 patients with type 2 diabetes mellitus (T2DM) referred to Shahid Beheshti hospital. These patients were randomly classified into case and control groups. Case group consumed 50,000 IU of vitamin D once a week for 12 weeks and control group placebo. Biochemical and lipid parameters and vitamin D3 were measured in two groups. Glycosylated hemoglobin (HbA1c) was assessed by latex enhance immunoturbidimetric assay. Results: There was no significant difference between case and control groups in terms of age, sex, body mass index and used medications. The mean vitamin D level in case and control groups before intervention was 15.06 ±3.307 and 15.83± 2.509 ng/ml and after intervention was 49.77 ±15.73 and 14.91±3.13 ng/ml respectively. The mean fast blood sugar in case and control groups after intervention was 156.565±32.23 and 147.75±35.06 mg/dl, respectively. The mean HbA1c in case and control groups before intervention was 7.59± 0.39 % and 7.66± 0.38 % and after intervention was 7.26 ± 0.60 and 7.60 ± 0.38, respectively. Moreover, significant difference was seen between case (20.2± 5.74 IU/L) and control groups (23.35± 7.80 IU/L) in terms of alanine aminotransferase, after intervention. Conclusion: According to these findings, vitamin D supplementation possibly through decreasing HbA1C and hepatic alanine aminotransferase could improve diabetes complications. 125 133 2021/01/312020/06/292020/02/122020/04/262019/10/23 1398/8/1 2021/04/102020/11/102020/11/102020/11/102020/12/13 1399/9/23 Majid Mozaffari Majid Mozaffari Department of Internal Medicine, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran Iran Mozaffari-m@kaums.ac.ir Hamed Hajmoradi Hamed Hajmoradi Department of Internal Medicine, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran Iran Alireza Moravveji Alireza Moravveji Social Determinants of Health Research Center, Kashan University of Medical Sciences, Kashan, Iran Iran Fatemeh Sadat Asgarian Fatemeh Sadat Asgarian Social Determinants of Health Research Center, Kashan University of Medical Sciences, Kashan, Iran Iran Parastoo Noory Parastoo Noory Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Iran Glycemic control Type 2 diabetes Vitamin D. Athanassiou I, Athanassiou P, Gkountouras A, Kaldrymides P. Vitamin D and glycemic control in diabetes mellitus type 2. Ther Adv Endocrinol Metab 2013; 4: 122-8. https://doi.org/10.1177/2042018813501189##Bently R. Significant independent predictors of Vitamin D deficiency in inpatients and outpatients of a nephrology unit. Int J Endocrinol 2013. https://doi.org/10.1155/2013/237869 ##Brijesh M, Saurav P. Prevalence of vitamin D deficiency in type 2 diabetes mellitus patients and its correlation with glycemic control. Int J Bioassays 2014; 3: 3313-7. ##Buhary BM, Almohareb O, Aljohani N, Alrajhi S, Elkaissi S, Sherbeeni S, et al. Association of glycosylated hemoglobin levels with vitamin D status. J Clin Med Res 2017; 9: 1013. https://doi.org/10.14740/jocmr3227w ##Calle C, Maestro B, García-Arencibia M. Genomic actions of 1,25-dihydroxyvitamin D3 on insulin receptor gene expression, insulin receptor number and insulin activity in the kidney, liver and adipose tissue of streptozotocin-induced diabetic rats. BMC Mol Biol 2008; 9: 1-2. https://doi.org/10.1186/1471-2199-9-65 ##Chagas CE, Borges MC, Martini LA, Rogero MM. Focus on vitamin D, inflammation and type 2 diabetes. Nutrients 2012; 4: 52-67. https://doi.org/10.3390/nu4010052 ##Christensen R, Lorenzen JK, Svith CR, Bartels EM, Melanson EL, Saris WH, et al. Effect of calcium from dairy and dietary supplements on faecal fat excretion: a meta-analysis of randomized controlled trials. Obes Rev 2009; 10: 475-86. https://doi.org/10.1111/j.1467-789X.2009.00599.x ##DeGiorgio CM, Hertling D, Curtis A, Murray D, Markovic D. Safety and tolerability of vitamin D3 5000 IU/day in epilepsy. Epilepsy Behav 2019; 94: 195-7. https://doi.org/10.1016/j.yebeh.2019.03.001 ##Eftekhari MH, Akbarzadeh M, Dabbaghmanesh MH, Hasanzadeh J. Effects of treatment with oral calcitriol on plasma glucose and insulin levels in non-insulin dependent diabetes mellitus patients. Iranian J Nutr Sci Food Technol 2011; 6: 1-0. ##Esteghamati A, Ashraf H, Khalilzadeh O, Rshidi A, Mohammad K, Asgari F, et al. Trends of diabetes according to body mass index levels in Iran: results of the national Surveys of Risk Factors of Non-Communicable Diseases (1999-2007). Diabet Med 2010; 27: 1233-40. https://doi.org/10.1111/j.1464-5491.2010.03103.x ##Esteghamati A, Gouya M, Abbasi M, Delavari A, Alikhani S, Alaedini F, et al. prevalence of diabetes and impaired fasting glucose in the adult population of Iran national survey of risk factors for non-communicable diseases of Iran. Diabetes Care 2008; 31: 96-8. https://doi.org/10.2337/dc07-0959 ##Fondjo LA, Owiredu WK, Sakyi SA, Laing EF. Vitamin D status and its association with insulin resistance among type 2 diabetics: a case -control study in Ghana. PLoS One 2017; 12. https://doi.org/10.1371/journal.pone.0175388 ##Foroughi M, Maghsoudi Z, Ghiasvand R, Iraj B, Askari G. Effect of Vitamin D supplementation on C-reactive protein in patients with nonalcoholic fatty liver. Int J Prev Med 2014; 5: 969. ##Hariri M, Zohdi S. Effect of vitamin D on non-alcoholic fatty liver disease: a systematic review of randomized controlled clinical trials. Int J Prev Med. 2019; 10: 14-18. https://doi.org/10.4103/ijpvm.IJPVM_499_17 ##Hidayat R, Setiati S, Soewondo P. The association between vitamin D deficiency and type 2 diabetes mellitus in elderly patients. Acta Med Indones 2010; 52: 66-7.##Infante M, Ricordi C, Sanchez J, Clare-Salzler MJ, Padilla N, Fuenmayor V, et al. Influence of vitamin D on islet autoimmunity and beta-cell function in type 1 diabetes. Nutrients 2019; 11: 2185. https://doi.org/10.3390/nu11092185 ##Jafari T. Effects of vitamin D on serum lipid profile in patients with type 2 diabetes: a metaanalysis of randomized controlled trials. Clin Nutr 2016; 35: 1259-68. https://doi.org/10.1016/j.clnu.2016.03.001 ##John WG, Noonan K, Mannan N, Boucher BJ. Hypovitaminosis D is associated with reductions in serum apolipoprotein A-I but not with fasting lipids in British Bangladeshis. American J Clin Nutr 2005; 82: 517-22. https://doi.org/10.1093/ajcn/82.3.517##Saeidlou SN, Vahabzadeh D, Babaei F, Vahabzadeh Z. Seasonal variations of vitamin D and its relation to lipid profile in Iranian children and adults. Journal of Health, Population and Nutrition. 2017 Dec;36(1):1-7. ##Kim S, Kim GS, Lee JH, Moon AE, Yoon H. The relationship between vitamin D and estimated glomerular filtration rate and urine microalbumin/creatinine ratio in Korean adults. J Clin Biochem Nutr 2018; 62: 94-9. https://doi.org/10.3164/jcbn.17-69 ##Komisarenko YI, Bobryk MI. Vitamin D deficiency and immune disorders in combined endocrine pathology. Front. Endocrinol 2018; 9: 600. https://doi.org/10.3389/fendo.2018.00600 ##Laway BA, Kotwal SK, Shah ZA. Pattern of 25 hydroxy vitamin D status in North Indian people with newly detected type 2 diabetes: a prospective case control study. Int J Endocrinol Metab 2014; 18: 726. ##Lim S, Kim MJ, Lim S, Kim MJ, Choi SH, Shin CS et al. Association of vitamin D deficiency with incidence of type 2 diabetes in high-risk Asian subjects. Am J Clin Nutr 2013; 97: 542-30. https://doi.org/10.3945/ajcn.112.048496 ##Lips P, Eekhoff M, van Schoor N, Oosterwerff M, de Jongh R, Krul-Poel Y, et al. Vitamin D and type 2 diabetes. J Steroid Biochem Mol Biol 2017; 173: 280-5. https://doi.org/10.1016/j.jsbmb.2016.11.021 ##Mariam W, Garg S, Singh MM, Koner BC, Anuradha S, Basu S. Vitamin D status, determinants and relationship with biochemical profile in women with type 2 diabetes mellitus in Delhi, India. Diabetes Metab Syndr: Clinical Rese Rev 2019; 13: 1517-21. https://doi.org/10.1016/j.dsx.2019.03.005##Akha O, Bahar A, Fooldi B, Kashi Z. Effect of vitamin D deficiency correction on glycemic control in patients with type II diabetes mellitus with moderate and severe vitamin D deficiency. Journal of Mazandaran University of Medical Sciences. 2015 Sep 10;25(128):66-76. ##Mezza T, Muscogiuri G, Sorice GP, Prioletta A, Salomone E, Pontecorvi A, et al. Vitamin D deficiency: a new risk factor for type 2 diabetes? Ann Nutr Metab 2012; 61: 337-48. https://doi.org/10.1159/000342771 ##Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 2011; 94: 486-94. https://doi.org/10.3945/ajcn.111.011684 ##Modi KD, Ahmed MI, Chandwani R, Kumar KH. Prevalence of vitamin D deficiency across the spectrum of glucose intolerance. J Diabetes Metab Disord 2015; 14: 1-4. https://doi.org/10.1186/s40200-015-0179-5 ##Mousa A, Naderpoor N, Teede HJ, De Courten MP, Scragg R, De Courten B. Vitamin D and cardiometabolic risk factors and diseases. Minerva Endocrinol 2015; 40: 213-30. ##Nathan DM, Davidson MB, Defronzo RA, Heine RJ, Henry RR, Pratley R, et al. Impaired fasting glucose and impaired glucose tolerance implications for care. Diabetes Care 2007: 3: 753-9. https://doi.org/10.2337/dc07-9920 ##Ostoglou-Athanassiou I, Athanassiou P. Vitamin D and glycemic control in diabetes mellitus type 2. Ther Adv Endocrinol Metab 2013; 4: 122-8. https://doi.org/10.1177/2042018813501189 ##Pittas AG, Lau J, Hu FB. and Dawson-Hughes, B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2017; 92: 2017-29. https://doi.org/10.1210/jc.2007-0298 ##Pittas AG, Nelson J, Mitri J, Hillmann W, Garganta C, Nathan D, et al. Plasma 25-hydroxyvitamin D and progression to diabetes in patients at risk for diabetes: an ancillary analysis in the Diabetes Prevention Program. Diabetes Care 2012; 35: 565-73. https://doi.org/10.2337/dc11-1795 ##Saedisomeolia A, Taheri E, Djalali M, Moghadam AM, Qorbani M. Association between serum level of vitamin D and lipid profiles in type 2 diabetic patients in Iran. J Diabetes Metab Disord 2014; 13: 1-5. https://doi.org/10.1186/2251-6581-13-7 ##Shehata E, Qayyum R. The effect of serum vitamin D on serum ALT levels in healthy individuals. J Clin Gastroenterol 2016; 50: 81-4. https://doi.org/10.1097/MCG.0000000000000459 ##Sheikhpour E, Sadri Z, Heydari S, Ghanizadeh F, Zare-Zardini H, Atefi A, et al. Vitamin D deficiency and its relation with cancer in children. Iran J Ped Hematol Oncol 2018; 8: 180-6. ##Sheikhpour R. A survey on herbal medicines for hypoglycemia in diabetic patients. Iran J Diabetes Obes 2012. ##Sheikhpour R, Jalali BA, Yaghmaei P, Afkhami-Ardekani M, Rashidi M. Comparison of two supplementary zinc doses on lipid peroxidation in diabetic patients. Iranian J Diab Obes 2010. ##Sheikhpour, Jalali-KhanAbadi B, Yaghmaei P, Salmani M H, Afkhami Ardakani M. The effect of zinc supplemention on glycosylated hemoglobin in type II diabetic patients. J Shahrekord Univ Med Sci 2011; 12: 58-63. ##Tavakoli H, Rostami H, Avan A, Bagherniya M, Ferns GA, Khayyatzadeh SS, et al. High dose vitamin D supplementation is associated with an improvement in serum markers of liver function. Biofactors 2019; 45: 335-42. https://doi.org/10.1002/biof.1496 ##Thnc O, Cetinkaya S, Kizilgün M, Aycan Z. Vitamin D status and insulin requirements in children and adolescent with type 1 diabetes. J Pediatr Endocrinol Metab 2011; 24: 1037-41. https://doi.org/10.1515/JPEM.2011.213 ##Wang Y, Si S, Liu J, Wang Z, Jia H, Feng K, et al. The associations of serum lipids with vitamin D status. PLoS One 2016; 11. https://doi.org/10.1371/journal.pone.0165157 ##Zaroudi M, Yazdani CJ, Mehrabi S, Ghorbani E, Norouzkhani J, Shirashiani H, et al. Dietary patterns are associated with risk of diabetes type 2: a population-based case-control study. Arch Iranian Med 2016.## ##

Oxidative stress profile following the co-administration of cisplatin and resveratrol in female rats: a preliminary study 2 2 Introduction: Cisplatin is one of the most widely used drugs for the treatment of various cancers but has oxidative tissue damage as one of its side effects. This study investigated the oxidative stress profile in some important body tissues following the co-administration of cisplatin (CIS) and resveratrol (RSV). Methods: Thirty-five adult female rats with an average body weight of 162g were divided into 5 groups (n=7) and used for this experimental study. Group A served as the normal control group and received distilled water only. Group B received only a single dose intraperitoneal injection of 10mg/kg CIS. Groups C, D and E were orally given 5, 10 and 20mg/kg of RSV respectively for 7 days, starting 24h after a single CIS dose intraperitoneal injection of 10mg/kg. Selected body tissues were harvested for oxidative stress profiling at the end of the experiment. Results: CIS significantly increased malondialdehyde levels and decreased glutathione, superoxide dismutase and catalase levels in all the tissues assessed (ovary, uterus, liver, kidney, pancreas, stomach and spleen) when compared to the normal control. The RSV treatment caused the reversal of these effects; malondialdehyde levels were significantly decreased, while glutathione, superoxide dismutase and catalase levels were significantly increased across all the examined tissues. Conclusion: RSV at different doses could be effective in the management of CIS-induced oxidative stress and lipid peroxidation across some body tissues. However, this effect may be dependent on the dose of CIS and RSV. 134 145 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/4 1399/3/15 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/23 1399/9/3 Izuchukwu Azuka Okafor Izuchukwu Azuka Okafor Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, PMB 5001, Nnewi, Nigeria Nigeria iza.okafor@unizik.edu.ng Cisplatin Oxidative stress Resveratrol Antioxidants. Akbel E, Arslan-Acaroz D, Demirel HH, Kucukkurt I, Ince S. The subchronic exposure to malathion, an organophosphate pesticide, causes lipid peroxidation, oxidative stress, and tissue damage in rats: the protective role of resveratrol. Toxicol Res 2018; 7: 503-12. https://doi.org/10.1039/C8TX00030A##Amin A, Hamza AA, Kambal A, Daoud S. Herbal extracts counteract cisplatin-induced cell death in rat testis. Asian J Androl 2008;10: 291-7. https://doi.org/10.1111/j.1745-7262.2008.00379.x##Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL. Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 2009; 486: 95-102. https://doi.org/10.1016/j.abb.2009.01.018##Bhattacharjee S. Reactive oxygen species and oxidative burst: roles in stress, senescence and signal transducation in plants. Curr Sci 2005; 10: 1113-21.##Bolis G, Favalli G, Danese S, Zanaboni F, Mangili G, Scarabelli C, et al. Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 1997; 15: 1938-44. https://doi.org/10.1200/JCO.1997.15.5.1938##Coppin CM, Gospodarowicz MK, James K, Tannock IF, Zee B, Carson J, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol 1996; 14: 2901-7. https://doi.org/10.1200/JCO.1996.14.11.2901##Coskun N, Hatipoglu MT, Özoğul C, Korkmaz C, Akyol SN, Mıcılı SC, et al. The protective effects of acetyl L-carnitine on testis gonadotoxicity induced by Cisplatin in rats. Balkan Med J 2013; 30: 235. https://doi.org/10.5152/balkanmedj.2013.7340##Frémont L. Biological effects of resveratrol. Life Sci 2000; 66: 663-73. https://doi.org/10.1016/S0024-3205(99)00410-5##Fukui M, Choi HJ, Zhu BT. Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death. Free Radic Biol Med 2010; 49: 800-13. https://doi.org/10.1016/j.freeradbiomed.2010.06.002##Gedik E, Girgin S, Ozturk H, Obay BD, Ozturk H, Buyukbayram H. Resveratrol attenuates oxidative stress and histological alterations induced by liver ischemia/reperfusion in rats. World J Gastroenterol 2008; 14: 7101. https://doi.org/10.3748/wjg.14.7101##Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox Biol 2015; 6: 524-51. https://doi.org/10.1016/j.redox.2015.08.020##Hamadi N, Mansour A, Hassan MH, Khalifi-Touhami F, Badagry O. Ameliorative effects of resveratrol on liver injury in streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 2012; 26: 384-92. https://doi.org/10.1002/jbt.21432##Hanchate LP, Sharma SR, Madyalkar S. Cisplatin induced acute myocardial infarction and dyslipidemia. J Clin Diagn Res 2017; 11. https://doi.org/10.7860/JCDR/2017/25546.10025##Ince S, Acaroz DA, Neuwirth O, Demirel HH, Denk B, Kucukkurt I, et al. Protective effect of polydatin, a natural precursor of resveratrol, against Cisplatin-induced toxicity in rats. Food Chem Toxicol 2014; 72: 147-53. https://doi.org/10.1016/j.fct.2014.07.022##Liu FC, Tsai HI, Yu HP. Organ-protective effect of red wine extract, resveratrol, in oxidative stress-mediated reperfusion injury. Oxid Med Cell Longev 2015. https://doi.org/10.1155/2015/568634##Loehrer Sr PJ, Gonin R, Nichols CR, Weathers T, Einhorn LH. Vinblastine plus ifosphamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998; 16: 2500-4. https://doi.org/10.1200/JCO.1998.16.7.2500##Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev 2017. https://doi.org/10.1155/2017/6501046##Mir M, Arab RM, Shahraki MR, Mashhadi MA, Salar MS, Aval FS, et al. Toxic effects of cisplatin on hepatocytes and liver enzymes of rats. Anat Sci 2015.##Nandi A, Yan LJ, Jana CK, Das N. Role of catalase in oxidative stress- and age-associated degenerative diseases. Oxid Med Cell Longev 2019. https://doi.org/10.1155/2019/9613090##National Health Research Ethics Committee of Nigeria. Federal Ministry of health. 2014. Available at http://nhrec.net/nhrec/wp-content/uploads/2018/10/Final-Sub-code-for-Research-involving-animal-use-v2.pdf. Accessed 20th October 2016.##National Research Council (US) Committee for the update of the Guild for the Care and Use of Laboratory Animals. Guild for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press (US). 2011. Available at https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf. Accessed 16th October 2016.##Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free Radic Res 2010; 44: 1125-71. https://doi.org/10.3109/10715762.2010.498478##Nematbakhsh M, Ashrafi F, Pezeshki Z, Fatahi Z, Kianpoor F, Sanei MH, et al. A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: Which one is the first observation as side effect of cisplatin-induced toxicity in animal model? J Nephropathol 2012; 1: 190. https://doi.org/10.5812/nephropathol.8122##Okafor IA, Ezejindu DN, Chukwujekwu IE, Dikeh CC. Evaluation of the side effects of cisplatin drug in a nephrotoxicity model of Wistar rats. J Biol Agricul Healthcare 2014; 4.##Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340: 1144-53. https://doi.org/10.1056/NEJM199904153401502##Rukkumani R, Aruna K, Varma PS, Rajasekaran KN, Menon VP. Comparative effects of curcumin and an analog of curcumin on alcohol and PUFA induced oxidative stress. J Pharm Sci 2004; 7: 274-83.##Shrikanta A, Kumar A, Govindaswamy V. Resveratrol content and antioxidant properties of underutilized fruits. J Food Sci Technol 2015; 52: 383-90. https://doi.org/10.1007/s13197-013-0993-z##Singh AP, Singh R, Verma SS, Rai V, Kaschula CH, Maiti P, et al. Health benefits of resveratrol: evidence from clinical studies. Med Res Rev 2019; 39: 1851-91. https://doi.org/10.1002/med.21565##Stakisaitis D, Dudeniene G, Jankunas RJ, Grazeliene G, Didziapetriene J, Pundziene B. Cisplatin increases urinary sodium excretion in rats: gender-related differences. Medicina 2010; 46: 45-50. https://doi.org/10.3390/medicina46010008##Sun YI, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1998; 34: 497-500. https://doi.org/10.1093/clinchem/34.3.497##Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol 2010; 635: 1-8. https://doi.org/10.1016/j.ejphar.2010.02.054##Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L. Resveratrol inhibition of lipid peroxidation. Free Radic Res 2000; 33: 105-14. https://doi.org/10.1080/10715760000300661##Wang G, Su C, Yin T. Paclitaxel and platinum based chemotherapy results in transient dyslipidemia in cancer patients. Mol Clin Oncol 2017; 6: 261-5. https://doi.org/10.3892/mco.2016.1107##Watanabe KI, Hess A, Bloch W, Michel O. Nitric oxide synthase inhibitor suppresses the ototoxic side effect of Cisplatin in guinea pigs. Anti-Cancer Drugs 2000; 11: 401-6. https://doi.org/10.1097/00001813-200006000-00011##Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci 2007; 334: 115-24. https://doi.org/10.1097/MAJ.0b013e31812dfe1e##Younus H. Therapeutic potential of superoxide dismutase. Int J Health Sci 2018; 12: 88## ##

Silymarin reduced cisplatin-induced hyperalgesia bysuppressing oxidative stress in male rats 2 2 Introduction: Cisplatin is an antineoplastic agent which is used in treatment of various cancers. However its clinical use is associated with oxidative stress-mediated neuropathic pain. This research aimed to explore the effect of silymarin on cisplatin-induced hyperalgesia (CIH) and oxidative stress biomarkers in male rats. Methods: Fifty-six male rats were allocated into seven equal groups. Hyperalgesia was caused by intraperitoneal single dose administration of cisplatin (1mg/kg) and assessed by utilizing tail-flick method. The impact of silymarin (25, 50 and 100 mg/kg/day for 15 days) on CIH was investigated on days 1, 5, 10 and 15. Blood samples were collected to assess malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) and total antioxidant status (TAS) on day fifteen. Results: Single dose injection of cisplatin (1mg/kg) could cause a significant hyperalgesia on days 5, 10 and 15. CIH was abolished by daily administration of silymarin (50 and 100mg/kg) on days 10 and 15. Serum MDA level was decreased in cisplatin and silymarin (100 mg/kg) co-treated rats, while there was an increase in GPx, SOD as well as TAS parameters. Conclusion: The results of this study revealed that silymarin prevents from CIH possibly by improving lipid peroxidation and oxidative stress biomarkers. Other clinical studies should be performed to establish possible use of silymarin for treatment of CIH in susceptible individuals. 146 153 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/42020/07/23 1399/5/2 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/232020/11/10 1399/8/20 Alireza Mohajjel Nayebi Alireza Mohajjel Nayebi Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran nayebia@tbzmed.ac.ir Ali Hashemian Ali Hashemian Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Iran Hassan Rezazadeh Hassan Rezazadeh Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran Mohammad Charkhpour Mohammad Charkhpour Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Iran Kiarash Fekri Kiarash Fekri Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Iran Rasool Haddadi Rasool Haddadi Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran * Iran Cisplatin Silymarin Hyperalgesia Oxidative stress. Arany I, Safirstein R L. Cisplatin nephrotoxicity. Seminars in nephrology 2003; 23: 460-464.##Areti A, Yerra V, Naidu V, Kumar A. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biology 2014; 2: 289–295.##Arthur J R, Boyne R. Superoxide dismutase and glutathione peroxidase activities in neutrophils from selenium deficient and copper deficient cattle. Life sciences 1985; 36: 1569-1575. ##Authier N, Fialip J, Eschalier A, Coudoré F. Assessment of allodynia and hyperalgesia after cisplatin administration to rats. Neuroscience letters 2000; 291: 73-76.##Balayssac D, Cayre A, Ling B, Maublant J, Penault-Llorca F, Eschalier A, et al. Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy. Neuroscience letters 2009; 465: 108-112.##Baluchnejadmojarad T, Roghani M, Khastehkhodaie Z. Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat. Phytotherapy research 2010a; 24: 1120-1125.##Baluchnejadmojarad T, Roghani M, Mafakheri M. Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: involvement of estrogen receptors and oxidative stress. Neuroscience letters 2010b; 480: 206-210.##Basiglio C L, Pozzi E J S, Mottino A D, Roma M G. Differential effects of silymarin and its active component silibinin on plasma membrane stability and hepatocellular lysis. Chemico-Biological Interactions 2009; 179: 297-303.##Cavaletti G, Ceresa C, Nicolini G, Marmiroli P. Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity. Anticancer research 2014; 34: 483-486.##Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon M-S, Kaube H, et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. Journal of Neuroscience 2007; 27: 9451-9457.##El-Marasy S A, Abd-Elsalam R M, Ahmed-Farid O A. Ameliorative effect of silymarin on scopolamine-induced dementia in rats. Open access Macedonian journal of medical sciences 2018; 6: 1215.##Gharagozloo M, Velardi E, Bruscoli S, Agostini M, Di Sante M, Donato V, et al. Silymarin suppress CD4+ T cell activation and proliferation: effects on NF-κB activity and IL-2 production. Pharmacological research 2010; 61: 405-409.##Gill J S, Windebank A J. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. The Journal of clinical investigation 1998; 101: 2842-2850.##Habibi asl B, Majidi Z, Fekri K, Delazar A, Vaez H. Evaluation of the effect of aerial parts of Scrophularia atropatana grossh total extracts on analgesic activity and morphine induced tolerance in mice. Pharmaceutical Sciences 2018; 24: 112-117.##Haddadi R, Brooshghalan S E, Farajniya S, Nayebi A M, Sharifi H. Short-term treatment with silymarin improved 6-OHDA-induced catalepsy and motor imbalance in hemi-Parkisonian rats. Advanced Pharmaceutical Bulletin 2015; 5: 463.##Haddadi R, Nayebi A M, Brooshghalan S E. Pre-treatment with silymarin reduces brain myeloperoxidase activity and inflammatory cytokines in 6-OHDA hemi-parkinsonian rats. Neuroscience letters 2013; 555: 106-111.##Haddadi R, Nayebi A M, Brooshghalan S E. Silymarin prevents apoptosis through inhibiting the Bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats. Biomedicine & Pharmacotherapy 2018; 104: 127-136.##Haddadi R, Nayebi A M, Farajniya S, Brooshghalan S E, Sharifi H. Silymarin improved 6-OHDA-induced motor impairment in hemi-parkisonian rats: behavioral and molecular study. DARU Journal of Pharmaceutical Sciences 2014; 22: 38.##Hassani F V, Rezaee R, Sazegara H, Hashemzaei M, Shirani K, Karimi G. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice. Iranian Journal of Basic Medical Sciences 2015; 18: 715.##Hirayama K, Oshima H, Yamashita A, Sakatani K, Yoshino A, Katayama Y. Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus. Brain Research 2016; 1646: 297-303.##Hunt E J, Lester C E, Lester E A, Tackett R L. Effect of St. John's wort on free radical production. Life sciences 2001; 69: 181-190.##Jadhav G, Upasani C. Analgesic effect of silymarin in experimental induced pain in animal models. Journal of Pharmacy Research 2009; 2: 1276-1278.##Joseph E K, Levine J D. Comparison of oxaliplatin-and cisplatin-induced painful peripheral neuropathy in the rat. The Journal of Pain 2009; 10: 534-541.##Karimi G, Fallah Huseini H, Ramezani M, Tahoonian Z. Protective effect of silybum marianum (l.) gaertn. seeds extract and silymarin against cisplatin-induced acute nephrotoxicity in rats. Journal of Medicinal Plants 2005a; 1: 42-45.##Karimi G, Ramezani M, Tahoonian Z. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evidence-Based Complementary and Alternative Medicine 2005b; 2.##Karimi G, Saradeghi Keisari M. Evaluation of antidepressant effect of ethanolic and aqueous extracts of Silybum marianum L. seed in mice. Journal of Medicinal Plants 2007; 4: 38-43.##Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M. “Silymarin”, a promising pharmacological agent for treatment of diseases. Iranian journal of basic medical sciences 2011; 14: 308.##Kaur M, Agarwal R. Silymarin and epithelial cancer chemoprevention: how close we are to bedside? Toxicology and applied pharmacology 2007; 224: 350-359.##Khasabova I A, Khasabov S G, Olson J K, Uhelski M L, Kim A H, Albino-Ramírez A M, et al. Pioglitazone, a PPARγ agonist, reduces cisplatin-evoked neuropathic pain by protecting against oxidative stress. Pain 2019; 160: 688-701.##Kim H-J, Lee J-H, Kim S-J, Oh G S, Moon H-D, Kwon K-B, et al. Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity. Journal of Neuroscience 2010; 30: 3933-3946.##Kittur S, Wilasrusmee S, Pedersen W A, Mattson M P, Straube-West K, Wilasrusmee C, et al. Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture. Journal of Molecular Neuroscience 2002; 18: 265-269.##Křen V, Walterová D. Silybin and silymarin-new effects and applications. Biomedical Papers 2005; 149: 29-41.##Kruidering M, Van De Water B, De Heer E, Mulder G J, Nagelkerke J F. Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. Journal of Pharmacology and Experimental Therapeutics 1997; 280: 638-649.##Lee J-H, Chae J-W, Kim J K, Kim H J, Chung J Y, Kim Y-H. Inhibition of cisplatin-resistance by RNA interference targeting metallothionein using reducible oligo-peptoplex. Journal of Controlled Release 2015; 215: 82-90.##Luo Y, Wang C Z, Sawadogo R, Tan T, Yuan C S. Effects of Herbal Medicines on Pain Management. American Journal of Chinese Medicine. 2020; 48: 1-16.##Lomeli N, Di K, Czerniawski J, Guzowski J F, Bota D A. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radical Biology and Medicine 2017; 102: 274-286.##Manna S K, Mukhopadhyay A, Van N T, Aggarwal B B. Silymarin suppresses TNF-induced activation of NF-κB, c-Jun N-terminal kinase, and apoptosis. The Journal of Immunology 1999; 163: 6800-6809.##Mayer K, Myers R, Lee S. Silymarin treatment of viral hepatitis: a systematic review. Journal of viral hepatitis 2005; 12: 559-567.##Miller N J, Rice-Evans C, Davies M J, Gopinathan V, Milner A. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clinical science 1993; 84: 407-412.##Morishima C, Shuhart M C, Wang C C, Paschal D M, Apodaca M C, Liu Y, et al. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology 2010; 138: 671-681. e2.##Namvaran-Abbas-Abad A, Tavakkoli F. Antinociceptive effect of salvia extract on cisplatin-induced hyperalgesia in mice. Neurophysiology 2012; 43: 452-458.##Nayebi A M, Sharifi H, Ramadzani M, Rezazadeh H. Effect of acute and chronic administration of carbamazepine on Cisplatin-induced hyperalgesia in rats. Jundishapur journal of natural pharmaceutical products 2012; 7: 27.##Pacharinsak C, Beitz A. Animal models of cancer pain. Comparative medicine 2008; 58: 220-233.##Pagalia D E, Valentine W N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. The Journal of laboratory and clinical medicine 1967; 70: 158-169##Paice J A. Mechanisms and management of neuropathic pain in cancer. The journal of supportive oncology 2003; 1: 107-120.##Parvizpur A, Fekri K, Fekri L, Ghadimi P, Charkhpour M. The role of duloxetine in changing the process of tolerance to morphine analgesic effects in male rats. Journal of Reports in Pharmaceutical Sciences 2020; 9: 215-220.##Podratz J L, Knight A M, Ta L E, Staff N P, Gass J M, Genelin K, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiology of disease 2011; 41: 661-668.##Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer letters 2008; 269: 352-362.##Sahib A S. Antinociceptive effect of silymarin in experimental animal. Al-Kindy College Medical Journal 2011; 7: 91-94.##Sedaghat R, Zarrinkhameh Z, Afshin-Majd S, Ansari F, Sharayeli M, Roghani M. The effect of silymarin on prevention of hippocampus neuronal damage in rats with temporal lob epilepsy. Journal of Basic and Clinical Pathophysiology 2017; 5: 45-50.##Shahbazi F, Dashti-Khavidaki S, Khalili H, Lessan-Pezeshki M. Potential renoprotective effects of silymarin against nephrotoxic drugs: a review of literature. Journal of Pharmacy & Pharmaceutical Sciences 2012; 15: 112-123.##Siddik Z H. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22: 7265-7279.##Surai P F. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants 2015; 4: 204-247.##Suttle N F. Copper deficiency in ruminants; recent developments. The Veterinary Record 1986; 21: 519-522.##Suttle N F, McMurray C H. Use of erythrocyte copper: zinc superoxide dismutase activity and hair or fleece copper concentrations in the diagnosis of hypocuprosis in ruminants. Research in veterinary science 1983; 35: 47-52.##Ta L E, Espeset L, Podratz J, Windebank A J. Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum–DNA binding. Neurotoxicology 2006; 27: 992-1002.##Todd R C, Lippard S J. Inhibition of transcription by platinum antitumor compounds. Metallomics 2009; 1: 280-291.##Vargas-Mendoza N, Madrigal-Santillán E, Morales-González Á, Esquivel-Soto J, Esquivel-Chirino C, y González-Rubio M G-L, et al. Hepatoprotective effect of silymarin. World journal of hepatology 2014; 6: 144.##Woolliams J A, Woolliams G, Anderson P H, McMurray C H. Variation in the activities of glutathione peroxidase and superoxide dismutase and in the concentration of copper in the blood in various breed crosses of sheep. Research in veterinary science 1983; 34: 253-256.##Yang Z, Schumaker L M, Egorin M J, Zuhowski E G, Guo Z, Cullen K J. Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clinical cancer research 2006; 12: 5817-5825.## ##

Quercetin ameliorates acetamiprid-inducedhepatotoxicity and oxidative stress 2 2 Introduction: Neonicotinoids are a new type of insecticides that have been introduced to the poison market during the last three decades. Acetamiprid (ACT) is a neonicotinoid and widely used for controlling pests. It targets the liver as a toxic agent and damages hepatic tissues through oxidative stress mechanisms. Quercetin is a flavonoid with potent antioxidant and hepatoprotective activity and protects tissues from oxidative damages. Thus, this study is aimed to assess the protective effect of quercetin on acetamiprid-induced hepatotoxicity. Methods: Thirty-six Wistar rats were classified into six groups including control, DMSO, ACT 20, ACT 40, quercetin, and ACT40+quercetin. All treatments were administered orally with gavage for 28 days. Alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) enzyme activity was measured in serum as biomarkers of hepatotoxicity. Lipid peroxidation, superoxide dismutase (SOD) enzyme activity and total thiol content were measured in hepatic tissues. Also, hepatic tissue sections were prepared and stained with hematoxylin and eosin and evaluated under optic microscope for any tissue injuries. Results: Findings showed that ACT, especially in high dose (40mg/kg), induced hepatic tissue destruction associated with increased hepatic enzyme activity, except ALP activity, in the serum. Besides, ACT increased the lipid peroxidation and decreased total thiol content and SOD activity, which indicates ACT-induced oxidative stress in hepatic tissues. Also, hepatic tissue injuries were observed in ACT-treated group. All these changes in liver were prevented by quercetin. Conclusion: Because of strong antioxidant properties, quercetin can cope effectively with ACT-induced hepatotoxicity. 154 161 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/42020/07/232020/01/14 1398/10/24 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/232020/11/102020/11/23 1399/9/3 Alireza Ghazanfari Alireza Ghazanfari Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Iran Maliheh Soodi Maliheh Soodi Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Iran soodi@modares.ac.ir Ameneh Omidi Ameneh Omidi Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Iran Acetamiprid Hepatotoxicity Quercetin Oxidative stress Rats. Alrawaiq NS, Abdullah A. A review of flavonoid quercetin: metabolism, bioactivity and antioxidant properties. Int J Pharmtech Res 2014; 6: 933-41.##Authority EFS. Peer review of the pesticide risk assessment of the active substance acetamiprid. EFSA J 2016; 14. https://doi.org/10.2903/j.efsa.2016.4610 ##Chakroun S, Ezzi L, Grissa I, Kerkeni E, Neffati F, Bhouri R, et al. Hematological, biochemical, and toxicopathic effects of subchronic acetamiprid toxicity in Wistar rats. Environ Sci Pollut Res 2016; 23: 25191-9. https://doi.org/10.1007/s11356-016-7650-9 ##Cohn C. Clinical blood chemistry. Textbook Clin Pathol 1975, pp. 235-78. ##de Boer VC, Dihal AA, van der Woude H, Arts IC, Wolffram S, Alink GM, et al. Tissue distribution of quercetin in rats and pigs. J Nutr 2005; 135: 1718-25. https://doi.org/10.1093/jn/135.7.1718 ##Devan RS, Mishra A, Prabu PC, Mandal TK, Panchapakesan S. Sub-chronic oral toxicity of acetamiprid in Wistar rats. Toxicol Environ Chem 2015; 97: 1236-52. https://doi.org/10.1080/02772248.2015.1092542 ##Dhouib IB, Annabi A, Doghri R, Rejeb I, Dallagi Y, Bdiri Y, et al. Neuroprotective effects of curcumin against acetamiprid-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: biochemical, histological, and behavioral changes. Environ Sci Pollut Res 2017; 24: 27515-24. https://doi.org/10.1007/s11356-017-0331-5 ##Ellman M. A spectrophotometric method for determination of reduced glutathione in tissues. Anal Biochem 1959; 74: 214-6. ##Flohe L. [10] Superoxide dismutase assays. Methods Enzymol 1984; 105: 93-104. https://doi.org/10.1016/S0076-6879(84)05013-8 ##Ghahremani S, Soodi M, Atashi A. Quercetin ameliorates chlorpyrifos-induced oxidative stress in the rat brain: possible involvment of PON2 pathway. J Food Biochem 2018; 42. https://doi.org/10.1111/jfbc.12530 ##Gulati K, Reshi MR, Rai N, Ray A. Hepatotoxicity: its mechanisms, experimental evaluation and protective strategies. Am J Pharmacol 2018; 1: 1004. ##Kei S. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 1978; 90: 37-43. https://doi.org/10.1016/0009-8981(78)90081-5 ##Miltonprabu S, Tomczyk M, Skalicka-Woźniak K, Rastrelli L, Daglia M, Nabavi SF, et al. Hepatoprotective effect of quercetin: from chemistry to medicine. Food Chem Toxicol 2017; 108: 365-74. https://doi.org/10.1016/j.fct.2016.08.034 ##Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016; 5. https://doi.org/10.1017/jns.2016.41##Pingili RB, Challa SR, Pawar AK, Toleti V, Kodali T, Koppula S. A systematic review on hepatoprotective activity of quercetin against various drugs and toxic agents: evidence from preclinical studies. Phytother Res 2020; 34: 5-32. https://doi.org/10.1002/ptr.6503 ##Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011; 82: 513-23. https://doi.org/10.1016/j.fitote.2011.01.018##Samples IB. Serial review: Flavonoids and isoflavones (phytoestrogens): absorption, metabolism, and bioactivity. Free Radic Biol Med 2004; 37: 1324-50. ##Selvakumar K, Bavithra S, Suganthi M, Benson CS, Elumalai P, Arunkumar R, et al. Protective role of quercetin on PCBs-induced oxidative stress and apoptosis in hippocampus of adult rats. Neurochem Res 2012; 37: 708-21. https://doi.org/10.1007/s11064-011-0661-5 ##Shakthi Devan RK, Prabu PC, Panchapakesan S. Immunotoxicity assessment of sub-chronic oral administration of acetamiprid in Wistar rats. Drug Chem Toxicol 2015; 38: 328-36. https://doi.org/10.3109/01480545.2014.966382 ##Tennant BC. Hepatic function. InClinical biochemistry of domestic animals. Academic Press, 1997, pp. 327-352. https://doi.org/10.1016/B978-012396305-5/50014-2 ##Tomizawa M, Casida JE. Neonicotinoid insecticide toxicology: mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005; 45: 247-68. https://doi.org/10.1146/annurev.pharmtox.45.120403.095930 ##Uzun FG, Kalender Y. Chlorpyrifos induced hepatotoxic and hematologic changes in rats: the role of quercetin and catechin. Food Chem Toxicol 2013; 55: 549-56. https://doi.org/10.1016/j.fct.2013.01.056 ##Valentová K, Vrba J, Bancířová M, Ulrichová J, Křen V. Isoquercitrin: pharmacology, toxicology, and metabolism. Food Chem Toxicol 2014; 68: 267-82. https://doi.org/10.1016/j.fct.2014.03.018 ##Verma RS, Srivastava N. Chlorpyrifos induced alterations in levels of thiobarbituric acid reactive substances and glutathione in rat brain. Indian J Exp Biol 2001. ##Wang X, Anadón A, Wu Q, Qiao F, Ares I, Martínez-Larrañaga MR, et al. Mechanism of neonicotinoid toxicity: impact on oxidative stress and metabolism. Annu Rev Pharmacol Toxicol 2018; 58: 471-507. https://doi.org/10.1146/annurev-pharmtox-010617-052429 ##Zhang JJ, Yi WA, Xiang HY, Li MX, Li WH, WANG XZ, et al. Oxidative stress: role in acetamiprid-induced impairment of the male mice reproductive system. Agric Sci China 2011; 10: 786-96. https://doi.org/10.1016/S1671-2927(11)60063-1## ##

Combination effects of gallic acid and cyclosporine A during ischemia/ reperfusion on rat electrocardiogram parameters and arrhythmia 2 2 Introduction: Myocardial ischemia leads to electrical disturbance in the heart because of reactive oxygen specious. This study aimed to investigate the effects of gallic acid and cyclosporine A (CsA) together on electrocardiogram parameters in myocardium following ischemia - reperfusion (I/R) in isolated hearts. Methods: In this research, 50 Wistar rats weighing 250-300g were randomly divided into the 5 following groups: control, sham and gallic acid (7.5, 15 and 30mg/kg) in combination with CsA (0.2μM). On the eleventh day, the hearts were removed and perfused with Krebs solution and ischemia was induced for 30min. Then, cyclosporine was administered for 10min at the 10 minutes before reperfusion and 10 minutes the beginning of reperfusion. By placing the electrode, the parameters of RR, PR, QT, TpeakTend, JT and QTcB interval, ST elevation, R, P, Q, S, T amplitude were recorded before ischemia and during reperfusion. Results: This study showed that RR, JT, interval, p duration, ST elevation and PVC numbers of control were increased during ischemia compared with sham and decreased using gallic acid (7.5, 15 and 30mg/kg) in combination with CsA. In addition, P, R, S, T amplitude during the ischemia were decreased in control compared with sham and increased with gallic acid (15mg/kg) in combination with CsA. Conclusion: In conclusion, the optimal combination of both drugs decreased arrhythmia occurrence while increased electrical velocity of conduction and wave amplitudes in isolated myocardium after ischemia reperfusion injury. 162 170 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/42020/07/232020/01/142020/01/27 1398/11/7 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/232020/11/102020/11/232020/11/23 1399/9/3 Najmeh Sadeghi Najmeh Sadeghi Sirjan School of Medical Sciences , Sirjan, Iran Iran Samira Saadatfard Samira Saadatfard Research Center for non. Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran Iran Mahin Dianat Mahin Dianat Department of Physiology, Faculty of Medicine, Ahvaz University of Medical Sciences, Ahvaz Iran Iran Hassanali Abedi Hassanali Abedi Department of Physiology, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran Iran Khatereh Dehghani Khatereh Dehghani Department of Cardiology, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran Iran dkh.dehghani@gmail.com Gallic acid Cyclosporine A Ischemia reperfusion injury. Adib, Ali, Seyed Masoom Masoompour, Hossein Molavi Vardanjani, Abdullah Gondomkar, Hossein Poustchi, Alireza Salehi, Farhad Islami, and Reza Malekzadeh. 2020. 'Smoking Water-Pipe, Opium Use and Prevalence of Heart Disease: A Cross-sectional Analysis of Baseline Data from the Pars Cohort Study, Southern Iran', Arch Iran Med, 23: 289-95.##Anderson, Corey L, Brian P Delisle, Blake D Anson, Jennifer A Kilby, Melissa L Will, David J Tester, Qiuming Gong, Zhengfeng Zhou, Michael J Ackerman, and Craig T January. 2006. 'Most LQT2 mutations reduce Kv11. 1 (hERG) current by a class 2 (trafficking-deficient) mechanism', Circulation, 113: 365-73.##Badavi, Mohammad, Najmeh Sadeghi, Mahin Dianat, and Alireza Samarbafzadeh. 2017. 'Gallic Acid and Cyclosporine Mixture and their Effects on Cardiac Dysfunction Induced by Ischemia/Reperfusion and eNOS/iNOS Expression', Int J Cardiovasc Sci, 30: 207-18.##Buja, L. M., and P. Weerasinghe. 2010. 'Unresolved issues in myocardial reperfusion injury', Cardiovasc Pathol, 19: 29-35.##Dianat, M., N. Sadeghi, M. Badavi, M. Panahi, and M. Taheri Moghadam. 2014. 'Protective Effects of Co-Administration of Gallic Acid and Cyclosporine on Rat Myocardial Morphology Against Ischemia/Reperfusion', Jundishapur J Nat Pharm Prod, 9: e17186.##Dianat, Mahin, Ghidafeh Akbari, and Mohammad Badavi. 2013. 'Antidysrhythmic Effects of Gallic acid on cacl2-induced arrhythmia in rat', Int J Res Dev Pharm L Sc, 2: 686-89.##Ebner, Florian (ed.)^(eds.). 2020. Carbon dioxide, oxygen, and serum biomarkers after out-of-hospital cardiac arrest.##Estrada, Manuel, Alejandra Espinosa, Marioly Müller, and Enrique Jaimovich. 2003. 'Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells', Endocrinology, 144: 3586-97.##Ghaffari M, Mohammad hasani M, Daemi M, Hakima H, Sahbaei F. 2014. 'Comparison of measuring blood pressure in patients with heart Society of America', Journal of Medical Council of Iran, 32: 336-28.##Ghorbani Baravati, H., S. Joukar, H. Fathpour, and Z. Kordestani. 2015. 'Nandrolone Plus Moderate Exercise Increases the Susceptibility to Lethal Arrhythmias', Res Cardiovasc Med, 4: e26233.##Giugliano, D. 2000. 'Dietary antioxidants for cardiovascular prevention', Nutr Metab Cardiovasc Dis, 10: 38-44.##Hausenloy, D. J., M. R. Duchen, and D. M. Yellon. 2003. 'Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury', Cardiovasc Res, 60: 617-25.##Hung, L. M., J. K. Chen, R. S. Lee, H. C. Liang, and M. J. Su. 2001. 'Beneficial effects of astringinin, a resveratrol analogue, on the ischemia and reperfusion damage in rat heart', Free Radic Biol Med, 30: 877-83.##Joukar, S., H. Najafipour, R. Malekpour-Afshar, F. Mirzaeipour, and H. R. Nasri. 2010. 'The effect of passive opium smoking on cardiovascular indices of rabbits with normal and ischemic hearts', Open Cardiovasc Med J, 4: 1-6.##Joukar, Siyavash, and Haleh Asadipour. 2015. 'Evaluation of Melissa officinalis (Lemon Balm) Effects on Heart Electrical System', Research in cardiovascular medicine, 4.##Kario, Kazuomi. 2010. 'Measuring the effects of stress on the cardiovascular system during a disaster: the effective use of self-measured blood pressure monitoring', Journal of hypertension, 28: 657-59.##Klawitter, P. F., H. N. Murray, T. L. Clanton, and M. G. Angelos. 2002. 'Reactive oxygen species generated during myocardial ischemia enable energetic recovery during reperfusion', Am J Physiol Heart Circ Physiol, 283: H1656-61.##Marin-Garcia, J., and M. J. Goldenthal. 2004. 'Heart mitochondria signaling pathways: appraisal of an emerging field', J Mol Med (Berl), 82: 565-78.##Moradi-Lakeh, Maziar, AA Kiadaliri, M Asadi-Lari, H Asayesh, AR Esteghamati, MS Farvid, SM Fereshtehnejad, P Heydarpour, A Khosravi, and J Khubchandani. 2017. 'Trend of socio-demographic index and mortality estimates in iran and its neighbors, 1990-2015; Findings of the global burden of diseases 2015 study', Archives of Iranian medicine, 20.##Pagliaro, Pasquale, Saveria Femminò, and Claudia Penna. 2019. 'Redox Aspects of Myocardial Ischemia/Reperfusion Injury and Cardioprotection.' in Sajal Chakraborti, Naranjan S. Dhalla, Nirmal K. Ganguly and Madhu Dikshit (eds.), Oxidative Stress in Heart Diseases (Springer Singapore: Singapore).##Priscilla, D. H., and P. S. Prince. 2009. 'Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats', Chem Biol Interact, 179: 118-24.##Rubart, M., and D. P. Zipes. 2005. 'Mechanisms of sudden cardiac death', Journal of Clinical Investigation, 115: 2305-15.##Sarre, A., N. Lange, P. Kucera, and E. Raddatz. 2005. 'mitoKATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways', American Journal of Physiology Heart and Circulatory Physiology, 288: H1611-9.##Shinno, E., M. Shimoji, N. Imaizumi, S. Kinoshita, H. Sunakawa, and Y. Aniya. 2005. 'Activation of rat liver microsomal glutathione S-transferase by gallic acid', Life Sciences, 78: 99-106.##Stanely Mainzen Prince, P., H. Priscilla, and P. T. Devika. 2009. 'Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats', Eur J Pharmacol, 615: 139-43.##Sun, X., J. Cai, X. Fan, P. Han, Y. Xie, J. Chen, Y. Xiao, and Y. J. Kang. 2013. 'Decreases in electrocardiographic R-wave amplitude and QT interval predict myocardial ischemic infarction in Rhesus monkeys with left anterior descending artery ligation', PLoS One, 8: e71876.##White, Charlize. 2020. 'Protein phosphorylation in Ischaemia and reperfusion of the heart: a focus on protein phosphatase 2A.' in.##Xie, J. R., and L. N. Yu. 2007. 'Cardioprotective effects of cyclosporine A in an in vivo model of myocardial ischemia and reperfusion', Acta Anaesthesiologica Scandinavica, 51: 909-13.##Yang, Pingliang, Pengfei Han, Jianglong Hou, Lizhi Zhang, Haibo Song, Yuping Xie, Yonglin Chen, Huiqi Xie, Fabao Gao, and Y James Kang. 2011. 'Electrocardiographic characterization of rhesus monkey model of ischemic myocardial infarction induced by left anterior descending artery ligation', Cardiovascular Toxicology, 11: 365.##Yellon, D. M., and D. J. Hausenloy. 2007. 'Myocardial reperfusion injury', N Engl J Med, 357: 1121-35.##Zheng, Jianwei, Huimin Chu, Daniele Struppa, Jianming Zhang, Sir Magdi Yacoub, Hesham El-Askary, Anthony Chang, Louis Ehwerhemuepha, Islam Abudayyeh, Alexander Barrett, Guohua Fu, Hai Yao, Dongbo Li, Hangyuan Guo, and Cyril Rakovski. 2020. 'Optimal Multi-Stage Arrhythmia Classification Approach', Scientific Reports, 10: 2898.##Žumbakytė-Šermukšnienė, Renata, Alma Kajėnienė, Kristina Berškienė, Algė Daunoravičienė, and Rasa Sederevičiūtė. 2012. 'Assessment of the effect of anthropometric data on the alterations of cardiovascular parameters in Lithuanian elite male basketball players during physical load', Medicina, 48: 566-71.## ##

Short-term regular moderate exercise improved male hypothalamic-pituitary-gonadal axis function via the reduction of hypothalamic neurokinin B expression in adult rats 2 2 Introduction: In the arcuate nucleus, kisspeptin, neurokinin-B and pro-dynorphin (KNDy) neurons control the function of gonadotropin-releasing hormone (GnRH) neurons. Early investigations indicated that exercise with various intensities affects luteinizing hormone (LH) and testosterone (T) in different ways. Meanwhile the molecular mechanisms underlying its function not yet been fully understood. Accordingly, the present study evaluated the role of alterations in the levels of KNDy mRNA upstream of GnRH neurons in conveying the effects of various short-term exercise intensities on the male hypothermic-pituitary-gonadal (HPG) axis. Methods: Twenty-one adult Wistar rats were randomly divided into 3 groups: control, one-month regular moderate exercise (ME) and one-month regular intensive exercise (IE). In ME (22m/min) and IE (35m/min) groups, the rats were treated 5 days a week for 60min each day. Finally, we assessed serum levels of LH and T using the ELIZA technique and KNDy and Gnrh mRNA expression by the real-time PCR method. Results: The results revealed that in ME group the expression of Nkb was reduced and the expression of Gnrh mRNA and the LH and T serum levels were increased. However, intensive exercise did not change the serum levels of LH and T or the relative expression of kiss1, Nkb, Pdyn and Gnrh genes. Conclusion: The results suggested that monthly moderate exercise improved male reproductive axis function, while intensive exercise did not have an adverse effect on the reproductive axis. These various effects on the male HPG axis may be propagated by the change in hypothalamic Nkb gene expression. 171 177 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/42020/07/232020/01/142020/01/272020/02/14 1398/11/25 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/232020/11/102020/11/232020/11/232020/11/10 1399/8/20 Nazli Khajehnasiri Nazli Khajehnasiri Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran Iran Homayoun Khazali Homayoun Khazali Department of Biological Sciences and Technology, Shahid Beheshti University, Tehran, Iran Iran Farzam Sheikhzadeh Hesari Farzam Sheikhzadeh Hesari Department of Animal Sciences, Faculty of Biological Sciences, University of Tabriz, Tabriz, Iran Iran Hamid Reza Sadeghnia Hamid Reza Sadeghnia Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Omid Mehrpour Omid Mehrpour Arizona Poison & Drug Information Center, University of Arizona, College of Pharmacy and University of Arizona, Tucson, AZ, USA USA Reihaneh Sadeghian Reihaneh Sadeghian Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran Iran sadeghian.r@skums.ac.ir Regular exercise Kisspeptin Neurokinin-B Pro-dynorphin Arcuate nucleus Reproductive axis. Amodei R, Gribbin K, He W, Lindgren I, Corder K R, Jonker S S, et al. Role for Kisspeptin and Neurokinin B in Regulation of Luteinizing Hormone and Testosterone Secretion in the Fetal Sheep. Endocrinology 2020; 161.##Chaikhun T, Sotthibandhu P, Suadsong S. The Role of Kisspeptin Signaling in Reproduction of Ruminant. The Thai Journal of Veterinary Medicine 2013a; 43: 7-14.##Chaikhun T, Sotthibandhu P, Suadsong S. The Role of Kisspeptin Signaling in Reproduction of Ruminants. The Thai veterinary medicine 2013b; 43: 7-14.##Dhillo W S, Chaudhri O B, Patterson M, Thompson E L, Murphy K G, Badman M K, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90: 6609-15.##Di Luigi L, Romanelli F, Sgro P, Lenzi A. Andrological aspects of physical exercise and sport medicine. Endocrine 2012; 42: 278-84.##Grachev P, Li X F, Lin Y S, Hu M H, Elsamani L, Paterson S J, et al. GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats. PLoS One 2012; 7: e44344.##Grandys M, Majerczak J, Duda K, Zapart-Bukowska J, Kulpa J, Zoladz J A. Endurance training of moderate intensity increases testosterone concentration in young, healthy men. Int J Sports Med 2009; 30: 489-95.##Hackney A C. Hypogonadism in Exercising Males: Dysfunction or Adaptive-Regulatory Adjustment? Frontiers in endocrinology 2020; 11: 11-11.##Hesari F S, Khajehnasiri N, Khojasteh S M, Soufi F G, Dastranj A. Attenuation of phosphorylated connexin-43 protein levels in diabetic rat heart by regular moderate exercise. Arch Iran Med 2014; 17: 569-73.##Homan G F, Davies M, Norman R. The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Human Reproduction Update 2007; 13: 209-223.##Kalló I, Vida B, Deli L, Molnár C S, Hrabovszky E, Caraty A, et al. Co-localisation of kisspeptin with galanin or neurokinin B in afferents to mouse GnRH neurones. J Neuroendocrinol 2012; 24: 464-76.##Khajehnasiri N, Khazali H, Sheikhzadeh F. Various responses of male pituitary-gonadal axis to different intensities of long-term exercise: Role of expression of KNDYrelated genes. J Biosci 2018; 43: 569-574.##Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden J M, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276: 34631-6.##Lehman M N, Coolen L M, Goodman R L. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010; 151: 3479-89.##Molaei A, Hatami H, Dehghan G, Sadeghian R, Khajehnasiri N. Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer's disease. Excli j 2020; 19: 596-612.##Pinilla L, Aguilar E, Dieguez C, Millar R P, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 2012; 92: 1235-316.##Rance N E, Krajewski S J, Smith M A, Cholanian M, Dacks P A. Neurokinin B and the hypothalamic regulation of reproduction. Brain research 2010; 1364: 116-128.##Salehi M S, Namavar M R, Shirazi M R J, Rahmanifar F, Tamadon A. A simple method for isolation of the anteroventral periventricular and arcuate nuclei of the rat hypothalamus. Anatomy 2012; 7.##Schmittgen T D, Livak K J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3: 1101-8.##Shahidi S, Komaki A, Sadeghian R, Asl S S. Different doses of methamphetamine alter long-term potentiation, level of BDNF and neuronal apoptosis in the hippocampus of reinstated rats. The Journal of Physiological Sciences 2019a; 69: 409-419.##Shahidi S, Mehrpour O, Sadeghian R, Soleimani Asl S, Komaki A. Alteration level of hippocampus BDNF expression and long-term potentiation upon microinjection of BRL15572 hydrochloride in a rat model of methamphetamine relapse. Brain Res Bull 2019b; 148: 18-24.##Smith A J, Phipps W R, Arikawa A Y, O'Dougherty M, Kaufman B, Thomas W, et al. Effects of aerobic exercise on premenopausal sex hormone levels: results of the WISER study, a randomized clinical trial in healthy, sedentary, eumenorrheic women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2011; 20: 1098-1106.##Sokoloff N, Misra M, Ackerman K. Exercise, Training, and the Hypothalamic-Pituitary-Gonadal Axis in Men and Women. Frontiers of hormone research 2016; 47: 27-43.##Yeo S H, Colledge W H. The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. Front Endocrinol (Lausanne) 2018; 9: 188.## ##

Hepatoprotective effects of hydroethanolic extracts of Crocus sativus tepals, stigmas and leaves on carbon tetrachloride induced acute liver injury in rats 2 2 Introduction: The present study investigated the hepatoprotective effects of stigmas, tepals and leaves of Crocus sativus on carbon tetrachloride (CCL4) induced liver injury in rats. Methods: Hydroethanolic extracts of Crocus sativus (stigmas, tepals and leaves) were administrated daily for 14 days by oral gavage. In the present study, 30 male rats divided into five groups were treated as 1: normal rats gavaged with distilled water; 2: intoxicated rats gavaged with distilled water and injected with CCL4; 3: rats treated with stigmas extract and injected with CCL4; 4: rats treated with tepal extract and injected with CCL4; 5: rats treated with leaf extract and injected with CCL4. Bodyweight and the relative liver weight were determined. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total cholesterol, triglycerides, bilirubin direct and total, total protein, albumin, urea and creatinine measured in plasma. Malondialdehyde (MDA) was quantified in liver homogenate. Results: The experimental data showed that the stigmas and tepals extracts significantly prevented weight body loss and improved the relative liver weight. They significantly protected against elevation of ALT, AST, direct bilirubin, total bilirubin, LDH, ALP, creatinine and MDA. Also, they enhanced significantly total proteins and albumin compared to the CCL4 control group. Moreover, leaves reduced ALT, AST, total bilirubin, LDH and MDA significantly. Conclusion: In conclusion, these results suggest that tepals, stigmas, and leaves extracts of Crocus sativus have hepatoprotective effects on CCL4 induced liver injury in rats. 178 188 2021/01/312020/06/292020/02/122020/04/262019/10/232020/06/42020/07/232020/01/142020/01/272020/02/142020/02/27 1398/12/8 2021/04/102020/11/102020/11/102020/11/102020/12/132020/11/232020/11/102020/11/232020/11/232020/11/102020/11/10 1399/8/20 Sabir Ouahhoud Sabir Ouahhoud Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco s.ouahhoud@ump.ac.ma Ilham Touiss Ilham Touiss Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Amine Khoulati Amine Khoulati Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Iliass Lahmass Iliass Lahmass Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Samira Mamri Samira Mamri Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Mouhssine Meziane Mouhssine Meziane Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Soufiane Elassri Soufiane Elassri Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Noureddine Bencheikh Noureddine Bencheikh Laboratory of Physiology, Genetics, and Ethnopharmacology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Redouane Benabbas Redouane Benabbas Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Abdeslam Asehraou Abdeslam Asehraou Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Mohammed Choukri Mohammed Choukri Laboratory of Biochemistry, Central Laboratory Service - CHU, Mohammed VI, Faculty of Medicine and Pharmacy, University Mohamed Premier, Oujda, Morocco Morocco Ennouamane Saalaoui Ennouamane Saalaoui Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco Hepatoprotective effects Liver injury CCL4 Crocus sativus L Saffron. Ahsan MR, Islam KM, Bulbul IJ, Musaddik MA, Haque E. Hepatoprotective activity of methanol extract of some medicinal plants against carbon tetrachloride-induced hepatotoxicity in rats. Eur J Sci Res 2009; 37: 302-10.##Bansal AK, Bansal M, Soni G, Bhatnagar D. Protective role of vitamin e pre-treatment on n-nitrosodiethylamine induced oxidative stress in rat liver. Chem Biol Interact 2005; 156: 101-11. https://doi.org/10.1016/j.cbi.2005.08.001##Basu S. Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients. Toxicology 2003; 189: 113-27. https://doi.org/10.1016/S0300-483X(03)00157-4##Bertolami MC. Mecanismos de hepatotoxicidade. Arq Bras Cardiol 2005; 85: 25-7.##Burtis CA, Ashwood ER, Hartmann AE. Tietz fundamentals of clinical chemistry. Arch Pathol Lab Med 1999; 123: 646. https://doi.org/10.5858/123.7.646b##Byun JH, Kim J, Choung SY. Hepaprotective effect of standardized ecklonia stolonifera formulation on ccl(4)-induced liver injury in sprague-dawley rats. Biomol Ther 2018; 26: 218. https://doi.org/10.4062/biomolther.2017.199##Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med 2004; 10: 429-34. https://doi.org/10.1038/nm1006##Chiu YJ, Chou SC, Chiu CS, Kao CP, Wu KC, Chen CJ, et al. Hepatoprotective effect of the ethanol extract of polygonum orientale on carbon tetrachloride-induced acute liver injury in mice. J Food Drug Anal 2018; 26: 369-79. https://doi.org/10.1016/j.jfda.2017.04.007##Debnath S, Ghosh S, Hazra B. Inhibitory effect of nymphaea pubescens willd. Flower extract on carrageenan-induced inflammation and ccl4-induced hepatotoxicity in rats. Food Chem Toxicol 2013; 59: 485-91. https://doi.org/10.1016/j.fct.2013.06.036##Farahmand SK, Samini F, Samini M, Samarghandian S. Safranal ameliorates antioxidant enzymes and suppresses lipid peroxidation and nitric oxide formation in aged male rat liver. Biogerontology 2013; 14: 63-71. https://doi.org/10.1007/s10522-012-9409-0##Friedman RB, Anderson RE, Entine SM, Hirshberg SB. Effects of diseases on clinical laboratory tests. Clin Chem 1980; 26: 1D-2D. https://doi.org/10.1093/clinchem/26.4.1D##Ghadami MR, Pourmotabbed A. The effect of crocin on scopolamine induced spatial learning and memory deficits in rats. Physiol Pharmacol 2009; 12: 287-95.##Goli SAH, Mokhtari F, Rahimmalek M. Phenolic compounds and antioxidant activity from saffron (crocus sativus l.) petal. J Agric Sci 2012; 4: 175. https://doi.org/10.5539/jas.v4n10p175##He J, Huang B, Ban X, Tian J, Zhu L, Wang Y. In vitro and in vivo antioxidant activity of the ethanolic extract from meconopsis quintuplinervia. J Ethnopharmacol 2012; 141: 104-10. https://doi.org/10.1016/j.jep.2012.02.006 ##Hosseinzadeh H, Ghenaati J. Evaluation of the antitussive effect of stigma and petals of saffron (crocus sativus) and its components, safranal and crocin in guinea pigs. Fitoterapia 2006; 77: 446-8. https://doi.org/10.1016/j.fitote.2006.04.012##Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of crocus sativus l. Stigma and petal extracts in mice. BMC Pharmacol 2002; 2: 1-8. https://doi.org/10.1186/1471-2210-2-1##Ingawale DK, Mandlik SK, Naik SR. Models of hepatotoxicity and the underlying cellular, biochemical and immunological mechanism(s): a critical discussion. Environ Toxicol Pharmacol 2014; 37: 118-33. https://doi.org/10.1016/j.etap.2013.08.015##Jaishree V, Badami S. Antioxidant and hepatoprotective effect of swertiamarin from enicostemma axillare against d-galactosamine induced acute liver damage in rats. J Ethnopharmacol 2010; 130: 103-6. https://doi.org/10.1016/j.jep.2010.04.019##Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 1990; 9: 515-40 https://doi.org/10.1016/0891-5849(90)90131-2##Kale I, Khan MA, Irfan Y, Veerana GA. Hepatoprotective potential of ethanolic and aqueous extract of flowers of sesbania grandiflora (linn) induced by ccl4. Asian Pac J Trop Biomed 2012; 2: S670-9. https://doi.org/10.1016/S2221-1691(12)60294-9##Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest 2017; 127: 55-64. https://doi.org/10.1172/JCI88881##Kumar V, Bhat ZA, Kumar D, Khan NA, Chashoo IA, Shah M. Evaluation of anti-inflammatory potential of petal extracts of crocus sativus “cashmerianus”. Int J Phytopharm 2012; 3: 27-31.##Lahmass I, Lamkami T, Delporte C, Sikdar S, Van Antwerpen P, Saalaoui E, et al. The waste of saffron crop, a cheap source of bioactive compounds. J Functl Foods 2017a; 35: 341-51. https://doi.org/10.1016/j.jff.2017.05.057##Lahmass I, Ouahhoud S, Elmansuri M, Sabouni A, Elyoubi M, Benabbas R, et al. Determination of antioxidant properties of six by-products of crocus sativus l. (saffron) plant products. Waste Biomass Valorization 2017b; 9: 1349-57. https://doi.org/10.1007/s12649-017-9851-y##Lee CP, Shih PH, Hsu CL, Yen GC. Hepatoprotection of tea seed oil (camellia oleifera abel.) against ccl4-induced oxidative damage in rats. Food Chem Toxicol 2007; 45: 888-95. https://doi.org/10.1016/j.fct.2006.11.007##Lin CC, Huang PC. Antioxidant and hepatoprotective effects of acathopanax senticosus. Phytother Res 2000; 14: 489-94. https://doi.org/10.1002/1099-1573(200011)14:7 <489::AID -PTR656>3.0.CO;2-G##Lin YC, Cheng KM, Huang HY, Chao PY, Hwang JM, Lee HH, et al. Hepatoprotective activity of chhit-chan-than extract powder against carbon tetrachloride-induced liver injury in rats. J Food Drug Anal 2014; 22: 220-9. https://doi.org/10.1016/j.jfda.2013.09.012##Lopresti AL, Drummond PD. Saffron (crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol, 2014; 29: 517-27. https://doi.org/10.1002/hup.2434##Manibusan MK, Odin M, Eastmond DA. Postulated carbon tetrachloride mode of action: a review. J Environ Sci Health Part C 2007; 25: 185-209. https://doi.org/10.1080/10590500701569398##Martin FX. Ireland in the time of st. Bernard, st. Malachy, st. Laurence o’toole. Seanchas Ardmhacha. Journal of the Armagh Diocesan Historical Society 1992; 15: 1-35. https://doi.org/10.2307/29742533##Melnyk JP, Wang S, Marcone MF. Chemical and biological properties of the world’s most expensive spice: Saffron. Food Res Int 2010; 43: 1981-9. https://doi.org/10.1016/j.foodres.2010.07.033##Moshiri E, Basti AA, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. Crocus sativus l. (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine 2006; 13: 607-11. https://doi.org/10.1016/j.phymed.2006.08.006##Ouahhoud S, Lahmass I, Bouhrim M, Khoulati A, Sabouni A, Benabbes R, et al. Antidiabetic effect of hydroethanolic extract of crocus sativus stigmas, tepals and leaves in streptozotocin-induced diabetic rats. Physiol Pharmacol 2019; 23: 9-20.##Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M. Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res 2011; 219: 197-204. https://doi.org/10.1016/j.bbr.2011.01.007##Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin chem 1992; 38: 1933-53. https://doi.org/10.1093/clinchem/38.10.1933##Recknagel RO, Glende Jr EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 1989; 43: 139-54. https://doi.org/10.1016/0163-7258(89)90050-8##Samarghandian S, Borji A. Anticarcinogenic effect of saffron (crocus sativus l.) and its ingredients. Pharmacogn Res 2014; 6: 99. https://doi.org/10.4103/0974-8490.128963##Sánchez-Vioque R, Rodríguez-Conde MF, Reina-Ureña JV, Escolano-Tercero MA, Herraiz-Peñalver D, Santana-Méridas O. In vitro antioxidant and metal chelating properties of corm, tepal and leaf from saffron (crocus sativus l.). Ind Crop Prod 2012; 39: 149-53. https://doi.org/10.1016/j.indcrop.2012.02.028##Sánchez-Vioque R, Santana-Méridas O, Polissiou M, Vioque J, Astraka K, Alaiz M, et al. Polyphenol composition and in vitro antiproliferative effect of corm, tepal and leaf from crocus sativus l. On human colon adenocarcinoma cells (caco-2). J Funct Foods 2016; 24: 18-25. https://doi.org/10.1016/j.jff.2016.03.032##Serrano-Díaz J, Sánchez AM, Martínez-Tomé M, Winterhalter P, Alonso GL. A contribution to nutritional studies on crocus sativus flowers and their value as food. J Food Compos Anal 2013; 31: 101-8. https://doi.org/10.1016/j.jfca.2013.03.009##Sheng L, Qian Z, Zheng S, Xi L. Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006; 543: 116-22. https://doi.org/10.1016/j.ejphar.2006.05.038##Smolskaite L, Talou T, Fabre N, Venskutonis PR. Volarization of saffron industry by-products: Bioactive compounds from leaves. Jelgava: Latvia University of Agriculture, Faculty of Food Technology 2011: 67-72.##Sun J, Wu Y, Long C, He P, Gu J, Yang L, et al. Anthocyanins isolated from blueberry ameliorates ccl4 induced liver fibrosis by modulation of oxidative stress, inflammation and stellate cell activation in mice. Food Chem Toxicol 2018; 120: 491-9. https://doi.org/10.1016/j.fct.2018.07.048##Thabrew MI, Joice PD, Rajatissa W. A comparative study of the efficacy of pavetta indica and osbeckia octandra in the treatment of liver dysfunction. Planta Med 1987; 53: 239-41. https://doi.org/10.1055/s-2006-962691##Tuberoso CI, Rosa A, Montoro P, Fenu MA, Pizza C. Antioxidant activity, cytotoxic activity and metabolic profiling of juices obtained from saffron (crocus sativus l.) floral by-products. Food Chem 2016; 199: 18-27. https://doi.org/10.1016/j.foodchem.2015.11.115##Uemitsu N, Nishimura C, Nakayoshi H. Evaluation of liver weight changes following repeated administration of carbon tetrachloride in rats and body-liver weight relationship. Toxicology 1986; 40: 181-90. https://doi.org/10.1016/0300-483X(86)90077-6##Vuda M, D’Souza R, Upadhya S, Kumar V, Rao N, Kumar V, et al. Hepatoprotective and antioxidant activity of aqueous extract of hybanthus enneaspermus against ccl4-induced liver injury in rats. Exp Toxicol Pathol 2012; 64: 855-9. https://doi.org/10.1016/j.etp.2011.03.006##Wu SJ, Lin YH, Chu CC, Tsai YH, Chao JC. Curcumin or saikosaponin a improves hepatic antioxidant capacity and protects against ccl4-induced liver injury in rats. J med food 2008; 11: 224-9. https://doi.org/10.1089/jmf.2007.555##Zeka K, Ruparelia KC, Continenza MA, Stagos D, Veglio F, Arroo RR. Petals of crocus sativus l. As a potential source of the antioxidants crocin and kaempferol. Fitoterapia 2015; 107: 128-34. https://doi.org/10.1016/j.fitote.2015.05.014##Zheng CJ, Li L, Ma WH, Han T, Qin LP. Chemical constituents and bioactivities of the liposoluble fraction from different medicinal parts of crocus sativus. Pharm Biol 2011; 49: 756-63. https://doi.org/10.3109/13880209.2010.547206## ##