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Effect of allopurinol and benzbromarone on diabetic cardiomyopathy and vasculopathy in streptozotocin-induced diabetic rats 2 2 Introduction: Allopurinol, a xanthine oxidase inhibitor, reduces both plasma uric acid (UA) and oxidative stress, and benzbromarone, a uricosuric agent, reduces the level of plasma UA. This study was designed to evaluate cardiac mechanical and endothelial functions of the allopurinol- and benzbromarone-treated diabetic rats, and to investigate the underlying mechanism (antioxidant or UA lowering activity) of allopurinol beneficial effects. Methods: Diabetes was induced by injecting streptozotocin to male Spargue-Dawley rats. Diabetic animals were treated with allopurinol and benzbromarone. After six weeks of treatment, left ventricular systolic/diastolic functions of hearts, contraction/relaxation responses to phenylephrine and acetylcholine of aortae, and serum levels of malondialdehyde, 8-isoprostane-2α and UA were measured. Results: Diabetic cardiomyopathy and vasculopathy were characterized by reduced myocardial performance and decreased aortic endothelial response to the vasorelaxation effect of acetylcholine. The serum levels of malondialdehyde and 8-isoprostane-2α levels were elevated in diabetic animals. Allopurinol attenuated the diabetes-induced diastolic impairment of the hearts, endothelial dysfunction of the aortae and decreased oxidative stress parameters in serum; however, benzbromarone had none of these effects. Both, allopurinol and benzbromarone, diminished the elevated levels of UA in diabetic animals. Conclusion: Allopurinol improved diabetic cardiomyopathy and aortic endothelial cell dysfunction in diabetic animals through antioxidant effects. 1 8 2018/08/9 1397/5/18 2019/01/21 1397/11/1 Mohammad Fathalipour Mohammad Fathalipour Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Iran Fathalipour@sums.ac.ir Hossein Mirkhani Hossein Mirkhani Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Iran mirkhanh@sums.ac.ir Mohsen Goharinia Mohsen Goharinia Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Iran M.goharinia@fums.ac.ir Allopurinol Benzbromarone Cardiomyopathy Endothelial dysfunction Diabetes. Afshari M, Larijani B, Rezaie A, Mojtahedi A, Zamani MJ, Astanehi-Asghari F, et al. In effectiveness of allopurinol in reduction of oxidative stress in diabetic patients; a randomized, double-blind placebo-controlled clinical trial. 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Antidiabetic effect of hydroethanolic extract of Crocus sativus stigmas, tepals and leaves in streptozotocin-induced diabetic rats 2 2 Introduction: The present study investigated for the first time, the antihyperglycemic effect of tepals and leaves of Crocus sativus in streptozotocin-induced diabetic rats. The effect of these by-products were compared with that of saffron stigma and glibenclamide. Methods: Hydroethanolic extracts (stigmas, tepals and leaves) and glibenclamide were administered orally in aqueous solution daily for 21 days. In the present study, 36 male rats were used. Six rats were used in each group. Group 1: normal control rats (N), received distilled water; group 2: diabetic control rats (D), received distilled water; group 3: treated diabetic rats (TPL), received tepal (TPL) extract; group 4: treated diabetic rats (STG), received stigma (STG) extract; group 5: treated diabetic rats (LF), received leaf (LF) extract and group 6: treated diabetic rats (GLB), received glibenclamide (GLB). Blood glucose, body weight, water intake, urine elimination, plasma triglycerides, cholesterol, urea, creatinine, aspartate amino transferase (AST) and alanine amino transferase (ALT) levels were evaluated. Results: The present data indicated that the tepals and stigmas extracts significantly prevented decreasing body weight and protected against elevation of water intake, urine elimination, blood glucose, plasma triglycerides, cholesterol, urea, creatinine, AST and ALT levels in treated diabetic rats as compared to untreated diabetic rats. Leaves extract significantly prevented decreasing body weight. It decreased water intake, blood glucose, plasma triglycerides, cholesterol, creatinine, AST and ALT. Conclusion: Based on our data, the oral administration of tepals, stigmas and leaves extract of Crocus sativus reduces blood glucose levels and improves control of diabetes complications. 9 20 2018/08/92018/10/11 1397/7/19 2019/01/212019/02/15 1397/11/26 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 Iliass Lahmass Iliass Lahmass Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco i.lahmass@ump.ac.ma Mohamed Bouhrim Mohamed Bouhrim Laboratory of Physiology, Genetic and Ethnopharmacology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco m.bouhrim@ump.ac.ma Amine Khoulati Amine Khoulati Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco a.khoulati@ump.ac.ma Assia Sabouni Assia Sabouni Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco a.sabouni@ump.ac.ma Redouanae Benabbes Redouanae Benabbes Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco r.benabbes@ump.ac.ma Abdeslam Asehraou Abdeslam Asehraou Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco a.asehraou@ump.ac.ma Mohammed Choukri Mohammed Choukri Laboratory of Biochemistry, Central Laboratory Service - CHU, Mohammed VI, Faculty of Medicine and Pharmacy, University Mohamed Premier, Oujda, Morocco Morocco m.choukri@ump.ac.ma Mohamed Bnouham Mohamed Bnouham Laboratory of Physiology, Genetic and Ethnopharmacology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco m.bnouham@ump.ac.ma Ennouamane Saalaoui Ennouamane Saalaoui Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Morocco e.saalaoui@ump.ac.ma Crocus sativus Antihyperglycemic effect Streptozotocine Saffron By-products. 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Ursolic acid increases SIRT1 protein level and β-cells number in diabetic rats 2 2 Introduction: Ursolic acid (UA) is a triterpenoid compound which widely found in the apple’s peel. It has wide health-promoting properties; as previous studies properly indicated to its abilities. In this scenario our attention has been paid to the application of UA as an anti-diabetic compound. Based on our recent studies in relating to SIRT1 protein/gene and UA, the aim of this research was to evaluate UA effects on the SIRT1 expression in diabetic rat’s pancreas. Methods: In this study we used 20 male diabetic wistar rats. To develop diabetic rats, they received 30mg/kg of streptozotocin for 2 days sequentially. Then, they classified to 2 groups, the ones received UA + corn oil twice daily for two weeks and others (the control group) just received corn oil. Results: Our findings obviously showed that UA enhanced SIRT1 (4±0.2 folds) proteins levels in pancreas (P<0.001), in comparison with control rats. In addition, the findings showed that UA significantly decreased fasting blood glucose from 416.17±12 mg/dl to 149.75±11 mg/dl. Moreover, we found that UA increased β-cell numbers and islet Langerhans diameters (~2 folds). Conclusion: Our results provide valuable information not only into the mechanisms underlying β-cells protection but also into the regulation of SIRT1 as a main target to attenuate β-cells damage. Therefore, UA is a promising pharmacological therapeutic target for β-cell regeneration through enhancing of SIRT1 over-expression. 21 27 2018/08/92018/10/112019/01/21 1397/11/1 2019/01/212019/02/152019/02/28 1397/12/9 Rozita Naseri Rozita Naseri Department of Endocrinology and Metabolism, Kermanshah University of Medical Sciences, Kermanshah, Iran Iran Rozita.Naseri@kums.c.ir Fatemeh Bakhtiari Fatemeh Bakhtiari Department of Internal- Medicine, Faculty of Medical-sciences, Medical University of Kermanshah, Kermanshah, Iran Iran fateme.bakhtiari@kums.c.ir Cyrus Jalili Cyrus Jalili Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran Iran cjalili@kums.ac.ir Nuredin Bakhtiari Nuredin Bakhtiari Department of Biochemistry, Faculty of Biological Sciences, North-Tehran Branches, Islamic Azad university, Tehran, Iran Introduction Diabetes is classified into two main categories based on the clinical presentation and pathophysiology. Type 1 diabetes is characterized by autoimmune β cell destruction. Conversely, type 2 diabetes is caused by a relative insulin deficiency in the face of insulin resistance. Interestingly, recent evidence suggests that silent mating type information regulation 2 homolog1 (SIRT1) modulates immune homeostasis and protection against autoimmunity through inducing of forkhead box P3 (FOXP3) and thereby influences Treg cell development (van Loosdregt et al., 2011). SIRT1 functions as class III histone deacetylases, binding to NAD+ and Physiology Physiology Physiology Physiology Physiology Physiology and PharmacologyPharmacology Pharmacology Pharmacology Pharmacology Physiol Pharmacol 23 (2019) 21-27 www.phypha.ir/ppj Abstract Introduction: Ursolic acid (UA) is a triterpenoid compound which widely found in the apple’s peel. It has wide health-promoting properties; as previous studies properly indicated to its abilities. In this scenario our attention has been paid to the application of UA as an anti-diabetic compound. Based on our recent studies in relating to SIRT1 protein/gene and UA, the aim of this research was to evaluate UA effects on the SIRT1 expression in diabetic rat’s pancreas. Methods: In this study we used 20 male diabetic wistar rats. To develop diabetic rats, they received 30mg/kg of streptozotocin for 2 days sequentially. Then, they classified to 2 groups, the ones received UA + corn oil twice daily for two weeks and others (the control group) just received corn oil. Results: Our findings obviously showed that UA enhanced SIRT1 (4±0.2 folds) proteins levels in pancreas (P<0.001), in comparison with control rats. In addition, the findings showed that UA significantly decreased fasting blood glucose from 416.17±12 mg/dl to 149.75±11 mg/dl. Moreover, we found that UA increased β-cell numbers and islet Langerhans diameters (~2 folds). Conclusion: Our results provide valuable information not only into the mechanisms underlying β-cells protection but also into the regulation of SIRT1 as a main target to attenuate β-cells damage. Therefore, UA is a promising pharmacological therapeutic target for β-cell regeneration through enhancing of SIRT1 over-expression. iD Iran nuredin.bakhtiary@modares.ac.ir SIRT1 Ursolic acid Diabetes. Bakhtiari N, Hosseinkhani S, Soleimani M, Hemmati R, Noori-Zadeh A, Javan M, et al. Short-term ursolic acid promotes skeletal muscle rejuvenation through enhancing of SIRT1 expression and satellite cells proliferation. Biomed Pharmacother 2016; 78: 185-196.##Bakhtiari N, Hosseinkhani S, Tashakor A, Hemmati R. Ursolic acid ameliorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation. Med Hypotheses 2015a; 85: 1-6.##Bakhtiari N, Mirzaie S, Hemmati R, Moslemee-jalalvand E, Noori AR, Kazemi J. Mounting evidence validates Ursolic Acid directly activates SIRT1: a powerful STAC which mimic endogenous activator of SIRT1. Arch Biochem Biophys 2018; 650: 39-48.##Bakhtiari N, Soulemani M, Javan M, Hemmati R, Hosseinkhani S. Ursolic acid induces myoglobin expression and skeletal muscle remodeling in mice. Physiol Pharmacol 2015b; 18: 373-82.##Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS biol 2015; 13: e1002346.##Castro AJ, Frederico MJ, Cazarolli LH, Mendes CP, Bretanha LC, Schmidt ÉC, et al. The mechanism of action of ursolic acid as insulin secretagogue and insulinomimetic is mediated by cross-talk between calcium and kinases to regulate glucose balance. Biochim Biophys Acta 2015; 1850: 51-61.##de Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C, et al. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 2010; 59: 1006-15.##Fröjdö S, Durand C, Molin L, Carey AL, El-Osta A, Kingwell BA, et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol Cell Endocrinol 2011; 335: 166-76.##Jang SM, Yee ST, Choi J, Choi MS, Do GM, Jeon SM, et al. Ursolic acid enhances the cellular immune system and pancreatic beta-cell function in streptozotocin-induced diabetic mice fed a high-fat diet. Int Immunopharmacol 2009; 9: 113-9.##Kitada M, Koya D. SIRT1 in type 2 diabetes: mechanisms and therapeutic potential. Diabetes Metab J 2013; 37: 315-25.##Kitada M, Kume S, Takeda-Watanabe A, Kanasaki K, Koya D. Sirtuins and renal diseases: relationship with aging and diabetic nephropathy. Clin Sci (Lond) 2013; 124: 153-64.##Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, et al. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab 2011; 13: 627-38.##Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, et al. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 2009; 58: 344-51.##Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Méneur C, et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2005; 2: 105-17.##van Loosdregt J, Brunen D, Fleskens V, Pals CE, Lam EW, Coffer PJ. Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PloS One 2011; 6: e19047.##Wang ZH, Hsu CC, Huang CN, Yin MC. Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice. 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Interferon-alpha reduced inflammatory effects of filgrastim (G-CSF) in the liver of Syrian mice 2 2 Introduction: granulocyte colony-stimulating factor (G-CSF) has been widely used for the treatment of chemotherapy-induced neutropenia. One of the major sideeffects of interferon-α (IFN-α) therapy is neutropenia. Previous studies have confirmed the beneficial effects of co-administration of G-CSF and IFN-α on neutropenia in patients infected with hepatitis C. In this study for the first time, the effects of co-administration of type I IFNs and G-CSF on liver and liver enzymes investigated. Methods: forty-two mice (male, eight weeks) were randomly divided into six groups of seven: distilled water, G-CSF (200μg/kg), IFN-α (200μg/kg), IFN-β (200μg/kg), IFN-α+G-CSF and IFN-β+G-CSF. After 28 days, blood was taken from the heart of each mouse and histological changes in the liver and liver enzymes including aspartate transaminase (AST) and alanine transaminase (ALT), as well as bilirubin, were measured. Results: Surprisingly, in most cases, the G-CSF and type one IFNs alone or simultaneously reduced the levels of AST and bilirubin. The levels of ALT induced by IFN-α, the addition of G-CSF to IFN-α reduced the level of this liver enzyme. G-CSF induced cell infiltrations into the liver tissue, addition of IFN-α but not IFN-β to G-CSF obviously reduced the cell infiltration into the liver. Conclusion: Since the changes in liver enzymes and bilirubin were not at harmful levels, and the administration of IFN-α to G-CSF reduced the cell infiltrations into the liver, our results suggested that co-administration of type I IFNs and G-CSF had no harmful effects on liver histology and functions. 28 35 2018/08/92018/10/112019/01/212018/03/17 1396/12/26 2019/01/212019/02/152019/02/282018/12/24 1397/10/3 Ensieh Namjou Ensieh Namjou Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Iran en_na981@stu.mail.um.ac.ir Roya Lari Roya Lari Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Iran rlari@um.ac.ir Nasser Mahdavi Shahri Nasser Mahdavi Shahri Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Iran mahdavin@um.ac.ir Ali Moghimi Ali Moghimi Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Iran moghimi@um.ac.ir Inflammation IFN-α IFN-β G-CSF Liver enzymes. Ameli M, Besharati S, Nemati K, Zamani F. Relationship between elevated liver enzyme with iron overload and viral hepatitis in thalassemia major patients in Northern Iran. Saudi Med J 2008; 29: 1611-5.##Benveniste EN, Qin H. Type I interferons as anti-inflammatory mediators. Sci STKE 2007 (416): pe70.##Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 2006; 91: 4287-94.##Crow MK. Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther 2010; 12 Suppl 1: S5.##Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003; 72: 82-93.##Dkhil MA, Al-Quraishy S, Diab MM, Othman MS, Aref AM, Abdel Moneim AE. The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity. Food Chem Toxicol 2014; 74: 98-106.##Eyles JL, Hickey MJ, Norman MU, Croker BA, Roberts AW, Drake SF, et al. A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 2008; 112: 5193-201.##Fiuza C, Salcedo M, Clemente G, Tellado JM. Granulocyte colony-stimulating factor improves deficient in vitro neutrophil transendothelial migration in patients with advanced liver disease. Clin Diagn Lab Immunol 2002; 9: 433-9.##Francis GS, Grumser Y, Alteri E, Micaleff A, O'Brien F, Alsop J, et al. Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance. Drug Saf 2003; 26: 815-27.##Gaia S, Smedile A, Omedè P, Olivero A, Sanavio F, Balzola F, et al. Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. J Hepatol 2006; 45: 13-9.##Ghezzi P, Saccardo B, Bianchi M. Induction of xanthine oxidase and heme oxygenase and depression of liver drug metabolism by interferon: a study with different recombinant interferons. J Interferon Res 1986; 6: 251-6.##Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005; 172: 367-79.##Gowda S, Desai PB, Hull VV, Math AA, Vernekar SN, Kulkarni SS. A review on laboratory liver function tests. Pan Afr Med J 2009; 3: 17.##Huang SS, Huang PH, Wu TC, Chen JW, Lin SJ. Association of serum bilirubin with contrast-induced nephropathy and future cardiovascular events in patients undergoing coronary intervention. PLoS One 2012; 7: e42594.##Koskinas J, Zacharakis G, Sidiropoulos J, Elefsiniotis J, Savvas S, Kotsiou S, et al. Granulocyte colony stimulating factor in HCV genotype-1 patients who develop Peg-IFN-alpha2b related severe neutropenia: a preliminary report on treatment, safety and efficacy. J Med Virol 2009; 81: 848-52.##Li N, Zhang L, Li H, Fang B. Administration of granulocyte colony-stimulating factor ameliorates radiation-induced hepatic fibrosis in mice. Transplant Proc 2010; 42: 3833-9.##Malekzadeh R, Mohamadnejad M, Rakhshani N, Nasseri-Moghaddam S, Merat S, et al. Reversibility of cirrhosis in chronic hepatitis B. Clin Gastroenterol Hepatol 2004; 2: 344-7.##Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol 1999; 31 Suppl 1: 9-16.##Nakamura H, Ueki Y, Sakito S, Matsumoto K, Yano M, Miyake S, et al. High serum and synovial fluid granulocyte colony stimulating factor (G-CSF) concentrations in patients with rheumatoid arthritis. Clin Exp Rheumatol 2000; 18: 713-8.##Palmer G, Mezin F, Juge-Aubry CE, Plater-Zyberk C, Gabay C, Guerne PA. Interferon beta stimulates interleukin 1 receptor antagonist production in human articular chondrocytes and synovial fibroblasts. Ann Rheum Dis 2004; 63: 43-9.##Pascussi JM, Vilarem MJ. Inflammation and drug metabolism: NF-kappB and the CAR and PXR xeno-receptors. Med Sci (Paris) 2008; 24: 301-5.##Refaat B, El-Shemi AG, Ashshi AM. The effects of pegylated interferon-α and ribavirin on liver and serum concentrations of activin-A and follistatin in normal Wistar rat: a preliminary report. BMC Res Notes 2015; 8: 265.##Renwick W, Pettengell R, Green M. Use of filgrastim and pegfilgrastim to support delivery of chemotherapy: twenty years of clinical experience. BioDrugs 2009; 23: 175-86.##Sharvadze L, Gochitashvili N, Tophuria A, Bolokadze N, Tsertsvadze T. IFN/RBV treatment induced neutropenia and its correction with neupogen in patients with hepatitis C. Georgian Med News 2007, p. 52-5.##Shen H, Zhang M, Minuk GY, Gong Y. Different effects of rat interferon alpha, beta and gamma on rat hepatic stellate cell proliferation and activation. BMC Cell Biol 2002; 3: 9.##Sookoian S, Pirola CJ. Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine. World J Gastroenterol 2015; 21: 711-25.##Stüve O, Dooley NP, Uhm JH, Antel JP, Francis GS, Williams G, et al. Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996; 40: 853-63.##Tajuddin T, Ryan EJ, Norris S, Hegarty JE, O'Farrelly C. Interferon-α suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist. J Gastroenterol Hepatol 2010; 25: 1883-90.##Todriia TV, Kaplanskaia IB. Side effect of granulocytic colony-stimulating factor on the structure and function of mouse liver. Ter Arkh 2006; 78: 56-9.##Wei Q, Hill WD, Su Y, Huang S, Dong Z. Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury. Am J Physiol Renal Physiol 2011; 301: F162-70.##Zhu H, Wang J, Jiang H, Ma Y, Pan S, Reddy S, et al. Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation. Exp Mol Med 2010; 42: 739-48.## ##

Atorvastatin attenuates D-galactose-induced hepatorenal toxicity in mice: an experimental study with histopathological evaluations 2 2 Introduction: Atorvastatin (Ator) is a lipid lowering drug with potent antioxidant and anti-inflammatory properties. The present investigation was designed to study the effect of Ator on D-galactose (GAL)-induced hepatorenal toxicity in mice. Methods: In this study, 40 mice were divided into 4 groups: normal, GAL (500 mg/kg), Ator 0.1 (0.1mg/kg)+GAL and Ator 1 (1mg/kg)+GAL. Ator and GAL were administered orally for 6 weeks simultaneously. Then on day 43, blood samples were collected to determine blood urea nitrogen (BUN), serum creatinine (sCr), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The kidneys and livers samples were used for histological examination. Results: Our results indicated that administration of GAL significantly increases sCr, BUN, ALT and AST. Co-administration of Ator 0.1 and 1mg/kg with GAL for 6 weeks (especially 1mg/kg) attenuated these changes. Histological changes in kidney such as infiltration of leukocyte, necrosis and oedema were observed in GAL group. Moreover, pyknosis, infiltration of inflammatory cell and fat deposit were observed in the livers of GAL-treated mice. Co-administration of Ator 0.1 and 1mg/kg with GAL for 6 weeks (especially 1mg/kg) could mitigate the histological lesions in kidneys and livers of GAL-administered animals. Conclusion: The results of this study suggested that Ator may have beneficial effects on hepatorenal toxicity induced by GAL. 36 43 2018/08/92018/10/112019/01/212018/03/172018/08/22 1397/5/31 2019/01/212019/02/152019/02/282018/12/242019/02/18 1397/11/29 Zahra Taghipour Zahra Taghipour Department of Anatomy, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran dr.taghipour@rums.ac.ir Elham Kaviani Elham Kaviani Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran ekaviani1394@gmail.com Ayat Kaeidi Ayat Kaeidi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran a.kaeidi@rums.ac.ir Ali Shamsizadeh Ali Shamsizadeh Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran ashamsi@rums.ac.ir Jalal Hassanshahi Jalal Hassanshahi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran hasanshahij@rums.ac.ir Iman Fatemi Iman Fatemi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran si_fatami@rums.ac.ir Hepatorenal toxicity D-galactose Atorvastatin. Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, et al. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol 2012; 27: 1353-61.##Ajamieh H, Farrell GC, McCuskey RS, Yu J, Chu E, Wong HJ, et al. Acute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation. Liver Int 2015; 35: 2174-86.##Amin KA, Abd El-Twab TM. Oxidative markers, nitric oxide and homocysteine alteration in hypercholesterolimic rats: role of atorvastatine and cinnamon. Int J Clin Exp Med 2009; 2: 254-65.##Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57: 728-34.##Bedi O, Dhawan V, Sharma PL, Kumar P. Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn Schmiedebergs Arch Pharmacol 2016; 389: 695-712.##Ehsani V, Amirteimoury M, Taghipour Z, Shamsizadeh A, Bazmandegan G, Rahnama A, et al. Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats. Ren Fail 2017; 39: 519-525.##El-Moselhy MA, El-Sheikh AA. Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed Pharmacother 2014; 68: 101-10.##Fan SH, Zhang ZF, Zheng YL, Lu J, Wu DM, Shan Q, et al. Troxerutin protects the mouse kidney from d-galactose-caused injury through anti-inflammation and anti-oxidation. Int Immunopharmacol 2009; 9: 91-6.##Fatemi I, Heydari S, Kaeidi A, Shamsizadeh A, Hakimizadeh E, Khaluoi A, et al. Metformin ameliorates the age-related changes of d-galactose administration in ovariectomized mice. Fundam Clin Pharmacol 2018a; 32: 392-399.##Fatemi I, Khaluoi A, Kaeidi A, Shamsizadeh A, Heydari S, Allahtavakoli MA. Protective effect of metformin on D-galactose-induced aging model in mice. Iran J Basic Med Sci 2018b; 21: 19-25.##Ghaznavi H, Fatemi I, Kalantari H, Hosseini Tabatabaei SMT, Mehrabani M, Gholamine B, et al. Ameliorative effects of gallic acid on gentamicin-induced nephrotoxicity in rats. J Asian Nat Prod Res 2017; 1-12.##Girona J, La Ville AE, Sola R, Plana N, Masana L. Simvastatin decreases aldehyde production derived from lipoprotein oxidation. Am J Cardiol 1999; 83: 846-51.##Haendeler J, Hoffmann J, Zeiher AM, Dimmeler S. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation 2004; 110: 856-61.##He X, Yang J, Li L, Tan H, Wu Y, Ran P, et al. Atorvastatin protects against contrast-induced nephropathy via anti-apoptosis by the upregulation of Hsp27 in vivo and in vitro. Mol Med Rep 2017; 15: 1963-1972.##Kalaz EB, Coban J, Aydin AF, Doğan-Ekici I, Doğru-Abbasoglu S, Oztezcan S, et al. Carnosine and taurine treatments decreased oxidative stress and tissue damage induced by D-galactose in rat liver. J Physiol Biochem 2014; 70: 15-25.##Kaviani E, Rahmani M, Kaeidi A, Shamsizadeh A, Allahtavakoli M, Mozafari N, et al. Protective effect of atorvastatin on d-galactose-induced aging model in mice. Behav Brain Res 2017; 334: 55-60.##Majsterek I, Gloc E, Blasiak J, Reiter RJ. A comparison of the action of amifostine and melatonin on DNA-damaging effects and apoptosis induced by idarubicin in normal and cancer cells. J Pineal Res 2005; 38: 254-63.##Mehrzadi S, Fatemi I, Malayeri AR, Khodadadi A, Mohammadi F, Mansouri E, et al. Ellagic acid mitigates sodium arsenite-induced renal and hepatic toxicity in male Wistar rats. Pharmacol Rep 2018; 70: 712-719.##Mehrzadi S, Kamrava SK, Dormanesh B, Motevalian M, Hosseinzadeh A, Hosseini Tabatabaei SM, et al. Melatonin synergistically enhances protective effect of atorvastatin against gentamicin-induced nephrotoxicity in rat kidney. Can J Physiol Pharmacol 2016; 94: 265-71.##Pisani A, Uccello F, Cesaro A, Comi N, Mirenghi F, Serio V, et al. Effects of atorvastatin on ischemic acute renal failure in aging rats. G Ital Nefrol 2002; 19: 534-9.##Prajapati SK, Garabadu D, Krishnamurthy S. Coenzyme Q10 prevents mitochondrial dysfunction and facilitates pharmacological activity of atorvastatin in 6-OHDA induced dopaminergic toxicity in rats. Neurotox Res 2017; 31: 478-492.##Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 2005; 19: 117-25.##Wei H, Li L, Song Q, Ai H, Chu J, Li W. Behavioural study of the D-galactose induced aging model in C57BL/6J mice. 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Effects of renal ischemia-reperfusion on biochemical factors and histopathological alterations in the liver of male rats 2 2 Introduction: One of the main reasons for acute renal failure is the renal ischemiareperfusion. It seems that renal ischemia-reperfusion-induced oxidative stress not only lead to alterations in renal function but also causes tissue alterations in distant organs such as the liver. The purposes of this study were to investigate the effects of renal ischemia-reperfusion on biochemical factors and histopathological changes in the liver of male rats. Methods: Forty male rats were randomly divided into 4 groups: control, the sham group (only laparotomy), right nephrectomy and ischemic-reperfusion (right nephrectomy + left ischemic- reperfusion). In the end, following anesthesia, blood and liver samples were taken for the measurement of biochemical factors (malondialdehyde (MDA), superoxide dismutase (SOD), aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) levels) and histopathological changes. Results: The result of this study indicated that renal ischemia-reperfusion significantly decreased SOD and increased MDA, AST, ALP and ALT compared to sham-control group (P<0.05). In addition, histopathological findings show that ischemia-reperfusion significantly increased apoptotic cells (P<0.05) and causes the disorganized arrangement of the hepatic plate, severe hepatocellular cytoplasmic vacuolation and extensive nuclear pyknosis. Conclusion: Our findings suggest that renal ischemia-reperfusion-induced liver damage, accompanied by decreasing of antioxidant capacity and increasing of oxidative stress and apoptosis in the liver. 44 50 2018/08/92018/10/112019/01/212018/03/172018/08/222018/09/16 1397/6/25 2019/01/212019/02/152019/02/282018/12/242019/02/182018/12/31 1397/10/10 Hadi Yousefi Hadi Yousefi Khoy University of Medical Sciences, Khoy, Iran Iran yousefi@tbzmed.ac.ir Nasser Ahmadiasl Nasser Ahmadiasl Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Iran ahmadyn@tbzmed.ac.ir Ramin Salimnejad Ramin Salimnejad Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran r.salimnejad@arums.ac.ir Elhameh Bagheri Elhameh Bagheri Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Iran bagheri@tbzmed.ac.ir Leila Roshangar Leila Roshangar Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Iran roshangar@tbzmed.ac.ir Alireza Alihemmati Alireza Alihemmati Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Iran hemmati@tbzmed.ac.ir Renal ischemia-reperfusion Oxidative Stress Liver Biochemical factors Histopathological alterations. Alihemmati A, Yousefi H, Ahmadiasl N, Habibi P. Apoptosis and histopathology of the heart after renal ischemia-reperfusion in male rat running title: Ischemia-reperfusion injury. Brazilian Archives of Biology and Technology 2017; 60.##Altunoluk B, Soylemez H, Oguz F, Turkmen E, Fadillioglu E. An angiotensin-converting enzyme inhibitor, zofenopril, prevents renal ischemia/reperfusion injury in rats. Annals of Clinical & Laboratory Science 2006; 36: 326-332.##Asaga T, Ueki M, Chujo K, Taie S. Jte-607, an inflammatory cytokine synthesis inhibitor, attenuates ischemia/reperfusion-induced renal injury by reducing neutrophil activation in rats. Journal of bioscience and bioengineering 2008; 106: 22-26.##Basireddy M, Isbell TS, Teng X, Patel RP, Agarwal A. Effects of sodium nitrite on ischemia-reperfusion injury in the rat kidney. American Journal of Physiology-Renal Physiology 2006; 290: F779-F786.##Bonventre JV. Mechanisms of ischemic acute renal failure. 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Protective effects of walnut extract against oxidative damage in acetic acid-induced experimental colitis rats 2 2 Introduction: Walnuts (Juglans regia), has been shown to exert anti-inflammatory and antioxidant effects. The present study was designed to evaluate the anti-inflammatory and antioxidant effects of walnut extract (WE) on an experimental model of ulcerative colitis caused by intracolonic administration of acetic acid in rats. Methods: A total number of 30 rats were used, randomly assigned to five groups of 6 rats each. Group I: colitis without treatment (colitis control), group II: normal animals (normal control), in groups III and IV colitis induced rats were treated with WE (10 and 20mg/kg) for 8 consecutive days, and group V were treated with sulfasalazine (SLS, 200mg/kg) as a standard drug. Several parameters, including macroscopic and histopathological scores and malondialdehyde (MDA), total sulfhydryl (SH) groups, colonic superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured using standard assay procedures. Results: Results revealed that treatment with 10mg/kg WE for 8 days attenuated the macroscopic and histopathological colonic damage scores as well as colonic levels of MDA, while increased the levels of total SH, SOD and GPx compared with colitis untreated group. The 20mg/kg dose had no protective effects. Conclusion: These findings suggest that protective effect of WE in the experimental model of colitis could be through an antioxidant mechanism. 51 58 2018/08/92018/10/112019/01/212018/03/172018/08/222018/09/162018/09/21 1397/6/30 2019/01/212019/02/152019/02/282018/12/242019/02/182018/12/312019/01/20 1397/10/30 Zakieh Keshavarzi Zakieh Keshavarzi Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran Iran Zakieh_Keshavarzi@nkums.ac.ir Fatemeh Nurmohammadi Fatemeh Nurmohammadi College of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran Fatemeh.Nur@nkums.ac.ir Saba Majlesi Saba Majlesi College of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Iran S_Majlesi@nkums.ac.ir Fatemeh Maghool Fatemeh Maghool Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran f.maghool@girc.ir Ulcerative colitis Walnut extract Antioxidant. 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Transient modulation of hydroxyzine, an antihistamine and anxiolytic agent, on the cardiac autonomic activity in healthy subjects 2 2 Introduction: Despite the experimental evidence available on the modulating effects of the H1 receptors on the autonomic function, limited research has been done the effects of such receptors through measuring the heart rate variability (HRV) indexes in human. The present study aims to assess the effect of the acute administration of different doses of hydroxyzine on the time and frequency domain of HRV indexes. Methods: Four experiment sessions were held for the fifteen healthy participants. In each session, after the 5-minute baseline electrocardiogram (ECG) recording, one of the four interventions (the intake of a 5, 10 or 20mg hydroxyzine or a placebo) was performed and then the 5-minute ECG recordings were repeated at 30, 60, 90, 120, 180 and 240 minutes after the oral administration. Results: The statistical analysis has shown that at minute 30, hydroxyzine has an inhibitory effect on the sympathetic index low frequency (LFnu), which is eliminated at minute 180. Moreover, from minute 60, hydroxyzine increases vagal HRV indexes, which are then eliminated at minute 240. Conclusion: The findings of the present study showed that histamines, mediated by H1 receptors, have a modulating effect on the cardiac autonomic; however, this modulating effect is then neutralized or eliminated in a short time probably by other cardiac regulatory mechanisms. 59 69 2018/08/92018/10/112019/01/212018/03/172018/08/222018/09/162018/09/212018/12/16 1397/9/25 2019/01/212019/02/152019/02/282018/12/242019/02/182018/12/312019/01/202019/02/22 1397/12/3 Fateme Rezaeyanzade Fateme Rezaeyanzade School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran Iran f.rezaeyanzade@mazums.ac.ir Nematollah Ahangar Nematollah Ahangar Pharmaceutical Sciences Research Center and Department of Toxicology and Pharmacology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran Iran n.ahangar@mazums.ac.ir Abbas Alipour Abbas Alipour Department of Community Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Iran alipour.abbas@mazums.ac.ir Ali Ghaemian Ali Ghaemian Mazandaran Heart Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Iran a.ghaemian@mazums.ac.ir Esmaeil Akbari Esmaeil Akbari Department of Physiology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Iran akbari_esmaeil@mazums.ac.ir Histamine Heart rate variability Hydroxyzine Autonomic nervous system. 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Task force of the european society of cardiology and the north american society of pacing and electrophysiology. Circulation 1996; 93: 1043-65.##Vybiral T, Bryg RJ, Maddens ME, Bhasin SS, Cronin S, Boden WE, et al. Effects of transdermal scopolamine on heart rate variability in normal subjects. Am J Cardiol 1990; 65: 604-8.##Watanabe T, Taguchi Y, Shiosaka S, Tanaka J, Kubota H, Terano Y, et al. Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res 1984; 295: 13-25.##Whyment AD, Blanks AM, Lee K, Renaud LP, Spanswick D. Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of h1 receptors. J Neurophysiol 2006; 95: 2492-500.##Yeh TL, Yang YK, Chiu NT, Yao WJ, Yeh SJ, Wu JS, et al. Correlation between striatal dopamine d2/d3 receptor binding and cardiovascular activity in healthy subjects. Am J Hypertens 2006; 19: 964-9.## ##