Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Effect of allopurinol and benzbromarone on diabetic cardiomyopathy and vasculopathy in streptozotocin-induced diabetic rats 1 8 EN Mohammad Fathalipour Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Hossein Mirkhani Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Mohsen Goharinia Department of Pharmacology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Antidiabetic effect of hydroethanolic extract of Crocus sativus stigmas, tepals and leaves in streptozotocin-induced diabetic rats 9 20 EN Sabir Ouahhoud Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Iliass Lahmass Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Mohamed Bouhrim Laboratory of Physiology, Genetic and Ethnopharmacology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Amine Khoulati Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Assia Sabouni Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Redouanae Benabbes Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Abdeslam Asehraou Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Mohammed Choukri Laboratory of Biochemistry, Central Laboratory Service - CHU, Mohammed VI, Faculty of Medicine and Pharmacy, University Mohamed Premier, Oujda, Morocco Mohamed Bnouham Laboratory of Physiology, Genetic and Ethnopharmacology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco Ennouamane Saalaoui Laboratory of Biochemistry and Biotechnology, Department of Biology, Faculty of Sciences, University Mohamed Premier, Oujda, Morocco 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Ursolic acid increases SIRT1 protein level and β-cells number in diabetic rats 21 27 EN Rozita Naseri Department of Endocrinology and Metabolism, Kermanshah University of Medical Sciences, Kermanshah, Iran Fatemeh Bakhtiari Department of Internal- Medicine, Faculty of Medical-sciences, Medical University of Kermanshah, Kermanshah, Iran Cyrus Jalili Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran 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 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Interferon-alpha reduced inflammatory effects of filgrastim (G-CSF) in the liver of Syrian mice 28 35 EN Ensieh Namjou Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Roya Lari Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Nasser Mahdavi Shahri Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran Ali Moghimi Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Atorvastatin attenuates D-galactose-induced hepatorenal toxicity in mice: an experimental study with histopathological evaluations 36 43 EN Zahra Taghipour Department of Anatomy, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Elham Kaviani Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Ayat Kaeidi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Ali Shamsizadeh Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Jalal Hassanshahi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iman Fatemi Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Effects of renal ischemia-reperfusion on biochemical factors and histopathological alterations in the liver of male rats 44 50 EN Hadi Yousefi Khoy University of Medical Sciences, Khoy, Iran Nasser Ahmadiasl Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 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 Elhameh Bagheri Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Leila Roshangar Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Alireza Alihemmati Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Protective effects of walnut extract against oxidative damage in acetic acid-induced experimental colitis rats 51 58 EN Zakieh Keshavarzi Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran Fatemeh Nurmohammadi College of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Saba Majlesi College of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Fatemeh Maghool Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran 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.

Iranian Society of Physiology and Pharmacology Physiology and Pharmacology 24765236 23 1 2019 3 1 Transient modulation of hydroxyzine, an antihistamine and anxiolytic agent, on the cardiac autonomic activity in healthy subjects 59 69 EN Fateme Rezaeyanzade School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran Nematollah Ahangar Pharmaceutical Sciences Research Center and Department of Toxicology and Pharmacology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran Abbas Alipour Department of Community Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Ali Ghaemian Mazandaran Heart Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Esmaeil Akbari Department of Physiology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran 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.