Exercise-related alterations in MCT1 and GLUT4 expressions in the liver and pancreas of rats with STZ-induced diabetes.

Background: The liver and pancreas tissues play a central role in controlling glucose homeostasis. In patients with type I diabetes mellitus (T1DM), the function of these tissues is impaired. The positive effects of exercise have been shown in diabetic patients. To demonstrate the positive effects of exercise in T1DM, we examined the effects of moderate-intensity endurance training (MIET) on the liver enzymes and expression of MCT1 and GLUT4 genes. Methods: Male Wistar rats were allocated into 4 groups of control (C), training (T), diabetic control (DC), and diabetes + training (DT). The serum levels of liver enzymes such as alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were determined by ELIZA. MCT1 and GLUT4 mRNA expressions in the liver and pancreas tissues were evaluated through real-time qPCR after 10 weeks of training. Results: The mRNA levels of MCT1 and GLUT4 decreased in DC group and increased in DT group. T1DM led to weight loss, but the weight loss was less in the DT group. T1DM caused an increase in liver enzymes such as ALT, AST and ALP, whereas endurance training preserved enzymatic levels. Conclusion: These results suggested that MIET increases levels of MCT1 and GLUT4 liver and pancreas in the diabetic rats and improves liver function tests. Upregulation of MCT1 and GLUT4 can probably improve the function of liver and pancreas tissues and promote glucose homeostasis in T1DM.

Moderate Endurance Training and MitoQ Improve Cardiovascular Function, Oxidative Stress, and Inflammation in Hypertensive Individuals: The Role of miR-21 and miR-222: A Randomized, Double-Blind, Clinical Trial.

OBJECTIVE: Hypertension (HTN) is among the leading causes of myocardial infarction, stroke, and kidney disease. The MitoQ supplement is a mitochondrial-targeted antioxidant that attenuates the generation of reactive oxygen species (ROS). miRNAs play an essential role in the pathophysiology of HTN. Regular aerobic exercise is recommended to decrease the risk of cardiovascular disease. We aimed to evaluate the effects of MitoQ supplementation and moderate endurance training (ET), alone and in combination, on cardiac function, blood pressure, the circulatory levels of miRNA-21 and miRNA-222, and oxidative status in individuals with HTN. MATERIALS AND METHODS: In a double-blind, randomized clinical trial (except for ET group), 52 male hypertensive subjects (40-55 years old) were randomly divided into four groups (n=13): Placebo, MitoQ (20 mg/day, oral), ET (Cycle ergometer, moderate intensity, 40-60% VO2 peak, three sessions/week for six weeks), and MitoQ+ET. Cardiac echocardiography indices, serum oxidative and inflammation status, and miRNAs 21 and 222 were assessed before and after interventions. RESULTS: Left ventricular mass [effect size (ES): -6.3, 95% confidence interval (CI): -11.2 to -1.4] and end-systolic/ diastolic diameters significantly improved in the intervention groups (ES: -0.05, 95% CI: -0.11 to 0.00 and -0.09, 95% CI: -0.16 to -0.02). Total serum antioxidant capacity (TAC) increased (ES: 36.0, 95% CI: 26.1 to 45.8), and malondialdehyde (MDA) (ES: -0.43, 95% CI: -0.53 to -0.32), IL-6 (ES: -1.6, 95% CI: -1.98 to -1.25), miR-21 (ES: -0.48, 95% CI: -0.61 to -0.35), and miR-222 (ES: -0.31, 95% CI: -0.44 to -0.18) significantly decreased in response to ET, MitoQ, and their combination. CONCLUSION: MitoQ and ET, individually and more pronouncedly in combination, can improve cardiovascular health in people with high blood pressure (BP) by reducing inflammation and increasing antioxidant defense, in association with reduction in circulatory miR-21 and miR-222 levels (registration number: IRCT20190228042870N1).

Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the pathophysiology of PAH. As the current treatments cannot prevent the progression of the disease, we investigated whether 3 plant derivatives, namely perillyl alcohol (PA), quercetin (QS), and berberine (BBR), can improve RV function and affect the expression of miR-204, miR-27a, and biochemical factors in monocrotaline-induced PAH (MCT-PAH). Thirty-six rats were divided into control (CTL), MCT, MCT+Veh (vehicle), MCT+PA, MCT+QS, and MCT + BBR groups (n = 6 each). After inducing PAH using MCT (60 mg/kg), PA (50 mg/kg), QS (30 mg/kg), and BBR (30 mg/kg) were administrated daily for 3 weeks. miR-204 expression, total antioxidant capacity, and antiapoptotic protein Bcl-2 significantly declined in the RV of PAH rats, and PA, QS, and BBR treatment significantly compensated for these decreases. Proapoptotic protein Bax and p21 cell cycle inhibitor increased in the RV. All 3 herbal derivatives compensated for Bax increase, and BBR caused a decrease in p21. TNFα, IL-6, and malondialdehyde increased in the RV, and PA, QS, and BBR significantly counterbalanced these increases. miR-27a expression was not affected by MCT and plant derivatives. Overall, PA, QS, and BBR improved ventricular disorders in rats with PAH by decreasing inflammation, apoptosis, and fibrosis and increasing the antioxidant-to-oxidant ratio. Therefore, these herbal derivatives may be considered as target therapeutic goals for this disease either alone or in combination with current medications.

Safety and efficacy of Berberis integerrima root extract in patients with type 2 diabetes. A parallel intervention based triple blind clinical trial.

PURPOSE: To evaluate the safety and efficacy of methanol extract of Berberis integerrima root on type 2 diabetes compared to metformin. METHODS: In a parallel triple blind clinical trial, 80 type 2 diabetic patients,, were randomized into two groups (treated with Berberis integerrima root, 480 mg (oral), compared to control group treated with metformin 1000 mg daily). Efficacy was evaluated by fasting and prandial glucose and HbA1c and side effects confirmed by physical examination, biology and hematology tests and urinalysis on days 15, 45 and 90. They were followed for 3 months. RESULTS: Two hundred and eighteen patients were recruited and 80 (55female and 25 male) patients randomized in two groups and 60 patient were analysed. The mean age of patients was 51.8 ± 9.3 and 46.5 ± 10 in the experimental (Berberis integerrima ) and control (metformin) groups respectively (P = 0.02). The mean HbA1c at baseline was 8.1 ± 1.6% and 7.9 ± 1.6% for B. integerrima and metformin group respectively (P = 0.53), and there was no significant difference between the two groups (7.5 vs. 7.2) after 3 months (P = 0.34).Weight loss was observed in both groups compared to baseline.No adverse event led to preventing the study was reported. CONCLUSION: Berberis integerrima root not only was effective as much as metformin in reducing blood glucose and controlling type 2 diabetes but also, no specific side effect was reported (in short term).So, it might be an effective and safe complementary therapy in diabetic patients.Iranian Research and Clinical Trial (IRCT) registeration number; 201,207,191,774 N5.Funding: Vice chancellor for research, Physiology Research Center of Kerman University of Medical Sciences and the Exir pharmaceutical company.

Downregulation of IL-22 can be considered as a risk factor for onset of type 2 diabetes.

There is some controversy as for the roles played by tumor growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß), and IL-22 in the onset process of type 2 diabetes (T2D). The main aim of this project was to examine serum levels of TGF-ß, IL-1ß, and IL-22 in the new cases and long period T2D patients as well as healthy controls. In this study, 115 new T2D patient cases (group 1), 434 T2D patients who have suffered from the disease more than 2 years (group 2), and 104 healthy controls have been selected from 6240 (3619 females) patients who were under study population from Kerman Coronary Artery Disease Risk Factor Study. Serum levels of TGF-ß, IL-1ß, and IL-22 have been evaluated using commercial kits. Serum levels of TGF-ß and IL-1ß significantly increased, while IL-22 decreased in 2 groups in comparison to healthy controls. Serum levels of IL-22, but not TGF-ß and IL-1ß, were significantly decreased in group 1 in comparison to healthy controls. There were no significant differences between groups 1 and 2 as for the cytokine levels. Serum levels of IL-22 increased in the females in group 2 when compared to females in group 1. It appears that TGF-ß and IL-1ß participate in the induction of inflammation after establishment of T2D, while decrease in IL-22 may be considered as a key factor for onset of the disease. Gender can also be considered as the main risk factor for variation in cytokine levels.

Effects of Subacute Administration of Co-Trimoxazole and Folic Acid on Ovarian Tissue in Adult Female Rats.

BACKGROUND: Previous studies have reported the antifertility activities of sulfonamides. This study was designed to evaluate the effects of co-trimoxazole and its co-administration with folic acid on ovarian tissue in female rats. METHODS: A total of 54 rats were randomly divided into 9 groups (n=6). Group I served as the control and group II (vehicle) received saline. Other groups, III to IX, received co-trimoxazole (30, 60, and 120 mg/kg; i.p.), folic acid (1 mg/kg; i.p.) or their combination for 14 days, respectively. The oocytes were obtained from each group at the end of the 14th days and scored for maturational status as germinal vesicle (GV), metaphase I (MI), or metaphase II (MII). The number of primordial follicle (PrF), primary follicle (PF), and secondary follicle in formalin-fixed ovaries were counted under light microscopy. The data were analyzed by one-way ANOVA followed by post-hoc Dunnet test using SPSS statistical software (version 17.0). Results were considered statistically significant at P<0.05. RESULTS: Co-trimoxazole (60 and 120 mg/kg) treatment for 14 days caused a significant decrease in the number of GV (P=0.02, P<0.001), MI and MII (P=0.03, P<0.001), a significant increase in structural abnormalities, including PrF, PF and secondary follicle (P<0.001) as well as congestion, inflammation and necrosis of ovarian tissue compared to the vehicle group. Folic acid co-administration with co-trimoxazole reversed partially all these parameters compared to the co-trimoxazole group (P<0.001). CONCLUSION: The data showed the adverse effects of co-trimoxazole on the ovarian maturational status and tissue structure which was reversed partially by folic acid co-administration in rats.

Effects of Methamphetamine on Testes Histopathology and Spermatogenesis Indices of Adult Male Rats.

BACKGROUND: Methamphetamine (MAMP) as a recreational drug has devastating effects on the central nervous system (CNS). Several studies have shown that MAMP has inhibitory effects on oogenesis and spermatogenesis, and causes impaired fertility. This study designed to investigate the effect of mAM Padministration on histological changes and spermatogenesis indices in the testis of adult male rats. METHODS: In this experimental study, 50 male Wistar rats were randomly divided into control (received no treatment, n = 10), vehicle (received saline for 7 and 14 days, n = 20), and experimental group [received MAMP, 5 ml/kg, intraperitoneal (IP) for 7 and 14 days, n = 20]. Testicular tissue samples were stained by hematoxylin and eosin (H&E) technique. For histological study, we counted the number of spermatogonia, spermatocytes and Leydig cells. Spermatogenesis indices which include: tubular differentiation index (TDI), spermiogenesis index (SI), repopulation index (RI) and the mean seminiferous tubules diameter (MSTD) were studied. Data were analyzed by one-way ANOVA, using SPSS software. P < 0.05 was considered statistically significant. FINDINGS: This study showed that MAMP caused a significant decrease in number of seminiferous tubules cells and spermatogenesis in treated group compared with the control group. Moreover, results showed a significant decrease in spermatogenesis indices including TDI, SI, RI, and MSTD in 14th day, compared to control group (P < 0.001). CONCLUSION: The data showed the adverse effects of MAMP administration (for 7 and 14 days) on testes structure and spermatogenesis indices in rat testis tissue. The underlying mechanism(s) needs further investigation.

The Effects of Methanolic Extract of Melissa officinalis on Experimental Gastric Ulcers in Rats.

BACKGROUND: Melissa officinalis (MO) has potent antioxidant activity. Recent research has demonstrated the anti-ulcer properties of some medicinal plants through their antioxidant properties. OBJECTIVES: The aim of this study was to evaluate the effects of methanolic extracts of MO on experimental gastric ulcers in rats. MATERIALS AND METHODS: Male Wistar rats (200 - 250 g) were starved for 24 hours prior to the induction of gastric ulceration by either indomethacin (48 mg/kg/oral) or water immersion restraint (WIR) stress. Experimental rats received either ranitidine (25 mg/kg) or MO extract (150, 300 and 450mg/kg) orally 2 hours prior to WIR stress or indomethacin treatment, for the evaluation of their gastroprotective effects. The control group received the same volume of saline. Gastric lesions were scored according to the surface of lesions on the ulcer index. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) were determined as measures of antioxidant defense, and malondialdehyde (MDA) was determined to measure tissue oxidation. RESULTS: MO extract (150 and 300 mg/kg) significantly decreased the ulcer index in both the indomethacin (1.3 ± 0.09 and 1.5 ± 0.19, respectively) and WIR stress groups (1.5 ± 0.17 and 1.5 ± 0.22, respectively), as compared to the control rats (2.5 ± 0.28) (P < 0.01). MO extract (450 mg/kg) significantly reduced ulcer index readings in WIR stress rats (1.8 ± 0.31 vs. 2.4 ± 0.15 in the WIR group), however, MO extract at a dose of 450 mg/kg did not prevent indomethacin-induced gastric ulceration (2.4 ± 0.26). There was no significant difference in the ulcer index for MO extract- (150 and 300 mg/kg) and ranitidine-treated rats (P > 0.05). Also, MO extract (150 and 300 mg/kg) significantly reduced MDA serum levels (0.69 ± 0.6 µmol/L and 0.85 ± 0.24 µmol/L, respectively, vs. 4.5 ± 1.9 µmol/L in the saline group) and significantly increased antioxidants' SOD activities (296.3 ± 146.4 U/mL and 561.4 ± 120 U/mL, respectively, vs. 190.2 ± 63.8U/mL in the control group) and GPX levels (8273 ± 3049 U/mL and 14574 ± 5012 U/mL, respectively), compared to the control (3236 ± 1699 U/mL). CONCLUSIONS: Our results showed that MO extract may have a gastroprotective effect against experimental gastric ulcers in rats. The exact mechanism has not yet been determined, but it may be due to enhancing enzymatic antioxidant defenses and inhibiting lipid peroxidation.

HYPERTHYROIDISM AND HYPERPROLACTINEMIA: IS THERE ANY ASSOCIATION?

OBJECTIVE: To compare the serum prolactin level in hyperthyroid and normal control females. Hyperthyroidism is a common disease. Although a direct association has been demonstrated between hypothyroidism and increased prolactin levels, this association has not been established for hyperthyroidism. METHODS: Cross-sectional study in cases and control groups. Control subjects were chosen from those participating in the Kerman Coronary Artery Disease Risk Factors study. To select the cases, all women referred to the laboratories of Kerman with a thyroid-stimulating hormone (TSH) level ≤0.5 mIU/L who met the inclusion criteria were entered in the study. A total of 231 women aged 15 to 50 years were enrolled. The case group included 71 hyperthyroid women, and the control group included 160 women with normal thyroid function matched by age. RESULTS: The mean (SD) serum level of prolactin was 16.56 (0.97) ng/mL (95% confidence interval [CI], 15.41 ng/mL to 15.71 ng/mL) in the controls and 23.07 (1.49) ng/mL (95% CI, 22.7 ng/mL to 23.4 ng/mL) in the case subjects. Hyperprolactinemia was more common in the hyperthyroid group (16.5 [0.97] ng/mL versus 23.07 [1.49] ng/mL; P<.001). The prolactin level decreased with age. Hyperthyroidism and estradiol increased the prolactin level. After adjusting for age and estradiol, hyperthyroidism increased the serum prolactin level (P<.001). CONCLUSION: The results of this study revealed that hyperprolactinemia is more frequent in hyperthyroid females. Serum prolactin level can be increased in hyperthyroidism. ABBREVIATIONS: PRL = prolactin T4 = thyroxine TRH = thyrotropin-releasing hormone TSH = thyroid-stimulating hormone.

The effect of interleukins 27 and 35 and their role on mediating the action of insulin Like Growth Factor -1 on the inflammation and blood flow of chronically inflamed rat knee joint.

INTRODUCTION: Previous studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow. METHOD: Male rats were divided into two main groups of histopathology (n=80) and blood flow (n=72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1+IL-27 antagonist, and IGF-1+IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed. RESULTS: Endogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1+IL-35 antagonist. CONCLUSION: IL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF.

The association between urinary lgM excretion and diabetic retinopathy in diabetic patients.

BACKGROUND: Diabetic Retinopathy is one of the most common causes of blindness among adults. Microvascular complications may have common origins. The objective of the present study is to analyze the correlation between urinary IgM excretion and diabetic retinopathy based on the type of diabetes. METHODS: The present study is cross-sectional analytic and was carried out on 140 type2 diabetic patients (of which 70 patients diagnosed with retinopathy) and 76 type1 diabetic patients (of which 37 patients diagnosed with retinopathy). For every patient in each of the test groups, fasting plasma glucose, triglyceride, cholesterol, creatinin and HbA1c tests were done. The value of IgM, the albumin- to- creatinine ratio and the urine analysis test were also used to rule out the significant proteinuria of the patients. Then, IgM Index was measured using the following equation: Igm Index = Urine IgM/Urine Cr. RESULTS: The level of IgM index in the diabetic patients (type1 and type2) had no significant correlation with retinopathy. Cut point = 1.49, sensitivity = 0.703 and specificity = 0.308 in type1 diabetes were used for screen retinopathy. In type1 diabetic patients, the duration of diabetes had a significant correlation with urinary protein while in type 2 diabetic patients, the diabetes duration and HbA1c were significantly correlated with retinopathy. CONCLUSION: The results of this study demonstrate that the level of urinary IgM in diabetic patients has no difference in those who have or lack retinopathy, but the urinary IgM level of more than 1.49 mg/dl can be considered as a cut point in type1 diabetic patients to screen retinopathy.