IGF-I combined with exercise improve diabetes-induced vascular dysfunction in heart of male Wistar rats.

Introduction: This research investigates the impact of insulin-like growth factor-I (IGF -I)and exercise on mediators associated with angiogenesis (VEGF-A, TSP-1, and NF-кß) and capillarization status of the diabetic rats' hearts. Methods: Splitting of forty Wistar male rats into five groups occurred as following: control,diabetes, diabetes+IGF-I, diabetes+exercise, and diabetes+exercise+IGF-I.Through intraperitoneal administration of 60 mg/kg streptozotocin, the condition of Type 1diabetes was escalated. After four weeks of treatment with IGF-I (2 mg/kg/day) or treadmill exercise (17 m/min, zero degrees slope, 30 min/day), in the heart, microvascular density and protein levels of VEGF-A, TSP-1, and NF-Ðºß were determined by H&E staining and ELISA,respectively. Results: Within the diabetic group, observations present a significant decrease in VEGF-A and MVD levels, whereas an increase in the TSP-1 and NF-Κb levels. While these impacts were reversed by either IGF-I or exercise treatments, simultaneous treatment had synergistic effects. Moreover, among diabetic rats, undesirable histologic alterations of the heart were demonstrated, including myonecrosis, interstitial edema, hemorrhage, and mononuclear immune cell infiltration, whereas treatments improved these changes. Conclusion: These data manifest that IGF-I and exercise can increase the cardiac angiogenesis of diabetic rats through increasing expression of VEGF-A, and decreasing TSP-1 and NF-кßproteins level, also can improve myocardial tissue damages.

Renoprotective effects of tropisetron through regulation of the TGF-ß1, p53 and matrix metalloproteinases in streptozotocin-induced diabetic rats.

Renal fibrosis is a major cause of renal failure in diabetic nephropathy. Tropisetron is an antagonist of the 5HT3 receptor that exhibits anti-fibrosis effects. The present research aimed to investigate the protected role of tropisetron against renal fibrosis of diabetic nephropathy and its molecular mechanisms. For this purpose, male Wistar rats were allocated into 5 groups of control, tropisetron, diabetes, tropisetron + diabetes, and glibenclamide + diabetes (n = 7). After induction of type 1 diabetes with a single injection of STZ, tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) were given to the rats daily by intraperitoneal injection for 2 weeks. The obtained data revealed that the treatment of diabetic rats with tropisetron led to a significant decrease in the elevated blood glucose, serum cystatin c, and urinary total protein (UTP) level, indicating the improvement of the impaired kidney function. Moreover, the results of Masson's trichrome staining showed that fibrosis attenuated in the kidney of diabetic rats after tropisetron treatment. RT-PCR and Western blotting revealed that TGF-ß1, the apoptotic mediator, and p53 were considerably declined in the kidney of diabetic rats in response to tropisetron treatment. Meanwhile, the expressions of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) were increased. These notable effects were equipotent with glibenclamide, as a standard drug, suggesting that tropisetron can alleviate renal fibrosis in diabetic nephropathy. Our data indicate that tropisetron could improve kidney function and attenuate renal fibrosis through regulation of TGF-ß1, p53, and expression of extracellular matrix metalloproteinases.

The effect of tropisetron on oxidative stress, SIRT1, FOXO3a, and claudin-1 in the renal tissue of STZ-induced diabetic rats.

Tropisetron is a 5-HT3 receptor antagonist that exerts protective effect against DN. The aim of this study was to investigate the possible molecular mechanisms associated with the renoprotective effects of tropisetron in STZ-induced diabetic rats. Animals were subdivided into 5 equal groups; control, tropisetron, diabetes, tropisetron + diabetes, and glibenclamide + diabetes (n = 7). For induction of type 1 diabetes, a single injection of STZ (55 mg/kg, i.p.) was administered to the animals. Diabetic rats were treated with tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) for 2 weeks. According to the conducted analysis, diabetes led to renal dysfunction (reduction in glomerular filtration rate and urine urea and creatinine as well as elevation in plasma urea and creatinine) and abnormalities in antioxidant defense system (reduction in TAC and elevation in MDA), compared with the control group, which was prevented by tropisetron treatment. Reverse transcription-quantitative polymerase chain reaction and western blotting analysis demonstrated that SIRT1 gene expression decreased while FOXO3a and NF-κB gene expression as well as phosphorylated FOXO3a/total FOXO3a protein ratios and claudin-1 protein level increased in the kidney of diabetic rats compared with the control group. Herein, the results of this research showed that tropisetron treatment reversed these changes. Besides, all these changes were comparable with those produced by glibenclamide as a positive control. Hence, tropisetron ameliorated renal damage due to diabetic nephropathy possibly by suppressing oxidative stress and alteration of SIRT1, FOXO3a, and claudin-1 levels.

Possible Protective Effects of Curcumin via Modulating of Androgen Receptor (AR) and Oct2 Gene Alterations in Cisplatin-Induced Testicular Toxicity in Rat.

BACKGROUND: Cisplatin is a chemotherapeutic drug used to treat testicular cancer that induces testicular toxicity. This study aimed to investigate the possible role of androgens, androgen receptor, and organic cation transporter 2 (OCT2) in the protective effects of curcumin on cisplatininduced testicular toxicity. METHODS: Thirty male Wistar rats were divided into five groups: 1- control (normal saline, 0.5 ml ip, daily for 10 consecutive days); 2- cisplatin (10 mg/kg ip, single dose at the first day); 3- cisplatin + curcumin (10 mg/kg ip, dissolved in 5% DMSO, daily for 10 consecutive days); 4- cisplatin + vehicle (DMSO 5%, 0.3 ml ip); and 5- curcumin (10 mg/kg ip). At the end of the study, a blood sample was obtained for testosterone measurement. The left testis was kept at -80. to measure androgen receptor (AR) and type 2 organic cation transporter (OCT2) gene expression and the right testis were kept in 10% formalin for histological analysis. RESULTS: Cisplatin significantly decreased serum testosterone, declined testis AR gene expression, and increased OCT2 gene expression in testis (p<0.01). Curcumin treatment significantly prevented these alterations in testosterone and gene expressions (p<0.01). Moreover, curcumin significantly reversed the cisplatin-induced kidney tissue injury and increased spermatid and spermatozoa. CONCLUSION: It is concluded that the ameliorative effect of curcumin in cisplatin-induced reproductive disorders was due to the modulation of testosterone and androgen receptors.

Tropisetron attenuates pancreas apoptosis in the STZ-induced diabetic rats: involvement of SIRT1/NF-κB signaling.

BACKGROUND: Diabetes mellitus (DM) is one of the most common diseases in the worldwide. Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency and beta cells apoptosis. Tropisetron as a 5-HT3 receptor antagonist has positive effects on the inflammation, apoptosis and glucose lowering. The aim of this study was to investigate the effect of tropisetron on ß-cells apoptosis and its possible pathways. METHODS: Animals were divided into five equal groups: the control, tropisetron, diabetes, tropisetron-DM and glibenclamide-DM (seven in each group). Tropisetron and glibenclamide were administrated for 2 weeks after type 1 diabetes induction. Real-time PCR, western blot analysis and TUNEL assay were performed. RESULTS: We found that tropisetron decreased blood glucose and increased insulin secretion. Protein expression of NF-κB was downregulated, while protein expression of SIRT1 upregulated after tropisetron treatment. Moreover, Bax/Bcl2 ratio decreased in tropisetron-DM group and finally, apoptosis improved in pancreas tissue. CONCLUSIONS: It seems that tropisetron administration improves STZ-induced apoptosis and diabetes in the animals. This effect might be resulted from involvement in NF-κB/ SIRT1 pathway.

Tropisetron improves pancreas function and increases insulin synthesis and secretion in the STZ-induced diabetic rats: involvement of UCP2/ZnT8 pathway.

OBJECTIVES: Diabetes mellitus is one of the most common metabolic diseases. Tropisetron, as a 5-HT3 receptor antagonist, has a considerable role in the inflammation and oxidative stress lowering. This study aimed to investigate the effect of this 5-HT3 receptor antagonist on insulin secretion in male diabetic rats and the possible mechanisms. METHODS: Animals were divided into five equal groups; the control, tropisetron, diabetes, tropisetron-diabetes and glibenclamide-diabetes (7 in each group). Tropisetron and glibenclamide were administrated for 2 weeks after inducing type 1 diabetes. KEY FINDINGS: We demonstrated that insulin secretion improved robustly in diabetes-tropisetron compared with the diabetic group. Oxidative stress biomarkers were lower in a diabetes-tropisetron group than in diabetic rats. Simultaneously, tropisetron administration promoted the expression of ZnT8 and GLUT2 and also beta-cell mass in pancreatic tissue, while the expression of uncoupling protein 2 (UCP2) was restrained. The histological evaluation confirmed our results. These effects were equipotent with glibenclamide, indicating that tropisetron can protect islets from the abnormal insulin secretion and morphological changes induced by type 1 diabetes. CONCLUSIONS: This effect might be partly related to the modulated UCP2/ZnT8 signal pathway and improved oxidative stress-induced damage.

Exercise and insulin-like growth factor 1 supplementation improve angiogenesis and angiogenic cytokines in a rat model of diabetes-induced neuropathy.

NEW FINDINGS: What is the central question of this study? Do changes in levels of angiogenesis-related mediators [vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB)] in the sciatic nerve mediate diabetic neuropathy in the streptozotocin-induced type 1 diabetic male rat? Can exercise and insulin-like growth factor 1 (IGF-I) treatment improve the diabetes-related decrease in angiogenesis in sciatic nerve in these animals? What is the main finding and its importance? Levels of VEGF-A, TSP-1 and NF-κB change in the sciatic nerve of diabetic rats and might mediate diabetic neuropathy. Treatment with IGF-I and exercise could increase angiogenesis in the diabetic rats by increasing VEGF-A and decreasing TSP-1 and NF-κB expression in the sciatic nerve. ABSTRACT: Diabetic neuropathy is a severe complication of diabetes that affects 40-50% of diabetic people in the world. The aim of this study was to characterize alterations in angiogenesis and related molecular mediators in the sciatic nerve in diabetic conditions alone or in diabetes in combination with exercise and/or administration of insulin-like growth factor 1 (IGF-I). Forty male Wistar rats were assigned into one of five groups, namely control, diabetes, diabetes + exercise, diabetes + IGF-I and diabetes + exercise + IGF-I. Type 1 diabetes was induced by i.p. injection of streptozotocin (60 mg kg-1 ). After 30 days of treatment with exercise or IGF-I alone or in combination, diabetic neuropathy was evaluated with a hotplate, glycated haemoglobin was measured, angiogenesis was determined by immunostaining for PECAM-1/CD31, and expressions of vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB) were determined by enzyme-linked immunosorbent assay.After 4 weeks, the diabetes group showed a significant decrease in capillary density and VEGF-A levels, but a significant increase in glycated haemoglobin in blood, TSP-1 and NF-κB levels in the sciatic nerve compared with the control group, and these effects were ameliorated by exercise and IGF-I. However, simultaneous treatment of diabetic rats with IGF-I and exercise did not have any synergistic effects. These findings indicate that diabetes-induced neuropathy may be associated, in part, with decreased angiogenesis mediated by overproduction of TSP-1 and NF-κB, in addition to reduced production of VEGF-A. The findings also showed that exercise and IGF-I can reduce neuropathy, followed by increased angiogenesis, by changes in TSP-1, NF-κB and VEGF-A production levels.

Endothelins and their receptors in embryo implantation.

As a critical stage of pregnancy, the implantation of blastocysts into the endometrium is a progressive, excessively regulated local tissue remodeling step involving a complex sequence of genetic and cellular interplay executed within an optimal time frame. For better understanding the causes of infertility and, more importantly, for developing powerful strategies for successful implantations and combating infertility, an increasing number of recent studies have been focused on the identification and study of newly described substances in the reproductive tree. The endothelins (ET), a 21-aminoacidic family of genes, have been reported to be responsible for the contraction of vascular and nonvascular smooth muscles, including the smooth muscles of the uterus. Therefore, this review aims to comprehensively discuss the physiological role of endothelins and signaling through their receptors, as well as their probable involvement in the implantation process.

Long-term ethanol consumption promotes changes in ß-defensin isoform gene expression and induces structural changes and oxidative DNA damage to the epididymis of rats.

Chronic alcohol ingestion causes sexual dysfunction, impairs sperm motility and fertility, and changes semen quality. Considering the key role of epididymis in sperm development, the aim of the present study was to evaluate the effects of long-term ethanol consumption on epididymis changes, including alterations in ß-defensin isoform gene expression, oxidative stress, and pathological changes, such as cell proliferation and fibrosis in the epididymis of rats. In this study, male Wistar rats were equally divided into control and ethanol (4.5 g/kg BW) groups. After six weeks of treatment, the results revealed the proliferation of epididymis cells, fibrosis in the epididymis tissue, and a significant rise in the level of 8-OHdG and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the ethanol group, compared with the control group. Moreover, the ethanol group showed an increase in the gene expression of epididymal ß-defensin isoforms 15 and 21 and a reduction in the gene expression of ß-defensin isoforms 27 and 30, compared with the controls. These findings indicate that ethanol-induced epididymal damage and sperm abnormalities might be partly associated with changes in ß-defensin isoforms and epididymal structure, mediated by the increased activities of 8-OHdG and NADPH oxidase.

Increased hepatic FAT/CD36, PTP1B and decreased HNF4A expression contributes to dyslipidemia associated with ethanol-induced liver dysfunction: Rescue effect of ginger extract.

The association between chronic alcohol consumption and the development of alcpholic liver disease is a very well known phenomenon, but the precise underlying molecular mediators involved in ethanol-induced liver disease remain elusive. This study aimed to characterize the lipid metabolism alterations and the molecular mediators which are related to lipid metabolism in liver under the heavy ethanol exposure alone or combined with ginger extract. Twenty-four male wistar rats were assigned into three groups, namely control, ethanol, and ginger extract treated ethanol (GETE) groups. Six weeks after the treatment, the ethanol group showed a significant increase in fatty acid translocase (FAT)/CD36, protein tyrosine phosphatase 1B (PTP1B) and decrease hepatocyte nuclear factor 4 Alpha (HNF4A) genes expressions compared to the control group. The ethanol administration also significantly increased plasma LDL, cholesterol, triglyceride, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared to the control group. Moreover, compared to the control group, the ethanol group showed liver histhological changes, such as fibrosis, focal microvesicular steatosis, some apoptotic hepatocytes, spotty necrosis, portal lymphocytic inflammation, mallory-denk bodies, giant mitochondria, piecemeal necrosis. Consumption of ginger extract along with ethanol, partially ameliorated gene expression alteration and histological changes, improved undesirable lipid profile and liver enzymes changes compare to those in the ethanol group. These findings indicate that ethanol-induced liver abnormalities may in part be associated with lipid homeostasis changes mediated by overexpression of FAT/CD36, PTP1B and downexpressionof HNF4A genes. It also show that these effects can be reduced by using ginger extract as an antioxidant and anti-inflammatory agent.

Chronic ethanol ingestion induces glomerular filtration barrier proteins genes expression alteration and increases matrix metalloproteinases activity in the kidney of rats.

BACKGROUND: Chronic alcohol ingestion-induced kidney structure and function alterations are very well known, but the precise underlying molecular mediators involved in ethanol-induced kidney abnormalities remain elusive. The aim of this study was to investigate the effect of chronic ethanol exposure on matrix metalloproteinase 2, 9 (MMP), glomerular filtration barrier proteins (nephrin and podocin), as well as vascular endothelial growth factor receptor 1, 2 (VEGFRs) isoforms gene expression in the kidney of rats. METHODS: Sixteen male Wistar rats with an initial body weight of 220 ± 10 g were divided into the following two groups: (1) control and (2) ethanol (4.5 g/kg BW). RESULTS: After 6 weeks of treatment, the results revealed a significant increase in isoforms VEGFR1 and VEGFR2 of VEGFR gene expression, significant increases of MMP2 and MMP9 activities, as well as significant decrease of nephrin and podocin gene expressions in the ethanol group, compared with that in the control group. CONCLUSION: These findings indicate that ethanol-induced kidney abnormalities may be in part associated with alteration in expressions of VEGFRs, nephrin, and podocin and in increasing activities of MMP2 and MMP9 as key molecular mediators in the kidney function.

The Effect of Chronic Ethanol Consumption on Sexual Motivation and Behavior of Adult Male Wistar Rats in the Copulatory Phase.

BACKGROUND: The interaction of ethanol consumption and sexual behavior has been evaluated over the past three decades; however, some studies have assessed how ethanol consumption affects the general behavioral aspects of the copulatory cycle patterns in male rats. The aim of this study was to investigate the effect of chronic ethanol consumption on adult male Wistar rats' sexual motivation and behavior alteration in pre-copulatory, copulatory, and executive phases of the copulatory cycle. METHODS: Male Wistar rats were randomly allocated to two groups (control and ethanol treated groups). After 42 days of treatment, male rats were given access to adult female rats for 2 hours and their sexual behavior were recorded in a fully dark room using an infrared camera. FINDINGS: Chronic ethanol consumption caused a significant increase in anogenital sniffing and mounting, intermission, and ejaculation latencies periods, as well as a significant decrease in the sexual activity index (SAI) and copulatory efficiency (CE) compared to the control group. CONCLUSION: It is suggested that chronic ethanol consumption suppresses sexual behavior and reduces male rats' tendency toward sexual interaction with female rats as manifested by the enhanced latency periods in the copulatory phases and reduced SAI of ethanol treated animals.