Tropisetron improved testicular inflammation in the streptozotocin-induced diabetic rats: The role of toll-like receptor 4 (TLR4) and mir146a.

As a serotonin antagonist, tropisetron positively affects blood glucose lowering, insulin synthesis, pancreas inflammation, and apoptosis in diabetes. Reproductive disorders are one of the diabetes-induced chronic complications. The present study aimed to evaluate the effect of tropisetron on diabetes-induced testicular inflammation, its signaling pathway, and mir146a. To this end, animals were assigned to the control, tropisetron, diabetes (DM), DM-tropisetron, and DM-glibenclamide groups. Streptozotocin (50 mg/kg) was intraperitoneally injected to provide diabetes. Tropisetron and glibenclamide were then administrated intraperitoneally for 2 weeks after diabetes induction. Testes histology, real-time polymerase chain reaction, western blot analysis, ELISA, and immunohistochemistry assays were also performed. The finding revealed that tropisetron significantly improved diabetes-induced testis damages, lowered TLR4, TRAF6, IRAK1, NF-κB, and caspase3 protein expressions, and decreased TNF-α and IL-1 levels. Moreover, the mir146a expression declined following the tropisetron treatment. This study demonstrated that the significant role of tropisetron in lowering testicular inflammation and apoptosis might have been due to the inhibition of the TLR4/IRAK1/TRAF6 signaling pathway and thereby the attenuation of NF-κB and caspase3 expression and inflammatory cytokines. Furthermore, the downregulation of mir146a, as an inflammatory microRNA interacting with TLR4, showed another pathway, through which tropisetron improved diabetes-induced testicular injuries.

Effect of exercise and curcumin on cardiomyocyte molecular mediators associated with oxidative stress and autophagy in aged male rats.

AIM: Aging can origin changes in the heart that may increase risk of developing cardiovascular disease. This study aimed to characterize autophagy alterations and related molecular mediators in the heart tissue in the aging alone or in combination with exercise and curcumin treatment. METHODS: Seven young and twenty-eight elderly male Wistar rats were assigned into five groups, namely: young control, age, exercise, curcumin, and curcumin+exercise. Aged rats in exercise group run on treadmill (17 m/min) and in the curcumin group received curcumin (50 mg/kg) by gavage daily for 8 weeks for 2 months. At the end, heart samples were collected and used for determination of autophagy by immunostaining for LC3-phosphatidylethanolamine conjugate (LC3-II), apoptosis by TUNEL assay, Malondialdehyde (MDA) level by enzymatic assay and determination of mediators' molecules by ELISA for NADPH Oxidase 4 (NOX4), sirtuin 1 (SIRT-1), phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-Ƙb) protein levels and Sequestosome-1 (P62). Also, histological changes such as fibrosis evaluated by Masson trichrome staining. RESULTS: Our results showed that autophagy, SIRT-1 level were significantly decreased and MDA, NOX4, p-NF-Ƙb and P62 levels were significantly increased in heart of aged group compared to young group. Also, significant increased apoptosis and fibrosis levels in the heart of aged rats were observed compared with young rats, whereas, these undesirable changes were improved by exercise and curcumin. Also, combination therapy of aged rats with curcumin and exercise showed more significant prominent effect on molecular mediators and histological changes in the heart compared with monotherapy. CONCLUSION: These findings indicate that stress oxidative increase and autophagy decrease in the heart tissue of aged rats. The age induced the mentioned changes in the heart may in part be associated with down-expression of SIRT-1 and overexpression of NOX4 proteins. It was also showed that these age induced effects can be alleviated by treatment with exercise and curcumin. Since NF-Ƙb increased in both the age and treatment groups, it seems the age heart increased NF-Ƙb to be due to a compensatory mechanism.

Curcumin improves angiogenesis in the heart of aged rats: Involvement of TSP1/NF-κB/VEGF-A signaling.

BACKGROUND: Cardiac aging is an irreversible process that is determined by a number of slowly deleterious changes in morphological and physiological properties of the heart. We investigated the effects of curcumin on cardiac angiogenesis, in old male rats. MATERIALS AND METHODS: Rats randomly divided into young, age (rats of 26-28 months of age) and curcumin-age (rats of 26-28 months of age treatment with curcumin 50mg/kg). Finally, the expression of VEGF, NF-κB, and TSP-1 were assessed by ELISA in cardiac tissue. Also, angiogenesis was determined by immunostaining for PECAM-1/CD31 and apoptosis was evaluated by TUNEL. RESULTS: After 2 months, curcumin-age had significantly higher cardiac VEGF-A and NF-κB and lower cardiac TSP-1 expression levels in comparison with age and young. A significant increase in levels of NF-κB and TSP-1 were observed in the age group. CONCLUSION: Results suggest that curcumin through regulation of cardiogenic mediators and improving cardiac angiogenesis can promote heart performance in the senescent rats.

Reduction in ischemic brain injury following the administration of pentoxifylline after transient global ischemia/ reperfusion in a rat model.

BACKGROUND: It is well known that the hippocampus, the CA1 Pyramidal cells in particular, is selectively vulnerable during global cerebral ischemia. Recently, it is observed that pentoxifylline has a neuroprotective effect. This study explored the pharmacological relationship between ischemiainduced cell death of the hippocampus and the efficacy of a vasodilator agent (pentoxifylline) in the prevention of delayed neuronal death. METHODS: This experimental study was performed on 4 groups: control, ischemia, experimental (200mg/kg pentoxifylline injection one hour prior to and one hour following ischemia) and vehicle (normal saline). Transient global ischemia was induced by bilateral common carotid arteries occlusion. To investigate the apoptotic bodies and caspase-3 activities as a central role in the execution phase of apoptosis, the brains were prepared for the TUNEL technique. RESULTS: Pentoxifylline administration limited apoptosis and caspase-3 activities in rats' hippocampi. Our data showed no significant difference between the number of apoptotic bodies in the CA1 region of the hippocampus in the control and pentoxifylline -treated groups (p= 0.994). The results of one- way ANOVA revealed that that ischemia significantly increased caspase-3 levels in the hippocampus (p< 0.05); however, the level of caspase-3 in pentoxifylline -treated rats was less than the ischemic group. CONCLUSION: These results suggest that the neuroprotective effect of pentoxifylline (200mg/kg) may be accompanied by a reduction in ischemic damage within the CA1 region of the hippocampus in rats subjected to transient global cerebral ischemia.

Effects of adenosine A2a receptor agonist and antagonist on cerebellar nuclear factor-kB expression preceded by MDMA toxicity.

BACKGROUND: Adenosine is an endogenous purine nucleoside that has a neuromodulatory role in the central nervous system. The amphetamine derivative (±)-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a synthetic amphetamine analogue used recreationally to obtain an enhanced affiliated emotional response. MDMA is a potent monoaminergic neurotoxin with the potential of damage to brain neurons. The NF-kB family of proteins are ubiquitously expressed and are inducible transcription factors that regulate the expression of genes involved in disparate processes such as immunity and ingrowth, development and cell-death regulation. In this study we investigated the effects of the A2a adenosine receptor (A2a-R) agonist (CGS) and antagonist (SCH) on NF-kB expression after MDMA administration. METHODS: Sixty three male Sprague-Dawley rats were injected to MDMA (10 and 20mg/kg) followed by intraperitoneal CGS (0.03 mg/kg) or SCH (0.03mg/kg) injection. The cerebellum were then removed forcresylviolet staining, western blot and RT- PCR analyses. MDMA significantly elevated NF-kB expression. Our results showed that MDMA increased the number of cerebellar dark neurons. RESULTS: We observed that administration of CGS following MDMA, significantly elevated the NF-kB expression both at mRNA and protein levels. By contrast, administration of the A2a-R antagonist SCH resulted in a decrease in the NF-kB levels. CONCLUSION: These results indicated that, co-administration of A2a agonist (CGS) can protect against MDMA neurotoxic effects by increasing NF-kB expression levels; suggesting a potential application for protection against the neurotoxic effects observed in MDMA users.

The effects of choline supplementation in mothers with hypothyroidism on the alteration of cognitive-behavioral, long-term potentiation, morphology, and apoptosis in the hippocampus of pre-pubertal offspring rats.

The mother's thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long-lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive-behavioral function, long-term potentiation (LTP), and morphological changes as well as apoptosis in pre-pubertal offspring rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase-3 stained cells in choline-receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats.

Protective effects of N-acetylcysteine on 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in male Sprague-Dawley rats.

Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) leads to spatial memory impairment and hippocampal cell death. In the present study we have examined the protective effects of N-acetyl-L-cysteine (NAC) on MDMA-induced neurotoxicity. A total of 56 male Sprague Dawley rats (200-250 g) received twice daily intraperitoneal (IP) injections of 5, 10 or 20 mg/kg MDMA plus NAC (100 mg/kg). Rectal temperatures were recorded before and after daily treatment. We used a Morris water maze (MWM) to assess spatial learning and memory. At the end of the study rats' brains were removed, cells were counted and the level of Bcl-2, Bax and caspase-3 expression in the hippocampi were measured. NAC pretreatment significantly reduced MDMA-induced hyperthermia. In the MWM, NAC significantly attenuated the MDMA-induced increase in distance traveled; however the observed increase in escape latency was not significant. The decrease in time spent in the target quadrant in MDMA animals was significantly attenuated (p < 0.001, all groups). NAC protected against MDMA-induced cell death and the up -regulation of Bax and Caspase-3, in addition to the down-regulation of Bcl-2. This data suggested a possible benefit of NAC in the treatment of neurotoxicity among those who use MDMA.

Decreased Cardiac NOX4 and SIRT-1 Protein Levels Contribute to Decreased Angiogenesis in the Heart of Diabetic Rats: Rescue Effects of IGF-1 and Exercise.

Purpose: Reduced angiogenesis in the heart tissue is a primary risk factor for heart disease in the diabetes condition. This study was aimed to evaluate the changes of two main angiogenesis mediators, NADPH oxidase 4 (NOX4) and sirtuin 1 (SIRT-1) protein levels in the heart of diabetic rats and the impact of Insulin-like growth factor 1 (IGF-1) and exercise on these proteins. Methods: Injection of 60 mg/kg of streptozotocin in 40 male Wistar rats led to the induction of type 1 diabetes. Angiogenesis was detected in the hearts by immunostaining for PECAM-1/ CD31 after 30 days of treatment with IGF-1 (2 mg/kg/day) and exercise. ELISA technique was utilized to establish the expression levels of NOX4 and SIRT-1 within the heart. Results: The results revealed a significant increase in HbA1c and a significant decrease in SIRT1, NOX4 levels and angiogenesis grade in the heart of diabetes group compared to control group. Meanwhile, IGF-1 and exercise alone or in combination completely masked these effects. Additionally, synergistic effect on SIRT-1, HbA1c levels and angiogenesis grade is evident when IGF-1 and exercise are applied simultaneously. Conclusion: Our findings suggest that reduction in angiogenesis in the heart of diabetic rats may be mediated by down expression of NOX4 and SIRT-1 protein levels. It was also displayed that IGF-1 and exercise as novel therapies increase NOX4 and SIRT-1 protein levels within the hearts of diabetic rats.

Effects of glibenclamide and troxerutin on the sperm parameters and histopathological changes of testis in streptozotocin-induced diabetic male rats: An experimental study.

Background: Oxidative stress is a major contributor to diabetes mellitus (DM), which leads to testicular damage and infertility. Objective: The aim of this study was to investigate the effects of glibenclamide (GL) as a chemical medicine and troxerutin (TR) as an herbal agent on sperm parameters and histopathological changes of testis in diabetic male rats. Materials and Methods: Forty male Wistar rats (230-260 gr) were randomly divided into 5 groups (n = 8/each), including control, diabetic (D), GL, TR, and GL+TR. DM was induced by the administration of 60 mg/kg streptozotocin intraperitoneally. The groups were treated with 5 mg/kg/day of GL or 150 mg/kg/day of TR via oral gavage for 4 wk. In the final stage of the treatment, blood sampling was done for biochemical analysis. The rats were then sacrificed and their left testis and epididymis were dissected for sperm analysis, histopathology, and morphometric assessment. Results: A significant decrease in the number, motility, viability, maturity, and chromatin quality of sperm was found in diabetic rats compared to control group. (p < 0.001). DM also increased the malondialdehyde level and decreased the level of the serum's total antioxidant capacity compared to the control group (p < 0.001). Furthermore, we observed a significant difference in seminiferous tubule diameter, germinal epithelium height, and testicular histological abnormalities in diabetic rats compared to control group (p < 0.001). Administration of GL, TR, and their combination improved the above-mentioned parameters, and treatment with TR provided a higher improvement (p < 0.001). Conclusion: According to these findings, it can be concluded that TR plays a more influential role than GL to treat diabetic-induced infertility.

The effect of tropisetron on peripheral diabetic neuropathy: possible protective actions against inflammation and apoptosis.

Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-ß (TNFα and IL-1ß) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.

Curcumin alleviates restraint stress-induced learning and memory deficit and activity via modulation of biochemical, morphology changes, and apoptosis in the prefrontal cortex and hippocampus.

Restraint stress indicated induction of morphology, biochemistry, and behavioral impairments. Several investigations have reported that curcumin has a protective effect against stress disturbance. The present study is designed to investigate the effects of curcumin on learning and memory, activity, biochemical, morphology changes, and apoptosis in the hippocampus and prefrontal cortex of restraint stress rats. For chronic restraint stress, the rats were kept in the restrainers for 2.5 h per day for 21 consecutive days. The animals received the gavage of curcumin every other day for 21 days. After stress, the animals were subjected to behavioral tests. In restraint stress rats, locomotor activity and step-through latency were decreased using open field and shuttle box, respectively. Then, the rats were sacrificed to assess their serum and brains. A reduction was seen in the serum malonedialdehyde levels and number of neurons in the hippocampus and prefrontal cortex. The significantly decreased serum total antioxidant capacity levels and increased apoptotic cells were observed in the hippocampus and prefrontal cortex. Finally, curcumin inhibited and reversed the changes of stress induced in the prefrontal cortex and hippocampus of the rats. These findings provided evidence for the protective effect of curcumin therapy on biochemical, morphology, and behavioral changes induced by restraint stress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells.

Introduction: In this study, the cytotoxic and anti-cancer effects of Irinotecan as a conventional chemotherapeutic agent compared to 17-(allyl amino)-17-demethoxygeldanamycin (17-AAG) as possible radiosensitizers in the HCT-116 cell line were investigated. Methods: HCT-116 cells were treated with various concentrations of irinotecan and 17-AAG and also irradiated with a 2-Gy of X-ray radiation. Then, the cell viability was examined by a water-soluble tetrazolium-1 assay after 24 hours. For single therapies and double and triple combination cases, IC50, 0.5×IC50 and 0.25×IC50 concentrations of each drug were selected respectively for a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and other tests. In treated and untreated cells, the caspase 3 and Bcl-2 gene expression ratios were evaluated by the real-time PCR method. Likewise, caspase 3 activity was detected with a colorimetric assay. Results: In all combined treatments, including 17-AAG- radiation, irinotecan - radiation, irinotecan -17-AAG, and irinotecan-17-AAG-radiation, decreased cellular viability and increased TUNEL positive cells were presented versus the control group (P < 0.05). There were increased TUNEL positive cells in the triple combination, in concentrations of 0.25×IC50 of each drug, in comparison with single and double agent treatments. Moreover, in triple combination, the caspase 3 mRNA level and caspase 3 activity increased versus related single treatments. Likewise, in the irinotecan-17-AAG-radiation combined treatment and the 17-AAG-radiation double treatment, the Bcl-2 gene expression level decreased in comparison with single therapies. Conclusion: It can be indicated that the combination of chemo-radiotherapy versus single treatments has significant anti-cancer effects.

Effects of liraglutide on sperm characteristics and fertilization potential following experimentally induced diabetes in mice.

The current study was conducted to analyze the dose-dependent effects of liraglutide against the diabetes-induced detrimental impact on sperm parameters and fertilization potential. For this purpose, 42 adult male mice were randomly divided into control (with no intervention) and experimental groups. Next, the experimental group was subdivided into diabetic, 1.20 mg kg-1 liraglutide-received diabetic, 1.80 mg kg-1 liraglutide-received diabetic, 1.20 mg kg-1 liraglutide-received non-diabetic and 1.80 mg kg-1 liraglutide-received non-diabetic groups. All chemicals were administrated subcutaneously. Following 42 days, the animals were euthanized, and sperm samples were collected. The sperm count, motility, viability, DNA integrity, and maturity were analyzed and compared between groups. Moreover, the sperm fertilization potential was investigated by in vitro fertilization (IVF). For this purpose, the preimplantation embryo development at 2-cell, 4-cell, morula, and blastocyst stages was investigated and compared. Observations revealed that diabetes significantly diminished sperm count, motility, viability, chromatin condensation, and DNA integrity percentages versus a control group. On the other hand, 1.20 mg kg-1 and 1.80 mg kg-1 of liraglutide did not improve sperm motility and viability, while ameliorated sperm count and chromatin condensation and DNA integrity in diabetic animals. The diabetic animals represented diminished preimplantation embryo development, which was not altered in liraglutide-received groups. In conclusion, at least in administrated doses, liraglutide could not improve the sperm viability and motility and, via this mechanism, could not induce an appropriate/beneficial effect on IVF outcome.

Effect of silymarin and metformin on the sperm parameters and histopathological changes of testes in diabetic rats: An experimental study.

BACKGROUND: Oxidative stress is a major contributor to diabetes, which can lead to testicular damage and infertility. OBJECTIVE: This study aimed to compare the effects of metformin as a chemical drug with silymarin as an herbal agent on the sperm parameters and histopathological changes of testes in diabetic rats. MATERIALS AND METHODS: Thirty-two male Wistar rats (250-270 gr) were randomly divided into four groups: 1) control; 2) diabetic; 3) diabetic+metformin 200 mg/kg; and 4) diabetic+silymarin 100 mg/kg. Daily injections were administered intraperitoneally for 56 days. At the end of the treatment, blood sampling was performed for biochemical assessment. Then, the rats were sacrificed and their left testis and epididymis were cut for sperm analysis as well as histopathology and morphometric evaluation. RESULTS: Diabetes was associated with a reduced sperm count, motility, viability, maturity, and chromatin quality of sperm (p ≤ 0.001). It was also associated with a higher malondialdehide level and lower total antioxidant capacity level of serum in comparison with the control group (p ≤ 0.001). There was a significant difference in the seminiferous tubule diameter, germinal epithelium height, and testicular histopathological alterations in the diabetic rats compared with the control rats (p ≤ 0.001). Treatment with metformin and silymarin improved the above-mentioned parameters and this improvement was more substantial in silymarin-treated animals (p ≤ 0.001). CONCLUSION: In diabetic rats, metformin and silymarin improved sperm parameters, sperm DNA integrity, seminiferous tubule diameter, germinal epithelium thickness, and testicular histopathological complications; this improvement was more substantial in the silymarin-treated group. So, the findings of this study suggest that silymarin is more effective than metformin in treating diabetic-induced infertility.

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.

Neurological effects of long-term exposure to low doses of pesticides mixtures in male rats: Biochemical, histological, and neurobehavioral evaluations.

Humans are usually exposed to multiple pesticides in real life, but little is known as yet about the safety of low-dose pesticides mixtures. This study was conducted to evaluate the effects of long-term exposure to very low doses of pesticide mixtures on biochemical, histological, and neurobehavioral alterations in the rat model. For 90 days, four groups of male Wistar rats were given a mixture of five pesticides (in drinking water) in doses of 0, 0.25, 1 and 5 times the legally permitted levels (mg/kg body weight/day). After three-month exposure, the neurobehavioral effects of pesticide mixtures were evaluated by the Morris water maze, elevated plus maze and the open field tests. Then the biochemical and histopathological alterations in the hippocampus of studied animals were evaluated. Results showed that long-term exposure to a combination of five pesticides affected the nervous system in dose-dependent manner. As expected, nearly all of the parameters determined in this study were adversely changed in the high dose group. Exposure to medium dose (permitted level of pesticides mixture) was also able to induce oxidative stress and impaired memory and learning ability, although not all parameters were significantly changed in this group. It means that pesticides may behave differently when mixed. Interestingly, the administration of low doses of these chemicals induced an adaptive response by stimulating the redox system. In conclusion, it seems that the prolonged exposure to pesticide mixtures may cause adverse neurobehavioral effects, even at permitted levels.

Modulatory effect of tropisetron in the liver of streptozotocin-induced diabetes in rats: biochemical and histological evidence.

Objectives There is an association between diabetes and liver disorders. Oxidative stress plays a crucial role in the pathology of hepatic abnormalities in diabetes. In this study, the effect of Tropisetron on the oxidative damage and histological alterations in the liver of type 1 diabetes mellitus (DM) were evaluated. Methods Thiry-five male Wistar rats were randomly divided into five experimental groups (n = 7): control (C), tropisetron (T), diabetes (D), diabetes + tropisetron (D + T) and diabetes + glibenclamide (D + G). A single injection of streptozotocin (STZ, 50 mg/kg; i.p) was used to induce diabetes. Tropisetron (3 mg/kg; i.p), as a 5-HT3 receptor antagonist and glibenclamide (1 mg/kg; i.p), as a positive control were given once daily for 2 weeks. Finally, animals were euthanized and liver samples were obtained for histopathological examination and biochemical measurements including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) levels. Results There is a significant increase in MDA (p < 0.001) level and a significant decrease (p < 0.001) in SOD and GPx contents in diabetic animals. Tropisetron attenuated MDA levels (p < 0.001) and enhanced SOD (p < 0.05) and GPx (p < 0.01) activities accompanied by histopathological improvement in the diabetes liver. Similar results were achieved in the rats treated with the standard drug, namely: glibenclamide. Conclusions Our findings indicate that tropisetron mitigates liver damage in the diabetes rats in part by attenuation of oxidative stress.

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.

Exercise improves aging-related decreased angiogenesis through modulating VEGF-A, TSP-1 and p-NF-Ƙb protein levels in myocardiocytes.

Introduction: Aging-dependent decline in the angiogenesis of heart is a risk factor for cardiovascular disease. This study was aimed to characterize effect of exercise on angiogenesis alterations and molecular mediators which are related to angiogenesis in the heart under aging condition. Methods: Twenty-one male Wistar rats were assigned into three groups: young, aged, and exercise. Aged animals in the exercise group run on treadmill for 8 weeks. At the end, heart samples were collected and used for histological evaluation , determination of angiogenesis by immunostaining for PECAM-1/ CD31 and expressions of vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor kappa B (NF-κB) levels by ELISA. P<0.05 is considered as statistically significant. Results: Our results showed that angiogenesis, and VEGF-A levels were significantly decreased, TSP1 (P >0.0001) and p-NF-κB (P >0.001) levels were significantly increased in the heart of aged group compared to young group. Exercise group showed significant increase in angiogenesis, VEGF-A (P >0.0001), and p-NF-κB (P >0.001) and showed significant decrease in TSP-1 levels (P >0.001) compared to aged group. Moreover, compared to the young group, aged group showed histological changes in the heart, such as interstitial edema, and congestion, whereas, treatment with exercise improved these undesirable changes in the heart of exercise groups. Conclusion: These findings indicated that aging-related decrease in angiogenesis in the heart may mediated by downexpression of VEGF-A and overexpression of TSP-1 proteins. Also, we showed that p-NF-κB protein was increased in the heart of aged rats, this probably mediated by compensatory mechanism. It was also showed that exercise as novel non-pharmacological therapy modifies VEGF-A and TSP-1 and increases p-NF-κB protein levels in the aged heart.

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.