The Effect of Different Exercise Modalities on Sertoli-germ Cells Metabolic Interactions in High-fat Diet-induced Obesity Rat Models: Implication on Glucose and Lactate Transport, Igf1, and Igf1R-dependent Pathways.

The study aimed to uncover a unique aspect of obesity-related metabolic disorders in the testicles induced by a high-fat diet (HFD) and explored the potential mitigating effects of exercise modalities on male fertility. Thirty mature male Wistar rats were randomly assigned to control, HFD-sole, moderate-intensity exercise with HFD (HFD+MICT), high-intensity continuous exercise with HFD (HFD+HICT), and high-intensity interval exercise with HFD (HFD+HIIT) groups (n=6/group). Intracytoplasmic carbohydrate (ICC) storage, expression levels of GLUT-1, GLUT-3, MCT-4, Igf1, and Igf1R, and testicular lactate and lactate dehydrogenase (LDH) levels were assessed. ICC storage significantly decreased in HFD-sole rats, along with decreased mRNA and protein levels of GLUT-1, GLUT-3, MCT-4, Igf1, and Igf1R. The HFD-sole group exhibited a notable reduction in testicular lactate and LDH levels (p<0.05). Conversely, exercise, particularly HIIT, upregulated ICC storage, expression levels of GLUT-1, GLUT-3, MCT-4, Igf1, and Igf1R, and enhanced testicular lactate and LDH levels. These results confirm that exercise, especially HIIT, has the potential to mitigate the adverse effects of HFD-induced obesity on testicular metabolism and male fertility. The upregulation of metabolite transporters, LDH, lactate levels, Igf1, and Igf1R expression may contribute to maintaining metabolic interactions and improving the glucose/lactate conversion process. These findings underscore the potential benefits of exercise in preventing and managing obesity-related male fertility issues.

Effect of running exercise training on inflammatory mediators and cytokines expression in testicular tissue; effect of exercise intensity.

The aim of this study is to investigate the impact of running exercise training protocols (ETPs) with varying intensities on inflammatory responses, with a specific focus on the interactions between inflammatory mediators, cytokines, and Leydig cell steroidogenic activity, as well as testosterone secretion. To this end, 24 Wistar rats were subdivided into sedentary control, low (LICT), moderate (MICT), and high (HICT) intensity continuous running ETP groups. After 8 weeks, the expression levels of Toll-like receptor-4 (TLR-4), nuclear factor-kappa-B (NF-KB), interleukin-6 (IL-6), interleukin-10 (IL-10), Tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the testicular nitric oxide (NO) content were assessed and compared between groups. Moreover, the mean distributions of Leydig cells/mm2 of interstitial connective tissue, their steroidogenic activity, and serum level of testosterone were assessed. The LICT did not show any significant (p > 0.05) change in the expression levels of all aforementioned biomarkers. In contrast, both the MICT and HICT groups demonstrated a significant (p < 0.05) increase in the expression levels of TLR-4, NFK-B, IL-6, TNF-α, iNOS, and COX-2 at both the mRNA and protein levels. The testicular NO has increased in HICT and MICT groups. Despite a decrease in the distribution of Leydig cells in both the MICT and HICT groups, the HICT group exhibited a significant (p < 0.05) reduction in Leydig cell steroidogenic activity and serum testosterone levels. In conclusion, our findings revealed that ETPs can influence Leydig cell steroidogenic activity and testosterone secretion, contingent on their intensity. These effects are attributed to alterations in the expression levels of pro-inflammatory mediators and cytokines.

Running exercise training-induced impact on oxidative stress and mitochondria-related apoptosis in rat's testicles.

The current study has been designed to explore the effects of running exercise training protocols (ETPs), with different intensities, on testicular redox and antioxidant capacities. Moreover, the crosstalk between oxidative stress (OS) and mitochondria-related apoptosis was analysed. To this end, 24 Wistar rats were subdivided into sedentary control, low- (LICT), moderate- (MICT), and high (HICT)-intensity continuous running ETP groups. Following 8 weeks, the Johnsen score, sperm count, testicular malondialdehyde (MDA) content, total oxidant status (TOS), and redox biomarkers, including glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) levels were evaluated. Additionally, the expression levels of Bcl-2, Bax, caspase-3, proteins involving in the mitochondria-related apoptosis, and the apoptotic index were analysed. The LICT and MICT running ETPs did not affect the spermatogenesis development, sperm count, and antioxidant and redox capacities. Accordingly, no significant changes were revealed in Bcl-2, Bax, and caspase-3 expression levels and apoptosis index compared to sedentary rats. In contrast, the HICT-induced rats showed a significant (p < 0.05) reduction in spermatogenesis development, sperm count, antioxidant and redox capacities versus control, LICT, and MICT groups. Moreover, the expression of Bcl-2 was decreased, while the Bax and caspase-3 expression levels were increased in the HICT-induced group. Finally, the apoptosis index was increased in the HICT group. In conclusion, the suppressed redox system after HICT can trigger the mitochondria-mediated ROS overload, result in OS condition in the testicular tissue, and reversely target the mitochondrial membrane permeability. All of these molecular alterations are suspected to initiate progressive mitochondria-related apoptosis after HICT.

Exercise and Urtica Dioica extract ameliorate mitochondrial function and the expression of cardiac muscle Nuclear Respiratory Factor 2 and Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha in STZ-induced diabetic rats.

INTRODUCTION: Diabetes mellitus can affect and disrupt the levels of PGC1α and NRF2 proteins in the mitochondrial biogenesis pathway. Considering the anti-diabetic properties of Urtica Dioica extract and exercise, this study aimed to investigate the beneficial effects of Urtica Dioica extract and endurance activity on PGC1α and NRF2 protein levels in the streptozotocin-induced diabetic rat heart tissue. MATERIALS AND METHODS: 58 male Wistar rats were divided into five groups (N = 12) including: healthy control (HC), diabetes control (DC), diabetes Urtica Dioica (D-UD), diabetes exercise training (DT), and diabetes exercise training Urtica Dioica (DT-UD). Diabetes was induced intraperitoneally by STZ (45 mg/kg) injection. Two weeks after the induction of diabetes, the rats were stimulated to carry out the exercise (moderate intensity/5day/week) and the gavage of UD extract (50 mg/kg/day) was administered to the rats for six weeks. In this study, the western blotting method was used to measure the levels of PGC1α and NRF2 proteins. Moreover, cardiography was used to evaluate the functional parameters of the heart (ejection fraction & fractional shortening). Finally, the bioluminescence and ELISA methods were used to determine the content of adenosine triphosphate and citrate synthase. RESULTS: The cardiac function parameters, the mitochondrial ATP and the CS content in DC group mice were impaired in comparison with the other study groups and showed a decreasing trend (P < 0.001). The treatment with EX + UD extract was able to minimize the rate of these disorders and acted as a protector of mitochondrial function. There were significant differences in the expression levels of NRF2 (F = 17.7, P = 0.001) and PGC-1α (F = 43.7, P = 0.001) mitochondrial proteins among the different groups. The levels of these proteins were significantly reduced in the DC group in comparison with the HC group (P < 0.001). The treatment with EX or UD extract increased the expression of PGC-1α and NRF2 proteins in the heart muscle of animals in the DT and D-UD groups in comparison with the DC group (P < 0.05). Moreover, the expression of these proteins was more pronounced in the DT-UD group. There was not a significant difference between the DT-UD group and the HC group regarding the expression of these proteins (P > 0.05). CONCLUSIONS: The results of this study showed that treatment with EX and UD extract could treat the disorders which were caused by diabetes in the parameters of cardiac function. Moreover, it was able to improve the expression of the levels of proteins which were involved in mitochondrial biogenesis and its function. Finally, this kind of treatment could attract more attention to the roles of EX and UD extract in the prevention of cardiovascular complications in future studies.

Moderate-Intensity Exercise Training in Association with Insulin Promotes Heat Shock Proteins 70 and 90 Expressions in Testicular Tissue of Experimental Type 1 Diabetes.

OBJECTIVE: The current research was designed to analyze the effect of moderate-intensity exercise training (MEXT), solely and simultaneous with insulin, on the network between oxidative stress and Hsp70 and Hsp90 chaperones after experimental type I diabetes (DM) induction in rats. MATERIALS AND METHODS: In the experimental study, 36 mature Wistar rats were assigned into control and experimental type I DM-induced groups, and then the diabetic animals were categorized to sedentary type I DM-induced (SDM), exercise training-sole without DM (E), exercise training DM-induced (EDM), insulin-treated sedentary DM-induced (ISDM), and exercise training insulin-treated DM-induced (EIDM) groups. After 6 weeks, Johnson's score was evaluated to analyze the spermatogenesis ratio. RESULTS: The Hsp70 and Hsp90 expression levels, testicular total antioxidant capacity (TAC), protein peroxidation ratio, testicular DNA fragmentation ratio, and mRNA damage were investigated. The animals in EDM and EIDM groups (solely and simultaneously) represented a significant (P<0.05) improvement in Johnson's score, spermatogenesis, and TAC ratios versus SDM animals. Moreover, the DM-induced DNA and mRNA damage and protein peroxidation ratio were significantly (P<0.05) recovered in EDM and ISDM groups, which was more remarkable in the EIDM group. The EDM and EIDM groups exhibited significant (P<0.05) increment in Hsp70 and Hsp90 expression levels versus the control and SEDT1 animals. However, the EIDM group exhibited no significant changes compared to the control animals. CONCLUSION: The EX could ameliorate the EDT1-induced detrimental impact by up-regulating Hsp70 and Hsp90 expressions. Meanwhile, it exerts potentially more effective impact, when it is considered simultaneously with insulin therapy.

ROS and metabolomics-mediated autophagy in rat's testicular tissue alter after exercise training; Evidence for exercise intensity and outcomes.

AIMS: Oxidative damage and altered metabolic reactions are suspected to initiate the autophagy. The exercise training significantly impacts testicular antioxidant and metabolic potentials. However, the underlying mechanism(s) that the exercise-induced alterations can affect the autophagy markers remained unknown. This study explored the effect of exercise training on antioxidant and metabolic statuses of testicular tissue and uncovered the possible cross-link between these statuses and autophagy-inducers expression. MAIN METHODS: Wistar rats were divided into sedentary control, low (LICT), moderate (MICT), and high (HICT) intensity continuous training groups. Following 8 weeks of training, the testicular total antioxidant capacity (TAC), total oxidant status (TOS), glutathione (GSH), and NADP+/NADPH as oxidative biomarkers along with intracytoplasmic carbohydrate and lipid droplet patterns, lactate dehydrogenase (LDH) activity, and lactate as metabolic elements were assessed. Finally, the autophagy-inducers expression and sperm count were examined. KEY FINDINGS: With no significant impact on the oxidative biomarkers and metabolic elements, the LICT and MICT groups exhibited statistically unremarkable (p < 0.05) impacts on spermatogenesis differentiation, spermiogenesis ratio, and sperm count while increased the autophagy-inducers expression. Reversely, the HICT group, simultaneous with suppressing the antioxidant biomarkers (TAC↓, GSH↓, TOS↑, NADP+/NADPH↑), significantly (p < 0.05) reduced the testicular LDH activity and lactate level, changed the intracytoplasmic carbohydrate and lipid droplet's pattern, and amplified the classical autophagy-inducers p62, Beclin-1, autophagy-related gene (ATG)-7, and light chain 3 (LC3)-II/I expression. SIGNIFICANCE: The autophagy-inducers overexpression has occurred after HICT induction, most probably to eliminate the oxidative damage cargoes, while increased to maintain the metabolic homeostasis in the LICT and MICT groups.

Different continuous exercise training intensities induced effect on sertoli-germ cells metabolic interaction; implication on GLUT-1, GLUT-3 and MCT-4 transporting proteins expression level.

Despite other tissues, the effect of different exercise training protocols (ETPs) on the expression levels of metabolic substrates transmembrane transporters in the testicular tissue, remains completely unexplored. Thus, the effects of low, moderate and high-intensity ETPs on the SCs and germ cells potentials in GLUT-1, GLUT-3 and MCT-4 expression levels was investigated in this study. The animals were assigned into 4 groups, including sedentary control, low-intensity continuous (LICT), moderate-intensity (MICT) and high-intensity (HICT) ETPs-induced groups (n = 6/group). The GLUT-1, GLUT-3 and MCT-4 expressions, cytoplasmic carbohydrate storages of SCs and germ cells, the SCs survival and the spermatogenesis and spermiogenesis rates were assessed. The LICT and MICT did not significantly alter the protein expression levels of GLUT-3 and MCT-4 in the SCs and germ cells, while decreased the GLUT-1 protein content versus the sedentary control animals. In contrast, the HICT remarkably suppressed the GLUT-1 and MCT-4 in both SCs, and germ cells and diminished GLUT-3 in SCs and increased in the germ cells. No significant changes were revealed in the cytoplasmic carbohydrate storage in the LICT and MICT groups, while significantly diminished in the HICT group. The HICT group showed a failed spermatogenesis and spermiogenesis, which were not demonstrated in the sedentary control, LICT and MICT groups. In conclusion, the HICT, by reducing the GLUT-1, GLUT-3 and MCT-4 protein contents in the SCs and reducing the SCs survival, can suppress the glucose transmembrane transport and inhibit the lactate export from SCs, which in turn, ends with failed spermatogenesis and spermiogenesis.

Effect of moderate-intensity exercise training on GDNF signaling pathway in testicles of rats after experimental diabetes type 1 induction.

AIMS: The spermatogenesis failure is reported as the main complication for diabetes and the moderate-intensity exercise (EX) is shown to ameliorate the diabetes-induced impairments both at spermatogenesis and sperm levels. Thus, the current study was done to investigate the possible effect of EX in the sole and simultaneous form with insulin on the network between Sertoli and spermatogonial stem cells (SSCs) by focusing on niche factor Glial cell-derived neurotrophic factor (GDNF). METHODS: For this purpose, 30 mature male Wistar rats were divided into control and experimental type 1 diabetes (T1D)-induced groups. Then the T1D-induced animals were subdivided to sedentary T1D-induced (ST1D), EX + T1D, insulin (INS) + T1D and EX + INS + T1D groups. The general histological changes of testicles, mRNA and protein contents of GDNF and its special receptors gfrα1 and c-RET were evaluated and compared between groups. RESULTS: EX in the sole and simultaneous form with INS significantly (p < 0.05) diminished the T1D-induced histological damages, amplified the GDNF expression, and enhanced the gfrα1 and c-RET mRNA and protein contents compared to ST1D group. CONCLUSION: In conclusion, the EX in the sole form promotes spermatogenesis by up-regulating the GDNF signaling system. Moreover, EX remarkably amplifies the insulin-induced ameliorative effect on spermatogenesis.

The effect of different types of exercise training on diet-induced obesity in rats, cross-talk between cell cycle proteins and apoptosis in testis.

Obesity is associated with germ cell apoptosis, spermatogenesis arrest, and testicular endocrine suppression. The aim of the present study was to investigate the crosstalk between germ cell apoptosis and cell cycle machinery in sedentary and obese rats after moderate-intensity continuous (MICT), high-intensity continuous (HICT) and High-intensity interval (HIIT) exercise trainings. Male Wistar rats (n = 30) were randomly divided into 5 groups; the control, sedentary high-fat diet (HFD)-received (HFD-sole), MICT, HICT and HIIT-induced HFD-received groups. The serum levels of LDL-C, HDL-C, triglyceride, and testosterone, mRNA and protein levels of Cyclin D1, Cdk4, p21, apoptotic cell number/mm2 of testicular tissue and testicular DNA fragmentation ratio were investigated. The obese animals in HFD-sole group represented a significant (p < 0.05) reduction in serum HDL-C and testosterone levels, Cyclin D1, Cdk4 expressions, and exhibited a remarkable (p < 0.05) increment in LDL-C, triglyceride, p21 expression, apoptotic cell number and DNA fragmentation ratio versus control animals. However, the animals in MICT, HICT, HIIT groups exhibited a significant (p < 0.05) increment in serum HDL-C and testosterone, Cyclin D1 and Cdk4 expressions and showed a significant (p < 0.05) reduction in serum LDL-C and triglyceride, p21 expression, apoptotic cell number and DNA fragmentation versus the HFD-sole group. In conclusion, a crosslink between cell cycle machinery and apoptosis of germ cells was revealed in the testicles of HFD-sole animals, and MICT, HICT and HIIT could ameliorate the obesity-induced impairments, respectively. This effect may be attributed to the effect of exercise training protocols on maintaining Cyclin D1 and Cdk4 and suppressing p21 expression levels in the testicles.

Moderate-intensity exercise training ameliorates the diabetes-suppressed spermatogenesis and improves sperm parameters: Insole and simultaneous with insulin.

The current study was conducted to investigate the ameliorative effect of moderate-intensity exercise training insole and simultaneous with insulin on diabetes (DM)-induced pathogenesis at the testicular tissue and sperm level. For this purpose, 36 mature male Wistar rats were divided into six groups, including sedentary control (Con), exercise training (EX), sedentary experimental DM-induced (SDM), exercise training + DM-induced (DM + EX), insulin-treated sedentary DM-induced (DM + INS) and exercise training and insulin-treated DM-induced (DM + INS + EX) groups. Following DM induction, the 6-week exercise training intervention (30 min of moderate-intensity running on a treadmill, once daily [5 days/week]) was considered in EX groups. The tubular differentiation (TDI) and spermiogenesis (SPI) indices, testicular total antioxidant capacity (TAC), superoxide dismutase (SOD) and glutathione peroxidase (GPX) contents, serum testosterone and insulin levels, the apoptosis ratio and sperm parameters were assessed. The exercise in sole (EX) and simultaneous forms with INS (DM + INS + EX group) ameliorated the DM-suppressed spermatogenesis and spermiogenesis indices, up-regulated the serum testosterone and insulin levels, enhanced testicular SOD content, inhibited the apoptosis and improved almost all sperm parameters. In conclusion, exercise training, when simultaneously considered with insulin, fairly boosts the insulin-induced impacts, including the up-regulated testicular endocrine and antioxidant status, spermatogenesis and sperm quality.

Moderate-intensity Exercise Training in Sole and Simultaneous Forms with Insulin Ameliorates the Experimental Type 1 Diabetes-induced Intrinsic Apoptosis in Testicular Tissue.

The aim of this study was to investigate the ameliorative effect of moderate-intensity exercise training in sole and simultaneous forms with insulin on experimental type 1 diabetes (T1D)-induced apoptosis. A total of 36 mature male Wistar rats were divided into six equally sized groups, including sedentary control (Con), moderate-intensity exercise training (E-sole), sedentary T1D-induced (D-sole), moderate-exercise-trained T1D-induced (DE), insulin-treated sedentary T1D-induced (DI) and exercise-trained, and insulin-treated T1D-induced (DEI) groups. The 6-week exercise training intervention was involved 30 min of moderate-intensity running on a treadmill once daily (5 days/week). Next, tubular differentiation (TDI) and spermiogenesis (SPI) indices were assessed. The Bcl-2, Bax and caspase-3 expressions were determined using RT-PCR, immunohistochemistry and western blot techniques. Finally, the TUNEL staining was used to analyze the apoptosis ratio. The moderate-intensity exercise training in the sole and when simultaneously considered with insulin (DEI) maintained testicular cellularity, up-regulated Bcl-2 expression, reduced Bax expression and ameliorated the diabetes-induced apoptosis. We failed to show remarkable alterations in caspase-3 mRNA and protein levels in the DE group versus D-sole animals. In conclusion, the moderate-intensity exercise training is able to potentially protect testicular cells from T1D-induced intrinsic apoptosis via up-regulating Bcl-2 and downregulating Bax expressions. Moreover, it amplifies the insulin-induced anti-apoptotic impacts.

Acute Interstitial Nephritis Induced by Citrullus Colocynthis.

Acute interstitial nephritis (AIN) is known as a common cause of acute kidney injury, found in 15% to 27% of kidney biopsies. Drug-induced AIN is currently the most common cause of AIN. The most common medications causing AIN are antibiotics and nonsteroidal anti-inflammatory drugs. We describe a case of Citrullus colocynthis (herbal remedy for diabetes mellitus and weight reduction) that induced AIN. A 31-year-old woman with major thalassemia, diabetes mellitus, and hepatitis C infection was admitted because of flank pain and unexpected increase in serum creatinine level. She had been using Citrullus colocynthis for 3 months. Kidney biopsy results suggested AIN. She did not respond to steroid therapy and underwent hemodialysis. We suggest the use of Citrullus colocynthis as a herbal medicine with extreme caution.

Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet: Randomized, controlled, double-blind trial.

BACKGROUND & AIMS: Despite evidence for beneficial effects of vitamin D, to our knowledge, no study has compared the effects of calcium supplementation with vitamin D on non-alcoholic fatty liver disease (NAFLD) regression during a hypo-energetic program. We compared the effect of the vitamin D supplementation with and without calcium on anthropometric measures and biochemical parameters in NAFLD patients during a weight-loss program. METHODS: A 12-week, randomized, controlled, double-blind trial was conducted in 120 NAFLD patients randomly assigned to receive 25 µg calcitriol (n = 37), 500 mg calcium carbonate + 25 µg calcitriol (n = 37), or placebo (n = 36) every day with their lunch meals while following a weight-loss program. RESULTS: Weight, BMI and fat mass reduction were significant in each group after 12 wk of intervention (p < 0.001), but differences among the groups was not significant after 12 wk of the study, adjusted to the baseline measurements. Significant reduction in fasting plasma glucose (FPG), insulin, insulin resistance (by HOMA-IR) and TG concentrations and an increase in HDL.C was seen over the 12 wk of study in each group (p < 0.001). Adjusting to the baseline measurements, there was significant difference in FPG (p < 0.001), HOMA-IR (p < 0.001), serum insulin (p = 0.01), TG (p = 0.01) and HDL.C (p < 0.001) among the groups after 12 wk of the study. The calcium plus calcitriol group showed a significant decrease in ALT and FPG and increase in HDL.C level compared with the calcitriol group, adjusted to the baseline measures (p < 0.001). CONCLUSIONS: Our results suggest that calcium plus calcitriol supplementation for 12 weeks may be potentially effective for biochemical parameters in NAFLD patients. Further additional larger controlled trials are needed to confirm these findings. REGISTRATION: Registered under ClinicalTrials.gov Identifier no. IRCT201408312709N29.

Study of the mutagenicity of "Hypiran" and "Sankol" in human blood cells and comparison with hydrogen peroxide by single cell gel electrophoresis (SCGE) or comet assay.

Due to the increased use and availability of herbal medicinal products, it has been necessary to perform investigations pertaining to their toxicological safety. The aim of this study was to use the rapid and sensitive technique of Single Cell Gel Electrophoresis (SCGE) or "Comet Assay" to assess the mutagenic potential of two such products: "Hypiran" and "Sankol." The results were compared against positive (hydrogen peroxide) and negative (no mutagen) control groups. The instances of DNA damage were observed in 25 randomly selected cells and viewed under a fluorescence microscope following electrophoresis and staining with ethidium bromide. Both microscopic inspection and calculation of the number of affected/damaged cells were encouraging and were comparable to the observations of previous studies using SCGE. The total instances of cell damage in the presence of "Hypiran" increased as the dose increased, with all 25 cells exhibiting fragmentation at the highest dose. However, "Sankol" only exhibited some damage (8-12% of cells) at all doses. The results obtained suggest that in vitro, "Hypiran" produces dose dependent DNA damage and therefore may possess some mutagenic potential. Compared to the positive control, no significant DNA damage was observed with "Sankol" and hence this compound may have no mutagenic potential. However, further study is required before a full evaluation of these products can be made.