Rafighe Ghiasi

Recently, the cGAS-STING signaling pathway has garnered significant attention due to its role in the pathogenesis of various disorders, including cancer, autoimmune diseases, and auto-inflammatory diseases. This pathway is a novel innate immune recognition mechanism that functions as a cytoplasmic DNA sensor. It mediates protective immune responses against tumor-derived DNA, DNA-containing pathogens, and cytoplasmic DNA (nuclear and mitochondrial DNA) by producing a range of inflammatory cytokines. Although the normal activation of cGAS-STING signaling induces innate immunity against infections, aberrant activation of the cGAS-STING axis is associated with excessive inflammatory responses, leading to an immune system attack on normal tissues and contributing to the development of autoimmune diseases. Activation of the cGAS-STING also emerges as a double-edged sword in different types of cancer. There are different perspectives on the abnormal function of the cGAS-STING pathway in various male reproductive disorders. Understanding the factors that regulate the cGAS-STING pathway and its involvement in male reproductive system issues can help develop new strategies for prevention and treatment. This review focuses on the role of the cGAS-STING signaling pathway in male reproductive-related diseases. We also explore targeting the cGAS-STING signaling pathway for the prevention and treatment of male reproductive diseases.

Diabetes is a multifactorial disorder that involves several molecular mechanisms and is still one of the key global health challenges with increasing prevalence and incidence. Gut microbiome dysbiosis could activate and recognize receptors that trigger the inflammation response and modulation of insulin sensitivity. In addition, the intricate role of gut microbiota dysbiosis in the onset and development of T2D (Type 2 diabetes mellitus) and associated microvascular complications was identified. These complications include diabetic nephropathy (DN) and diabetic retinopathy (DR), diabetic neuropathy, cerebrovascular disorders, and coronary heart disease. A recent interesting strategy to improve these complications is probiotics administration. The safety and health effects of probiotics against various diseases have been validated by various in vitro, in vivo and clinical studies. In this review, the related mechanisms between the gut microbiome, initiation, and progression of T2D and its common microvascular complications (DN and DR) have been discussed.

Objectives: Investigation the association of pro-inflammatory markers interleukin (IL)-1β and IL- 10 expression, serum levels of C-reactive protein (CRP), cyclooxygenase-2 (COX2), High-density lipoprotein (HDL), Apolipoprotein A1 (ApoA1), and ATP Binding Cassette Subfamily A Member 1 (ABCA1) inflammatory proteins with atherosclerosis index (homocysteine) in normal-weight and obese male subjects. Methods: 59 males including 30 obese (Body mass index (BMI) of ≥30 kg/m ² ) and 29 normal-weight (BMI of 18.5–24.9 kg/m ² ) were joined to this study. Plasma levels of IL-1β and IL-10 (pg/mL), CRP (pg/mL), COX-2 (ng/mL), APOA1 (mg/dL), ABCA1 (ng/mL), HDL, Cholesterol, and Triglyceride (TG) (mg/dL), and homocysteine (µmol/L) was measured. Association of these biomarkers with homocysteine was determined. Results: Obese subjects had higher serum levels of IL10, IL1β, CRP, COX-2, TG, and cholesterol concentrations (all p<0.05 except IL-10 and cholesterol) and low levels of HDL, APOA1, and ABCA1 (non-significant differences) in comparison to normal-weight group. Homocysteine levels were high in obese men with no significant differences between the two groups. In obese subjects, homocysteine had a significant inverse correlation with APOA1, ABCA1, and HDL, and a strong and moderate positive correlation was found with CRP and TG levels, respectively. Conclusions: High level of homocysteine and its correlation with inflammation proteins and markers in obese subjects appear to be contributed with atherosclerosis development.

Over the past decades, obesity and infertility in men increased in parallel, and the association between both phenomena have been examined by several researchers. despite the fact that there is no agreement, obesity appears to affect the reproductive potential of men through various mechanisms, such as changes in the hypothalamic-pituitary-testicular (HPT) axis, spermatogenesis, sperm quality and/or alteration of sexual health. Leptin is a hormone produced by the adipose tissue, and its production elevates with increasing body fat. Many studies have supported the relationship between raised leptin production and reproductive function regulation. In fact, Leptin acts on the HPT axis in men at all levels. However, most obese men are insensitive to increased production of endogenous leptin and functional leptin resistance development. Recently, it has been recommended that Kisspeptin neurons mediate the leptin’s effects on the reproductive system. Kisspeptin binding to its receptor on gonadotropin-releasing hormone (GnRH) neurons, activates the mammal’s reproductive axis and stimulates GnRH release. Increasing infertility associated with obesity is probably mediated by the Kisspeptin-GnRH pathway. In this review, the link between obesity, kisspeptin, leptin, and male fertility will be discussed.

Objective(s): Most male patients with type 2 diabetes mellitus (T2DM) experience infertility. It is well established that regular physical activity could alleviate diabetic infertility symptoms. This study was designed to determine the effect of voluntary exercise on sperm malformation. Materials and Methods: Thirty-two male Wistar rats were randomly divided into control (C), diabetic (D), voluntary exercise (Ex), and diabetic-voluntary exercise (D-Ex) groups. Diabetes was induced by an intraperitoneal injection of streptozotocin (35 mg/kg) followed by a high-fat diet for four weeks. Voluntary exercise was performed by placing the animals in the rotary wheel cages for ten weeks. Sperm malformations were analyzed. Moreover, the hypothalamic leptin, kisspeptin, kisspeptin receptors (KissR), as well as plasma LH, FSH, testosterone, and leptin levels were evaluated. Results: Results showed that induction of T2DM caused increased sperm malformation, plasma, and hypothalamic leptin as well as decreased hypothalamic kisspeptin, KissR, and plasma LH levels compared with the C group (P<0.001 to P<0.01). Voluntary exercise in the Ex group increased hypothalamic KissR, plasma FSH, LH, and testosterone levels compared with the C group; however, it decreased sperm malformation and hypothalamic leptin levels (P<0.001 to P<0.05). Voluntary exercise in the D-Ex group reduced sperm malformation, hypothalamic leptin, and plasma testosterone while elevated hypothalamic kisspeptin and KissR protein levels compared with the D group (P<0.001 to Conclusion: The results illustrated voluntary exercise reduces sperm malformations by improving the HHG axis and kisspeptin/leptin signaling in rats with T2DM.

Introduction: Obesity resulted by imbalance between the intake of energy and energy consumption can lead to growth and metabolic disease development in people. Both in obese men and animal models, several studies indicate that obesity leads to male infertility.Objective: This review has discussed some mechanisms involved in obesity-induced male infertility.Method: Online documents were searched through Science Direct, Pubmed, Scopus, and Google Scholar websites dating from 1959 to recognize studies on obesity, kisspeptin, leptin, and infertility.Results: Obesity induced elevated inflammatory cytokines and oxidative stress can affect male reproductive functions, including spermatogenesis disorders, reduced male fertility power and hormones involved in the hypothalamus-pituitary-gonadal axis.Conclusion: There is significant evidence that obesity resulted in male infertility. Obesity has a negative effect on male reproductive function via several mechanisms such as inflammation and oxidative stress.

Objectives: High fat diet can lead to testicular structural and functional disturbances, spermatogenesis disorders as well as infertility. So, the present investigation was proposed to clarify whether voluntary exercise could prevent high fat diet induced reproductive complications in rats through testicular stress oxidative and apoptosis. Methods: Forty male Wistar rats were randomly divided into four groups; control (C), voluntary exercise (VE), high fat diet (HFD) and high fat diet and voluntary exercise (VE + HFD) groups. The rats in the VE and VE + HFD groups were accommodated in apart cages that had running wheels and the running distance was assessed daily for 10 weeks. In VE + HFD group, animals were fed with HFD for five weeks before commencing exercise. The sperm parameters, the expressions of testicular miR-34a gene, and P53 and SIRT1 proteins as well as testicular apoptosis were analyzed in all groups. Results: The results indicated that voluntary exercise in VE + HFD group led to significantly increased GPX and SOD activities, SIRT1 protein expression, sperm parameters, and decreased the expression of miR34a gene and Acp53 protein, and cellular apoptosis index compared to HFD group (p<0.001 to p<0.05). The SOD and catalase activities, SIRT1 protein expression, sperm parameters in VE + HFD group were lower than of those of VE group, however, MDA content, expression of Acp53 protein, apoptosis indexes in VE + HFD group was higher than that of VE group (p<0.001 to p<0.05). Conclusion: This study revealed that voluntary exercise improved spermatogenesis, in part by decreasing the testicular oxidative stress status, apoptosis through alteration in miR-34a/SIRT1/p53 pathway.

Objective The present study sought to evaluate the miR-34a/Sirtuin1/p53 pro-apoptotic pathway, and reveal its modulation in diabetic rats undergoing swimming exercise. Methods Twenty-eight male Wistar rats were divided into four groups. They were inducted to develop diabetes by injection of streptozotocin. After 12 weeks of swimming, the pancreatic tissue of these rats were removed to be evaluated for the expression level of Sitruin1/P53/miR-34a through qPCR. Results Findings indicated a marked rise in the expression of miR-34 and P53 (P < 0.01) as well as a significant decrease in expression of Sitruin1 (P < 0.01) in the diabetic group. In contrast, swimming resulted in a significant decrease in miR-34a expression (P < 0.01), and a prominent rise in the level of Sitruin1 in the swimming-trained-diabetic group (P < 0.01). Additionally, high, moderate and low apoptosis rate were observed in the pancreatic tissue of the diabetic, swimming-trained diabetic, and control groups, respectively. Conclusion Our findings suggested a correlation between pancreatic tissue apoptosis rate and miR-34a/Sitruin1/p53 signaling, that was subject to modulation by training. Graphical abstract

Background: Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and type-2 diabetes Objective: This study aimed to evaluate the effect of swimming exercise on pancreatic expression levels of inflammatory cytokines, miR-146a and NF-кB in type-2 diabetic male rats. Method: Twenty- eight male Wistar rats were divided into four groups: control (Con), exercise, diabetes and diabetic exercise (n = 7). Diabetes induction performed by the combination of high-fat diet (HFD, 4 weeks) and streptozotocin (35 mg/kg. ip). After induction of diabetes, the rats swam in the exercise groups for 12 weeks. Then, blood and tissue samples were collected. Result: Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1β) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group. Conclusion: Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1β) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group.

Introduction: microRNAs (miRs) play a critical role in both physiological and pathological processes. Recent studies have shown that garlic and exercise training have many beneficial effects in different disorders including cardiovascular disease. However, their mechanisms have not been fully understood. This study sought to investigate the impact of garlic and voluntary training alone or together on the miR-126 and miR-210 gene expressions and cardiac angiogenesis. Methods: Male Wistar rats were divided into four groups (n=7): (1) Control, (2) Garlic, (3) Exercise, and (4) Garlic+Exercise. Animals were gavaged with raw fresh garlic homogenate (250 mg/kg body weight/day) or were subjected to voluntary training alone or together for about 6 weeks. The expressions of miR-126 and miR-210 in the heart tissue were measured by real-time PCR and lipid profile in serum was assessed by enzymatic kits. Angiogenesis was determined by immunostaining detection of PECAM-1 and CD31 in the heart tissue. Results: Garlic and exercise up-regulated myocardial miR-126 (P<0.01), miR-210 (P<0.001) expressions, and angiogenesis (P<0.001) which was evidenced by higher CD31 expression. Besides, combination of garlic and exercise amplified their effects on those parameters (P<0.001). Moreover, both voluntary exercise and garlic alone (P<0.01) or together (P<0.001) markedly modulated serum lipid profile. Conclusion: Voluntary exercise and garlic treatment for 6 weeks enhanced myocardial angiogenesis. These alterations were partly due to the increment of miR-126 and miR-210 expressions in the heart tissue in relation to improvement in lipid profile.