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Approximately 90% of diabetic males have varying degrees of testicular dysfunction. The current study investigates the possible beneficial consequences of ranolazine against T1DM-induced testicular dysfunction in rats. Thirty-two male Sprague Dawley rats were assorted into 4 groups; normal, diabetic (single 50 mg/kg STZ, I.P.) and ranolazine (40 and 80 mg/kg, orally). The present investigation revealed that the hypoglycemic impact of ranolazine significantly improved the testicular weight and body weight of the final rats, as well as the concentration of blood testosterone, sperm count, and viability, all of which were associated with STZ-induced testicular dysfunction. Furthermore, as demonstrated by elevated reduced glutathione (GSH) activity and lowered malondialdehyde (MDA) levels, diabetic rats administered ranolazine showed a noteworthy improvement in the oxidant/antioxidant ratio. Furthermore, a substantial rise in beclin-1 concentration was seen in conjunction with a significant decrease in thioredoxin-interacting protein (TXNIP) and interleukin-18 (IL-18) concentrations when ranolazine was administered. Although ranolazine exhibited a reduction in inflammation as seen by lower expression of nuclear factor-κB (NF-κB) and cluster of differentiation (CD68) in the testicles, these biochemical findings were validated by improvements in the morphological and histopathological outcomes of both the pancreatic and testicular tissues. In conclusion, daily oral administration of ranolazine (40 and 80 mg/kg) for 8 weeks could be a promising therapy for T1DM-induced testicular dysfunction through its dose-dependent anti-oxidant and anti-inflammatory effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Obesity is a well-known risk factor for testicular function; however, dulaglutide's effect on the testis in obesity has received little attention. Currently, clinicians prescribe the antidiabetic drug dulaglutide only off-label for weight management in non-diabetics. Investigating the impact of this novel compound on obesity is critical for determining whether it has any disruptive effects on testicular cells. We used a well-known animal model of high-fat diet-induced obesity in this investigation, and testicular dysfunction was determined by sperm DNA damage, spermatocyte chromosomal abnormalities, and spermiogram analysis. Following a 12-week high-fat diet challenge, mice were randomly assigned to dulaglutide (0.6 mg/kg/day) or saline treatments for five weeks. Testes and sperm cells were collected 24 h after the last dulaglutide injection. Untreated obese mice had a lower testes/body weight ratio, more sperm DNA damage, diakinesis-metaphase I chromosomal abnormalities, a lower sperm count/motility, more cell morphological defects, and an altered testicular redox balance. In obese mice, dulaglutide injection efficiently restored all disturbed parameters to their control levels. Dulaglutide injection into healthy mice exhibited no significant harmful effects at the applied regimen. As a result, we infer that dulaglutide therapy might bring obese men additional benefits by recovering testicular dysfunction induced by obesity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

One of the adverse effects of the antineoplastic drug cisplatin (CS) is damage to testicular tissue. This study aimed to examine the potential therapeutic effect of thymoquinone (TQ), a strong antioxidant, against testicular damage caused by CS. In the experiment, 28 rats were used, and the rats were randomly divided into four groups: control (n = 7), CS (n = 7), CS + TQ (n = 7), and TQ (n = 7). The experiment was called off after all treatments were finished on day 15. Blood serum and testicular tissues were utilized for biochemical, histological, immunohistochemical, mRNA expression, and gene protein investigations. The testosterone level decreased and oxidative stress, histopathological damage, dysregulation in mitochondrial dynamics, inflammation and apoptotic cells increased in testicular tissue due to CS administration. TQ supplementation showed anti-inflammatory, antioxidant, and anti-apoptotic effects in response to CS-induced testicular damage. In addition, TQ contributed to the reduction of CS-induced toxic effects by regulating the TNF-α/OTULIN/NF-κB pathway. TQ supplementation may be a potential therapeutic strategy against CS-induced testicular damage by regulating the TNF-α/OTULIN/NF-κB axis, inhibiting inflammation, oxidative stress, and apoptosis., (© 2024. The Author(s).)

The prevalence of testicular dysfunction is increasing as it is a common diabetes mellites (DM) complication. The objective of this study is to explore the potential protective effect of sulbutiamine against testicular hypofunction associated with streptozotocin (STZ)-induced DM in rats. Sulbutiamine was administered orally (60 mg/kg) to male Wistar rats for 8 weeks starting 72 h after a single injection of STZ (45 mg/kg, i.p.). Blood glucose level (BGL), serum testosterone level, sperm number, and motility were determined. Testicular tissue was examined histopathologically, and the Johnson score was evaluated. Levels of malondialdehyde (MDA), protein kinase C (PKC), nuclear factor erythroid-derived 2-like 2 (Nrf2), and proliferating cell nuclear antigen (PCNA) were measured. Apoptosis was evaluated by immunohistochemical determination of B-cell lymphoma protein 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and caspase-3. Sulbutiamine administration managed to reduce BGL and boost testicular function as manifested by increased testicular weight, testosterone level, sperm number, and motility compared to the STZ group. Additionally, histopathological examination revealed an improved histological picture and Johnson score of testicular tissue after sulbutiamine treatment. Sulbutiamine administration reduced testicular PKC, MDA, and PCNA levels and increased Nrf2 compared to the untreated group. Moreover, sulbutiamine treatment suppressed apoptosis triggered by STZ as evidenced by elevated Bcl-2, decreased Bax and reduced caspase-3. The present work revealed for the first time a promising protective role of sulbutiamine against STZ-induced testicular dysfunction which may add to the clinical utility of sulbutiamine. The underlying mechanisms involve reducing BGL and PKC, activating Nrf2 and inhibiting apoptosis., (© 2024 International Union of Biochemistry and Molecular Biology.)

Testicular dysfunction is a prevalent health problem frequently reported in individuals with diabetes mellitus (DM). Oxidative-inflammatory reactions, hormonal and spermatic abnormalities often accompany this illness. Herbal remedies "particularly wild plants" including chicory (Chicorium Intybus) and purslane (Portulaca Oleracea) are emerging as popular agents for people dealing with these issues due to their ability to act as antioxidants, reduce inflammation, and exhibit antidiabetic effects. According to the collected data, the daily administration of chicory (Ch) seed-extract (250 mg/kg) or purslane (Pu) seed-extract (200 mg/kg) to streptozotocin (STZ)-induced diabetic rats (50 mg/kg) for 30 days resulted in the normalization of fasting blood glucose (FBG), serum fructosamine, insulin levels, and insulin resistance (HOMA-IR), as well as reducing lipid peroxidation end-product malondialdehyde (MDA) level, aldehyde oxidase (AO) and xanthene oxidase (XO) activities. While caused a considerable improvement in glutathione (GSH) content, superoxide dismutase (SOD), catalase (CAT) activity, and total antioxidant capacity (TAC) when compared to diabetic rats. Ch and Pu extracts had a substantial impact on testicular parameters including sperm characterization, testosterone level, vimentin expression along with improvements in body and testis weight. They also mitigated hyperlipidemia by reducing total lipids (TL), total cholesterol (TC) levels, and low-density lipoprotein cholesterol (LDL-C), while increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, oral administration of either Ch or Pu notably attuned the elevated proinflammatory cytokines as tumor necrotic factor (TNF-α), C-reactive protein (CRP), and Interleukin-6 (IL-6) together with reducing apoptosis and DNA damage. This was achieved through the suppression of DNA-fragmentation marker 8OHdG, triggering of caspase-3 immuno-expression, and elevation of Bcl-2 protein. The histological studies provided evidence supporting the preventive effects of Ch and Pu against DM-induced testicular dysfunction. In conclusion, Ch and Pu seed-extracts mitigate testicular impairment during DM due to their antihyperglycemic, antilipidemic, antioxidant, anti-inflammatory, and antiapoptotic properties., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Saad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Studies have identified Coenzyme Q10 (CoQ10) as a promising agent in improving idiopathic male infertility; however, its role in chemically or environmentally induced testicular dysfunction is not well-established. We investigated the potential of CoQ10 to attenuate methotrexate (MTX)-induced testicular damage and to identify molecular targets of CoQ10 effects. Wistar rats received a single intraperitoneal dose of 20 mg/kg MTX on the fifth day of the 10-day experimental protocol. 100 mg/kg CoQ10 was given orally daily for ten days, alone or combined with MTX. The testes of MTX-treated animals showed thickened tunica albuginea, distortion of seminiferous tubules with a marked reduction of germinal lining, a few primary spermatocytes with no spermatozoa, apoptotic cells, congested sub-capsular and interstitial blood vessels, and interstitial edema. Reduction of reproductive hormones and increased oxidative, inflammatory, and apoptotic biomarkers levels were also seen in the MTX-treated rats. CoQ10 + MTX-treated rats were protected against MTX-induced testicular histological changes and showed improvement in testosterone, luteinizing-, and follicle-stimulating hormone serum levels compared to the MTX group. The testes of the CoQ10 + MTX-treated rats showed reduced malondialdehyde, myloperoxidase, tumor necrosis factor -α, interleukin-6 and -1β and Bax: Bcl2 ratio and enhanced glutathione, and catalase compared to MTX alone. CoQ10 enhanced MTX-induced downregulation of Nrf2 and PPAR-γ signaling and modulated its downstream targets, the inducible nitric oxide synthase, NF-κB, Bax, and Bcl2. In conclusion, CoQ10 targeted the Nrf2-PPAR-γ signaling loop and its downstream pathways, mitigating MTX-induced oxidative stress-related damages and alleviating the testicular dysfunction MTX caused. Our data suggest Nrf2-PPAR-γ signaling as a potential therapeutic target in testicular toxicity, where oxidative stress, inflammation, and apoptosis trigger damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Busulfan (BUS) is an anticancer agent with serious adverse effects on various body organs, including the lung and testis. Sitagliptin was proven to have antioxidant, anti-inflammatory, antifibrotic, and antiapoptotic effects. This study aims to evaluate whether sitagliptin, a DPP4I, ameliorates BUS-induced pulmonary and testicular injury in rats. Male Wistar rats were split into control, sitagliptin (10 mg/kg), BUS (30 mg/kg), and sitagliptin + BUS groups. Weight change, lung and testis indices, serum testosterone, sperm parameters, markers of oxidative stress [malondialdehyde (MDA) and reduced glutathione (GSH)], inflammation [tumor necrosis factor-alpha (TNF-α)], and relative expression of sirtuin1 (SIRT1) and forkhead box protein type O1 (FOXO1) genes were estimated. Histopathological examination of lung and testicular tissues was done to detect architectural changes [Hematoxylin & Eosin (H&E)], fibrosis (Masson's trichrome), and apoptosis (caspase-3). Sitagliptin treatment reduced body weight loss, lung index, lung and testis MDA, serum TNF-α and sperm abnormal morphology, and increased testis index, lung and testis GSH, serum testosterone, sperm count, viability and motility. SIRT1/FOXO1 balance was restored. Also, sitagliptin attenuated fibrosis and apoptosis in lung and testicular tissues via reducing collagen deposition and caspase-3 expression. Accordingly, sitagliptin ameliorated BUS-induced pulmonary and testicular damage in rats via attenuating oxidative stress, inflammation, fibrosis, and apoptosis., (© 2023. The Author(s).)

The testis is susceptible to ionizing radiation, and male infertility and sexual dysfunction are prevalent problems after whole-body or local radiation exposure. Currently, there is no approved agent for the prevention or treatment of radiation-induced testicular injury. Herein, we investigated the radioprotective effect of dimethyl sulfoxide (DMSO), an organosulfur compound that acts as a free radical scavenger, on testicular injury. Treatment of mice with a single dose of DMSO prior to 5 Gy irradiation restored sex hormones and attenuated the reduction in testis weight. Histological analyses revealed that DMSO alleviated the distorted architecture of seminiferous tubules and promoted seminiferous epithelium regeneration following irradiation. Moreover, DMSO provided quantitative and qualitative protection for sperm and preserved spermatogenesis and fertility in male mice. Mechanistically, DMSO treatment enhanced GFR α -1 + spermatogonial stem cell and c-Kit + spermatogonial survival and regeneration after radiation. DMSO also alleviated radiation-induced oxidative stress and suppressed radiation-induced germ cell apoptosis in vivo and in vitro . Additionally, DMSO efficiently reduced DNA damage accumulation and induced the expression of phosph-BRCA1, BRCA1, and RAD51 proteins, indicating that DMSO facilitates DNA damage repair with a bias toward homologous recombination. In summary, our findings demonstrate the radioprotective efficacy of DMSO on the male reproductive system, which warrants further studies for future application in the preservation of male fertility during conventional radiotherapy and nuclear accidents., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Zeze Huang et al.)

Background: Testicular torsion is still an urgent surgical condition and without any treatment it can cause infertility. The main pathophysiology of testicular torsion ischaemic injury however; the main sequalae of detorsion is reperfusion injury. Furthermore; treatments to prevent ischemic reperfusion injury due to decreased blood flow are important to preserve testicular function., Aims: Human chorionic gonadotropin β (β-hCG) is an anabolic hormone that supports steroidogenesis and spermatogenesis. Vitamin C (Vit-C) is one of the water-soluble vitamins and is also a potent antioxidant in ischemic damage. Moreover, it has protective effects by increasing blood and lymph flow in the testicles. The aim of this study is to investigate the effects of β-hCG, Vit-C and their combination on ischemic reperfusion injury occurring after surgical treatment of testicular torsion., Study Design: Animal research studies., Methods: The study was performed on 25 male Wistar albino rats. The animals were divided equally into 5 groups. In the first group "Control Group," left orchiectomy was performed. In the second group "Sham Group," a 720° clockwise torsion was created and after 4 h of left testicular torsion it was detorsioned for 4 h and then left orchiectomy was performed. In the third group same procedure was applied with 30 mg vitamin C was administered via intraperitoneal route once a week for 3 weeks. In the fourth group after same surgical procedures 75 IU β-hCG was administered via intraperitoneal route once a week for 3 weeks. In the fifth group after 4 h left testicle torsion it was detorsioned for 4 h then, 75 IU β-hCG and vitamin C together were administered via intraperitoneal route once a week for 3 weeks. Left orchiectomy was performed after 3 weeks in the third, fourth and fifth groups. Specimens were evaluated histologically., Results: Testicular tissue histopathological evaluations were performed. A high histopathological stage indicates more testicular damage, and a low one was indicated less testicular damage. The average histopathological grade of vitamin C + β-hCG group was significantly higher than the average histopathological grade of the control, the sham group and vitamin C group. The average histopathological grade of the vitamin C group was significantly lower than the average histopathological grade of sham and β-hCG groups. The ratio of the testicular atrophy of the Vitamin C + β-hCG group (100%) was higher than sham (40%) and β-hCG (40%) groups with a significant difference. A significant statistical difference was found among all groups histopathological grades of testicular tissue., Conclusion: In animals taking vitamin C, an improvement of histopathological findings and a significant decrease in histological stages has been provided. However, it was observed that the histological findings of β-hCG and β-hCG + vitamin C groups worsened. It was found that β-hCG increased oxidative damage in the testicles and this damage can be so severe that exceeding the capacity of potent antioxidants such as Vitamin C. We believe that β-hCG can be harmful to testicles exposed to oxidative damage., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

The testicles and sperm are extremely susceptible to inflammation and oxidative stress. Although Zhibai Dihuang Pill (ZDP) has been reported to treat various infertilities including male infertility induced by Ureaplasma urealyticum (UU) infection, its mechanism is still poorly understood. This study is aimed at clarifying the underlying mechanism of ZDP to protect against UU-infected male infertility. We found that UU-infected infertile rats exhibited weight loss, reduced food intake, and decreased sperm count and vitality. The administration of ZDP improved the general state and sperm motility of rats. In addition, UU infection led to spermatogenesis disorders, impaired secretory function and blood-testis barrier (BTB) of Sertoli cells, and elevated inflammation and oxidative stress. As expected, ZDP suppressed inflammation and oxidative stress to alleviate spermatogenesis disorders. Our research showed that ZDP could improve spermatogenesis disorders and testicular function primarily through the mitogen-activated protein kinase (MAPK) signaling pathway. ZDP exerts its anti-inflammatory and antioxidant effects via the MAPK signaling pathway, thus playing an important role in ameliorating spermatogenesis failure and testicular dysfunction., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Kai Zhang et al.)

Background: Cancer and its therapies can impact fertility in various ways, and therefore a growing number of cancer survivors face fertility as a significant concern. The cytotoxic alkylating agent cyclophosphamide (CP) is commonly used as an antineoplastic agent; unfortunately, its use is significantly associated with male infertility and damage to the reproductive system., Aim: The present study aimed to assess the possible beneficial effects of Irbesartan (IRB) in a rat model of CP-induced testicular toxicity., Main Methods: The effects of treatment were assessed by measuring peroxisome proliferator-activated receptor gamma (PPAR-γ) expression via qRT-PCR, the immunohistochemical (IHC) assessment of apoptotic markers, NOD-like receptor protein 3 (NLRP3), and nuclear factor-κB (NF-κB), determination of the count and viability of epididymal sperm, oxidative stress markers via biochemical analysis, serum testosterone, caspase-1, and interleukin-18 (IL-18) levels via ELISA, histopathological assessment, and fibrosis by Masson's trichrome (MT) stain., Key Findings: There was a significant increase in malondialdehyde (MDA), caspase-1, and IL-18 contents, NF-κB, NLRP3, Bcl-2-associated X protein (Bax), caspase-3, and MT staining in testicular tissue after CP administration compared to the normal control group. Whereas reduced glutathione (GSH), superoxide dismutase (SOD), PPAR-γ expression, B-cell lymphoma-2 (Bcl-2) staining, serum testosterone, and the count and viability of epididymal sperm were decreased compared to the normal control group. The IRB treatment has reversed CP-induced testicular toxicity., Significance: It is possible to conclude that IRB revealed a significant testicular protective effect against CP via antioxidant, anti-apoptotic, and anti-inflammatory effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clinical utilization of doxorubicin (DOX), which is a commonly used chemotherapeutic, is restricted due to toxic effects on various tissues. Using hesperetin (HST), an antioxidant used in Chinese traditional medicine protects testis against DOX-induced toxicity although the molecular mechanisms are not well-known. The study was aimed to examine the possible role of the mechanistic target of rapamycin kinase (mTOR) and dynamin 1-like dynamin-related protein 1 (DRP1) in the therapeutic effects of HST on the DOX-induced testicular toxicity. Rats were divided into Control, DOX, DOX + HST, and HST groups (n = 7). Single-dose DOX (15 mg/kg) was administered intraperitoneally and HST (50 mg/kg) was administered by oral gavage every other day for 28 days. Total antioxidant status (TAS), histopathological evaluations, immunohistochemistry, and gene expression level detection analyses were performed. Histopathologically, DOX-induced testicular damage was ameliorated by HST treatment. DOX reduced testicular TAS levels and increased oxidative stress markers, 8-Hydroxy-deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE). Also, upregulated mTOR and DRP1 expressions with DOX exposure were decreased after HST treatment in the testis (p < 0.05). On the other hand, DOX-administration downregulated miR-150-5p and miR-181b-2-3p miRNAs, targeting mTOR and mRNA levels of beclin 1 (BECN1) and autophagy-related 5 (ATG5), autophagic markers. Furthermore, these levels were nearly similar to control testis samples in the DOX + HST group (p < 0.05). The study demonstrated that HST may have a therapeutic effect on DOX-induced testicular toxicity by removing reactive oxygen species (ROS) and by modulating the mTOR and DRP1 expressions, which have a critical role in regulating the balance of generation/elimination of ROS., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The aim of the study is to investigate the protective effect of taxifolin (3,5,7,3,4-pentahydroxy flavanone), a strong antioxidant, against testicular I/R injury in rats biochemically and histopathologically., Materials and Methods: 50mg/kg taxifolin was administered to taxifolin+testicular torsion-detorsion (TTTD, n-10) group of Albino Wistar male rats by oral gavage. Distilled water .5ml as a solvent was administered to testicular torsion-detorsion (TTD, n-10) and Healthy Control (SG, n-10) groups using the same method. An hour after the administration of taxifolin and distilled water, anaesthesia (ketamine 60mg/kg) was administered to all animal groups. TTD and TTTD group animals were subjected to testicular torsion at 720 degrees for four hours during anaesthesia. At the end of this period, testicular detorsion was applied and perfusion was allowed for four hours. Sham operation was applied to SG group., Results: Our biochemical experiment results showed that the amount of malondialdehyde (MDA) in testicular tissue of TTD group presented a significant increase compared to SG and TTTD groups whereas total glutathione (tGSH) and superoxide dismutase (SOD) levels decreased. In addition, while TTD group presented severe histopathological damage in germinal epithelium cell and seminiferous tubule, mild damage was observed in TTTD group., Conclusions: The results of our experiment indicate that taxifolin could be useful in the treatment of testicular I/R damage., (Publicado por Elsevier España, S.L.U.)

Background: Di-(2-ethylhexyl) phthalate (DEHP) is a well-known endocrine-disrupting compound inducing degeneration of testes. Gallic acid (GA) is a polyphenol with various pharmacological properties, including antioxidant and anti-inflammatory effects. Purpose: This research evaluated effects of different doses of GA on DEHP-induced testicular injury in adult mice. Research Design: Male mice were randomly divided into five groups and treated with agents for two weeks; group (I) received normal saline and corn oil (5 mL/kg/day, p. o.), group (II) received DEHP (2 g/kg/day, dissolved in corn oil, p. o.), groups (III, IV, and V) received DEHP + GA (25, 50, and 100 mg/kg/day, p. o.). Body and testes weights, serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels were evaluated. The number of sperms and sperm motility and viability were analyzed in the cauda epididymis. Histological changes, oxidative/nitrosative stress markers, and inflammatory cytokines levels were examined in testes. Results: Body and testes weights, the number of spermatogonia, primary spermatocyte and early spermatid, and late spermatid and sperm vitality, and progressive motility were significantly reduced in mice exposed to DEHP. Serum testosterone level decreased and serum LH and FSH levels increased in DEHP-exposed mice. These alterations were associated with the increased oxidative stress level and inflammatory responses in testicular tissue. Treatment with GA (50 and 100 mg/kg/day) attenuated DEHP-induced alterations in oxidative stress markers and inflammatory cytokines and reversed abnormality in sperm characteristic and number, tissue structure, and serum hormones levels. Conclusions: Results indicated that GA might be a promising agent against male gonadal toxicity induced by endocrine disrupting chemicals including DEHP.

Twisting of the spermatic cord is a common dangerous health problem that may be accompanied with testicular necrosis and infertility. Cilostazol (CLZ) is a selective phosphodiesterase (PDE) 3A inhibitor used for treatment of intermittent claudication. It has a great role in myocardial, spinal cord and hepatic ischaemia/reperfusion. However, till now, there are no researches evaluating its role in testicular ischaemia/reperfusion (TIR). The current work studies its capability to improve TIR induced injury with more concentration on the mechanisms involved in such effect. Four groups of animals were included: sham, TIR induced group, TIR plus CLZ low dose (10 mg/kg), TIR plus CLZ high dose (30 mg/kg). Our results proved that TIR had significant decrease of the serum ELISA of testosterone, marked disturbances in oxidative stress evaluated parameters as malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), ELISA measurement of tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL1β) inflammatory mediators, apoptotic marker (caspase3) using western blotting, immunohistochemistry of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). TIR reduced the protective agents as cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT1) by ELISA method with marked germinal cell apoptosis. The biochemical results were confirmed by the histopathological findings that showed marked decrease in both Johnsen's score and Cosentino's score. However, treatment with CLZ significantly reversed the profound TIR damaging effects, on the basis of its anti-inflammatory, anti-oxidant, and anti-apoptotic activities with recuperation of the testicular vascularity. Modulation of HIF/VEGF and cAMP/SIRT1 pathways showed a great role in mediating such effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Raffia palm (Raphia hookeri G. Mann & H. Wendl) wine (RPW) is a natural beverage obtained from the R. hookeri consumed for refreshment and medicinal purposes. For medicinal purposes, it is used singly or as macerating agent for other medicinal plants for the treatment of several diseases., Aim: This study investigates the effect of Raffia palm wine on dysregulated lipid metabolic pathways in testicular tissues of type 2 diabetic (T2D) rats., Methods: Raffia palm wine (150 and 300 mg/kg bodyweight) was administered to two T2D groups respectively, another T2D group was not administered treatment and served as negative control, while metformin served as the standard drug. After 6 weeks of treatment, the rats were sacrificed, and the testes collected. After weighing, the organs were homogenized in 20% methanol/ethanol and centrifuged at 20,000 g to extract the lipid metabolites., Results: GC-MS analysis of the supernatants revealed an alteration of the metabolites on induction of T2D, with concomitant generation of 10 metabolites. Raffia palm wine inhibited the T2D-generated metabolites while replenishing cholesterol and squalene levels, with concomitant generation of 7 and 8 metabolites for low and high dose treatment respectively. Pathway enrichment analysis of the metabolites revealed a decreased level of steroid biosynthesis and increased level of fatty acid biosynthesis. Raffia palm wine inactivated glycerolipid, fatty acid, and arachidonic acid metabolisms, fatty acid biosynthesis and fatty acid elongation in mitochondria pathways, and activated pathways for plasmalogen synthesis, mitochondrial beta-oxidation of long chain saturated fatty acids., Conclusion: The replenishment and generation of these metabolites and additional ones as well as activation of pathways involved in energy generation, phospholipids, antioxidant activity, steroidogenesis and spermatogenesis suggest a therapeutic effect of Raffia palm wine against hyperglycemic-induced testicular dysfunction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Chronic exposure to fluoride causes tissue damage induced by oxidative imbalance, Cyperus esculentus (CE) possess anti-inflammatory and immunostimulatory properties. This study focused on Salutary role of Cyperus esculentus in sodium fluoride (NaF) induced testicular degeneration and sperm quality deteriorations., Methods: Sexually mature male Sprague-Dawley rats were randomly divided into four groups (n=6). Animals in control group received 2 mls of normal saline per day; CE group received 500mg/kg bw of CE; NaF group received 5mg/kg bw of NaF; NaF+CE group received 500mg/kg bw of CE (for 14 days pre-treatment) and NaF co-treatment till 56 days via gastric gavage. Parameters tested include: testicular histology, sperm parameters, sex hormone, fertility test, malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione, glutathione peroxidase (GPX), catalase (CAT), testicular fluoride and testicular cholesterol., Results: Sodium fluoride significantly (p<.05) decrease testicular antioxidant (SOD, CAT, GSH and GPx), sperm quality, hormone profiles (TT, FSH, LH, estrogen levels), testicular cholesterol, morphometric parameters, Johnsen's Score and number of implantations in female rats with corresponding (p<.05) increase in oxidative stress makers and abnormal sperm morphology. Also depleted seminiferous epithelium and degenerate spermatogenic cells. Pretreatment with 500mg/kg bw of CE lowered NaF toxicity by significantly reducing the lipid peroxidation products, fluoride accumulation in the testis, histopathological changes of the testes and spermatozoa abnormalities and reverted observed NaF-induced inhibition in antioxidant parameters and weight of accessory sex organs., Conclusions: Cyperus esculentus attenuated NaF-induced testicular injuries and protected the seminiferous epithelium, reduced oxidative stress and promoted spermatogenesis., (Copyright © 2020 Asociación Española de Andrología, Medicina Sexual y Reproductiva. Publicado por Elsevier España, S.L.U. All rights reserved.)

Backround/aim: Cyclophosphamide (CP) is a drug used for treatment of many malignant diseases. However, it can cause serious side effects such as hemorrhagic cystitis and male infertility. Hydrogen sulfide (H2S) is a gaseous mediator and is suggested to have antioxidant, antiinflammatory, and antiapoptotic effects. In this study, dose-dependent effects of H2S donor sodium hydrosulfide (NaHS) on cyclophosphamide-induced hemorrhagic cystitis and testicular dysfunction were investigated in rats., Material and Methods: Rats were divided into 5 groups (n = 8): control, CP, NaHS25 μmol/kg, NaHS50 μmol/kg, and NaHS100 μmol/ kg. After treatment for 7 days intraperitoneally (ip), a single ip dose of CP 200 mg/kg was given on the 8th day. Then, treatment was continued for 7 days. In bladder and testicular tissues, IL 6, IL 10, cGMP, NO, H2S, FSH, LH, and testosterone levels were measured by ELISA. Histopathological examination with H&E staining, as well as immunohistochemical staining for acrolein in bladder and caspase-3 and APAF-1 in testis were performed., Results: NaHS prevented the increased IL 6 and IL 10 values induced by CP as well as prevented the decrease in cGMP values associated with CP. There was no significant change in FSH values, but the LH value, which increased with CP, decreased with 25, 50, and 100 μmol/kg NaHS. In contrast, testosterone decreased in the CP group and increased in the treatment groups. NaHS was effective in many biochemical and histopathological parameters at 25 and 50 μmol/kg doses, and this effect decreased at 100 μmol/kg dose., Conclusion: H2S has a protective and therapeutic effect on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide. It can be suggested that H2S is a promising molecule in facilitating cancer treatment., Competing Interests: none declared., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Aims: Cadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways., Materials and Methods: The testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks., Key Findings: Sitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx., Significance: Sitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The insulin enhancing activity, histological analysis and, testicular degeneration by a V IV O-complex containing the 2,2'-(ethane-1,2-diylbis(azanediyl))diethanolate ligand, VO IV (C 6 H 14 N 2 O 2 -κ 2 N,κ 2 O), abbreviated V IV O(BHED), were investigated in diabetic male Wistar rats. The complex was administered by oral gavage of freshly prepared solutions of vanadium complex. Biological studies demonstrated that the vanadium complex normalized the elevated glucose levels in male Wistar rats with streptozotocin-induced diabetes and these compounds also avoided common responses in diabetic animals such as weight loss and reduction in the size of the epididymis, prostate, testis and seminal gland. The 51 V NMR and EPR studies showed the formation of V IV O(BHED) and the oxidation product [V V O 2 BHED] - with two possible decomposition pathways. In summary, these studies demonstrate that the V IV O(BHED) complex or its decomposition products show similar effects as insulin in decreasing elevated blood glucose levels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of the current work was to compare the roles of caffeine and antioxidants in prevention of cadmium-induced testicular damage when given, in addition to cadmium, in adult male albino rats. Histopathological and ultra-structural examination as well as biochemical and molecular assessments were done. Cadmium chloride (4 mg/kg body weight) was administered via oral gavage from day 21 to 28 of the experiment. Caffeine (25 mg/kg) via intra-peritoneal injection and antioxidant preparation (Antox) 10 mg/kg via oral gavage were given as a pre-treatment for 21 days and concomitantly with Cd from day 21 to 28. Real-time PCR was done for determination of 3, 17 β hydroxy steroid dehydrogenase steroidogenic acute regulatory protein, caspase-9 and mitofusin 1,2 gene expression. Testosterone level, glutathione S-transferase enzyme activity, reactive oxygen species, malondialdehyde and superoxide dismutase were measured spectrophotometrically by ELISA. Histological and ultra-structural evaluation revealed disturbance of normal architecture, vacuolisation and necrosis. Vascular dilatation and congestion and collagen fibre deposition were present. A statistically significant difference was seen in all parameters when caffeine and antioxidants were given against cadmium-induced testicular injury. Overall, we conclude that both caffeine and antioxidants have the ability to reverse cadmium-induced testicular injury when given as pre-treatment prior to cadmium exposure., (© 2020 Wiley-VCH GmbH.)

Aims: To explore the mechanisms of diabetes mellitus (DM)-induced testicular injury caused by modulation of testicular glycolysis and gut microbiota (GM), and evaluation of the efficacy of catalpol in reversing testicular morbidity., Main Methods: A model of DM-induced testicular injury was established using a high-fat diet in KK-Ay mice. Microbial communities in the feces of mice in normal, model and catalpol (Cat) groups were analyzed by 16S gene sequencing. Correlations between the GM and lactate metabolism levels, lactate dehydrogenase activity, and indicators of testicular injury were analyzed., Key Findings: Cat significantly reduced general indicators of diabetes in mice with DM-induced reproductive injury, mitigated damage to the testicular tissue, and increased sperm count and motility. Additionally, the levels of products of glycolysis metabolism (e.g. lactate) increased following Cat treatment compared with the Model group. Disorders in the GM were also reversed in the Cat group., Significance: Cat ameliorated DM-induced testicular injury in KK-Ay mice by increasing the energy available to germ cells through glycolysis, principally through modulation of the GM and a reduction in the quantities of associated pathogenic bacteria., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/aim: Cisplatin (CP), a chemotherapeutic drug, causes damage to spermatogenic serial cells, Sertoli cells, and Leydig cells in rat testicles. It was aimed to investigate the protective effect of caffeic acid phenethyl ester (CAPE), one of the active ingredients of propolis, in eliminating CP-induced testicular damage., Materials and Methods: Group 1 (control group) was given physiological saline solution intraperitoneally (IP) throughout the experiment. Group 2 (CP group) was given a single dose of CP (7 mg/kg) IP on the day 7. Group 3 (CP + CAPE group), was given CAPE (10 μmol/kg/day) IP for 12 days and a single dose of CP (7 mg/kg) IP on day 7. Group 4 (CAPE group) was given CAPE (10 μmol/kg/day) IP for 12 days. On day 14 of the experiment, the rats were decapitated under xylazine and ketamine anesthesia and their testicles were removed. The sections obtained from the testicles were stained with hematoxylin-eosin and histopathological damage was evaluated. Malondialdehyde (MDA) levels, and superoxide dismutase (SOD) and catalase (CAT) enzymatic activities were measured in the testicular tissue samples. Testosterone (TES) levels were measured in the blood serum. The Johnsen testicular biopsy score (JTBS) was used to evaluate testicular tubules. DNA damage was evaluated in sperm samples taken from the ductus epididymis using the comet assay technique., Results: In Group 2, which was given CP, the testicles were severely damaged.It was observed that histological damage was reduced in the testes by administering CAPE in Group 3. Moreover, according to the JTBS, the value was significantly higher in the testicular tubules (P < 0.05). Moreover, the MDA level decreased in Group 3. However, the SOD, CAT, and TES levels increased in Group 3. DNA damage also decreased significantly in Group 3 when compared to Group 2 (P < 0.05)., Conclusion: The results showed that CAPE may be protective against damage caused by CP in the testicles of rats., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Purpose: This study was designed to determine the probable protection mechanisms of nitroglycerin, a widely used medication for treatment of heart failure and angina, in amelioration of testicular ischemia/reperfusion damage., Methods: 24 adult male rats were randomly divided into three equal groups; with eight rats in each group: Group 1 (Sham) was sham-operated. Group 2 (T&#95;D): 2 h testicular torsion was induced, afterward detorsion was performed and maintained for 2 h. Group 3 (NG): Nitroglycerin was administered immediately after detorsion. Sperm quality parameters such as viability, motility, morphology, and concentration, levels of antioxidant enzymes (glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC)), and amount of malondialdehyde (MDA) in the blood plasma were examined in each group, thereafter histopathological parameters including germinal epithelial cell thickness (GECT), mean seminiferous tubular diameter (MSTD), Johnson's score and Cosentino's score were assessed., Results: Testicular T&#95;D significantly reduced sperm viability, motility, and normal morphology, whereas the NG administration remarkably increased the percentage of live, motile, and normal spermatozoa (p < 0.05). Levels of GPx, CAT, and TAC significantly reduced and the MDA level significantly increased in the T&#95;D group in comparison to the sham group (p < 0.05). The NG treated group demonstrated significantly reduced MDA concentrations as well as elevated levels of GPx and CAT compared to the T&#95;D group (p < 0.05). Induction of testicular torsion significantly reduced Johnson's score, GESCT (μm), and MSTD (μm), and remarkably increased the Cosentino's score (P < 0.05), while NG injection significantly increased Johnson's score, GESCT (μm), and MSTD (μm) and reduced the Cosentino's score (P < 0.05)., Conclusion: According to the findings in this research, nitroglycerin was able to protect the testicular tissue from ischemia-reperfusion damage caused by induced torsion/detorsion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated the palliative effect of Artemisia judaica extract (AjE) on testicular deterioration induced by DM in high-fat diet/streptozocin (HFD/STZ)-injected rats. Forty rats were allocated to the following five groups: control, AjE, HFD/STZ, HFD/STZ-AjE, and HFD/STZ-metformin. HFD/STZ-diabetic rats showed a marked decrease in testicular weight and male sex hormones. There was significant suppression of testicular antioxidant enzymes and glutathione content in HFD/STZ-diabetic rats. However, rats that had received the STZ injection and the high-fat diet displayed increased malondialdehyde content and nitric oxide levels as well as tumour necrosis factor-alpha. High levels of Bax and low levels of Bcl-2 were detected after the STZ injection. Obvious pathological alterations were found in the testicular tissue of the HFD/STZ-diabetic rats. Thus, the administration of AjE attenuated the biochemical, molecular, and histopathological changes in the testes of the diabetic rats. The obtained findings showed that AjE treatment attenuated the diabetes-induced reprotoxicity in male rats via its antioxidant, anti-inflammatory, and antiapoptotic properties.

Testicular damage contributes to cyclosporine A (CsA) induced male infertility. However, the exact underlying molecular mediators involved in CsA-induced testis disorder remains unclear. The present study aimed to characterize the role of mir-34a/sirt-1 in CsA induced testicular injury alone or in combination with curcumin. A total of twenty-eight male Wistar rats were subdivided into four groups: control (Con), sham, cyclosporine A (CsA), cyclosporineA + curcumin (CsA + cur). The animals received cyclosporine A (30 mg/kg) and curcumin (40 mg/kg) for 28 days by oral gavage. At the end of the experiment, CsA administration significantly resulted in a decrease in testis weight and testis coefficient. The molecular analysis demonstrated that CsA exposure increased 8-OHdg and Nox4 protein contents in the testis tissue. TUNEL staining indicated that CsA caused the number of apoptotic cells to increase in the testes of male rats. In addition, exposure to CsA resulted in an increased expression of Bax, and a decreased expresion in that of Bcl-2, with a concomitant up-regulation of the Bax/Bcl-2, c-Caspase-3/p-Caspase-3 ratio and cytochrome c level. Meanwhile, exposure to CsA increased the expression of mir-34a and decreased sirt-1 protein level in the testis tissue samples compared to the control group. Taken together, our findings suggested that CsA can cause damage to testicular germ cells via oxidative stress and mitochondrial apoptotic pathway, and probably mir-34a/sirt-1 play a crucial role in this process. It also demonstrates that these negative effects of CsA can be reduced by using curcumin as an antioxidant and anti-inflammatory agent., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study investigated the effect of ketogenic diet on monosodium glutamate (MSG)-induced testicular dysfunction. Forty-six male rats (180 ± 40 g) were grouped into two groups (23 rats each); control group and MSG-induced group (4 mg/kg bw) for 28 days. At the 29th day, 5 rats from both group were sacrificed to establish testicular dysfunction. The remaining animals from the control group was further divided into three sub-groups and treated for 42 days; untreated group, ketogenic diet only and curcumin only as the standard drug (150 mg/kg bw). In the pre-treatment, the administration of MSG resulted in a significant (p < 0.05) decrease in the testis-body weight ratio, alkaline phosphatase (ALP), acetylcholine esterase (AChE), cholesterol, triglycerides (TG), nitric oxide (NO), glycogen, protein and antioxidant enzymes in the testis. In the post treatment, the MSG only group significantly reduced testicular cholesterol, catalase (CAT) and NO. In contrast, MSG + ketogenic diet group showed a significant increase in levels of rat testicular acid phosphatase (ACP), ALP, cholesterol, HMG-CoA, TG, malondialdehyde (MDA), reduced glutathione (GSH) and NO. The ketogenic diet showed a significant increase (p < 0.05) in the levels of NO, ALP, cholesterol, HMG CoA reductase and (TG). In addition, significant increases in levels of rat testicular ACP, ALP, HMG-CoA, (CAT), SOD and GSH were recorded for MSG + Curcumin group. Taken together, the findings support the prospects of ketogenic diet to enhance the testicular function in rats., Competing Interests: Declaration of Competing Interest The authors have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The testosterone deficiency syndrome (TDS) is a very common clinical and biochemical condition that affects approximately 2-5% men over the age of 40. From a clinical point of view, it is usually associated with decreased sexual desire and activity, erectile dysfunction, low energy and mood swings, along with T<8-12 nmol/l levels. Questionnaires are not useful in screening but may be useful for diagnosis and follow-up. Its diagnosis requires the presentation of multiple hypogonadism symptoms together with two morning T tests below the acceptable limits. LH and SHBG levels can be useful to determine the cause and the free T level, respectively. Contraindications for treatment are active prostate cancer, stage IV heart failure, breast cancer, desired fertility and hematocrit values over 54%. Treatment is based on the cause of TDS, if any, along with testosterone supplementation. The objective is to achieve normal testosterone levels. Follow-up includes clinical history, analysis (PSA, T+SHBG, hematocrit, glucose and lipid profile) and rectal examination, 3, 6 and 12 months after beginning treatment., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Objective: The vast majority of type 1 diabetes leads to a higher prevalence of reproductive system's impairments. Troxerutin has attracted much attention owing to its favorable properties, including antihyperglycemic, anti-inflammatory, and antiapoptotic effects. This investigation was proposed to evaluate whether pretreatment with troxerutin could prevent apoptosis-induced testicular disorders in prepubertal diabetic rats., Methods: Fifty prepubertal male Wistar rats were randomly allocated into five groups: control (C), troxerutin (TX), diabetic (D), diabetic+troxerutin (DTX), and diabetic+insulin (DI). Diabetes was induced by 55 mg/kg of streptozotocin applied intraperitoneally. In TX and DTX groups, 150 mg/kg troxerutin was administered by oral gavage. Diabetic rats in DI group received 2-4 U NPH insulin subcutaneously. Troxerutin and insulin treatments were begun immediately on the day of diabetes confirmation. After 30 days, the testicular lipid peroxidation and antioxidant activity, apoptosis process, and stereology as well as serum glucose and insulin levels were assessed., Results: The results showed that diabetes caused a significant increase in the blood glucose, the number of TUNEL positive cells and tubules, and the malondialdehyde level as well as a significant decrease in serum insulin level compared to controls. The stereological analysis also revealed various alterations in diabetic rats compared to controls. Troxerutin treatment improved these alterations compared to the diabetic group., Conclusion: Troxerutin-pretreatment may play an essential role in the management of the type-1 diabetes-induced testicular disorders by decreasing blood glucose and modulating apoptosis.

Male reproductive dysfunction represents one of the overlooked consequences of diabetes that still deserve more scientific attention. We designed this study to explore the therapeutic potential of hydroxytyrosol (HT) on diabetic testicular damage and to investigate its relationship with adenosine monophosphate-activated protein kinase (AMPK) expression. In this context, 30 adult male Wistar rats were utilized and subdivided into control, diabetic and HT-treated diabetic groups. Testicular sections were prepared for histopathological examination and immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine, Sertoli cell vimentin, myoid cell α-SMA, androgen receptors and caspase-3. We also assessed oxidative enzymatic and lipid peroxidation biochemical profiles, sperm count, morphology and motility. Real-time PCR of AMPK expression in tissue homogenate was performed. We observed that HT restored testicular histopathological structure and significantly reduced oxidative DNA damage and the apoptotic index. The HT-treated group also exhibited significantly higher Sertoli cell vimentin, myoid cell α-SMA and androgen receptor immune expression than the diabetic group. A rescue of the oxidative enzymatic activity, lipid peroxidation profiles, sperm count, morphology and motility to control levels was also evident in the HT-treated group. Significant upregulation of AMPK mRNA expression in the HT-treated group clarified the role of AMPK as an underlying molecular interface of the ameliorative effects of HT. We concluded that HT exhibited tangible antioxidant and antiapoptotic impacts on the testicular cytomorphological and immunohistochemical effects of experimentally induced diabetes. Furthermore, AMPK has an impactful role in the molecular machinery of these effects.

Tramadol is a centrally acting opioid analgesic that is extensively used. The chronic exposure to tramadol induces oxidative stress and toxicity especially for patients consuming it several times a day. Previously, we and others reported that tramadol induces testicular damage in rats. This study was conducted to investigate the possible protective effect of pomegranate seed extract (PgSE) against tramadol-induced testicular damage in adult and adolescent rats. Male rats were orally treated with tramadol or in a combination with PgSE for three weeks. Testes were then dissected and analyzed. Histological and ultrastructural examinations indicated that tramadol induced many structural changes in the testes of adult and adolescent rats including hemorrhage of blood vessels, intercellular spaces, interstitial vacuoles, exfoliation of germ cells in lumen, cell apoptosis, chromatin degeneration of elongated spermatids, and malformation of sperm axonemes. Interestingly, these abnormalities were not observed in tramadol/PgSE cotreated rats. The morphometric analysis revealed that tramadol disrupted collagen metabolism by elevating testicular levels of collagen fibers but that was protected in tramadol/PgSE cotreatment at both ages. In addition, DNA ploidy revealed that S phase of the cell cycle was diminished when adult and adolescent rats were treated with tramadol. However, the S phase had a normal cell population in the cotreated adult rats, but adolescent rats had a lower population than controls. Furthermore, the phytochemistry of PgSE revealed a high content of total polyphenols and total flavonoids within this extract; besides, the DPPH free radical scavenging activity was high. In conclusion, this study indicated that PgSE has a prophylactic effect against tramadol-induced testicular damage in both adult and adolescent ages, although the tramadol toxicity was higher in adolescent age to be completely protected. This prophylactic effect might be due to the high antioxidant compounds within the pomegranate seeds., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Fatma M. Minisy et al.)

This study aimed at investigating the effects of intraperitoneal (IP) administration of magnesium sulfate (MgSO4) on testicular ischemia-reperfusion (IR) injury in rats. In total, 50 adult Wistar rats were randomly divided into 5 groups. Group 1 received no injection (control); however, group 2 was subjected to 2 h of I and 24 h of R. Subsequently, group 3 was subjected to 2 h of 1, and after 1 h of I, 125 mg/kg MgSO4 was injected intraperitoneally followed by 24 h of R. Groups 4 and 5 were subjected to the same process as group 3, whereas the rats were injected with 250 and 500 mg/kg of MgSO4, respectively. After 24 h, the left testes of all rats were removed for histological analysis and antioxidant activities. According to the results, there was a significant increase in tissue malondialdehyde (MDA) among I/R rats (P&lt;0.05), whereas MgSO4 decreased I/R-induced MDA (P&lt;0.05). Furthermore, experimental I/R diminished glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels significantly (P&lt;0.05). Moreover, MgSO4 (250 and 500 mg/kg) increased GPx and SOD activity significantly in I/R rats (P&lt;0.05). Furthermore, seminiferous tubules degenerated, and few spermatocytes were observed in the testis tubules of the I/R rats. Regarding pathological parameters, seminiferous tubules and spermatocyte were normal in the testes of MgSO4 (250 and 500 mg/kg)-treated experimental I/R-induced rats. In conclusion, this study demonstrated the beneficial effects of MgSO4 on testicular IR injury in rats., (Copyright © 2020, Archives of Razi Institute. Published by Kowsar.)

Background and Purpose: Reduced male fertility has been regarded as a serious complication of rheumatoid arthritis. Phytochemicals have been described as protective agents against rheumatoid arthritis-linked testicular impairment. The current study aimed to investigate the potential protective effects of ellagic acid on rheumatoid arthritis-evoked testicular dysfunction vis-à-vis the reference anti-inflammatory celecoxib., Experimental Approach: Ellagic acid (50 mg/kg/day) and celecoxib (5 mg/kg/day) were administered orally for 20 days in adjuvant-induced arthritic rats., Key Findings: Current data revealed that ellagic acid counteracted rheumatoid arthritis-evoked testicular histopathologic changes, disrupted sperm characteristics and low gonadosomatic index with comparable efficacy to celecoxib. Ellagic acid also enhanced the testicular steroidogenesis via upregulating the gene expression of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein with consequent boosting of serum testosterone. Notably, ellagic acid attenuated the testicular inflammatory responses through suppression of myeloperoxidase, tumor necrosis factor-α and cyclo-oxygenase-2 protein expression together with enhancing the anti-inflammatory signal interleukin 10. Ellagic acid also curbed the redox alterations via lowering the production of lipid peroxides and nitric oxide and elevation of the anti-oxidant reduced glutathione. In support of cell survival, ellagic acid combated testicular apoptosis through downregulating caspase-3 protein expression., Significance: The present work accentuates the beneficial actions of ellagic acid in rheumatoid arthritis-incurred testicular impairment and disrupted spermatogenesis via combating the inflammatory, oxidative and apoptotic aberrations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Protective effects of standardised extract of Costus afer leaves (CAME), an extract with good antioxidants on cadmium-induced reproductive toxicity in male rats, were investigated in this study. Forty-two adult male Wistar rats were randomly divided into six groups and were treated every day regularly for 4 weeks. G1 (control) rats received 1 ml of vehicle treatment. G2 rats were intoxicated with 2.5 mg kg -1  day -1 s.c cadmium chloride for 1 week. G3 and G4 rats were intoxicated with cadmium as in G2 rats and were treated orally with 100 and 200 mg/kg bwt/day of CAME, respectively, for 4 weeks. Group G5 and G6 rats were orally treated with 100 and 200 mg kg -1  day -1 bwt of CAME, respectively, for 4 weeks. Significant changes (p < 0.05) in andrological parameters (sperm count, sperm morphology, serum testosterone and nitric oxide concentration) and testicular antioxidant parameters (reduced glutathione, lipid peroxidation and activities of catalase, glutathione S-transferase and glutathione peroxidase) caused by Cd toxicity were improved in cadmium-intoxicated rats treated with 100 mg/kg body weight of CAME. Administration of 200 mg/kg body weight of CAME to cadmium-intoxicated rats potentiated reproductive toxic effects of cadmium. In conclusion, lower dose of CAME is preferred over high dose in treatment of cadmium-induced reproductive toxicity in rats., (© 2019 Blackwell Verlag GmbH.)

Testis is a rich organ with blood vessels. For this reason, it is possible that the toxic substances of the cigarette carried in the blood change the balance between the oxidant and the antioxidant system in this organ. In this study, it was aimed to investigate the effects of N-nitro L-arginine methyl ester and α-tocopherol on testicular oxidative stress caused by exposure to cigarette smoke. 45 wistar male rats were used in the study. Five groups were formed: control, cigarette smoke, cigarette smoke + α-tocopherol, cigarette smoke + N-nitro L-arginine methyl ester and cigarette smoke + α-tocopherol + N-nitro L-arginine methyl ester. Biochemical and histological evaluations were performed to determine the damage caused by cigarette smoke. It was observed that there were structural and functional disturbances at the cellular and hormonal level in the smoking group. Biochemical evaluations showed that cellular damage was reduced in treatment groups. Histological examinations were revealed that the damage caused by cigarette smoke exposure was eliminated in treatment groups. As a result of our study, we think that oxidative damage and hormonal irregularity in the testes tissue caused by cigarette smoke exposure can be improved with α-tocopherol and N-nitro L-arginine methyl ester application., (© 2019 Blackwell Verlag GmbH.)

Testicular dysfunction or damage is among the critical side effects of chemotherapeutic drugs like cisplatin. This study was mapped out to assess the possible therapeutic effect of eugenol on cisplatin-induced testicular damage. In this experimental study, a single dose of cisplatin (15 mg/kg) was given intraperitoneally. After 72 hr of cisplatin injection, rats were sacrificed and testis tissues were removed. Tissues were examined by biochemical, histopathological and immunohistochemical methods. While tissue lipid peroxidation product and apoptotic marker levels increased, antioxidant enzyme activities of testis tissue were decreased in the cisplatin group. Additionally, histopathological damage was also determined in testis tissue. Contrary to all these results, the severity of damage in the tissue was reduced histopathologically owing to eugenol treatment. The lipid peroxidation decreased and antioxidant enzyme activities increased in the eugenol treatment group. It has been determined that eugenol has a therapeutic effect on oxidative stress and apoptosis against cisplatin-induced testicular damage., (© 2019 Blackwell Verlag GmbH.)

Testicular structural and functional impairment is a serious complication in male diabetes mellitus (DM) patients that leads to impaired fertility in adulthood. In contrast to other endocrine therapies, islet transplantation (IT) can effectively prevent and even reverse diabetic nephropathy and myocardial damage. However, whether IT can alleviate diabetes-induced testicular injury remains unclear. In this study, we sought to investigate the effect of IT on diabetes-induced testicular damage. A diabetic rat model was established by streptozotocin injection. DM, IT, and insulin treatment (INS) groups were compared after 4 weeks of respective treatment. We confirmed that IT could effectively attenuate diabetes-induced testicular damage and recover sperm counts more extensively compared with INS in diabetic rats. In addition, significantly higher levels of superoxide dismutase (SOD) activity and lower contents of malondialdehyde (MDA) were detected in the testes of the IT group versus diabetic rats. Mechanism studies revealed that IT significantly activates the expression of Nrf-2, HO-1, and NQO-1 and inhibits upregulation of the NF- κ B expression in response to DM, while INS only exhibit slight impact on the protein expression. Therefore, we speculate that IT may prevent the progression of testicular damage by downregulating oxidative stress and inhibiting inflammation via Nrf-2/HO-1 and NF- κ B pathways., Competing Interests: All authors declare that there are no financial or nonfinancial competing interests regarding the publication of this paper., (Copyright © 2019 Xiandong Zhu et al.)

Impact Statement: Cisplatin is a commonly used drug in the treatment of solid tumors and its application is associated with testicular toxicity. The effect of candesartan in cisplatin-induced testicular toxicity and its fundamental mechanism of action were investigated. Candesartan had certainly repaired the testicular injury and ameliorated both biochemical and histopathological changes. Candesartan mitigated the gonadotoxicity induced by cisplatin via antioxidative, anti-inflammatory, and antiapoptotic actions.

Diabetes affects the reproductive system. This study was conducted to find out the potent dose of the hydro-methanol 60:40 extract of Curcuma amada rhizomes for the management of diabetes-induced testicular dysfunction in albino rats. The extract was administered at the doses of 10, 20, 40, and 80 mg/100 g body weight/day for 28 days. Oxidative stresses, reproductive parameters, histological, and gene expressions of the testicular tissue were assessed. Out of the doses used, the 20-mg dose showed maximum recovery as the minimum dose (e.g., sperm motility 112.03%, testicular cholesterol 34.86%, Bax gene expression 49.77%), whereas 40- and 80-mg doses did not vary statistically with each other (e.g., sperm motility 95.37% and 89.19%, testicular cholesterol 30.42% and 28.41%, Bax gene expression 47.33% and 46.18%, respectively) as well as with the 20-mg dose. It may be concluded that the 20-mg dose is the threshold dose for this purpose. PRACTICAL APPLICATIONS: The hydro-methanol 60:40 extract of rhizomes of Curcuma amada has a strong antioxidant property that can manage diabetes-induced oxidative injuries in testes which may raise a hope to the pharmaceutical industries to develop a herbal drug for diabetes-linked testicular hypofunction management., (© 2019 Wiley Periodicals, Inc.)

Leprosy is a chronic neglected and stigmatizing disease. Due to involvement of the peripheral nerves, it can result in physical disabilities, deformities, and emotional damage if not diagnosed and treated promptly. This is the case of a young patient with testicular pain and swelling and no improvement after a specific therapeutic scheme for tuberculosis. Clinical and laboratory reevaluation revealed hypoesthetic skin patches associated with post-burn crusted ulcers on the left arm, thickening of ulnar nerves, atrophy of interosseous muscles of the hands, positive skin smear microscopy, and testicular histopathology with numerous bacilli forming globi. These findings indicated lepromatous leprosy with type II reaction.

We investigated the protective effect of the folic acid (FA) against bisphenol-A (BPA) induced toxicity in rat testis. We used four groups of seven adult male Wistar albino rats. The control group was fed corn oil, the BPA group was given BPA, the FA group was given FA and the FA + BPA group was given FA initially followed by BPA 1 h later. The BPA, FA and corn oil were administered by oral gavage for 14 days. At the end of the experiment, testis sections were examined for histological and histomorphometric characteristics. The TUNEL method was used to detect apoptosis and immunohistochemistry was used to examine the distribution of spermatogonial stem cells. Levels of serum testosterone were measured, and sperm viability and morphology were determined. The histological structure of the testis was normal in the control and FA groups. Although the number of TUNEL positive cells/tubule increased, the seminiferous epithelium height (SEH) at stages VII-VIII decreased in the BPA group compared to the control, FA and FA + BPA groups. The number of TUNEL positive cells/tubule decreased and the SEH at stages VII-VIII increased in the FA + BPA group compared to the BPA group. No significant difference in spermatogonial stem cells was found among groups. The level of serum testosterone and percentage of viable sperm was significantly lower, while the head, midpiece and total sperm abnormalities were significantly higher in the BPA treated group compared to control, FA, FA + BPA groups. It appears that the toxic effects of BPA on testis might be minimized by FA treatment.

New Findings: What is the central question of this study? Can low-dose inorganic nitrate supplementation prevent testicular structural and functional alterations in streptozotocin-induced type 1 diabetic male rats? What is the main finding and it's important? Treatment with a low dose of inorganic nitrate for 2 months had protective effects on the male reproductive system in diabetic rats including improved body weight loss, sperm and testis parameters, spermatogenesis index and testicular histology as well as increased serum testosterone levels. These favourable effects may be associated with increased serum insulin and decreased serum glucose, and with modulation of apoptosis in testis., Abstract: Inorganic nitrate supplementation is a possible therapeutic agent in diabetes. The aim of this study was to evaluate the effect of nitrate on the reproductive system in streptozotocin-induced diabetic male rats. Fifty male Wistar rats were allocated randomly to five groups: control (C), control plus nitrate (CN), diabetic (D), diabetic plus insulin (DI) and diabetic plus nitrate (DN). Sodium nitrate was administered for 2 months in the drinking water (100 mg l -1 ) of the CN and DN groups. Insulin was injected at 2-4 U daily in the DI group. Serum glucose level and body weight were measured at the beginning of the study and at regular intervals. At the end of the study, serum levels of glucose, insulin, nitrogen oxides (NOx), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were assessed as well as sperm parameters, testis morphometry and histology, and testicular miR-34b and p53 mRNA expression. Nitrate treatment in diabetic rats significantly improved sperm parameters, epididymal weight, spermatogenesis and testicular histology as well as decreasing serum glucose and testicular p53 gene and miR-34b expression, although it had no effect on serum LH and FSH levels. In diabetic rats, serum insulin and NOx, body weight, testicular and epididymal weight, sperm count and motility, testis morphology, spermatogenesis indices, Johnsen's score, and testosterone were significantly lower than in controls. Nitrate administration increased serum insulin, NOx and testosterone levels in the DN group. Consuming water supplemented with sodium nitrate could improve diabetes-induced testicular functional and structural disorders; these favourable effects may be related to increased serum insulin and decreased serum glucose, as well as modulation of apoptosis in testis., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Cerium oxide nanoparticles (CNPs) as an antioxidant have been used frequently to attenuate hyperglycaemia oxidative damage in different organs. We investigated the impact CNPs on the qualitative and quantitative sperm parameters, spermatogenesis and NFE2-related factor 2 (Nrf2) expression as a major contributor of antioxidant defence in the male diabetic rats. Twenty-four male rats were divided into four groups. Controls received only mouse food and water. Second group were treated with CNPs (30 mg kg -1  day -1 ) for 2 weeks. Rats in third group received streptozotocin (STZ) (60 mg/kg). In fourth group, animals became diabetic and received CNPs (30 mg kg -1  day -1 ) for 2 weeks. The results showed a significant abnormality in the sperm parameters and histopathological patterns of testes in the diabetic group compared to the control group and CNPs treatment significantly improved all testicular parameters. Following CNPs administration, sperm DNA fragmentation significantly reduced in the STZ-treated rats. Moreover, after CNPs intake in the STZ-treated rats, Nfr2 expression levels increased significantly. Overall, CNPs administration on the diabetic rates can attenuate detrimental effects of diabetes on the sperm potential fertility, sperm parameters, DNA integrity and Nrf2 expression levels. This study gives a future prospect to determine the role of CNPs in the context of diabetes., (© 2018 Blackwell Verlag GmbH.)

This study was designed to determine the effects of daily oral administration (250 mg/kg) of the hydroalcoholic extract of Fumaria parviflora (FP) for 14 days on the sperm parameters, oxidative stress parameters, serum testosterone levels, expression of Bax and Bcl-2 genes, and apoptosis index of germ cells after testicular torsion-detorsion (ischaemia-reperfusion, IR) injury model in rats. Twenty-eight adult male Wistar rats were divided randomly into four groups of seven each: sham operation, torsion-detorsion (TD), TD plus the hydroalcoholic extract FP (TDFP) and only FP without TD application (FP). Testicular torsion was created by rotating the left testis 720° in a counterclockwise direction; then, after 4 hr, detorsion was performed. The Johnson's score, mean seminiferous tubule diameter (MSTD) and height (thickness) of seminiferous tubule epithelium (HST) were significantly increased in TDFP and FP groups as compared to TD group. The gene expression of Bcl-2, level of serum testosterone hormone and antioxidant parameters-GPx and SOD-were significantly higher in TDFP and FP groups than TD group. The index of apoptosis, the gene expression of Bax and the level of MDA were significantly higher in TD group than TDFP and FP groups. Therefore, F. parviflora could decrease oxidative stress induced by testicular torsion-detorsion., (© 2018 Blackwell Verlag GmbH.)

Testosterone is a natural hormone which is essential to maintain physical and emotional wellbeing in men. Male hypogonadism is an endocrine condition of testosterone deficiency with the potential to cause multiple morbidities and psychosocial complaints. The condition can be of primary (testicular), secondary (hypothalamic-pituitary) or so-called functional origin (as a result of inflammatory conditions, obesity or chronic illness). Testosterone deficiency can cause symptoms of sexual nature, insulin resistance, osteoporosis, anemia among others. A replacement of testosterone should not be initiated in case of desired paternity, unclear processes of the prostate, mammary gland, or high hematocrit. Diagnosis and treatment as well as surveillance of the therapy of hypogonadism are clearly regulated by international guidelines and replacement therapy is proven to be effective to ameliorate the above-named complaints when performed according to these guidelines., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Di (2-ethylhexyl) phthalate (DEHP) is one of the environmental pollutants that causes testicular damage. Lycopene (LYCO), the main active carotenoid in red fruits and vegetables, has well-known antiinflammatory and antioxidant activities. The present study aimed to investigate the effects of LYCO on DEHP-induced testicular injury in male mice. DEHP (2 g/kg, p.o.) was given for two weeks to mice. LYCO was given at 4 mg/kg, p.o., for two weeks, starting the same day of DEHP insult. Serum testosterone, luteinizing hormone and follicle stimulating hormone and testicular total antioxidant status, malondialdehyde, nitric oxide, glutathione, superoxide dismutase, glutathione peroxidase, catalase, tumor necrosis factor-α, interleukin-1β were measured. Also, testicular histopathological examination and sperm analysis were evaluated. Results showed that administration of LYCO significantly attenuated the DEHP-induced gonadotoxicity. Also, the gonadoprotective effects of LYCO were confirmed by the histopathological examination of the testes. Our results suggested that LYCO has produced attenuation of inflammatory, oxidative stress and hormonal parameters against DEHP-induced gonadotoxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oxidative damage, inflammation, and apoptosis are the primary features of diabetic testicular damage. Curcumin protects against diabetic testicular injury, but the underlying mechanisms remain obscure. This study examined the effect of curcumin on type 2 diabetes mellitus- (T2DM-) induced testicular injury, oxidative stress, and apoptotic changes. T2DM rats were intraperitoneally injected with 40 mg/kg STZ after being fed a high-fat diet for 8 weeks. One week after STZ injection, 100 or 200 mg/kg curcumin was administered orally to the diabetic rats for 16 weeks. Histological changes in the testes were determined by HE staining. Serum testosterone was measured. Markers of superoxide levels, such as SOD activity and MDA content, and markers of cell death, including the expression of Bax, Bcl-2, and MAPK family members, were measured by molecular biology or immunohistochemical techniques. Degeneration and disruption of seminiferous tubule structure were observed in diabetic rats. Serum testosterone levels were markedly lower in diabetic rats than in control rats. Moreover, testicular apoptosis and Bax expression were much higher in diabetic rats than in control rats. Superoxide generation, the NADP + /NADPH ratio, and NADPH oxidase subunit expression, including expression of the gp91 phox , p47 phox , and p67 phox subunits, increased, while antioxidant enzyme levels decreased in diabetic rats. Furthermore, the MAPK signaling pathway was activated in diabetic rats. Curcumin partially prevented diabetes-induced microstructural abnormalities and significantly increased serum testosterone levels compared to untreated T2DM rats. Additionally, curcumin reduced testicular apoptosis by regulating apoptotic proteins and markedly inhibited oxidative stress levels by downregulating MDA expression, decreasing NADPH activity, and restoring antioxidant enzymes. Remarkably, curcumin treatment also suppressed MAPK activation. Thus, curcumin may have therapeutic value in the treatment of diabetes-induced testicular injury due to its prevention of testicular apoptosis and attenuation of oxidative stress.