Natural products against cisplatin-induced male reproductive toxicity: A comprehensive review.

Cisplatin is widely used as one of the most effective anticancer agents in the treatment of some neoplasms. Reproductive toxicity is the most common outcome associated with cisplatin testicular damage. Alternative natural medicines for treating male testicular disorders and infertility have received extensive attention in research. Natural products, medicinal herbs, and their secondary metabolites have been shown as promising agents in the management of testicular damage induced by chemotherapy drugs. This study aimed to review the research related to natural substances that are promising in mitigation of the cisplatin-induced toxicity in the reproductive system. PubMed and Scopus were searched for studies on various natural products for their potential protective property against reproductive toxicity induced by cisplatin from 2000 to 2020. Eligibility was checked based on selection criteria. Fifty-nine articles were included in this review. Mainly in animal studies, several natural agents have positively affected cisplatin-reproductive-toxicity factors, including reactive oxygen species, inflammatory mediators, DNA damage, and activation of the mitochondrial apoptotic pathway. Most of the natural agents were investigated in short-term duration and high doses of cisplatin exposure, considering their antioxidant activity against oxidative stress. Considering antioxidant properties, various natural products might be effective for the management of cisplatin reproductive toxicity. However, long-term recovery of spermatogenesis and management of low-dose-cisplatin toxicity should be considered as well as the bioavailability of these agents before and after treatment with cisplatin without affecting its anticancer activity.

Ameliorative Potential of Hydroethanolic Leaf Extract of Parquetina nigrescens on d-Galactose-Induced Testicular Injury.

BACKGROUND: There is an increasing need for botanicals to be used as an alternative and complementary medicine in the management of male infertility. Male infertility has been a major health/social challenge to people all over the world. This study, therefore, investigated the ameliorative potential of hydroethanolic leaf extract of Parquetina nigrescens (HELEPN) against d-galactose-induced testicular injury. METHODS: Thirty male Wistar rats were randomly allotted into six groups (n = 5). Group I (Normal control), Group II (300 mg/kg b.w. d-galactose), Group III and IV (250 and 500 mg/kg b.w. HELEPN, respectively), Group V and VI (both received 300 mg/kg b.w. of d-galactose with 250 and 500 mg/kg b.w of HELEPN, respectively). d-galactose administration started two weeks prior to HELEPN treatment which lasted for six weeks. All assays were carried out using established protocols. RESULTS: Administration of HELEPN at 250mg/kg and 500mg/kg concomitantly with d-galactose improved paired and relative testicular weights, levels of gonadotropins (LH and FSH) and testosterone, and poor sperm quality. HELEPN treatment reduced the levels of oxidative stress biomarkers (MDA, 8-OHDG, and AGEs) and inflammatory response (TNF-alpha and NO) to normal, as well as restoring the reduced activities of antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase). In addition, HELEPN treatment mitigated testicular DNA fragmentation and down-regulated caspase 3-activities. HELEPN at 500 mg/kg was observed to have the greatest ameliorative effect. CONCLUSION: HELEPN protects against d-galactose-induced testicular injury through antioxidative, anti-inflammatory, and antiapoptotic mechanisms.

Role of nitric oxide donor in methotrexate-induced testicular injury via modulation of pro-inflammatory mediators, eNOS and P-glycoprotein.

Methotrexate (MTX) is a widely used chemotherapeutic agent but its clinical use is challenged with different forms of toxicities including testicular injury. The aim of the current study was to evaluate the potential protective effect of potassium channel opener, nicorandil (NIC) (3 and 10 mg/kg/day) on MTX-induced testicular injury in a rat model. Rats were randomly divided into four groups (nine rats each) and treated for 2 weeks as follows: (I) normal control (CON group) received vehicle, (II) model group (MTX group) given MTX (20 mg/kg) single intraperitoneal (i.p.) injection dose on 11th day, (III) MTX + NLD group treated with NIC (3 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. dose on 11th day, and (IV) MTX + NHD group treated with NIC (10 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. injection on the 11th day. The testicular injury was assessed biochemically via serum testosterone, total antioxidant capacity, testicular oxidative stress parameters, P-glycoprotein, tumor necrosis factor-alpha, and interleukin-1ß. Furthermore, histopathological evaluation, endothelial nitric oxide synthase (eNOS) immunoexpression, and detection of p53 expression level using Western blotting were performed. Results showed that MTX induced testicular injury which was proved by both biochemical and histopathological evaluations. Our results concluded that NIC pretreatment attenuated MTX-induced testicular injury via significantly increased eNOS immunoexpression, antiapoptotic, anti-inflammatory, and antioxidant properties. Interestingly, NIC high dose is more protective than low dose.

Investigating the sperm parameters, oxidative stress and histopathological effects of salvia miltiorrhiza hydroalcoholic extract in the prevention of testicular ischemia reperfusion damage in rats.

AIMS: One of the most common urologic emergencies is spermatic cord torsion, which can damage testicular tissue and reduce fertility. Salvia miltiorrhiza (SM) hydroalcoholic extract possess high antioxidant properties, and its efficacy in ischemia-reperfusion (I/R) injury prevention has been demonstrated in cardiac, renal, and liver tissues. Therefore, the purpose of this study was to assess the protective mechanism of SM extract on testicular I/R damage. MAIN METHODS: 18 mature male Wistar albino rats were randomly divided into 3 groups; with six rats in each group: Group 1 (Sham) was sham-operated. Group 2 (T-D): torsion was performed, and after 2 hours (h) detorsion was done. Group 3 (SM): (200 mg kg-1) SM was intraperitoneally injected thirty minutes before detorsion. Then testicular and epididymal weight and size alterations, sperm parameters (motility, livability, concentration, and morphology), both plasma and testicular tissue levels of malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) were evaluated. Also, histopathological changes included mean seminiferous tubular diameter (MSTD), testicular capsule thickness (TCT), mean testicular biopsy scoring (MTBS), and germinal epithelial cell thickness (GECT) were examined. RESULTS: Testicular I/R significantly reduced sperm motility, viability, and normality, while SM extract administration remarkably increased sperm motility, and normality (P < 0.05). Induction of testicular T-D caused a significant increment in the level of MDA and notable decline in the levels of GPX, CAT, and TAC both in plasma and testis tissue, whereas administration of SM extract significantly decreased MDA level and increased GPX, CAT, and TAC levels in plasma and testicular tissue (P < 0.05). Histopathological parameters including MSTD, GECT, MTBS, and TCT were significantly lower in the T-D group, while pretreatment with SM extract remarkably increased MSTD, GECT, and MTBS amounts (P < 0.05). CONCLUSION: Since the SM extract increased the activity of antioxidant enzymes, improved sperm parameters and reduced the damage to testicular tissue, therefore, its use as a potent antioxidant in reducing testicular I/R damage is suggested.

A Chinese herbal prescription Yiqi Jiedu decoction attenuates irradiation induced testis injury in mice.

OBJECTIVE: Yiqi Jiedu (YQJD) decoction is a Chinese herbal prescription, based on an experienced expert of traditional Chinese medicine. It is used for the injuries caused by radiotherapy. The current study was designed to investigate the protective effects of YQJD decoction on radiation damage of testis in mice, and to explore its potential mechanisms. METHODS: Mice were randomly divided into blank control group (Ctrl), model group (IR), positive drug group (IRA), and YQJD decoction group (IRY). After 10-day period intervention, they were whole-body irradiated with 2 Gy 60Co γ-rays and sacrificed on 7th day after irradiation. The indicators including the index and histopathology examination of testis, spermatogenic cell types and apoptosis, and the expression of TLR5, MyD88, NF-κB, TNF-α, IL-6 and Bcl-2 in testis. RESULTS: The testis atrophied significantly on 7th day of exposure to radiation, while YQJD decoction promoted the recovery of testis index and structure. Moreover, spermatogenic cell types and apoptosis had significant changes after irradiation. YQJD decoction protected the testicular function of spermatogenesis, as while as reduced the apoptosis rate of spermatogenic cells. In addition, RT-PCR and immunohistochemical analysis showed that YQJD decoction up-regulated the expression of TLR5 in testis. The levels of TLR5's downstream factors were also up-regulated in YQJD decoction group, which indicated that TLR5 signaling pathway might play an important role in the protective effects of YQJD decoction. CONCLUSIONS: The results showed that YQJD decoction attenuated irradiation induced testis injury in mice. Its potential mechanism was related to TLR5 signaling pathway.

Ameliorative effects of Spirulina maxima and Allium sativum on lead acetate-induced testicular injury in male albino rats with respect to caspase-3 gene expression.

The present study was conducted to evaluate the ameliorative effects of Allium sativum (garlic) as well as Spirulina maxima on lead acetate toxicity in rat testes. Forty adult, male, albino rats were divided into four groups (10 rats/each): group I served as the control; group II contained rats that received lead acetate (100 mg/kg); group III contained rats that received both lead acetate (100 mg/kg) and garlic (600 mg/kg); and group IV contained rats that received both lead acetate (100 mg/kg) and spirulina (500 mg/kg). All treatments were performed daily for one month. Serum testosterone levels, oxidative stress parameters, expression of the caspase-3 gene and histological, histo-morphometric and ultrastructure alterations in the testes were investigated. The results revealed that the Pb-treated group exhibited a significant increase in MDA concentration concomitantly with a decrease in serum testosterone levels, antioxidative marker levels and caspase-3 gene expression. Several histological and histo-morphometric alterations were observed in this group. Co-administration with spirulina or garlic caused a significant increase in testosterone levels, testicular SOD and CAT activities, and caspase-3 gene expression and a decrease in MDA levels, with improvement in histological and histo-morphometric alterations. These results suggested that spirulina was more effective at providing protection against Pb-induced reproductive damage in rats than garlic, indicating the beneficial role of spirulina in improvement of spermatogenesis and steroidogenesis after lead exposure.

Cyanidin-3- O-glucoside at Low Doses Protected against 3-Chloro-1,2-propanediol Induced Testis Injury and Improved Spermatogenesis in Male Rats.

In recent decades, the capability of mankind spermatogenesis is declining due to various threats. Anthocyanins as colorful polyphenols possess beneficial functions for the organisms, including Leydig cells, but their effects on male spermatogenesis remain underexplored. In our study, the protective effect of cyanidin-3- O-glucoside (C3G) was investigated on the 3-chloro-1,2-propanediol (3-MCPD) caused rat spermatogenic disorders. At low doses, C3G improved the number and motility of the sperms, alleviating the seminiferous tubule injury. Interestingly, C3G showed no influence on sexual hormone but increased the androgen receptor expression. Meanwhile, C3G reduced the oxidative stress and number of apoptotic cells and promoted the integrity of the blood-testis barrier in the testis. Additionally, C3G mediated the activation of p-ERK, p-JNK, and p53, which are related to the protection of Sertoli cells and spermatogenesis. In conclusion, C3G protected against the 3-MCPD caused testis damage and spermatogenic disorders under appropriate doses, which indicates the potential protection of anthocyanins on male reproduction.

Cilostazol alleviates streptozotocin-induced testicular injury in rats via PI3K/Akt pathway.

AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4 weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-κB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed. KEY FINDINGS: Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-κB level by both drugs. SIGNIFICANCE: Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects.

Rosemary extract modulates fertility potential, DNA fragmentation, injury, KI67 and P53 alterations induced by etoposide in rat testes.

Etoposide is a semi-synthetic compound derived from the plant podophyllum pelltatum and are antineoplastic agents long been used for treatment of human malignancies. The present study was conducted to examine the possible modifying effects of rosemary aqueous extract against sperm abnormalities, testes injury, DNA fragmentation, apoptosis and Ki67 alterations induced by Etoposide in male rats. A total of 50 adult male rats were divided into 5 groups (1st, control; 2nd, rosemary; 3rd, Etoposide; 4th, co-treated Etoposide with rosemary; 5th, post-treated Etoposide with rosemary). Sperms counts, motility and viability and KI67 immunoreactivity in testes were significantly decreased while; sperm abnormalities, testicular injury, P53 and DNA damage were a significantly increased in Etoposide group as compared to control group. Co-administration of rosemary with Etoposide improved the sexual toxicity, fertility potential, testicular injury, KI67, P53 and DNA damage induced by Etoposide. Etoposide treatment induced depletion in counts, motility and viability of rat sperms. Etoposide treatment induced testicular DNA damage, injury and decreased in KI67 and P53 expressions. Treatment with rosemary with Etoposide improved these alterations.

Effect of Zinc and Melatonin on Oxidative Stress and Serum Inhibin-B Levels in a Rat Testicular Torsion-Detorsion Model.

The present study was aimed to examine the effects of 3-week zinc and melatonin administration on testicular tissue injury and serum Inhibin-B levels caused by unilateral testicular torsion-detorsion in rats. The study was performed on 60 Wistar Albino-type adult male rats. The animals were allocated to 6 groups in equal numbers. 1. Control; 2. Sham; 3. Ischemia-reperfusion; 4. Zinc + ischemia-reperfusion; 5. Melatonin + ischemia-reperfusion; 6. Zinc + melatonin + ischemia-reperfusion. Zinc and melatonin were administered before ischemia-reperfusion at doses of 5 and 3 mg/kg respectively, by intraperitoneal route for a period of 3 weeks. Testicular torsion-detorsion procedures consisted of ischemia for 1 h and then reperfusion for another hour of the left testis. Blood and testicular tissue samples were collected to analyze erythrocyte and tissue GSH and plasma and tissue MDA, Inhibin-B levels. The highest erythrocyte and testis GSH values were found in zinc, melatonin, and zinc + melatonin groups (p < 0.001). Torsion-detorsion group has significantly lower erythrocyte GSH levels and higher plasma MDA values (p < 0.001). Serum inhibin-B and spermatogenic activity levels in the torsion-detorsion group were also significantly lower than those in the other groups (p < 0.001). However, zinc-, melatonin-, and melatonin + zinc-supplemented groups have higher inhibin-B and spermatogenetic activity (p < 0.001). The results of the study show that zinc, melatonin, and melatonin + zinc administration partially restores the increased oxidative stress, as well as the reduced inhibin-B and spermatogenic activity levels in testes ischemia-reperfusion in rats. Suppressed inhibin-B levels in the testicular tissue may be a marker of oxidative stress.