Cisplatin-induced Testicular Toxicity Research Articles

Mitigative Effects of l-Arginine and N-Acetyl Cysteine against Cisplatin-Induced Testicular Dysfunction and Toxicity through the Regulation of Antioxidant, Anti-inflammatory, and Antiapoptotic Markers: Role of miR-155 and miR-34c Expression

Mitigative Effects of <scp>l</scp>-Arginine and N-Acetyl Cysteine against Cisplatin-Induced Testicular Dysfunction and Toxicity through the Regulation of Antioxidant, Anti-inflammatory, and Antiapoptotic Markers: Role of miR-155 and miR-34c Expression

Testicular toxicity in cisplatin-treated Wistar rats is mitigated by Daflon and associated with modulation of Nrf2/HO-1 and TLR4/NF-kB signaling

BackgroundTesticular toxicity is a complication of cisplatin therapy and it limits its use. Since cisplatin-induced testicular damage is mediated by inflammation and oxidative stress, evaluation of the protective role of antioxidant and anti-inflammatory molecules such as micronized purified flavonoid fraction (Daflon®) is pertinent. Aim: Therefore, this study investigated the mitigating effect of daflon against cisplatin-induced testicular toxicity. Also, the impact of daflon on Nrf2/HO-1 and TLR4/NF-kB pathways, which are key pathways in cisplatin toxicity, was explored. Materials and methods: After 2 weeks of acclimatization, 20 male albino Wistar rats were allotted at random into 4 equal groups; control, daflon-treated, cisplatin-treated, and cisplatin+daflon-treated. Results: Daflon significantly restored cisplatin-induced reductions in body weight (112.20±9.01 vs. 129.60±5.68, P= 0.0175), body weight gain (-39.80±9.52 vs. -16.80±16.53, P= 0.0154), and testicular weight (1.69±0.08 vs. 1.95±0.13, P= 0.0980) and alterations in testicular histology. In addition, daflon abrogated cisplatin-induced rise in testicular CK (55.53±2.77 vs. 37.40±3.29, P< 0.0001) and LDH (74.52±3.20 vs. 65.89±2.08, P= 0.0009) activities, and lactate content (180.50±4.19 vs. 166.20±2.78, P< 0.0001). Also, daflon alleviated cisplatin-induced suppression of GnRH (5.09±0.60 vs. 10.17±0.51, P< 0.0001), LH (1.33±0.07 vs. 2.77±0.13, P< 0.0001), FSH (0.51±0.10 vs. 1.82±0.09, P< 0.0001), and testosterone (2.39±0.11 vs. 4.70±0.33, P< 0.001) as well as lowered sperm quality. More so, daflon attenuated cisplatin-induced testicular oxidative stress, inflammation, and apoptosis evidenced by daflon-driven suppression of MDA (14.16±0.66 vs. 9.22±0.52, P< 0.0001), TNF-α (79.42±5.66 vs. 54.13±3.56, P< 0.0001), IL-1β (8.63±0.41 vs. 3.37±0.43, P< 0.0001), IL-6 (6.87±0.48 vs. 3.67±0.32, P< 0.0001), and caspase 3 activity (4.20±0.26 vs. 0.72±0.23, P< 0.0001) and DNA fragmentation (34.60±3.05 vs. 17.20±3.19, P< 0.0001), and upregulation of GSH level (0.07±0.03 vs. 0.36±0.03, P< 0.0001), and GPx (5.96±0.46 vs. 11.88±1.05, P< 0.0001), GST (5.16±0.71 vs. 11.50±0.81, P< 0.0001), SOD (1.29±0.15 vs. 2.81±0.29, P< 0.0001), and catalase activities (6.18±0.69 vs. 10.71±0.74, P< 0.0001). Furthermore, daflon upregulated testicular Nrf2 expression (40.25±2.65 vs. 66.62±4.01, P< 0.0001) and HO-1 (4.18±0.56 vs. 8.79±0.55, P< 0.0001) activity but downregulated TLR4 (11.63±0.89 vs. 7.23±0.43, P< 0.0001) and NF-kB levels (113.20±3.36 vs. 78.22±3.90, P< 0.0001) in cisplatin-treated rats. Conclusion: Collectively, the ameliorative effect of daflon on cisplatin-induced testicular toxicity is associated with inhibition of oxidative stress and TLR4/NF-kB-mediated inflammatory pathways and activation of Nrf2/HO-1 signaling.

Protective effect of dental pulp stem cells' conditioned medium against cisplatin-induced testicular damage in rats

Cisplatin is a highly effective chemotherapy drug used to treat most solid tumors. However, one of its side effects is testicular toxicity, which can lead to fertility abnormalities. This study investigated the effectiveness of dental pulp mesenchymal stem cells conditioned medium (DPSC-CM) on cisplatin-induced testicular toxicity. In this study, 36 eight-week-old male Wistar rats were randomly divided into three groups equally (n = 12). Group 1 control "CTR", which received normal saline (0.5 ml) intraperitoneally (i.p), group 2 "Cis" which received an intraperitoneal dose of cisplatin (7 mg/kg), and group 3 "Cis+CM" which received an i.p injection of DPSC-CM (0.5 mg/kg) after cisplatin injection. Biochemical, histomorphometric, and histopathological studies were performed on the testis. Our results exhibited that cis administration led to a decline in total body weight, testis weight, diameter, and volume. A decrease in testosterone and IL-6 serum levels, as well as a decrease in IL-6 and TNFα levels, the activity of catalase and SOD enzymes, and an increase in MDA in testicular tissue were detected. Testicular tissue damage was associated with a significant decrease in tube diameter, germinal epithelium height, number of spermatogonia and Sertoli cells, along with a noticeable increase in basement membrane thickness, and perivascular fibrosis. DMSC-CM improved all the mentioned parameters. Taken together, our results demonstrated that DMSC-CM due to its antioxidant and anti-inflammatory properties, could be effective in reversing cisplatin-induced testicular toxicity.

Pioglitazone ameliorates cisplatin-induced testicular toxicity by attenuating oxidative stress and inflammation via TLR4/MyD88/NF-κB signaling pathway

BackgroundCisplatin (CIS) is a chemotherapeutic agent widely used to cure several cancers. It exerts detrimental cellular effects that restrain its clinical application as an antineoplastic agent, as testicular damage. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is used to treat type-2 diabetes mellitus. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. The present study aimed to investigate the effect of PIO in a rat model of cisplatin-induced testicular toxicity and address the possible role of the Toll-like receptors (TLR4) / myeloid differentiation factor 88 (MyD88) / nuclear factor-kappa B (NF-kB) signal pathway. MethodsRats received a single dose of cisplatin (7 mg/kg, IP) on the first day and PIO (10 mg/kg, P.O.) for 7 days. At the end of the treatment period, rats were killed. Testicular weights, histopathological alterations, and serum testosterone levels were determined. Moreover, tissue samples were collected for the estimation of oxidative stress parameters, inflammatory markers, and the determination of TLR4 /MyD88/NF-kB signaling. ResultsConcurrent PIO administration with CIS markedly improved testicular weights, histopathological alteration, and serum testosterone level changes. Moreover, Concurrent PIO administration abrogated oxidative stress status and inflammatory markers caused by CIS administration. Furthermore, PIO inhibited the expression levels of TLR4, MyD88, and NF-κBp65, proteins that are activated by CIS administration. Conclusion: These findings suggested that PIO can protect against cisplatin-induced testicular toxicity in rats through inhibition of the TLR4 /MyD88/NF-kB signal pathway.

Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways.

Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa β, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.

Pomegranate nanoparticle mitigates cisplatin-induced testicular toxicity and improves cisplatin anti-cancer efficacy in Ehrlich carcinoma model

Cisplatin (CISP) ranks among the most used chemo-therapeutic agents with exceptional efficacy against testicular cancer among other diverse types of cancers. However, it has been associated with nephrotoxicity among other side effects. Pomegranate (PE) is an effective anti-inflammatory and antioxidant compound, protecting against several chemotherapy-linked toxicities. The use of PE are limited due to its low bioavailability and poor solubility. We investigated the potential of a novel nanoparticle (NP) encapsulating PE formulation to surmount its poor solubility, improve its bioavailability, and augment its protective efficacy against CISP-induced testicular toxicity in an Ehrlich solid carcinoma (ESC) mice model. All animals were randomly grouped into four treatment groups: 1) control, 2) tumor, 3) CISP, and 4) CISP + PE-NPs. The results obtained demonstrated that PE-NPs efficiently prevented testicular toxicity induced by CISP in ESC mice and enhanced its functions. PE-NPs effectively improved CISP-induced oxidative stress in testicular tissues by elevating the levels of antioxidants (GSH, SOD and CAT). Importantly, PE-NPs, also, substantially decreased testicular inflammation induced by CISP, via reducing the levels of IL-1β, TNF-α, and NF-kB. PE-NPs did not impede the CISP’s antitumor activity as shown by histological examination data and tumor weight. It is, therefore, conceivable that PE-NPs may serve as an adjuvant therapy to CISP in the treatment of cancer, to ameliorate the associated testicular toxicity and other unwanted effects without compromising the antitumor efficacy of CISP.

The Mechanistic Perspective of Bilobetin Protective Effects against Cisplatin-Induced Testicular Toxicity: Role of Nrf-2/Keap-1 Signaling, Inflammation, and Apoptosis.

Cisplatin (CP) is a productive anti-tumor used to treat numerous tumors. However, multiple toxicities discourage prolonged use, especially toxicity on the reproductive system. This experiment was mapped out to determine the potential therapeutic impact of Bilobetin on CP-induced testicular damage. Herein, Bilobetin was isolated from Cycas thouarsii leaves R. Br ethyl acetate fractions for the first time. A single dose of CP (7 mg/kg, IP) was used to evoke testicular toxicity on the third day. Rats were classified into five groups; Normal control, Bilobetin 12 mg/kg, Untreated CP, and CP treated with Bilobetin (6 and 12 mg/kg, respectively) orally daily for ten days. Bilobetin treatment ameliorated testicular injury. In addition, it boosted serum testosterone levels considerably and restored relative testicular weight. Nevertheless, apoptosis biomarkers such as P53, Cytochrome-C, and caspase-3 decreased significantly. Additionally, it enhanced the testes’ antioxidant status via the activation of Nrf-2, inhibition of Keap-1, and significant elevation of SOD activity in addition to a reduction in lipid peroxidation. Histopathologically, Bilobetin preserved testicular architecture and improved testicular immunostaining of Ki67 substantially, showing evidence of testicular regeneration. Bilobetin’s beneficial effects on CP-induced testicular damage are associated with enhanced antioxidant effects, lowered apoptotic signals, and the restoration of testes’ regenerative capability. In addition, Bilobetin may be used in combination with CP in treatment protocols to mitigate CP-induced testicular injury.

Impact of Resveratrol in Attenuating Cisplatin Induced Testicular Toxicity in Male adult Rats

Background and Objective: Resveratrol is a poly-hydroxyphenol plant toxin that alleviates oxidative stress by increasing endogenous antioxidant levels and prevents tissue damage. The study aimed to investigate the anti-oxidative role of Resveratrol by histochemical, ultrastructural, and biochemical methods in Cisplatin-induced testicular toxicity in Wistar Albino rats.&#x0D; Material and Methods: Quasi-experimental study was conducted at the Department of Pharmacology, Anatomy and Postgraduate Laboratory of ISRA University Hyderabad from October 2020 to March 2021. Twenty-four male, normal adult Wistar albino rats were recruited and distributed equally into; Group-A (Control), Group-B (Experimental group or Cisplatin group), Group-C (Experimental group or Cisplatin + Resveratrol combination group). Pre and post-experimental body weight, analysis of oxidative markers, semen parameters, and histomorphology were carried out in all three groups. SPSS version 24.0 was used for the analysis of Data.&#x0D; Results: A statistically significant decline in the body weight and testicular weight in group B and C respectively (p&lt;0.05). While reduction in sperm count, motility and viability was observed in Group-B compared with Group-C (p&lt;0.05). Oxidative markers were also significantly depleted in Group-B in comparison to Group-C (p&lt;0.05). Evident changes were observed in the testicular histology of Group-B compared with Group-C (p&lt;0.05). Irregular, regressive, and atrophic seminiferous tubules were seen in Group-B. Most seminiferous tubules having normal morphology were observed in Group-C while the number of atrophic and degenerative seminiferous tubules also decreased significantly. &#x0D; Conclusion: Resveratrol is a potent protective agent with promising results in attenuating cisplatin-induced oxidative stress and eventually testicular toxicity.

Sinapic acid ameliorates cisplatin-induced disruptions in testicular steroidogenesis and spermatogenesis by modulating androgen receptor, proliferating cell nuclear antigen and apoptosis in male rats.

The chemotherapeutic cisplatin, which is widely used in many cancer types, causes testicular toxicity. Sinapic acid has many therapeutic effects such as antioxidant, anti-inflammatory and antihyperglycaemic. This study aimed to investigate the improving effects of sinapic acid in cisplatin-induced testicular toxicity. Twenty-eight rats were distributed into 4groups. Control group: saline was applied intraperitoneal. Cisplatin group: A single dose of 7mg/kg of cisplatin was injected into rats. Cisplatin +Sinapic acid group: 3days after a single dose of 7mg/kg cisplatin was injected, 25mg/kg of sinapic acid was given for 7days. Sinapic acid group: rats were received 25mg/kg/day of sinapic acid. Numerical density of spermatogonium, Leydig and volume density of germinal epithelial were calculated. Caspase-3, Bcl-2, AR and PCNA expressions in testis were evaluated and testosterone and LH levels were measured. Cisplatin application decreased the numerical density of spermatogonium and Leydig, volume density of germinal, epididymal sperm count, testosterone, LH and the expressions of Bcl-2, AR and PCNA in testis. However, sinapic acid treatment significantly restored the parameters of our study. The results of the present study revealed that cisplatin can cause male reproductive toxicity and sinapic acid can have improving effects against cisplatin-induced male reproductive toxicity.

The ameliorative effects of Alpinia officinarum rhizome hydroalcoholic extract on cisplatin-induced testicular toxicity in rats.

In this study we evaluated the influence of Alpinia officinarum rhizome extract (AO) on the alleviation of testicular damage induced by cisplatin in rats. The study groups included the control group, AO-administered group, cisplatin-administered group, and three groups administered with cisplatin and AO (different concentrations of 100, 200, and 400 mg/kg). On the 14th day we removed the testes of the rats, and the testicular organ parameters were measured. Moreover, through the malondialdehyde concentration we assessed the oxidative stress and superoxide dismutase (SOD) activity of the testes and ran a histopathological analysis. The results demonstrated that cisplatin-induced oxidative stress and severe testicular damage on the AO-administered group showed no harm compared with the control group. AO- treatment in cisplatin-received rats led to the reduction of oxidative stress, enhancement of SOD activity, and prevention of testicular damage. The lowest testis damage was attributed to the group which received 400 mg/kg of AO compared to 100 and 200 mg/kg. Overall, the Cis+/AO+400 group had the best antioxidant effect. The findings could lead to changes in cancer care guidelines that incorporate phytochemicals, making cancer therapies safer.

The Effect of Selenium Nanoparticles versus Royal Jelly against Cisplatin-Induced Testicular Toxicity in Adult Male Albino Rats: A Light and Transmission Electron Microscopic Study.

Cisplatin (Cis) is a highly effective chemotherapeutic agent. However, it produces severe testicular toxicity. It was reported that some antioxidants could overcome this toxicity. Selenium nanoparticles and royal jelly (RJ) were among these reported antioxidants. Therefore, this study was designed to compare these two antioxidants in protecting the testes against Cis-induced toxicity. This study was conducted on sixty healthy adult male albino rats (weight: 200-220 g) randomized into six groups, ten animals each. Group I (control), Group II (animals received intragastric Nano Selenium), Group III (animals received intragastric RJ), Group IV (animals received an IP injection of Cis 7 mg/kg), Group V (animals received intragastric Nano Selenium, and Cis injection), and Group VI (animals received intragastric RJ and Cis injection). After 10 days, the animals were sacrificed by cervical decapitation. The testes were weighted, and specimens from the left testis were processed for histological and immunohistochemical techniques, whereas specimens from the right testes were prepared for transmission electron microscopic examination. Cis-treated animals had significantly reduced weight of their testes. Light microscopic examination revealed severe histopathological changes in the germinal epithelium and Leydig cells, confirmed with electron microscopic examination. There was a significant increase in the color area percentage of Caspase-3 immunostaining of the germinal epithelium and Leydig cells, compared to that of the control group. Group II and III were similar to control group. Both Groups V and VI revealed significant preservation compared to the Cis group. Selenium nanoparticles and RJ partially improved testis from Cis-induced toxicity, However, there was no significant difference between both groups.

Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-κB-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling

Cisplatin (CIS)-induced testicular injury is a major obstacle in its application as antineoplastic agent. In this study, we investigated the protective effect and mechanism of roflumilast (ROF), a PDE4 inhibitor, against CIS-induced testicular toxicity in rats. Besides, the cytotoxic effect of CIS, with and without ROF, was evaluated on PC3 cell line. ROF reversed CIS-induced abnormalities in sperm characteristics, normalized serum testosterone level, and ameliorated CIS-induced alterations in testicular and epidydimal weights and restored normal testicular structure. Moreover, ROF increased intracellular cAMP level, PKA and HO-1 activities and Nrf2, NQO-1 and HO-1 gene expression, improved testicular oxidative stress parameters (TBARS, NO, GSH levels, and CAT activity) and inflammatory mediators (IL-1β and TNF-α, and NF-κβ p65gene expression) and reduced the proapoptotic proteins, caspase-3, Bax and increased Bcl-2. Lastly, in vitro analyses showed that ROF augmented the anticancer efficacy of CIS and enhanced the increase in gene expression of Nrf2, HO-1, and NQO-1 and the inhibition of gene expression of NF-κβ p65 induced by CIS and enhanced its apoptotic effect in PC3 cells. Conclusively, PDE4 inhibition with induction of Nrf2/HO-1, NQO-1 is a potential therapeutic approach to protect male reproductive system from the detrimental effects with augmenting, the antineoplastic effect of CIS.

The novel role of resveratrol in attenuating cisplatin induced testicular toxicity in rats.

Objectives: To evaluate the anti-oxidative role of Resveratrol in Cisplatin-induced testicular toxicity in Albino Wistar rats. Study Design: Quasi-experimental study. Settings: Department of Physiology and Postgraduate Laboratory of ISRA University Hyderabad. Period: Six months from March to September 2019. Material &amp; Methods: Twenty-four male albino Wistar rats were distributed equally into; Group-I (Control), Group-II (Cisplatin), Group-III (Cisplatin + Resveratrol). Difference in mean pre and post-experimental body weight was observed while analysis of oxidative markers, semen parameters, and histomorphology was carried out in all three groups. SPSS ver. 22 was used to analyze the data. Results: The mean body weight decreased from 241.7±8.5 gm to 196.50±9.34 gm and from 237±7.4 gm to 210.0 ± 6.50gm in groups II and III respectively. Statistically significant reduction in semen parameters (sperm count, motility and viability) was observed in Group-II compared with Group-C (p&lt;0.05). Oxidative markers were also significantly depleted in Group-II in comparison to Group-C (p&lt;0.05). Histologically, testicular structure was found to be intact in Group-I. Marked changes were observed in testicular histology of Group-II while Group-III displayed less testicular damage. Irregular, regressive and atrophic seminiferous tubules were seen in Group-II. Most seminiferous tubules having normal morphology were observed in Group-III while the number of atrophic and degenerative seminiferous tubules also decreased significantly. Conclusion: Resveratrol therapy is a potent protective regime showing promising results in cisplatin-induced testicular toxicity and oxidative stress.

Microwave-assisted synthesized zinc nanoparticles attenuate cisplatin-induced testicular toxicity in mice

The purpose of this study was to investigate the protective effects of zinc nanoparticles against cisplatin-induced testicular toxicity in mice. Zinc nanoparticles were produced by microwave-assisted synthesis using Lavandula vera extract as reducing agent. Single doses of cisplatin (7 mg/kg, intraperitoneally) and ZnSO4 (10 mg/kg, orally), and various doses of zinc nanoparticles (10 − 50 mg/kg, orally) and vitamin E (100 mg/kg, interaperitoneally) were administered. The protective role of zinc nanoparticles was determined biochemically and histologically. Gradual reduction in malondialdehyde levels and elevation in glutathione levels and in the activities of superoxide dismutase and catalase upon administration of zinc nanoparticles were observed. The pathology of mice treated with cisplatin/vitamin E and cisplatin/zinc nanoparticles were apparently equal, but vitamin E treatment was more effective in lowering oxidative stress markers than zinc nanoparticles. These findings suggest that co-administration of zinc nanoparticles with cisplatin could prevent adverse effects on the male reproductive system via their potential antioxidant properties.

Possible Protective Effects of Curcumin via Modulating of Androgen Receptor (AR) and Oct2 Gene Alterations in Cisplatin-Induced Testicular Toxicity in Rat.

Cisplatin is a chemotherapeutic drug used to treat testicular cancer that induces testicular toxicity. This study aimed to investigate the possible role of androgens, androgen receptor, and organic cation transporter 2 (OCT2) in the protective effects of curcumin on cisplatininduced testicular toxicity. Thirty male Wistar rats were divided into five groups: 1- control (normal saline, 0.5 ml ip, daily for 10 consecutive days); 2- cisplatin (10 mg/kg ip, single dose at the first day); 3- cisplatin + curcumin (10 mg/kg ip, dissolved in 5% DMSO, daily for 10 consecutive days); 4- cisplatin + vehicle (DMSO 5%, 0.3 ml ip); and 5- curcumin (10 mg/kg ip). At the end of the study, a blood sample was obtained for testosterone measurement. The left testis was kept at -80. to measure androgen receptor (AR) and type 2 organic cation transporter (OCT2) gene expression and the right testis were kept in 10% formalin for histological analysis. Cisplatin significantly decreased serum testosterone, declined testis AR gene expression, and increased OCT2 gene expression in testis (p<0.01). Curcumin treatment significantly prevented these alterations in testosterone and gene expressions (p<0.01). Moreover, curcumin significantly reversed the cisplatin-induced kidney tissue injury and increased spermatid and spermatozoa. It is concluded that the ameliorative effect of curcumin in cisplatin-induced reproductive disorders was due to the modulation of testosterone and androgen receptors.

Assessment of the effect of sodium hydrogen sulfide (hydrogen sulfide donor) on cisplatin-induced testicular toxicity in rats.

Cisplatin (CIS) is an antineoplastic drug able to produce free radicals that are capable to induce various side effects in different tissues. Hydrogen sulfide (H2S) has notable antioxidant, anti-apoptotic, and anti-inflammatory effects in different systems but its role in male reproductive system is not fully understood. In the present research, the effect of sodium hydrosulfide (NaHS) on cisplatin-induced testicular toxicity in male rats was studied. Thirty-two Sprague-Dawley rats were equally divided into 4 groups. The control group was treated with normal saline by intraperitoneal injection. The NaHS group received NaHS (200μg/kg/day) intraperitoneally for 15days. The CIS group received single dose of cisplatin (5mg/kg) intraperitoneally, while the combination of CIS and NaHS was given to the CIS+ NaHS group. At the end of the study, body and testicular weights, plasma testosterone level, histological and morphometrical alterations, inflammation via IL-1β protein, lipid peroxidation, and activity of antioxidant enzymes (including glutathione peroxidase, superoxide dismutase, and catalase) of testicular tissue were evaluated. CIS injection revealed a significant decrease (p < 0.01) in body and testis weights, plasma testosterone concentration, diameter of seminiferous tubules, germinal epithelium thickness, the number of Sertoli cells, spermatogonia and spermatocyte, Johnsen's testicular score, and testicular antioxidant enzymes, whereas it caused a significant increase (p < 0.01) in lumen diameter of the seminiferous tubules, level of lipid peroxidation, and IL-1β protein expression when compared with the control group. NaHS administration to CIS-treated rats provided marked improvement (p < 0.05) in all biochemical, histological, and morphometrical changes induced by CIS. The beneficial effects of NaHS were mediated, at least partly, by its antioxidant and anti-inflammatory properties.

Candesartan in a rat model of testicular toxicity: New insight on its protective mechanism.

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.

The role of mesenchymal stem cells in chemotherapy-induced gonadotoxicity

BackgroundThe therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) against cisplatin-induced nephrotoxicity has been reported, however, its efficacy in gonadotoxicity still has not been addressed. Herein, we investigated the effect of BM-MSCs in cisplatin-induced testicular toxicity and its underlying mechanism of action.MethodsThirty male Sprague–Dawley rats were divided into a control group: injected with phosphate-buffered saline (PBS) intraperitoneal (ip), a cisplatin group: injected with a single dose of 7 mg/kg cisplatin ip to induce gonadotoxicity and a BM-MSCs group: received cisplatin ip followed by BM-MSCs injection 1 day after cisplatin. In testicular tissues, malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) levels were assessed. Additionally, gene expressions of inducible nitric oxide synthase (iNOS), caspase-3, and p38 mitogen-activated protein kinase (MAPK) were measured. The testicular tumor necrosis factor alpha (TNF-α) protein contents and Bcl-2 associated X protein (BAX) expression were determined. Histopathology of testicular tissues was examined.ResultsCisplatin injection showed a significant decrease in GSH and SOD testicular levels besides a significant increase of MDA and TNF-α testicular levels and upregulation of testicular gene expressions of iNOS, caspase-3, and p38-MAPK in comparison to the control group. Moreover, a marked increase in BAX protein expression was observed in the cisplatin group when compared with the control one. Histopathological examination exhibited significant seminiferous tubules atrophy in cisplatin-treated rats.ConclusionsThe BM-MSCs injection significantly repaired the testicular injury and improved both biochemical and histopathological changes. The MSCs mitigated the gonadotoxicity induced by cisplatin through antioxidative, anti-inflammatory, and antiapoptotic mechanisms.

Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats.

Cisplatin is an effective antineoplastic drug that is usually used to treat a number of different types of cancer in the clinic. One of the most notable side effects of cisplatin use is infertility. The present study was designed to determine the non-oxidative testicular effects caused by the use of cisplatin in rats. The rats were randomly allocated to the experimental groups. The untreated rats represented the control group (group I) and the treatment groups were as follows: cisplatin alone (group II), cisplatin+amifostine (group III), cisplatin+curcumin (group IV), and cisplatin+caffeic acid phenethyl ester (CAPE; group V). The present study observed that following cisplatin administration, the expression of nuclear factor-κB (NF-κβ)/p65, caspase-3 and 8-deoxyguanosine (8-OHdG) increased in germinal epithelium and Leydig cells. However, the expression of these markers decreased in groups III–V, most notably in the group treated with amifostine. cisplatin induced-damage was countered by amifostine and curcumin. The results revealed that the activation of NF-κB, caspase-3 and 8-OHdG had a significant role in cisplatin-induced testicular toxicity. Thus, amifostine, curcumin and, to a lesser extent, CAPE have the potential for use as therapeutic adjuvants in cisplatin-induced testis injury.

Transmembrane BAX Inhibitor Motif-6 (TMBIM6) protects against cisplatin-induced testicular toxicity.

Is the Transmembrane BAX Inhibitor Motif-6 (TMBIM6) involved in the molecular mechanism by which cisplatin causes reproductive toxicity? TMBIM6 protects against cisplatin-induced testicular toxicity through up-regulation of heme oxygenase-1 (HO-1),-which maintains the levels of steroidogenic enzymes by decreaseing oxidative stress in the endoplasmic reticulum (ER). Testosterone production is highly suppressed as a main complication of cisplatin (cis-diamminedichloroplatinum) anticancer therapy. Groups of seven wild type or Tmbim6 KO C57BL/6J mice were given a single i.p., injection of cisplatin (30 mg/kg body wt) and testis and serum were collected 3 days later. Tmbim6-lentivirus-mediated testicular expression-rescued KO mice were analyzed to confirm function was restored. Tmbim6-over expressing TM3 mouse Leydig cells were exposed to cisplatin in vitro. After collection of the specimens serum testosterone level and testicular weight and structure were compared between the groups. Quantitative PCR, immunoblot, and assays for ROS, HO-1 activity and protein disulfide isomerase (PDI) carbonylation were performed. Phospho protein kinase B (p-Akt), nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), and its downstream gene product HO-1 and the levels of testosterone synthesis-associated enzymes, including steroidogenic acute regulatory protein (StAR), a rate limiting enzyme for testosterone production, were significantly expressed in the presence of Tmbim6 and maintained after cisplatin treament. Excessive post-translational oxidation of protein disulfide isomerase (PDI), altered folding capacitance and ROS accumulation, and ER stress were also decreased in the presence of Tmbim6. Higher levels of ER stress and protein hypercarbonylation were consistently observed in KO testis, compared with WT testis. In the Tmbim6 KO mice, lentivirus-mediated testicular expression of Tmbim6 rescued the above phenotypes. Furthermore, the protective role of Tmbim6 against testicular toxicity was consistently shown in Tmbim6-overexpressing TM3 Leydig cells (testosterone producing cells). We conclude that TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 and enhancing ER folding capacitance. N/A. This study was performed using a short, 3-day cisplatin treatment condition. Therefore, the results need to be cautiously interpreted with regard to cisplatin-associated chronic toxicity. Moreover, to determine the clinical relevance of the role of TMBIM6, further studies in testicular cancer are needed. Cisplatin-associated ER stress and redox imbalance might be implicated as toxicity mechanisms associated with anticancer therapy. This study was supported by the National Research Foundation of Korea (2015R1A2A1A13001849). The authors have no competing interests to disclose.