Protective effect of Trillium tschonoskii saponin on CCl4-induced acute liver injury of rats through apoptosis inhibition

2016 ◽  
Vol 94 (12) ◽  
pp. 1291-1297 ◽  
Author(s):  
Hao Wu ◽  
Yong Qiu ◽  
Ziyang Shu ◽  
Xu Zhang ◽  
Renpeng Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Caspase 3 ◽  
Acute Liver Injury ◽  
Protective Role ◽  
High Dose ◽  
Dependent Manner ◽  
Hepatocyte Apoptosis ◽  
Liver Index ◽  
Tnf Α ◽  
Trillium Tschonoskii

To explore hepatoprotective role and underlying mechanisms of Trillium tschonoskii Maxim (TTM), 36 rats were randomly divided into control, CCl4-induced liver injury model, and biphenyl dimethyl dicarboxylate (DDB) and low-, moderate-, and high-dose TTM treatment groups. After CCl4-induced model establishment, the rats from DDB and TTM groups were administrated with DDB at 0.2 g/kg per day and TTM at 0.1, 0.5, and 1.0 g/kg per day, while the rats from control and model groups were administrated with saline. After 5 days of treatments, all rats were sacrificed for determining serum ALT and AST levels and liver index, examining histopathological changes in liver through HE and TUNEL staining, and evaluating TNF-α and IL-6 mRNA expression by real-time PCR, and caspase-3, Bcl-2, and Bax expression by Western blot. Results indicated that CCl4 could induce acute liver injury and abnormal liver function in rats with obvious hepatomegaly, increased liver index, high ALT and AST levels, up-regulated TNF-α and IL-6, and overexpressed Bax and caspase-3. However, DDB and TTM could execute protective role in CCl4-induced liver injury in rats through reducing ALT and AST levels, rescuing hepatomegaly, down-regulating inflammatory factors and inhibiting hepatocyte apoptosis in a dose-dependent manner. Therefore, TTM has obvious protective role in CCl4-induced liver injury of rats through inhibiting hepatocyte apoptosis.

scholarly journals The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Zhao Gao ◽  
Jiecheng Zhang ◽  
Li Wei ◽  
Xingping Yang ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Farnesoid X Receptor ◽  
Sirtuin 1 ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Protective Effects ◽  
Hepatocyte Apoptosis ◽  
Apap Overdose ◽  
First Time

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

The Protective Effect of Aesculus hippocastanum (Venoplant®) Against Concanavalin A-Induced Liver Injury

Pharmacology ◽  
2019 ◽  
Vol 104 (3-4) ◽  
pp. 196-206 ◽  
Author(s):  
Shujin Wu ◽  
Rina Sa ◽  
Zhirong Gu ◽  
Pei Zhao ◽  
Jing Yu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cytochrome C ◽  
Concanavalin A ◽  
Cell Apoptosis ◽  
Liver Tissue ◽  
Caspase 3 ◽  
Acute Liver Injury ◽  
Aesculus Hippocastanum ◽  
Tnf Α ◽  
Ifn Γ

Aim: The present study was performed to investigate the effect of Aesculus hippocastanum (AH; Venoplant®) on concanavalin A (ConA)-induced acute liver injury and explore the mechanism in mice. Methods: ConA (20 mg/kg) was administered via tail vein injection to induce hepatic damage. The groups of AH (Venoplant®) were given at 65.8, 131.6, and 263.2 mg/kg by oral gavages for 20 days. The serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), total protein (TP), and albumin (Alb) were determined by automatic biochemical analyzer, and the Alb/globulin (A/G) ratio was calculated. Tumor necrosis factor-α (TNF-α) and IFN-γ levels were assayed by enzyme-linked immunosorbent assay. The liver tissue was attained by hematoxylin and eosin, and the histopathological changes were calculated. The cell apoptosis was assayed by terminal dUTP nick-end labeling. The malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) content of liver tissue were assayed by related kits. The activity of caspase-3 was detected by spectrophotometry. The expressions of cytochrome c, Bax, Bcl-2, c-Jun N-terminal kinase (JNK), and p-JNK were detected by western blot. Results: The results showed that the levels of ALT, AST, IFN-γ, and TNF-α in AH (Venoplant®) groups were significantly lower than those in ConA-injured group, while the levels of TP, Alb, and A/G were significantly higher. The SOD and GSH levels were significantly increased, and the MDA level was decreased; liver histopathology was changed consistently with the serological indicators, AH (Venoplant®) treatment significantly reduced the pathological damage and cell apoptosis; while in AH (Venoplant®) group, the expressions of cytochrome c, caspase-3, Bax/Bcl-2 ratio, and p-JNK were significantly decreased. Conclusion: AH (Venoplant®) could significantly protect the ConA-induced acute liver injury in mice via inhibition of reactive oxygen species and JNK pathway.

scholarly journals AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury

2019 ◽  
Vol 316 (3) ◽  
pp. G387-G396 ◽  
Author(s):  
Zhen-Tang Jing ◽  
Wei Liu ◽  
Chao-Rong Xue ◽  
Shu-Xiang Wu ◽  
Wan-Nan Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Metabolic Activation ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Hepatocyte Apoptosis ◽  
Akt Inhibitor ◽  
Inhibitory Protein ◽  
Tnf Α ◽  
Induced Apoptosis

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.

scholarly journals SHED ameliorated concanavalin A-induced autoimmune hepatitis by protecting hepatocytes from apoptosis

2020 ◽  
Author(s):  
Yikun Zhou ◽  
Ruili Yang ◽  
Lingsu Zhu ◽  
Huaming Huang ◽  
Shengjie Cui ◽  
...  
Keyword(s):  
Liver Injury ◽  
Autoimmune Hepatitis ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Deciduous Teeth ◽  
Protective Effects ◽  
Hepatocyte Apoptosis ◽  
Con A ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background：Autoimmune hepatitis (AIH) is serious autoimmune liver diseases that threaten people’s health worldwide, emphasizing the need to identify novel treatment. Stem cells from human exfoliated deciduous teeth (SHED), which is easy to obtain and non-invasive, showed pronounced proliferation and immunomodulation capacity. This study aims to investigate the effect of SHED on ConA-induced AIH and the potential underlying mechanisms.Methods: We used a concanavalin A (ConA) induced acute hepatitis mouse model and in vitro co-culture system to study the protective effects of SHED on ConA-induced autoimmune hepatitis and the underlying mechanisms.Results: SHED infusion could prevent aberrant histopathological architecture of liver with infiltration of abundant of CD3+, CD4+, TNF-α+ and IFN-γ+ inflammatory cells induced by ConA. The expression of ALT and AST which indicated the liver function significantly elevated in hepatitis mice. While SHED infusion could block the elevation of ALT and AST induced by ConA. Mechanistically, Con-A upregulated TNF-α and IFN-γ expression activated NF-κB pathways to induced hepatocyte apoptosis, resulting in acute liver injury. SHED administration protected hepatocytes from Con-A-induced apoptosis. Conclusions: These results demonstrated that SHED alleviated ConA-induced acute liver injury via inhibition of hepatocyte apoptosis mediated by the NF-κB pathways. Our findings could provide a potential prevention and therapeutic strategy for hepatitis and acute hepatic injury.

scholarly journals Hepatoprotective Effects of Lactobacillus on Carbon Tetrachloride-Induced Acute Liver Injury in Mice

2018 ◽  
Vol 19 (8) ◽  
pp. 2212 ◽  
Author(s):  
Xiaoyong Chen ◽  
Jing Zhang ◽  
Ruokun Yi ◽  
Jianfei Mu ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Lactobacillus Plantarum ◽  
Protein Level ◽  
Caspase 3 ◽  
Acute Liver Injury ◽  
Lactobacillus Fermentum ◽  
Expression Levels ◽  
Tnf Α

The aim of this study was to investigate and compare the effects of heat-killed and live Lactobacillus on carbon tetrachloride (CCl4)-induced acute liver injury mice. The indexes evaluated included liver pathological changes, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in the serum, related gene expression (IL-1β, TNF-α, Bcl-2, and Bax), and related proteins levels (Bax, Bcl-2, Caspase 3, and NF-κB p65). Compared with the model group, the results indicated that the levels of ALT, AST, and MDA in the serum, the expression levels of IL-1β, TNF-α, and Bax, and the protein levels of Bax, Caspase 3, and NF-κB p65 significantly decreased, and the pathologic damage degree all significantly reduced after live Lactobacillus fermentum (L-LF) and live Lactobacillus plantarum (L-LP) treatment. Additionally, the levels of SOD and GSH in the serum, the gene expression of Bcl-2, and the protein level of Bcl-2 significantly increased after L-LF and L-LP treatment. Although HK-LF and HK-LP could also have obvious regulating effects on some of the evaluated indexes (ALT, AST, the expression levels of TNF-α and Bax, and the protein level of Bcl-2) and play an important role in weakening liver damage, the regulating effects of L-LF or L-LP on these indexes were all better compared with the corresponding heat-killed Lactobacillus fermentum (HK-LF) and heat-killed Lactobacillus plantarum (HK-LP). Therefore, these results suggested that LF and LP have an important role in liver disease.

scholarly journals The Protective Effects of Zornia diphylla (L.) Pers. Against Acute Liver Injury Induced by Carbon Tetrachloride in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Su-Zhi Xie ◽  
Xiang-Yang Zhai ◽  
Sheng-Yan Xi ◽  
Ying-Kun Qiu ◽  
Yu-Mei Zhang ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Protein Expression ◽  
Liver Tissue ◽  
Intraperitoneal Injection ◽  
Acute Liver Injury ◽  
Peanut Oil ◽  
Protective Effects ◽  
Liver Index ◽  
Tnf Α

Background:Zornia diphylla (L.) Pers. (ZDP) is a traditional Chinese herbal medicine that has been used for several decades to treat patients with liver diseases. Whether ZDP is best administered as a single agent or adjunctive therapy has yet to be determined as does the mechanism whereby it exerts its effects on antagonizing acute liver injury (ALI).Aim of the study: To investigate the protective effects of ZDP on ALI induced by carbon tetrachloride (CCl4) and the potential underlying mechanisms.Materials and Methods: Sixty adult mice were randomized into six study groups (n = 10/group). Three groups were treated with different concentrations of ZDP (2.5, 1.25, 0.625 g/kg), one with bifendate (0.0075 g/kg) alone (positive control) and one with physiologic saline (normal, negative control). All groups were treated for 14 days. Two hours after the last administration, the normal group received an intraperitoneal injection of peanut oil, and the other five groups received an intraperitoneal injection of an equal dose of CCl4 peanut oil solution. At 24 h, the liver index, histology and serum or tissue levels and/or protein expression of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), alkaline phosphatase (ALP), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione (GSH), Akt, phosphorylated Akt (p-Akt), nuclear factor kappa B p65 (NF-κB p65), inhibitor of NF-κB α (IκB-α), interleukin-1 β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), E-cadherin and vimentin were determined.Results: Compared to the model controls, the degree of inflammatory cell infiltration and hepatocyte injury of liver tissue was relieved in the bifendate and three ZDP groups; liver index in the ZDP (2.5, 1.25 g/kg) groups and serum liver function indices in the ZDP (2.5, 1.25 and 0.625 g/kg) groups were decreased; antioxidants SOD, CAT and GSH in liver tissue were increased but the lipid peroxidation index MDA was decreased; protein expression of inflammatory cytokines Akt, p-Akt, NF-κB p65, IκB-α, IL-1β, IL-6 and TNF-α in the liver was ameliorated, and E-cadherin expression was increased. The results of liver histopathology also showed that ZDP had a significant effect on ALI.Conclusion: ZDP has obvious protective effects on CCl4-induced ALI as a single therapy and appears to act by inhibiting oxidation, reducing the release of inflammatory factors and promoting hepatocyte repair.

scholarly journals Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia

2021 ◽  
Vol 10 (12) ◽  
pp. 2718
Author(s):  
Omid Madadi-Sanjani ◽  
Gunnar Bohlen ◽  
Fabian Wehrmann ◽  
Julia Andruszkow ◽  
Karim Khelif ◽  
...  
Keyword(s):  
Liver Injury ◽  
Biliary Atresia ◽  
Caspase 3 ◽  
Serum Levels ◽  
Healthy Individuals ◽  
Serological Detection ◽  
Caspase Activation ◽  
Hepatocyte Apoptosis ◽  
Non Invasive ◽  
Cholestatic Diseases

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

scholarly journals Genistein reduced the neural apoptosis in the brain of ovariectomised rats by modulating mitochondrial oxidative stress

2010 ◽  
Vol 104 (9) ◽  
pp. 1297-1303 ◽  
Author(s):  
Yan-Hong Huang ◽  
Qing-Hong Zhang
Keyword(s):  
Oxidative Stress ◽  
Learning And Memory ◽  
Caspase 3 ◽  
Visual Learning ◽  
Morris Water Maze Test ◽  
High Dose ◽  
Dependent Manner ◽  
Ovx Rats ◽  
Neural Apoptosis ◽  
The Brain

The present study was undertaken to investigate the antioxidant effect of chronic ingestion of genistein (Gen) against neural death in the brain of ovariectomised (Ovx) rats. The rats were randomly divided into five groups, i.e. sham-operated (sham), Ovx-only, Ovx with 17β-oestradiol, Ovx with low (15 mg/kg) and high (30 mg/kg) doses of Gen (Gen-L and Gen-H), and were orally administered daily with drugs or vehicle for 6 weeks. The learning and memory abilities were measured by Morris water maze test. Oxidative damages in the brain were evaluated by the level of superoxide dismutase (SOD), malondialdehyde (MDA) and monoamine oxidase (MAO) activities. Neural apoptosis was shown by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining and caspase-3 activity. In the visual learning and memory test, there were no significant differences among the population means of the five groups. While in the probe trial test, the Gen-L group instead of the Gen-H group exhibited reduced escape latency and increased memory frequency than the Ovx group. Although both doses of Gen could reduce acetylcholinesterase activity, only a low dose of Gen could diminish MDA activity significantly in frontal cortex and enhance SOD content in the hippocampus. In contrast, MAO content was decreased in the cortex by either dose of Gen, while in the hippocampus, only a high dose of Gen appeared to be effective. Interestingly, Gen at both the doses could attenuate the increased number of TUNEL-positive neurons and caspase-3 activity in Ovx rats. These results suggest that Gen confers protection against Ovx-induced neurodegeneration by attenuating oxidative stress, lipid peroxidation and the mitochondria-mediated apoptotic pathway in a region- and dose-dependent manner.

scholarly journals Differential role of SIRT1/MAPK pathway during cerebral ischemia in rats and humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sireesh Kumar Teertam ◽  
Phanithi Prakash Babu
Keyword(s):  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Mapk Pathway ◽  
Protective Role ◽  
Akt Signaling ◽  
Sirtuin 1 ◽  
Neurological Dysfunction ◽  
Dependent Manner ◽  
Erk Mapk

AbstractCerebral ischemia (CI) is a severe cause of neurological dysfunction and mortality. Sirtuin-1 (Silent information regulator family protein 1, SIRT1), an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, plays an important role in protection against several neurodegenerative disorders. The present study aims to investigate the protective role of SIRT1 after CI in experimental young and aged rats and humans. Also, the study examines the possible regulatory mechanisms of neuronal death in CI settings. Immunoblotting and immunohistochemistry were used to evaluate changes in the expression of SIRT1, JNK/ERK/MAPK/AKT signaling, and pro-apoptotic caspase-3 in experimental rats and CI patients. The study findings demonstrated that, in aged experimental rats, SIRT1 activation positively influenced JNK and ERK phosphorylation and modulated neuronal survival in AKT-dependent manner. Further, the protection conferred by SIRT1 was effectively reversed by JNK inhibition and increased pro-apoptotic caspase-3 expression. In young experimental rats, SIRT1 activation decreased the phosphorylation of stress-induced JNK, ERK, caspase-3, and increased the phosphorylation of AKT after CI. Inhibition of SIRT1 reversed the protective effect of resveratrol. More importantly, in human patients, SIRT1 expression, phosphorylation of JNK/ERK/MAPK/AKT signaling and caspase-3 were up-regulated. In conclusion, SIRT1 could possibly be involved in the modulation of JNK/ERK/MAPK/AKT signaling pathway in experimental rats and humans after CI.

P–061 Protective effect of melatonin against bleomycin, etoposide, and cisplatin (BEP) chemotherapy-induced testicular toxicity in Wistar rats: A biochemical, immunohistochemical and apoptotic genes based evidence

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Moradi ◽  
A Faramarzi ◽  
N Goodarzi ◽  
A H Hashemian ◽  
H Cheraghi ◽  
...  
Keyword(s):  
Testosterone Level ◽  
Wistar Rats ◽  
Caspase 3 ◽  
Treated Group ◽  
Serum Testosterone Level ◽  
Dependent Manner ◽  
Qrt Pcr ◽  
Tnf Α ◽  
Significant Difference ◽  
Bep Chemotherapy

Abstract Study question Does exogenous melatonin (MLT) attenuate BEP-induced damage in testicular cells and spermatogenesis in a dose-dependent manner? Summary answer Melatonin protected the testes against BEP-induced testis damage through ameliorating nitro-oxidative stress, apoptosis, and inflammation. However, there was no significant difference between melatonin-treated groups. What is known already Recently, the prevalence of testicular cancer (TC), accounting for the most common cancer among young people of reproductive age (15–40 years), has risen internationally. BEP chemotherapy has increased the 5-year survival rate of TC patients at all stages of testicular germ cell tumors to 90–95%. However, BEP creates a high incidence of male infertility and even long-term genotoxic effects, which emerges as a critical health issue. Melatonin is a well-known potent antioxidant with widespread clinical applications that recently has been giving increasing attention to its role in male sub/infertility. Study design, size, duration 60 Adult male Wistar rats were randomly assigned to six groups (n = 10/group). Group 1, 3, and 4 were injected with vehicle, 10 and 20 mg/kg of melatonin, respectively. Other groups received one cycle of bleomycin, etoposide, and cisplatin for a total of 3 weeks with or without melatonin. Melatonin administration started daily one week before BEP initiation continued on days 2, 9, and 16; and one week after the completion of the BEP cycle. Participants/materials, setting, methods Bodyweight, testes weight, Sperm parameters (count, motility, viability, and morphology), testosterone hormone level, testicular histopathology, stereological parameters, testicular level of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), the expression of Bcl–2, Bax, Caspase–3, p53, and TNF-α (Real-time PCR and immunohistochemistry) were evaluated at the end of the study (day 35). Main results and the role of chance Our findings showed that melatonin restores the BEP-induced reduction in the body and testes weight (P<.05). the evaluation of quantitative analysis of the testes stereological procedures, QRT-PCR examination and immunohistochemical (IHC) staining revealed that melatonin reverses the BEP-induced impaired spermatogenesis (P<.05). Furthermore, melatonin rectifies BEP-induced disturbance on sperm count, motility, viability, and morphology. The testosterone level in the BEP-treated group was decreased significantly by comparison with the control group (P<.01). By contrast, co-administration of 10 and 20 mg/kg of melatonin could enhance the serum testosterone level significantly (P<.05). Moreover, melatonin enhanced the antioxidant status of the testis by elevating TAC and ameliorating MDA and NO levels. More notably, QRT-PCR examination indicated that melatonin therapy suppressed BEP-induced apoptosis by modulating apoptosis-associated genes such as Bcl–2, Bax, Caspase–3, p53 in the testis (P<.01). Besides, Co-administration of 10 and 20 mg/kg of melatonin with BEP regimen decreased significantly the population of p53 (54.21 ±6.18% and 51.83±8.45, respectively) and TNF-α positive cells (42.91±9.92% and 33.57±2.97, respectively) by comparison to the BEP group. Also, melatonin with low and high doses could enhance the expression of Bcl–2 protein in spermatogenic cells line (59.19±10.18%, 63.08±5.23, respectively) compared to the BEP-treated group. Limitations, reasons for caution Owing to limited laboratory facilities we were not able to perform further studies to verify the mechanism of melatonin in the specific targets by using transfection technique and transgenic. Wider implications of the findings: These findings can draw attention to the clinical application of melatonin and also suggest that melatonin may be an attractive agent for attenuating chemotherapy-associated male sub/infertility. This indolamine also may shorten the fertility recovery period in patients undergoing chemotherapy with the BEP regimen. Trial registration number N/A

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