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de Almeida AL, Gonçalves A, Barros A, Sousa M, Sá R. Bleomycin in vitro exposure decreases markers of human male gamete competence. F&S SCIENCE 2025; 6:5-15. [PMID: 39393570 DOI: 10.1016/j.xfss.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 10/13/2024]
Abstract
OBJECTIVE To investigate the in vitro impact of bleomycin on human sperm deoxyribonucleic acid (DNA) integrity, functionality, and morphology, with the aim of elucidating the underlying mechanism and anticipating potential repercussions on patients' reproductive function. DESIGN Controlled laboratory-based in vitro investigation. SUBJECTS Surplus human ejaculate donated for research by 45 reproductive-age participants exhibiting normozoospermic sperm parameters after clinical semen analysis. None of the participants had received a cancer diagnosis or undergone radiotherapy, chemotherapy, or both. EXPOSURE After clinical semen analysis, sperm samples were centrifuged, diluted in sperm preparation medium, and exposed to bleomycin (100 μg/mL) for 2 hours at 37 °C in a humidified incubator with 5% CO2. MAIN OUTCOME MEASURES In vitro human sperm competence was evaluated by comparing raw sperm, sperm incubated with sperm preparation medium, and sperm exposed to bleomycin. Competence indicators included sperm motility, vitality, DNA and acrosome integrity, and mitochondrial membrane potential. Transmisson electron microscopy was employed to correlate the ultrastructural morphological findings with functional assays. RESULTS Exposure to bleomycin for 2 hours in vitro significantly decreased sperm vitality, motility, and chromatin condensation compared with raw and control sperm. It also significantly increased sperm DNA fragmentation and the proportion of sperm with low mitochondrial membrane potential. Additionally, bleomycin significantly retarded the acrosomal response compared with control but did not affect the formation of intracellular and extracellular reactive oxygen species. Bleomycin-induced ultrastructural morphological changes supported the detected functional alterations. CONCLUSIONS Bleomycin negatively impacts male gamete competency in humans. Healthcare professionals should vigilantly monitor and further investigate the gonadotoxicity effects of bleomycin, in addition to its recognized lung toxicity. Meanwhile, it is recommended that patients with cancer undergoing bleomycin-containing chemotherapy regimens receive guidance on fertility preservation strategies.
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Affiliation(s)
- Ana Lobo de Almeida
- Laboratory of Cell Biology, Department of Microscopy, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), UP, Porto, Portugal
| | - Ana Gonçalves
- Centre for Reproductive Genetics Alberto Barros, Porto, Portugal
| | - Alberto Barros
- Centre for Reproductive Genetics Alberto Barros, Porto, Portugal; Faculty of Medicine of UP (FMUP), Porto, Portugal; RISE-Health, Porto, Portugal
| | - Mário Sousa
- Laboratory of Cell Biology, Department of Microscopy, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), UP, Porto, Portugal
| | - Rosália Sá
- Laboratory of Cell Biology, Department of Microscopy, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), UP, Porto, Portugal; Faculty of Medicine of UP (FMUP), Porto, Portugal.
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Makipour A, Hosseinifar S, Khazaeel K, Tabandeh MR, Jamshidian J. Protective effect of Chlorella vulgaris on testicular damage, sperm parameters, androgen production, apoptosis and oxidative stress index in male rats following doxorubicin administration. Reprod Toxicol 2024; 128:108653. [PMID: 38960208 DOI: 10.1016/j.reprotox.2024.108653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/18/2024] [Accepted: 06/29/2024] [Indexed: 07/05/2024]
Abstract
Doxorubicin (DOX) is a chemotherapy agent associated with adverse effects on male reproductive health. Chlorella vulgaris (ChV) is a potent natural antioxidant with promising applications in maintaining health and preventing oxidative stress-related diseases. The present study aimed to investigate the protective effect of ChV on DOX-induced testicular toxicity. Twenty-five Wistar rats (230 ± 20 g) were randomly assigned to five groups (n = 5), including the control group, sham group (received normal saline by oral gavage daily and intraperitoneally (IP) once a week), DOX group (3 mg/kg; once a week; IP), ChV group (300 mg/kg/day; by oral gavage), and DOX (3 mg/kg; once a week; IP) + ChV (300 mg/kg/day; by oral gavage) group. After 8 weeks of treatment, the rats were euthanized and serum testosterone level, testes histomorphometry, gonadosomatic index (GSI), apoptotic gene expression, oxidative stress index, and sperm parameters were assessed. The results showed that DOX led to a significant decrease in histological indexes, testosterone level, GSI, sperm parameters, and Bcl-2 gene expression and increased expression of P-53 and Bax genes, and oxidative stress markers (P<0.05). The administration of ChV in the DOX+ChV group significantly improved testosterone levels, sperm parameters, testicular tissue apoptosis, antioxidant enzymes, and structural integrity of the testes (P<0.05). The findings suggest that the co-administration of ChV can be a promising therapeutic agent to reduce the adverse effects of DOX on male reproductive performance.
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Affiliation(s)
- Azam Makipour
- Department of Basic Sciences, Division of Histology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Shima Hosseinifar
- Department of Basic Sciences, Division of Histology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Kaveh Khazaeel
- Department of Basic Sciences, Division of Anatomy and Embryology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran; Stem Cells and Transgenic Technology Research Center (STTRC), Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Mohammad Reza Tabandeh
- Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran; Stem Cells and Transgenic Technology Research Center (STTRC), Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Javad Jamshidian
- Department of Basic Sciences, Division of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
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Huang Q, Wu H, Xiao X, Qin X, Liu S. Preparation of oyster peptide and Pfaffia glomerata pressed candy and its ameliorative effect on sexual dysfunction in male mice. Food Sci Nutr 2024; 12:5572-5586. [PMID: 39139926 PMCID: PMC11317697 DOI: 10.1002/fsn3.4213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/24/2024] [Accepted: 04/27/2024] [Indexed: 08/15/2024] Open
Abstract
Oyster peptide (OP) and Pfaffia glomerata extract (PGE) were used as raw materials. The optimal formulation of the pressed candy (PC) was optimized by one-way experiment and D-optimal mixture experiment design, and animal experiment was used to evaluate the effect of PC on male sexual dysfunction. The results showed that PC intervention significantly improved the sexual behavior of male mice with sexual dysfunction, including a significant shortening of the mount latency (ML) and intromission latency, and a significant increase in the mount frequency (MF) and intromission frequency (IF). At the same time, the concentrations of serum testosterone (T) and luteinizing hormone (LH) in mice were restored, and the erectile parameters and pathological changes of penile tissue were improved. Further studies found that PC intervention increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and reduced the content of malondialdehyde (MDA) in testicular tissue. In addition, PC intervention improved testicular tissue morphology. In conclusion, the obtained PC has good taste quality, and the relevant quality indicators are qualified. It has a good ameliorative effect on male sexual dysfunction and may be a potential dietary supplement.
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Affiliation(s)
- Qianqian Huang
- College of Food Science and TechnologyGuangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Science and Technology Innovation Center for Subtropical Fruit and Vegetable ProcessingZhanjiangChina
- National Research and Development Branch Center for Shellfish ProcessingZhanjiangChina
| | - Haiying Wu
- College of Food Science and TechnologyGuangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Science and Technology Innovation Center for Subtropical Fruit and Vegetable ProcessingZhanjiangChina
- National Research and Development Branch Center for Shellfish ProcessingZhanjiangChina
| | - Xiangxin Xiao
- College of Food Science and TechnologyGuangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Science and Technology Innovation Center for Subtropical Fruit and Vegetable ProcessingZhanjiangChina
- National Research and Development Branch Center for Shellfish ProcessingZhanjiangChina
| | - Xiaoming Qin
- College of Food Science and TechnologyGuangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Science and Technology Innovation Center for Subtropical Fruit and Vegetable ProcessingZhanjiangChina
- National Research and Development Branch Center for Shellfish ProcessingZhanjiangChina
| | - Suqing Liu
- College of Coastal Agricultural SciencesGuangdong Ocean UniversityZhanjiangChina
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Moradi M, Hashemian MA, Faramarzi A, Goodarzi N, Hashemian AH, Cheraghi H, Jalili C. Therapeutic effect of sodium alginate on bleomycin, etoposide and cisplatin (BEP)-induced reproductive toxicity by inhibiting nitro-oxidative stress, inflammation and apoptosis. Sci Rep 2024; 14:1565. [PMID: 38238398 PMCID: PMC10796429 DOI: 10.1038/s41598-024-52010-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/12/2024] [Indexed: 01/22/2024] Open
Abstract
Impaired spermatogenesis and male infertility are common consequences of chemotherapy drugs used in patients with testicular cancer. The present study investigated the effects of sodium alginate (NaAL) on testicular toxicity caused by bleomycin, etoposide, and cisplatin (BEP). Rats in group 1 received normal saline, while groups 2 and 3 were treated with 25 and 50 mg/kg of NaAL, respectively. Group 4 was treated with a 21-day cycle of BEP (0.5 mg/kg bleomycin, 5 mg/kg etoposide, and 1 mg/kg cisplatin), and groups 5 and 6 received BEP regimen plus 25 and 50 mg/kg of NaAL, respectively. Then, sperm parameters, testosterone levels, testicular histopathology and stereological parameters, testicular levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), and the expression of apoptosis-associated genes including Bcl2, Bax, Caspase3, p53, and TNF-α were evaluated. Our findings revealed that NaAL improved sperm parameters, testosterone levels, histopathology, and stereology parameters in BEP-administrated rats. NaAL also improved testis antioxidant status by enhancing TAC and ameliorating MDA and NO. Further, modifications to the expression of Bcl2, Bax, Caspase3, p53, and TNF-α suggested that NaAL alleviated BEP-induced apoptosis and inflammation. Collectively, NaAL protects rats' testes against BEP-evoked toxicity damage through the modulation of nitro-oxidative stress, apoptosis, and inflammation.
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Affiliation(s)
- Mojtaba Moradi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Azita Faramarzi
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Nader Goodarzi
- Department of Basic and Pathobiological Sciences, Faculty of Veterinary Medicine, Razi Universtiy, Kermanshah, Iran.
| | - Amir Hossein Hashemian
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hadi Cheraghi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Cyrus Jalili
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Liu J, Zhang J, Zheng Y, Zhao G, Jiang H, Yuan B. miR-302d Targeting of CDKN1A Regulates DNA Damage and Steroid Hormone Secretion in Bovine Cumulus Cells. Genes (Basel) 2023; 14:2195. [PMID: 38137018 PMCID: PMC10743266 DOI: 10.3390/genes14122195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
(1) Background: DNA damage in cumulus cells hinders oocyte maturation and affects steroid hormone secretion. It is crucial to identify the key factors that regulate cellular DNA damage and steroid hormone secretion. (2) Methods: Treatment of bovine cumulus cells with bleomycin to induce DNA damage. The effects of DNA damage on cell biology were determined by detecting changes in DNA damage degree, cell cycle, viability, apoptosis, and steroid hormones. It was verified that mir-302d targeted regulation of CDKN1A expression, and then affected DNA damage and steroid hormone secretion in cumulus cells. (3) Results: Bleomycin induced increased DNA damage, decreased G1-phase cells, increased S-phase cells, inhibited proliferation, promoted apoptosis, affected E2 and P4 secretion, increased CDKN1A expression, and decreased miR-302d expression. Knockdown of CDKN1A reduced DNA damage, increased G1-phase cells, decreased G2-phase cells, promoted proliferation, inhibited apoptosis, increased E2 and P4 secretion, and increased the expression of BRCA1, MRE11, ATM, CDK1, CDK2, CCNE2, STAR, CYP11A1, and HSD3B1. The expression of RAD51, CCND1, p53, and FAS was decreased. Overexpression of CDKN1A resulted in the opposite results. miR-302d targets CDKN1A expression to regulate DNA damage and then affects the cell cycle, proliferation, apoptosis, steroid hormone secretion, and the expression of related genes. (4) Conclusions: miR-302d and CDKN1A were candidate molecular markers for the diagnosis of DNA damage in bovine cumulus cells.
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Affiliation(s)
- Jianbo Liu
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
- Experimental Testing Center, Jilin Agricultural Science and Technology University, Jilin 132101, China
| | - Jiabao Zhang
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
| | - Yi Zheng
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
| | - Guokun Zhao
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
| | - Hao Jiang
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
| | - Bao Yuan
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China; (J.L.); (J.Z.); (G.Z.); (H.J.)
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Alawadhi M, Kilarkaje N, Mouihate A, Al-Bader MD. Role of progesterone on dexamethasone-induced alterations in placental vascularization and progesterone receptors in rats†. Biol Reprod 2023; 108:133-149. [PMID: 36322157 DOI: 10.1093/biolre/ioac192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/04/2022] [Accepted: 10/18/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Intrauterine growth restriction (IUGR) is manifested by lower maternal progesterone levels, smaller placental size, and decreased placental vascularity indicated by lower expression of vascular endothelial growth factor (VEGF). Studies showed that progesterone increases angiogenesis and induces VEGF expression in different tissues. Therefore, the aim of the present study is to evaluate the effect of progesterone on placental vascular bed and VEGF expression and the modulation of nuclear and membranous progesterone receptors (PR) in dexamethasone-induced rat IUGR model. METHODS Pregnant Sprague-Dawley rats were allocated into four groups and given intraperitoneal injections of either saline, dexamethasone, dexamethasone, and progesterone or progesterone. Injections started on gestation day (DG) 15 and lasted until the days of euthanization (19 and 21 DG). Enzyme-linked immunosorbent assay was used to evaluate plasma progesterone levels. Real-time PCR and western blotting were used to evaluate gene and protein expressions of VEGF, and PR in labyrinth and basal placental zones. Immunohistochemistry was used to locate VEGF and different PRs in placental cells. Immunofluorescence was used to monitor the expression of blood vessel marker (αSMA). RESULTS Dexamethasone decreased the vascular bed fraction and the expression of VEGF in both placental zones. Progesterone co-treatment with dexamethasone prevented this reduction. Nuclear and membrane PRs showed tissue-specific expression in different placental zones and responded differently to both dexamethasone and progesterone. CONCLUSIONS Progesterone treatment improves the outcomes in IUGR pregnancy. Progesterone alleviated DEX-induced IUGR probably by promoting placental VEGF and angiogenesis.
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Affiliation(s)
- Mariam Alawadhi
- Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Narayana Kilarkaje
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Abdeslam Mouihate
- Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Maie D Al-Bader
- Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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Shafiey SI, Abo-Saif AA, Abo-Youssef AM, Mohamed WR. Protective effects of rivaroxaban against cisplatin-induced testicular damage in rats: Impact on oxidative stress, coagulation, and p-NF-κB/VCAM-1 signaling. Food Chem Toxicol 2022; 169:113419. [PMID: 36122812 DOI: 10.1016/j.fct.2022.113419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/16/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
Coagulation is a main pathway in various diseases pathogenesis including testicular damage. This study evaluated rivaroxaban (RVX) protective effects in testicular impairment by cisplatin (CP). Rats were randomly allocated into five groups: Control, RVX (7 mg/kg/day), CP (10 mg/kg), RVX 5 mg + CP and RVX 7 mg + CP. Serum testosterone and testicular ALT, AST, and ALP were assessed. Testicular oxidative stress and antioxidant parameters and inflammatory indicators including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. qRT-PCR was used to determine mRNA expression of 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (stAR). Protein expressions of p-Nuclear factor kappa B (p- NF-κB) and vascular cell adhesion protein-1 (VCAM-1) were analyzed by Western blot analysis. Tissue factor (TF) expression was immunohistochemically analyzed. Results revealed that RVX significantly increased serum testosterone and sperm count while significantly reduced IL-1β and TNF-α. It significantly decreased tissue MDA and NO contents while increased SOD and GPx. In addition, RVX attenuated CP-induced histopathological aberrations and normalized TF. It also decreased the VCAM-1 and p-NF-κB expression and showed strong expression of 3β-HSD, 17β-HSD, and stAR, indicating improvement of steroidogenesis. In conclusion, RVX counteracted testicular damage by CP via suppressing oxidative stress, inflammation, and coagulation and downregulating p-NF-κB/VCAM-1 signaling.
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Affiliation(s)
- Sara I Shafiey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt
| | - Ali A Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt
| | - Amira M Abo-Youssef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
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Zhang J, Fang Y, Tang D, Xu X, Zhu X, Wu S, Yu H, Cheng H, Luo T, Shen Q, Gao Y, Ma C, Liu Y, Wei Z, Chen X, Tao F, He X, Cao Y. Activation of MT1/MT2 to Protect Testes and Leydig Cells against Cisplatin-Induced Oxidative Stress through the SIRT1/Nrf2 Signaling Pathway. Cells 2022; 11:cells11101690. [PMID: 35626727 PMCID: PMC9139217 DOI: 10.3390/cells11101690] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/05/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
There is growing concern that chemotherapy drugs can damage Leydig cells and inhibit the production of testosterone. Increasing evidence shows that melatonin benefits the reproductive process. This study mainly explores the protective effect and possible molecular mechanism of melatonin regarding cisplatin-induced oxidative stress in testicular tissue and Leydig cells. We found that there were only Leydig and Sertoli cells in the testes of gastrointestinal tumor patients with azoospermia caused by platinum chemotherapeutic drugs. Melatonin (Mel) receptor 1/melatonin receptor 2 (MT1/MT2) was mainly expressed in human and mouse Leydig cells of the testes. We also observed that the melatonin level in the peripheral blood decreased and oxidative stress occurred in mice treated with cisplatin or gastrointestinal tumor patients treated with platinum-based chemotherapeutic drugs. iTRAQ proteomics showed that SIRT1/Nrf2 signaling and MT1 proteins were downregulated in cisplatin-treated mouse testes. The STRING database predicted that MT1 might be able to regulate the SIRT1/Nrf2 signaling pathway. Melatonin reduced oxidative stress and upregulated SIRT1/Nrf2 signaling in cisplatin-treated mouse testes and Leydig cells. Most importantly, after inhibiting MT1/MT2, melatonin could not upregulate SIRT1/Nrf2 signaling in cisplatin-treated Leydig cells. The MT1/MT2 inhibitor aggravated the cisplatin-induced downregulation of SIRT1/Nrf2 signaling and increased the apoptosis of Leydig cells. We believe that melatonin stimulates SIRT1/Nrf2 signaling by activating MT1/MT2 to prevent the cisplatin-induced apoptosis of Leydig cells.
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Affiliation(s)
- Junqiang Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
| | - Yuan Fang
- Department of Blood Transfusion, Anhui NO. 2 Provincial People’s Hospital, Hefei 230041, China;
| | - Dongdong Tang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
| | - Xingyu Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;
| | - Xiaoqian Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
| | - Shusheng Wu
- Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230031, China;
| | - Hui Yu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Department of Obstetrics and Gynecology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China
| | - Huiru Cheng
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
| | - Ting Luo
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China;
| | - Qunshan Shen
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China;
| | - Yang Gao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China;
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China
| | - Cong Ma
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China;
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China
| | - Yajing Liu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China
| | - Zhaolian Wei
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China;
| | - Xiaoyu Chen
- Department of Histology and Embryology, Anhui Medical University, Hefei 230032, China;
| | - Fangbiao Tao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
| | - Xiaojin He
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
- Correspondence: (X.H.); (Y.C.)
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; (J.Z.); (D.T.); (X.Z.); (H.Y.); (H.C.); (Q.S.); (Y.G.); (C.M.); (Y.L.); (Z.W.); (F.T.)
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei 230032, China
- Correspondence: (X.H.); (Y.C.)
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Ijaz MU, Tahir A, Ahmed H, Ashraf A, Ahmedah HT, Muntean L, Moga M, Irimie M. Chemoprotective effect of vitexin against cisplatin-induced biochemical, spermatological, steroidogenic, hormonal, apoptotic and histopathological damages in the testes of Sprague-Dawley rats. Saudi Pharm J 2022; 30:519-526. [PMID: 35693443 PMCID: PMC9177451 DOI: 10.1016/j.jsps.2022.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 03/04/2022] [Indexed: 11/21/2022] Open
Abstract
Cisplatin (CP) is one of the most widely used antineoplastic drugs, which possesses the potential to treat a variety of malignancies. However, it displays numerous side effects as well. Male reproductive dysfunction is one of the most adverse side effects of CP. Vitexin is a naturally occurring flavonoid, which exhibits remarkable antioxidant properties. Present study was designed to evaluate the protective effects of vitexin on CP-induced damages on testes. 48 Sprague-Dawley rats were equally distributed into 4 groups: control, cisplatin (CP), cisplatin + vitexin (CP + VIT) and vitexin (VIT). After 14 days of treatment, evaluation of biochemical, spermatogenic, steroidogenical, hormonal, apoptotic and histopathological parameters was carried out. CP damaged the biochemical profile by reducing activity of CAT, SOD, GPx and GSR, while level of MDA and ROS was increased. It also decreased sperm motility, viability, number of hypo-osmotic tail swelled spermatozoa and epididymal sperm count, besides increasing the sperm morphological anomalies. Moreover, levels of LH, FSH and plasma testosterone were reduced. CP reduced the gene expression of testicular anti-apoptotic marker (Bcl-2) and steroidogenic enzymes (3β-HSD, 17β-HSD and StAR), but upregulated the gene expressions of apoptotic markers (Bax and Caspase-3). Besides, CP led to histopathological damages in testicular tissues. However, vitexin reversed all aforementioned damages in testes. Therefore, it is concluded that vitexin could play an effective role as a therapeutic agent against CP-prompted testicular toxicity due to its antioxidant, anti-apoptotic and androgenic potential.
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Affiliation(s)
- Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad 38040, Pakistan
| | - Arfa Tahir
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad 38040, Pakistan
| | - Hussain Ahmed
- Department of Zoology, The University of Buner, 17290 Khyber Pakhtunkhwa, Pakistan
| | - Asma Ashraf
- Department of Zoology, Government College University, Faisalabad 38000, Pakistan
| | - Hanadi Talal Ahmedah
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Rabigh 25732, Saudi Arabia
| | - Liviu Muntean
- Faculty of Medicine, Transilvania University of Brasov, Romania
| | - Marius Moga
- Faculty of Medicine, Transilvania University of Brasov, Romania
| | - Marius Irimie
- Faculty of Medicine, Transilvania University of Brasov, Romania
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10
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Goutam Mukherjee A, Ramesh Wanjari U, Renu K, Vellingiri B, Valsala Gopalakrishnan A. Heavy metal and metalloid - induced reproductive toxicity. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 92:103859. [PMID: 35358731 DOI: 10.1016/j.etap.2022.103859] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/12/2022] [Accepted: 03/24/2022] [Indexed: 06/14/2023]
Abstract
Heavy metals and metalloid exposure are among the most common factors responsible for reproductive toxicity in human beings. Several studies have indicated that numerous metals and metalloids can display severe adverse properties on the human reproductive system. Metals like lead, silver, cadmium, uranium, vanadium, and mercury and metalloids like arsenic have been known to induce reproductive toxicity. Moderate to minute quantities of lead may affect several reproductive parameters and even affect semen quality. The ecological and industrial exposures to the various heavy metals and metalloids have disastrous effects on the reproductive system ensuing in infertility. This work emphasizes the mechanism and pathophysiology of the aforementioned heavy metals and metalloids in reproductive toxicity. Additionally, this work aims to cover the classical protective mechanisms of zinc, melatonin, chelation therapy, and other trending methods to prevent heavy metal-induced reproductive toxicity.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Kaviyarasi Renu
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India; Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077 Tamil Nadu, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
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Alawadhi M, Mouihate A, Kilarkaje N, Al-Bader M. Progesterone partially recovers placental glucose transporters in dexamethasone-induced intrauterine growth restriction. Reprod Biomed Online 2022; 44:595-607. [PMID: 35232674 DOI: 10.1016/j.rbmo.2021.10.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/17/2021] [Accepted: 10/20/2021] [Indexed: 10/20/2022]
Abstract
RESEARCH QUESTION How does progesterone improve fetal outcome and change the expression of placental glucose transporters (GLUT) in dexamethasone-induced intrauterine growth restriction (IUGR)? DESIGN A total of 64 rats were divided randomly into four different treatment groups based on daily i.p. injections of either saline or dexamethasone in the presence or absence of progesterone. Injections started on the 15th day of gestation (15dg) and lasted until the day of sacrifice at 19dg or 21dg. Maternal plasma progesterone concentrations were measured by enzyme-linked immunosorbent assay. The gene and protein expression of placental GLUT1 and GLUT3 were evaluated in the placental labyrinth and basal zones by real-time polymerase chain reaction and Western blotting, respectively. The localization of GLUT1 and GLUT3 was evaluated by immunohistochemistry. RESULTS Dexamethasone induced significant decreases in maternal serum progesterone concentrations (P = 0.029) and placental (P < 0.001) and fetal body (P = 0.009) weights. Dexamethasone also reduced the expression of GLUT1 in the labyrinth zone (P = 0.028) and GLUT3 in both the labyrinth (P = 0.002) and basal zones (P = 0.026). Coadministration of dexamethasone and progesterone prevented the reduction in fetal body weight, placental weight and placental GLUT expression compared with that seen in dexamethasone-treated groups. CONCLUSION These results suggest that progesterone prevents the significant reduction in fetal and placental weights in dexamethasone-induced IUGR, possibly through improving the expression of placental GLUT.
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Affiliation(s)
- Mariam Alawadhi
- Department of Physiology, Faculty of Medicine, Kuwait University Safat PO Box 13060, Kuwait
| | - Abdeslam Mouihate
- Department of Physiology, Faculty of Medicine, Kuwait University Safat PO Box 13060, Kuwait
| | - Narayana Kilarkaje
- Department of Anatomy, Faculty of Medicine, Kuwait University Safat PO Box 13060, Kuwait
| | - Maie Al-Bader
- Department of Physiology, Faculty of Medicine, Kuwait University Safat PO Box 13060, Kuwait.
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12
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The effect of progesterone administration on the expression of metastasis tumor antigens (MTA1 and MTA3) in placentas of normal and dexamethasone-treated rats. Mol Biol Rep 2022; 49:1935-1943. [PMID: 35037193 DOI: 10.1007/s11033-021-07005-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 11/23/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Dexamethasone (DEX) induces intrauterine growth restriction (IUGR) in pregnant rats. IUGR can occur due to apoptosis of trophoblasts, which is believed to be inhibited by progesterone (P4). A group of genes called MTAs play a role in proliferation and apoptosis. MTA1 upregulates trophoblasts proliferation and differentiation, while MTA3 downregulates proliferation and induces apoptosis. Hence, we hypothesized that during IUGR, placental MTA1 decreases and MTA3 increases and this is reversed by P4 treatment. METHODS Pregnant Sprague-Dawley rats were divided into 4 groups based on daily intraperitoneal injections: control (C, saline), DEX (DEX, 0.2 mg/kg/day), DEX and P4 (DEX + P4, DEX: 0.2 mg/kg/day, P4: 5 mg/kg/day) and P4-treated (P4, 5 mg/kg/day) groups. Injections were started on 15 dg until the day of dissection (19 or 21 dg). Gene and protein expressions of MTA1 and MTA3 were studied in the labyrinth (LZ) and basal (BZ) zones using real-time PCR and Western blotting, respectively. RESULTS DEX treatment induced 18% reduction in fetal body weight (p < 0.001) and 30% reduction in placental weight (p < 0.01). Maternal P4 level was also significantly lower in DEX treated groups (p < 0.05). MTA1 expression was decreased in the LZ (gene, p < 0.001) and BZ (protein p < 0.01), while MTA3 protein expression was upregulated in the LZ with DEX treatment (p < 0.001). These changes were reversed with P4 treatment. CONCLUSION The findings of the present study indicate that DEX induces IUGR through changing the expression of placental MTA1 and MTA3 antigens and P4 improved pregnancy outcome by preventing the changes in MTAs expression.
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Synergistic effect of combined oyster peptide and ginseng extracts on anti-exercise-fatigue and promotion of sexual interest activity in male ICR mice. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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Adelakun SA, Ogunlade B, Iteire KA, Adedotun OA. Ameliorating potential and fertility enhancing activities of nutritional dietary supplementation of D-Ribose -l-Cysteine in cisplatin induced oligoasthenoteratozoospermia and seminiferous epithelium degeneration in adult male Sprague-Dawley rats. Metabol Open 2021; 12:100128. [PMID: 34647003 PMCID: PMC8501771 DOI: 10.1016/j.metop.2021.100128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/29/2021] [Accepted: 09/19/2021] [Indexed: 12/16/2022] Open
Abstract
Background Cisplatin (CN) is considered as a cytotoxic agent and DNA synthesis inhibitor. D-Ribose-l-Cysteine (DRLC) is an active ingredient of riboceine, help cells to produce glutathione on body demand. Aim Current study focused on ameliorating potential and fertility enhancing activities of D-Ribose–l-Cysteine in cisplatin induced oligoasthenoteratozoospermia and seminiferous epithelium degeneration. Materials and method Sixty (60) male rats randomized into six groups of ten (n = 10) rats each. Group A (control) received 2.0 ml distilled water, group B received single dose of 8 mg/kg bwt CN, group C received 30 mg/kg bwt DRLC, group D received single dose of 8 mg/kg CN follow by 30 mg/kg bwt DRLC, group E received single dose of 8 mg/kg CN and vitamin C, group F received single dose of 8 mg/kg cisplatin follow by DRLC + Vit.C for 56 days. Parameters tested include: Sperm parameters, testosterone (TT), luteinizing hormone (LH), Follicle stimulating Hormone, (FSH), Prolactin, and testicular 17β-HSD activity, Blood hydroperoxide (BHP), Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT), testicular histology and fertility test. Results Cisplatin significantly reduced testicular volume, body weight, sperm quality, fertility indices, TT, FSH, LH, 17β-HSD, SOD, GSH, CAT, diameter and cross-sectional area of seminiferous tubules, spermatogenesis score. And elevate prolactin, testicular injury score, BHP and MDA compared with control group. Cisplatin only treated rats showed degenerated seminiferous epithelium with empty lumen. Intervention of D-Ribose-Cysteine ameliorated toxic impacts of CN on testis and improved the male fertility. Conclusion D-Ribose-l-Cysteine therefore, preserves testicular integrity and functions thereby, preventing the deleterious impact of CN.
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Affiliation(s)
| | - Babatunde Ogunlade
- Department Human Anatomy, Federal University of Technology, Akure, Nigeria
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15
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Oludare GO, Afolayan GO, Semidara GG. Potential anti-toxic effect of d-ribose-l-cysteine supplement on the reproductive functions of male rats administered cyclophosphamide. J Basic Clin Physiol Pharmacol 2021; 32:925-933. [DOI: 10.1515/jbcpp-2020-0267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/22/2020] [Indexed: 04/11/2023]
Abstract
Abstract
Objectives
This study aimed to access the protective effects of d-ribose-l-cysteine (DRLC) on cyclophosphamide (CPA) induced gonadal toxicity in male rats.
Methods
Forty-eight male Sprague-Dawley rats were divided into six groups of eight rats each. Group I the control, received distilled water (10 ml/kg), Group II received a single dose of CPA 100 mg/kg body weight intraperitoneally (i.p), Groups III and IV received a single dose of CPA at 100 mg/kg (i.p) and then were treated with DRLC at 200 mg/kg bodyweight (b.w) and 400 mg/kg b.w for 10 days, respectively. Rats in Groups V and VI received DRLC at 200 and 400 mg/kg b.w for 10 days, respectively. DRLC was administered orally.
Results
Results showed that CPA increased percentage of abnormal sperm cells and reduced body weight, sperm count, sperm motility, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels (p<0.05). CPA also induced oxidative stress as indicated by the increased malondialdehyde (MDA) content and reduced activities of the oxidative enzymes measured (p<0.05). Liver enzymes were elevated while the blood cells production was decreased in the rats administered CPA. DRLC supplementation enhanced the antioxidant defence system as indicated in the reduced MDA levels and increased activities of the antioxidant enzymes when compared with CPA (p<0.05). Bodyweight, sperm count, sperm motility, FSH, and testosterone levels were increased in the CPA + DRLC II group compared with CPA (p<0.05).
Conclusions
The results of this present study showed that DRLC has a potential protective effect on CPA-induced gonadotoxicity.
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Affiliation(s)
- Gabriel O. Oludare
- Department of Physiology , College of Medicine of the University of Lagos , Lagos , Nigeria
| | - Gbenga O. Afolayan
- Department of Pharmacology, Therapeutics and Toxicology , College of Medicine, University of Lagos , Lagos , Nigeria
| | - Ganbotei G. Semidara
- Department of Physiology , College of Medicine of the University of Lagos , Lagos , Nigeria
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Effects of chemotherapeutic agents on male germ cells and possible ameliorating impact of antioxidants. Biomed Pharmacother 2021; 142:112040. [PMID: 34416630 DOI: 10.1016/j.biopha.2021.112040] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/16/2021] [Accepted: 08/07/2021] [Indexed: 11/22/2022] Open
Abstract
Treatment of cancer in young adults is associated with several side effects, particularly in the reproductive system. Detrimental effects of chemotherapy on the germ cells depend on many factors including primary semen parameters, the way of drug administration, the kind and dose of chemotherapeutic regimens, and the phase of spermatogenesis during the time of drug administration. Lack of appropriate fertility preservation treatments particularly in the affected children necessitates the introduction of methods to amend the harmful effects of chemotherapeutic agents on male germ cells. Several studies have assessed the toxic effects of chemotherapeutic agents in rodent models and tested a number of antioxidants to evaluate their possible impact on the preservation of sperm cells. In the present manuscript, we describe the effects of the mostly investigated chemotherapeutic drugs in this regard i.e., cisplatin, doxorubicin, paclitaxel, 5-fluorouracil, and cyclophosphamide. As several in vivo and in vitro studies have shown the impact of antioxidants on chemotherapy-induced damage of sperms, we also describe the protective effects of antioxidants in this regard.
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Kilarkaje N, Al-Qaryyan M, Al-Bader MD. Trans-resveratrol imparts disparate effects on transcription of DNA damage sensing/repair pathway genes in euglycemic and hyperglycemic rat testis. Toxicol Appl Pharmacol 2021; 418:115510. [PMID: 33775663 DOI: 10.1016/j.taap.2021.115510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/12/2021] [Accepted: 03/23/2021] [Indexed: 11/25/2022]
Abstract
Prevention or repair of DNA damage is critical to inhibit carcinogenesis in living organisms. Using quantitative RT2 Profiler™ PCR array, we investigated if trans-resveratrol could modulate the transcription of DNA damage sensing/repair pathway genes in euglycemic and non-obese type 2 diabetic Goto-Kakizaki rat testis. Trans-resveratrol imparted disparate effects on gene expressions. In euglycemic rats, it downregulated 79% and upregulated 2% of genes. However, in diabetic rats, it upregulated only 2% and downregulated 4% of genes. As such, diabetes upregulated 16% and downregulated 4% of genes. Trans-resveratrol normalized the expression of 9 (60%) out of 15 upregulated genes in diabetic rats. In euglycemic rats, trans-resveratrol inhibited ATM/ATR, DNA damage repair, pro-cell cycle progression, and apoptosis signaling genes. However, it increased Cdkn1a and Sumo1, indicating cell cycle arrest, apoptosis, and cytostasis in conjunction with increased DNA double-strand breaks and apoptosis. Diabetes increased DNA damage and apoptosis but did not affect ATM/ATR and double-strand break repair genes, although it increased few single-strand repair genes. Diabetes increased Abl1 and Sirt1, which may be related to apoptosis, but their increase may well suggest the enhanced cell cycle progression and putative carcinogenicity. The transcription of Rad17 and Smc1a increased in diabetic rats indicating G2 phase arrest and increases in a few DNA single-strand breaks repair genes suggesting DNA damage repair. Trans-resveratrol inhibits the cell cycle and causes cell death in euglycemic rat testis but normalizes diabetes-induced genes related to DNA damage and cell cycle control, suggesting its usefulness in maintaining DNA integrity in diabetes.
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Affiliation(s)
| | - Mariam Al-Qaryyan
- Department of Physiology Faculty of Medicine, Kuwait University, Kuwait
| | - Maie D Al-Bader
- Department of Physiology Faculty of Medicine, Kuwait University, Kuwait
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Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis. Biomed Pharmacother 2021; 138:111481. [PMID: 33752059 DOI: 10.1016/j.biopha.2021.111481] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/01/2021] [Accepted: 03/06/2021] [Indexed: 12/18/2022] Open
Abstract
There is growing concern that some cytotoxic regimens for cancer adversely affect spermatogenesis and male fertility. Increasing evidence demonstrated that melatonin has beneficial impacts on reproductive processes; however, whether melatonin can protect against bleomycin, etoposide, and cisplatin (BEP) chemotherapy regimen-induced testicular toxicity, remains obscure. The present study aimed to explore the effect of melatonin on BEP-evoked testicular injury in rats. Adult male Wistar rats (n = 10/group) were intraperitoneally (i.p.) injected with one cycle of 21 days of 0.33 therapeutically relevant dose levels of BEP (.5 mg/kg bleomycin, 5 mg/kg etoposide, and 1 mg/kg cisplatin) with or without melatonin. At the end of the study, sperm parameters, testosterone level, stereology of testes, testicular levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), the expression of apoptosis-associated genes such as Bcl2, Bax, Caspase-3, p53, and TNF-α (Real-time PCR and Immunohistochemistry) were evaluated. Our findings showed that melatonin restored spermatogenesis by improving sperm count, motility, viability, and morphology. Testosterone level, histopathology, and stereology of testes were significantly improved in melatonin-administrated groups. Furthermore, melatonin recovered the oxidative status of the testes through elevating TAC and ameliorating MDA and NO levels. More importantly, melatonin therapy suppressed BEP-evoked apoptosis by modulating Bcl-2, Bax, Caspase-3, p53, and TNF-α expression in testes. In conclusion, melatonin protects the testes against BEP-induced testicular damage by attenuating nitro-oxidative stress, apoptosis, and inflammation, which provides evidence for melatonin as a possible clinical therapy against BEP-associated gonadotoxicity and male sub/infertility.
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Erfani Majd N, Hajirahimi A, Tabandeh MR, Molaei R. Protective effects of green and chemical zinc oxide nanoparticles on testis histology, sperm parameters, oxidative stress markers and androgen production in rats treated with cisplatin. Cell Tissue Res 2021; 384:561-575. [PMID: 33433689 DOI: 10.1007/s00441-020-03350-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/16/2020] [Indexed: 11/26/2022]
Abstract
Cancer treatment with cisplatin (CP) is associated with adverse side effects on male reproductive tissues. Although beneficial effects of zinc oxide nanoparticles (ZnO NPs) in cancer therapy have received considerable attention, data related to the protective effects of green ZnO NPs against CP-induced male reproductive dysfunctions are limited. Forty-five rats were divided into 9 groups including G1 (control), G2 (sham), G3 (ZnO bulk), G4 (green ZnO NPs), G5 (chemical ZnO NPs), G6 (CP), G7 (CP + ZnO bulk), G8 (CP + green ZnO NPs), and G9 (CP + chemical ZnO NPs). CP was administrated (5 mg/kg/week) for 4 weeks, and animals were simultaneously treated with different forms of ZnO (5 mg/kg/day). Testis histology, sperm parameters, oxidative stress markers, testosterone concentration, and expression of genes related in steroidogenesis were analyzed in different experimental groups. Testis tissue damage and epididymal sperm disorders induced by CP attenuated when animals were treated with different forms of ZnO, especially green ZnO NPs. Decreased testosterone concentration and increased MDA level in CP-treated rats were reversed following administration different forms of ZnO, especially green and chemical ZnO NPs. Co-administration of ZnO NPs to CP-treated rats restored the suppressive effects of CP on activities of antioxidant enzymes (SOD, GPX, CAT) and the transcription of the STAR gene. None of the ZnO forms had a significant regulatory effect on the expression of CYP11A1 in CP-treated rats. The results showed that in most of the evaluated factors, green ZnO NPs showed a greater protective effect than other forms of ZnO.
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Affiliation(s)
- Naeem Erfani Majd
- Department of Basic Sciences, Faculty of Veterinary Medicine, Division of Histology , Shahid Chamran University of Ahvaz, Ahvaz, Iran.
- Stem Cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Akram Hajirahimi
- Department of Basic Sciences, Faculty of Veterinary Medicine, Division of Histology , Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohammad Reza Tabandeh
- Stem Cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Rahim Molaei
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
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20
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Nguyen HT, Couture R, Touaibia M, Martin LJ. Transcriptome modulation following administration of luteolin to bleomycin-etoposide-cisplatin chemotherapy on rat LC540 tumor Leydig cells. Andrologia 2021; 53:e13960. [PMID: 33400304 DOI: 10.1111/and.13960] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/09/2020] [Accepted: 12/22/2020] [Indexed: 01/11/2023] Open
Abstract
Leydig cell tumours represent 1%-3% of all cases of testicular tumours in men. Such tumours respond poorly to radiation or chemotherapy, including bleomycin-etoposide-cisplatin (BEP) combinatorial therapy. In this study, we investigated an alternative approach involving luteolin to improve the efficacy of chemotherapy. LC540 tumour Leydig cells were treated with BEP (bleomycin 40 µg/ml, etoposide 4 µg/ml, cisplatin 8 µg/ml) and/or luteolin 10 µM for comparison with DMSO-treated cells. We performed a transcriptome analysis using RNA-Seq to characterise changes in biological processes and signalling pathways. Treatments of LC540 tumour Leydig cells with luteolin significantly decreased the expression of genes involved in cholesterol biosynthesis, while increasing the expression of genes related to glutathione conjugation (p < .05). Genes being significantly upregulated in response to BEP treatment were involved in the response to toxic substances and transcriptional regulation. Oppositely, genes being significantly downregulated by BEP treatment were enriched for intracellular signal transduction, cell migration, cell adhesion, reproductive system development and cholesterol biosynthesis. BEP chemotherapy proved to be effective in increasing gene expression related to apoptosis of tumour Leydig cells. However, addition of luteolin to BEP treatment had no other effects on biological processes or pathways related to cancer treatment.
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Affiliation(s)
- Ha Tuyen Nguyen
- Biology Department, Université de Moncton, Moncton, NB, Canada
| | - Roxanne Couture
- Biology Department, Université de Moncton, Moncton, NB, Canada
| | - Mohamed Touaibia
- Chemistry and Biochemistry Department, Université de Moncton, Moncton, NB, Canada
| | - Luc J Martin
- Biology Department, Université de Moncton, Moncton, NB, Canada
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A A Aly H, G Eid B. Cisplatin induced testicular damage through mitochondria mediated apoptosis, inflammation and oxidative stress in rats: impact of resveratrol. Endocr J 2020; 67:969-980. [PMID: 32507773 DOI: 10.1507/endocrj.ej20-0149] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The target of this study was to explore the role of mitochondria mediated apoptosis and inflammation in cisplatin-induced testicular damage and to evaluate the ameliorative effect of resveratrol. Adult male Wistar rats were randomly allocated to 4 groups. Group I (Control) received normal saline, Group II (Resveratrol) received resveratrol (50 mg/kg/day), Group III (Cisplatin) received cisplatin (7.5 mg/kg/week, i.p.) and Group IV (Resveratrol + Cisplatin) received resveratrol and cisplatin in the same regimen of treatment. Treatment with resveratrol in Groups II and IV started 48h before cisplatin injection and continued for further 4 successive weeks. Cisplatin-treated rats showed reduced body weight, absolute testes weight and sperm count, motility and viability. On the other hand, cisplatin treatment increased the percentage of sperm abnormalities. It also decreased serum testosterone level, mitochondrial membrane potential while, increased cytochrome C liberation from the mitochondria into the cytosol. The activities of caspase-3 & -9 were increased. The level of TNF-α, IL-6 and Bax were increased whereas Bcl-2 was decreased. Oxidative stress markers were found to increase with a concomitant reduction in the antioxidant enzymes and GSH levels. These results were confirmed by immunohistochemical and histopathological analysis. Contrary to all these results, there were improvements in cisplatin induced testicular damage through attenuation of mitochondria mediated apoptosis, inflammation, and oxidative stress owing to resveratrol pretreatment. Thus, resveratrol, as a potential therapeutic agent, may hold promise in preventing mitochondria mediated apoptosis and inflammation in cisplatin-induced testicular damage in rats.
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Affiliation(s)
- Hamdy A A Aly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Basma G Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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Nayak G, Rao A, Mullick P, Mutalik S, Kalthur SG, Adiga SK, Kalthur G. Ethanolic extract of Moringa oleifera leaves alleviate cyclophosphamide-induced testicular toxicity by improving endocrine function and modulating cell specific gene expression in mouse testis. JOURNAL OF ETHNOPHARMACOLOGY 2020; 259:112922. [PMID: 32422360 DOI: 10.1016/j.jep.2020.112922] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 04/13/2020] [Accepted: 04/26/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Moringa oleifera Lam. is known for its nutritional and ethno medicinal values due to the presence of wide array of phytochemicals with multiple biological activities. We have previously reported that ethanolic extract of Moringa oleifera leaves (MOE) ameliorated cyclophosphamide (CP)-induced testicular toxicity and improved functional integrity of spermatozoa as well as spermatogenic cells. AIM OF THE STUDY The present study was planned to investigate whether the mitigation of CP-induced testicular toxicity by MOE is mediated via modulation of endocrine profile, genes associated with function of different cell types and enhancement of DNA repair response in spermatogonial cells. MATERIALS AND METHODS Adult Swiss albino mice (8 week) were injected with CP (100 mg/kg, one dose in a week for 3 weeks) and MOE (100 mg/kg, 5 doses in a week for 4 weeks) either alone or in combination intraperitoneally. At 35 day post CP injection (first dose), the functional characteristics such as count, motility, head morphology and DNA integrity were assessed in epididymal spermatozoa. Key reproductive hormones like testosterone, follicle stimulating hormone (FSH) and Inhibin B concentration were analyzed in serum and testis. In addition, mRNA expression of genes pertaining to the function of Leydig, Sertoli and spermatogonial cells as well as antioxidant enzymes were evaluated in the testis. To understand the DNA damage and repair process in germ cells, prepubertal (2 week) mice were administered with single dose of CP (200 mg/kg) and/or MOE (100 mg/kg) and analyzed for expression of DNA damage (γ-H2AX, P53 and Caspase3) and repair genes (Rad51 and Ku80) in isolated spermatogonial cells at various time points after treatment. RESULTS CP administration resulted in decrease in count, motility and increase in morphological defects and DNA damage in spermatozoa. Testosterone level was marginally decreased while there was a significant increase in FSH (p < 0.001) and decrease in inhibin B (p < 0.05) observed in CP treated mice. Administration of MOE prior to CP, improved sperm functional characteristics, decreased FSH and increased inhibin B levels. Expression of Abp was down-regulated while Transferrin, Fshr and Gata4 (Sertoli cell specific genes) were up-regulated in testis treated with CP. Administration of CP down-regulated the expression of Oct4 and Ddx4 (Spermatogonia specific genes). MOE administration was shown to ameliorate CP-induced damage by modulating the expression of genes specific to Sertoli and spermatogenic cells. Furthermore, MOE treatment reduced CP-induced DNA damage as evident from lower percentage of γ-H2AX positive spermatogonial cells. CONCLUSION Administration of MOE mitigated CP-induced testicular damage by improving blood and, intra-testicular hormonal milieu as well as modulating the expression of genes pertaining to Sertoli and spermatogonial cells.
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Affiliation(s)
- Guruprasad Nayak
- Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Arpitha Rao
- Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Prashansha Mullick
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Sneha Guruprasad Kalthur
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Satish Kumar Adiga
- Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Guruprasad Kalthur
- Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Delessard M, Saulnier J, Rives A, Dumont L, Rondanino C, Rives N. Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility. Int J Mol Sci 2020; 21:ijms21041454. [PMID: 32093393 PMCID: PMC7073108 DOI: 10.3390/ijms21041454] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/09/2020] [Accepted: 02/13/2020] [Indexed: 01/23/2023] Open
Abstract
Over the last decade, the number of cancer survivors has increased thanks to progress in diagnosis and treatment. Cancer treatments are often accompanied by adverse side effects depending on the age of the patient, the type of cancer, the treatment regimen, and the doses. The testicular tissue is very sensitive to chemotherapy and radiotherapy. This review will summarize the epidemiological and experimental data concerning the consequences of exposure to chemotherapy during the prepubertal period or adulthood on spermatogenic progression, sperm production, sperm nuclear quality, and the health of the offspring. Studies concerning the gonadotoxicity of anticancer drugs in adult survivors of childhood cancer are still limited compared with those concerning the effects of chemotherapy exposure during adulthood. In humans, it is difficult to evaluate exactly the toxicity of chemotherapeutic agents because cancer treatments often combine chemotherapy and radiotherapy. Thus, it is important to undertake experimental studies in animal models in order to define the mechanism involved in the drug gonadotoxicity and to assess the effects of their administration alone or in combination on immature and mature testis. These data will help to better inform cancer patients after recovery about the risks of chemotherapy for their future fertility and to propose fertility preservation options.
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Ekinci Akdemir FN, Yildirim S, Kandemir FM, Aksu EH, Guler MC, Kiziltunc Ozmen H, Kucukler S, Eser G. The antiapoptotic and antioxidant effects of eugenol against cisplatin-induced testicular damage in the experimental model. Andrologia 2019; 51:e13353. [PMID: 31243800 DOI: 10.1111/and.13353] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 12/23/2022] Open
Abstract
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.
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Affiliation(s)
- Fazile N Ekinci Akdemir
- Department of Nutrition and Dietetics, High School of Health, Ağrı İbrahim Çeçen University, Ağrı, Turkey
| | - Serkan Yildirim
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
| | - Fatih M Kandemir
- Department of Biochemistry, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
| | - Emrah H Aksu
- Department of Reproduction and Artificial Insemination, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
| | - Mustafa C Guler
- Department of Physiology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Hilal Kiziltunc Ozmen
- Department of Radiation Oncology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Sefa Kucukler
- Department of Biochemistry, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
| | - Gizem Eser
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
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Prihatno SA, Padeta I, Larasati AD, Sundari B, Hidayati A, Fibrianto YH, Budipitojo T. Effects of secretome on cisplatin-induced testicular dysfunction in rats. Vet World 2018; 11:1349-1356. [PMID: 30410245 PMCID: PMC6200560 DOI: 10.14202/vetworld.2018.1349-1356] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 08/16/2018] [Indexed: 12/17/2022] Open
Abstract
Background Testicular dysfunction is a degenerative disorder characterized by failure in the synthesis of reproductive hormones and spermatogenesis. Secretome derived from the human umbilical mesenchymal stem cell (MSC) has been reported to repair some degenerative disorders. Aim This study aimed to investigate the effect of secretome derived from the human umbilical MSCs on cisplatin-induced testicular dysfunction in rats. Materials and Methods Thirty-six male Wistar rats were divided into the control and secretome-treated groups. In the secretome-treated group, testicular dysfunction was induced by 3 mg/kg BW of cisplatin intraperitoneally 3 times with 3-day intervals. The secretome-treated group was divided according to dose: Low-dose (0.2 mL/kg BW) and high-dose (0.5 mL/kg BW) groups. Secretomes were injected intraperitoneally once a week for 3 weeks. 1 week after the injection of secretome, the cauda epididymis of the rats was removed for spermatozoa evaluation and histological examination. Result After the injection of secretome, the sperm motility of the high-dose group showed thin wave-like, rare, and slow movements. No abnormal sperm morphology was observed in all the treated groups. The number of spermatozoa increased gradually in the high-dose group after the injection of secretome. The developmental stages of the spermatogenic cells were complete in both spermatozoa groups after the injection of secretome. However, the spermatozoa in the seminiferous tubules of the high-dose group were denser. Vimentin and cytokeratin immunoreactivities were very strong in the high-dose group 1 week after the second secretome injection. Conclusion High-dose secretome derived from the human fetal umbilical cord could increase the number and motility of sperms in rats with cisplatin-induced testicular dysfunction. The administration of high-dose secretome was effective 1 week after the second dose, as indicated by very strong immunoreactivity for vimentin and cytokeratin. Moreover, secretome could promote the regeneration of the seminiferous tubules of both the groups.
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Affiliation(s)
- Surya Agus Prihatno
- Department of Reproduction and Obstetrics, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Irma Padeta
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Arinda Devi Larasati
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Betty Sundari
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Annisa Hidayati
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Yuda Heru Fibrianto
- Department of Physiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
| | - Teguh Budipitojo
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55821, Indonesia
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Tian M, Liu F, Liu H, Zhang Q, Li L, Hou X, Zhao J, Li S, Chang X, Sun Y. Grape seed procyanidins extract attenuates Cisplatin-induced oxidative stress and testosterone synthase inhibition in rat testes. Syst Biol Reprod Med 2018; 64:246-259. [DOI: 10.1080/19396368.2018.1450460] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Minmin Tian
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Fangfang Liu
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Han Liu
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Qiong Zhang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Lei Li
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Xiangbo Hou
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Jianxin Zhao
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Sheng Li
- Lanzhou Municipal Center for Disease Control, Lanzhou, China
| | - Xuhong Chang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
| | - Yingbiao Sun
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China
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Mercantepe T, Unal D, Tümkaya L, Yazici ZA. Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats. Exp Ther Med 2018; 15:3404-3412. [PMID: 29545862 PMCID: PMC5840930 DOI: 10.3892/etm.2018.5819] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 01/24/2018] [Indexed: 02/02/2023] Open
Abstract
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.
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Affiliation(s)
- Tolga Mercantepe
- Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize 53010, Turkey
| | - Deniz Unal
- Department of Histology and Embryology, Faculty of Medicine, Atatürk University, Erzurum 25000, Turkey
| | - Levent Tümkaya
- Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize 53010, Turkey
| | - Zihni Acar Yazici
- Department of Medical Microbiology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize 53010, Turkey
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Toxic effects of Tripterygium wilfordii Hook F on the reproductive system of adolescent male rats. Biomed Pharmacother 2017; 95:1338-1345. [DOI: 10.1016/j.biopha.2017.09.038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/17/2017] [Accepted: 09/10/2017] [Indexed: 11/19/2022] Open
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Singh I, Goyal Y, Ranawat P. Potential chemoprotective role of resveratrol against cisplatin induced testicular damage in mice. Chem Biol Interact 2017; 273:200-211. [DOI: 10.1016/j.cbi.2017.05.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/02/2017] [Accepted: 05/31/2017] [Indexed: 12/18/2022]
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Peak TC, Haney NM, Wang W, DeLay KJ, Hellstrom WJ. Stem cell therapy for the treatment of Leydig cell dysfunction in primary hypogonadism. World J Stem Cells 2016; 8:306-315. [PMID: 27822338 PMCID: PMC5080638 DOI: 10.4252/wjsc.v8.i10.306] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/07/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
The production of testosterone occurs within the Leydig cells of the testes. When production fails at this level from either congenital, acquired, or systemic disorders, the result is primary hypogonadism. While numerous testosterone formulations have been developed, none are yet fully capable of replicating the physiological patterns of testosterone secretion. Multiple stem cell therapies to restore androgenic function of the testes are under investigation. Leydig cells derived from bone marrow, adipose tissue, umbilical cord, and the testes have shown promise for future therapy for primary hypogonadism. In particular, the discovery and utilization of a group of progenitor stem cells within the testes, known as stem Leydig cells (SLCs), has led not only to a better understanding of testicular development, but of treatment as well. When combining this with an understanding of the mechanisms that lead to Leydig cell dysfunction, researchers and physicians will be able to develop stem cell therapies that target the specific step in the steroidogenic process that is deficient. The current preclinical studies highlight the complex nature of regenerating this steroidogenic process and the problems remain unresolved. In summary, there appears to be two current directions for stem cell therapy in male primary hypogonadism. The first method involves differentiating adult Leydig cells from stem cells of various origins from bone marrow, adipose, or embryonic sources. The second method involves isolating, identifying, and transplanting stem Leydig cells into testicular tissue. Theoretically, in-vivo re-activation of SLCs in men with primary hypogonadism due to age would be another alternative method to treat hypogonadism while eliminating the need for transplantation.
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Carbenoxolone exposure during late gestation in rats alters placental expressions of p53 and estrogen receptors. Eur J Pharmacol 2016; 791:675-685. [PMID: 27693517 DOI: 10.1016/j.ejphar.2016.09.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 09/20/2016] [Accepted: 09/27/2016] [Indexed: 12/31/2022]
Abstract
Gestational carbenoxolone exposure inhibits placental 11β-hydroxysteroid dehydrogenase (11β-HSD), the physiological barrier for glucocorticoids, which increases fetal exposure to glucocorticoids and induces intrauterine growth restriction (IUGR). We hypothesized that carbenoxolone exposure influences the expression of placental estrogen receptors-α and β (ERα & ERβ) and p53 leading to inhibited fetal and placental growth. Pregnant Sprague-Dawley rats were injected twice daily with either carbenoxolone (10mg/kg; s.c.) or vehicle (control group) from gestational days (dg) 12 onwards. Maternal blood and placentas were collected on 16 dg, 19 dg and 21 dg. The expression of ERα, ERβ and p53 were studied in placental basal and labyrinth zones by RT-PCR, Western blotting and immunohistochemistry. Carbenoxolone did not affect placental and fetal body weights, but ELISA showed decreased estradiol levels on 19 dg and 21 dg, and increased maternal luteinizing hormone levels on all dg. The follicle stimulating hormone levels decreased on 16 dg and 19 dg, and increased on 21 dg. Carbenoxolone decreased ERα mRNA levels on 16 dg in both zones and its protein level on 19 dg in the labyrinth zone. However, carbenoxolone increased ERβ mRNA levels on 19 dg and 21 dg and protein levels on 16 dg and 19 dg in the labyrinth zone. The p53 mRNA levels increased on all dg, but its protein levels increased on 21 dg in both zones. In conclusion, carbenoxolone exposure changes placental p53, ERα, ERβ expression in favor of cell death but these changes do not induce IUGR in rats.
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Reddy KP, Madhu P, Reddy PS. Protective effects of resveratrol against cisplatin-induced testicular and epididymal toxicity in rats. Food Chem Toxicol 2016; 91:65-72. [DOI: 10.1016/j.fct.2016.02.017] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/22/2016] [Accepted: 02/23/2016] [Indexed: 01/09/2023]
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Zhang XF, Gurunathan S, Kim JH. Effects of silver nanoparticles on neonatal testis development in mice. Int J Nanomedicine 2015; 10:6243-56. [PMID: 26491295 PMCID: PMC4599714 DOI: 10.2147/ijn.s90733] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Metal nanoparticles (MNPs) play an important role in consumer products. An increasing use of MNPs has raised concerns about potential risks for human health. Therefore, in vivo tests of MNPs are urgently required. Using mice as a model animal, the aim of the present study was designed to investigate the effect of biologically synthesized silver nanoparticles (AgNPs) on spermatogenesis in neonatal mice. Methods AgNPs were synthesized using Bacillus funiculus. The prepared nanoparticles were characterized using various analytical techniques such as UV–visible spectroscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, and transmission electron microscopy. The prepared AgNPs were used to investigate testis development in neonatal mice. Institute of Cancer Research neonatal male mice were used in all experiments and were treated with different doses (0, 1, and 5 mg/kg) of AgNPs five times (interval of 3 days from postnatal day [PND] 8–21) by abdominal subcutaneous injection. Results The results showed that the sperm abnormalities such as quality and quantity were significantly increased by the synthesized AgNPs. The diameter of the convoluted tubules shrank significantly in mice treated with AgNPs on PND28 and PND42. The results of reverse transcription-quantitative polymerase chain reaction indicated that the E1f1ay, Gsta4, and Fdx1 genes were up-regulated, and the Amh, Cx43, and Claudin-11 genes were down-regulated in response to AgNPs exposure on PND28; however, these genes recovered at PND60. AgNPs had no effect on the recombination levels of chromosomes in germ cells. Conclusion These results demonstrated the adverse effects of AgNPs on the male reproductive tract, particularly spermatogenesis and the quality of sperm. This study suggests that the development of nanomaterials should be safer and non-toxic to the living organisms and the potential reprotoxicity of AgNPs should be investigated more carefully.
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Affiliation(s)
- Xi-Feng Zhang
- Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea ; College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, People's Republic of China
| | | | - Jin-Hoi Kim
- Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea
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