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Kiani M, Mehranjani MS, Shariatzadeh MA. Empagliflozin improves sperm quality in diabetic rats by lowering oxidative stress and reducing apoptosis-related genes expression. Reprod Biol 2025; 25:100971. [PMID: 39579749 DOI: 10.1016/j.repbio.2024.100971] [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: 08/30/2024] [Revised: 10/08/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
Type 2 diabetes mellitus (T2DM) negatively impacts sperm health by increasing oxidative stress. Empagliflozin, a type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, not only reduces blood glucose levels in T2DM but also has antioxidant properties. This study aimed to investigate the antioxidant effects of empagliflozin on sperm quality and spermatogenesis indices in rats with T2DM.Male rats were divided into three groups (n = 6): control, diabetes mellitus (DM, induced by streptozotocin + nicotinamide), and DM treated with empagliflozin (10 mg/kg, 56 days, via gavage). Sperm parameters including sperm count, viability, motility, normal morphology, DNA integrity, maturation, tail length, and daily sperm production were analyzed. Additionally, spermatogenesis indices, Bax/Bcl2 ratio and serum levels of superoxide dismutase (SOD), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. In the DM group, there was a significant decrease in the mean sperm parameters, SOD, TAC, and spermatogenesis indices, along with a significant increase in the percentage of single-stranded DNA (AO+), immature sperm nuclei (AB+), MDA levels, and Bax/Bcl2 ratio, compared to the control group. In the DM + empagliflozin group, there was a significant increase in the mean sperm parameters, SOD levels (P˂0.001), and spermatogenesis indices. Additionally, there was a significant decrease in the mean AB+ (P˂0.01), AO+, MDA levels (P˂0.001), and Bax/Bcl2 ratio compared to the DM group. The results showed that empagliflozin can mitigate the adverse effects of diabetes and improve sperm quality and increase sperm production in diabetic rats.
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Affiliation(s)
- Mina Kiani
- Department of Biology, Faculty of Science, Arak University, Arak 384817758, Iran
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2
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Peña FJ, Martín-Cano FE, Becerro-Rey L, da Silva-Álvarez E, Gaitskell-Phillips G, Aparicio IM, Gil MC, Ortega-Ferrusola C. Redox Regulation and Glucose Metabolism in the Stallion Spermatozoa. Antioxidants (Basel) 2025; 14:225. [PMID: 40002411 PMCID: PMC11852293 DOI: 10.3390/antiox14020225] [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: 01/20/2025] [Revised: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Stallion spermatozoa are cells which exhibit intense metabolic activity, where oxidative phosphorylation in the mitochondria is the primary ATP generator. However, metabolism must be viewed as a highly interconnected network of oxidation-reduction reactions that generate the energy necessary for life. An unavoidable side effect of metabolism is the generation of reactive oxygen species, leading to the evolution of sophisticated mechanisms to maintain redox homeostasis. In this paper, we provide an updated overview of glucose metabolism in stallion spermatozoa, highlighting recent evidence on the role of aerobic glycolysis in these cells, and the existence of an intracellular lactate shuttle that may help to explain the particular metabolism of the stallion spermatozoa in the context of their redox regulation.
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3
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Qu W, Xu Y, Yang J, Shi H, Wang J, Yu X, Chen J, Wang B, Zhuoga D, Luo M, Liu R. Berberine alters the gut microbiota metabolism and impairs spermatogenesis. Acta Biochim Biophys Sin (Shanghai) 2024; 57:569-581. [PMID: 39420836 PMCID: PMC12040761 DOI: 10.3724/abbs.2024174] [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: 03/19/2024] [Accepted: 07/21/2024] [Indexed: 10/19/2024] Open
Abstract
Berberine (BBR) is used to treat diarrhea clinically. However, its reproductive toxicity is unclear. This study aims to investigate the impact of BBR on the male reproductive system. Intragastric BBR administration for 14 consecutive days results in a significant decrease in the serum testosterone concentration, epididymal sperm concentration, mating rate and fecundity of male mice. Testicular treatment with testosterone propionate (TP) partially reverses the damage caused by BBR to the male reproductive system. Mechanistically, the decrease in Muribaculaceae abundance in the gut microbiota of mice is the principal cause of the BBR-induced decrease in the sperm concentration. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment demonstrate that Muribaculaceae is necessary for spermatogenesis. The intragastric administration of Muribaculaceae intestinale to BBR-treated mice restores the sperm concentration and testosterone levels. Metabolomic analysis reveals that BBR affects arginine and proline metabolism, of which ornithine level is downregulated. Combined analysis via 16S rRNA metagenomics sequencing and metabolomics shows that Muribaculaceae regulates ornithine level. The transcriptomic results of the testes indicate that the expressions of genes related to the low-density lipoprotein receptor (LDLR)-mediated testosterone synthesis pathway decrease after BBR administration. The transcriptional activity of the Ldlr gene in TM3 cells is increased with increased ornithine supplementation in the culture media, leading to increased testosterone synthesis. Overall, this study reveals an association between a BBR-induced decrease in Muribaculaceae abundance and defective spermatogenesis, providing a prospective therapeutic approach for addressing infertility-related decreases in serum testosterone triggered by changes in the gut microbiota composition.
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Affiliation(s)
- Wei Qu
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Yumin Xu
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Jing Yang
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Hanqing Shi
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Junli Wang
- Reproductive Medicine Centerthe Affiliated Hospital of Youjiang Medical University for NationalitiesBaise53300China
| | - Xinnai Yu
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Jiemin Chen
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Binyi Wang
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Deqing Zhuoga
- Institute of Livestock ResearchTibet Academy of Agriculture and Animal Husbandry ScienceLhasa850000China
| | - Mengcheng Luo
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
| | - Rong Liu
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhan430071China
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4
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Zafar MI, Chen X. Effects of Calorie Restriction on Preserving Male Fertility Particularly in a State of Obesity. Curr Obes Rep 2024; 13:256-274. [PMID: 38489002 DOI: 10.1007/s13679-024-00557-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2024] [Indexed: 03/17/2024]
Abstract
PURPOSE OF REVIEW Highlight the importance of exploring nutritional interventions that could be applied as alternative or supplementary therapeutic strategies to enhance men's fertility. RECENT FINDINGS Lifestyle choices have prompted extensive discussions regarding its implications and applications as a complementary therapy. The growing concern over the decline in sperm quality underscores the urgency of investigating these alternative interventions. Calorie restriction (CR) has emerged as a promising strategy to improve male fertility. The efficacy of CR depends on factors like age, ethnicity and genetics. Clinical studies, such as CALERIE, have shown an improvement in serum testosterone level and sexual drive in men with or without obesity. Additionally, CR has been shown to positively impact sperm count and motility; however, its effects on sperm morphology and DNA fragmentation remain less clear, and the literature has shown discrepancies, mainly due to the nature of technically dependent assessment tools. The review advocates a personalized approach to CR, considering individual health profiles to maximize its benefits. It underscores the need for routine, accessible diagnostic techniques in male reproductive health. It suggests that future research should focus on personalized dietary interventions to improve male fertility and overall well-being in individuals with or without obesity and unravel CR's immediate and lasting effects on semen parameters in men without obesity.
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Affiliation(s)
- Mohammad Ishraq Zafar
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, N1 Shangcheng Avenue, Yiwu, Zhejiang, China.
| | - Xiao Chen
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, N1 Shangcheng Avenue, Yiwu, Zhejiang, China.
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Italiano E, Ceccarelli G, Italiano G, Piazza F, Iannitti RG, Puglisi T. Positive Effects of a Resveratrol-Based Nutraceutical in Association with Surgical Scleroembolization: A Pilot Retrospective Clinical Trial. J Clin Med 2024; 13:2925. [PMID: 38792465 PMCID: PMC11122415 DOI: 10.3390/jcm13102925] [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: 03/27/2024] [Revised: 05/08/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Background: Varicocele still today represents a common cause of infertility in young men. The treatment strategy remains a surgical approach such as scleroembolization; however, the complete restoration of spermatic parameters afterward requires an average of six or more months to fully regain optimal seminal parameters. Recently, many studies have demonstrated the beneficial effects of Resveratrol in male fertility, given its potential anti-inflammatory, antiapoptotic, and mitochondrial effects. Therefore, Resveratrol-based nutraceuticals could be promising as an adjuvant to mitigate subfertility in patients with varicocele. Methods: In the present study, we retrospectively analyzed the effects of the administration of a Resveratrol-based nutraceutical after the scleroembolization procedure. The improvement of sperm quality in terms of number, motility, and morphology were considered to be the study's main endpoints. A spreadsheet program was used for data analysis, and a p-value of <0.05 was considered significant. Results: We found a statistically significant improvement in the spermatic parameters (sperm count and total motility) and an increase in normal sperm after only 4 months of treatment. The supplementation with a Resveratrol-based nutraceutical associated with the surgical procedure showed encouraging results if compared to data from a control group and the results reported in the literature linked to scleroembolization practice alone. In fact, there was a clear improvement in the seminal parameters at 4 months. Conclusions: This suggests the positive impact of the Resveratrol-based nutraceutical in synergizing with scleroembolization in reducing the time needed to fully recover sperm function.
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Affiliation(s)
| | | | - Giovanna Italiano
- Policlinico Brescia, Unità Operativa di Urologia, 25128 Brescia, Italy;
| | - Fulvio Piazza
- Azienda Ospedaliera “Cervello-Villa Sofia“, 90146 Palermo, Italy; (F.P.); (T.P.)
| | | | - Tiziana Puglisi
- Azienda Ospedaliera “Cervello-Villa Sofia“, 90146 Palermo, Italy; (F.P.); (T.P.)
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6
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Ma X, Ren X, Zhang X, Griffin N, Liu H, Wang L. Rutin ameliorates perfluorooctanoic acid-induced testicular injury in mice by reducing oxidative stress and improving lipid metabolism. Drug Chem Toxicol 2023; 46:1223-1234. [PMID: 36373176 DOI: 10.1080/01480545.2022.2145483] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/16/2022]
Abstract
This study investigated the protective effect of rutin on reproductive and blood-testis barrier (BTB) damage induced by perfluorooctanoic acid (PFOA) exposure. In this study, male ICR mice were randomly divided into three groups, Ctrl group (ddH2O, 5 mL/kg), PFOA group (PFOA, 20 mg/kg/d, 5 mL/kg), PFOA + rutin group (PFOA, 20 mg/kg/d, 5 mL/kg; rutin, 20 mg/kg/d, 5 mL/kg). Mice were exposed to PFOA for 28 days by gavage once daily in the presence or absence of rutin. Histopathological observations demonstrated that rutin treatment during PFOA exposure can reduce structural damage to testis and epididymis such as atrophy of spermatogenic epithelium and stenosis of epididymal lumen, while increase in the number and layers of spermatogenic cells. Biochemical detection demonstrated that rutin can reduce 8-hydroxy-2'-desoxyguanosine (8-OHdG) concentration in the serum and testis tissues. Rutin can also ameliorate glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) content, and reduce malondialdehyde (MDA) and total cholesterol (TC) content in testis tissues. Biotin tracking immunofluorescence and transmission electron microscopy demonstrated that rutin can ameliorate BTB structural damage during PFOA exposure. Rutin ameliorated the stress expression of tight junction proteins occludin and claudin-11. In conclusion, our findings suggested that rutin has a degree of protection in reproductive and BTB damage, which could put forward a new perspective on the application of rutin to prevent reproductive damage.
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Affiliation(s)
- Xinzhuang Ma
- School of Public Health, Bengbu Medical College, Bengbu, PR China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, PR China
| | - Xijuan Ren
- School of Public Health, Bengbu Medical College, Bengbu, PR China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, PR China
| | - Xuemin Zhang
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, PR China
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, PR China
| | - Nathan Griffin
- Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA
| | - Hui Liu
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, PR China
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, PR China
| | - Li Wang
- School of Public Health, Bengbu Medical College, Bengbu, PR China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, PR China
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7
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Romano M, Cirillo F, Spadaro D, Busnelli A, Castellano S, Albani E, Levi-Setti PE. High sperm DNA fragmentation: do we have robust evidence to support antioxidants and testicular sperm extraction to improve fertility outcomes? a narrative review. Front Endocrinol (Lausanne) 2023; 14:1150951. [PMID: 37867514 PMCID: PMC10585152 DOI: 10.3389/fendo.2023.1150951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 09/01/2023] [Indexed: 10/24/2023] Open
Abstract
To date, infertility affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to 50% of cases. Oral supplementation with antioxidants could be helpful to improve sperm quality by reducing oxidative damage. At the same time, there is a growing interest in the literature on the use of testicular sperm in patients with high DNA fragmentation index (DFI). This narrative review aims to evaluate the effectiveness of supplementation of oral antioxidants in infertile men with high DFI compared to testicular sperm retrieval. The current evidence is non-conclusive because of serious risk of bias due to small sample sizes and statistical methods. Further large well-designed randomised placebo-controlled trials are still required to clarify the exact role of these to different therapeutic approaches.
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Affiliation(s)
- Massimo Romano
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Federico Cirillo
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
| | - Daria Spadaro
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Andrea Busnelli
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Stefano Castellano
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Elena Albani
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Paolo Emanuele Levi-Setti
- Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Humanitas Research Hospital, IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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8
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Ma HZ, Chen Y, Guo HH, Wang J, Xin XL, Li YC, Liu YF. Effect of resveratrol in gestational diabetes mellitus and its complications. World J Diabetes 2023; 14:808-819. [PMID: 37383595 PMCID: PMC10294056 DOI: 10.4239/wjd.v14.i6.808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/23/2023] [Accepted: 04/20/2023] [Indexed: 06/14/2023] Open
Abstract
The incidence rate of diabetes in pregnancy is about 20%, and diabetes in pregnancy will have a long-term impact on the metabolic health of mothers and their offspring. Mothers may have elevated blood glucose, which may lead to blood pressure disease, kidney disease, decreased resistance and secondary infection during pregnancy. The offspring may suffer from abnormal embryonic development, intrauterine growth restriction, obesity, autism, and other adverse consequences. Resveratrol (RSV) is a natural polyphenol compound, which is found in more than 70 plant species and their products, such as Polygonum cuspidatum, seeds of grapes, peanuts, blueberries, bilberries, and cranberries. Previous studies have shown that RSV has a potential beneficial effect on complex pregnancy, including improving the indicators of diabetes and pregnancy diabetes syndrome. This article has reviewed the molecular targets and signaling pathways of RSV, including AMP-activated protein kinase, mitogen-activated protein kinases, silent information regulator sirtuin 1, miR-23a-3p, reactive oxygen species, potassium channels and CX3C chemokine ligand 1, and the effect of RSV on gestational diabetes mellitus (GDM) and its complications. RSV improves the indicators of GDM by improving glucose metabolism and insulin tolerance, regulating blood lipids and plasma adipokines, and modulating embryonic oxidative stress and apoptosis. Furthermore, RSV can ameliorate the GDM complications by reducing oxidative stress, reducing the effects on placentation, reducing the adverse effects on embryonic development, reducing offspring's healthy risk, and so on. Thus, this review is of great significance for providing more options and possibilities for further research on medication of gestational diabetes.
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Affiliation(s)
- Hui-Zhong Ma
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Yuan Chen
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Hao-Hao Guo
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Jing Wang
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Xiu-Lan Xin
- College of Bioengineering, Beijing Polytechnic, Beijing 100176, China
| | - Yan-Cheng Li
- Department of Epidemiology, University of Florida, Gainesville, FL 32608, United States
| | - Yu-Feng Liu
- School of Pharmaceutical Sciences, Natural Products Pharmaceutical Engineering Technology Research Center of Liaoning Province, Liaoning University, Shenyang 110036, Liaoning Province, China
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9
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Moudgil KD, Venkatesha SH. The Anti-Inflammatory and Immunomodulatory Activities of Natural Products to Control Autoimmune Inflammation. Int J Mol Sci 2022; 24:95. [PMID: 36613560 PMCID: PMC9820125 DOI: 10.3390/ijms24010095] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.
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Affiliation(s)
- Kamal D. Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore VA Medical Center, Baltimore, MD 21201, USA
| | - Shivaprasad H. Venkatesha
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Vita Therapeutics, Baltimore, MD 21201, USA
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10
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Peña FJ, Ortiz-Rodríguez JM, Gaitskell-Phillips GL, Gil MC, Ortega-Ferrusola C, Martín-Cano FE. An integrated overview on the regulation of sperm metabolism (glycolysis-Krebs cycle-oxidative phosphorylation). Anim Reprod Sci 2022; 246:106805. [PMID: 34275685 DOI: 10.1016/j.anireprosci.2021.106805] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/14/2022]
Abstract
An overview of the sperm metabolism is presented; using the stallion as a model we review glycolysis, Krebs Cycle and oxidative phosphorylation, paying special attention to the interactions among them. In addition, metabolism implies a series of coordinated oxidation-reduction reactions and in the course of these reactions reactive oxygen species (ROS) and reactive oxoaldehydes are produced ; the electron transport chain (ETC) in the mitochondria is the main source of the anion superoxide and hydrogen peroxide, while glycolysis produces 2-oxoaldehydes such as methylglyoxal as byproducts; due to the adjacent carbonyl groups are strong electrophiles (steal electrons oxidizing other compounds). Sophisticated mechanisms exist to maintain redox homeostasis, because ROS under controlled production also have important regulatory functions in the spermatozoa. The interactions between metabolism and production of reactive oxygen species are essential for proper sperm function, and deregulation of these processes rapidly leads to sperm malfunction and finally death. Lastly, we briefly describe two techniques that will expand our knowledge on sperm metabolism in the coming decades, metabolic flow cytometry and the use of the "omics" technologies, proteomics and metabolomics, specifically the micro and nano proteomics/metabolomics. A better understanding of the metabolism of the spermatozoa will lead to big improvements in sperm technologies and the diagnosis and treatment of male factor infertility.
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Affiliation(s)
- Fernando J Peña
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain.
| | - José M Ortiz-Rodríguez
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Gemma L Gaitskell-Phillips
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Maria C Gil
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Cristina Ortega-Ferrusola
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Francisco E Martín-Cano
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
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11
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Peña FJ, O'Flaherty C, Ortiz Rodríguez JM, Martín Cano FE, Gaitskell-Phillips G, Gil MC, Ortega Ferrusola C. The Stallion Spermatozoa: A Valuable Model to Help Understand the Interplay Between Metabolism and Redox (De)regulation in Sperm Cells. Antioxid Redox Signal 2022; 37:521-537. [PMID: 35180830 DOI: 10.1089/ars.2021.0092] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Significance: Proper functionality of the spermatozoa depends on the tight regulation of their redox status; at the same time these cells are highly energy demanding and in the energetic metabolism, principally in the electron transport chain in the mitochondria, reactive oxygen species are continuously produced, in addition to that observed in the Krebs cycle and during the β-oxidation of fatty acids. Recent Advances: In addition, in glycolysis, elimination of phosphate groups from glyceraldehyde 3-phosphate and dihydroxyacetone phosphate results in the byproducts glyoxal (G) and methylglyoxal (MG); these products are 2-oxoaldehydes. The presence of adjacent carbonyl groups makes them strong electrophiles that react with nucleophiles in proteins, lipids, and DNA, forming advanced glycation end products. Critical Issues: This mechanism is behind subfertility in diabetic patients; in the animal breeding industry, commercial extenders for stallion semen contain a supraphysiological concentration of glucose that promotes MG production, constituting a potential model of interest. Future Directions: Increasing our knowledge of sperm metabolism and its interactions with redox regulation may improve current sperm technologies in use, and shall provide new clues to understanding infertility in males. Moreover, stallion spermatozoa due to its accessibility, intense metabolism, and suitability for proteomics/metabolomic studies may constitute a suitable model for studying regulation of metabolism and interactions between metabolism and redox homeostasis. Antioxid. Redox Signal. 37, 521-537.
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Affiliation(s)
- Fernando J Peña
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Cristian O'Flaherty
- Urology Division, Department of Surgery, Faculty of Medicine, McGill University, Montréal, Quebec, Canada.,Department of Pharmacology and Therapeutics and Faculty of Medicine, McGill University, Montréal, Quebec, Canada.,Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montréal, Quebec, Canada
| | - José M Ortiz Rodríguez
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Francisco E Martín Cano
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Gemma Gaitskell-Phillips
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - María C Gil
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Cristina Ortega Ferrusola
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
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12
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Pekary AE, Sattin A. A resveratrol derivative modulates
TRH
and
TRH
‐like peptide expression throughout the brain and peripheral tissues of male rats. Endocrinol Diabetes Metab 2022; 5:e356. [PMID: 35875858 PMCID: PMC9471588 DOI: 10.1002/edm2.356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/23/2022] [Accepted: 06/26/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Methods Results Conclusion
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Affiliation(s)
- Albert Eugene Pekary
- Research VA Greater Los Angeles Healthcare System Los Angeles California USA
- Center for Ulcer Research and Education VA Greater Los Angeles Healthcare System Los Angeles California USA
- Department of Medicine University of California Los Angeles California USA
| | - Albert Sattin
- Research VA Greater Los Angeles Healthcare System Los Angeles California USA
- Psychiatry Services VA Greater Los Angeles Healthcare System Los Angeles California USA
- Department of Psychiatry & Biobehavioral Sciences University of California Los Angeles California USA
- Brain Research Institute University of California Los Angeles California USA
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13
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da Costa Nunes Gomes AC, Bellin CS, da Silva Dias S, de Queiroz de Rosa T, Araújo MP, Miraglia SM, Mendes TB, Vendramini V. Increased sperm DNA damage leads to poor embryo quality and subfertility of male rats treated with methylphenidate hydrochloride in adolescence. Andrology 2022; 10:1632-1643. [PMID: 36029003 DOI: 10.1111/andr.13277] [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: 04/01/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Methylphenidate hydrochloride (MPH) is a psychostimulant widely used in the treatment of attention deficit hyperactive disorder (ADHD), as well as a performance enhancer, for at least 60 years. Despite the notable effectiveness as a psychostimulant, ADHD is a chronic disorder and has a two-third chance of accompanying the individual throughout life. Long-term use of MPH has been associated not only with an increase in the development of neurodegenerative diseases, but it also has side effects on male fertility in experimental animals. OBJECTIVES To investigate whether methylphenidate poses a risk to sperm DNA structure and to the quality of embryos conceived after treatment during adolescence in rats. MATERIALS AND METHODS Wistar rats at 38 days of age were treated either with 5 mg/kg body weight of MPH, in a single daily dose for 30 days, via gavage or with distilled water-only protocol. Levels of oxidative stress in testicular and epididymal tissues were evaluated. Sperm chromatin quality and acrosome integrity was assessed under flow cytometry. From 107 days of age, animals were mated with untreated females. The effects of the paternal contribution at two different embryo development moments - cleavage stage (2.5 days post coitum) and late gestation (20 days post coitum) - were analyzed. RESULTS MPH caused high levels of sperm DNA damage, which was reflected in 40% of decrease in early embryo quality and a lower number of live pups at 20 dpc. DISCUSSION The high level of fragmentation seen in the embryos sired from the MPH group is consistent with the poor chromatin structure of the sperm, and does not seem to be a result of oxidative stress in the reproductive tissues. CONCLUSIONS The results presented here suggest that the subchronic use of MPH during male prepubertal phase may cause long term subfertility and compromise embryo survival. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ana Clara da Costa Nunes Gomes
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil
| | - Camila Souza Bellin
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil.,Paulista School of Nursing, Federal University of Sao Paulo - EPE/UNIFESP, Sao Paulo, Brazil
| | - Stephanie da Silva Dias
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil.,Paulista School of Nursing, Federal University of Sao Paulo - EPE/UNIFESP, Sao Paulo, Brazil
| | - Thalita de Queiroz de Rosa
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil.,Paulista School of Nursing, Federal University of Sao Paulo - EPE/UNIFESP, Sao Paulo, Brazil
| | - Marina Pereira Araújo
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil.,Paulista School of Nursing, Federal University of Sao Paulo - EPE/UNIFESP, Sao Paulo, Brazil
| | - Sandra Maria Miraglia
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil
| | - Talita Biude Mendes
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil
| | - Vanessa Vendramini
- Department of Morphology and Genetics, Laboratory of Reproductive and Developmental Biology (LabReD), Paulista School of Medicine, Federal University of Sao Paulo - EPM/UNIFESP, Sao Paulo, Brazil
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14
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Tsampoukas G, Tharakan T, Narayan Y, Khan F, Cayetano A, Papatsoris A, Buchholz N, Minhas S. Investigating the therapeutic options for diabetes-associated male infertility as illustrated in animal experimental models. Andrologia 2022; 54:e14521. [PMID: 35934995 DOI: 10.1111/and.14521] [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: 03/31/2022] [Revised: 05/15/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022] Open
Abstract
Diabetes is a rising global health concern and an increasingly common cause of male infertility. Although the definitive pathophysiological mechanisms underpinning the association between diabetes and infertility is unclear, there are several animal studies showing diabetes to be a detrimental factor on reproductive health through apoptosis, oxidative stress and impairment of steroidogenesis. Furthermore, as reflected in animal models, antidiabetic strategies and relevant treatments are beneficial in the management of infertile men with diabetes as the recovery of euglycemic status affects positively the spermatogenesis. However, the available data are still evolving and specific conclusion in human populations are not possible yet. In this review, we are discussing the current literature concerning the association of diabetes and male infertility, focusing on the therapeutic approach as illustrated in animals' models.
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Affiliation(s)
- Georgios Tsampoukas
- U-merge Ltd. (Urology for emerging countries), London, UK.,Department of Urology, Great Western Hospital NHS Trust, Swindon, UK
| | - Tharu Tharakan
- Department of Urology, Imperial Healthcare NHS Trust, Charing Cross Hospital, London, UK.,Section of Investigative Medicine, Department of Medicine, Imperial College London, London, UK
| | - Yash Narayan
- Department of Surgery, Cairns Hospital, Cairns North, Queensland, Australia
| | - Faisal Khan
- Department of Urology, North Devon Hospital, Barnstaple, UK
| | - Axel Cayetano
- Department of Urology, Imperial Healthcare NHS Trust, Charing Cross Hospital, London, UK
| | - Athanasios Papatsoris
- U-merge Ltd. (Urology for emerging countries), London, UK.,Department of Urology, Sismanoglio University Hospital of Athens, Athens, Greece
| | - Noor Buchholz
- U-merge Ltd. (Urology for emerging countries), London, UK
| | - Suks Minhas
- Department of Urology, Imperial Healthcare NHS Trust, Charing Cross Hospital, London, UK
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15
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Moretti E, Signorini C, Noto D, Corsaro R, Collodel G. The relevance of sperm morphology in male infertility. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 4:945351. [PMID: 36303645 PMCID: PMC9580829 DOI: 10.3389/frph.2022.945351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/11/2022] [Indexed: 11/23/2022] Open
Abstract
This brief report concerns the role of human sperm morphology assessment in different fields of male infertility: basic research, genetics, assisted reproduction technologies, oxidative stress. One of the best methods in studying sperm morphology is transmission electron microscopy (TEM) that enables defining the concept of sperm pathology and classifying alterations in non-systematic and systematic. Non-systematic sperm defects affect head and tail in variable ratio, whereas the rare systematic defects are characterized by a particular anomaly that marks most sperm of an ejaculate. TEM analysis and fluorescence in situ hybridization represent outstanding methods in the study of sperm morphology and cytogenetic in patients with altered karyotype characterizing their semen quality before intracytoplasmic sperm injection. In recent years, the genetic investigations on systematic sperm defects, made extraordinary progress identifying candidate genes whose mutations induce morphological sperm anomalies. The question if sperm morphology has an impact on assisted fertilization outcome is debated. Nowadays, oxidative stress represents one of the most important causes of altered sperm morphology and function and can be analyzed from two points of view: 1) spermatozoa with cytoplasmic residue produce reactive oxygen species, 2) the pathologies with inflammatory/oxidative stress background cause morphological alterations. Finally, sperm morphology is also considered an important endpoint in in vitro experiments where toxic substances, drugs, antioxidants are tested. We think that the field of sperm morphology is far from being exhausted and needs other research. This parameter can be still considered a valuable indicator of sperm dysfunction both in basic and clinical research.
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16
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Abstract
Summary
High rates of infertility in type 2 diabetic (T2DM) men have led to attempts to understand the mechanisms involved in this process. This condition can be investigated from at least two aspects, namely sperm quality indices and epigenetic alterations. Epigenetics science encompasses the phenomena that can lead to inherited changes independently of the genetics. This study has been performed to test the hypothesis of the relationship between T2DM and the epigenetic profile of the sperm, as well as sperm quality indices. This research included 42 individuals referred to the infertility clinic of Royan Institute, Iran in 2019–2021. The study subjects were assigned to three groups: normozoospermic non-diabetic (control), normozoospermic diabetic (DN) and non-normozoospermic diabetic (D.Non-N). Sperm DNA fragmentation was evaluated using the sperm chromatin structure assay technique. The global methylation level was examined using 5-methyl cytosine antibody and the methylation status in differentially methylated regions of H19, MEST, and SNRPN was assessed using the methylation-sensitive high-resolution melting technique. The results showed that the sperm global methylation in spermatozoa of D.Non-N group was significantly reduced compared with the other two groups (P < 0.05). The MEST and H19 genes were hypomethylated in the spermatozoa of D.Non-N individuals, but the difference level was not significant for MEST. The SNRPN gene was significantly hypermethylated in these individuals (P < 0.05). The results of this study suggest that T2DM alters the methylation profile and epigenetic programming in spermatozoa of humans and that these methylation changes may ultimately influence the fertility status of men with diabetes.
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17
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Francisco CM, Fischer LW, Vendramini V, de Oliva SU, Paccola CC, Miraglia SM. Resveratrol reverses male reproductive damage in rats exposed to nicotine during the intrauterine phase and breastfeeding. Andrology 2022; 10:951-972. [PMID: 35472028 DOI: 10.1111/andr.13183] [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: 10/21/2021] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Nicotine leads to reproductive changes culminating in male infertility and subfertility. Resveratrol, a polyphenol, is a biological modulator. Sirtuin 1 (SIRT1) protein can positively act on male reproduction, and its expression can be affected by nicotine and modulated by resveratrol. OBJECTIVES The capability of resveratrol to reverse the reproductive damage in adult male offspring, which was nicotine-exposed during the intrauterine phase and breastfeeding, was investigated. MATERIALS AND METHODS Four groups were established with male offspring born from nicotine-exposed and non-exposed rat dams during pregnancy and lactation. Forty-eight male Wistar rats were distributed into four groups: sham control (SC), resveratrol (R), nicotine (N), and nicotine + resveratrol (NR). Rat dams of the N and NR offspring were exposed to nicotine (2 mg/kg/day) during pregnancy and lactation using a subcutaneously implanted minipump. The offspring of the R and NR groups received resveratrol (300 mg/kg of body weight, gavage) for 63 days from puberty. At 114 days of age, the male rats were euthanized. RESULTS Nicotine did not alter the body weight, biometry of reproductive organs, or quantitative sperm parameters of adult offspring but caused an evident worsening of all sperm qualitative parameters studied. Daily treatment with resveratrol from puberty up to adulthood improved all qualitative sperm parameters significantly, leading some of them close to the control values. Resveratrol also improved the morphological integrity and expression of SIRT1 in the seminiferous epithelium of nicotine-exposed offspring. CONCLUSION AND DISCUSSION Resveratrol reversed the male reproductive damage caused by nicotine. Nicotine crosses the blood-placental membrane and is present in the breast milk of mothers who smoke. Resveratrol restored the altered reproductive parameters in the male adult offspring that were nicotine-exposed during intrauterine life and breastfeeding. The epigenetic modulating action of resveratrol can be involved in this nicotine damage reversion. Resveratrol may be a promising candidate to be investigated regarding the adjuvant strategies in the treatment of male infertility.
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Affiliation(s)
| | | | - Vanessa Vendramini
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
| | - Samara Urban de Oliva
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
| | - Camila Cicconi Paccola
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
| | - Sandra Maria Miraglia
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
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18
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Jiang Q, Linn T, Drlica K, Shi L. Diabetes as a potential compounding factor in COVID-19-mediated male subfertility. Cell Biosci 2022; 12:35. [PMID: 35307018 PMCID: PMC8934536 DOI: 10.1186/s13578-022-00766-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 02/21/2022] [Indexed: 01/09/2023] Open
Abstract
Recent work indicates that male fertility is compromised by SARS-CoV-2 infection. Direct effects derive from the presence of viral entry receptors (ACE2 and/or CD147) on the surface of testicular cells, such as spermatocytes, Sertoli cells, and Leydig cells. Indirect effects on testis and concentrations of male reproductive hormones derive from (1) virus-stimulated inflammation; (2) viral-induced diabetes, and (3) an interaction between diabetes and inflammation that exacerbates the deleterious effect of each perturbation. Reproductive hormones affected include testosterone, luteinizing hormone, and follicle-stimulating hormone. Reduction of male fertility is also observed with other viral infections, but the global pandemic of COVID-19 makes demographic and public health implications of reduced male fertility of major concern, especially if it occurs in the absence of serious symptoms that would otherwise encourage vaccination. Clinical documentation of COVID-19-associated male subfertility is now warranted to obtain quantitative relationships between infection severity and subfertility; mechanistic studies using animal models may reveal ways to mitigate the problem. In the meantime, the possibility of subfertility due to COVID-19 should enter considerations of vaccine hesitancy by reproductive-age males.
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Affiliation(s)
- Qingkui Jiang
- grid.430387.b0000 0004 1936 8796Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers The State University of New Jersey, Newark, NJ USA
| | - Thomas Linn
- grid.8664.c0000 0001 2165 8627Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany
| | - Karl Drlica
- grid.430387.b0000 0004 1936 8796Public Health Research Institute and Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers The State University of New Jersey, Newark, NJ USA
| | - Lanbo Shi
- grid.430387.b0000 0004 1936 8796Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers The State University of New Jersey, Newark, NJ USA
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19
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Ashrafizadeh M, Kumar AP, Aref AR, Zarrabi A, Mostafavi E. Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications. Int J Nanomedicine 2022; 17:1229-1253. [PMID: 35340823 PMCID: PMC8943613 DOI: 10.2147/ijn.s350250] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/07/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus (DM) is among the chronic metabolic disorders that its incidence rate has shown an increase in developed and wealthy countries due to lifestyle and obesity. The treatment of DM has always been of interest, and significant effort has been made in this field. Exosomes belong to extracellular vesicles with nanosized features (30-150 nm) that are involved in cell-to-cell communication and preserving homeostasis. The function of exosomes is different based on their cargo, and they may contain lipids, proteins, and nucleic acids. The present review focuses on the application of exosomes in the treatment of DM; both glucose and lipid levels are significantly affected by exosomes, and these nanostructures enhance lipid metabolism and decrease its deposition. Furthermore, exosomes promote glucose metabolism and affect the level of glycolytic enzymes and glucose transporters in DM. Type I DM results from the destruction of β cells in the pancreas, and exosomes can be employed to ameliorate apoptosis and endoplasmic reticulum (ER) stress in these cells. The exosomes have dual functions in mediating insulin resistance/sensitivity, and M1 macrophage-derived exosomes inhibit insulin secretion. The exosomes may contain miRNAs, and by transferring among cells, they can regulate various molecular pathways such as AMPK, PI3K/Akt, and β-catenin to affect DM progression. Noteworthy, exosomes are present in different body fluids such as blood circulation, and they can be employed as biomarkers for the diagnosis of diabetic patients. Future studies should focus on engineering exosomes derived from sources such as mesenchymal stem cells to treat DM as a novel strategy.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, 34956, Istanbul, Turkey
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Translational Sciences, Xsphera Biosciences Inc., Boston, MA, 02210, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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20
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Mendes TB, Simas JN, Fischer LW, Paccola CC, de Oliva SU, Vendramini V, Miraglia SM. Resveratrol benefits on sperm DNA, chromatin structure and reproductive outcomes of varicocelized rats. Andrologia 2022; 54:e14417. [PMID: 35297074 DOI: 10.1111/and.14417] [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: 12/06/2021] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 11/27/2022] Open
Abstract
In varicocele, the main cause of sperm DNA damage is oxidative stress (OS). Resveratrol, a polyphenol with antioxidant properties, can protect cells from injuries caused by OS. We investigated the benefits of resveratrol against reproductive damage caused by experimental varicocele induced from peripuberty. Eighty peripubertal male rats were distributed into 4 groups: sham-control (S), varicocele (V), resveratrol (R) and varicocele treated with resveratrol (VR). Varicocele was induced through the partial ligature of the left renal vein. Resveratrol was given in a daily dose of 300 mg/kg body weight (gavage). Sperm samples were collected at 100 days of age for vitality, DNA fragmentation and chromatin protamination evaluations. OS analyses were carried out. Rats from all groups were mated with healthy primiparous females for evaluation of reproductive capacity and embryonic quality. The V group showed reduction of sperm vitality, altered chromatin protamination and sperm DNA integrity and high levels of OS. The VR group showed an improvement of oxidative status, sperm vitality, DNA integrity and chromatin structure, and an enhancement in the gestational index and embryonic quality. Therefore, we showed in this experimental model that resveratrol is a promising nutraceutical adjuvant and should be deeply studied to mitigate subfertility in varicocele.
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Affiliation(s)
- Talita Biude Mendes
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Joana Noguères Simas
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Leonardo Wensing Fischer
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Camila Cicconi Paccola
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Samara Urban de Oliva
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Vanessa Vendramini
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
| | - Sandra Maria Miraglia
- Laboratory of Reproduction and Developmental Biology (LaBReD), Department of Morphology and Genetics, Federal University of Sao Paulo, UNIFESP, Sao Paulo, Brazil
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21
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Qi X, Zhang M, Sun M, Luo D, Guan Q, Yu C. Restoring Impaired Fertility Through Diet: Observations of Switching From High-Fat Diet During Puberty to Normal Diet in Adulthood Among Obese Male Mice. Front Endocrinol (Lausanne) 2022; 13:839034. [PMID: 35518932 PMCID: PMC9063411 DOI: 10.3389/fendo.2022.839034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/02/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Obesity is associated with a decrease in testicular function, yet the effects and mechanisms relative to different stages of sexual development remain unclear. The aim of this study is to determine whether high-fat diet-induced obesity impairs male fertility during puberty and in adulthood, and to ascertain its underlying mechanisms. This study aims to further reveal whether restoring to a normal diet can improve impaired fertility. METHODS Male mice were divided into 6 groups: the group N and H exposed to a normal diet or high-fat diet during puberty. The group NN or NH were further maintained a normal diet or exposed to high-fat diet in adulthood, the group HH or HN were further maintained high-fat diet or switched to normal diet in adulthood. Metabolic parameters, fertility parameters, testicular function parameters, TUNEL staining and testicular function-related proteins were evaluated, respectively. RESULTS The fertility of the mice in the high-fat diet group was impaired, which validated by declines in pregnancy rates and litter weight loss. Further analysis demonstrated the increased level of oxidative stress, the increased number of spermatogenic cell apoptosis and decreased number of sperm and decreased acrosome integrity. The expression of steroidogenic acute regulatory (StAR) and spermatogenesis related proteins (WT-1) decreased. Fertility among the HN group recovered, accompanied by the recovery of metabolism, fertility and testicular function parameters, StAR and WT-1 expression. CONCLUSIONS The findings suggest that high-fat diet-induced obesity impairs male fertility during puberty and in adulthood. The loss of acrosome integrity, the increase of oxidative stress, the increase of cells apoptosis and the down-regulation of StAR and WT-1 may be the underlying mechanisms. Switching from high-fat diets during puberty to normal diets in adulthood can improve male fertility.
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Affiliation(s)
- Xiangyu Qi
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
| | - Meijie Zhang
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Jing’an District Center Hospital, Fudan University, Shanghai, China
| | - Mingqi Sun
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- General Practice, Jinan Forth People’s Hospital, Jinan, China
| | - Dandan Luo
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
| | - Qingbo Guan
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
| | - Chunxiao Yu
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- Shandong Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital, Jinan, China
- *Correspondence: Chunxiao Yu,
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22
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De Luca MN, Colone M, Gambioli R, Stringaro A, Unfer V. Oxidative Stress and Male Fertility: Role of Antioxidants and Inositols. Antioxidants (Basel) 2021; 10:antiox10081283. [PMID: 34439531 PMCID: PMC8389261 DOI: 10.3390/antiox10081283] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022] Open
Abstract
Infertility is defined as a couple’s inability to conceive after at least one year of regular unprotected intercourse. This condition has become a global health problem affecting approximately 187 million couples worldwide and about half of the cases are attributable to male factors. Oxidative stress is a common reason for several conditions associated with male infertility. High levels of reactive oxygen species (ROS) impair sperm quality by decreasing motility and increasing the oxidation of DNA, of protein and of lipids. Multi-antioxidant supplementation is considered effective for male fertility parameters due to the synergistic effects of antioxidants. Most of them act by decreasing ROS concentration, thus improving sperm quality. In addition, other natural molecules, myo-inositol (MI) and d-chiro–inositol (DCI), ameliorate sperm quality. In sperm cells, MI is involved in many transduction mechanisms that regulate cytoplasmic calcium levels, capacitation and mitochondrial function. On the other hand, DCI is involved in the downregulation of steroidogenic enzyme aromatase, which produces testosterone. In this review, we analyze the processes involving oxidative stress in male fertility and the mechanisms of action of different molecules.
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Affiliation(s)
- Maria Nunzia De Luca
- The Experts Group on Inositol in Basic and Clinical Research (EGOI), 00161 Rome, Italy; (M.N.D.L.); (R.G.); (V.U.)
- System Biology Group Lab, 00161 Rome, Italy
| | - Marisa Colone
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
| | - Riccardo Gambioli
- The Experts Group on Inositol in Basic and Clinical Research (EGOI), 00161 Rome, Italy; (M.N.D.L.); (R.G.); (V.U.)
- System Biology Group Lab, 00161 Rome, Italy
| | - Annarita Stringaro
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
- Correspondence:
| | - Vittorio Unfer
- The Experts Group on Inositol in Basic and Clinical Research (EGOI), 00161 Rome, Italy; (M.N.D.L.); (R.G.); (V.U.)
- System Biology Group Lab, 00161 Rome, Italy
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Responses and coping methods of different testicular cell types to heat stress: overview and perspectives. Biosci Rep 2021; 41:228844. [PMID: 34060622 PMCID: PMC8209165 DOI: 10.1042/bsr20210443] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/09/2021] [Accepted: 05/24/2021] [Indexed: 01/27/2023] Open
Abstract
To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body temperature to ensure the normal progression of spermatogenesis. Rising temperatures affect spermatogenesis and eventually lead to a decline in male fertility or even infertility. However, the testes are composed of different cell types, including spermatogonial stem cells (SSCs), spermatocytes, spermatozoa, Leydig cells, and Sertoli cells, which have different cellular responses to heat stress. Recent studies have shown that using different drugs can relieve heat stress-induced reproductive damage by regulating different signaling pathways. Here, we review the mechanisms by which heat stress damages different cells in testes and possible treatments.
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24
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Gantenbein KV, Kanaka-Gantenbein C. Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing. Nutrients 2021; 13:nu13061951. [PMID: 34204057 PMCID: PMC8227318 DOI: 10.3390/nu13061951] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023] Open
Abstract
It has been established, worldwide, that non-communicable diseases such as obesity, diabetes, metabolic syndrome, and cardiovascular events account for a high percentage of morbidity and mortality in contemporary societies. Several modifiable risk factors, such as sedentary activities, sleep deprivation, smoking, and unhealthy dietary habits have contributed to this increase. Healthy nutrition in terms of adherence to the Mediterranean diet (MD), rich in fruits, legumes, vegetables, olive oil, herbs, spices, and high fiber intake may contribute to the decrease in this pandemic. The beneficial effects of the MD can be mainly attributed to its numerous components rich in anti-inflammatory and antioxidant properties. Moreover, the MD may further contribute to the improvement of reproductive health, modify the risk for neurodegenerative diseases, and protect against depression and psychosocial maladjustment. There is also evidence highlighting the impact of healthy nutrition in female people on the composition of the gut microbiota and future metabolic and overall health of their offspring. It is therefore important to highlight the beneficial effects of the MD on metabolic, reproductive, and mental health, while shaping the overall health of future generations. The beneficial effects of MD can be further enhanced by increased physical activity in the context of a well-balanced healthy lifestyle.
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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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