Melatonin promotes goat spermatogonia stem cells (SSCs) proliferation by stimulating glial cell line-derived neurotrophic factor (GDNF) production in Sertoli cells

Niu, Bowen; Li, Bo; Wu, Chongyang; Wu, Jianli; Yan, Yuan; Shang, Rui; Bai, Chunling; Li, Guangpeng; Hua, Jinlian

doi:10.18632/oncotarget.12720

Cited by 40 publications

(31 citation statements)

References 47 publications

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“…In a previous study, we demonstrated for the first time that melatonin activated Akt phosphorylation following FCI in mice [14], which was later shown in various tissues, including brain [4], [5], [15], seminiferous tubules [31] as well as in cancer cells [32]. Melatonin-induced apoptosis of cancer cells is intervened by Pi3K/Akt pathway [32].…”

Section: Discussionmentioning

confidence: 86%

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

et al. 2017

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Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonin's neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. However, PI3K/Akt inhibition did not inhibit melatonin's positive effect on brain swelling and IgG extravasation. Additionally, phosphorylation of mTOR, PTEN, AMPKα, PDK1 and RSK1 were increased, while phosphorylation of 4E-BP1, GSK-3α/β, S6 ribosomal protein were decreased in melatonin treated animals. In addition, melatonin decreased apoptosis through reduced p53 phosphorylation by the PI3K/Akt pathway. In conclusion, we demonstrated the activation profiles of PI3K/Akt signaling pathway components in the pathophysiological aspect of ischemic stroke and melatonin's neuroprotective activity. Our data suggest that Akt phosphorylation, preferably at the Thr308 site of the activation loop via PDK1 and PTEN, mediates melatonin's neuroprotective activity and increased Akt phosphorylation leads to reduced apoptosis.

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Section: Discussionmentioning

confidence: 86%

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

et al. 2017

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“…A couple of studies revealed that melatonin alleviates Cd-induced cellular stress and germ cell apoptosis in testes [50] and prevents bisphenol A-induced apoptosis by controlling BCL2 expression and ameliorating oxidative stress in the testes and sperm [51]. Furthermore, melatonin had a positive influence on the efficiency of male germ cell differentiation [52], and it can promote goat SSC proliferation by stimulating GDNF production in Sertoli cells [53]. …”

Section: Discussionmentioning

confidence: 99%

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Cui

Ren

et al. 2017

Cell Physiol Biochem

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Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

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“…Melatonin has been shown to be involved in male reproduction by modulating steroid hormone secretion 16 as well as by being involved in the proliferation of spermatogenic cells. 17 Moreover, melatonin protects the testis against hyperthermia, environmental toxins, and drug-induced damage [18][19][20] due to its lipophilic and hydrophilic free radical scavenging characteristics. 21 Indeed, previous studies have demonstrated the beneficial effects of melatonin treatment on testicular cells under pathological conditions; however, it is unclear whether melatonin can prevent obesity-associated male infertility, specifically in PAinduced testicular damage.…”

Section: Introductionmentioning

confidence: 99%

Melatonin protects mouse testes from palmitic acid‐induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner

Liu

Zhao

et al. 2020

Journal of Pineal Research

139

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Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA-induced lipotoxicity may contribute to obesity-related male infertility. Melatonin has beneficial effects on reproductive processes; however, the effect and the underlying molecular mechanism of melatonin's involvement in PA-induced cytotoxicity in the testes are poorly understood. Our findings showed that lipotoxicity was observed in mouse testes after long-term PA treatment and that melatonin therapy restored spermatogenesis and fertility in these males. Moreover, melatonin therapy suppressed PA-induced apoptosis by modulating apoptosis-associated proteins such as Bcl2, Bax, C-Caspase3, C-Caspase12, and CHOP in type B spermatogonial stem cells. Changes in the expression of endoplasmic reticulum (ER) stress markers (p-IRE1, p-PERK, ATF4) and intracellular Ca 2+ levels showed that melatonin relieved PA-induced ER stress. Mechanistically, melatonin stimulated the expression and nuclear translocation of SIRT1 through its receptors and prevented PA-induced ROS production and mitochondrial dysfunction via SIRT1 signaling pathway. Furthermore, melatonin promoted SIRT1-mediated p53 deacetylation, thereby relieving G2/M arrest in response to PA-stimulated DNA damage. Collectively, these findings indicate that melatonin protects the testes from PA-induced lipotoxicity through the activation of SIRT1, which alleviates oxidative stress, ER stress, mitochondrial dysfunction, and DNA damage.

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Melatonin promotes goat spermatogonia stem cells (SSCs) proliferation by stimulating glial cell line-derived neurotrophic factor (GDNF) production in Sertoli cells

Cited by 40 publications

References 47 publications

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Melatonin protects mouse testes from palmitic acid‐induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner

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