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Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

ABSTRACT: Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during in vitro expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages in vitro, we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-?B signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-?B and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.

SUBMITTER: Fang J

PROVIDER: S-EPMC6224246 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

Fang Jia J Yan Yuan Y Teng Xin X Wen Xinyu X Li Na N Peng Sha S Liu Wenshuai W Donadeu F Xavier FX Zhao Shanting S Hua Jinlian J

Aging 20181001 10

Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during <i>in vitro</i> expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages <i>in vi ...[more]

PMID: 30362962

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Project description:Exogenous melatonin inhibited the senescence of preosteoblast cells in type 1 diabetic (T1D) mice and those cultured in high glucose (HG) by multiple regulations. Exogenous melatonin had a protective effect on diabetic osteoporosis, which may depend on the inhibition of senescence.IntroductionSenescence is thought to play an important role in the pathophysiological mechanisms underlying diabetic bone loss. Increasing evidence has shown that melatonin exerts anti-senescence effects. In this study, we investigated whether melatonin can inhibit senescence and prevent diabetic bone loss.MethodsC57BL/6 mice received a single intraperitoneal injection of 160 mg/kg streptozotocin, followed by the oral administration of melatonin or vehicle for 2 months. Then, tissues were harvested and subsequently examined. MC3T3-E1 cells were cultured under HG conditions for 7 days and then treated with melatonin or not for 24 h. Sirt1-specific siRNAs and MT1- or MT2-specific shRNA plasmids were transfected into MC3T3-E1 cells for mechanistic study.ResultsThe total protein extracted from mouse femurs revealed that melatonin prevented senescence in T1D mice. The micro-CT results indicated that melatonin prevented bone loss in T1D mice. Cellular experiments indicated that melatonin administration prevented HG-induced senescence, whereas knockdown of the melatonin receptors MT1 or MT2 abolished these effects. Sirt1 expression was upregulated by melatonin administration but significantly reduced after MT1 or MT2 was knocked down. Knockdown of Sirt1 blocked the anti-senescence effects of melatonin. Additionally, melatonin promoted the expression of CDK2, CDK4, and CyclinD1, while knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the expression of the polycomb repressive complex (PRC), but knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the protein levels of Sirt1, PRC1/2 complex-, and cell cycle-related proteins.ConclusionThis work shows that melatonin protects against T1D-induced bone loss, probably by inhibiting senescence. Targeting senescence in the investigation of diabetic osteoporosis may lead to novel discoveries.

Project description:BackgroundDoxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options. We previously reported that Red Ginseng (steamed and dried the root of Panax Ginseng cultivated for over six years; RGin) is beneficial for the treatment of DICM. However, the mechanism underlying the action of RGin remains unclear. In this study, we investigated the mechanism of action underlying the efficacy of RGin in the treatment of DICM.MethodsFour-week-old DBA/2 mice were divided into: vehicle, DXR, RGin, and DXR + RGin (n = 10/group). Mice were treated with DXR (4 mg/kg, once a week, accumulated 20 mg/kg, i.p.) or RGin (0.5 g/kg, three times a week, i.p.). To evaluate efficacy, the survival rate and left ventricular ejection fraction (LVEF) were measured as a measure of cardiac function, and cardiomyocytes were subjected to Masson trichrome staining. To investigate the mechanism of action, western blotting was performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, transferrin receptor (TfR), and other related proteins. Data were analyzed using the Easy R software. Between-group comparisons were performed using one-way analysis of variance and analyzed using a post-hoc Tukey test. Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. P < 0.05 was considered statistically significant in all analyses.ResultsRGin treatment prolongs survival and protects against reduced LVEF. In the DXR group, Nrf2 was not activated and cell death was accelerated. Furthermore, there was an increase in the TfR levels, suggesting abnormal iron metabolism. However, the DXR + RGin group showed activation of the Nrf2 pathway and suppression of myocardial cell death. Furthermore, there was no increase in TfR expression, suggesting that there were no abnormalities in iron metabolism. Therefore, the mechanism of action of RGin in DICM involves an increase in antioxidant activity and inhibition of cell death through activation of the Nrf2 pathway.ConclusionRGin is a useful therapeutic candidate for DICM. Its efficacy is supported by the activation of the Nrf2 pathway, which enhances antioxidant activity and inhibits cell death.

Dataset Information

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

Publications

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

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