Oligosaccharide attenuates aging‐related liver dysfunction by activating Nrf2 antioxidant signaling

Wang, Yueming; Xiong, Yanlei; Zhang, Aiping; Zhao, Nannan; Zhang, Jiashen; Yu, Zhenhai; Xu, Ning; Yin, Yancun; Luan, Xiying

doi:10.1002/fsn3.1681

Cited by 29 publications

(23 citation statements)

References 37 publications

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“…In aging, increasing oxidative stress was induced by various metabolites, on the contrary, as the primary lines of defense, the activity of antioxidant enzymes decreased. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial regulator of the cellular antioxidant system, which regulates the expression of a variety of key antioxidant enzymes [ 6 – 8 ]. There is evidence that activated Nrf2 protection against the phenotypic changes and mitochondrial function in memory T cells, relieve aged-related oxidant injury [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

hPMSCs protects against d-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

et al. 2020

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Background Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a d-gal-induced mouse aging model. Methods In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, d-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. Results We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells. Conclusions Our results indicate that hPMSCs attenuate d-gal-induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

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Section: Introductionmentioning

confidence: 99%

hPMSCs protects against d-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

et al. 2020

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“…Cells were seeded into 96-well plates at the density of 5,000 cells/well. After 24 h incubation, cells were treated with 2 and 5 µM salinomycin, 10 µM tBHQ (Nrf2 activator) or 10 µM ML385 (Nrf2 inhibitor) for 72 h (22)(23)(24). Salinomycin (Sigma-Aldrich; Merck KGaA) was dissolved in DMSO to create the stock solution.…”

Section: Methodsmentioning

confidence: 99%

Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling

Yang

et al. 2021

Exp Ther Med

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Salinomycin is a polyether antiprotozoal antibiotic that is widely used as an animal food additive. Some antifungal, antiparasitic, antiviral and anti-inflammatory activities have been reported for salinomycin. Recently, the anti-cancer effect of salinomycin has been demonstrated in breast cancer; however, the underlying mechanism remains unknown. The present study aimed to investigate the functional roles of salinomycin in the progression of prostate cancer cells using the DU145 and PC-3 cell lines. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression of oxidative stress and endoplasmic reticulum stress-related molecules, and flow cytometry was performed to detect the apoptosis rate of DU145 and PC-3 cells after salinomycin treatment. The results demonstrated that salinomycin inhibited the viability and induced the apoptosis of PC-3 and DU145 cells in a dose-dependent manner. Furthermore, salinomycin increased the production of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and the lipid peroxidation. In addition, salinomycin induced the activation of unfolded protein response and endoplasmic reticulum stress in DU145 and PC-3 cells, as indicated by the elevated expression of binding immunoglobulin protein, activating transcription factor 4, phosphorylated eukaryotic initiation factor 2α, phosphorylated protein kinase RNA-like endoplasmic reticulum kinase and C/EBP homologous protein.In addition, salinomycin significantly downregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 and glutamate-cysteine ligase catalytic subunit and decreased the activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in PC-3 and DU145 cells. Furthermore, the Nrf2 activator, tert-butylhydroquinone, significantly reversed the therapeutic effects of salinomycin by stimulating the Nrf2 pathway and increasing the activity of antioxidant enzymes. Taken together, these findings demonstrated that salinomycin may trigger apoptosis by inducing oxidative and ER stress in prostate cancer cells via suppressing Nrf2 signaling.

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“…Nrf2 regulates various downstream antioxidation and detoxification enzymes such as NQO1, HO-1, SOD, catalase (CAT), and glutamate-cysteine ligase catalytic subunit (GCLC) by binding to the antioxidant response element in their promoter regions [ 35 ]. For example, trehalose and chitosan oligosaccharide all showed an antiaging effect by promoting the nuclear translocation of Nrf2 and subsequently activating the expression of downstream target genes HO-1, NQO1, and CAT in aging mice [ 36 , 37 ]. Furthermore, recent studies showed that the activation of multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK), facilitates the release of Nrf2 from Keap1 and subsequent translocation for the induction of various antioxidant and detoxification enzyme expressions [ 19 , 38 , 39 ].…”

Section: Activation Of Nrf2 and Agingmentioning

confidence: 99%

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

Chao

Xiao

2021

Oxidative Medicine and Cellular Longevity

270

136

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Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

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Oligosaccharide attenuates aging‐related liver dysfunction by activating Nrf2 antioxidant signaling

Cited by 29 publications

References 37 publications

hPMSCs protects against d-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

hPMSCs protects against d-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

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