<scp>AMPK</scp>
            activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular
            <scp>NAD</scp>
            <sup>+</sup>
            elevation

Han, Xiaobin; Tai, Haoran; Wang, Xiaobo; Wang, Zhe; Zhou, Jiao; Wei, Xiawei; Ding, Yi; Gong, Hui; Mo, Chunfen; Zhang, Jie; Qin, Jianqiong; Ma, Yuanji; Huang, Ning; Xiang, Rong; Xiao, Hengyi

doi:10.1111/acel.12446

Cited by 246 publications

(207 citation statements)

References 40 publications

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“…Indeed, although we attempted, we did not obtain evidence that rapamycin could facilitate the nuclear translocation of TFEB. 39 This finding implies 2 possibilities: MTOR may regulate the function of autolysosomes via a TFEB-independent mechanism; and/or TFEB may be functionally regulated independent of MTOR. Thus, further assessments are currently underway.…”

Section: Discussionmentioning

confidence: 98%

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

et al. 2016

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Macroautophagy/autophagy has profound implications for aging. However, the true features of autophagy in the progression of aging remain to be clarified. In the present study, we explored the status of autophagic flux during the development of cell senescence induced by oxidative stress. In this system, although autophagic structures increased, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence and the activity of lysosomal proteolytic enzymes all decreased in senescent cells, indicating impaired autophagic flux with lysosomal dysfunction. The influence of autophagy activity on senescence development was confirmed by both positive and negative autophagy modulators; and MTOR-dependent autophagy activators, rapamycin and PP242, efficiently suppressed cellular senescence through a mechanism relevant to restoring autophagic flux. By time-phased treatment of cells with the antioxidant N-acetylcysteine (NAC), the mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and ambroxol, a reagent with the effect of enhancing lysosomal enzyme maturation, we found that mitochondrial dysfunction plays an initiating role, while lysosomal dysfunction is more directly responsible for autophagy impairment and senescence. Interestingly, the effect of rapamycin on autophagy flux is linked to its role in functional revitalization of both mitochondrial and lysosomal functions. Together, this study demonstrates that autophagy impairment is crucial for oxidative stressinduced cell senescence, thus restoring autophagy activity could be a promising way to retard senescence.

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Section: Discussionmentioning

confidence: 98%

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

et al. 2016

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“…Both CTRP3 and adiponectin belong to the C1q/TNF superfamily CTRP3 and suppress hepatic gluconeogenesis 113 and are decreased with obesity 114 . Activation of AMPK by metformin restored ROS-impaired autophagy in senescent cells 115 . The impairment of autophagy will be reviewed further in section 3.3.…”

Section: Macrophage and Adipocyte Dysfunction In Obese Adipose Tissuementioning

confidence: 98%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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“…In addition, monitoring of autophagic flux includes assessment of p62 degradation and the activity of autolysosomal hydrolases28, as well as examination of the quenching of GFP-tagged LC3 protein2930. Autophagy is regulated by AMPK signalling3132. The most commonly described mechanism is suppression of the mTORC1 pathway313334.…”

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confidence: 99%

The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

Wang

Yuan

Zou

et al. 2016

Sci Rep

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Autophagy is protective in cadmium (Cd)-induced oxidative damage. Endoplasmic reticulum (ER) stress has been shown to induce autophagy in a process requiring the unfolded protein response signalling pathways. Cd treatment significantly increased senescence in neuronal cells, which was aggravated by 3-MA or silencing of Atg5 and abolished by rapamycin. Cd increased expression of ER stress regulators Bip, chop, eIf2α, and ATF4, and activated autophagy as evidenced by upregulated LC3. Moreover, the ER stress inhibitor mithramycin inhibited the expression of ER stress protein chaperone Bip and blocked autophagic flux. Downregulating Bip significantly blocked the conversion of LC3-I to LC3-II, decreased LC3 puncta formation, and prevented the increase of senescence in PC12 cells. Interestingly, knocking down Bip regulated the expression of p-AMPK, p-AKT and p-s6k induced by Cd. BAPTA, a Bip inhibitor, decreased the expression of p-AMPK and LC3-II, but enhanced neuronal senescence. In addition, we found that siRNA for Bip enhanced GATA4 expression after 6 h Cd exposure in PC12 cells, while rapamycin treatment decreased GATA4 levels induced by 24 h Cd exposure. These results indicate that autophagy degraded GATA4 in a Bip-dependent way. Our findings suggest that autophagy regulated by Bip expression after ER stress suppressed Cd-induced neuronal senescence.

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AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

Cited by 246 publications

References 40 publications

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

Macrophage functions in lean and obese adipose tissue

The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

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AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

Cited by 246 publications

References 40 publications

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

Macrophage functions in lean and obese adipose tissue

The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

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Product

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AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation