H 2 O 2 and mTOR control the senescence-associated secretory phenotype by coordinating Ca 2+ transients through TRPC6 expression and activation

Chandrasekaran, Akshaya; Zhang, Xuexin; Lee, May Y; Shapiro, Russell; Trebak, Mohamed; Meléndez, J. Andrés

doi:10.1016/j.freeradbiomed.2017.10.075

Cited by 2 publications

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“…The fact that the effects caused by simulated microgravity (reduced proliferation, retarded cell cycle progression and increased senescence) were recapitulated by TRPC channel inhibition and were accompanied by downregulation of TRPC6 expression suggests that TRPC6 may potentially play a role in the underlying mechanisms. In fact, TRPC6 has also been associated with cell senescence in lung fibroblasts [30], a contributor to pulmonary hypertension [55], consequentially motivating first studies on the therapeutic potential of TRPC6 modulation [55]. This study thus reveals TRPC6 as a potential target for further studies aiming to investigate IVD degeneration.…”

Section: Discussionmentioning

confidence: 80%

“…Therefore, TRPC6 could potentially be of importance in the progression of IVD degeneration linked to cell senescence, but further studies are needed. In fact, the role of TRP channels in modulating senescence is also known for other cell types, such as endothelial cells (TRPC5) [47], pancreatic adenocarcinoma cells (TRPM7, TRPM8) [48,49] and lung fibroblasts (TRPC6) [30].…”

Section: Discussionmentioning

confidence: 99%

“…Aside from TRPC6, the isoform TRPC1 may also be of specific relevance. TRPC1 and TRPC6 are both known to affect cell cycle progression in various cell types [27][28][29], and TRPC6 was shown to modulate cellular senescence [30]. Therefore, their modulation and (dys-)regulation may play a crucial role in IVD health, but also degeneration.…”

Section: Introductionmentioning

confidence: 99%

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TRPC6 in simulated microgravity of intervertebral disc cells

et al. 2018

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Purpose Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. Methods Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5 days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. Results Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3 days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. Conclusions Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies.Graphical abstract These slides can be retrieved under Electronic Supplementary Material.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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TRPC6 in simulated microgravity of intervertebral disc cells

et al. 2018

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“…As noted above, polyphenols activate SIRT1, which leads to the downregulation of mTOR [211,212]. It is important to highlight the fact that mTOR is one of the key mechanisms of initiation of the SASP [216][217][218][219]. The underlying mechanism that causes SASP activation via mTOR is regulation the translation of the MK2/MAPKAPK2 kinase, which inhibits the ability of protein ZFP36L1 to degrade the transcripts of numerous SASP components [216].…”

Section: The Role Of Autophagy and Sasp In Senescence And Their Regulation By Polyphenolsmentioning

confidence: 97%

“…The underlying mechanism that causes SASP activation via mTOR is regulation the translation of the MK2/MAPKAPK2 kinase, which inhibits the ability of protein ZFP36L1 to degrade the transcripts of numerous SASP components [216]. Other mechanisms of SASP control are based on inhibition of cytokine IL1A which causes suppression NF-κB transcriptional activity [219] or via mTOR-mediated regulation of TRPC6 channel [218].…”

Section: The Role Of Autophagy and Sasp In Senescence And Their Regulation By Polyphenolsmentioning

confidence: 99%

Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research

et al. 2020

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It has been thought that caloric restriction favors longevity and healthy aging where autophagy plays a vital role. However, autophagy decreases during aging and that can lead to the development of aging-associated diseases such as cancer, diabetes, neurodegeneration, etc. It was shown that autophagy can be induced by mechanical or chemical stress. In this regard, various pharmacological compounds were proposed, including natural polyphenols. Apart from the ability to induce autophagy, polyphenols, such as resveratrol, are capable of modulating the expression of pro- and anti-apoptotic factors, neutralizing free radical species, affecting mitochondrial functions, chelating redox-active transition metal ions, and preventing protein aggregation. Moreover, polyphenols have advantages compared to chemical inducers of autophagy due to their intrinsic natural bio-compatibility and safety. In this context, polyphenols can be considered as a potential therapeutic tool for healthy aging either as a part of a diet or as separate compounds (supplements). This review discusses the epigenetic aspect and the underlying molecular mechanism of polyphenols as an anti-aging remedy. In addition, the recent advances of studies on NAD-dependent deacetylase sirtuin-1 (SIRT1) regulation of autophagy, the role of senescence-associated secretory phenotype (SASP) in cells senescence and their regulation by polyphenols have been highlighted as well. Apart from that, the review also revised the latest information on how polyphenols can help to improve mitochondrial function and modulate apoptosis (programmed cell death).

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H 2 O 2 and mTOR control the senescence-associated secretory phenotype by coordinating Ca 2+ transients through TRPC6 expression and activation

Cited by 2 publications

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TRPC6 in simulated microgravity of intervertebral disc cells

TRPC6 in simulated microgravity of intervertebral disc cells

Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research

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