Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress

Exercise is among the most effective interventions for age-associated mobility decline and metabolic dysregulation. Although long-term endurance exercise promotes insulin sensitivity and expands respiratory capacity, genetic components and pathways mediating the metabolic benefits of exercise have remained elusive. Here, we show that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits. In both fly and mouse models, genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism. Among the various targets modulated by Sestrin in response to exercise, AKT and PGC1α are critical for the Sestrin effects in extending endurance. These results indicate that Sestrin is a key integrating factor that drives the benefits of chronic exercise to metabolism and physical endurance.

/pdf/sestrins-are-evolutionarily-conserved-mediators-of-exercise-2sn7q9avfd.pdf

Sestrins are evolutionarily conserved mediators of exercise benefits

Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1α (Hif-1α), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor β (TGF-β) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns.

/pdf/recent-insights-into-the-biological-functions-of-sestrins-in-1c64gxny1n.pdf

Recent Insights into the Biological Functions of Sestrins in Health and Disease.

Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a new mechanism that depends on the terminal complement components (C5b-C9). We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane by a 'bystander' mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1 activation and IL-1β and IL-18 secretion. Inflammasome activation is not induced when macrophages phagocytize unopsonized particles or particles opsonized with serum deficient in one of the terminal complement components. The secretion of IL-1β and IL-18 by macrophages depends on NLRP3, ASC (also known as PYCARD) and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes T helper 17 cell (TH17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.

/pdf/complement-mediated-bystander-damage-initiates-host-nlrp3-1wh3lo7dd6.pdf

Complement-mediated 'bystander' damage initiates host NLRP3 inflammasome activation.

Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in cellular responses to various stresses. SESN2 has a protective effect on physiological and pathological states mainly via regulating oxidative stress, endoplasmic reticulum stress, autophagy, metabolism, and inflammation. In recent years, breakthrough investigations with regard to the regulation and signaling mechanisms of SESN2 have markedly deepened our understanding of its potential role as well as its significance in host response. However, the functions of SESN2 in the immune system and inflammation remain elusive. It has been documented that many immune cells positively express SESN2 and, in turn, that SESN2 might modulate cellular activities. This review incorporates recent progress and aims to provide novel insight into the protective role and regulatory pathway of SESN2, which acts as a potential biomarker and therapeutic target in the context of various diseases.

/pdf/sestrin2-its-potential-role-and-regulatory-mechanism-in-host-4tyhwud7wl.pdf

Chang Ho Jang

Papers

Regulation of Toll-like receptor-mediated Sestrin2 induction by AP-1, Nrf2, and the ubiquitin-proteasome system in macrophages.