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      Recent Advances in Studies of Molecular Hydrogen against Sepsis

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          Abstract

          Sepsis is a syndrome comprised of a series of life-threatening organ dysfunctions caused by a maladjusted body response to infection with no effective treatment. Molecular hydrogen is a new type of antioxidant with strong free radical scavenging ability, which has been demonstrated to be effective for treating various diseases, such as infection, trauma, poisoning, organ ischemia-reperfusion, metabolic diseases, and tumors. Molecular hydrogen exerts multiple biological effects involving anti-inflammation, anti-oxidation, anti-apoptosis, anti-shock, and autophagy regulation, which may attenuate the organ and barrier damage caused by sepsis. However, the underlying molecular mechanisms remain elusive, but are likely related to the signaling pathways involved. This review focuses on the research progress and potential mechanisms of molecular hydrogen against sepsis to provide a theoretical basis for clinical treatment.

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          Most cited references95

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          Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

          Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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            Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis

            Key Points The cellular degradative process of autophagy participates in multiple aspects of immunity, including cell-autonomous defence, innate immune signalling and antigen presentation. Extensive crosstalk between autophagy and inflammatory signalling cascades ensures a robust immune response towards pathogens while avoiding collateral damage to the host. Several chronic inflammatory disorders are associated with autophagy dysfunction. Pathways that induce autophagy, such as those downstream of pattern recognition receptors, are conversely subject to regulation by autophagy. Autophagy can increase and decrease different components of the same inflammatory signalling cascade in a context-dependent manner. Many immune-related functions of conserved autophagy proteins reflect non-canonical functions of the autophagy machinery, representing new opportunities for therapeutic intervention. Supplementary information The online version of this article (doi:10.1038/nri.2016.100) contains supplementary material, which is available to authorized users.
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              ROCK and Dia have opposing effects on adherens junctions downstream of Rho.

              Adherens junctions (AJs) are crucial for maintaining the integrity of epithelial tissues and are often disrupted during tumour progression. Rho family proteins have been shown to regulate adherens junctions. We find that activation of the effector kinase ROCK and acto-myosin contraction disrupts AJs downstream of Rho. In contrast, signalling through the Rho effector Dia1 is required to ensure a dynamically stable interface between cells and the maintenance of adherens junction complexes. The ability of Dia1 to regulate the actin network is crucial for the localization of adherens junction components to the cell periphery.
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                Author and article information

                Journal
                Int J Biol Sci
                Int. J. Biol. Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2019
                11 May 2019
                : 15
                : 6
                : 1261-1275
                Affiliations
                [1 ]Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
                [2 ]Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
                Author notes
                ✉ Corresponding author: Jin Zhang, Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China. E-mail: zhangj_sj@ 123456163.com Tel.: +86 18940259646

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijbsv15p1261
                10.7150/ijbs.30741
                6567800
                31223285
                04f5ebb8-72b6-436a-85cd-36d19be9a833
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 27 November 2018
                : 9 January 2019
                Categories
                Review

                Life sciences
                molecular hydrogen,sepsis,oxidative stress,apoptosis,shock,autophagy
                Life sciences
                molecular hydrogen, sepsis, oxidative stress, apoptosis, shock, autophagy

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