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      • Record: found
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      Ac-YVAD-cmk ameliorated sevoflurane-induced cognitive dysfunction and revised mitophagy impairment

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      Publication date (Electronic):
      Journal: PLOS ONE
      Publisher: Public Library of Science

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          Abstract

          It is common for elderly patients to develop postoperative cognitive dysfunction (POCD), but the pathophysiological mechanisms have not yet been fully explored. NLRP3 inflammasome activation and mitophagy impairment was involved in neurodegenerative disease. This study investigated the interaction of NLRP3 inflammasome and mitophagy in sevoflurane-induced cognitive dysfunction. We found that sevoflurane induced cleaved caspase-1 level, IL-1β and IL-18 maturation, and activated NLRP3 inflammasome in aged mice and the primary hippocampus neuron. The cleaved caspase-1 was demonstrated in microglia of hippocampus. Ac-YVAD-cmk, a selected caspase-1 inhibitor, reduced the expression of cleaved caspase-1, IL-1β, IL-18 and NLRP3 inflammasome activation induced by sevoflurane. Ac-YVAD-cmk ameliorated learning ability impairment in aged mice induced by sevoflurane using Morris water maze. Moreover, Ac-YVAD-cmk reversed the mitophagy flux dysfunction induced by sevoflurane in aged mice by western blotting, immunostaining and mt-Keima reporters. For the first time, we found caspase-1 inhibitor mitigated mitochondria dysfunction and revised mitophagy impairment induced by sevoflurane.

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          A role for mitochondria in NLRP3 inflammasome activation.

          Rongbin Zhou, Amir Yazdi, Philippe Menu … (2011)
          An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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            Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.

            Xing-Xing Liu, Zhibin Zhang, Jianbin Ruan … (2016)
            Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.
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              A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

              Rebecca Coll, Avril A B Robertson, Jae Jin Chae … (2015)
              The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.
              Article 0 comments Cited 688 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Du Zheng: Role: Data curationRole: Investigation
                Hongwei Wang: Role: InvestigationRole: Software
                Youfa Zhou: Role: MethodologyRole: Software
                Yeru Chen: Role: SupervisionRole: Writing – original draft
                Gang Chen:
                ORCID: https://orcid.org/0000-0003-4262-9491
                Role: SupervisionRole: Writing – original draft
                David Chau: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS One
                Journal ID (publisher-id): plos
                Title: PLOS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 25 January 2023
                Publication date Collection: 2023
                Volume: 18
                Issue: 1
                Electronic Location Identifier: e0280914
                Affiliations
                [001] Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
                University College London, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-4262-9491
                Article
                Publisher ID: PONE-D-22-21471
                DOI: 10.1371/journal.pone.0280914
                PMC ID: 9876368
                PubMed ID: 36696410
                SO-VID: 544ccfec-21a9-408f-ab75-08eb92abedbf
                Copyright © © 2023 Zheng et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 30 July 2022
                Date accepted : 11 January 2023
                Page count
                Figures: 5, Tables: 0, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004731, Natural Science Foundation of Zhejiang Province;
                Award ID: LZ19H090003
                Award Recipient :
                ORCID: https://orcid.org/0000-0003-4262-9491
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82171176
                Award Recipient :
                ORCID: https://orcid.org/0000-0003-4262-9491
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82001424
                Award Recipient :
                ORCID: https://orcid.org/0000-0003-4262-9491
                This research was supported by the Key Program of the Natural Science Foundation of Zhejiang, China (No. LZ19H090003) and the National Natural Science Foundation of China (No.82171176 and No.82001424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Brain
                Subject: Hippocampus
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Brain
                Subject: Hippocampus
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Inflammasomes
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Inflammasomes
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Immune System Proteins
                Subject: Inflammasomes
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Bioenergetics
                Subject: Energy-Producing Organelles
                Subject: Mitochondria
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Structures and Organelles
                Subject: Energy-Producing Organelles
                Subject: Mitochondria
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Neurons
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neurons
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Science
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Reactive Oxygen Species
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Science
                Subject: Cognitive Psychology
                Subject: Learning
                Subject: Biology and Life Sciences
                Subject: Psychology
                Subject: Cognitive Psychology
                Subject: Learning
                Subject: Social Sciences
                Subject: Psychology
                Subject: Cognitive Psychology
                Subject: Learning
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Learning and Memory
                Subject: Learning
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                Data Availability All relevant data are within the paper and its Supporting Information files.

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