Mitochondrial VDAC1: A Potential Therapeutic Target of Inflammation-Related Diseases and Clinical Opportunities

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3174 - 3174

Published: Oct. 10, 2022

The multifunctional protein, voltage-dependent anion channel 1 (VDAC1), is located on the mitochondrial outer membrane. It a pivotal protein that maintains function to power cellular bioactivities via energy generation. VDAC1 involved in regulating production, oxidase stress, Ca2+ transportation, substance metabolism, apoptosis, autophagy (mitophagy), and many other functions. malfunction associated with disorders affect inflammatory responses, resulting an up-regulation of body's defensive response stress stimulation. Overresponses inflammation may cause chronic diseases. Mitochondrial DNA (mtDNA) acts as danger signal can further trigger native immune system activities after its secretion. mediates release mtDNA into cytoplasm enhance cytokine levels by activating responses. regulates lipid metabolism mitophagy, which are inflammation-related disease pathogenesis. Many scientists have suggested approaches deal overresponse issues specific targeting therapies. Due broad functionality VDAC1, it become useful target for therapy mechanisms role require exploration. We comprehensively systematically summarized response, hope our research will lead novel therapeutic strategies order treat disorders.

Language: Английский

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Ginsenoside Rd Inhibited Ferroptosis to Alleviate CCl₄-Induced Acute Liver Injury in Mice via cGAS/STING Pathway

The American Journal of Chinese Medicine, Journal Year: 2022, Volume and Issue: 51(01), P. 91 - 105

Published: Nov. 28, 2022

Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd considered active ingredient ginseng. Evidence suggests that ginsenoside may improve ischaemic stroke, nerve damage, cancer other diseases involving apoptosis, inflammation, stress, mitochondrial autophagy. However, the effects on CCl4-induced ALI its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a model. treatment group, (10, 20[Formula: see text]mg/kg) doses were 1[Formula: text]h before 23[Formula: after administration. Ferroptosis inducer imidazole ketone erastin (IKE) 4[Formula: administration explore mechanism. The blood collected 24[Formula: investigate effect ALI. Our results showed inhibited mice. also downregulated serum iron, 4-hydroxynonenal, 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione peroxidase 4 addition, expression cGAS STING. Subsequently, ferroptosis significantly reversed hepatoprotective influence regard indicators mentioned above. study confirmed ameliorated mice, which related reduction ferroptosis. Simultaneously, Rd-mediated inhibition cGAS/STING pathway contributed antiferroptosis effect. conclusion, our suggested via pathway, thereby protecting from These be used as potential intervention against

Language: Английский

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ROS and DRP1 interactions accelerate the mitochondrial injury induced by polystyrene nanoplastics in human liver HepG2 cells

Chemico-Biological Interactions, Journal Year: 2023, Volume and Issue: 379, P. 110502 - 110502

Published: April 19, 2023

Language: Английский

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Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: July 8, 2023

Aged livers have shown aggravated liver ischemia and reperfusion (IR) injury. Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive inflammation tissue Here, we investigated the alteration by aged macrophages its role in regulating macrophage STING (stimulator interferon genes) signaling IR young mice were subjected to partial model. Liver injury measured. Efferocytosis underlying regulatory analyzed as well. exhibited impaired with decreased MerTK (c-mer proto-oncogene tyrosine kinase) activation, which was reversed treatment CRISPR activation plasmid. Increased cleavage ADAM17 (a disintegrin metalloproteinase 17) due enhanced ROS (reactive oxygen species) levels contributed defective macrophages. suppressing or improved efferocytosis, leading reduced inflammatory Moreover, increased hepatocytes, DNA accumulation, observed ischemic livers. Improvement via suppressed Our study demonstrates that aging suppresses MerTK- mediated promote injury, suggesting new potential therapy resolution

Language: Английский

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IQGAP1 promotes mitochondrial damage and activation of the mtDNA sensor cGAS-STING pathway to induce endothelial cell pyroptosis leading to atherosclerosis

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 123, P. 110795 - 110795

Published: Aug. 17, 2023

Language: Английский

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CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP‐43 and Encoding A Novel TMEFF1‐339aa Protein

Advanced Science, Journal Year: 2023, Volume and Issue: 10(17)

Published: April 23, 2023

Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that involved in various physiological pathological processes, but their role remains unknown. Global circRNA expression profiling indicated circRNAs the pathophysiological processes atrophy. circTmeff1 identified as potential candidate influences It further highly expressed multiple types vivo vitro. Moreover, overexpression triggers vitro vivo, while knockdown rescues vivo. In particular, partially mass mice during established atrophic settings. Mechanistically, directly interacts with TAR DNA-binding protein 43 (TDP-43) promotes aggregation TDP-43 mitochondria, which release mitochondrial DNA (mtDNA) into cytosol activation cyclic GMP-AMP synthase (cGAS)/ stimulator interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa novel encoded by mediates its pro-atrophic effects. Collectively, inhibition represents therapeutic approach for skeletal

Language: Английский

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Mitochondrial (mt)DNA–cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 27, 2024

Abstract Background Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate cellular immune suppression during process SAP, where cyclic GMP–AMP synthase (cGAS)–stimulator interferon genes (STING) plays an important role. However, function mechanism cGAS–STING in SAP-induced lung injury (LI) remains unknown. Methods Lipopolysaccharide (LPS) was combined with caerulein-induced SAP wild type, cGAS −/− sting mice . Primary macrophages were extracted via bronchoalveolar lavage peritoneal lavage. Ana-1 cells pretreated LPS stimulated nigericin sodium salt induce pyroptosis vitro. Results triggered NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated alveolar mouse model. Knockout / STING could ameliorate NLRP3 pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria induced a cGAS- dose-dependent manner. Upregulated signal promote inflammasome-mediated increase serum interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α levels thus, SAP-associated LI (SAP-ALI). Downstream molecules STING, IRF7, IRF3 connect mtDNA–cGAS–STING axis NLRP3–pyroptosis axis. Conclusions Negative regulation any molecule mtDNA–cGAS–STING–IRF7/IRF3 pathway affect inflammasomes, thereby reducing improving SAP-ALI

Language: Английский

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ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Hepatology Communications, Journal Year: 2024, Volume and Issue: 8(4)

Published: March 18, 2024

Background: Fatty livers are widely accepted as marginal donors for liver transplantation but more susceptible to ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty IR Here, we investigate precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain–associated 3 (NLRP3) signaling regulating mitochondrial calcium overload IR. Methods: Control- high-fat diet-fed mice were subjected a partial model. The ER stress, levels, NLRP3 pathway macrophages analyzed. Results: Liver steatosis exacerbated injury enhanced activation macrophages. Myeloid deficiency attenuated intrahepatic following Mechanistically, increased observed obtained from mouse after Suppression tauroursodeoxycholic acid effectively downregulated accumulation suppressed macrophages, leading decreased inflammatory livers. Moreover, Xestospongin-C–mediated inhibition influx reactive oxygen species (ROS) expression Scavenging ROS mito-TEMPO livers, indicating that excessive production was responsible induced overload. Patients with also exhibited upregulated Conclusions: Our findings suggest promotes activate ROS/NLRP3 pathways within during IR-stimulated responses associated

Language: Английский

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FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 8, 2024

Abstract Background Subarachnoid hemorrhage (SAH) represents a form of cerebrovascular event characterized by notable mortality and morbidity rate. Fibroblast growth factor 21 (FGF21), versatile hormone predominantly synthesized the hepatic tissue, has emerged as promising neuroprotective agent. Nevertheless, precise impacts underlying mechanisms FGF21 in context SAH remain enigmatic. Methods To elucidate role inhibiting microglial cGAS-STING pathway providing protection against SAH-induced cerebral injury, series cellular molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, RNA sequencing, behavioral assays, were employed. Results Administration recombinant fibroblast (rFGF21) effectively mitigated neural apoptosis, improved edema, attenuated neurological impairments post-SAH. Transcriptomic analysis revealed that triggered upregulation numerous genes linked to innate immunity, particularly those involved type I interferon (IFN-I) function, which notably suppressed upon adjunctive rFGF21 treatment. Mechanistically, intervention facilitated mitophagy an AMP-activated protein kinase (AMPK)-dependent manner, thereby preventing mitochondrial DNA (mtDNA) release into cytoplasm dampening activation DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator (STING) signaling pathway. Conditional knockout STING microglia markedly ameliorated inflammatory response secondary brain injuries Conclusion Our results present initial evidence confers protective effect neuroinflammation-associated damage subsequent SAH. we have elucidated novel exerts this neuroprotection through inhibition cascade.

Language: Английский

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IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114088 - 114088

Published: April 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2

Language: Английский

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