Mechanism of metformin regulation in central nervous system: Progression and future perspectives DOI Creative Commons

Gui Cao,

Ting Gong, Yue Du

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 156, P. 113686 - 113686

Published: Oct. 13, 2022

Metformin as a first-line drug for type 2 diabetes mellitus(T2DM) treatment is widely studied. can reduce liver glucose output and improve insulin resistance. Recent evidence from in vivo vitro has confirmed that metformin transport across the blood-brain barrier(BBB) activate specific neurons neuroglia to exert neurological actions, however, effect of regulation on CNS still obscure. In this review, we summarized current preclinical focusing regulatory role found potential neuroprotective, neurotrophic, neurogenesis-stimulated actions; besides, also exerts antiinflammatory by inhibiting microglial activates regulating polarization. These findings indicate there might be extensive pharmacological efficacy therapeutic insights diseases' clinical application.

Language: Английский

Mitochondrial control of inflammation DOI Open Access
Saverio Marchi, Emma Guilbaud, Stephen W. G. Tait

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(3), P. 159 - 173

Published: July 25, 2022

Language: Английский

Citations

560
Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling DOI Creative Commons
Hongxu Xian, Kosuke Watari, Elsa Sánchez‐López

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(8), P. 1370 - 1385.e8

Published: July 13, 2022

Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, is unknown how and in which form Ox-mtDNA exits non-apoptotic macrophages. We found that diverse NLRP3 activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, induce generation. Within mitochondria, was either repaired by glycosylase OGG1 cleaved the endonuclease FEN1 500–650 bp fragments exited mPTP- VDAC-dependent channels initiate also activated signaling gave rise pro-inflammatory extracellular DNA. Understanding this process will advance development potential treatments for chronic inflammatory diseases, exemplified inhibitors suppressed interleukin-1β (IL-1β) production release mice.

Language: Английский

Citations

388
Metformin: update on mechanisms of action and repurposing potential DOI Open Access
Marc Foretz, Bruno Guigas, Benoı̂t Viollet

et al.

Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(8), P. 460 - 476

Published: May 2, 2023

Language: Английский

Citations

344
The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19 DOI
Christoph Schultheiß, Edith Willscher, Lisa Paschold

et al.

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(6), P. 100663 - 100663

Published: June 1, 2022

Language: Английский

Citations

322
Inflammasome activation at the crux of severe COVID-19 DOI Creative Commons

Setu M. Vora,

Judy Lieberman, Hao Wu

et al.

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(11), P. 694 - 703

Published: Aug. 9, 2021

Language: Английский

Citations

294
SARS-CoV-2, COVID-19 and the aging immune system DOI Creative Commons
Juliet M. Bartleson, Dina Radenković, Anthony J. Covarrubias

et al.

Nature Aging, Journal Year: 2021, Volume and Issue: 1(9), P. 769 - 782

Published: Sept. 14, 2021

Language: Английский

Citations

289
XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury DOI Creative Commons
Zheng Liu,

Mingming Wang,

Xun Wang

et al.

Redox Biology, Journal Year: 2022, Volume and Issue: 52, P. 102305 - 102305

Published: March 28, 2022

Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, function mechanism in thioacetamide (TAA)-induced acute injury (ALI) remains unknown. Here, we investigated effects inhibition on promoting hepatocellular pyroptosis activate STING signaling ALI. While both TAA- LPS-induced ALI triggered hepatocytes, hepatocyte-specific knockout mice exhibited exacerbated with increased enhanced activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing a cGAS- dose-dependent manner. deficiency ROS production promote activating NLRP3/caspase-1/GSDMD signaling, facilitated extracellular release mtDNA. Moreover, impaired mitophagy was found deficient reversed PINK1 overexpression. Mitophagy restoration also inhibited mice. Activation XBP1-mediated pathway were observed human livers Collectively, these findings demonstrate that promotes hepatocyte impairing mtDNA/cGAS/STING providing potential therapeutic targets for

Language: Английский

Citations

209
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation DOI Creative Commons

Leah K. Billingham,

Joshua S. Stoolman,

Karthik Vasan

et al.

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(5), P. 692 - 704

Published: April 28, 2022

Abstract The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the through several mechanisms including generation mitochondrial reactive oxygen species (ROS). Here, we report that electron transport chain (ETC) complex I, II, III V inhibitors all prevent activation. Ectopic expression Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement functional loss I III, respectively, without ROS, rescued activation in absence endogenous function. Metabolomics revealed phosphocreatine (PCr), sustain ATP levels, a common metabolite diminished by ETC inhibitors. PCr depletion decreased levels Thus, sustains PCr-dependent ATP, but via ROS-independent mechanism.

Language: Английский

Citations

208
Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 DOI Open Access
Carolyn T. Bramante, Jared D. Huling, Christopher J. Tignanelli

et al.

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 387(7), P. 599 - 610

Published: Aug. 17, 2022

Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response acute respiratory syndrome 2 (SARS-CoV-2) pandemic.

Language: Английский

Citations

207
Mitochondrial DNA Release in Innate Immune Signaling DOI Creative Commons
Laura Newman, Gerald S. Shadel

Annual Review of Biochemistry, Journal Year: 2023, Volume and Issue: 92(1), P. 299 - 332

Published: March 31, 2023

According to the endosymbiotic theory, most of DNA original bacterial endosymbiont has been lost or transferred nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is present-day mitochondrial (mtDNA). The ability mtDNA escape mitochondria and integrate into nuclear genome was discovered budding yeast, along with genes regulate this process. Mitochondria have emerged as key regulators innate immunity, it now recognized released cytoplasm, outside cell, circulation activates multiple immune signaling pathways. Here, we first review mechanisms through which including several inducible pores defective mitophagy autophagy. Next, cover how different forms activate specific nucleic acid sensors inflammasomes. Finally, discuss intracellular extracellular release, circulating cell-free promotes systemic inflammation, are implicated human diseases, viral infections, senescence aging.

Language: Английский

Citations

106