Mitochondrial ROS, a trigger for mitochondrial dysfunction and inflammasome activation and a therapeutic target in liver diseases DOI Creative Commons

Hala Saeed Jaara,

Sandra Torres

Published: Dec. 10, 2024

Mitochondria are essential organelles responsible for intracellular energy production and play crucial roles in cellular metabolism, inflammation, apoptosis. Reactive oxygen species (ROS) primarily produced the mitochondria endoplasmic reticulum of hepatocytes due to activity cytochrome P450 enzymes. Under ideal conditions, cells have specific molecular mechanisms that manage oxidative stress levels, thus ensuring a balance between oxidants antioxidants. The interplay ROS-induced mitochondrial dysfunction activation NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome context liver diseases has been extensively studied. However, exact by which promote contribute onset disease remain unclear. This review aims elucidate recently discovered regulation disorders, including alcohol-related (ALD), metabolic-associated steatotic (MASLD), hepatocellular carcinoma (HCC). Finally, it summarizes various natural pharmaceutical agents can mitigate damage modulating through pathways. work serves as an important resource identifying new therapeutic approaches provides further support advancing understanding diseases.

Language: Английский

Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation DOI Creative Commons
Vlad Țâru, Gyöngyi Szabó, Wajahat Z. Mehal

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(5), P. 895 - 910

Published: June 20, 2024

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting fibrosis, cirrhosis, portal hypertension failure. Thus, an improved understanding of inflammasomes - as key molecular drivers may result the development novel diagnostic or prognostic biomarkers effective therapeutics. In disease, innate immune cells respond insults by activating cell-intrinsic via toll-like receptors NF-κB, releasing cytokines (such IL-1β, IL-18, TNF-α IL-6). Subsequently, adaptive system are recruited fuel inflammation undergo gasdermin D-mediated programmed death, termed pyroptosis. With progression, there is shift towards type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation occur at extrahepatic sites, such white adipose MASH (metabolic dysfunction-associated steatohepatitis). end-stage flares (e.g., severe alcohol-related hepatitis) spark on dysfunctional system, contribute inflammasome-mediated potentially organ dysfunction/failure, seen ACLF (acute-on-chronic failure). This review provides overview current concepts regarding inflammasome with focus related therapeutic approaches being developed for patients disease.

Language: Английский

Citations

38
NLRP3 Inflammasome in Acute and Chronic Liver Diseases DOI Open Access

Katia Sayaf,

Sara Battistella, Francesco Paolo Russo

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4537 - 4537

Published: April 20, 2024

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the inflammasome. The inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well IL-18 IL-1β production. Acute chronic liver diseases are characterized by massive influx pro-inflammatory enriched in reactive oxygen species (ROS) damage-associated molecular patterns (DAMPs) promote assemblage activation As major cause cytokine storm, exacerbates diseases, even though it might exert protective effects regards to hepatitis C B virus infection (HCV HBV). Here, we summarize current knowledge concerning function both acute disease post transplant setting, focusing on mechanisms involved activity.

Language: Английский

Citations

8
Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease DOI Creative Commons

Hui Gao,

Yanchao Jiang,

Zeng Ge

et al.

eGastroenterology, Journal Year: 2024, Volume and Issue: 2(4), P. e100104 - e100104

Published: Dec. 1, 2024

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation well-established key factor, recent evidence highlights critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced injury. This review provides comprehensive analysis complex interactions within hepatic microenvironment ALD. It examines contributions both parenchymal cells, like hepatocytes, non-parenchymal such as stellate Kupffer neutrophils, sinusoidal endothelial driving progression disease. Additionally, we explored involvement mediators, including cytokines, chemokines inflammasomes, which regulate inflammatory responses promote injury fibrosis. A particular focus has been placed on extracellular vesicles (EVs) essential mediators intercellular communication beyond liver. These facilitate transfer signalling molecules, microRNAs proteins, modulate immune responses, fibrogenesis lipid metabolism, thereby influencing progression. Moreover, underscore importance organ-to-organ crosstalk, particularly gut-liver axis, where dysbiosis increased intestinal permeability lead to microbial translocation, exacerbating inflammation. The adipose-liver axis also highlighted, impact adipokines free fatty acids from adipose tissue steatosis inflammation context alcohol consumption.

Language: Английский

Citations

8
Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression DOI Creative Commons
Natalia A. Osna, Irina Tikhanovich, Martí Ortega‐Ribera

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 404 - 404

Published: March 27, 2024

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide represents spectrum injury beginning with hepatic steatosis (fatty liver) progressing to inflammation culminating in cirrhosis. Multiple factors contribute ALD progression severity. Here, we overview several crucial mechanisms related end-stage outcome development, such as epigenetic changes, cell death, hemolysis, stellate cells activation, fatty acid binding protein 4. Additionally, this review, also present two clinically relevant models using human precision-cut slices organoids examine pathogenesis progression.

Language: Английский

Citations

7
IRGM/Irgm1 increases autophagy to inhibit activation of NLRP3 inflammasome in inflammatory injury induced acute liver failure DOI Creative Commons
Xing Zhang, Yangyang Hu, Wei Wang

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 7, 2024

Abstract Immune-related GTPase M (IRGM) induces autophagy and suppresses inflammation, but its putative role signaling mechanism remain undefined in the pathogenesis of liver failure. This study aimed to address how IRGM attenuates inflammatory injury by regulating In this study, a total 10 patients with hepatitis B virus-related acute-on-chronic failure (HBV-ACLF) healthy controls were prospectively enrolled. Intrahepatic expression IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, caspase-1), autophagy-related proteins (LC3II, P62), cytokines (IL-1β, TNF-α) measured. Autophagy was activated rapamycin (4 mg/kg) an acute (ALF) mouse model, which used further Irgm1, inflammasome, proteins, using both qRT-PCR Western blot analyses. Irgm1 knocked down short hairpin RNA (shRNA) lipopolysaccharide (LPS)-induced AML12 cells investigate effects deletion on inflammation. We found that significantly downregulated while upregulated livers HBV-ACLF ALF model (all P < 0.05). Rapamycin-induced ameliorated intrahepatic activation decreased inflammation necrosis mice. knockdown also protected against hepatocyte following LPS stimulation vitro inhibiting activation. Thus, IRGM/Irgm1 alleviates inflammation-mediated autophagy. provides new insight into potential molecular targets treat

Language: Английский

Citations

4
The role of macrophages in liver fibrosis: composition, heterogeneity, and therapeutic strategies DOI Creative Commons

Xiaocao Ma,

Jia Qiu,

Shubiao Zou

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 20, 2024

Macrophages, the predominant immune cells in liver, are essential for maintaining hepatic homeostasis and responding to liver injury caused by external stressors. The macrophage population is highly heterogeneous plastic, mainly comprised of resident kuffer (KCs), monocyte-derived macrophages (MoMφs), lipid-associated (LAMs), capsular (LCMs). KCs, a macrophages, localized can self-renew through situ proliferation. However, MoMφs recruited from periphery circulation. LAMs self-renewing subgroup near bile duct. While LCMs located capsule derived peripheral monocytes. also involved damage induced various factors. Hepatic exhibit distinct phenotypes functions depending on specific microenvironment liver. KCs critical initiating inflammatory responses after sensing tissue damage, while infiltrated implicated both progression resolution chronic inflammation fibrosis. regulatory function fibrosis has attracted significant interest current research. Numerous literatures have documented that dual impact be categorized into two subtypes based their Ly-6C expression level: with high (referred as hi macrophages) reparative low lo macrophages). conducive occurrence fibrosis, associated degradation extracellular matrix (ECM) regression Given this, play pivotal role occurrence, progression, Based these studies, treatment therapies targeting being studied gradually. This review aims summarize researches composition origin heterogeneity anti-fibrosis therapeutic strategies

Language: Английский

Citations

4
BRISC inactivation alleviates alcohol-induced liver injury in mice DOI Creative Commons
Ting Wang, Wen Zhang, Xian Liu

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 12, 2025

BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure, while its functional contribution alcoholic disease (ALD) still unclear. In this study, we found the expression components was increased tissues hepatitis (AH) animal models patients with AH. Mice lacking either scaffold subunit ABRO1 or catalytic showed attenuated steatosis, inflammation, injury compared control mice after chronic plus binge ethanol feeding. Moreover, pharmacological inhibition activity by inhibitor thiolutin potently protected from ALD development. Preliminary mechanistical studies deficiency did not directly affect alcohol-induced hepatocyte translocation LPS through damaged gut mucosa feeding, but prevented liver. Collectively, our work previously unknown suggested may serve as promising therapeutic target treatment.

Language: Английский

Citations

0
Gut microbiota and HMGB1/NLRP3/GSDMD inflammasome-dependent pyroptosis: mechanisms by physcion ameliorates alcoholic liver fibrosis DOI Creative Commons
Tao Bai,

Haolin Guo,

Fei Wang

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 27, 2025

Alcoholic liver fibrosis (ALF) developed from long-term excessive alcohol consumption, which causes inflammatory reactions, lipid accumulation and cirrhosis. An imbalance in gut microbiota is a crucial driving factor for through the gut-liver axis. This study aimed to explore effect of physcion on ALF associated with HMGB1/NLRP3 pathways microbiota. C57BL/6 mice were used establish animal model ALF, LX-2 cells alcohol-activated cell model, intestinal contents collected analyzed by 16S rRNA sequencing. Physcion effectively ameliorated ALF-induced inflammation, collagen deposition, SirT1, AMPK phosphorylation SREBP1 expression. Moreover, pyroptosis-related proteins (Caspase-1, IL-1β, GSDMD) significantly reduced after treatment. Interestingly, diversity bacteria abundance treatment was higher, while harmful lower than that mice. Importantly, it found inhibit both vivo vitro , suppress extracellular matrix inhibiting Collagen-I α-SMA finally reverse hepatic stellate activation. Continuous administration HMGB1 NLRP3 inhibitors showed hepato-protection model. siRNA-mediated knock-down impaired physcion-mediated protection. Regulation pathway recovered injury further contributed physcion’s beneficial effects. Taken together, results reveal diminishes inflammasome/pyroptosis this diminishment hepato-protective against ALF.

Language: Английский

Citations

0
Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury DOI
Zhaodi Che, Mingxiang Cai, Xiaowu Dong

et al.

Metabolism, Journal Year: 2025, Volume and Issue: unknown, P. 156275 - 156275

Published: April 1, 2025

Language: Английский

Citations

0
NLRP3 inflammasome: structure, mechanism, drug-induced organ toxicity, therapeutic strategies, and future perspectives DOI
Desh Deepak Singh

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

This review aims to shed light on how drugs cause toxicity and summarizes developing therapies prospective therapeutic approaches that will target the NLRP3 inflammasome unit.

Language: Английский

Citations

0