Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation

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

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Role of Selenoprotein W in participating in the progression of non-alcoholic fatty liver disease

Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103114 - 103114

Published: March 5, 2024

Non-alcoholic fatty liver disease (NAFLD) is a chronic worldwide. Numerous evidence has demonstrated that metabolic reprogramming serves as hallmark associated with an elevated risk of NAFLD progression. Selenoprotein W (SelW) extensively expressed hepatic selenoprotein plays crucial role in antioxidant function. Here, we first SelW significantly distinct factor the tissue patients through Gene Expression Omnibus (GEO) database. Additionally, loss alleviated steatosis induced by high-fat diet (HFD), and was accompanied regulation inflammatory pathways verified transcriptomic analysis. Moreover, co-immunoprecipitation (CO-IP), liquid chromatography-tandem mass spectrometry (LC-MS), laser scanning confocal microscopy (LSCM) molecular docking analysis were subsequently implemented to identify Pyruvate Kinase M2 (PKM2) potential interacting protein SelW. Meanwhile, modulated PKM2 translocation into nucleus trigger transactivation HIF-1α, further mediating mitochondrial apoptosis, eventually resulting damage, ROS excessive production mtDNA leakage. mito-ROS accumulation activation NLRP3 inflammasome-mediated pyroptosis, thereby facilitating extracellular leakage mtDNA. The escaped then evokes cGAS-STING signaling pathway macrophage, thus inducing shift macrophage phenotype. Together, our results suggest promotes hepatocyte apoptosis pyroptosis regulating activate cGAS/STING macrophages, exacerbating progression NAFLD.

Language: Английский

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Novel bioactive peptides alleviate Western diet-induced MAFLD in C57BL/6J mice by inhibiting NLRP3 inflammasome activation and pyroptosis via TLR4/NF-κB and Keap1/Nrf2/HO-1 signaling pathways

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 148, P. 114177 - 114177

Published: Jan. 27, 2025

Metabolic-associated fatty liver disease (MAFLD) has emerged as a leading chronic disease. This condition is characterized by an abnormal accumulation of fat within and can progress from simple steatosis to more severe stages involving inflammation oxidative stress. In this study, we investigated the potential therapeutic effects underlying mechanism novel bioactive peptides (EWYF EWFY) on Western diet-induced MAFLD in C57BL/6J mice. Mice fed normal chow diet (ND group) (WD treatment groups) for 8 weeks. Treatment groups received EWYF EWFY low (10 mg/kg/day) high (50 doses were divided into four groups: EWYF10, EWYF50, EWFY10, EWFY50. body weight gain increased along with visceral adiposity, which markedly reversed dose-dependent manner. Additionally, significantly reduced hepatic steatosis, injury proinflammatory response. glucose tolerance insulin resistance, whereas improved sensitivity. Persistent intake triggered stress, alleviated via inhibiting NOD-like receptor protein 3 (NLRP3) inflammasome activation mitigated pyroptosis modulating TLR4/NF-κB Keap1/Nrf2/HO-1 signaling pathways. Furthermore, molecular docking studies suggest that act fructokinase antagonists TLR4 inhibitors, potentially alleviates MAFLD. Collectively, these findings highlight promising candidates due their potent antioxidant anti-inflammatory properties specific inhibition.

Language: Английский

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The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3067 - 3067

Published: Feb. 4, 2023

Acute liver injury (ALI) is a globally important public health issue that, when severe, rapidly progresses to acute failure, seriously compromising the life safety of patients. The pathogenesis ALI defined by massive cell death in liver, which triggers cascade immune responses. Studies have shown that aberrant activation nod-like receptor protein 3 (NLRP3) inflammasome plays an role various types and NLRP3 causes programmed (PCD), these effectors can turn regulate activation. This indicates inextricably linked PCD. In this review, we summarize PCD (APAP, ischemia reperfusion, CCl4, alcohol, Con A, LPS/D-GalN induced ALI) analyze underlying mechanisms provide references for future relevant studies.

Language: Английский

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Role of the inflammasome in insulin resistance and type 2 diabetes mellitus

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 13, 2023

The inflammasome is a protein complex composed of variety proteins in cells and which participates the innate immune response body. It can be activated by upstream signal regulation plays an important role pyroptosis, apoptosis, inflammation, tumor regulation, etc. In recent years, number metabolic syndrome patients with insulin resistance (IR) has increased year year, closely related to occurrence development diseases. directly or indirectly affect conduction signaling pathway, involvement IR type 2 diabetes mellitus (T2DM). Moreover, various therapeutic agents also work through treat diabetes. This review focuses on T2DM, pointing out association utility value. Briefly, we have discussed main inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6 AIM2, as well their structure, activation were described detail. Finally, current options-associated for treatment T2DM. Specially, NLRP3-related options are widely developed. summary, this article reviews research progress

Language: Английский

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GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(7), P. 1829 - 1848

Published: June 19, 2023

Language: Английский

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Radical oxygen species: an important breakthrough point for botanical drugs to regulate oxidative stress and treat the disorder of glycolipid metabolism

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: May 12, 2023

Background: The incidence of glycolipid metabolic diseases is extremely high worldwide, which greatly hinders people’s life expectancy and patients’ quality life. Oxidative stress (OS) aggravates the development in metabolism. Radical oxygen species (ROS) a key factor signal transduction OS, can regulate cell apoptosis contribute to inflammation. Currently, chemotherapies are main method treat disorders metabolism, but this lead drug resistance damage normal organs. Botanical drugs an important source new drugs. They widely found nature with availability, practicality, low cost. There increasing evidence that herbal medicine has definite therapeutic effects on diseases. Objective: This study aims provide valuable for treatment botanical from perspective ROS regulation by further promote effective clinical Methods: Using herb*, plant medicine, Chinese phytochemicals, natural phytomedicine, extract, drug, ROS, free radicals, radical, oxidizing agent, glucose lipid saccharometabolism, glycometabolism, blood glucose, lipoprotein, triglyceride, fatty liver, atherosclerosis, obesity, diabetes, dysglycemia, NAFLD, DM as keywords or subject terms, relevant literature was retrieved Web Science PubMed databases 2013 2022 summarized. Results: regulating mitochondrial function, endoplasmic reticulum, phosphatidylinositol 3 kinase (PI3K)/protein B (AKT), erythroid 2-related 2 (Nrf-2), nuclear κB (NF-κB), other signaling pathways improve OS glucolipid Conclusion: multi-mechanism multifaceted. Both studies animal experiments have demonstrated effectiveness ROS. However, safety need be improved, more needed support application

Language: Английский

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Programmed cell death in hepatic fibrosis: current and perspectives

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

Published: Dec. 12, 2023

Abstract The initiation, development and resolution of hepatic fibrosis are influenced by various cytokines, chemokines, damage-associated molecular patterns (DAMPs) signaling pathways. A significant number studies in recent years have indicated that the progression is closely linked to programmed cell death processes such as apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, cuproptosis, PANoptosis. Inducement stellate cells (HSCs) or preventing other liver can delay even reverse fibrosis. Nevertheless, roles not been reviewed. Therefore, this review summarizes characteristics death, focuses on latest progress promotion regression fibrosis, highlights different HSCs In end, possible therapeutic approaches targeting for treating discussed prospected.

Language: Английский

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Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 8162 - 8162

Published: May 3, 2023

We are witnessing the globalization of a specific type arteriosclerosis with rising prevalence, incidence and an overall cardiovascular disease burden. Currently, atherosclerosis increasingly affects younger generation as compared to previous decades. While early preventive medicine has seen improvements, research advances in laboratory clinical investigation promise provide us novel diagnosis tools. Given physio-pathological complexity epigenetic patterns discovery new molecules involved, therapeutic field room for substantial growth. Thus, scientific community is currently investigating role nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, crucial component innate immune system different inflammatory disorders. NLRP3 activated by distinct factors numerous cellular molecular events which trigger inflammasome assembly subsequent cleavage pro-interleukin (IL)-1β pro-IL-18 pathways via caspase-1 activation, eliciting endothelial dysfunction, promotion oxidative stress inflammation process atherosclerosis. In this review, we introduce basic mechanisms activation its also emphasize promising pharmaceutical potential.

Language: Английский

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Lycopene prevents non-alcoholic fatty liver disease through regulating hepatic NF-κB/NLRP3 inflammasome pathway and intestinal microbiota in mice fed with high-fat and high-fructose diet

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: March 23, 2023

Lycopene (LY) belongs to carotenoids and is abundant in red fruits vegetables. Several previous studies suggested that LY beneficial for ameliorating non-alcoholic fatty liver disease (NAFLD), while the potential mechanisms are unclear. The present study aimed clarify of preventing NAFLD via exploring hepatic NF-κB/NLRP3 inflammasome pathway intestinal microbiota composition high-fat high-fructose diet (HFFD)-fed mice. Fifty eight-week-old male C57BL/6J mice were randomly assigned into 5 groups: Normal control group (NC); HFFD group; with low dose lycopene (LLY, 20 mg/kg/d); high (HLY, 60 mg/kg/d) resveratrol (RSV, 50 mg/kg/d, positive control). After 8 weeks, feces collected 12 h fasted sacrificed acquire tissues blood parameters measurement. results showed LLY, HLY RSV groups had significantly lower body weight gain, white adipose tissue, serum levels density lipoprotein-cholesterol (HDL-C), (LDL-C), lipopolysaccharide (LPS), alanine aminotransferase (ALT), concentrations triglyceride (TG) interleukin-6 (IL-6) than (p < 0.05). also displayed TG, total cholesterol (TC) tumor necrosis factor-α (TNF-α) Liver protein expressions NLRP3, Pro-Caspase-1, Caspase-1 NF-κB those -treated higher relative SCFAs producing bacteria Allobaculum destructive bacteria, including Firmicutes, Lachnospiraceae_NK4A136_group, Desulfovibrio, Alistipes over fecal In conclusion, might prevent by suppressing attenuating gut dysbiosis.

Language: Английский

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