Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Янв. 26, 2023

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% the population and is leading cause cirrhosis hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) monocyte-derived act as key players in progression NAFLD. Caspases are family endoproteases that provide critical connections cell regulatory networks sense risk factors, control inflammation, mediate inflammatory death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) induce pyroptosis defends against bacterial pathogens invade cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 promote

Язык: Английский

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Life’s Essential 8 and Mortality in US Adults with Chronic Kidney Disease

American Journal of Nephrology, Год журнала: 2023, Номер 54(11-12), С. 516 - 527

Опубликована: Янв. 1, 2023

<b><i>Introduction:</i></b> The current prevalence of chronic kidney disease (CKD) is substantial, and CKD individuals face a heightened risk mortality, encompassing both all-cause cause-specific outcomes. study aims to investigate the potential impact adhering Life’s Essential 8 (LE8) on reducing mortality among individuals. <b><i>Methods:</i></b> Using National Health Nutrition Survey (NHANES) data from 2005 2018, we analyzed 22,420 US adults (≥20 years old). defined by urinary albumin-to-creatinine ratio (≥30 mg/g or 3 mg/mmol) estimated glomerular filtration rate (&lt;60 mL/min/1.73 m²). components LE8, including diet, physical activity (PA), nicotine exposure, sleep, body mass index, blood lipids, glucose, pressure (BP), were measured given score 0–100. total LE8 was unweighted average all divided into low cardiovascular health (CVH) (0–49), moderate CVH (50–79), high (80–100). A Cox proportional hazards regression model used explore associations with all-cause, (CVD), cancer which followed prospectively Center for Statistics until December 31, 2019. <b><i>Results:</i></b> In overall population, had 47% lower CKD, while linked 55% compared CVH. During median follow-up 7.58 years, 93% higher 149% CVD those without CKD. Among individuals, every 10-point increase in associated reduced risks 17% (especially PA, BP), 18% PA), 12% PA sleep health). additional sensitivity analysis, results remained significant after further consideration confounding renal function. Additionally, demonstrated superior stratification patients LS7. Interaction observed between age, education level, marital status, drinking status. <b><i>Conclusion:</i></b> demonstrates that adherence levels within mortality.

Язык: Английский

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STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury

Cell Death and Disease, Год журнала: 2024, Номер 15(3)

Опубликована: Март 14, 2024

Abstract Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged a critical component immune inflammatory responses. However, role STING in pathogenesis septic AKI remains unclear. This study demonstrated that was significantly activated tubular cells induced lipopolysaccharide (LPS) vivo vitro. Tubule-specific knockout attenuated LPS-induced renal dysfunction pathological changes. Mechanistically, pathway promotes NOD-like receptor protein 3 (NLRP3) activation. triggers endoplasmic reticulum (ER) stress induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting activation association with NLRP3. Eventually, NLRP3 inflammasome leads cell pyroptosis. revealed STING-regulated network further identified STING/ER stress/mtROS/NLRP3 axis an emerging contributing damage AKI. Hence, targeting may be promising therapeutic strategy preventing

Язык: Английский

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Innate immunity of vascular smooth muscle cells contributes to two-wave inflammation in atherosclerosis, twin-peak inflammation in aortic aneurysms and trans-differentiation potential into 25 cell types

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 24, 2024

Introduction Vascular smooth muscle cells (VSMCs) are the predominant cell type in medial layer of aorta, which plays a critical role aortic diseases. Innate immunity is main driving force for cardiovascular Methods To determine roles innate VSMC and pathologies, we performed transcriptome analyses on aortas from ApoE –/– angiotensin II (Ang II)-induced aneurysm (AAA) time course, atherosclerosis as well VSMCs stimulated with danger-associated molecular patterns (DAMPs). Results We made significant findings: 1) 95% 45% upregulated immune pathways (UIIPs, based data 1226 genes) Ang II-induced AAA at 7 days were different that 14 28 days, respectively; showed twin peaks UIIPs major peak minor days; 2) all 6 weeks 32 78 (two waves); 3) additional 12 lists immune-related genes 1325 cytokine chemokine genes, 2022 plasma membrane protein 373 clusters differentiation (CD) marker 280 nuclear 1425 nucleoli 6750 nucleoplasm 1496 transcription factors (TFs) including 15 pioneer TFs, 164 histone modification enzymes, 102 oxidative death 68 necrotic 47 efferocytosis confirmed two-wave inflammation twin-peak AAA; 4) DAMPs-stimulated judged by upregulation lists; 5) increased trans-differentiation potential upregulating not only some 82 markers VSMC-plastic types, fibroblast, osteogenic, myofibroblast, macrophage, adipocyte, foam cell, mesenchymal but also 18 new types (out 79 human 8065 markers); 6) analysis gene deficient transcriptomes indicated antioxidant factor NRF2 suppresses, however, other five inflammatory master regulators, AHR, NF-KB, NOX (ROS enzyme), PERK, SET7 promote twelve atherosclerosis, AAA, DAMP-stimulated VSMCs; 7) both trained tolerance-promoting metabolite itaconate contributed to cytokines AAA. Discussion Our findings have provided novel insights responses stresses development immunology therapeutic targets treating those cerebrovascular

Язык: Английский

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The gut microbiota derived metabolite trimethylamine N-oxide: Its important role in cancer and other diseases

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 177, С. 117031 - 117031

Опубликована: Июнь 25, 2024

An expanding body of research indicates a correlation between the gut microbiota and various diseases. Metabolites produced by act as mediators host, interacting with multiple systems in human to regulate physiological or pathological functions. However, further investigation is still required elucidate underlying mechanisms. One such metabolite involved choline metabolism microbes trimethylamine (TMA), which can traverse intestinal epithelial barrier enter bloodstream, ultimately reaching liver where it undergoes oxidation catalyzed flavin-containing monooxygenase 3 (FMO3) form N-oxide (TMAO). While some TMAO eliminated through renal excretion, remaining amounts circulate leading systemic inflammation, endoplasmic reticulum (ER) stress, mitochondrial disruption normal functions humans. As representative microbial originating from gut, has significant potential both biomarker for monitoring disease occurrence progression tailoring personalized treatment strategies patients. This review provides an extensive overview sources its blood, well impact on several major Additionally, we explore latest areas related along future directions.

Язык: Английский

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Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers – Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer

Pharmacology & Therapeutics, Год журнала: 2024, Номер 255, С. 108604 - 108604

Опубликована: Фев. 13, 2024

Язык: Английский

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Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5806 - 5806

Опубликована: Март 18, 2023

Endothelial function is essential in the maintenance of systemic homeostasis, whose modulation strictly depends on proper activity tissue-specific angiocrine factors physiopathological mechanisms acting at both single and multi-organ levels. Several take part vascular itself by modulating tone, inflammatory response, thrombotic state. Recent evidence has outlined a strong relationship between endothelial gut microbiota-derived molecules. In particular, direct involvement trimethylamine N-oxide (TMAO) development dysfunction its derived pathological outcomes, such as atherosclerosis, come to light. Indeed, role TMAO related dysfunction, nitric oxide, adhesion molecules (ICAM-1, VCAM-1, selectins), IL-6, been widely accepted. The aim this review present latest studies that describe primarily involved pathologies.

Язык: Английский

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Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus

Antioxidants and Redox Signaling, Год журнала: 2024, Номер 40(16-18), С. 968 - 989

Опубликована: Март 18, 2024

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with development progression CVDs. Patients diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) substantially increased risk for

Язык: Английский

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Trimethylamine N-oxide: a meta-organismal axis linking the gut and fibrosis

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Авг. 23, 2024

Abstract Background Tissue fibrosis is a common pathway to failure in many organ systems and the cellular molecular driver of myriad chronic diseases that are incompletely understood lack effective treatment. Recent studies suggest gut microbe-dependent metabolites might be involved initiation progression multiple systems. Main body manuscript In meta-organismal begins gut, microbiota convert dietary precursors such as choline, phosphatidylcholine, L-carnitine into trimethylamine (TMA), which absorbed subsequently converted N-oxide (TMAO) via host enzyme flavin-containing monooxygenase 3 (FMO3) liver. Chronic exposure elevated TMAO appears associated with vascular injury enhanced propensity diverse conditions, including kidney disease, heart failure, metabolic dysfunction-associated steatotic liver systemic sclerosis. Conclusion Despite high prevalence fibrosis, little known date about role dysbiosis its pathogenesis. This review summarizes recent important advances understanding complex metabolism functional pathologic highlights unanswered questions.

Язык: Английский

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Role of Trimethylamine N-Oxide in Heart Failure

Reviews in Cardiovascular Medicine, Год журнала: 2024, Номер 25(7)

Опубликована: Июль 2, 2024

Heart failure (HF) is a clinical syndrome characterizing by typical physical signs and symptomatology resulting from reduced cardiac output and/or intracardiac pressure at rest or under stress due to structural functional abnormalities of the heart. HF often final stage all cardiovascular diseases significant risk factor for sudden arrest, death, liver kidney failure. Current pharmacological treatments can only slow progression recurrence HF. With advancing research into gut microbiome its metabolites, one such trimethylamine N-oxide (TMAO)—has been implicated in advancement correlated with poor prognosis patients However, precise role TMAO has not yet clarified. This review highlights concludes available evidence potential mechanisms associated HF, hope contributing new insights diagnosis prevention

Язык: Английский

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