Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF

eGastroenterology, Год журнала: 2025, Номер 3(1), С. e100151 - e100151

Опубликована: Янв. 1, 2025

Background Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation cell death, which are both linked GSDM-D activation. However, its role alcohol-induced acute-on-chronic failure (ACLF) remains unclear. Methods ACLF was induced GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus single 5 g/kg alcohol binge leading acute decompensation. Nine hours after the binge, blood, liver, kidney cerebellum specimens were collected for analysis. Results Active significantly humans livers compared with healthy controls cirrhotic livers. showed decreased inflammation, neutrophil infiltration fibrosis together reduction pyroptotic, apoptotic necroptotic WT mice. Notably, also regeneration hepatocyte function. This associated an increase senescence expression stem-like/cholangiocyte markers liver. Interestingly, kidney, histopathological damage score, function necroptosis-related genes. In cerebellum, deficiency neuroinflammation markers, astrocyte apoptosis-related Conclusion Our data indicate that has organ-specific effects ACLF. While it reduces activation, death impairs synthetic increases hepatocytes. injury

Язык: Английский

---

The Jieduan-Niwan Formula Reduces Inflammatory Responses in Acute-on-Chronic Liver Failure Rats by Inhibiting HMGB1-Induced Hepatocyte Pyroptosis

Drug Design Development and Therapy, Год журнала: 2025, Номер Volume 19, С. 2503 - 2517

Опубликована: Апрель 1, 2025

Acute-on-chronic liver failure (ACLF) is a global intractable disease. HMGB1-induced hepatocyte pyroptosis expanding inflammatory responses contributes to the pathogenesis of ACLF. The JDNW formula (JDNWF) has significant clinical effect on ACLF, but its hepatoprotective mechanisms remain elusive. To explore potential molecular JDNWF in ACLF by pyroptosis. Rats were divided into normal, Caspase-1 inhibitor, HMGB1 JDNW, JDNW+Caspase-1 inhibitor and JDNW+HMGB1 groups. rat model was established 40% carbon tetrachloride-induced fibrosis, followed intraperitoneal injection D-galactosamine lipopolysaccharide. function, coagulation pathological damage ultrastructural changes hepatocytes evaluated. Triple-immunostaining active Caspase-1, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) albumin performed evaluate percentage pyroptotic hepatocytes. Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) quantitative real-time PCR (RT-qPCR) used analyze expressions key genes proteins pathways level factors. improved function damage, reduced responses, down-regulated rats. better than those (glycyrrhizin) (VX-765). Compared with glycyrrhizin or VX-765, there no differences above indicators after combination VX-765. These results indicated that inhibited inflammation rats through pathways. protects livers inhibiting reducing suggesting may be therapeutic target

Язык: Английский

---

Inflammation in MASLD Progression and Cancer

JHEP Reports, Год журнала: 2025, Номер unknown, С. 101414 - 101414

Опубликована: Апрель 1, 2025

Язык: Английский

---

Role of metabolic dysfunction-associated fatty liver disease in atrial fibrillation and heart failure: molecular and clinical aspects

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Апрель 8, 2025

Metabolic dysfunction-associated fatty liver disease (MASLD) is a rising global health concern. In addition to direct hepatic complications, extra-hepatic including cardiovascular diseases (CVD), type 2 diabetes (T2D), gastroesophageal reflux disease, chronic kidney and some malignancies, are increasingly recognized. CVD, atrial fibrillation (AF) heart failure (HF), the leading cause of death in patients with MASLD. External factors, excess energy intake, sedentary lifestyle xenobiotic use, induce inflammation-related complications. MASLD, AF, HF associated immune system activation, reprogramming cells establishment memory. Emerging evidence suggests that cross-talk each other through diverse spectrum autocrine, paracrine endocrine mechanisms. Pro-inflammatory cytokines produced from circulate systemically orchestrate metabolic derangements promote systematic dysregulation heart-liver axis development end-organ Cardio-hepatic syndrome describes clinical biochemical dysfunction cardiac pathology due interaction between liver. Activation inflammatory cascades, oxidative stress underlie key mechanisms bringing about such pathological changes. This review focuses on current molecular cross-talk. It summarizes epidemiological pathophysiological associations AF HF. addition, we will discuss how repurposing currently available emerging pharmacotherapies may help tackle risks resulting

Язык: Английский

---

Mechanistic Studies on the Role of IL-17/NLRP3 in Arsenic-Induced Activation of Hepatic Stellate Cells Through Hepatocyte Proptosis

Toxics, Год журнала: 2025, Номер 13(4), С. 287 - 287

Опубликована: Апрель 9, 2025

Long-term exposure to arsenic, a prevalent environmental contaminant, has been implicated in the pathogenesis of various hepatic conditions. Hepatic stellate cells (HSCs) are central development liver fibrosis. Recently, involvement interleukin-17 (IL-17) and NOD-like receptor protein 3 (NLRP3) inflammasome pathologies attracted significant research interest. Hepatocyte pyroptosis, form programmed cell death, is critical factor occurrence inflammation. The objective this study was investigate specific roles IL-17 NLRP3 arsenic-induced activation HSCs through hepatocyte pyroptosis. We pretreated MIHA with MCC950 (1 5 μM) secukinumab (10 100 nM) for 4 h, then NaAsO2 (25 24 h at 37 °C under 5% CO2. After incubation, cell-culture supernatant collected mixed serum-free high-glucose DMEM medium 1:1 ratio prepare conditioned medium, which subsequently used culture LX-2 cells. results showed that induced hepatocellular led release inflammatory cytokines IL-18 IL-1β subsequent HSCs. Treatment inhibitors significantly reduced secretion Extracellular matrix (ECM) components attenuated HSC activation. These demonstrate blocking signaling pathways reduces attenuates fibrogenesis. provide novel molecular targets prevention treatment arsenic-related

Язык: Английский

---

Ginseng and its functional components in non-alcoholic fatty liver disease: therapeutic effects and multi-target pharmacological mechanisms

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 9, 2025

Non-alcoholic fatty liver disease (NAFLD) is a common type of chronic and its incidence increasing. Its progression closely related to non-alcoholic steatohepatitis fibrosis. Effective treatment currently lacking. The traditional Chinese medicine ginseng (Panax ginseng) shows unique advantages in NAFLD intervention, but complex compositional system molecular mechanism network still need be systematically analyzed. This paper integrates evidence from nearly 20 years research elucidate the multi-target pharmacological for NAFLD. Relevant information was sourced Pubmed, Web science, Embase CNKI databases. Using BioRender visio draw biomedical illustrations. active ingredients contain 2 classes saponins (tetracyclic triterpene saponins, pentacyclic other modified types) non-saponins. Different cultivation methods, processing techniques extraction sites have expanded variety constituents demonstrated different activities. Studies shown that functional components ability regulate lipid metabolism disorders, inflammation, oxidative stress, endoplasmic reticulum insulin resistance, disruption intestinal flora structure, cell death senescence. Demonstrates potential study reveals first time integrative through tertiary mode action "multi-component multi-pathway". multilevel modulatory provides new direction development comprehensive therapeutic strategies

Язык: Английский

---

Peripheral Blood Mesenchymal Stem Cell–Derived Exosomes Improve Renal Sympathetic Denervation Efficacy Through β-Catenin-Mediated Cardiac Reprogramming

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Objectives To explore the role of self-peripheral blood mesenchymal stem cell (PBMSC)-derived exosomes (Exos) in enhancing renal sympathetic denervation (RD)-mediated cardiac repair following myocardial infarction (MI) a porcine model.Methods Pigs (EF < 40% post-MI) were randomized to early sham RD or RD. At 2 weeks post-MI, autologous PBMSC-Exos collected. 30 days pigs received either (2 × 10¹³ particles) PBS and followed until 90 days. Another cohort underwent biopsy at 14 post-MI assess effects on ischemic cardiomyocyte (CM) reprogramming, by AAV therapy with miR-141-200-429 sponges negative control (NC) clusters reprogramming.Results Two hearts showed increased Exos uptake inhibited nervous system. By days, + group had 11–26% higher EF than single-treatment groups (all P 0.001), improved survival reduced fibrosis. enhanced inhibiting renin-angiotensin-aldosterone system transferring cluster into CMs. CMs from RD-treated co-cultured PBMSC-Exos^RD exhibited more immature state, promoting reprogramming. β-catenin overexpression further effects, while inhibition blocked RD-induced CM reprogramming survival. Ultimately, Dkk1 expression activated GSK3β phosphorylation, thereby stimulating Wnt/β-catenin pathway.Conclusions enhances RD-mediated activating pathway via cluster, offering novel therapeutic strategy for MI-induced heart failure. Our findings unveil strategy, highlighting that maintains its efficacy safety when integrated complementary approaches over extended periods.

Язык: Английский

---

TRIM25‐Mediated INSIG1 Ubiquitination Promotes MASH Progression Through Reprogramming Lipid Metabolism

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Апрель 15, 2025

Abstract The global incidence of Metabolic dysfunction‐associated steatohepatitis (MASH) is increasing, highlighting the urgent need for new treatment strategies. This study aimed to investigate involvement tripartite motif‐containing 25 (TRIM25) in MASH progression and explore therapeutic potential TRIM25 inhibitor, C 27 H 26 N 2 O 4 S. Functional studies reveal that promoted lipid accumulation inflammation by ubiquitinating degrading insulin‐induced gene 1 (INSIG1), thereby enhancing nuclear translocation sterol regulatory element‐binding protein (SREBP2) upregulating biosynthesis genes. In vivo experiments using knockout mice demonstrated deletion ameliorated progression, reduced fibrosis, decreased inflammatory cell infiltration. It identifies S as a specific inhibitor TRIM25. effectively INSIG1 ubiquitination attenuated hepatocytes. To enhance hepatic delivery S, it utilizes exosomes derived from stellate cells (HSC‐EVs). Biodistribution analysis confirmed HSC‐EVs preferentially accumulated liver. mouse model, HSC‐EV‐encapsulated (C S@HSC‐EV) significantly alleviated severity fibrosis. highlights critical role presents S@HSC‐EV promising approach treatment.

Язык: Английский

---

TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy

International Immunopharmacology, Год журнала: 2025, Номер 156, С. 114678 - 114678

Опубликована: Апрель 18, 2025

Язык: Английский

---

Astragaloside IV as a promising therapeutic agent for liver diseases: current landscape and future perspectives

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 23, 2025

Astragaloside IV (C 41 H 68 O 14 , AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to low toxicity as well anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated potential prevention treatment various liver diseases, including multifactorial injury, metabolic-associated fatty disease, fibrosis cancer. Given promising growing interest research, this review provides comprehensive summary current state research on effects AS-IV, based literature available databases such CNKI, PubMed, ScienceDirect, Google Scholar Web Science. The mechanisms multifaceted, encompassing inhibition inflammatory responses, reduction oxidative stress, improvement insulin leptin resistance, modulation gut microbiota, suppression hepatocellular carcinoma cell proliferation induction tumour apoptosis. Notably, key molecular pathways involved these include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 Akt/GSK-3β/β-catenin. Toxicity indicate that high level safety. addition, discusses sources, physicochemical challenges development clinical application providing valuable insights into agent pharmaceutical nutraceutical industries.

Язык: Английский

---