Cell senescence in liver diseases: pathological mechanism and theranostic opportunity

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(7), P. 477 - 492

Published: March 14, 2024

Language: Английский

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Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

BMC Gastroenterology, Journal Year: 2024, Volume and Issue: 24(1)

Published: Feb. 2, 2024

Abstract Background Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate effects intervention on hallmarks molecular signatures hepatocellular Gubra-Amylin (GAN) diet-induced obese (DIO) biopsy-confirmed mouse model NASH. Methods GAN DIO-NASH mice with liver fibrosis received by switching chow feeding (chow reversal) 8, 16 or 24 weeks. Untreated chow-fed C57BL/6J served as controls. Pre-to-post biopsy histology was performed within-subject evaluation NAFLD Activity Score stage. Terminal endpoints included blood/liver biochemistry, quantitative histology, mitochondrial respiration RNA sequencing. Results Chow-reversal promoted substantial benefits metabolic outcomes demonstrated robust weight loss, complete resolution hepatomegaly, hypercholesterolemia, elevated transaminase levels hepatic steatosis addition attenuation inflammatory markers. Notably, all ≥ 2 point significant improvement following intervention. While not improving stage, chow-reversal reduced markers (PSR, collagen 1a1, α-SMA), concurrent improved respiration, reversal p21 overexpression, lowered γ-H2AX widespread suppression gene expression senescence. Conclusions Dietary substantially improves metabolic, biochemical histological mice. These were reflected progressive clearance senescent cells, making suitable profiling potential senotherapeutics preclinical drug discovery

Language: Английский

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Dietary Curcumin Attenuates Hepatic Cellular Senescence by Suppressing the MAPK/NF-κB Signaling Pathway in Aged Mice

Antioxidants, Journal Year: 2023, Volume and Issue: 12(6), P. 1165 - 1165

Published: May 27, 2023

Dietary interventions with bioactive compounds have been found to suppress the accumulation of senescent cells and senescence-associated secretory phenotypes (SASPs). One such compound, curcumin (CUR), has beneficial health biological effects, including antioxidant anti-inflammatory properties, but its ability prevent hepatic cellular senescence is unclear. The objective this study was investigate effects dietary CUR as an on determine benefits aged mice. We screened transcriptome that supplementation led downregulation gene expressions in both usually fed nutritionally challenged Our results showed enhanced properties suppressed mitogen-activated protein kinase (MAPK) signaling cascades liver, particularly c-Jun N-terminal (JNK) mice p38 diet-induced obese Furthermore, decreased phosphorylation nuclear factor-κB (NF-κB), a downstream transcription factor JNK p38, inhibited mRNA expression proinflammatory cytokines SASPs. potency administration demonstrated via insulin homeostasis along declined body weight. Taken together, these suggest may be nutritional strategy senescence.

Language: Английский

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Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment

Biochemistry (Moscow), Journal Year: 2024, Volume and Issue: 89(5), P. 839 - 852

Published: May 1, 2024

Language: Английский

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Impact of Endocrine Disruptors on Key Events of Hepatic Steatosis in HepG2 Cells

Food and Chemical Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 115241 - 115241

Published: Jan. 1, 2025

Language: Английский

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MAP17 is a Novel NASH Progression Biomarker Associated with Macrophage Infiltration, Immunotherapy Response, and Oxidative Stress

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 601 - 619

Published: Jan. 1, 2025

Background: Nonalcoholic steatohepatitis (NASH) has recently garnered increased attention due to immune infiltration.However, the role of membrane-associated protein 17 (MAP17) in NASH remains unclear, which prompted this study explore its relationship with infiltration and regulatory mechanisms.Methods: We employed weighted correlation network analysis (WGCNA) construct a gene co-expression aimed at identifying key genes associated progression.Our further analyses included differential expression evaluation, protein-protein interaction (PPI) analysis, Venn diagram discover novel targets.The CIBERSORT algorithm assessed between MAP17 cell within tumor microenvironment (TME), while TIDE predicted responses immunotherapy.Additionally, we conducted ontology (GO), Kyoto Encyclopedia Genes Genomes (KEGG), set enrichment (GSEA) elucidate mechanisms by operates.The was validated using liver tissues obtained from patients mice diet-induced or CCl4-induced fibrosis.Results: Our findings identified as target progression NASH.Correlation demonstrated positive association M1 macrophage infiltration, well negative M2 infiltration.TIDE results positioned potential biomarker for predicting checkpoint blockade.Mechanistic studies revealed that induced oxidative stress, subsequently activated p53, PI3K-AKT, Wnt signaling pathways.Validation confirmed levels significantly fibrosis, patients.Conclusion: is linked immunotherapy patients.The stress activates pathways, all contribute NASH.

Language: Английский

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Prohibitions in the meta-inflammatory response: a review

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: May 15, 2024

Prohibitins are the central regulatory element of cellular homeostasis, especially by modulating response at different levels: Nucleus, mitochondria and membranes. Their localization interaction with various proteins, homons, transcription nuclear factors, mtDNA indicate globality complexity their pleiotropic properties, which remain to be investigated. A more detailed deciphering metabolism in relation prohibitins under normal conditions metabolic diseases will allow us understand precise role signaling cascades PI3K/Akt, Raf/MAP/ERK, STAT3, p53, others fathom mutual influence. valuable research perspective is investigate molecular interactions between two major players pathogenesis obesity—adipocytes macrophages - that form basis meta-inflammatory response. Investigating subtle intercellular communication triggered these cells propose new therapeutic strategies eliminate persistent inflammation, taking into account novel genetic approaches activate/inactivate prohibitins.

Language: Английский

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Phosphorylation: new star of pathogenesis and treatment in steatotic liver disease

Lipids in Health and Disease, Journal Year: 2024, Volume and Issue: 23(1)

Published: Feb. 17, 2024

Abstract Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens chronic worldwide. Currently, research mechanism is not clear, there no specific targeted drug for direct treatment. Phosphorylation widely regarded common type protein modification, closely linked steatotic in previous studies. However, systematic review clarify relationship investigate from perspective phosphorylation. been found mainly regulate molecule stability, affect localization, transform molecular function, cooperate with other modifications. Among them, adenosine 5’-monophosphate-activated kinase (AMPK), serine/threonine (AKT), nuclear factor kappa-B (NF-kB) are considered core mechanisms disease. As treatment, lifestyle changes, prescription drugs, herbal ingredients can alleviate symptoms by influencing It demonstrates role phosphorylation occurrence therapeutic target disease, which could be new star future exploration.

Language: Английский

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Analysis of culture and RNA isolation methods for precision-cut liver slices from cirrhotic rats

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 3, 2024

Precision-cut liver slices (PCLS) are increasingly used as a model to investigate anti-fibrotic therapies. However, many studies use PCLS from healthy animals treated with pro-fibrotic stimuli in culture, which reflects only the early stages of fibrosis. The effects different culture conditions on cirrhotic has not been well characterized and there is no consensus optimal methods. In this study, we report method for collection compare effect common viability, function, gene expression. Additionally, compared three methods RNA isolation identified protocol high yield purity. We observed significantly increased albumin production when cultured insulin-transferrin-selenium dexamethasone, incubated rocking platform. Culturing dexamethasone maintained expression closer levels fresh slices. despite stable viability function up 4 days, found significant changes key genes by day 2. Interestingly, also that maintain longer than animals. Due influence matrix stiffness fibrosis hepatocellular it important evaluate prospective therapies platform preserves tissue biomechanics. represent promising tool development treatments chronic disease.

Language: Английский

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Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity—A Narrative Review

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7943 - 7943

Published: July 20, 2024

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction generate reactive oxygen species with DNA damage. triggers adipocyte hypertrophy hypoxia, inhibition adiponectin secretion adipogenesis, increased endoplasmic reticulum stress maladaptive unfolded protein response, metaflammation, polarization macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or repair mechanisms, resulting in transmissible senescence via autocrine, paracrine, endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, renal podocytes. The senescence-associated secretory phenotype is closely related visceral adipose expansion metaflammation; SIRT-1, adiponectin, autophagy; release exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, saturated free fatty acids. hypernefemia, insulin resistance, diminished acid β-oxidation lead lipotoxicity progressive metabolic syndrome, physical cognitive functional decline. Weight cycling continuing immunosenescence exposure palmitate. Cellular release, contribute obesity syndrome. Targeted therapies have interrelated synergistic effects on premature aging.

Language: Английский

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