Irisin alleviates hepatic steatosis by activating the autophagic SIRT3 pathway

Chinese Medical Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Background: Disruption of hepatic lipid homeostasis leads to excessive triglyceride accumulation and the development metabolic dysfunction-associated steatotic liver disease (MASLD). Autophagy, a critical process in metabolism, is impaired MASLD pathogenesis. Irisin, skeletal muscle-driven myokine, regulates but its impact on metabolism not well understood. Here, we aimed explore role irisin steatosis underlying mechanisms involved. Methods: A high-fat diet (HFD)-induced mouse model was used, recombinant protein, herein referred as “Irisin”, intraperitoneally administered for 4 weeks evaluate effects accumulation. Liver tissues were stained with Oil red O (ORO), (TG) total cholesterol (TC) contents measured serum homogenates. The expression autophagosome marker microtubule-associated protein 1 light chain 3 (LC3), autophagy receptor sequestosome-1 (SQSTM1/p62), initiation complex unc-51-like kinase (ULK1) lysosomal functional cathepsin B via Western blotting, transcription factor EB (TFEB) analyzed immunofluorescence autophagic changes. effect flux further evaluated palmitic acid-induced HepG2 cells by measuring degradation chloroquine (CQ), analyzing colocalization LC3 lysosome-associated (LAMP1). possible mechanism examined sirtuin (SIRT3) pathway validated using overexpression SIRT3 plasmid transfection or siRNA-mediated knockdown. Student’s t -test utilized statistical analysis. Results: Irisin significantly reduces mice fed HFD, accompanied enhanced hepatocyte upregulation pathway. In cells, attenuated accumulation, which partially dependent levels. Mechanistically, treatment upregulated phosphorylated AMP-activated (AMPK), inhibited mammalian target rapamycin (mTOR) activity, promoted TFEB nucleus translocation, increased expression, degradation, alleviated steatosis. No significant changes phosphorylation ULK1 hepatocytes observed. However, when siRNA used knock down , those reversed, exacerbated. Conclusions: Our findings highlight potential therapeutic modulating potentially providing novel management MASLD. Further research needed elucidate clinical applications this approach

Language: Английский

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Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 7, 2024

Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's (PD), and Alzheimer's (AD). Although a great deal energy financial resources have been invested in disease-related research, breakthroughs therapeutic approaches remain elusive. The breakdown cells usually happens together with the onset diseases. However, mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which iron-dependent, causes specific type cell death called ferroptosis, there evidence its involvement pathogenic cascade mechanisms still not well known. present article highlights basic processes underlie ferroptosis corresponding signaling networks. Furthermore, it provides an overview discussion current research on role across variety conditions.

Language: Английский

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Inflammation-induced sialin mediates nitrate efflux in dysfunctional endothelium affecting NO bioavailability

Nitric Oxide, Journal Year: 2024, Volume and Issue: 146, P. 37 - 47

Published: April 4, 2024

Language: Английский

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Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 12, 2025

Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating energy metabolism, triggering an acute metabolic response, and sustaining adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting 1 (FNIP1), leading the nuclear translocation transcription factor EB (TFEB) in response functions. While function is tightly linked finely-tuned energy-sensing mobility, FNIP1 plays critical roles glucose transport sensing, autophagy, cellular stress muscle fiber contraction. Consequently, emerges as promising novel target for addressing aberrant metabolism. Recent evidence indicates that implicated biology various pathways, including AMPK, mTOR, ubiquitination, oxidative responses, skeletal Nonetheless, there dearth literature discussing physiological mechanism action therapeutic target. This review outlines how regulates metabolic-related signaling pathways enzyme activities, such catalytic activity enzymes, homeostasis products, controlling fate different contexts. Our focus will be on elucidating these metabolite-mediated processes inflammatory diseases.

Language: Английский

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Mediators of the causal associations between protein ratios and ischemic stroke: a two-step Mendelian randomization study

Neurological Research, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 12

Published: April 3, 2025

Proteomics has revealed links between plasma proteins and ischemic stroke (IS), but the relationship protein ratios, IS, effects of blood cells serum uric acid (SUA) is underexplored. Using two-sample Mendelian randomization (MR), we assessed causal relationships 2,821 91 phenotypes, SUA, IS subtypes. FDR correction was applied specifically to ratio analyses account for multiple comparisons in primary MR step. Significant associations were further validated through co-localization analysis, which shared genetic architecture exposure outcome loci. This analysis used GWAS data from MEGASTROKE, GISCOME, minimizing confounding bias reverse causation. Additionally, total levels on decomposed into direct indirect mediated pathways. Sensitivity ensured robustness. The CD34/ITGAV exhibited distinct risk, showing 34.9% increased odds LAS (OR=1.349, 95% CI=1.097-1.658) while demonstrating protective against progression (OR=0.564, CI=0.380-0.838). Bayesian complete overlap (PPH4 = 1) key ratio-stroke subtype pairs: AIS with TGFBR2/THBD ratio, LGALS8/VWF CES BST2/CEACAM1 CD209/CLEC4G ratios. In mediation pathways, neutrophil parameters accounted 54.4% prognosis effect ABHD14B/STAMBP-IS association, whereas SUA only 1.3% PODXL2/SDC1 ratio-IS relationship. Our study combined identifies interactions highlighting potential targets disrupt pathways connecting changes incidence outcomes, offering promising intervention avenues.

Language: Английский

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mTOR inhibitors in targeting autophagy and autophagy-associated signaling for cancer cell death and therapy

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189342 - 189342

Published: May 1, 2025

Language: Английский

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Ubiquitination-activated TAB–TAK1–IKK–NF-κB axis modulates gene expression for cell survival in the lysosomal damage response

Published: May 9, 2025

Abstract The lysosomal damage response is important for the maintenance of cellular homeostasis. Although mechanisms underlying repair and autophagic elimination damaged lysosomes have been elucidated, early signal transduction pathways genes induced in to remain elusive. We performed transcriptome proteome analyses found that TAB–TAK1–IKK–NF-κB axis activated by K63-linked ubiquitin chains accumulate on lysosomes. This activates expression various transcription factors cytokines promote anti-apoptosis intercellular signaling. findings highlight crucial role ubiquitin-regulated gene cell survival cell–cell communication damage. results suggest system not only involved removal lysophagy, but also functions activation signaling survival.

Language: Английский

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Ubiquitination-activated TAB–TAK1–IKK–NF-κB axis modulates gene expression for cell survival in the lysosomal damage response

Published: May 9, 2025

Abstract The lysosomal damage response is important for the maintenance of cellular homeostasis. Although mechanisms underlying repair and autophagic elimination damaged lysosomes have been elucidated, early signal transduction pathways genes induced in to remain elusive. We performed transcriptome proteome analyses found that TAB–TAK1–IKK–NF-κB axis activated by K63-linked ubiquitin chains accumulate on lysosomes. This activates expression various transcription factors cytokines promote anti-apoptosis intercellular signaling. findings highlight crucial role ubiquitin-regulated gene cell survival cell–cell communication damage. results suggest system not only involved removal lysophagy, but also functions activation signaling survival.

Language: Английский

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PRKAA2 Promotes Tumor Growth and Inhibits Ferroptosis through SLC7A11/GSH/GPX4 Pathway in Non‐Small Cell Lung Cancer

Biotechnology and Applied Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

ABSTRACT Non‐small cell lung cancer (NSCLC) is the most pervasive sort of with deadly outcome. According to recent studies, a number neoplastic disorders and ferroptosis are intimately connected. This study aims identify role key ferroptosis‐related gene (protein kinase AMP‐activated catalytic subunit alpha 2, PRKAA2) explore new directions for diagnosis treatment NSCLC. The PRKAA2 expression its influence on survival were analyzed in multiple public databases (TCGA, TIMER2.0, GEPIA). And mRNA level NSCLC cells examined by qRT‐PCR. Silencing (sh‐PRKAA2) used transfection. CCK‐8, EdU, flow cytometry assays measure proliferation apoptosis. protein levels markers (SLC7A11, GPX4, NRF2) determined western blotting. Meanwhile, related analysis, such as malondialdehyde (MDA) glutathione (GSH), reactive oxygen species (ROS), iron, Fe 2+ also detected transfected cells. Moreover, relationship between SLC7A11 was analyzed. xenograft mouse models vivo verification function. Here, our data revealed that upregulated Additionally, strengthened attenuated apoptosis depletion enhanced erastin‐induced inhibition effect growth, notably increased MDA, ROS, , while decreased GSH In mechanism exploration, we discovered could activate SLC7A11/GSH/GPx4 antioxidant pathway. rescue experiments showed abrogated inhibitive impacts repression cellular proliferation, apoptosis, Besides, animal proved tumor growth vivo. results accelerated malignant progression, diminished through SLC7A11/GSH/GPX4 provide novel target application treatment.

Language: Английский

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LRRK2 and RAB8A regulate cell death after lysosomal damage in macrophages through cholesterol-related pathways

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 202, P. 106728 - 106728

Published: Nov. 1, 2024

Activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are among the most common genetic causes of Parkinson's disease (PD). The mechanistic path from LRRK2 to PD is not established, but several lines data suggest that modulation lysosomal function involved. It has previously been shown recruited lysosomes upon damage leading increased phosphorylation its RAB GTPase substrates macrophage-derived RAW 264.7 cells. Here, we find kinase inhibition reduces cell death induced by lysosomotropic compound LLOMe cells showing and functionally interacts both directions: can lead activation signaling attenuate LLOMe-induced death. effect lysosome specific, as only stressors a variety other inducers could be modulated inhibition. We show with timing Lysotracker experiments does affect immediate permeabilization LLOMe, rather modulates subsequent cellular response damage. siRNA-mediated knockdown main substrates, GTPases, showed RAB8A death, GTPases tested. An RNA sequencing study was done identify downstream pathways striking finding almost all cholesterol biosynthesis genes were strongly downregulated upregulated combination treatment. To explore functional relevance transcriptional changes, pretreated NPC1 inhibitor U18666A accumulation cholesterol. U18666A-treated less sensitive attenuation reduced suggesting overlapping mechanisms. Thus, our demonstrates LRRK2- RAB8A-mediated

Language: Английский

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