Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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The Evolution of Single-Cell RNA Sequencing Technology and Application: Progress and Perspectives

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2943 - 2943

Published: Feb. 2, 2023

As an emerging sequencing technology, single-cell RNA (scRNA-Seq) has become a powerful tool for describing cell subpopulation classification and heterogeneity by achieving high-throughput multidimensional analysis of individual cells circumventing the shortcomings traditional detecting average transcript level populations. It been applied to life science medicine research fields such as tracking dynamic differentiation, revealing sensitive effector cells, key molecular events diseases. This review focuses on recent technological innovations in scRNA-Seq, highlighting latest results with scRNA-Seq core technology frontier areas embryology, histology, oncology, immunology. In addition, this outlines prospects its innovative application Chinese (TCM) discusses issues currently being addressed great potential exploring disease diagnostic targets uncovering drug therapeutic combination multiomics technologies.

Language: Английский

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Mechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 92, P. 101191 - 101191

Published: May 24, 2023

Language: Английский

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Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 95, P. 101231 - 101231

Published: Dec. 5, 2023

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury well persistent activation inflammatory response and fibrogenesis. fibrosis is a major determinant for disease (CLD) progression in the last two decades our understanding on molecular cellular mechanisms underlying fibrogenic CLD has dramatically improved, boosting pre-clinical studies clinical trials designed to find novel therapeutic approaches. From these several critical concepts have emerged, starting reveal complexity pro-fibrotic microenvironment which involves very complex, dynamic interrelated interactions between different hepatic extrahepatic cell populations. This review will offer first recapitulation established pathophysiological basic principles by intentionally focus attention NAFLD/NASH, metabolic-related form with high impact general population emerging leading cause worldwide. NAFLD/NASH-related pro-inflammatory profibrogenic be analysed information cells, mediators signalling pathways taken advantage methodological approaches techniques (single genomics, imaging mass cytometry, vitro two- three-dimensional models, etc.). We next overview recent advancement diagnostic prognostic tools, including serum biomarkers polygenic scores, support analysis biopsies. Finally, this provide current therapies treatment NAFLD/NASH patients.

Language: Английский

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Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114472 - 114472

Published: March 2, 2023

Liver fibrosis is the common consequence of various chronic liver injuries and mainly characterized by imbalance between production degradation extracellular matrix, which leads to accumulation interstitial collagen other matrix components. Matrix metalloproteinases (MMPs) their specific inhibitors, that is, tissue inhibitors (TIMPs), play a crucial role in synthesis lysis. Previous vivo vitro studies our laboratory found repressing (ECM) restoring balance MMPs TIMPs can alleviate fibrosis. We conducted review articles published PubMed Science Direct last decade until February 1, 2023, were searched for using these words "MMPs/TIMPs" "Hepatic Fibrosis." Through literature review, this article reviews experimental based on MMPs/TIMPs, summarizes components may exert an anti-liver effect affecting expression or activity attempts clarify mechanism MMPs/TIMPs regulating homeostasis, so as provide support development drugs. MMP-TIMP-ECM interaction result better understanding pathogenesis progression hepatic from different angle, targeting be promising therapeutic strategy Additionally, we summarized analyzed drugs have been reduce changing ratio including medicine natural products.

Language: Английский

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Role of Insulin Resistance in the Development of Nonalcoholic Fatty Liver Disease in People With Type 2 Diabetes: From Bench to Patient Care

Diabetes Spectrum, Journal Year: 2024, Volume and Issue: 37(1), P. 20 - 28

Published: Feb. 1, 2024

Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis, even hepatocellular carcinoma, which known be more common people with type 2 diabetes. This article reviews role insulin metabolic dysfunction observed obesity, diabetes, atherogenic dyslipidemia, hypertension how it a driver natural history NAFLD by promoting glucotoxicity lipotoxicity. The authors also review genetic environmental factors that stimulate steatohepatitis fibrosis their relationship cardiovascular summarize guidelines supporting treatment diabetes medications reduce resistance, such as pioglitazone or glucagon-like peptide 1 receptor agonists.

Language: Английский

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Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(16)

Published: Jan. 9, 2024

During liver fibrogenesis, the reciprocal crosstalk among capillarized sinusoidal endothelial cells (LSECs), activated hepatic stellate (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating disease condition weakening therapeutic effect. Limited by malignant cellular interactions, previous single-cell centric treatment approaches show unsatisfactory efficacy fail to meet clinical demand. Herein, cycle-breaking strategy is proposed target repair pathological separately terminate progression of fibrosis. Chondroitin sulfate-modified vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed efficiently normalize fenestrae phenotype LSECs restore HSCs quiescent state inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified silybin-loaded (GA-NPs/SIB) prepared function relieving oxidative stress. The results successful interruption cycle as well distinct fibrosis resolution in two animal models through multiregulation cells. This work not only highlights significance modulating but also provides promising avenue for developing antifibrotic regimens.

Language: Английский

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Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7873 - 7873

Published: July 18, 2024

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic injury leads to inflammation and fibrosis (LF) as critical determinants long-term outcomes such cirrhosis, cancer, mortality. LF a wound-healing process characterized by excessive deposition extracellular matrix (ECM) proteins due the activation hepatic stellate cells (HSCs). In healthy liver, quiescent HSCs metabolize store retinoids. Upon fibrogenic activation, transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; produce proinflammatory soluble mediators, collagens, inhibitors ECM degradation. Activated are main effector during fibrogenesis. addition, accumulation profibrogenic macrophages in response hepatocyte death play role initiation HSC survival. source myofibroblasts resident HSCs. migrate site active fibrogenesis initiate formation fibrous scar. Single-cell technologies revealed that highly homogenous, while activated HSCs/myofibroblasts much more heterogeneous. complex results from various hepatocellular inflammatory signals related intrahepatic pathways or extrahepatic mediators. Inflammatory processes modulate activating and, turn, drive immune mechanisms via cytokines chemokines. Increasing evidence also suggests cellular stress responses contribute Recent data demonstrated can revert even advanced stages cirrhosis if underlying cause eliminated, which inhibits cells. However, despite numerous clinical studies on plausible drug candidates, approved antifibrotic therapy still remains elusive. This state-of-the-art review presents molecular involved its resolution, well comprehensively discusses drivers linking LF.

Language: Английский

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Current Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1778 - 1778

Published: Feb. 19, 2025

In recent years, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been proposed to better connect disease metabolic dysfunction, which is the most common chronic worldwide. MASLD affects more than 30% of individuals globally, and it diagnosed by combination hepatic steatosis obesity, type 2 diabetes, or two risk factors. begins with buildup extra fat, often greater 5%, within liver, causing hepatocytes become stressed. This can proceed a severe form, steatohepatitis (MASH), in 20–30% people, where inflammation causes tissue fibrosis, limits blood flow over time. As fibrosis worsens, MASH may lead cirrhosis, failure, even cancer. While pathophysiology not fully known, current “multiple-hits” concept proposes that dietary lifestyle factors, genetic epigenetic factors contribute elevated oxidative stress inflammation, fibrosis. review article provides an overview pathogenesis evaluates existing therapies as well pharmacological drugs are currently being studied clinical trials for MASH.

Language: Английский

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MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(4)

Published: April 28, 2022

Abstract During liver fibrosis, quiescent HSCs (qHSCs) are activated to become (aHSCs)/myofibroblasts. The signal adapter MyD88, an essential component of TLR signaling, plays important role in fibrosis. However, far less is known about the specific effects MyD88 signaling both qHSCs and aHSCs progress Here, we used a CCl 4 -induced mouse fibrosis model which was selectively depleted (GFAP MyD88−/− mice) or (α-SMA mice). deficiency attenuated mice inhibited α-SMA-positive cell activation. Inhibition decreased α-SMA collagen I levels, inflammatory infiltration, pro-inflammatory gene expression. Furthermore, increased secretion CXCL10, promoted macrophage M1 polarization through CXCR3, leading activation JAK/STAT1 pathway. CXCL10 reduced Thus, crucially contributes provides promising therapeutic target for prevention treatment

Language: Английский

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