Targeting integrin pathways: mechanisms and advances in therapy

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

Published: Jan. 2, 2023

Abstract Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical mechanical signals between cells their environment a wide range of states health diseases. Integrin functions dependable on delicate balance active inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, trafficking. Due to exposure cell surface sensitivity molecular blockade, integrins have been investigated pharmacological targets for nearly 40 years, but given complexity sometimes opposite characteristics, targeting integrin therapeutics has challenge. To date, only seven drugs successfully marketed, abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, carotegrast. Currently, there approximately 90 kinds integrin-based therapeutic or imaging agents clinical studies, small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, agents, etc. A serious lesson from past drug discovery research efforts is successes rely both deep understanding integrin-regulatory mechanisms unmet needs. Herein, we provide systematic complete review all family members integrin-mediated downstream signal transduction highlight ongoing develop new therapies/diagnoses bench clinic. In addition, further discuss trend development, how improve success rate trials therapies, key points research, basic translational research.

Language: Английский

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Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form NAFL, can be progressive and more susceptible to developing cirrhosis hepatocellular carcinoma. Currently, lifestyle interventions are most essential effective strategies for preventing controlling NAFL without development fibrosis. While there still limited appropriate drugs specifically treat NAFL/NASH, growing progress is being seen in elucidating pathogenesis identifying therapeutic targets. In this review, we discussed recent developments etiology prospective targets, as well pharmacological candidates pre/clinical trials patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, Importantly, evidence elucidates that disruption gut-liver axis microbe-derived metabolites drive NAFL/NASH. Extracellular vesicles (EVs) act signaling mediator, resulting accumulation, macrophage stellate cell activation, further promoting inflammation fibrosis progression during Targeting gut microbiota or EVs may serve new treatment Finally, other mechanisms, such therapy genetic approaches, also have enormous potential. Incorporating different mechanisms personalized medicine improve efficacy better benefit patients

Language: Английский

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Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets

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

Published: July 31, 2023

Abstract Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical regarding cell activities and metabolism. Typical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, viscosity. Mechanotransduction has been expected trigger multiple such as embryonic development, repair regeneration. However, prolonged excessive stimulation can result pathological multi-organ fibrosis, tumorigenesis, cancer immunotherapy resistance. Although associations between normal homeostasis diseases have identified, regulatory mechanisms among different are not yet comprehensively illustrated, no effective therapies currently available targeting cue-related signaling. This review systematically summarizes characteristics typical conditions with updated evidence. The key effectors responding stimulations listed, Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator PDZ-binding motif (TAZ), transient receptor potential vanilloid 4 (TRPV4). We also reviewed signaling pathways, therapeutic targets cutting-edge clinical applications related cues.

Language: Английский

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Single‐Cell Transcriptomic Analysis Reveals a Hepatic Stellate Cell–Activation Roadmap and Myofibroblast Origin During Liver Fibrosis in Mice

Hepatology, Journal Year: 2021, Volume and Issue: 74(5), P. 2774 - 2790

Published: June 5, 2021

Background and Aims HSCs portal fibroblasts (PFs) are the major sources of collagen‐producing myofibroblasts during liver fibrosis, depending on different etiologies. However, mechanisms by which their dynamic gene expression directs transition from quiescent to activated state—as well as contributions fibrotic myofibroblasts—remain unclear. Here, we analyze activation PFs in CCL 4 ‐induced bile duct ligation–induced fibrosis mouse models, using single‐cell RNA sequencing lineage tracing. Approach Results We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with sequential inflammatory, migrative, extracellular matrix–producing programs. The data also reveal exclusive source ‐treated liver, while early cholestatic fibrosis. Single‐cell lineage‐tracing analysis uncovers differential gene‐expression features between PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed but not PFs. stimulator Riociguat potently reduced livers showed no therapeutic efficacy ligation livers. Conclusions This study provides a transcriptional roadmap yields comprehensive evidence along relative etiologies, should be considered developing effective antifibrotic strategies.

Language: Английский

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Novel therapeutic targets for cholestatic and fatty liver disease

Gut, Journal Year: 2021, Volume and Issue: 71(1), P. 194 - 209

Published: Oct. 6, 2021

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) ligand-activated transcriptional regulators of metabolic processes including hepatic lipid glucose metabolism, energy expenditure bile acid (BA) homoeostasis, as well inflammation, fibrosis cellular proliferation. Dysregulation these contributes to the pathogenesis progression cholestatic disease, placing NRs at forefront approaches. This includes BA activated such farnesoid-X receptor (FXR) peroxisome proliferator-activated receptors, respectively, high affinity ligands targeting specific or multiple isoforms have been developed. Moreover, liver-specific thyroid hormone beta 1 complete spectrum available NR-targeted drugs. Apart from FXR ligands, signalling mimetics FXR-activated fibroblast growth factor 19, modulation their enterohepatic circulation through uptake inhibitors in hepatocytes enterocytes, derivatives undergoing cholehepatic shunting (instead circulation). Other approaches more directly target inflammation and/or critical events progression. Combination strategies synergistically disturbances, may ultimately necessary successful treatment complex multifactorial disorders.

Language: Английский

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Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies

Cancer Letters, Journal Year: 2023, Volume and Issue: 561, P. 216157 - 216157

Published: April 1, 2023

Language: Английский

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Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 186, P. 114319 - 114319

Published: May 8, 2022

Language: Английский

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Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 30, 2023

Abstract To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to are required. Here, we screen the lysyl-oxidase (LOX) family clarify its contribution resistance in liver cancer. LOXL3 depletion significantly sensitizes Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives interact with TOM20, causing it be hijacked into mitochondria, where activity is reinforced phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes preventing ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates turn inhibiting chemotherapy-induced mitochondrial CRISPR-Cas9-mediated site-mutation of mouse D704 causes a reduction lipid peroxidation. Using an advanced model, further reveal that low-dose combination DHODH-inhibitor Leflunomide effectively inhibit progression ferroptosis, increased sensitivity decreased toxicity.

Language: Английский

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Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy

World Journal of Hepatology, Journal Year: 2023, Volume and Issue: 15(2), P. 180 - 200

Published: Feb. 24, 2023

Chronic liver disease (CLD) is a continuous process that causes reduction of function lasting more than six months. CLD includes alcoholic (ALD), non-alcoholic fatty (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to fibrosis, cirrhosis, cancer. Liver inflammation oxidative stress are commonly associated with the development progression CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, peroxisome proliferator-activated receptors (PPARs) implicated in pathogenesis Therefore, antioxidant anti-inflammatory agents from natural products new potent therapies for ALD, NAFLD, hepatocellular carcinoma (HCC). In this review, we summarize some powerful be potential applied all stages CLD, ALD/NAFLD HCC. The selected β-sitosterol, curcumin, genistein, silymarin regulate activation several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, lysyl oxidase-like proteins. addition, clinical trials undergoing evaluate their efficacy safety.

Language: Английский

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Treatment of liver fibrosis: Past, current, and future

World Journal of Hepatology, Journal Year: 2023, Volume and Issue: 15(6), P. 755 - 774

Published: June 25, 2023

Liver fibrosis accompanies the progression of chronic liver diseases independent etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty disease. It is commonly associated with injury, inflammation, cell death. characterized by abnormal accumulation extracellular matrix components that are expressed myofibroblasts collagens alpha-smooth actin proteins. Activated hepatic stellate cells contribute to major population myofibroblasts. Many treatments for have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment simtuzumab), drug pegbelfermin natural herbs), genetic regulation non-coding RNAs), transplantation stem hematopoietic cells). However, none these has approved Food Drug Administration. The efficacy can be evaluated histological staining methods, imaging serum biomarkers, well scoring systems, fibrosis-4 index, aspartate aminotransferase platelet ratio, non-alcoholic disease score. Furthermore, reverse slowly frequently impossible advanced or cirrhosis. To avoid life-threatening stage fibrosis, anti-fibrotic treatments, especially combined behavior prevention, treatment, drugs herb medicines, needed. This review summarizes past studies current future fibrosis.

Language: Английский

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