Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

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

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

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Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 77(4), P. 1136 - 1160

Published: June 22, 2022

Language: Английский

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Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(8), P. 487 - 503

Published: March 17, 2023

Language: Английский

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An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 552 - 566

Published: April 14, 2023

Language: Английский

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Obese visceral fat tissue inflammation: from protective to detrimental?

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Dec. 27, 2022

Abstract Obesity usually is accompanied by inflammation of fat tissue, with a prominent role visceral fat. Chronic in obese tissue lower grade than acute immune activation for clearing the from an infectious agent. It loss adipocyte metabolic homeostasis that causes resident cells supporting functions and regaining homeostasis. Initially, excess influx lipids glucose context overnutrition met growth proliferation. Eventual lipid overload hypertrophic adipocytes leads to endoplasmic reticulum stress secretion variety signals causing increased sympathetic tone, lipolysis adipocytes, uptake macrophages, matrix remodeling, angiogenesis, cell activation. Pro-inflammatory signaling system release amounts pro-inflammatory other mediators resulting enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, death as well senescence several types seen. This structural damage expression or immunostimulatory components monocytes many types, contribution stromal cells. Matrix remodeling angiogenesis further intensified possibly detrimental fibrosis. The accumulation senescent also may be via eventual spread state affected neighboring microRNA-containing vesicles. Obese can viewed initially response order cope ambient nutrients restore but contribute at later stage.

Language: Английский

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Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)

Pharmacological Research, Journal Year: 2023, Volume and Issue: 192, P. 106786 - 106786

Published: May 3, 2023

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis subsequent onset NAFLD-related cirrhosis hepatocellular carcinoma (HCC). Due central role metabolism, NAFLD regarded as result contribution metabolic abnormalities seen syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, govern expression genes responsible for energy cellular development, inflammation, differentiation. The agonists PPARα, such fenofibrate clofibrate, have been used lipid-lowering drugs clinical practice. Thiazolidinediones (TZDs) ligands PPARγ, rosiglitazone pioglitazone, are also treatment type 2 diabetes (T2D) insulin resistance (IR). Increasing evidence suggests PPARβ/δ potential therapeutic effects improving sensitivity metabolism disorders. In addition, PPARs considered hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate significance PPARs-targeting medical research drug discovery. Here, it reviews activities, ligand selectivity functions family, discusses relationship between pathogenesis This will open new possibilities application medicine, provide idea related diseases.

Language: Английский

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Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis

ESMO Open, Journal Year: 2022, Volume and Issue: 7(6), P. 100591 - 100591

Published: Oct. 6, 2022

A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy.We carried out a retrospective analysis prospectively collected data consecutive patients with advanced HCC, treated atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers 4 countries (Italy, Japan, Republic Korea, and UK). The primary endpoint was overall survival (OS) bevacizumab versus lenvatinib. Secondary endpoints were progression-free (PFS) OS PFS sorafenib. For the secondary endpoints, we on whole population first, then divided cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) non-NAFLD/NASH population.One hundred ninety received 569 210 In population, multivariate showed treatment lenvatinib associated longer [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] (HR 0.67; CI 0.51-0.86; 0.002) compared to bevacizumab. NAFLD/NASH confirmed 0.46; 0.26-0.84; 0.0110) 0.55; 0.38-0.82; 0.031) subgroup patients, no difference observed between those All these results following propensity score matching analysis. By comparing receiving statistically significant observed.The present conducted large number HCC for first time is particular NAFLD/NASH-related HCC.

Language: Английский

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MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 65, P. 101581 - 101581

Published: Aug. 23, 2022

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of ranging from simple hepatic steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which may progress cirrhosis and cancer. NAFLD rapidly becoming global health challenge, there need for improved diagnostic- prognostic tools effective pharmacotherapies treat NASH. The molecular mechanisms development progression remain incompletely understood, though ample evidence supports role microRNAs (miRNAs) - small non-coding RNAs regulating gene expression in the metabolic disease.In this review, we summarise currently available miRNA profiling studies people with various stages NAFLD. We further describe mechanistic three most extensively studied species, miR-34a, miR-122 miR-21, highlight selected findings on novel NAFLD-linked miRNAs. also examine literature exosomal (exomiRs) as inter-hepatocellular or -organ messengers Furthermore, address status utilizing circulating NAFLD-associated miRNAs minimally invasive diagnosis, staging prognosis well their potential use NASH pharmacotherapeutic targets. Finally, reflect future directions research field.NAFLD associated changes patterns at early, intermediate late stages, specific species appear be involved NAFL cirrhosis. These act either within between hepatocytes other cell types such stellate cells Kupffer inter-organ carrying signals extra-hepatic tissues, including adipose tissues cardiovascular system. Among linked NAFLD, miR-192 are best candidates biomarkers diagnosis staging. To date, no miRNA-targeting pharmacotherapy has been approved treatment NASH, therapy under clinical development. Further should conducted translate contribution into innovative therapeutic strategies.

Language: Английский

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Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2668 - 2668

Published: Feb. 28, 2022

Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic diseases in the global population that can lead to end-stage hepatocellular carcinoma (HCC). NAFLD is closely linked metabolic syndrome, comorbidities such as type 2 diabetes, obesity insulin resistance aggravate disease, while promotes cardiovascular risk affected patients. The pathomechanisms are multifaceted, combining hepatic factors including lipotoxicity, mechanisms cell death inflammation with extrahepatic disturbance dysbiosis. Nuclear receptors (NRs) family ligand-controlled transcription regulate glucose, fat cholesterol homeostasis modulate innate immune functions, macrophages. In parallel derangement NAFLD, altered NR signaling frequently observed might be involved pathogenesis. Therapeutically, clinical data indicate single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies multiple or drugs actions could possibly bring advantages, by providing more holistic therapeutic approach. this context, peroxisome proliferator-activated (PPARs) other NRs great interest they wide-ranging multi-organ activities associated NASH progression regression. review, we summarize recent advances understanding pathogenesis focusing on death, immunometabolism role NRs. We outline novel discuss remaining challenges.

Language: Английский

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Kupffer cell–like syncytia replenish resident macrophage function in the fibrotic liver

Science, Journal Year: 2023, Volume and Issue: 381(6662)

Published: Sept. 7, 2023

Kupffer cells (KCs) are localized in liver sinusoids but extend pseudopods to parenchymal maintain their identity and serve as the body's central bacterial filter. Liver cirrhosis drastically alters vascular architecture, how KCs adapt is unclear. We used a mouse model of fibrosis human tissue examine immune adaptation. Fibrosis forced lose contact with cells, down-regulating "KC identity," which rendered them incapable clearing bacteria. Commensals stimulated recruitment monocytes through CD44 spatially distinct compartment. There, recruited formed large aggregates multinucleated (syncytia) that expressed phenotypical KC markers displayed enhanced capture ability. Syncytia via CD36 were observed possible antimicrobial defense evolved fibrosis.

Language: Английский

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