SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(3), С. 1662 - 1689

Опубликована: Янв. 23, 2024

Sirtuins catalyze deacetylation of lysine residues with a NAD

Язык: Английский

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Adenosine triphosphate-binding pocket inhibitor for mixed lineage kinase domain-like protein attenuated alcoholic liver disease via necroptosis-independent pathway

World Journal of Gastroenterology, Год журнала: 2025, Номер 31(6)

Опубликована: Янв. 10, 2025

Mixed lineage kinase domain-like protein (MLKL) serves as a critical mediator in necroptosis, form of regulated cell death linked to various liver diseases. This study aims specifically investigate the role MLKL's adenosine triphosphate (ATP)-binding pocket facilitating necroptosis-independent pathways that may contribute disease progression. By focusing on this mechanism, we seek identify potential therapeutic targets can modulate MLKL activity, offering new strategies for prevention and treatment liver-related pathologies. To possibility using ATP-binding pocket-associated, pathway target Cell following necroptosis stimuli was evaluated proliferation assays, flow cytometry, electron microscopy cells. The human organoid system used evaluate whether ATP pocket-binding inhibitor could attenuate inflammation. Additionally, alcoholic non-alcoholic fatty diseases animal models were determine inhibitors injury. While an did not prevent necroptosis-induced RAW 264.7 cells, it reduce necroptosis-led expression CXCL2, ICAM, VCAM. Notably, diminishes VCAM by inhibiting IκB nuclear factor kappa-B without inducing two-dimensional culture well human-derived system. Although ineffective models, attenuated hepatic inflammation model. exerted anti-inflammatory effects through model disease.

Язык: Английский

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What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver?

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Фев. 8, 2024

Liver fat storage, also called hepatic steatosis, is increasingly common and represents a very frequent diagnosis in the medical field. Excess not without consequences. In fact, steatosis contributes to progression toward liver fibrosis. There are two main types of fatty disease, alcoholic disease (AFLD) nonalcoholic (NAFLD). Although AFLD NAFLD similar their initial morphological features, both conditions involve same evolutive forms. Moreover, there various mechanisms underlying diseases, including NAFLD, which commonalities. this Review, authors explore downstream signaling events involved onset entities but completely different entities, predominantly focusing on gut microbiome. Downstream molecular events, such as roles sirtuins, cytokeratins, adipokines others, should be considered. Finally, complete feature, some new tendencies therapeutic approach presented.

Язык: Английский

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Recent advances in label-free imaging and quantification techniques for the study of lipid droplets in cells

Current Opinion in Cell Biology, Год журнала: 2024, Номер 87, С. 102342 - 102342

Опубликована: Фев. 29, 2024

Язык: Английский

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(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 20, 2024

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles NAFLD pathogenesis. The unfolded protein response mitochondria (UPRmt) an adaptive mechanism that aims to restore mitochondrial homeostasis mitigate cellular stress. This study aimed investigate effects ( +)-Lipoic acid (ALA) on UPRmt, inflammation, oxidative vitro model using HepG2 cells treated with palmitic oleic induce steatosis. Results Treatment acids increased UPRmt-related proteins HSP90 HSP60 (heat shock protein), decreased CLPP (caseinolytic protease P), indicating ER activation. ALA treatment at 1 μM 5 restored levels. PA:OA (palmitic acid:oleic acid)-induced markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin BAX (Bcl-2-associated X protein) were significantly reduced treatment. also enhanced ER-mediated glycosylation stress, as evidenced GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi GSR (glutathione-disulfide reductase) expression GSH (Glutathione) levels, improved senescence shown β-galactosidase, γH2Ax Klotho-beta. Conclusions In conclusion, ameliorated inflammation acids, potentially offering therapeutic benefits for providing possible biochemical underlying beneficial effects. Graphical

Язык: Английский

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Caffeic acid ameliorates metabolic dysfunction-associated steatotic liver disease via alleviating oxidative damage and lipid accumulation in hepatocytes through activating Nrf2 via targeting Keap1

Free Radical Biology and Medicine, Год журнала: 2024, Номер 224, С. 352 - 365

Опубликована: Авг. 28, 2024

Язык: Английский

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Cigarette Smoke Contributes to the Progression of MASLD: From the Molecular Mechanisms to Therapy

Cells, Год журнала: 2025, Номер 14(3), С. 221 - 221

Опубликована: Фев. 4, 2025

Cigarette smoke (CS), an intricate blend comprising over 4000 compounds, induces abnormal cellular reactions that harm multiple tissues. Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic (CLD), encompassing non-alcoholic (NAFL), steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Recently, the term NAFLD has been changed to metabolic dysfunction-associated steatotic (MASLD), NASH renamed (MASH). A multitude of experiments have confirmed association between CS incidence progression MASLD. However, specific signaling pathways involved need be updated with new scientific discoveries. exposure can disrupt lipid metabolism, induce inflammation apoptosis, stimulate fibrosis through promote Currently, there no officially approved efficacious pharmaceutical intervention in clinical practice. Therefore, lifestyle modifications emerged as primary therapeutic approach for managing Smoking cessation application series natural ingredients shown ameliorate pathological changes induced by CS, potentially serving effective decelerating MASLD development. This article aims elucidate which smoking promotes MASLD, while summarizing reversal factors identified recent studies, thereby offering novel insights future research on treatment

Язык: Английский

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Recent development of mitochondrial metabolism and dysfunction in osteoarthritis

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Фев. 13, 2025

Osteoarthritis is a degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and altered subchondral bone structure. Recent insights have identified mitochondrial dysfunction as pivotal factor in OA pathogenesis, contributing to chondrocyte apoptosis, oxidative stress, extracellular matrix degradation. Disruptions dynamics, including impaired biogenesis, mitophagy, metabolic shifts from phosphorylation glycolysis, exacerbate damage promoting the production of reactive oxygen species matrix-degrading enzymes such ADAMTS MMPs. This review explores molecular mechanisms underlying OA, emphasizing its role homeostasis inflammation. Furthermore, it highlights emerging therapeutic strategies targeting pathways, antioxidants, mitophagy enhancers, modulators, potential interventions mitigate disease progression, which offer promising avenues for advancing personalized disease-modifying treatments OA.

Язык: Английский

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Metabolic-Associated Fatty Liver Disease: The Influence of Oxidative Stress, Inflammation, Mitochondrial Dysfunctions, and the Role of Polyphenols

Pharmaceuticals, Год журнала: 2024, Номер 17(10), С. 1354 - 1354

Опубликована: Окт. 10, 2024

Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical-pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which considered significant cause liver conditions and contributes an increased risk death worldwide. Even though possible causes MAFLD can involve interaction genetics, hormones, nutrition, lifestyle (diet sedentary lifestyle) most influential factor developing this condition. Polyphenols comprise many natural chemical compounds be helpful managing metabolic diseases. Therefore, aim review was investigate impact oxidative stress, inflammation, mitochondrial dysfunction, role polyphenols MAFLD. Some reverse part damage related or among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, silymarin. These have actions reducing plasma enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, fat content, steatosis fibrosis. On other hand, they improve HDL-c, adiponectin levels, fibrogenesis markers. results show promising prevention treatment

Язык: Английский

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Prioritising genetic findings for drug target identification and validation

Atherosclerosis, Год журнала: 2024, Номер 390, С. 117462 - 117462

Опубликована: Янв. 26, 2024

The decreasing costs of high-throughput genetic sequencing and increasing abundance sequenced genome data have paved the way for use in identifying validating potential drug targets. However, number identified targets are often prohibitively large to experimentally evaluate wet lab experiments, highlighting need systematic approaches target prioritisation.In this review, we discuss principles genetically guided development, specifically addressing loss-of-function analysis, colocalization Mendelian randomisation (MR), contexts which each may be most suitable. We subsequently present a range biomedical resources can used annotate prioritise disease-associated proteins by these studies including 1) ontologies map genes, proteins, disease, 2) determining druggability target, 3) tissue cell expression gene encoding 4) key biological pathways involving target.We illustrate concepts through worked example, prioritised set plasma associated with non-alcoholic fatty liver disease (NAFLD). five strong support involvement NAFLD: CYB5A, NT5C, NCAN, TGFBI DAPK2. All were expressed both adipose tissues, DAPK2 being potentially druggable.In conclusion, current review provides an overview evidence identification, how databases provide actionable prioritisation, fully informing downstream experimental validation.

Язык: Английский

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