NOX Dependent ROS Generation and Cell Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2086 - 2086

Published: Jan. 20, 2023

Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, superoxide anion radical (O2·-) is key redox signaling molecule prominently generated by NADPH oxidase (NOX) enzyme family and mitochondrial electron transport chain. Notably, altered balance deregulated are recognized hallmarks cancer involved in malignant progression resistance to drugs treatment. Since oxidative stress metabolism cells strictly intertwined, this review, we focus on emerging roles NOX enzymes as important modulators metabolic reprogramming cancer. The includes seven isoforms different activation mechanisms, widely expressed several tissues. In particular, dissect contribute NOX1, NOX2, NOX4 modulation highlight their potential role new therapeutic target for tumor rewiring.

Language: Английский

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Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Jan. 12, 2024

Abstract This review provides an update on recent findings from basic, translational, and clinical studies the molecular mechanisms of mitochondrial dysfunction apoptosis hepatocytes in multiple liver diseases, including but not limited to alcohol-associated disease (ALD), metabolic dysfunction-associated steatotic (MASLD), drug-induced injury (DILI). While ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via microsomal ethanol system, it also metabolizing many xenobiotics, pollutants, chemicals, drugs, specific diets abundant n-6 fatty acids, into toxic metabolites organs, liver, causing pathological insults through organelles such as mitochondria endoplasmic reticula. Oxidative imbalances (oxidative stress) promote covalent modifications lipids, proteins, nucleic acids enzymatic non-enzymatic mechanisms. Excessive changes stimulate various post-translational (PTMs) transcription factors, histones. Increased PTMs proteins inactivate enzymes involved reduction oxidative species, acid metabolism, mitophagy pathways, leading dysfunction, energy depletion, apoptosis. Unique other organelles, control signaling cascades bioenergetics (fat metabolism), inflammation, apoptosis/necrosis hepatocytes. When homeostasis shifted, these pathways become altered or shut down, likely contributing death with activation inflammation hepatic stellate cells, fibrosis cirrhosis. will encapsulate how contributes hepatocyte several types diseases order provide recommendations targeted therapeutics.

Language: Английский

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The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 23, 2023

Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it emerged as one of the major diseases modern world. NAFLD constitutes a simple to chronic non-alcoholic steatohepatitis (NASH), which often leads fibrosis or cirrhosis, serious health condition with limited treatment options. Many time, progresses fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such X receptor-α (LXR-α) closely associated farnesoid receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions repression play role in controlling pathophysiology human liver. Withaferin A is multifaceted potent natural dietary compound huge beneficial properties plays vital an anti-inflammatory molecule. Methods:In vivo: Swill albino mice were fed western diet sugar water (WDSW) for 12, 16, 20 weeks suitable controls. Post necropsy, enzymes (AST, ALT, ALP) lipid profile measured by commercially available kits using semi-auto analyzer serum samples. Liver histology was assessed H&E MTS stains check inflammation fibrosis, respectively, paraffin-embedded sections mRNA these markers qRT-PCR method. TGF-β1 levels samples quantified ELISA. In vitro: Steatosis induced HepG2 Huh7 cells free acids [Sodium Palmitate (SP) Oleate (OA)]. After induction, treated dose-dependent manner (1, 2.5, 5 μM, respectively). vitro steatosis confirmed Oil-Red-O staining. Molecular Docking: Studies conducted Auto Dock Vina software binding affinity Withaferin-A LXR-α FXR. Results: We explored dual receptor-activating nature docking studies, potently improves high-fat diet-induced suppresses hepatic via LXR/FXR. Our studies also indicated inhibits droplet accumulation sodium palmitate oleate-treated cells, may occur through FXR-mediated signaling pathways. known inhibitor NF-κB-mediated inflammation. Intriguingly, both FXR activation negatively regulating NF-κB. Additionally, significantly inhibited TGF-β-induced expression, contributes reduced fibrosis. Discussion: Thus, LXR/ activator NAFLD-associated mouse models under conditions, makes possibly pharmacological therapeutic agent NAFLD.

Language: Английский

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NADPH-oxidases as potential pharmacological targets for thrombosis and depression comorbidity

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103060 - 103060

Published: Feb. 1, 2024

There is a complex interrelationship between the nervous system and cardiovascular system. Comorbidities of diseases (CVD) with mental disorders, vice versa, are prevalent. Adults disorders such as anxiety depression have higher risk developing CVD, people CVD an increased being diagnosed disorders. Oxidative stress one many pathways associated pathophysiology brain disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) major generators reactive oxygen species (ROS) in mammalian cells, it enzyme that specifically produces superoxide. This review summarizes recent findings on consequences NOX activation thrombosis depression. It also discusses therapeutic effects pharmacological strategies inhibitors A better comprehension these processes could facilitate development new approaches for prevention treatment comorbidity

Language: Английский

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AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion

Nature Biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Abstract Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently specifically than AAV5, AAV8 AAV6, which are most commonly used clinically, AAV-NP59, is better transducing engrafted immune-deficient mice. preferentially periportal normal liver, whereas AAV5 targeted pericentral steatotic liver. sinusoidal endothelial cells as hepatocytes. steatosis influenced vector episome formation, determines durability, with delaying concatemerization. Our findings inform choice clinical therapy, including consideration disease-relevant hepatocyte zonation effects steatosis, facilitate the development capsids that transduce or other therapeutically relevant cell types maximum efficiency specificity.

Language: Английский

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Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(24), P. 16226 - 16226

Published: Dec. 19, 2022

In alcohol-induced liver disease (ALD) and in non-alcoholic fatty (NAFLD), there are abnormal accumulations of fat the liver. This phenomenon may be related to excessive alcohol consumption, as well combination consumption medications. There is an evolution from simple steatosis steatohepatitis, fibrosis cirrhosis leading hepatocellular carcinoma (HCC). Hepatic pathology very similar regarding (NAFLD) ALD. Initially, lipid accumulation parenchyma progression lobular inflammation. The morphological changes mitochondria, perivenular perisinusoidal fibrosis, ballooning, apoptosis necrosis lead development HCC. Medical history ethanol laboratory markers chronic intake, AST/ALT ratio on one hand features metabolic syndrome other hand, help estimating contribution intake syndrome, respectively, steatosis.

Language: Английский

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Novel Therapeutic Approaches to Liver Fibrosis Based on Targeting Oxidative Stress

Antioxidants, Journal Year: 2023, Volume and Issue: 12(8), P. 1567 - 1567

Published: Aug. 5, 2023

Chronic liver disease (CLD) constitutes a growing global health issue, with no effective treatments currently available. Oxidative stress closely interacts other cellular and molecular processes to trigger pathways in different hepatic cells fuel the development of fibrosis. Therefore, inhibition reactive oxygen species (ROS)-mediated effects modulation major antioxidant responses counteract oxidative stress-induced damage have emerged as interesting targets prevent or ameliorate injury. Although many preclinical studies shown that dietary supplements properties can significantly CLD progression animal models, this strategy has not proved reduce fibrosis when translated into clinical trials. Novel more specific therapeutic approaches are thus required alleviate We reviewed relevant literature concerning crucial role alterations redox homeostasis cell types during discussed current pharmacological by reducing focusing on selective enzymatic oxidant sources, systems ROS-mediated pathogenic processes.

Language: Английский

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Dietary Patterns, Foods, and Nutrients to Ameliorate Non-Alcoholic Fatty Liver Disease: A Scoping Review

Nutrients, Journal Year: 2023, Volume and Issue: 15(18), P. 3987 - 3987

Published: Sept. 14, 2023

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic without pharmacological treatment yet. There also a lack specific dietary recommendations and strategies to treat negative health impacts derived from NAFLD. Objective: This scoping review aimed compile patterns, foods, nutrients ameliorate Methods: A literature search was performed through MEDLINE, Scopus, Web Science, Google Scholar. Results: Several guidelines are available literature. Hypocaloric Mediterranean diet accepted pattern tackle Coffee consumption (sugar free) may have protective effect for Microbiota plays role in NAFLD; hence, fibre intake should be guaranteed. Conclusions: high-quality could improve steatosis. Weight loss hypocaloric together with physical activity limited sugar good managing Specific plate been proposed

Language: Английский

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Non-alcoholic fatty liver disease in type 1 diabetes: Prevalence and pathophysiology

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 1, 2022

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic in general population with a global prevalence of 25%. It often associated metabolic syndrome and type 2 diabetes, as insulin resistance hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence NAFLD 1 diabetes (T1D) well. Although increasing these patients seems explain part this increase NAFLD, other underlying mechanisms may participate emergence NAFLD. Notably, some genetic factors more disease, but their T1D has not been evaluated. Moreover, oxidative stress, poor glucose control long-lasting hyperglycemia, well exogenous administration play an important role intrahepatic fat homeostasis. The main differential diagnosis glycogenic hepatopathy, which needs considered mostly glycemic control. This article aims review pathophysiology open perspectives for clinicians taking care potential hepatopathy.

Language: Английский

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Research progress on rodent models and its mechanisms of liver injury

Life Sciences, Journal Year: 2023, Volume and Issue: 337, P. 122343 - 122343

Published: Dec. 15, 2023

The liver is the most important organ for biological transformation in body and crucial maintaining body's vital activities. Liver injury a serious pathological condition that commonly found many diseases. It has high incidence rate, difficult to cure, prone recurrence. can cause harm body, ranging from mild severe fatty disease. If continues worsen, it lead fibrosis cirrhosis, ultimately resulting failure or cancer, which seriously endanger human life health. Therefore, establishing an rodent model mimics pathogenesis severity of clinical great significance better understanding patients developing more effective treatment methods. author this article summarizes common chemical models, immune alcoholic drug-induced systematically elaborates on modeling methods, mechanisms action, pathways advantages disadvantages each type model. aim study establish reliable models researchers use exploring anti-liver hepatoprotective drugs. By creating accurate theoretical frameworks, we hope provide new insights into

Language: Английский

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