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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Mitochondrial quality control in alcohol-associated liver disease

Hepatology Communications, Journal Year: 2024, Volume and Issue: 8(11)

Published: Oct. 24, 2024

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis crucial for identifying potential targets. Central intricate interplay between metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in liver, critical energy production metabolic functions. However, they vulnerable alcohol-induced damage due their involvement metabolism. Alcohol disrupts mitochondrial function, impairing ATP triggering oxidative stress, which leads inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, mitophagy, maintaining optimal function. Chronic checkpoints, dysfunction that impairs fatty acid oxidation contributes hepatic steatosis ALD. Moreover, promotes accumulation damaged mitochondria release proinflammatory components, exacerbating Preserving presents promising approach mitigate progression. In this review, we provide comprehensive overview effects on function highlighting role pathogenesis. these mechanisms may pave way development novel interventions

Language: Английский

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Crocin and gallic acid attenuate ethanol-induced mitochondrial dysfunction via suppression of ROS formation and inhibition of mitochondrial swelling in pancreatic mitochondria

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Language: Английский

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Mitochondrial Dysfunction and Atherosclerosis: The Problem and the Search for Its Solution

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 963 - 963

Published: April 15, 2025

Background/Objectives: This review has been prepared to promote interest in the interdisciplinary study of mitochondrial dysfunction (MD) and atherosclerosis. aims describe state this problem indicate direction for further implementation knowledge clinical medicine. Methods: Extensive research literature was implemented elucidate role molecular mechanisms MD pathogenesis Results: A view on atherosclerosis through prism about is presented. cause primary mechanism onset progression It proposed that be considered context a continuum. Conclusions: are united by common pathogenesis. Knowledge should used argue healthy lifestyle as way prevent The development new approaches diagnosing treating an urgent task challenge modern science.

Language: Английский

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Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(49), P. 19531 - 19550

Published: Dec. 1, 2023

Increasing evidence points to the critical role of calcium overload triggered by mitochondrial dysfunction in development alcoholic liver disease (ALD). As an important organelle for aerobic respiration with a double-layered membrane, mitochondria are pivotal targets alcohol metabolism-mediated lipid peroxidation, wherein mitochondria-specific phospholipid cardiolipin oxidation 4-hydroxynonenal (4-HNE) ultimately leads integrity and function impairment. Therefore, it is absolutely essential identify effective nutritional intervention targeting redox alternative therapy ALD, order compensate difficulty achieving withdrawal due addiction. In this study, we confirmed significant advantages astaxanthin (AX) against toxicity among various carotenoids via cell experiments identified potential mitochondrion morphogenesis signaling pathway bioinformatics analysis. The ALD model Sprague–Dawley (SD) rats was also generated investigate effectiveness AX on alcohol-induced injury, underlying mechanisms were further explored. attenuated oxidative stress peroxidation as well characterized degenerative morphology changes collapsed membrane potential. Also, reduced production 4-HNE activating Nrf2-ARE pathway, which closely associated balance mitochondria. addition, relieved Ca2+ accumulation caused observed both vivo vitro. Furthermore, revealed structure–activity relationship channel proteins MCU VDAC1, implying acting targets. Altogether, our data indicated new mechanism protects injury through restoring homeostasis mitochondria, provided novel insights into therapeutic option management ALD.

Language: Английский

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Repurposing Niclosamide as a Therapeutic Drug against Acute Liver Failure by Suppressing Ferroptosis

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(7), P. 1950 - 1950

Published: July 14, 2023

Acute liver failure (ALF) is a severe disease with high mortality rate without effective therapeutic drugs. Ferroptosis form of programmed cell death that plays an important role in ALF. In this study, we aimed to identify ferroptosis-related genes ALF, thereby predicting promising compounds treat First, mRNA microarray data were utilized the differentially expressed (DEGs). Hub screened protein-protein interaction network and validated. Subsequently, potential drugs ALF predicted. One predicted was tested model mice. examination molecular docking analyzed explore mechanism. A total 37 DEGs identified, ten hub extracted, their expression The drug niclosamide mitigated lipopolysaccharide/D-galactosamine-induced hepatotoxicity, decreased mice model. Mechanically, may combine signal transducer activator transcription 3 inhibit progression by suppressing ferroptosis. This study help advance our understanding ferroptosis be for efficacy patients

Language: Английский

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Prevalence of lymphopenia in the American population: Insights from demographic, BMI, and lifestyle factors

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(11), P. e0312540 - e0312540

Published: Nov. 4, 2024

Objective To determine the difference in prevalence of lymphopenia American population according to demographic characteristics, body mass index (BMI) and living habits. Methods A total 33,365 participants aged over 1 were included 2009–2018 National Health Nutrition Survey (NHANES). All analyses used weighted samples considered layering clustering design. Results Using white as a reference, Mexican-American was significantly lower than that ( P = 0.018). There no significant between black 0.376) participants. The 1.81% (95%CI, 1.53%-2.10%) for participants, 1.08% 0.78%-1.39%) 0.42% 0.17%-0.68%) increases with age, reaching peak 6.84% among elderly 75 above. In terms gender difference, men is higher women <0.001). Individuals who smoke <0.001), consume alcohol 0.032), engage regular exercise 0.031), have sleep disorders <0.001) those classified having an unhealthy weight had average lymphocyte count. without 0.014). However, differences observed classification variables smoking, drinking, exercise, BMI. Conclusion diagnosis treatment lymphopenia, clinicians should consider influence factors such race, gender, disorders, other lifestyle habits improve accuracy treatment, thereby reducing high mortality risk associated lymphopenia. Consequently, we propose novel perspective be tailored levels specific subpopulations, rather applying generalized approach.

Language: Английский

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Cannabis (THC) Aggravates the Deleterious Effects of Alcohol (EtOH) on Skeletal Muscles’ Mitochondrial Respiration: Modulation by Age and Metabolic Phenotypes

Biology, Journal Year: 2024, Volume and Issue: 13(12), P. 1080 - 1080

Published: Dec. 21, 2024

The anti-inflammatory and analgesic properties of cannabis might be useful to treat muscle diseases, including those linked or not alcohol. Nevertheless, delta 9 tetrahydrocannabinol (THC) ethanol (EtOH), often used concomitantly, can have deleterious effects on cardiac mitochondria. We therefore determined whether EtOH, alone associated with THC, impairs skeletal mitochondrial respiration. Further, we investigated potential modulation by metabolic phenotype age analyzing predominantly glycolytic gastrocnemius oxidative soleus muscles in young middle-aged rats (12 49 weeks). Considering the gastrocnemius, EtOH impaired respiration a similar manner young- (-34.97 ± 2.97% vs. -37.50 6.03% at 2.1 × 10-5 M; p < 0.05). Interestingly, concomitant THC aggravated EtOH-related impairment (-49.92 1.69%, -34.97 2.97 Concerning soleus, mainly decreased (-42.39 2.42% -17.09 7.61% M, 0.001, 12 was less weeks association than ±1.69 -27.22 8.96% respectively, In conclusion, significantly aggravates EtOH-induced muscle. Age phenotypes modulate these effects, being more prone impairments muscles.

Language: Английский

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Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation

Molecules, Journal Year: 2023, Volume and Issue: 28(21), P. 7325 - 7325

Published: Oct. 29, 2023

Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and acknowledged as potential therapeutic target for the treatment of alcohol use disorder other addictive behaviors. Using previously reported ALDH2 inhibitors Daidzin, CVT-10216, CHEMBL114083 reference molecules, here we perform ligand-based virtual screening world-approved drugs via 2D/3D similarity search methods, followed by assessments molecular docking, toxicity prediction, simulation, mechanics Poisson–Boltzmann surface area (MM–PBSA) analysis. The 2D fingerprinting ECFP4 FCFP4 3D molecule-shape-based USRCAT methods show good performances selecting compounds with strong binding behavior ALDH2. Three Zeaxanthin (q = 0), Troglitazone Sequinavir +1 e) are singled out inhibitors; can only be hit USRCAT. These displayed stronger strength compared to potent inhibitor CVT-10216. Sarizotan Netarsudil 0/+1 well, whereas they shallow penetration into substrate-binding tunnel could not fully occupy it. This likely left space substrate binding, thus were ideal inhibitors. MM–PBSA results indicate that selected negatively charged from Vina scoring thermodynamically unfavorable, mainly due electrostatic repulsion receptor −6 e ALDH2). attraction positively compounds, however, yielded very findings reveal deficiency modeling interactions (in particular, between moieties) docking system.

Language: Английский

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Sarcopenia and gut microbiota alterations in patients with hematological diseases before and after hematopoietic stem cell transplantation

Chinese Journal of Cancer Research, Journal Year: 2023, Volume and Issue: 35(4), P. 386 - 398

Published: Jan. 1, 2023

The aim of this study was to investigate the prevalence sarcopenia (SP) and its relationship with gut microbiota alterations in patients hematological diseases before after hematopoietic stem cell transplantation (HSCT).A total 108 various disorders were selected from Peking University People's Hospital. SP screened diagnosed based on 2019 Asian Sarcopenia Diagnosis Strategy. Physical measurements fecal samples collected, 16S rRNA gene sequencing conducted. Alpha beta diversity analyses performed evaluate composition diversity.After HSCT, significant decreases calf circumference body mass index (BMI) observed, accompanied by a decline physical function. Gut revealed differences relative abundance Enterococcus, Bacteroides, Blautia Dorea species HSCT (P<0.05). Before sarcopenic had lower levels higher Phascolarctobacterium than non-sarcopenia (P<0.01). After no observed. analysis showed among groups, highest post-HSCT 90-day group lowest 30-day group. Beta between pre- time points but not groups. Linear discriminant effect size (LEfSe) identified Alistipes, Rikenellaceae, Alistipes putredinis, Prevotellaceae defectiva coccoides as biomarkers for pre-HSCT Functional predictions anaerobic, biofilm-forming oxidative stress-tolerant functions groups (P<0.05).This demonstrated function potential functional associated disorders. Further research is needed explore underlying mechanisms therapeutic targets.

Language: Английский

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