Integrated network toxicology, molecular docking, and in vivo experiments to elucidate molecular mechanism of aflatoxin B1 hepatotoxicity

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 275, P. 116278 - 116278

Published: April 1, 2024

Due to the rise in temperature and sea level caused by climate change, detection rate of aflatoxin B1 (AFB1) food crops has increased dramatically, frequency severity aflatoxicosis humans animals are also increasing. AFB1 strong hepatotoxicity, causing severe liver damage even cancer. However, mechanism hepatotoxicity remains unclear. By integrating network toxicology, molecular docking vivo experiments, this research was designed explore potential mechanisms AFB1. Thirty-three intersection targets for AFB1-induced were identified using online databases. PI3K/AKT1, MAPK, FOXO1 signaling pathways, apoptosis significantly enriched. In addition, proteins ALB, AKT1, PIK3CG, MAPK8, HSP90AA1, PPARA, MAPK1, EGFR, FOXO1, IGF1 exhibited good affinity with significant pathological changes occurred mice. induction expression levels ERK, decreased levsls PI3K AKT1. Moreover, treatment an increase Caspase3 expression, a decrease Bcl2/Bax ratio. combining toxicology study confirms first time that promotes pathway inactivating PI3K/AKT1 activating EGFR/ERK hence aggravating hepatocyte apoptosis. This provides new strategies studying toxicity environmental pollutants possible development hepatoprotective drugs.

Language: Английский

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Epigenetic modifications in obesity‐associated diseases

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

The global prevalence of obesity has reached epidemic levels, significantly elevating the susceptibility to various cardiometabolic conditions and certain types cancer. In addition causing metabolic abnormalities such as insulin resistance (IR), elevated blood glucose lipids, ectopic fat deposition, can also damage pancreatic islet cells, endothelial cardiomyocytes through chronic inflammation, even promote development a microenvironment conducive cancer initiation. Improper dietary habits lack physical exercise are important behavioral factors that increase risk obesity, which affect gene expression epigenetic modifications. Epigenetic alterations occur in early stage some reversible, while others persist over time lead obesity-related complications. Therefore, dynamic adjustability modifications be leveraged reverse obesity-associated diseases interventions, drugs, bariatric surgery. This review provides comprehensive summary impact regulation on initiation cancers, type 2 diabetes, cardiovascular diseases, establishing theoretical basis for prevention, diagnosis, treatment these conditions.

Language: Английский

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Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

Background Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells monocytes, play pivotal role in driving systemic inflammation T2DM; however, the underlying single-cell mechanisms remain inadequately defined. Methods Single-cell RNA sequencing of peripheral blood mononuclear (PBMCs) from 37 patients with T2DM 11 healthy controls (HC) was conducted. cell types were identified through clustering analysis, followed differential expression pathway analysis. Metabolic heterogeneity within subpopulations evaluated using Gene Set Variation Analysis (GSVA). Machine learning models constructed to classify subtypes based on metabolic signatures, T-cell-monocyte interactions explored assess crosstalk. Transcription factor (TF) activity analyzed, drug enrichment analysis performed identify potential therapeutic targets. Results In T2DM, increase monocytes decrease CD4+ observed, indicating dysregulation. Significant diversity led classification into three distinct (A-C), HC grouped as D. Enhanced intercellular communication, particularly MHC-I pathway, evident subtypes. effectively classified achieving an AUC > 0.84. TF regulators, NF-kB, STAT3, FOXO1, associated disturbances T2DM. Drug highlighted agents targeting these TFs related pathways, Suloctidil, Chlorpropamide, other compounds modulating inflammatory pathways. Conclusion This study underscores significant immunometabolic dysfunction characterized alterations composition, communication. The identification critical development profiles highlight for personalized strategies, emphasizing need integrated immunological approaches management.

Language: Английский

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Post-Translational Modifications and Diabetes

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 310 - 310

Published: March 6, 2024

Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy type 1 diabetes (T1D) small-molecule drugs 2 (T2D). Despite these advances, the complex nature of necessitates innovative clinical interventions effective treatment complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, SUMOylation, play important roles in pathological consequences. Therefore, investigation PTMs not only sheds light on mechanistic regulation but also opens new avenues targeted therapies. Here, we offer a comprehensive overview role several diabetes, focusing most recent advances understanding their functions regulatory mechanisms. Additionally, summarize pharmacological targeting advanced into trials diabetes. Current future perspectives are provided.

Language: Английский

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USP11 promotes autophagy to attenuate LPS-induced oxidative stress in lung epithelial cells by stabilizing FOXO1 levels

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: unknown, P. 151368 - 151368

Published: Jan. 1, 2025

Language: Английский

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Pathogenetic therapeutic approaches for endocrine diseases based on antisense oligonucleotides and RNA-interference

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 29, 2025

Molecular therapy uses nucleic acid-based therapeutics agents and becomes a promising alternative for disease conditions unresponsive to traditional pharmaceutical approaches. Antisense oligonucleotides (ASOs) small interfering RNAs (siRNAs) are two well-known strategies used modulate gene expression. RNA-targeted can precisely the function of target RNA with minimal off-target effects be rationally designed based on sequence data. ASOs siRNA-based drugs have unique capabilities using in groups patients or tailored as patient-customized N-of-1 therapeutic approach. utilized not only treatment monogenic diseases but also holds significant promise addressing polygenic complex by targeting key genes molecular pathways involved pathogenesis. In context endocrine disorders, is particularly effective modulating pathogenic mechanisms such defective insulin signaling, beta-cell dysfunction hormonal imbalances. Furthermore, siRNA ability downregulate overactive signaling that contribute complex, non-monogenic thereby these at their origin. being studied worldwide candidates developing therapies therapies. The sequence-specific binding provides exceptional accuracy approaches, when oligonucleotide targeted patient’s exact mutant sequence. this review we focus system discuss potential opportunities diabetes mellitus, including beta cell diabetes, obesity, syndrome obesity well disorders. We provide an overview currently developed available antisense molecules, describe potentials antisense-based rare «ultrarare» diseases.

Language: Английский

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Emerging role of hsa_circ_0000652, hsa-miR-21, SMAD2, and Foxo1 in type 2 diabetes mellitus pathogenesis

Human Gene, Journal Year: 2025, Volume and Issue: 43, P. 201386 - 201386

Published: Feb. 1, 2025

Language: Английский

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Proarrhythmic Lipid Inflammatory Mediators: Mechanisms in Obesity Arrhythmias

Journal of Cellular Physiology, Journal Year: 2025, Volume and Issue: 240(2)

Published: Feb. 1, 2025

ABSTRACT The prevalence of obesity and associated metabolic disorders such as diabetes is rapidly increasing; therefore, concerns regarding their cardiovascular consequences, including cardiac arrhythmias, are rising. As progresses, the excessively produced lipids accumulate in unconventional areas epicardial adipose tissue (EAT) around myocardium. Metabolic alterations contribute to transformation these ectopic fat deposits into arrhythmogenic substrates. However, despite advances therapeutic approaches, particularly lowering EAT volume thickness through sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors glucagon‐like peptide‐1 (GLP‐1) receptor agonists, obese diabetic patients still suffer from fatal arrhythmias that may lead sudden death. Therefore, an investigation how unappreciated underlying pathways lipid mediators tissues proinflammatory substrates significance. Leukotriene B4 (LTB4) eicosanoid derived arachidonic acid acts a mediator. LTB4 has recently been identified be with ion channel modulations conditions diabetes. increases circulatory free fatty acids (FFAs) adipocyte hypertrophy. also interferes insulin signaling pathways, instigating resistance (IR). In addition, LTB4, potent chemoattractant, contributes mobilization immune cells monocytes promotes inflammatory macrophage polarization dysfunction. Thus, this review provides comprehensive overview LTB4's obesity; illustrates might channels, currents, arrhythmias; shows they pose target for metabolic‐associated arrhythmias.

Language: Английский

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Parkinson's disease and glucose metabolism impairment

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Feb. 17, 2025

Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD patients exhibit varying degrees of abnormal glucose metabolism throughout stages. Abnormal closely linked to pathogenesis and progression. Key processes involved in include transport, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, pentose phosphate pathway, gluconeogenesis. Recent studies suggest that a potential therapeutic target for PD. In this review, we explore connection between metabolism, focusing on underlying pathophysiological mechanisms. We also summarize drugs related based results from current cellular animal model studies.

Language: Английский

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Harnessing the FOXO-SIRT1 axis: insights into cellular stress, metabolism, and aging

Biogerontology, Journal Year: 2025, Volume and Issue: 26(2)

Published: Feb. 26, 2025

Language: Английский

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