Lipid rafts: novel therapeutic targets for metabolic, neurodegenerative, oncological, and cardiovascular diseases

Lipids in Health and Disease, Journal Year: 2025, Volume and Issue: 24(1)

Published: April 17, 2025

Lipid rafts are specialized microdomains within cellular membranes enriched with cholesterol and sphingolipids that play key roles in organization, signaling, homeostasis. This review highlights their involvement protein clustering, energy metabolism, oxidative stress responses, inflammation, autophagy, apoptosis. These findings clarify influence on trafficking, adhesion while interacting the extracellular matrix, cytoskeleton, ion channels, making them pivotal progression of various diseases. further addresses contributions to immune including autoimmune diseases, chronic cytokine storms. Additionally, role as entry points for pathogens has been demonstrated, raft-associated receptors being exploited by viruses bacteria increase infectivity evade defenses. Disruptions lipid raft dynamics linked signaling defects, which contribute metabolic, neurodegenerative, cardiovascular underscores potential therapeutic targets, discussing innovations such engineered transplantation. Advances analytical techniques mass spectrometry have expanded our understanding composition dynamics, opening new directions research. By consolidating current insights, we highlight need exploration molecular mechanisms.

Language: Английский

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Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease

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

Published: Jan. 14, 2025

The impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject debate. This Mendelian randomization (MR) study aims to elucidate the potential effects drug targets CKD development. We extracted 11 genetic variants encoding drugs from published genome-wide association (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A analysis was conducted targeting these drug-related genes. risk designated as primary outcome, while estimated glomerular filtration rate (eGFR) blood urea nitrogen (BUN) were assessed secondary outcomes. Additionally, mediation performed utilizing 731 immune cell phenotypes identify mediators. meta-analysis revealed significant between ANGPTL3 inhibitors reduced (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists significantly linked an increased 1.11 [1.02-1.22]). Regarding outcomes, did not affect eGFR BUN levels. Mediation indicated that reduction in by mediated through modulation phenotype, specifically HLA-DR CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899). Through drug-targeted MR analysis, we identified causal relationship CKD. may represent promising candidate for treatment.

Language: Английский

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Antiseizure medications and their differing effects on cardiovascular risk

Epilepsy & Behavior Reports, Journal Year: 2025, Volume and Issue: 29, P. 100746 - 100746

Published: Feb. 1, 2025

This review discusses the differing effects of enzyme-inducing and non-inducing antiseizure medications on cardiovascular risk their implications for management strategies epilepsy patients. Traditional markers, including low density lipoprotein, high lipoprotein triglycerides, can be altered by both enzyme induction inhibition. Other markers vascular risk, c-reactive protein, non-high-density homocysteine, are affected medications, although adults children may have different responses. The overall atherosclerotic picture is more complex due to indirect such as neuroendocrine function metabolic syndrome. Large scale data shows an evolving understanding risk. Long term risks inducing valproic acid apparent when studies examine individually. Finally, cardiac rhythm possibly autonomic control discussed with respect clinical relevance practicing clinician.

Language: Английский

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Evolving concepts of low‐density lipoprotein: From structure to function

European Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Low-density lipoprotein (LDL) is a central player in atherogenesis and has long been referred to as 'bad cholesterol.' However, emerging evidence indicates that LDL functions multifaceted ways beyond cholesterol transport include roles inflammation, immunity, cellular signaling. Understanding LDL's structure, metabolism function essential for advancing cardiovascular disease research therapeutic strategies. This narrative review examines the history, structural properties, of health disease. We analyze key milestones research, from its early identification recent advancements molecular biology omics-based investigations. Structural functional insights are explored through imaging, proteomic analyses lipidomic profiling, providing deeper understanding heterogeneity. metabolism, biosynthesis receptor-mediated clearance, plays crucial role lipid homeostasis atherogenesis. Beyond transport, contributes plaque modulates adaptive immunity regulates signaling pathways. studies reveal heterogeneous composition, which influences pathogenic potential. Evolving perspectives on redefine clinical significance, affecting risk assessment interventions. A holistic challenges traditional underscores complexity health. Future should focus further elucidating diversity refine prediction models strategies, ultimately improving outcomes.

Language: Английский

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Effect of incorporating tributyrin and tricaproin in milk replacer on the hepatic metabolome of calves

Journal of Dairy Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

This study investigated the effects of incorporating tributyrin (TB) and tricaproin (TC) in MR on liver metabolome dairy calves. Forty-five male calves (46.1 ± 4.6 kg BW; 2.1 0.63 d age; mean SD) were blocked order arrival at research facility. Within each block, randomly assigned to 3 treatments (n = 15 per group): (1) an containing milk fat serving as biolical reference for composition (MF), (2) a control (CON) blend vegetable fats, (3) (TRI) same mixture fats CON, which TB TC incorporated. All isoenergetic with 36% lactose, 27% fat, 24% protein DM basis. Calves housed individually received (13.5% solids) via nipple buckets twice daily 0630 1730 h. Daily allowance was 6.0 L from 1-5, 7.0 6-9, 8.0 10-35. had ad libitum access water chopped straw but no starter feed fed. On 35 after arrival, euthanized tissue samples collected analyzed using targeted metabolomics approach. Liquid chromatography flow injection electrospray ionization triple quadrupole mass spectrometry MxP® Quant 500 kit used. Distinct metabolic profiles emerged, principal component analysis (PCA) indicating differences between fed MF those other treatments, collectively accounting almost 50% total variation. Partial Least Squares Discriminant Analysis (PLS-DA) confirmed significant metabolomes treatments. Volcano plot showed that compared NC, 51 metabolites higher MF, including 34 phosphatidylcholines, 8 sphingomyelins, lysophosphatidylcholines, 1 ceramide, hexosylceramides, eicosapentaenoic acid (EPA) glycochenodeoxycholic (GUDCA), while lower, 2 sphingomyelin (SM C22:3), diacylglycerol (DG 16:0_18:2), lysophosphatidylcholine (lysoPC C18:2), nitrogen-containing compounds (putrescine serine) C5 acylcarnitine. In addition, when comparing TRI, 37 4 ceramides, EPA GUDCA, 7 putrescine valerylcarnitine (C5). Importantly, found CON suggesting effect metabolome. These results demonstrate (CON TRI) significantly modulate underscore importance addressing formulations optimize outcomes.

Language: Английский

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From genes to clinic: Genomic and cross-sectional cohort analysis of oxidative stressors and lipid metabolism in European ancestry

Cytokine, Journal Year: 2025, Volume and Issue: 191, P. 156941 - 156941

Published: April 20, 2025

Language: Английский

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NSAIDs, from COX Inhibitors to PAF-AH Modulators: Exploring Unconventional Enzymatic Targets for Antitumor Therapy

Published: April 29, 2024

A novel interaction between the enzyme platelet-activating factor acetyl hydrolase (PAF-AH) and certain non-steroidal anti-inflammatory drugs (NSAIDs), such as sulindac, celecoxib, diclofenac nimesulide, has been uncovered by this in-silico research. PAF-AH is known for its critical role in maintaining fluidity functionality of cell membranes hydrolysing phospholipids removing oxidized fatty acids. Since tumour microenvironments are largely marked inflammation oxidative stress, discovery that these can bind to active pocket PAF-AH. Suggests they may be able modulate activity thereby influence cancer pathogenesis. Such modulation could lead significant anti-tumour effects, including reduction inflammation, inhibition angiogenesis suppression metastasis, particularly cancers breast, colon, prostate, lung. However, con-texts, cause opposite effect, leading development. Therefore, study a gateway development therapeutic strategies based on highlights importance microenvironment assessment potential effects NSAIDs. Furthermore, finding guide selection NSAIDs treatment patients, ruling out in-discriminate use promote neoplastic progression. This also indicate repositioning specific within treatment, contributing more precise personalized approaches.

Language: Английский

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Exacerbation of atherosclerosis by STX17 knockdown: Unravelling the role of autophagy and inflammation

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(10)

Published: May 1, 2024

Abstract Syntaxin 17 (STX17) has been identified as a crucial factor in mediating the fusion of autophagosomes and lysosomes. However, its specific involvement context atherosclerosis (AS) remains unclear. This study sought to elucidate role mechanistic contributions STX17 initiation progression AS. Utilizing both vivo vitro AS model systems, we employed ApoE knockout (KO) mice subjected high‐fat diet human umbilical vein endothelial cells (HUVECs) treated with oxidized low‐density lipoprotein (ox‐LDL) assess expression. To investigate underlying mechanisms, shRNA‐STX17 lentivirus knock down expression, followed by evaluating autophagy inflammation HUVECs. In models, expression was significantly upregulated. Knockdown exacerbated HUVEC damage, without ox‐LDL treatment. Additionally, observed that knockdown impaired autophagosome degradation, impeded flux also resulted accumulation dysfunctional lysosomes Moreover, intensified inflammatory response following treatment Further exploration revealed an association between STING; reducing increased STING levels. enhanced flux. summary, our findings suggest worsens impeding amplifying response. interaction may play STX17‐mediated autophagy.

Language: Английский

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Proteogenomic Analysis Identifies a Causal Association between Plasma Apolipoprotein B Levels and Liver Cancer Risk

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(9), P. 4055 - 4066

Published: Aug. 2, 2024

Liver oncogenesis is accompanied by discernible protein changes in the bloodstream. By employing plasma proteomic profiling, we can delve into molecular mechanisms of liver cancer and pinpoint potential biomarkers. In this nested case-control study, applied liquid chromatography-tandem mass spectrometry for proteome profiling baseline samples. Differential expression was determined subjected to functional enrichment, network, Mendelian randomization (MR) analyses. We identified 193 proteins with notable differential levels between groups. Of these proteins, MR analysis offered a compelling negative association apolipoprotein B (APOB) cancer. This further corroborated UK Biobank cohort: genetically predicted APOB were associated 31% (95% CI 19–42%) decreased risk cancer; phenotypic indicated an 11% 8–14%) every 0.1 g/L increase circulating levels. Multivariable suggested that hepatic fat content might fully mediate APOB-liver connection. summary, some particularly APOB, as biomarkers Our findings underscore intricate link lipid metabolism cancer, offering hints targeted prophylactic strategies early detection.

Language: Английский

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ANGPTL3 as a target for treating lipid disorders in type 2 diabetes patients

Lipids in Health and Disease, Journal Year: 2024, Volume and Issue: 23(1)

Published: Nov. 1, 2024

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) significant cause of mortality morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play crucial role the development CVD complications. Diabetic dyslipidemia characterized by elevated levels triglyceride (TG)-rich lipoproteins small dense low-density lipoprotein (LDL) particles, reduced high-density (HDL) cholesterol, impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) liver-derived protein that plays regulating plasma metabolism inhibiting lipase influencing levels. Inhibiting ANGPTL3 has shown promising effects promoting HDL-mediated cholesterol reverse transport reducing TG-rich LDL cholesterol. Here, we explore potential as therapeutic target for management patients.

Language: Английский

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