Search Results (1,017)

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disability-adjusted life years (DALYs) and all-cause mortality worldwide, imposing an increasing global health burden. Atherosclerosis (AS) is a complex multifactorial disease, and the concept of organ crosstalk has provided a new perspective for understanding its pathogenesis. Although circulating chemerin levels are closely associated with the development and adverse prognosis of ASCVD, the functional heterogeneity and regulatory characteristics of chemerin derived from different tissues have not been systematically investigated. This review elucidates the tissue-specific roles of chemerin in AS from both endocrine and paracrine perspectives, with a focus on chemerin derived from the liver, white adipose tissue, perivascular adipose tissue, and epicardial adipose tissue. Endocrine chemerin primarily contributes to systemic metabolic dysfunction and endothelial injury, whereas locally produced chemerin regulates vascular smooth muscle cell remodeling and vascular inflammation through paracrine signaling. Collectively, endocrine and paracrine chemerin constitute a dual regulatory network that links metabolic abnormalities with vascular remodeling during AS progression. Full article

Perivascular adipose tissue (PVAT) has emerged as a central regulator of vascular homeostasis in large arteries, with its dysfunction driving the pathogenesis of atherosclerosis, hypertension, and metabolic diseases. In the past, our understanding of PVAT was limited by bulk omics approaches that obscured the tissue’s profound spatial, cellular, and functional heterogeneity. Here, we review how multimodal single-cell technologies, including single-cell RNA sequencing, spatial transcriptomics, and AI integration, are now decoding the PVAT ecosystem with unprecedented resolution. These approaches have generated an integrated atlas that reveals depot-specific cellular architectures, dynamic phenotypic plasticity, and spatially organized crosstalk between biological circuits that drive vasculopathy. We highlight novel biomarkers and actionable therapies emerging from these insights, such as Dpp4⁺ preadipocytes and BMP4-induced browning. Finally, we propose a translational roadmap that prioritizes human PVAT biobanking, CRISPR-based lineage tracing, and AI-driven modeling to transform these mechanistic discoveries into precision interventions. Ultimately, by establishing PVAT as a central orchestrator of vascular homeostasis, these single-cell insights provide the mechanistic foundation to therapeutically intercept cardiometabolic disease at its cellular source. Full article

Adipose tissue dysfunction drives obesity-associated metabolic disease, yet the transcriptional regulators of pathological adipose remodeling remain undefined. Here, we identify adipocyte Gata3 as a diet-inducible regulator that is dispensable for basal adipogenesis but necessary and sufficient for diet-induced obesity and systemic metabolic dysfunction. Adipocyte-specific Gata3 deletion redirects adipose expansion from hypertrophic to hyperplastic growth and improves glucose tolerance, insulin sensitivity, and adipose inflammation, whereas human GATA3 re-expression in adipocytes restores obesity and metabolic dysfunction, suggesting cross-species conservation and establishing both necessity and sufficiency for a causal driver. Multi-omic profiling, integrating proteomics, metabolomics, and single-cell mass cytometry, reveals that Gata3 loss suppresses a STAT3-anchored inflammatory myeloid program while enhancing mitochondrial oxidative capacity. Through further tracing of this adipocyte-intrinsic program to distal metabolic organs, systemic lipidomic and chemokine profiling identifies a two-pronged mechanism through which adipocyte Gata3 drives hepatic dysfunction: selective remodeling of lipoprotein-surface lipids and a coordinated CXCL5/CXCL2/CXCL9 chemokine axis. Collectively, these findings reposition Gata3 from a putative anti-adipogenic brake to a diet-inducible master regulator of pathological adipose remodeling and nominate adipocyte-targeted Gata3 inhibition as a strategy to uncouple adipose expansion from systemic metabolic disease. Full article

Obesity is one of the most pressing public health challenges of our time, with a growing impact on metabolic and reproductive dysfunction in women. The expansion of visceral adipose tissue drives a chronic, low-grade systemic inflammatory state that has been associated with functional changes in the ovary, the endometrium, and the placenta across different stages of the reproductive process. This structured narrative review, guided by a PICo-framed research question and literature searches across PubMed/MEDLINE, Scopus, Web of Science, Embase, and ScienceDirect, examined the main immunometabolic mechanisms underlying female obesity and their reported associations with ovarian dysfunction, implantation failure, placental dysfunction, infertility, and preeclampsia. The evidence indicates that chronic low-grade inflammation, insulin resistance (IR), and functional hyperandrogenemia may impair folliculogenesis, oocyte quality, and ovarian reserve, while cytokine and adhesion-molecule dysregulation in the endometrium has been linked to impaired decidualization and a narrower implantation window. At the maternal–fetal interface, this same inflammatory substrate has been associated with deficient trophoblast invasion, inadequate spiral artery remodeling, and angiogenic imbalance, mechanisms widely implicated in the pathophysiology of preeclampsia. Rather than demonstrating a proven longitudinal chain within the same individual, the evidence reviewed here, drawn from heterogeneous populations, study designs, and experimental models, supports a conceptual, hypothesis-generating model in which obesity-related systemic inflammation may contribute to dysfunction across the ovary, endometrium, and placenta. Clinically, these findings support further investigation of reproductive biomarkers and early screening strategies for women with obesity, particularly in the context of assisted reproduction, alongside emerging preconception therapeutic approaches that remain largely investigational. Female obesity should therefore be understood not merely as a metabolic disorder, but as an immunometabolic condition potentially associated with dysfunction across the ovary–endometrium–placenta axis, an integrative framework that may help guide future preventive and therapeutic strategies for reproductive health, pending confirmation in longitudinal studies. Full article

Type 2 diabetes (T2D) is increasingly understood as a chronic, low-grade inflammatory disease in which immune and metabolic signalling are bidirectionally coupled. Nutrient excess drives glucolipotoxic stress in adipose tissue, liver, skeletal muscle and pancreatic islets, engaging innate immune sensors. Responding immune cells then reconfigure their own intermediary metabolism, and the resulting metabolites—succinate, which stabilises hypoxia-inducible factor-1α, and the itaconate that opposes it—themselves specify inflammatory output. These signals converge on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, gasdermin D-mediated pyroptosis and interleukin-1β (IL-1β) release, which interrupt insulin signalling through inhibitory serine phosphorylation of insulin receptor substrate-1. Mitochondrial dysfunction, impaired mitophagy and cytosolic mitochondrial DNA sensing sustain the loop, while gut barrier failure supplies a parallel systemic input that converges on beta-cell dysfunction. This narrative review synthesises these mechanisms and examines how metformin, glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter 2 inhibitors and inflammasome-directed agents intersect with them. The chain described is that of obesity-associated T2D, and the heterogeneity that limits its generalisation across the recognised subgroups of the disease is addressed explicitly rather than assumed away. We give particular weight to a dissociation that constrains the field: sustained IL-1β neutralisation reduced cardiovascular events without preventing incident diabetes. Establishing why is, in our view, the central question for immunometabolic therapeutics in T2D. Full article

Cellular senescence of adipose tissue-derived mesenchymal stromal cells (AD-MSCs) is associated with chronic low-grade inflammation, metabolic dysfunction, and impaired adipogenesis contributing to the development of obesity, insulin resistance, and the progression of age-associated diseases. The aim of this study was to develop a model of cellular aging based on AD-MSCs to study the senolytic efficacy of the natural fisetin preparation for the subsequent development of geroprotective therapeutic strategies. The senescent markers SA-β-gal, SASP factors, and cell cycle arrest markers p16, p21, and p53 were assessed in models of replicative and stress-induced aging of AD-MSCs. H₂O₂ was identified as the most effective inducer of AD-MSC cellular senescence in comparison with LPS. It has been shown in the model of H₂O₂-induced senescence of AD-MSCs that the proportion of SA-β-gal+ cells was 2.0 (0.7)% in non-stimulated AD-MSCs, 81.7 (12.1)% in H₂O₂-stimulated AD-MSCs, and 19.1 (5.2)% and 13.0 (3.2)% after short-term (24 h) and long-term (7 days) fisetin treatment, respectively, indicating that fisetin treatment was associated with a lower proportion of SA-β-gal+ cells. Fisetin treatment resulted in a statistically significant decrease in the secretion of MCP-1, especially during long-term incubation. IL-1β showed a significant decrease after 7 days of fisetin treatment compared to H₂O₂, but the effect at 24 h was only significant in the group of 7 days of fisetin treatment. Fisetin treatment was also associated with higher p53 and p21 concentrations. Thus, in the present study, a model of H₂O₂-induced cellular senescence of AD-MSCs was developed, which can be used to evaluate the geroprotective potential of senotherapeutic preparations; fisetin warrants further evaluation as a potential senotherapeutic agent in this model. Full article

Background: Obesity is a multifaceted metabolic disorder characterized by systemic disturbances, particularly impaired energy homeostasis, chronic low-grade inflammation, and mitochondrial dysfunction across the brain, gut, adipose tissue, and liver axes. Objectives: This review aims to examine the metabolic properties and molecular mechanisms of six key phytochemicals (berberine, resveratrol, catechins, capsaicin, thymoquinone, and phycocyanin) and the exercise-induced myokine irisin, and their roles in mitochondrial signaling and metabolic reprogramming. Sources of Evidence: A comprehensive literature search was conducted across major electronic databases, including PubMed, Web of Science, and Scopus, to identify relevant mechanistic, in vivo, and in vitro studies. Results: Both the selected phytochemicals and irisin act as multi-target regulators that modulate key signaling pathways, including AMPK, PI3K/Akt/mTOR, SIRT1, Nrf2, and PPARγ. These phytochemicals and irisin can drive cell- and tissue-specific metabolic reprogramming, promoting the browning of white adipocytes, suppressing de novo lipogenesis in hepatocytes, and enhancing fatty acid oxidation in skeletal myocytes. This synergistic metabolic reprogramming enhances thermogenesis and increases energy expenditure. Conclusions: Co-targeting redox signaling and metabolic pathways via phytochemicals and irisin offers a powerful strategy against obesity. This integrative framework restores multi-organ homeostasis, laying the groundwork for targeted metabolic therapies. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has become the most common chronic liver disease in childhood, paralleling the global increase in pediatric obesity and metabolic dysfunction. Once considered a benign condition, pediatric MASLD is now recognized as a heterogeneous and potentially progressive disease that may advance from simple steatosis to steatohepatitis, fibrosis, and, rarely, cirrhosis, with lifelong hepatic and cardiometabolic consequences. Its pathogenesis is multifactorial, involving insulin resistance, adipose tissue dysfunction, chronic low-grade inflammation, genetic and epigenetic susceptibility, environmental factors, and alterations in the gut microbiome. Most affected children are asymptomatic, and diagnosis is often prompted by elevated liver enzymes or incidental imaging findings. Noninvasive tools, including ultrasonography, elastography, serum biomarkers, and emerging multi-omics approaches, are improving disease detection and risk stratification, although liver biopsy remains the reference standard in selected cases. Lifestyle modification, including dietary optimization, increased physical activity, and gradual weight reduction, remains the cornerstone of management, while pharmacological therapies are still under investigation in pediatric populations. The marked variability in disease susceptibility; progression; and treatment response underscores the need for a personalized medicine approach. Integrating clinical characteristics with genomic, epigenomic, metabolomic, and microbiome data may enable early identification of high-risk children, more accurate prognostic assessment, and individualized preventive and therapeutic strategies. Early detection and multidisciplinary care involving pediatricians, hepatologists, endocrinologists, dietitians, and families may help reduce disease progression and the risk of long-term hepatic and cardiometabolic complications. This review summarizes current evidence on the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of pediatric MASLD, with a particular emphasis on precision diagnostics, biomarker discovery, and personalized therapeutic approaches. It also discusses current challenges and future directions for implementing personalized medicine to improve outcomes and reduce the lifelong burden of pediatric MASLD. Full article

Mesenteric panniculitis (MP) is an uncommon inflammatory disorder of mesenteric adipose tissue. Its pathophysiology remains unclear. Gut dysbiosis, intestinal barrier dysfunction, metabolic endotoxemia, glycemic variability (GV), and vascular dysfunction have been implicated in inflammatory and metabolic disorders, but their specific involvement in MP has not been established. This narrative review integrates MP-specific clinical evidence with indirect mechanistic evidence from related metabolic, inflammatory, and experimental settings to examine the possible relationships between these mechanisms and MP and their integration within a proposed gut–mesentery–metabolic axis. The literature was reviewed through structured searches of PubMed, Scopus, and Web of Science for relevant publications from 2018 to 2026, supplemented by earlier foundational studies identified through reference-list screening and targeted searches. Current data suggest that dysbiosis and impaired intestinal barrier function may facilitate microbial-product translocation and lipopolysaccharide-mediated inflammatory signaling, while GV may contribute to oxidative stress, endothelial dysfunction, and pro-inflammatory responses. Mesenteric vascular anatomy and impaired regional perfusion may represent additional factors influencing local tissue susceptibility. Recent randomized controlled trials of microbiome-targeted interventions in metabolic disorders have shown heterogeneous effects on glycemic, inflammatory, and microbiota-related outcomes, indicating a need for further investigation of individualized microbiome-directed strategies. Direct evidence that microbial, metabolic, or vascular mechanisms initiate or sustain MP is currently limited. Accordingly, the proposed gut–mesentery–metabolic axis should be interpreted as a hypothesis-generating framework rather than an established causal model. Prospective MP-specific studies integrating microbiome profiling, validated measures of intestinal barrier function, metabolic phenotyping, GV, vascular assessment, and imaging are required to test the proposed relationships. Full article

The mitochondrial DNA copy number (mtDNA-CN) is considered an indirect indicator of the number of mitochondria and of mitochondrial dysfunction; its decrease may indirectly reflect mitochondrial DNA (mtDNA) alterations. A reduction in mtDNA-CN is associated with the development of cardiovascular diseases, including coronary artery disease (CAD). The study evaluates the association of relative blood mtDNA-CN with premature CAD (pCAD) and cardiometabolic factors among Mexican individuals from the GEA (Genetics of Atherosclerotic Disease) Mexican cohort. Relative blood mtDNA-CN was quantified by real-time PCR in 835 patients with pCAD and 896 control subjects (defined as a coronary artery calcium score of zero, assessed by computed tomography). Associations were evaluated using logistic regression (odds ratio [95% confidence interval]) adjusted for potential confounders. Compared with controls, patients with pCAD exhibited significantly lower relative blood mtDNA-CN (5.6 [3.5–9.8] vs. 9.1 [5.1–13.2]. p < 0.001). Similar results were observed in the sex-stratified analysis. Specifically, relative blood mtDNA-CN in women (6.2 [3.8–9.9]) and men (5.5 [3.4–9.7]) with pCAD was lower than that in women (9.5 [6.3–13.7]) and men (8.2 [5.5–12.5]) from the control group (p < 0.001). After adjusting for age, sex, body mass index, smoking status, LDL-cholesterol, type 2 diabetes mellitus, hypertension and physical activity, higher relative blood mtDNA-CN showed a negative association with pCAD (0.903 [0.881–0.927], p = 4.96 × 10⁻¹⁵). This association remained significant in men (0.894 [0.866–0.922], p = 2.90 × 10⁻¹²) and women (0.917 [0.876–0.960], p = 2.1 × 10⁻⁴). Among patients with pCAD, an inverse correlation was observed between relative blood mtDNA-CN and total abdominal fat (p = 0.001), visceral fat (p = 0.015), and subcutaneous fat (p = 0.004). Overall, our results show that reduced relative blood mtDNA-CN is associated with pCAD, which could be indicative of mitochondrial alterations. Furthermore, the inverse correlation between relative blood mtDNA-CN and total, visceral, and subcutaneous abdominal fat suggests a link between mitochondrial dysfunction and abdominal adiposity in patients with pCAD. These findings support that decreased relative blood mtDNA-CN may serve as a marker associated with the presence of pCAD and for adipose tissue alterations in Mexican women and men. Full article

Current studies have elucidated the mechanisms of radiation-induced skin injury (RISI) and identified several medical countermeasures to reduce its severity. However, no treatment has yet proven effective in preventing or reversing radiation-induced skin fibrosis. Here, we show that radiation upregulates lipoprotein-associated phospholipase A2 (Lp-PLA₂) expression and induces endothelial cell dysfunction, characterized by an increased DNA damage response and reduced tube-forming capacity and mitochondrial function. To define the role of Lp-PLA₂ in the progression of RISI, we treated human dermal microvascular endothelial cells and the skin of SKH1 hairless mice with darapladib, a selective Lp-PLA₂ inhibitor. In endothelial cells, darapladib attenuated radiation-induced cellular damage and suppressed endothelial-to-mesenchymal transition (EndoMT). In irradiated mouse skin, darapladib reduced radiation-induced inflammation, adipose tissue disruption, dermal thickness, and skin fibrosis. Notably, darapladib modulated macrophage polarization and inhibited radiation-induced macrophage infiltration in irradiated skin. These findings suggest that Lp-PLA₂ inhibition may reveal potential targets for the treatment of RISI and other fibrotic skin diseases. Full article

Obesity is increasingly recognized as a complex metabolic disorder characterized by persistent redox imbalance, rather than merely excess body weight. Its pathophysiology extends beyond energy imbalance to encompass chronic redox disruption. Expansion of adipose tissue, particularly in visceral depots, exceeds mitochondrial capacity, impairs antioxidant defenses such as superoxide dismutase, catalase, and glutathione peroxidase, and perpetuates chronic low-grade inflammation via nuclear factor kappa B (NF-kB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways. This review synthesizes preclinical evidence for diverse interventions, including vitamins A, B, C, E, and D; minerals such as zinc and selenium; amino acids such as N-acetylcysteine (NAC), L-carnitine, and taurine; various antioxidant compounds; and approved drugs including metformin, exenatide, fenofibrate, and orlistat. Despite differing structures and mechanisms, these interventions converge on restoring redox balance by activating nuclear factor erythroid 2–related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK), increasing glutathione, and stabilizing mitochondria. However, translation of these preclinical findings into clinical practice requires further clarification of dosing, delivery methods, and long-term safety. Full article

Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach. Full article

Background/Objectives: Sarcopenia is an age-associated skeletal muscle disorder that may be aggravated by a high-fat diet (HFD). Given the multifactorial pathogenesis of sarcopenia, single-nutrient interventions may be insufficient. This study investigated whether a specialized multinutrient formula could attenuate muscle dysfunction and intramuscular lipid accumulation in adult mice under standard-diet and HFD-fed conditions. Methods: Male C57BL/6J mice were assigned to five groups: young control (YC), adult control (OC), adult control supplemented with the nutritional formula (OCN), adult HFD-fed mice (OH), and adult HFD-fed mice supplemented with the formula (OHN). A specialized multinutrient formula containing enriched whey protein, β-glucan, antioxidant vitamins, and essential trace minerals was orally administered five times per week for 12 weeks. Body composition, muscle histology, grip strength, intramuscular lipid accumulation, inflammatory gene expression, and protein markers related to caspase-associated apoptosis, proteolysis-related signaling, and tissue remodeling were assessed. Results: Compared with YC mice, adult control and HFD-fed mice exhibited reduced muscle strength and fiber cross-sectional area, increased adiposity, intramuscular lipid deposition, elevated TNF-α expression, and alterations in selected protein markers related to caspase-associated apoptosis, proteolysis-related signaling, and tissue remodeling. Nutritional supplementation improved muscle strength and fiber morphology, reduced intramuscular lipid deposition, lowered TNF-α expression, reduced cleaved caspase marker abundance, decreased p38 MAPK and MuRF-1 expression, and increased collagen type III expression. Conclusions: HFD aggravated muscle dysfunction and sarcopenic obesity-related features in adult mice, as evidenced by impaired muscle function, reduced muscle fiber cross-sectional area, increased intramuscular lipid accumulation, and changes in selected inflammatory, cleaved caspase-, protein turnover-related, and remodeling markers. Nutritional supplementation mitigated these alterations and improved muscle structure and function. Full article

Adipotoxicity is a major contributor to insulin resistance and type 2 diabetes, and increasing evidence highlights the gut–adipose axis as a promising therapeutic target. Soursop (Annona muricata) is rich in phytochemicals that can be biotransformed by the gut microbiota into bioactive metabolites with metabolic benefits. The present study investigated whether metabolites generated by in vitro fecal fermentation of soursop fruit (SWSF) and peel (SWSFP) protect against fructose-induced adipotoxicity. SWSF and SWSFP were fermented with rat fecal microbiota, and the resulting metabolites were evaluated in an ex vivo fructose-induced adipotoxicity model using perigonadal white adipose tissue. Activities of enzymes involved in glucose metabolism, the polyol pathway, glutathione metabolism, glyoxalase-1 activity, purinergic signaling, and inflammatory lipid metabolism were determined. GC–MS-based metabolomics and pathway enrichment analyses were performed on fecal and adipose tissues. Soursop fermentation significantly remodeled the fecal metabolome, enriching metabolites associated with fatty acid metabolism, glycerolipid metabolism, β-oxidation, sterol metabolism, and arachidonic acid metabolism. Fructose-induced adipotoxicity disrupted glucose metabolism, activated the polyol pathway, impaired glutathione metabolism and glyoxalase-1 activity, suppressed ATPase and ENTPDase activities, and elevated 5-LOX and 12/15-LOX activities. Treatment with soursop-enriched fecal metabolites significantly reversed these alterations in a dose-dependent manner. Adipose metabolomics further demonstrated restoration of pathways associated with fatty acid biosynthesis, mitochondrial β-oxidation, glycerolipid metabolism, steroid biosynthesis, and polyunsaturated fatty acid metabolism, indicating improved lipid homeostasis and reduced inflammatory lipid signaling. SWSF and SWSFP generally exhibited greater metabolic protection than the reference antioxidant compound, gallic acid. Soursop-derived gut metabolites attenuate fructose-induced adipotoxicity by coordinately restoring glucose metabolism, redox homeostasis, carbonyl detoxification, purinergic signaling, and lipid metabolism through the gut–adipose axis. These results suggest soursop as a potential functional food for preventing and managing adipose tissue dysfunction and metabolic disorders. Full article