Search Results (632)

Cardiovascular diseases remain the leading cause of mortality worldwide and are closely associated with obesity and metabolic dysfunction. Adipose tissue is now recognized as a heterogeneous endocrine and immunometabolic organ that actively communicates with the cardiovascular system through adipokines, inflammatory mediators, metabolites, and extracellular vesicles. Under physiological conditions, adipose–cardiac crosstalk contributes to metabolic and cardiovascular homeostasis, whereas adipose tissue dysfunction promotes inflammation, fibrosis, endothelial injury, and cardiac remodeling. This review summarizes the heterogeneity of adipose depots and their secretomes, discusses the molecular mechanisms underlying adipose–cardiac communication, and highlights their contributions to atherosclerosis, heart failure, hypertension, diabetic cardiomyopathy, and atrial fibrillation. We further discuss emerging biomarkers, therapeutic strategies, and precision medicine approaches targeting the adipose–cardiac axis. Understanding depot-specific signaling networks may facilitate the development of novel diagnostic and therapeutic interventions for cardiometabolic diseases. Full article

Background/Objectives: Postbiotics are increasingly recognized as biologically active products of microorganisms with emerging potential as microbiome-inspired therapeutic interventions. While most microbiome-based strategies focus on modifying microbial composition, restoration of microbial signaling has received comparatively less attention. This review examines postbiotics through the lens of microbial signaling restoration and proposes a unified Metabolite–Immune–Redox (MIR) axis linking microbial-derived signals with immune regulation, redox homeostasis, endothelial integrity, and host resilience. Methods: This narrative review synthesizes current evidence on postbiotics, microbial metabolites, structural microbial components, and extracellular vesicles, with emphasis on their roles in immunometabolic regulation, redox biology, endothelial function, and host-directed interventions. Results: Current evidence suggests that short-chain fatty acids, indole derivatives, bile acid metabolites, and microbial extracellular vesicles are important mediators of host–microbe communication. These signals influence interconnected pathways involving mitochondrial function, inflammasome activity, immune calibration, endothelial and glycocalyx homeostasis, and disease tolerance. The review highlights the endothelium as an underrecognized therapeutic target and discusses biomarkers, including soluble thrombomodulin, von Willebrand factor, and D-dimer, as potential tools for identifying patients most likely to benefit from host-directed interventions. Major translational challenges include product heterogeneity, incomplete mechanistic characterization, uncertain exposure–response relationships, and unresolved regulatory considerations. Conclusions: The proposed MIR axis provides a hypothesis-generating framework for understanding how restoration of microbial signaling may contribute to precision host-directed therapeutic strategies. Further mechanistic and clinical studies are needed to validate this concept and define its translational potential in inflammatory, infectious, and critical illness settings. Full article

Pulsatile blood flow is a fundamental characteristic of cardiovascular physiology that regulates endothelial function, vascular homeostasis, microcirculatory integrity, and organ adaptation through complex mechanobiological pathways. The widespread use of continuous-flow left ventricular assist devices (CF-LVADs) has created a unique clinical model of chronic pulsatility deprivation, whereas heart transplantation restores physiological pulsatile hemodynamics. This review examines the molecular, cellular, and systemic consequences of these contrasting circulatory states. Evidence from experimental and clinical studies indicates that reduced pulsatility during CF-LVAD support is associated with impaired endothelial mechanotransduction, glycocalyx disruption, oxidative stress, inflammatory activation, angiogenic dysregulation, acquired von Willebrand syndrome, and microvascular remodeling. These alterations contribute to bleeding, thrombosis, neurological events, and progressive end-organ dysfunction. In contrast, restoration of pulsatile flow following heart transplantation promotes recovery of endothelial signaling, nitric oxide bioavailability, vascular responsiveness, and tissue perfusion, although persistent immune-mediated injury may limit complete vascular normalization. Emerging concepts involving Piezo1 signaling, YAP/TAZ mechanotransduction, extracellular vesicles, immunometabolism, and multi-omics profiling further support the role of pulsatility as a biological regulator rather than a simple hemodynamic consequence of cardiac contraction. Understanding pulsatility-dependent cardiovascular remodeling may facilitate the development of next-generation circulatory support technologies and novel therapeutic strategies to preserve vascular health. Full article

Compelling research has consistently demonstrated a strong relationship between immunometabolism and infectious disease, including the ways in which viral infections alter the metabolic state of immune cells to promote survival. Human immunodeficiency virus (HIV) has been particularly noted for its ability to reprogram the metabolism of cells that contribute to viral persistence. The purpose of this review is to summarize current knowledge of the metabolic state of CD4 T cells and myeloid cells (monocytes/macrophages), two of the primary cell types targeted by HIV. The studies discussed reveal distinct metabolic profiles in both cell types during initial infection, active replication, and latency. In addition, we examine how these metabolic alterations may contribute to the increased frequency and severity of comorbidities observed in people with HIV (PWH). Understanding the impact of HIV infection and latency on immunometabolism may provide deeper insight into long-term viral persistence and support the identification of novel therapeutic targets to reduce chronic inflammation and inform future cure strategies for PWH. Full article

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid–metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts. Full article

Cardiomyopathies have traditionally been regarded as disorders driven primarily by cardiomyocyte injury resulting from genetic defects, infection, metabolic stress, or toxic exposure. This paradigm has substantially advanced diagnosis and treatment. Still, it does not fully account for the marked heterogeneity in disease progression, persistent fibrosis, or variable therapeutic responses among patients with similar phenotypes. Increasing evidence indicates that immune remodeling is not merely a secondary consequence of myocardial injury but a dynamic process that actively shapes disease evolution. In this review, we integrate recent advances in cardiovascular immunology, single-cell and spatial transcriptomics, immunometabolism, and systems biology to propose a unified framework of immunological reprogramming in cardiomyopathies. We discuss how danger-associated molecular patterns, inflammasome activation, trained immunity, the cGAS–STING pathway, fibroblast–immune interactions, and the cardio–bone marrow axis converge to establish chronic inflammatory circuits that promote fibrosis, electrical remodeling, and progressive ventricular dysfunction. We further examine the emerging concept of immunotypes, emphasizing that distinct immune programs may underlie the biological heterogeneity of cardiomyopathies beyond conventional phenotypic or genetic classification. Finally, we discuss the translational potential of immune profiling, advancing a shift toward viewing cardiomyopathies as disorders of a dysregulated cardiac immune ecosystem. We propose that immune ecosystem organization constitutes an additional biological dimension that complements traditional phenotypic and genetic classifications of cardiomyopathies. Full article

Pediatric sarcopenic obesity (PSO) is an emerging conceptual framework characterized by the coexistence of excess visceral adiposity and impaired skeletal muscle accretion. Evidence suggests that this pathology is driven by systemic meta-inflammation rooted in the gut microbiota–immunometabolism axis. Dysbiosis, particularly the depletion of infant-type Bifidobacterium, compromises the intestinal barrier, potentially causing metabolic endotoxemia. In preclinical models, this triggers a pro-inflammatory, “Warburg-like” glycolytic shift in innate immune cells, releasing cytokines (IL-6, TNF-$\mathsf{\alpha }$) that heavily upregulate the ubiquitin–proteasome system in developing muscle. To address this cascade, we hypothesize that a targeted synbiotic approach utilizing dietary anthocyanins (e.g., cyanidin-3-O-galactoside) and prebiotic galacto-oligosaccharides (GOS) may offer metabolic benefits. This review clarifies the pharmacokinetic distinction between the systemic toxicity of high-dose injected galactose and the safety of dietary galactosides. Preclinical data suggest that ingested galactosides resist upper gastrointestinal digestion and undergo colonic cleavage by commensal $\mathsf{\beta }$-galactosidase, yielding short-chain fatty acids (SCFAs) that support intestinal permeability while releasing bioactive phenolic aglycones. Systemically, these aglycones may attenuate skeletal muscle catabolism by supporting PI3K/Akt signaling. Synthesizing current preclinical and adult-derived evidence, this review highlights the theoretical therapeutic potential of early-life synbiotic interventions as adjunctive therapies to support healthy muscle developmental trajectories in pediatric populations. Full article

Epicardial adipose tissue (EAT) is a distinct form of visceral adipose tissue that lies within the pericardium and directly adjacent to the myocardium. Individuals with type 2 diabetes mellitus (T2DM) exhibit excessive and metabolically active EAT, which contributes to the development of early diabetic myocardial disease, formerly referred to as diabetic cardiomyopathy. Recent studies have demonstrated that excess EAT is characterized by a proinflammatory profile that may adversely affect the underlying myocardium, leading to impaired diastolic and systolic function. In this review, we discuss the role of excessive EAT as a source of proinflammatory and profibrotic cytokines that influence adjacent ventricular and atrial myocardium through local tissue crosstalk. In addition to metabolic alterations, enlarged EAT induces hemodynamic changes that result in pericardial constraint and enhanced ventricular interdependence, both of which are hallmarks of diabetic pericardial disease. We further analyze the interplay among T2DM, inflammation, obesity, and increased EAT on the one hand, and myocardial dysfunction characterized by myocardial stiffness, elevated filling pressures, and diastolic and systolic dysfunction on the other. We emphasize that the distinct immunometabolic activity of perivascular adipose tissue may lead to a paradigm shift in the understanding of coronary artery disease, moving from a predominantly endoluminal to an exoluminal perspective. A wide range of dietary, lifestyle, and pharmacological interventions are available within this emerging diabeto-cardiometabolic continuum, each with a potential role; however, the timing of intervention is crucial. This review also explores the potential effects of antidiabetic and other pharmacological agents that modulate EAT thickness, volume, and/or activity, and discusses directions for future mechanistic and clinical research. Full article

Acute-on-chronic liver failure (ACLF) is a rapidly progressing and highly lethal clinical syndrome characterized by multiorgan failure, driven primarily by a severe systemic inflammatory response. The pathophysiological cascade, triggered by a “cytokine storm,” subsequently evolves into profound immune paralysis. This phenomenon is driven by the dysfunction of monocytes, neutrophils, and other immune cells, compounded by their impaired cellular energetics resulting from a metabolic shift toward less efficient energy-yielding mechanisms, mainly aerobic glycolysis, with the pentose phosphate pathway contributing NADPH and biosynthetic precursors rather than ATP. This process is further exacerbated by disruptions within the gut–liver axis, wherein severe dysbiosis and impaired intestinal barrier integrity promote pathogen translocation. Beyond the gut, the liver–spleen axis constitutes a second amplification loop: the congested and immunologically remodeled spleen is proposed to sustain portal hypertension, to contribute to the circulating cytokine pool and to relay profibrogenic signals back to the liver. Coupled with generalized endothelial dysfunction, this is thought to contribute to the failure of peripheral organs. This cascade is presented as a synthesizing model of partially overlapping mechanistic hypotheses and heterogeneous evidence—much of it derived from studies in cirrhosis or animal models and still requiring deeper, ACLF-specific investigation rather than a fully established, strictly linear sequence. To date, no specific targeted therapies are available, and liver transplantation remains the sole intervention capable of substantially improving patient prognosis. Experimental immunomodulatory approaches including granulocyte colony-stimulating factor (G-CSF), intravenous albumin supplementation, therapeutic plasma exchange, mesenchymal stem cell therapy, and anti-cytokine agents represent promising therapeutic avenues. Nevertheless, appropriately tailoring these interventions to the evolving pathophysiological phases of the disease remains a significant clinical challenge, underscoring the critical need for developing precision therapies targeted at specific molecular pathways. Full article

Megakaryocytes (MKs) and platelets are increasingly recognized as active regulators of the bone marrow (BM) microenvironment rather than passive effectors of thrombopoiesis and hemostasis. Recent single-cell and lineage-tracing studies have established that megakaryopoiesis generates functionally heterogeneous populations, including immune-biased and niche-supporting subsets that shape hematopoietic stem cell (HSC) behavior, inflammatory tone, and vascular homeostasis. In leukemia, these regulatory circuits are systematically rewired to establish a marrow niche that suppresses normal hematopoiesis while sustaining leukemic stem cell (LSC) fitness through cytokine gradients, stromal remodeling, and direct cell-to-cell communication. In this focused review, we propose that the immune MK (iMK)–platelet axis is a central driver of leukemic niche remodeling. We discuss how iMK states arise under leukemic pressure, how MK heterogeneity encodes distinct niche instructions, and how platelet-derived extracellular vesicles (EVs) distribute inflammatory signals across the marrow and systemic circulation. Within this framework, we position mitochondrial stress outputs—such as reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) release, metabolic rewiring, and mitochondria-containing EV secretion—not as isolated phenomena, but as mechanistic amplifiers embedded within the broader inflammatory and niche-regulatory programs of MKs and platelets. We further highlight preleukemic inflammatory states as an underappreciated entry point for therapeutic intervention, and propose three clinically actionable axes: inflammatory niche interruption, mitochondrial stress modulation, and platelet–leukemia communication blockade. This framework aligns with emerging concepts in MK heterogeneity, innate immune sensing, endothelial remodeling, and preleukemic signaling, and positions the MK–platelet axis as a promising therapeutic framework in leukemia-associated niche remodeling. Full article

Schizophrenia spectrum disorders are associated with visceral obesity and chronic low-grade inflammation. However, the role of inflammatory mediators in anxiety and depressive symptoms remains unclear. This study aimed to investigate associations between body fat distribution, circulating inflammatory mediators, and affective symptoms in schizophrenia. In this cross-sectional study, 67 patients with schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS), with anxiety (G2) and depression (G6) items analyzed separately. Body composition, including visceral fat area (VFA), percent body fat (PBF), and skeletal muscle mass (SMM), was measured using bioelectrical impedance analysis. Serum concentrations of 38 immune mediators were determined using Multiplex technology. Multivariable regression analyses were performed to identify predictors of affective symptoms. Among all analyzed immune mediators, only interleukin-1 receptor antagonist (IL-1ra) was consistently associated with adiposity measures, showing the strongest correlation with VFA (rho = 0.53; p < 0.001). Higher VFA was independently associated with greater anxiety severity (β = 0.32; p = 0.017), whereas depressive symptom severity was associated with higher PBF (β = 0.32) and younger age (β = −0.25). Visceral adiposity was associated with anxiety severity in schizophrenia and may represent a potential marker warranting further investigation. The observed association between IL-1ra and adiposity supports a potential immunometabolic link between metabolic status and affective symptoms in this population. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become increasingly common, a trend driven by obesity, excess nutritional intake, and dysfunctional adipose tissue. While continuous dietary stress triggers adipose-tissue-derived lipotoxicity and disrupts hepatic metabolic homeostasis and provokes inflammation, the transcriptional scaffolds that mitigate this lipotoxicity remain incompletely understood. We investigated the role of zinc finger protein 90 (ZFP90) in defending against diet-induced metabolic stress and MASLD pathogenesis. Methods: Wild-type and ZFP90-knockout mice were subjected to a high-fat diet (HFD) to model nutrient-overload-induced MASLD. Hepatic phenotypes were characterized using metabolic profiling and RNA sequencing. Mechanistic dynamics were evaluated through protein interaction assays, and clinical relevance was validated using human MASLD liver biopsies. Results: ZFP90 deficiency significantly accelerated HFD-induced steatosis, systemic insulin resistance, and inflammatory infiltration. Crucially, ZFP90 depletion drove severe white adipose tissue (WAT) dysfunction, characterized by impaired lipogenic capacity, exacerbated lipolysis, and diminished local insulin signaling. This was accompanied by a pro-inflammatory secretory shift in WAT, evident from decreased Adipoq and increased Cd68/Ccl3 expression. In the liver, transcriptomic analysis revealed a profound induction of pathways related to fatty acid uptake and cytokine signaling. Mechanistically, ZFP90 forms a repressive complex with TRIM28, acting as a crucial molecular brake on NF-kB signaling. Loss of ZFP90 unleashes p65-mediated hyper-inflammation. Clinically, hepatic ZFP90 expression is significantly upregulated in patients with MASLD. Conclusions: ZFP90 is a novel regulator of immunometabolic homeostasis under dietary stress. By forming of complex with Trim28 to inhibit the nuclear translocation of NF-κB, ZFP90 suppresses pro-inflammatory responses and protects the liver from obesity-associated systemic lipotoxicity. These findings provide critical insights into the adipo-hepatic axis and highlight ZFP90 as a promising therapeutic target to mitigate the progression to metabolic dysfunction-associated steatohepatitis (MASH). Full article

Metabolic reprogramming is a unifying characteristic of cancer and involves orchestrated changes in glucose, amino acid, lipid, and mitochondrial metabolism that go beyond the well-known Warburg effect. Evidence is accumulating that these metabolic states are actively remodeled by oncogene signaling and tumor suppressor loss, allowing cancer cells to sustain anabolic growth, redox homeostasis, and therapeutic stress. This review provides an overview of new findings on tumor metabolism, mechanisms, and the molecular networks governing this reprogramming. We discuss how the major oncogenic pathways, such as MYC, mTOR, HIF, and AMPK, reprogram metabolism using transcriptional, epigenetic, and post-translational control of metabolic flux. A focus is placed on mitochondrial bioenergetics, dynamics, and metabolite signaling such as cancer cell fitness and stress tolerance-defining factors. We also discussed metabolic crosstalk in the tumor ecosystem, including nutrient competition, metabolite coupling, and immunometabolic reprogramming to coordinate metabolism-mediated effects on tumorigenesis and therapeutic response. The review further considers the mechanistic basis for metabolism-targeted therapies, including pathway dependencies, adaptive responses, and micro-environmental context that constrain clinical benefit. Recent innovations such as spatial metabolomics, single-cell metabolic profiling, and systems-level models have unveiled significant intratumoral heterogeneity of metabolism, and they have provided important information about diverse vulnerabilities to therapeutic intervention. Accordingly, understanding the complex crosstalk between these metabolic networks is crucial to rationally designing combination strategies that selectively leverage cancer-specific metabolic liabilities with minimal toxicities against normal tissues. Full article

Hyperuricemia (HUA) is a common immunometabolic disorder associated with gout, renal dysfunction, and systemic inflammation, yet the molecular targets through which non-starch polysaccharides (NSPs) may modulate HUA-related inflammation remain unclear. Here, we applied an integrative bioinformatics and computational workflow combining public transcriptomic datasets, curated NSP-related targets, protein–protein interaction analysis, enrichment analysis, single-cell RNA sequencing, and Mendelian randomization. We further included GutMGene-based orthogonal support analysis, guided docking, structural dynamics analysis, exploratory ADMET profiling, and in silico TLR4 knockout to extend target prioritization. This approach prioritized a TLR4-centered inflammatory module, with TLR4, MSR1, TIRAP, and CXCL8 emerging as candidate genes. Enrichment analyses linked these genes to innate immune and NF-$\kappa$B-related pathways, whereas single-cell analyses localized the prioritized signals mainly to myeloid compartments during gout flares. Mendelian randomization suggested positive associations between genetically predicted expression of TLR4-axis genes and serum uric acid levels. Under electrostatic-guided docking conditions, fucoidan and alginate yielded plausible interaction models with TLR4, and normal mode and RMSF analyses suggested altered flexibility in the MD-2 region. In silico Tlr4 knockout further perturbed urate-handling programs in renal proximal tubule-enriched cells. Together, these findings do not establish TLR4 as a newly discovered hyperuricemia gene or confirm direct receptor antagonism by NSPs, but they provide an NSP-oriented integrative framework that prioritizes the TLR4 axis, highlights myeloid-cell relevance, and nominates fucoidan and alginate for experimental follow-up. Full article

The mammalian gut microbiome functions as a metabolically active immunological organ and has co-evolved with its host to maintain systemic homeostasis. This review integrates current evidence on the molecular mechanisms governing bidirectional microbiota–immune communication, emphasizing evolutionary conservation, receptor-mediated signaling, and translational implications. Microbial structural ligands and metabolites—including short-chain fatty acids, bile-acid derivatives, and tryptophan catabolites—engage host receptors such as G-protein-coupled receptors, FXR/TGR5, and the aryl hydrocarbon receptor (AhR), thereby regulating epithelial barrier integrity, regulatory T-cell differentiation, Th17 polarization, mucosal IgA production, and systemic immune tone. Riboflavin-derived metabolites presented via major histocompatibility complex class-I-related molecule (MR1) further shape mucosal-associated invariant T-cell development (MAIT), illustrating metabolite-driven immune system programming. Dysbiosis induced by antibiotics, dietary perturbation, or aging disrupts these molecular networks, promoting chronic inflammatory, metabolic, autoimmune, and neuroimmune disorders. Comparative analyses across mammalian systems underscore conserved pathways of host–microbe coadaptation and immune education. Therapeutically, microbiota-modulating strategies—including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), postbiotics, and IgY-based passive immunotherapy—aim to restore immunometabolic signaling. Emerging in vitro and in silico platforms further provide mechanistic precision while supporting ethically aligned translational research. Collectively, these insights position microbiota-derived molecular signaling as a central determinant of adaptive immune architecture and a targetable axis in precision immunotherapy. Full article