Search Results (14,043)

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications. Full article

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer. Full article

Obesity drives chronic low-grade inflammation and endothelial dysfunction, key contributors to subclinical atherosclerosis. This review focuses on the netrin 1/UNC5B axis and its role in promoting macrophage retention within adipose tissue and atherosclerotic plaques, thereby perpetuating local inflammation and vascular injury. Complementary inflammatory markers—including IL 6, hsCRP, and IL 15—are discussed as indicators of systemic inflammatory burden, whereas endocan and ICAM 1 are briefly addressed as markers of endothelial activation. Among emerging pharmacological strategies, glucagon-like peptide-1 receptor agonists (GLP 1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) show the most consistent evidence for improving these biomarkers and reducing endothelial damage, with GLP 1RAs demonstrating direct effects on carotid intima–media thickness. Integrating biomarker profiling with obesity phenotypes may improve early risk stratification and support more precise management of subclinical atherosclerosis. Full article

Unravelling the cellular and molecular mechanisms underlying lung injury and repair requires precise spatial context. Profiling cell-to-cell transcriptional variability and spatial orientation has become increasingly sophisticated, but validating results at the protein level still remains challenging, particularly for low-expressed proteins or small-scale samples. Here, we present a workflow established by our group for spatial protein analysis in the lung by combining two commercially available platforms: (1) laser-assisted microdissection (LMD) with (2) a capillary electrophoretic-based immunoassay (CEI). Using this workflow, we demonstrate a simple, accessible, and sensitive method for spatially capturing regions of interest to investigate small-scale samples or low-expressed proteins. This workflow provides an additional option for orthogonal validation for researchers using omics-based approaches. Furthermore, we validated transcriptome analysis results at the protein level by applying this workflow to a pre-clinical model of cigarette smoke (CS)-induced lung injury. In line with the previous findings, the results showed a significant downregulation of the endothelial cell marker in LMD-enriched alveolar regions, suggesting spatial capillary rarefaction, and activation of the mitogen-activated protein kinase (MAPK) signalling pathway in pulmonary vasculature of CS-exposed mice. Our approach overcomes traditional challenges and provides new opportunities for understanding complex disease pathomechanisms and identifying potential therapeutic targets. Full article

Pulmonary arterial hypertension (PAH) is a severe and progressive cardiopulmonary disorder with limited treatment options. Camellia petelotii (Merr.) Sealy (CP) contains multiple flavonoids and other phytochemicals, but its active compounds and molecular mechanisms in PAH remain unclear. Active compounds of CP were screened by comprehensive literature mining and absorption, distribution, metabolism, and excretion (ADME) evaluation. PAH-related hub targets were identified from transcriptomic data using weighted gene co-expression network analysis (WGCNA), machine learning, and external validation. Functional enrichment, immune infiltration, and single-cell RNA-sequencing analyses were performed to characterize their biological roles and cellular localization. Molecular docking and molecular dynamics simulations assessed compound–target interactions. The effects of CP were further evaluated in hypoxia-induced rat pulmonary artery smooth muscle cells (RPASMCs). Five core bioactive compounds were identified, among which luteolin and quercetin were prioritized for further analysis. HSP90AA1 and ROCK2 were screened as hub targets. Bioinformatic analyses suggested that these targets were mainly associated with the “Lipid and atherosclerosis” pathway, metabolic reprogramming, and modulation of the immune microenvironment. Single-cell analysis showed broad expression of HSP90AA1 and enrichment of ROCK2 in fibroblasts and endothelial cells. Molecular docking and molecular dynamics simulations supported stable binding of luteolin to HSP90AA1. In vitro, CP extract inhibited hypoxia-induced hyperproliferation of RPASMCs and reduced HSP90AA1 protein expression. HSP90AA1 may represent a candidate molecular mediator of CP in PAH, and CP inhibited hypoxia-induced RPASMC proliferation in association with downregulation of HSP90AA1. Full article

Background: Sepsis remains a leading cause of mortality in the intensive care unit (ICU). Platelets (PLTs) are central to coagulation, inflammation, and the maintenance of endothelial integrity. Although thrombocytopenia is an established prognostic marker in sepsis, alterations in PLT function and morphology may provide additional insight into disease progression. Methods: This retrospective pilot study examined adult ICU patients diagnosed with sepsis or septic shock. Extracted data included demographic characteristics, clinical variables, and laboratory parameters. Platelet function was evaluated using impedance aggregometry and rotational thromboelastometry (ROTEM), while PLT morphology metrics were obtained from complete blood counts. Statistical analyses comprised Spearman’s rank correlation and logistic regression. Results: Twenty patients were included. Platelet aggregation was impaired across ASPI, ADP, and TRAP-6 assays despite normal PLT counts and morphology. ROTEM-derived measure of PLT contribution to clot strength was within normal ranges. No correlations were observed between PLT function and PLT morphology parameters. An inverse correlation was identified between ROTEM-derived PLT contribution to clot strength and SOFA score (r = −0.60, p = 0.03). Neither PLT function nor PLT morphology was associated with ICU mortality. Conclusions: Functional PLT deficits may occur in sepsis in the absence of structural abnormalities. ROTEM-derived PLT contribution to clot strength may inversely reflect sepsis severity. Platelet function parameters appear unlikely to predict short-term mortality in septic patients. Full article

Peritoneal dialysis (PD) is limited by insufficient phosphate removal, leading to adverse cardiovascular outcomes in patients with chronic kidney disease. To advance the understanding of the molecular mechanisms of peritoneal phosphate transport, RNAseq data of phosphate transporters in four PD-relevant cell lines were analyzed. The expression and localization of the respective proteins were validated by immunostaining in these cells. The transcriptomics of omental arterioles from children on PD were analyzed. In vitro Transwell models of an immortalized mesothelial cell line (MeT-5A) and human umbilical vein endothelial cells (HUVECs) and respective co-cultures were established, enabling quantification of phosphate transport across mesothelial and endothelial monolayers. Sodium phosphonoformate tribasic hexahydrate (PFA) and Tenapanor were used to inhibit transcellular and paracellular transport pathways. Cell viability and integrity markers were measured over the experimental periods. SLC20A1 and SLC20A2 were expressed across all studied cell types, while SLC34A2 and SLC34A3 were mesothelial cell-specific. Omental arterioles of children on low-glucose-degradation-product (GDP) PD showed higher SLC20A1 expression vs. stage 5 chronic kidney disease (CKD5) and healthy controls. Permeability for phosphate was lower across MeT-5A compared with HUVEC monolayers and was not further reduced in co-culture. Inhibitors reduced both transcellular and paracellular transport to 75% in MeT-5A and 65% in co-cultures, while no effects were observed in HUVEC alone, suggesting the mesothelial cell layer as a significant barrier for phosphate transport. Our studies provide first analyses combining findings on molecular phosphate transporters in peritoneal cells and arterioles and introducing a Transwell model for quantitative studies of phosphate kinetics. Full article

Sickle cell anemia (SCA) is a genetic disorder characterized by chronic hemolysis, primarily driven by red blood cell lysis. Its pathophysiology is centered, though not exclusively, on the increased release of intracellular components, such as hemoglobin degradation products, which are known to stimulate innate immune responses and promote prothrombotic states. Current therapies alleviate symptoms, yet patients remain exposed to a chronic inflammatory milieu punctuated by episodes of acute pain. The recurrence of these crises can be life-threatening due to ischemia–reperfusion injury, hypercoagulability, and respiratory complications. Central mechanisms are marked by elevated hemolysis, heightened inflammatory signaling, and increased procoagulant activity, largely driven by soluble molecules released into the plasma, such as hemoglobin, nuclear molecules and other products. These compounds are recognized from sensors on immune and endothelial cells, named Pattern Recognition Receptors (PRRs), and constitute canonical pathways for intracellular activation. Four main types have been extensively studied in the literature over recent years in both infectious and sterile inflammatory contexts; still, only a few have elucidated the mechanisms underlying acute and chronic inflammation in patients with SCA. Although Toll receptors were shown to be major in triggering immunity, other receptors were found to be important regarding this function, which suggested a multifactorial mechanism for this triggering. Therefore, here, we propose a comprehensive review of previously published findings regarding the expression, activation, and dynamics of Toll-like, NOD-like, and RIG-I–like receptors in the progression of SCA and its associated inflammatory features. Full article

Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is increasingly recognized as a contributor to cognitive decline and a potential risk factor for neurodegeneration. Previous studies have also identified various associated comorbidities such as vascular dysfunction, metabolic alterations, and neuroinflammatory changes. Positive airway pressure (PAP) therapy has been associated with cognitive improvement in some studies, but its long-term effects on cognitive function remain uncertain. This study employs a prospective, observational, longitudinal cohort design to examine longitudinal associations between disease severity, PAP therapy and cognition. Additionally, we aim to examine the relationships between cognitive dysfunction, brain structure and associated OSA-related risk factors. A total of 100 eligible participants with mild to severe OSA will be recruited. All participants will undergo comprehensive assessments at baseline and after 12 months, including neurological, pulmonary, and ear, nose and throat clinical examinations, polysomnography, neuropsychological testing, brain magnetic resonance imaging with volumetry, anthropometric measurements, blood and saliva sampling for the assessment of the selected laboratory parameters, gut microbiome analysis, and evaluation of endothelial function and baroreflex sensitivity. This study may improve understanding of how PAP therapy and OSA-related pathophysiological processes influence cognitive outcomes. Full article

Objectives: This study assessed the association between physical activity and vascular endothelial function and carotid atherosclerotic plaques in older adults using ultrasound imaging. Methods and Results: A total of 60 older adults were divided into three groups based on weekly physical activity: low (<4 h/week), moderate (4–12 h/week), and high (>12 h/week). All participants underwent flow-mediated dilation (FMD) assessment and carotid ultrasound to determine plaque burden. Participants with moderate physical activity demonstrated greater FMD (12.3 ± 2.5%) than those with low (1.2 ± 1.8%) or high activity (7.1 ± 1.3%), and a lower carotid plaque burden. In adjusted logistic regression models, moderate activity remained independently associated with a lower likelihood of impaired FMD (OR 0.22; 95% CI 0.18–0.27) and lower carotid plaque burden (OR 0.16; 95% CI 0.11–0.19). Conclusions: Moderate physical activity was associated with more favorable vascular endothelial function and reduced carotid atherosclerosis in older adults, indicating an association with a more favorable vascular profile. Full article

Vascular diseases (VD) remain a leading global cause of morbidity and mortality, often developing silently before manifesting as severe complications like stroke or ischemia. Traditional diagnostic imaging provides essential anatomical data but frequently fails to capture the dynamic molecular processes underlying vascular pathology. This narrative review summarizes current evidence regarding Extracellular Vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, as emerging biomarkers and mediators in vascular conditions. The review evaluates the biological mechanisms of EVs across several disorders, including arterial aneurysms, peripheral artery disease, carotid stenosis, and venous thromboembolism. Findings indicate that EVs concentration and molecular cargo, particularly microRNAs and proteins, reflect the physiological state of parent cells, offering a “liquid biopsy” for vascular inflammation, endothelial dysfunction, and plaque vulnerability. Furthermore, the review explores the therapeutic potential of stem cell-derived EVs in promoting angiogenesis and tissue repair in chronic vascular ulcers. Despite these advances, the review concludes that the clinical implementation of EV-based diagnostics faces significant hurdles, primarily due to the lack of standardized isolation and characterization methods. Addressing these methodological challenges is crucial for translating EV research into routine clinical practice. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Resveratrol (RSV), a bioactive polyphenol, has emerged as a pleiotropic modulator within the integrated pathophysiology of cardiovascular disease (CVD) across the life course. Effective CVD management requires a transition from organ-centric frameworks to systems-level models that acknowledge dynamic crosstalk among metabolic, renal, and cardiovascular networks. Oxidative stress constitutes a central unifying axis in this interconnected biology, propagating cross-organ injury from early developmental stages onward. Mechanistically, RSV acts as a redox-responsive gene regulator by activating the Nrf2–ARE pathway, restoring nitric oxide bioavailability, and orchestrating SIRT1, AMPK, and NF-κB signaling to recalibrate mitochondrial function, inflammatory tone, and endothelial integrity. Within the Developmental Origins of Health and Disease (DOHaD) paradigm, RSV exhibits reprogramming potential that attenuates the intergenerational transmission of hypertension, kidney disease, and metabolic dysfunction. Although clinical translation is constrained by limited bioavailability and rapid metabolism, advanced delivery systems and artificial intelligence-enabled optimization strategies provide promising avenues to enhance therapeutic precision and scalability. This narrative review integrates mechanistic and translational insights to position RSV as a systems-oriented life-course intervention with sustained and intergenerational relevance in CVD. Full article

Nutraceuticals are emerging as promising agents for the prevention and treatment of atherosclerosis, particularly in light of the limitations associated with current pharmacotherapies. Pomegranate-derived polyphenols, especially punicalagin (PC), possess multiple cardioprotective properties. However, their direct biological effects are constrained by poor absorption and low bioavailability. Instead, many of their actions are mediated by gut microbiota-derived metabolites known as urolithins. Despite this, the roles of PC and its metabolites in atherosclerosis remain inadequately defined. The objective of this study was to investigate the anti-atherogenic effects and underlying mechanisms of PC and its major metabolites—ellagic acid and urolithins A, B, C, and D—using in vitro and in vivo approaches. In vitro, these compounds broadly inhibited key pro-atherogenic processes in macrophages and endothelial cells, including reactive oxygen species production and inflammatory gene expression, with notable metabolite-specific differences. Urolithin A (UA), identified as the most effective compound, was further evaluated in LDL receptor-deficient mice fed a high-fat diet. UA supplementation improved peripheral blood immune cell profile, reduced atherosclerotic plaque burden and inflammation, and enhanced markers of plaque stability. RNA sequencing of the thoracic aorta revealed key molecular pathways underlying the protective actions of UA. Collectively, these findings highlight the therapeutic potential of PC-derived metabolites, particularly UA, in combating atherosclerosis and support the need for future human clinical studies. Full article

Integrins and other cell adhesion molecules play a critical role in the migration and homing of leukocytes. This study investigates whether metastatic tumor cells can exploit leukocyte-like rolling and arrest mechanisms during early vascular steps of metastatic dissemination. B16 melanoma cell adhesion to activated bEnd.3 endothelial monolayers or immobilized VCAM-1 were analyzed under defined shear flow using a parallel-plate chamber. Function-blocking antibodies, divalent cation modulation, pertussis toxin, and low-temperature conditions were used as classical controls. B16-BL6 melanoma cells exhibited robust VLA-4-dependent rolling and arrest on activated endothelial monolayers and on immobilized VCAM-1 under physiological shear stresses (0.7–2 dyn/cm²), independent of chemokine-related Gαi signaling. These findings identify a chemokine-independent mechanism of VLA-4-mediated vascular capture by melanoma cells under shear flow, providing a potential mechanistic basis for early steps in metastatic dissemination. Full article