Search Results (2,019)

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Clinically established biomarkers such as KL-6 and surfactant protein-D (SP-D) for SSc-associated interstitial lung disease (ILD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for pulmonary arterial hypertension (PAH), are already used as adjunctive tools in routine clinical assessment, whereas many other candidate biomarkers, including interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers remain at varying stages of clinical validation. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and future precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone. However, most candidate biomarkers still require external validation, assay standardization, and demonstration of incremental value over conventional clinical variables before routine clinical implementation. Full article

Introduction: Cutaneous T cell lymphoma (CTCL), most commonly known as mycosis fungoides (MF), is characterized by an increasingly immunosuppressive tumor microenvironment (TME) as the disease progresses. Cancer-associated fibroblasts (CAFs) are key stromal components that support a permissive niche, in part through the secretion of small extracellular vesicles (sEVs), predominantly exosomes, that mediate intercellular communication. We investigated the immunomodulatory role of exosome-enriched sEVs derived from MF fibroblasts (MF-Fs) compared to normal fibroblasts (N-Fs). Materials and Methods: Primary MF-Fs from early-stage MF biopsies and N-Fs from healthy skin were cultured in vitro. sEVs enriched with exosomes were isolated by ultracentrifugation and characterized by flow cytometry (CD81), electron microscopy, Nanosight analysis, and protein quantification, and their uptake by normal peripheral blood mononuclear cells (nPBMCs) was confirmed using PKH26-labeled sEVs. nPBMCs, monocytes, CD4⁺ and CD8⁺ T cells from healthy donors were exposed to MF-F or N-F sEVs. Cell viability was assessed using MTT and trypan blue exclusion assays. Mass cytometry (CyTOF) profiled immune subsets and regulatory proteins for preliminary observation. Monocyte polarization was evaluated by flow cytometry for M1 (CD80, CD86) and M2 (CD163, CD206) markers and PD-L1 expression; M1/M2-associated cytokines and sEV-microRNAs were quantified by qRT-PCR. Results: Both MF-F and N-F sEVs were internalized by nPBMCs and reduced their viability, with a more pronounced effect observed for MF-F sEVs. In nPBMCs, MF-F sEVs also increased the frequency of M2-like macrophages, decreased M1 polarization, and enhanced PD-L1 expression. In primary monocytes, MF-F- compared with N-F-derived sEVs upregulated M2-associated cytokines (IL-10, TGF-β), increased PD-L1 expression, and generated M2-like cells that suppressed CD4⁺ and CD8⁺ T cell viability. Conclusions: MF-F sEVs promote an immunosuppressive TME and represent potential therapeutic or biomarker targets in MF. Full article

Introduction: Endothelial dysfunction (ED) is a key pathogenetic mechanism underlying cardiovascular and cerebrovascular diseases and is increasingly recognized as a common link between ischemic heart pathology and cerebral vascular impairment. In addition to postnatal risk factors, adverse intrauterine conditions, particularly prenatal hypoxia (PH), may program long-term endothelial alterations. The aim of this study was to investigate the structural and molecular features of ED in the myocardial and cerebral vessels in experimental chronic heart failure (CHF) and PH, as well as to evaluate the endothelioprotective potential of pharmacological agents targeting the nitric oxide system. Methods: This study was conducted on Wistar rats using experimental models of CHF (doxorubicin administration, cumulative dose 15 mg/kg) and PH (sodium nitrite 50 mg/kg administered to pregnant females on gestational days 16–21). The endothelial status of cerebral and myocardial vessels was assessed using immunohistochemistry, ELISA, morphometric analysis, and real-time PCR. Key markers of endothelial function, inflammation, nitric oxide metabolism, oxidative stress, and angiogenesis were evaluated. The endothelioprotective potential of nitric oxide-modulating pharmacological agents was also evaluated. Results: CHF and PH induced pronounced structural and functional endothelial alterations in the microcirculatory and muscular-type vessels of the heart and brain. These changes were characterized by reduced endothelial cell density, suppressed eNOS expression, increased iNOS expression, nitric oxide deficiency, elevated nitrotyrosine levels, and activation of proinflammatory cytokines. VEGF levels were significantly decreased, while apoptotic features of endothelial cells were intensified. Angiolin and Hypertril demonstrated the most pronounced endothelioprotective effects among the tested agents. Conclusions: CHF and PH induce persistent ED in cerebral and myocardial vessels through disruption of the nitric oxide system, oxidative stress, and inflammatory activation. PH may act as an early trigger increasing susceptibility to cardiovascular and cerebrovascular diseases later in life. These findings support the rationale for targeted endothelioprotective therapy in ischemic cardiovascular pathology. Full article

Background/Objective: Francisella tularensis is a highly infectious intracellular pathogen that causes severe pulmonary tularemia following aerosol exposure, yet no licensed vaccine exists. Because infection initiates at the respiratory mucosa, understanding mechanisms of protective pulmonary immunity is critical for mucosal vaccine development. This study investigated the role of lung-resident γδ T cells following intranasal immunization with inactivated F. tularensis (iFt) and subsequent lethal challenge with live vaccine strain (LVS). Methods: Mice were intranasally immunized with iFt and later challenged with lethal LVS. Pulmonary immune responses were evaluated using flow cytometry and cytokine analysis. Recruitment of γδ and αβ T cells, production of IL-17 and IFN-γ, neutrophil infiltration, and γδ T cell memory phenotypes were assessed in naïve and immunized mice following infection. Results: Primary LVS infection induced rapid recruitment of γδ T cells to the lung beginning on Day 2 post-infection, preceding significant αβ T cell accumulation. Increased pulmonary IL-17 and IFN-γ correlated with expansion of IL-17– and IFN-γ–associated γδ T cell populations. Following iFt immunization, mice demonstrated enhanced survival after lethal LVS challenge, accompanied by early increases in pulmonary IL-17 and IL-17 producing γδ T cells. Immunized mice also exhibited expansion of effector memory and central memory γδ T cell populations associated with IL-17 production. Conclusions: These findings identify IL-17 producing γδ T cells as contributors to early mucosal immunity following intranasal vaccination against F. tularensis and suggest that targeting lung-resident γδ T cells may support the development of next-generation mucosal vaccines against respiratory pathogens. Full article

Objective: Intracranial infection is a severe complication that can occur following neurosurgery, and early diagnosis is crucial for improving patient prognosis. In this study, we aimed to investigate, from an exploratory perspective, whether the immune microenvironment of intraoperative cerebrospinal fluid (CSF) is associated with postoperative intracranial infection (PII) in patients undergoing craniotomy for benign brain tumors. Methods: A total of 134 patients undergoing neurosurgery for benign brain tumors were included and categorized into an infection group (n = 18) and a non-infection group (n = 116). CSF samples were collected aseptically immediately after dural opening during surgery. The concentrations of 16 cytokines, including monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein-1α (MIP-1α) and MIP-1β; interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17; interferon (IFN)-α and IFN-γ; tumor necrosis factor-α (TNF-α); and granulocyte colony-stimulating factor (G-CSF), were quantified using Cytometric Bead Array (CBA) technology. An independent samples t-test was used for normally distributed data, while the Mann–Whitney U test was applied for non-normally distributed data. Group comparisons were performed using independent-samples t-tests or Mann–Whitney U tests for continuous variables and χ² tests or Fisher’s exact tests for categorical variables. The Benjamini–Hochberg false discovery rate (FDR) correction was applied to all 16 cytokines to control for multiple testing. Receiver operating characteristic (ROC) curve analysis was performed to assess discriminatory capacity. Statistical significance was defined as p < 0.05. Results: PII developed in 18 of 134 patients (13.4%). Age (47.78 vs. 54.86, p = 0.028) and operative duration (390 vs. 244 min, p = 0.005) showed differences in unadjusted analyses. In the unadjusted comparisons, MCP-1 and IL-4 levels were found to be significantly lower in the infection group (MCP-1: 57.78 vs. 116.03 pg/mL, p = 0.003; IL-4: 24.38 vs. 28.18 pg/mL, p = 0.032). No cytokine remained significant after FDR correction. The ROC analysis showed that age and IL-4 demonstrated mild discriminatory performance, with AUC values of 0.665 (95% CI 0.526–0.803, p = 0.025) and 0.657 (95% CI 0.540–0.774, p = 0.032), while MCP-1 and operative duration demonstrated modest discriminatory performance, with AUC values of 0.716 (95% CI 0.595–0.838, p = 0.003) and 0.708 (95% CI 0.578–0.838, p = 0.002). Conclusions: In this study, single-point intraoperative CSF cytokines were not significantly associated with PII after stringent correction for multiple testing, and did not provide a validated clinical prediction tool. The unadjusted and direction-corrected findings for MCP-1 and IL-4 remain exploratory and require validation. Full article

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed haematological-malignancy care, but its dermatologic safety profile remains incompletely characterised across products and indications. Methods: We analysed 8,431,841 deduplicated FDA Adverse Event Reporting System reports from 2016 Q3 to 2026 Q1. Seven approved CAR T-cell products were identified. The primary outcome was any dermatologic adverse event, defined using the MedDRA Skin and subcutaneous tissue disorders system organ class. Secondary outcomes included broad severe cutaneous adverse reactions, narrow Stevens-Johnson syndrome/toxic epidermal necrolysis, and 14 phenotype-specific categories. Multivariable models adjusted for demographics, polypharmacy, cancer, immune checkpoint inhibitor exposure, lymphodepleting chemotherapy and cytokine release syndrome. Additional sensitivity analyses evaluated HSCT/GVHD co-reporting proxies, infection and cytopenia/bleeding proxies, severe-event clinical characteristics, comparator robustness and multiplicity correction. Results: Dermatologic adverse events were identified in 996,654 reports, including 425 CAR-T-associated cases. CAR T-cell exposure was associated with reduced adjusted reporting odds for the primary outcome (adjusted odds ratio 0.13, 95% confidence interval 0.09–0.20) and broad severe cutaneous adverse reactions (0.35, 0.23–0.52). The primary SKIN_ANY reduced-reporting pattern was consistent across all-FAERS, haematological-malignancy and active haematology-oncology comparators. HSCT/GVHD proxy co-reporting was uncommon and did not materially alter estimates. Severe dermatologic reports frequently co-mentioned CRS and serious outcomes. The tisagenlecleucel vascular cutaneous signal was nominally significant but attenuated after excluding infection-attributable and cytopenia/bleeding-proxy reports. Conclusions: Within spontaneous reporting systems, CAR T-cell therapy showed reduced relative reporting of dermatologic adverse events across broad, phenotype-specific and product-level analyses. These results should be interpreted as differences in reporting behaviour, not as evidence of reduced true clinical incidence or lower patient-level risk. Early severe cutaneous reports frequently overlapped with cytokine release syndrome, while infection, cytopenia/bleeding proxies and supportive-care drugs were important alternative explanations for selected cutaneous signals. Full article

The etiology of inflammatory bowel disease (IBD) is not precisely defined. However, it involves environmental factors, genetic predisposition, the involvement of gut microbiota, and abnormal immune response. Angiogenesis seems to be an integral part of IBD. Impairment of the intestinal barrier may represent an initiating or early feature of the disease. Disruption of the epithelial barrier leads to the translocation of microbiota and other antigens into the mucosa, resulting in an enhanced immune response, whereas damage to the vascular barrier is related to endothelial activation and pathologic angiogenesis, both of which promote inflammation. Angiogenesis during IBD is a very complex phenomenon that includes endothelial and immune cells, growth factors, cytokines, adhesion molecules, intestinal microbiota, and signal transduction. It seems that intestinal microvascular hemostasis shifts toward a prothrombotic state, and microthrombi formation exacerbates ischemia. The angiogenic process in IBD is regulated, at least in part, by the intestinal microbiota. Antiangiogenic therapy represents a novel and significant approach to the treatment of IBD. Biologic anti-inflammatory therapy for IBD simultaneously attenuates angiogenesis to a similar degree. However, the expression of VEGF and other growth factors may have dual and opposing effects, probably depending on the stage of the disease. Thus, anti-angiogenic treatment in patients with IBD remains controversial, and clinical trials of anti-angiogenic agents are warranted. Full article

Background/Objectives: Cisplatin (CP) is a widely used chemotherapeutic agent; however, its dose-dependent effects on different tissues are not fully understood. This study aimed to investigate the early dose-related cardiorenal toxicity of CP at biochemical, molecular, and histopathological levels. Methods: Male Wistar albino rats were divided into four groups: Control, 5 mg/kg CP, 7.5 mg/kg CP, and 12 mg/kg CP. Cardiac and renal tissues were collected three days after administration. Oxidative stress and inflammatory parameters were analyzed using ELISA. Histopathological evaluation and semi-quantitative scoring were performed on tissue sections. Apoptosis-related proteins were assessed using Western blotting and immunohistochemistry. Results: In both renal and cardiac tissues, LPO, MDA, and SOD levels showed significant dose-dependent changes, whereas inflammatory parameters did not differ significantly among the groups. Although Bax and Bcl-2 proteins displayed significant dose-dependent variations in both tissues at the protein level, immunohistochemical analyses showed no notable differences in cardiac tissue. Conclusions: Acute cisplatin exposure produced dose-related biochemical, molecular, and histopathological alterations in both cardiac and renal tissues. Oxidative stress-related changes were more prominent than cytokine-mediated inflammatory responses during the acute experimental period. Within the conditions of this acute model, lower cisplatin doses were associated with less pronounced tissue alterations. Full article

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD’s, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies. Full article

Allogeneic T cell therapies have emerged as a promising strategy to overcome the logistical and manufacturing limitations of autologous approaches, enabling scalable, off-the-shelf cancer immunotherapy. While early clinical efforts have focused predominantly on αβ T cell-based platforms, including CAR- and TCR-engineered approaches, a growing spectrum of alternative cell types, such as γδ T cells, invariant natural killer T cells, mucosal-associated invariant T cells, and induced pluripotent stem cell-derived effectors, is expanding the design landscape of allogeneic therapies. However, clinical translation remains constrained by immune rejection, limited persistence, lymphodepletion-associated toxicity, manufacturing variability, and impaired efficacy in solid tumors. To address these barriers, engineering strategies have increasingly integrated T cell receptor disruption, human leukocyte antigen modulation, cytokine support, checkpoint editing, and synthetic circuit design. This review provides an oncology-focused, cross-platform framework for evaluating diverse allogeneic T cell and T cell-like platforms according to clinical maturity, safety, manufacturability, persistence, and tumor-targeting capacity. We further discuss how platform-specific biological properties and clinical evidence can be integrated with modular engineering strategies to optimize antitumor performance. These insights support a shift from platform-centric development toward a design-driven paradigm for next-generation allogeneic cellular immunotherapies with improved efficacy, safety, and scalability. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article

Background: Type 2 inflammatory diseases are among the most common chronic inflammatory conditions in childhood and represent a growing global health burden. Increasing evidence suggests that early-life nutritional exposures may influence immune programming and allergic disease development. This Position Paper aims to summarize the current evidence regarding the immunomodulatory role of polyunsaturated fatty acids (PUFAs), particularly omega-3 long-chain fatty acids, in the prevention of allergic diseases during early life. Methods: A scoping literature review and consensus process were conducted to map biological mechanisms and clinical evidence linking omega-3 PUFAs with allergic disease prevention. This document analyzed experimental, observational, and randomized controlled studies evaluating maternal prenatal/lactational omega-3 exposure. The clinical evidence was qualitatively appraised using study-design-specific Joanna Briggs Institute (JBI) Critical Appraisal Tools. Particular attention was given to immune modulation, inflammatory pathways, epithelial barrier function, gut microbiota interactions, and the ferroptosis–immune–metabolic axis. Results: Omega-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert immunomodulatory and anti-inflammatory effects through multiple mechanisms, including specialized pro-resolving mediator production, regulation of T-helper cell responses, cytokine modulation, maintenance of epithelial barrier integrity, and microbiota interaction. Emerging evidence also supports their involvement in oxidative stress and ferroptosis regulation. Current clinical evidence, particularly from higher-quality prenatal randomized trials and evidence syntheses, suggests that adequate maternal omega-3 intake during pregnancy and lactation may reduce the risk of respiratory allergic outcomes, especially wheezing and asthma, in selected offspring. Conclusions: Adequate omega-3 PUFA intake, such as 2 g/die, during critical windows of immune maturation may represent a valuable strategy for the primary prevention of allergic diseases. Current evidence most strongly supports supplementation during pregnancy and lactation, particularly in populations with low dietary omega-3 intake or increased allergic risk. Omega-3 supplementation should be considered within a broader multifactorial preventive approach aimed at promoting immune tolerance and reducing the future burden of allergic diseases. Full article

Vibrio tubiashii infection has led to several Babylonia areolata pandemics on the southeast coast of China, yet the immune response of the ivory shell against V. tubiashii and the specific pathogen–host interaction remain unclear. This dynamic study aimed to characterize the response of B. areolata to V. tubiashii infection with the use of pathology, transcriptomics, an enzymatic assay, and inflammatory cytokines. Hepatopancreatic cells showed marked vacuolar degeneration with intact cell membrane and extensive cytoplasmic vacuolization after infection. The dynamic transcriptome of the hepatopancreatic tissue was analyzed by RNA-seq after V. tubiashii infection, and a total of 2733 (3 h), 5610 (24 h), 3323 (48 h), and 418 (72 h) differentially expressed genes (DEGs) were identified during infection. The GO and KEGG analyses showed that the DEGs were enriched in metabolic regulation, lysosome, and multiple immune-related pathways such as the MAPK signaling pathway. The immune response of B. areolata was distinct, where the early stage of immune response (3 h) showed binding, focal adhesion, and apoptosis, as well as an activated antioxidant system. Here, expression of TNF-α, IL-1, and IL-8 was significantly increased in the hepatopancreas, whereas expression of IL-6 and IL-17 increased afterward. During the middle stage (24 h and 48 h), a large number of DEGs were suppressed, especially those associated with metabolism and lysosomes, although their expression returned to normal during prolonged infection (72 h). The PPI network showed that ppp2, atp6, and sos1 were the top immune-related DEGs during infection. Key infection-related and time-course-related genes were analyzed by WGCNA. This study illustrates that oxidative stress, inflammation, and apoptosis are strategies of the hepatopancreatic immune response in B. areolata against V. tubiashii infection and enlightens conservation and production by furthering our understanding of gastropod immunity. Full article

Background/Objective: Bisphenol AF (BPAF), a fluorinated analogue of bisphenol A, is an environmental contaminant associated with hepatotoxicity and metabolic disruption. However, the systematic molecular mechanisms linking early transcriptional events to metabolic dysfunction in the liver remain poorly defined. The aim of this study is to elucidate the association between BPAF exposure and hepatic lipid accumulation by integrating transcriptomics, cellular metabolomics, and targeted phenotypic assays. Methods: We performed RNA-sequencing on livers from mice exposed to BPAF (0.1–10 mg/kg/day, 28 days), and performed non-targeted metabolomics on AML12 murine hepatocytes co-cultured with RAW264.7 macrophages in a Transwell system (0–2500 nM BPAF, 48 h). Key metabolic pathways were identified through integrated bioinformatics and validated using enzymatic assays, qRT-PCR, Western blotting, and phenotypic staining (lipid droplets, ROS). Results: Multi-omics integration revealed significant disruption of PPAR signaling and the tricarboxylic acid (TCA) cycle. A striking dose-dependent accumulation of succinate was observed in exposed cells, concomitant with a significant inhibition of succinate dehydrogenase (SDH) activity (52% reduction at 2500 nM, p < 0.001). Transcriptomic data confirmed the downregulation of mitochondrial fatty acid β-oxidation genes. Phenotypic validation indicated that BPAF exposure is associated with oxidative stress, pro-inflammatory cytokine release (TNF-α, IL-6), and pronounced intracellular lipid droplet accumulation in hepatocytes. Conclusions: This study suggests that BPAF exposure is associated with SDH dysfunction, TCA cycle arrest, and lipid dysregulation. Whether BPAF directly inhibits SDH or acts through upstream mitochondrial targets warrants further structural and kinetic investigation. Full article

Endothelial dysfunction (ED) is an early event in cardiovascular and metabolic diseases, including atherosclerosis, diabetes, and hypertension. Emerging evidence highlights the interplay between chronic inflammation and oxidative stress, collectively termed OxInflammation, as a major driver of vascular injury and impaired tissue repair. Among the key mediators of this response is the Nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that promotes the release of inflammatory cytokines, including Interleukin 1β (IL-1β) and Interleukin-18 (IL-18), and induces gasdermin D-mediated pyroptotic cell death. Activation of NLRP3 disrupts endothelial function, reduces nitric oxide availability, and accelerates vascular inflammation and injury. This review discusses current evidence on pharmacological strategies targeting NLRP3 inflammasome signaling using both natural and synthetic inhibitors. Studies have shown that inhibiting NLRP3 can reduce inflammation and oxidative stress, preserve endothelial integrity, improve vascular function, and support tissue repair. Several NLRP3-targeting compounds have advanced into early-phase clinical trials, showing encouraging safety profiles and efficacy in individuals with cardiovascular risk factors. By integrating the emerging concept of OxInflammation with endothelial dysfunction, this review critically evaluates the therapeutic and translational potential of NLRP3 inflammasome inhibition in cardiovascular and metabolic disorders. Collectively, the available evidence supports NLRP3 as a promising therapeutic target for restoring endothelial homeostasis and promoting vascular repair. However, further clinical studies are needed to establish long-term efficacy, optimal dosing strategies, and appropriate patient selection criteria. Full article