Search Results (8,112)

Since emerging in late 2019, SARS-CoV-2 has caused over 7 million deaths globally and remains a public health concern. Understanding SARS-CoV-2 pathogenesis is vital, especially as factors like environmental exposures are still poorly understood. Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BP), found in pollutants like cigarette smoke, diesel exhaust, and charcoal-broiled steaks, are known to injure the lungs. We aimed to evaluate if BP exacerbates SARS-CoV-2 pathogenesis in a mouse model of disease. One day following intranasal administration of BP (20 mg/kg) or vehicle control, we infected male and female K18-hACE2 mice with ancestral SARS-CoV-2 and assessed lung viral load, weight change, clinical scores, immune cell recruitment, and survival in the presence and absence of BP exposure. We found that BP-exposed mice had decreased survival compared to mock-exposed mice. Additionally, BP did not alter innate or adaptive immune cell populations in the lungs of SARS-CoV-2-infected mice. These findings suggest that PAH exposure exacerbates severe COVID-19 outcomes by unknown mechanisms, highlighting the need to further explore environmental impacts on SARS-CoV-2 infection. Full article

The oral microbiota represents a complex and dynamic microbial ecosystem that plays a critical role in preserving both oral and systemic homeostasis. Emerging evidence suggests that alterations in oral microbial milieu (dysbiosis) may contribute to the pathogenesis of neurodegenerative disorders, especially Alzheimer’s disease (AD), through the oral–brain axis. This review synthesizes current evidence on the pathways linking oral microbiota to cognitive decline, integrating microbial, immunological, and vascular perspectives. Oral pathogens may access the central nervous system via hematogenous dissemination or neural routes, including the trigeminal nerve, while simultaneously promoting systemic inflammation, immune activation, and blood–brain barrier disruption. These processes converge on key neurodegenerative mechanisms, including chronic neuroinflammation, amyloid-β accumulation, and tau pathology. In parallel, alterations in oral microbial composition have been linked to disease severity, supporting a potential role of dysbiosis in both initiation and progression of cognitive impairment. Diet emerges as a critical modifiable determinant of oral microbial ecology. Diets rich in refined sugars may promote dysbiosis and inflammatory signaling, whereas (poly)phenols, probiotics, and prebiotics may support microbial eubiosis and exert neuroprotective effects through modulation of host–microbe interactions. Although current evidence remains largely observational and mechanistic, the diet–oral microbiota–brain axis represents a promising target for preventive and therapeutic strategies aimed at mitigating cognitive decline and promoting healthy aging. Future longitudinal and interventional studies are required to establish causality and translate these insights into clinical practice. 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

Apical periodontitis (AP), a localized inflammatory bone disease, and osteoporosis (OP), a systemic metabolic bone disorder, are both characterized by chronic inflammation and dysregulated bone metabolism, yet the molecular mechanisms underlying their association remain unclear. This study aimed to identify shared biomarkers and pathogenic pathways linking AP and OP. Gene expression datasets for AP and OP were obtained from the Gene Expression Omnibus database, and shared differentially expressed genes were identified and analyzed using functional enrichment, Gene set enrichment analysis (GSEA), Gene set variation analysis GSVA, and single-sample gene set enrichment analysis (ssGSEA)-based immune infiltration approaches. A random forest model was applied to prioritize candidate genes, followed by validation using single-cell RNA sequencing datasets, clinical samples, and in vitro assays. Forty-three shared differentially expressed genes were identified, among which FAM87B, ASCL2, and PACS1 were prioritized as candidate genes. PACS1 showed consistent upregulation in both AP and OP and was further validated in clinical samples. Integrated analyses suggested that shared molecular alterations were associated with NF-κB signaling and immune-metabolic dysregulation, while single-cell analysis supported PACS1 expression in cell subsets involved in inflammatory bone remodeling. Functionally, PACS1 knockdown promoted osteoblast differentiation, accompanied by increased ALP, RUNX2, and OPN expression. These findings suggest that PACS1 may serve as a shared candidate biomarker linking AP and OP and provide insight into immune-bone crosstalk in inflammatory bone loss. Full article

Iodine is an essential micronutrient required for coordinating thyroid hormone synthesis, growth, neurodevelopment, metabolism, and immune function across humans and domesticated mammals. Molecular iodine can act as an antioxidant, anti-inflammatory, and anti-proliferative agent in several tissues, but these mechanistic effects require confirmation in well-designed human studies. Recommended intakes fall within a narrow optimal range, reflecting a U-shaped response curve in which adequate intake supports systemic homeostasis, while both deficient and excessive intakes can impact immune function. Chronic deficiency impairs neurodevelopment and reproductive performance and weakens the host microbial defences, while sustained excess promotes oxidative stress, alters cytokine profiles, and in genetically susceptible individuals, increases the risk of subclinical or overt thyroid dysfunction and autoimmune thyroid disease. This review summarizes iodine nutrikinetics, dose-dependent outcomes and susceptibility in humans and domesticated mammalian species, emphasizing the importance of maintaining appropriate iodine status to support immunocompetence while minimizing adverse effects. Full article

Anti-CD38 monoclonal antibodies have substantially improved outcomes in multiple myeloma (MM). Although daratumumab and isatuximab target the same antigen, accumulating evidence indicates that they differ in epitope recognition, biological activity, and immunomodulatory properties, suggesting these agents may not be therapeutically interchangeable. This review summarizes the molecular and immunological mechanisms underlying their distinct antitumor effects and their implications for treatment selection. Isatuximab binds near the catalytic site of CD38, resulting in potent enzymatic inhibition, enhanced antibody internalization, FOXM1 suppression, and reactive oxygen species-mediated cytotoxicity, which may preferentially target MM cells harboring 1q21 amplification. In contrast, daratumumab exerts prominent Fc-dependent immune effects, including trogocytosis-mediated downregulation of CD38 and VLA-4, suppression of cell adhesion-mediated drug resistance, and modulation of the immune microenvironment, potentially enhancing subsequent T-cell-redirecting therapies. We further discuss the relevance of these mechanistic differences to measurable residual disease, extramedullary disease, and sequencing with BCMA- and GPRC5D-directed immunotherapies. Finally, we propose a biology-guided treatment-selection model integrating genomic alterations, tumor biology, and immune remodeling to support precision medicine for patients with MM. Full article

Metabolic syndrome (MetS) is a multifactorial disorder characterized by central obesity, insulin resistance, dyslipidemia, hypertension, and impaired glucose metabolism, significantly increasing the risk of type 2 diabetes and cardiovascular disease. Recent evidence highlights the important role of the gut–brain axis in the pathogenesis of MetS through complex interactions between the gut microbiota, immune system, endocrine signaling, and host genetics. This narrative review provides an integrative overview of the mechanisms linking dysbiosis to metabolic dysfunction, with particular emphasis on gut microbiota alterations, intestinal permeability, chronic low-grade inflammation, and microbial metabolites such as short-chain fatty acids and lipopolysaccharides. The review also discusses the neural, endocrine, and immune pathways involved in gut–brain communication, including the role of gut-derived neurotransmitters in metabolic regulation. In addition, the contribution of host genetic susceptibility and epigenetic regulation is explored, highlighting how gene–microbiome interactions influence individual metabolic responses and disease risk. Recent advances in multi-omics technologies and precision medicine suggest that personalized approaches targeting both microbial and genetic factors may improve prevention and treatment strategies for MetS. Furthermore, microbiota-targeted interventions, including dietary modifications, probiotics, prebiotics, and fecal microbiota transplantation, are discussed as emerging therapeutic perspectives. Overall, this review emphasizes the importance of considering MetS as a systemic disorder driven by interconnected biological networks involving microbiota, metabolism, immunity, and genetics. Full article

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas, are rare, biologically heterogeneous thoracic malignancies with limited therapeutic advances since platinum-based regimens were adopted decades ago. Recent genomic and immunophenotypic profiling has uncovered recurrent genomic alterations and high programmed death-ligand 1 (PD-L1) expression, particularly in thymic carcinoma, yet few targeted or immunotherapies have achieved regulatory approval. This mini-review synthesizes current knowledge on TET heterogeneity and the genomic landscape, evaluates the clinical evidence supporting targeted agents and immune checkpoint inhibitors, and examines emerging biomarkers, including circulating tumor DNA. We also address practical barriers to precision oncology in TETs: challenges of next-generation sequencing implementation and cost in resource-limited settings; scarcity of large, biomarker-driven trials; and safety concerns unique to TETs (immune-related toxicity). Finally, we discuss the translational hurdles for antibody–drug conjugates and cellular therapies, limited validated cell surface targets, antigen heterogeneity, and preclinical model gaps and outline strategic paths forward to enable rational, safe, and equitable precision therapeutics for TET patients. Full article

Mastitis remains the most economically damaging disease in the global dairy industry, and conventional genetic selection based on somatic cell score (SCS) has produced only limited gains in resistance. Epigenetic mechanisms—mitotically heritable yet environmentally responsive and largely reversible modifications that regulate gene expression without altering the DNA sequence—are now emerging as a complementary layer of biological information that can sharpen the prediction of disease susceptibility. This review summarizes current evidence on three classes of epigenetic markers associated with bovine mastitis resistance: DNA methylation, non-coding RNAs (with emphasis on microRNAs, long non-coding RNAs, circular RNAs, and small nucleolar RNAs), and histone modifications, alongside the increasingly important epitranscriptomic layer of N6-methyladenosine (m6A) RNA modification. Particular attention is given to differentially methylated regions and discriminant methylation haplotype blocks in immune-related genes, circulating and milk-derived non-coding RNA biomarkers, m6A-mediated regulation of inflammatory transcripts, and histone-mark dynamics in mammary epithelial cells challenged with Staphylococcus aureus and Escherichia coli. We conclude with current limitations and perspectives on translating these markers into selection tools and therapeutic targets. Across all marker classes, current evidence remains constrained by small cohort sizes, breed-specific study designs, a scarcity of longitudinal and multi-generational data, and limited functional validation, so most candidate markers are still at the discovery stage and require cautious interpretation before deployment. Full article

Background: Multiple sclerosis and periodontal disease are chronic inflammatory conditions that may share immune-mediated mechanisms, including cytokine activation, oral dysbiosis, oxidative stress, and systemic inflammatory burden. This systematic review aimed to synthesize recent evidence on common inflammatory pathways linking periodontal disease and multiple sclerosis. Methods: The review was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Cochrane Library, and Scopus were searched for English-language studies published between June 2020 and June 2026. Eligible studies addressed multiple sclerosis, periodontal disease, oral microbiome alterations, systemic inflammation, or neuroinflammatory outcomes. Study selection and data extraction were performed independently by three reviewers. Risk of bias was assessed using AMSTAR 2, the Newcastle–Ottawa Scale, and the Joanna Briggs Institute checklist, according to study design. Results: Seventeen studies were included in the qualitative synthesis. The main shared mechanisms were cytokine-mediated inflammation involving TNF-α, IL-1β, IL-6, and IL-17; NF-κB signaling; Th17/Treg imbalance; blood–brain barrier disruption; oxidative stress; matrix metalloproteinase activity; complement activation; and oral–gut–brain axis dysregulation. The evidence suggests that periodontal inflammation may contribute to systemic immune activation and may amplify neuroinflammatory processes in multiple sclerosis. Conclusions: Current evidence supports a biologically possible association between periodontal disease and multiple sclerosis through shared inflammatory and microbial pathways. However, causality remains unproven, and further longitudinal and interventional studies are needed. 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

(1) Fibromyalgia syndrome (FMS) is a chronic pain disorder with a multifactorial pathogenesis involving neuroinflammation, oxidative stress, and immune dysfunction. This study aimed to evaluate serum biomarkers related to purinergic signaling, inflammasome activation, pyroptosis, and oxidative stress in patients with FMS. (2) Methods: A total of 93 patients with FMS and 93 age- and sex-matched healthy controls were enrolled. Serum levels of pannexin-1 (PANX1), purinergic receptor P2X7 (P2RX7), NLRP3, caspase-1 (CASP1), interleukin-1β (IL-1β), interleukin-18 (IL-18), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured using enzyme-linked immunosorbent assays (ELISA). (3) Results: Total antioxidant status (TAS) and total oxidant status (TOS) were determined. Patients with FMS exhibited significantly increased serum CASP1, GSDME, PANX1, P2RX7, and total oxidative stress (TOS) levels, whereas GSDMD, NLRP3, IL-18, and TAS levels were significantly decreased compared with controls (all p < 0.05). No significant differences were observed in IL-1β levels. Receiver operating characteristic analysis demonstrated exploratory discriminatory performance within this case–control cohort for CASP1 and TAS (AUC = 0.898), followed by TOS (AUC = 0.849) and P2RX7 (AUC = 0.757). (4) Conclusions: These findings indicate alterations in circulating biomarkers related to purinergic signaling, inflammasome-associated pathways, pyroptosis-related proteins, and oxidative stress in patients with FMS. These alterations may contribute to the pathophysiology of FMS and provide a foundation for future mechanistic studies investigating their potential as biomarkers and therapeutic targets. Full article

Aging is driven by progressive epigenetic alterations—DNA methylation drift, aberrant histone modifications, chromatin remodeling, and non-coding RNA dysregulation. Vitamin D, acting through its nuclear receptor vitamin D receptor (VDR), modulates the epigenetic landscape to potentially counteract these age-related changes. This review first describes age-related epigenetic alterations, then outlines vitamin D signaling and its interface with the epigenetic machinery. Next, tissue-specific epigenetic actions of vitamin D in the immune, musculoskeletal, and nervous systems are discussed. Finally, clinical trial evidence is examined, interindividual variability is highlighted, and future research directions are proposed. However, large randomized controlled trials (RCTs) consistently show limited benefits of vitamin D monotherapy, with measurable anti-aging effects observed when combined with exercise and nutritional interventions. Its efficacy is constrained by interindividual variability, J-shaped dose–response, and tissue-specific barriers. For deficient individuals (serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/L), guided supplementation—typically 800–2000 international units (IU)/day—is warranted to achieve tentative target serum concentrations of 75–125 nmol/L, the range linked to favorable epigenetic and immune effects. For those already sufficient (e.g., serum 25(OH)D ≥ 50 nmol/L), indiscriminate supplementation without biochemical indication is not supported. Therefore, promoting healthy aging through vitamin D requires serum-monitored, individually titrated, and multimodal regimens, with supplementation reserved primarily for documented deficiency and integrated with lifestyle interventions. Full article

Injectable dermal fillers are widely used in aesthetic medicine for soft-tissue augmentation and facial rejuvenation; however, systematic comparative data on their physicochemical properties and biological activities remain limited. This study aimed to characterise five commercially available dermal filler products—Facetem^®, cCaHA, PDLLA, PLLA, and PCL—with respect to particle morphology and size distribution, in vitro cytotoxicity, collagen-stimulating gene expression, and macrophage cytokine secretion profiles. Particle size and distribution were determined by laser diffraction. Cytotoxicity was assessed in L929 mouse fibroblasts using the CCK-8 assay at concentrations of 0.1–5 mg/mL. Collagen-stimulating activity was evaluated by measuring COL1A1 and COL3A2 mRNA expression in primary human fibroblasts via quantitative RT-PCR. Macrophage immune responses were profiled by a multiplexed cytokine array (40 analytes) in lipopolysaccharide/interferon-γ-polarised M1 and interleukin-4/interleukin-13-polarised M2 macrophages. Scanning electron microscopy revealed distinct morphological differences among the five products. PDLLA exhibited the smallest median particle size (d(0.5) = 24.9 μm) and highest specific surface area (701.4 m²/kg), while PLLA showed the broadest size distribution (Span = 1.617). All products maintained cell viability above 85% at all tested concentrations, indicating acceptable biocompatibility. Facetem^®, PDLLA, and PLLA significantly upregulated COL1A1 expression in human fibroblasts; PDLLA and Facetem^® also significantly increased COL3A2 expression. Cytokine profiling demonstrated that the products did not substantially alter pro-inflammatory cytokine secretion in M1 macrophages, whereas selected products at high concentrations modulated several mediators in M2 macrophages, suggesting a tissue-remodelling rather than inflammatory response. These findings demonstrate product-specific physicochemical and biological profiles that may guide clinician selection and formulation development of injectable dermal fillers. Facetem^® exhibited a favourable combination of biocompatibility, collagen-stimulating activity, and immune-modulatory properties comparable or superior to established reference products. Full article

Background: Colorectal cancer (CRC) is driven by genetic alterations, epigenetic dysregulation and tumor microenvironment remodeling. Histone modification reader proteins serve as key epigenetic regulators of anti-tumor immunity, yet their synergistic immune networks, combined prognostic roles and immune subtype heterogeneity remain poorly understood. Methods: Here, we integrated multi-omics data and graph attention networks (GAT) to systematically screen prognostic-associated histone reader genes. We then conducted analyses using the immunoassay pipeline and ultimately identified hub immune-related genes validated in independent external cohorts. Additional analyses, including single-cell RNA sequencing (scRNA-seq), molecular docking and multiple in silico functional assays, were performed based on retrospective public datasets. Results: Four core genes (CUL7, GPC1, NFYA, SLC25A5) exhibited robust prognostic performance and strong correlations with anti-tumor immunity. Both core and auxiliary genes participate in critical metabolic and immune pathways. Candidate drugs present differential binding affinity for their encoded proteins, with sapitinib designated as a promising agent. Conclusions: This work constructs an epigenetic immune regulatory network and a four-gene signature, offering promising biomarkers and actionable therapeutic targets for precision immunotherapy against CRC. Full article