Search Results (10,661)

Metastatic uveal melanoma (MUM) remains largely refractory to immune-checkpoint inhibition, so recent research has turned to bispecific T-cell engagers (BTCEs), adoptive-cell therapies (ACTs), and oncolytic viruses (OVs). To summarize the available clinical evidence, we performed a structured literature search across PubMed, Scopus, and Europe PMC for primary studies published between 1 January 2010 and 31 May 2025 that enrolled at least three adults with MUM, treated with one of these modalities, and that reported efficacy or grade-3+ safety outcomes; two reviewers independently performed screening, data extraction, and risk-of-bias assessment, and because of notable heterogeneity, we synthesized the findings narratively. Twenty-two studies met the criteria—thirteen phase I–III trials, eight observational cohorts, and one case series—covering fifteen BTCE cohorts, four ACT cohorts, and three OV cohorts. Tebentafusp, the dominant BTCE evaluated in roughly 1150 HLA-A*02:01-positive patients, extended median overall survival from 16.0 to 21.7 months (hazard ratio 0.51, with three-year follow-up HR 0.68) in its pivotal phase-III trial despite objective response rates of only 5–12%, with early skin rash and week-12 circulating-tumor-DNA clearance emerging as consistent markers of benefit. Tumor-infiltrating lymphocyte therapy, administered to about thirty patients, produced objective responses in 11–35% and occasional durable complete remissions, although median progression-free survival remained 2–6 months and severe cytopenias were universal. Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40–70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events. Full article

Acute lung injury may occur after cardiac arrest (CA), with innate immunity likely playing an important role in lung inflammation after CA. This study aimed to survey serial changes in the toll-like receptor (TLR) 4 signaling pathway in post-resuscitation lung injury in CA rats. A randomized animal study was conducted in rats with CA followed by successful cardiopulmonary resuscitation (CPR). The expression of TLR4 pathway biomarkers was analyzed and compared to the sham controls at different time points after CA with CPR. Lung tissues were collected for histological analysis to assess structural damage. Bronchoalveolar lavage fluid (BALF) was analyzed to quantify inflammatory cytokines and to assess changes in regulatory B cells (Bregs) and regulatory T cells (Tregs). Histological examination revealed marked pulmonary hemorrhage and structural injury shortly after CA. CA with CPR increased myeloid differentiation factor 88 (MyD88) mRNA and protein expression compared to controls at 2 h after CA. Cytokine analysis of BALF showed elevated IFN-γ, interleukin (IL)-1α, IL-1β, IL-2, IL-6, and IL-10 at 2 h after CA. A reduction in Bregs was noted at 2 h, whereas Tregs transiently increased between 2 and 4 h but declined at 6 h after CA. The MyD88-dependent signaling pathway appears to be rapidly activated in rats with CA after CPR, which may contribute to the early pulmonary inflammation observed as soon as 2 h after CA. Full article

This study aims to characterise the B cell compartment in a cohort of Sicilian centenarians by analysing absolute CD3⁻CD19⁺ lymphocyte counts, in association with age, sex, cytomegalovirus (CMV) serostatus, related to immune ageing, and interleukin (IL)-6 levels, representative of inflamm-ageing. It also investigates age-related changes in the CD4⁺/CD19⁺ ratio as a marker of immune ageing, reflecting shifts in immune homeostasis. B cell counts were assessed by flow cytometry on 53 Sicilians aged 19–110 years: 20 Adults, 15 Older adults, 11 long-living individuals, and 7 oldest centenarians. A multiple negative binomial regression was applied to evaluate the effects of age, sex, CMV serostatus, and Il-6 levels on values of B cells. The results showed a non-significant trend toward age-related decline without sex-based differences. A significant reduction in B cell count was observed in individuals with high anti_CMV titres, while IL-6 levels showed a borderline inverse correlation. CD4⁺/CD19⁺ ratio values showed an age-related increase. Our findings suggest that the age-related decline in B cell numbers may be mostly related to CMV infection and IL-6 values, without sex contribution. The age-related increase in the CD4⁺/CD19⁺ ratio, most pronounced in oldest centenarians, may represent a compensatory adaptation promoting immune regulation and chronic inflammation control. Full article

Background and Objectives: Many “food–medicine homologous traditional Chinese medicines (TCMs)” have been shown to delay vascular aging. In this study, we will select “food–medicine homologous TCMs” with the most potential to delay human-origin vascular aging and predict their core targets and mechanisms. Methods: Human-origin vascular-aging-related genes were screened from the NCBI and Aging Atlas databases. Candidate “food–medicine homologous TCMs” were initially filtered by constructing a protein–protein interaction network, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Key targets were validated in the Gene Expression Omnibus database and further screened by least absolute shrinkage and a selection operator. Finally, molecular docking and molecular dynamics simulations identified core targets. Results: Ten core “food–medicine homologous TCMs” with potential to delay human-derived vascular aging were identified: Crocus Sativus L., Glycyrrhiza uralensis Fisch., Chrysanthemum morifolium Ramat., Astragalus membranaceus (Fisch.) Bunge, Sophora japonica L., Hippophae rhamnoides L., Portulaca oleracea L., Lonicera japonica Thunb., Citrus aurantium L. var. amara Engl., and Morus alba L. Further analysis indicated that β-Carotene within these core “food–medicine homologous TCMs” may represent a potential active component targeting matrix metalloproteinase-1, with its action potentially linked to the interleukin-17 signaling pathway. The present study highlights the new hypothesis that immunosenescence (Th17/IL-17) is involved in vascular aging, suggesting that the top ten core “food–medicine homologous TCMs” may delay vascular aging by regulating immune cell function. Conclusions: The top ten “food–medicine homologous TCMs” provide potential candidates for functional products that delay vascular aging and provide computationally predicted mechanistic insights and a scientific basis for novel therapies. Full article

Chronic low-grade inflammation, or “inflammaging,” represents a central mechanism linking dietary patterns, gut microbiome composition, and biological aging. Evidence from Blue Zone populations and Mediterranean diet studies demonstrates that specific nutritional interventions are associated with up to 23% lower all-cause mortality, with analyses suggesting that part of this association may be mediated by measurable improvements in inflammatory biomarkers. This paper synthesizes published evidence from Mediterranean diet trials, centenarian microbiome studies, and digital health platforms to propose a comprehensive digital health framework that integrates quarterly inflammation and microbiome monitoring with continuous lifestyle tracking to deliver personalized longevity interventions. This paper introduces the Longevity-Inflammation Index (L-II), a composite score combining high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and microbiome-derived markers, with scoring algorithms derived from centenarian population studies. The proposed platform leverages artificial intelligence to generate evidence-based recommendations adapted from centenarian and Mediterranean dietary patterns. Published evidence from multiple randomized controlled trials demonstrates that Mediterranean dietary interventions reduce hs-CRP by 18–32%, increase microbiome diversity by 6–28%, and improve metabolic markers including HOMA-IR and TG/HDL ratios. Digital health platforms demonstrate sustained engagement rates of 58–84% at 12 months, with dietary logging frequencies of 4–6 days per week. Cost-effectiveness analyses of dietary interventions show incremental cost-effectiveness ratios of USD 2100–4800 per quality-adjusted life year gained. This inflammation-centered digital health framework offers a scalable approach for translating longevity research into practical interventions for healthy aging, with validation studies needed to confirm the integrated platform’s efficacy and real-world implementation feasibility. Full article

Oxidative stress represents a critical threat to aquatic animal health and aquaculture productivity. Allicin, a natural plant extract, has not been systematically investigated for its antioxidant mechanisms in aquatic crustaceans. This study established in vitro and in vivo models of tert-butyl hydroperoxide (T-BHP)-induced oxidative stress in Chinese mitten crabs (Eriocheir sinensis) to evaluate the hepatoprotective effects of allicin. Integrating biochemical, transcriptomic, and ultrastructural analyses, we found that allicin significantly alleviated T-BHP-induced cytotoxicity and oxidative damage in vitro. Mechanistically, allicin up-regulated antioxidant genes including glutathione peroxidase (gpx) and thioredoxin reductase 1 (trxr1), and down-regulated pro-inflammatory cytokines such as interleukin-1 beta (il-1β), suggesting the concomitant activation of the Nrf2 signaling pathway and inhibition of the p38-MAPK/NF-κB pathway. Transcriptomics further indicated its role in restoring proteostasis and mitochondrial function. A 35-day feeding trial validated these findings in vivo; dietary supplementation with 300 mg·kg⁻¹ allicin effectively reversed T-BHP-induced disturbances in antioxidant enzyme activities and immune-related gene expression. These consistent findings demonstrate that allicin alleviates hepatopancreatic oxidative damage through multi-pathway synergism, supporting its potential as a green and effective antioxidant feed additive in aquaculture. Full article

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

Chemokines play a central role in orchestrating neutrophil recruitment from the bloodstream and determining their effector functions at sites of infection. Chemokine activity is determined by three key properties: reversible monomer–dimer equilibrium, binding to glycosaminoglycans (GAGs), and signaling through the GPCR class of receptors CXCR1 and CXCR2. In this study, we investigated the structural basis of CXCL8 monomer and dimer binding to GAG chondroitin sulfate (CS) using nuclear magnetic resonance (NMR) spectroscopy, docking, and molecular dynamics (MD) measurements. Our studies reveal that both the monomer and dimer use essentially the same set of basic residues for binding, that the interface is extensive, that the dimer is the high-affinity CS ligand, and that the CS-binding residues form a contiguous surface within a monomer. Several of these residues also participate in receptor interactions, suggesting that CS-bound CXCL8 is likely impaired in its ability to bind receptors. Notably, we observe that the same basic residues are involved in binding CS and heparin/heparan sulfate, even though these GAGs differ in backbone structures and sulfation patterns. We conclude that the strategic distribution and topology of basic residues on the CXCL8 scaffold enable engagement with diverse GAG structures, which likely allows fine-tuning receptor signaling to regulate neutrophil trafficking and effector functions. Full article

Neonatal neuroinflammation, driven by microglial activation and cytokine signaling, contributes to brain injury and adverse neurodevelopment outcomes. Perinatal inflammatory mediators, including interleukin-6, cyclooxygenase-2, and interleukin-17, prime microglia and influence circuit vulnerability. This study investigated whether oxytocin pretreatment attenuates lipopolysaccharide-induced inflammatory priming in BV-2 microglial cells. BV-2 microglia were preincubated with oxytocin (33 ng/mL) for 2 h, followed by lipopolysaccharide (0.5 µg/mL) for 2 h. Expression of ionized calcium-binding adapter molecule 1, a microglia marker, in BV-2 cells was assessed by immunofluorescence. After lipopolysaccharide treatment, the gene expression of BV-2 cells was assayed at 1, 2, and 6 h post stimulation by RT-qPCR and RNA-seq. Functional characterization of gene expression profile was performed. Analyses of gene expression profile of BV-2 cells by RT-qPCR and RNA-seq revealed that oxytocin pretreatment attenuated lipopolysaccharide-induced transcriptional activation, including interleukin-6 and cyclooxygenase-2 upregulation. Pathway enrichment analyses suggested that oxytocin-responsive genes were linked to the interleukin-17 signaling pathway. Gene Ontology enrichment analysis showed enrichment for genes related to cytokine production, membrane raft, and chemokine activity. Oxytocin pretreatment mitigates lipopolysaccharide-induced microglial activation by modulating the interleukin-17–interleukin-6/cyclooxygenase-2 axis, suggesting its potential role for oxytocin as an endogenous modulator of neuroinflammation during early brain development. Full article

Juniperus communis L. is a conifer widely used in traditional European medicine for the management of inflammatory disorders. However, its effects on oxidative stress and inflammation remain incompletely characterized. The present study investigated the antioxidant and anti-inflammatory potential of an ethanolic needle extract of J. communis using in vitro assays and an in vivo model of acute inflammation induced by turpentine oil in rats. Phytochemical profiling by HPLC–DAD–ESI–MS revealed a polyphenol-rich extract dominated by flavonols, flavanols, and hydroxybenzoic acids, with quercetin derivatives and taxifolin as major constituents. In vitro analyses demonstrated radical-scavenging and reducing capacities, exceeding or comparable to reference antioxidants in DPPH, hydrogen peroxide, ferric-reducing, and nitric oxide scavenging assays. In vivo, both therapeutic and prophylactic administration of the extract significantly attenuated oxidative and nitrosative stress, as evidenced by reductions in total oxidant status, oxidative stress index, malondialdehyde, advanced oxidation protein products, nitric oxide, 3-nitrotyrosine, and 8-hydroxy-2′-deoxyguanosine, alongside restoration of total antioxidant capacity and thiol levels. These effects were concentration-dependent. Concomitantly, inflammatory signaling was suppressed, with decreased NF-κB activity and reduced levels of interleukin-1β and interleukin-18. These results support the use of these extracts, whose benefits have been observed in traditional medicine, providing scientific support for the anti-inflammatory and antioxidant capacity of J. communis extract. Full article

Rosemary extract (RE), rich in carnosic and rosmarinic acid, which have antibacterial/antioxidant/anti-inflammatory effects, is a potential natural feed supplement for heat-stressed dairy buffaloes. This study systematically evaluated dietary RE effects on dairy buffaloes during hot weather. Twenty Mediterranean dairy buffaloes were randomly allocated into two groups for a 35-day trial: the control (CON) group receiving a basal diet, and the RE group receiving the same basal diet supplemented with 20 g/d of RE. Results showed RE tended to reduce buffalo body surface temperature; increased milk production, 4% fat-corrected milk, milk protein, lactose, and solids-not-fat; and optimized milk fatty acid profiles. In regard to blood, the RE group exhibited higher catalase activity, total antioxidant capacity, and concentrations of immunoglobulin A and M, together with lower concentrations of the pro-inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Additionally, RE markedly elevated concentrations of total volatile fatty acid, acetate, propionate, and butyrate; improved microbial α-diversity indices (Sobs and Ace); and increased the abundances of Rikenellaceae_RC9_gut_group and Butyrivibrio spp., as well as the enrichment of multiple genera belonging to the family Lachnospiraceae. In conclusion, supplementing the diet of heat-stressed dairy buffaloes with 20 g/d of RE improves milk production and composition-related performance by optimizing the rumen ecosystem and enhancing systemic health status, with these effects observed as short-term responses under the conditions of the present study. Full article

(1) Background: Neonatal sepsis continues to be one of the leading causes of mortality and morbidity, particularly in underdeveloped countries. We aimed to compare laboratory parameters between clinical early-onset sepsis (clinEOS) and NNNon-clinEOS groups and to evaluate the association between TLR2-Arg753Gln, TLR4-Asp299Gly, IL6-174G/C, and IL10-1082G/A gene single-nucleotide polymorphisms and clinical EOS susceptibility in preterm newborns. (2) Materials and Methods: Genotyping of the TLR2, TLR4, IL6, and IL10 polymorphisms was performed in 36 preterm neonates with polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP). Logistic regression analysis was used to test the associations between the studied gene polymorphisms and EOS susceptibility. (3) Results: Statistically significant differences in gestational age and birth weight were observed between the two groups, with preterm neonates with clinical EOS having a lower mean gestational age (mean (SD): 29.4 (2.8) weeks vs. 32.6 (1.1); p = 0.00002) and a lower mean birth weight (1342.1 (446.5) gr. Vs. 1984 (376.9)) than preterm neonates without clinical EOS. C-reactive protein (CRP) values measured on the first day significantly increased in the clinEOS group compared with the non-clinEOS group (median, 95% CI: 0.80 [0.40, 1.15] vs. 0.30 [0.02, 0.50]). The mean number of neutrophils significantly decreased in the preterm neonates with clinical EOS (mean difference: 17.3%; 95% CI: [4.0%, 30.5%]; p = 0.0126) and non-clinEOS group (mean difference: 20.8%; 95% CI: [1.8%, 39.9%]; p = 0.0354) between the first and seventh hospitalization days. In the dominant model, the A/G + A/A variant genotype of the IL10-1082G/A polymorphism significantly increased the odds of clinical EOS compared with the GG genotype (OR = 5.25; p = 0.0322), but the gestational-age-group adjusted model yielded p = 0.0752. (4) Conclusions: The results of the current study suggest that IL10-1082G/A gene polymorphism is a significant risk factor for clinical early-onset sepsis development in preterm neonates, but there was no evidence of a gestational age-group independent direct effect of IL10-1082G/A gene polymorphism on clinical EOS susceptibility. The results should be considered as exploratory. Full article

Background: Cardiovascular risk models, such as the Framingham and atherosclerotic cardiovascular disease (ASCVD) calculators, have improved risk prediction but often fail to identify individuals who experience ASCVD events despite low or intermediate predicted risk. This suggests that underrecognized, non-traditional risk factors may contribute significantly to the development of atherosclerosis. Objective: This narrative review synthesizes and summarizes recent evidence on high-yield non-traditional risk factors for atherosclerosis, with a focus on clinically significant, emerging, and applicable contributors beyond conventional frameworks. This review is distinct in that it aggregates a wide array of non-traditional risk factors while also consolidating recent data on ASCVD in more vulnerable populations. Unlike the existing literature, this manuscript integrates in a single comprehensive review various domains of non-traditional atherosclerotic risk factors, including inflammatory, metabolic, behavioral, environmental, and physical pathways. An additional unique highlight in the same manuscript is the discussion of non-traditional risk factors for atherosclerosis in more vulnerable populations, specifically South Asians. We also focus on clinically actionable factors that can guide treatment decisions for clinicians. Results: Key non-traditional risk factors identified include inflammation and biomarker-based risk factors such as C-reactive protein or interleukin-6 levels, metabolic and microbial risk factors, behavioral factors such as E-cigarette use, and environmental or infectious risk factors such as air and noise pollution. We explore certain physical exam findings associated with atherosclerotic burden, such as Frank’s sign and Achilles tendon thickness. Conclusions: Atherosclerosis is a multifactorial process influenced by diverse and often overlooked factors. Integrating non-traditional risks into clinical assessment may improve early detection, guide prevention and personalize care. Future risk prediction models should incorporate molecular, behavioral, and environmental data to reflect the complex nature of cardiovascular disease. Full article

Ultraviolet (UV) radiation is a primary environmental factor responsible for skin photodamage, and exposure to UV rays is strongly linked to a variety of skin diseases. This study examined the prophylactic and therapeutic effects of Seed Oil of Lycium barbarum L. from the Qaidam basin (QLBSO) in a UV-induced skin photodamage model in BALB/c mice, exploring potential mechanisms by analyzing the skin microbiota and metabolites using 16S rDNA sequencing and metabolomics. The results showed that QLBSO effectively alleviated UV-induced histopathological changes in mouse skin. It also significantly increased the activity of superoxide dismutase (SOD) and catalase (CAT) in UV-damaged skin tissue, while reducing levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as matrix metalloproteinases-1 (MMP-1) and MMP-3. Omics analysis revealed that QLBSO successfully restored the balance of the skin microbiota and corrected disruptions in amino acid metabolism caused by UV exposure. Notably, Firmicutes_A and Kineothrix, along with cysteine, cystine, glycine, arginine, proline, and choline, were identified as key microbial species and metabolites responsive to QLBSO’s prophylactic and therapeutic effects. In conclusion, QLBSO likely protects against UV-induced skin photodamage by modulating the skin microbiota and amino acid metabolism, providing a scientific foundation for its potential use in skin health protection. Full article

Vasculitides are a heterogeneous group of disorders characterized by inflammation of blood vessel walls, leading to tissue ischemia and organ injury. Traditional inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are widely used but lack diagnostic specificity. This has driven the search for more informative biomarkers across vasculitis subtypes. This review summarizes current evidence for validated and emerging biomarkers in large-, medium-, small-, and variable-vessel vasculitis, as well as single-organ vasculitis. Key analytes reflect systemic inflammation, such as serum amyloid A (SAA) and interleukin-6 (IL-6), as well as endothelial activation, complement pathways, neutrophil and macrophage activation, and organ-specific damage. Promising candidates include pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9) in large-vessel vasculitis; N-terminal pro-B-type natriuretic peptide (NT-proBNP) and S100 proteins in Kawasaki disease; galactose-deficient immunoglobulin A1 (Gd-IgA1) and urinary angiotensinogen (AGT) in IgA vasculitis; and tissue inhibitor of metalloproteinases-1 (TIMP-1), S100 proteins, complement C3, and PTX3 in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Although these biomarkers provide mechanistic insight, most lack disease-specificity, external validation, or standardized assays. Future progress will require multicenter studies, harmonized testing, and integrated biomarker panels combined with imaging modalities to improve diagnosis, activity assessment, and monitoring. Full article