Search Results (22,022)

Aging populations worldwide face increasing burdens from physiological deterioration. Bioactive peptides derived from milk proteins have attracted interest for their biological activities, yet systematic evidence against aging remains limited. Here, we investigated casein hydrolysates in a D-galactose-induced murine aging model. Following eight weeks of oral administration at graded doses, we quantified systemic oxidative stress markers, inflammatory cytokine profiles, hepatic and cerebral histopathology, and multiple immune competence parameters. Our data demonstrate that casein peptides dose-dependently suppressed lipid peroxidation, elevated endogenous antioxidant enzyme activities, and rebalanced cytokine networks toward an anti-inflammatory state. Concurrently, peptide treatment attenuated tissue lesions in both liver and brain, while restoring thymus and spleen indices, normalizing T-cell subset distributions, and recovering serum immunoglobulin levels. These findings indicate that oral administration of the casein hydrolysate peptide preparation was associated with improvements in redox homeostasis, inflammatory status, tissue integrity, and immune function in D-galactose-induced aging mice. This work provides mechanistic insights into casein peptides as a multi-target protective agent against age-associated physiological decline, supporting further exploration of their therapeutic potential in aging biology. Full article

Exercise-induced molecular signaling is transient, resolving within hours, whereas the structural and functional adaptations to repeated training develop over weeks to months. The processes that convert signaling into durable adaptation, the conditions that best support this conversion, and the sources of interindividual variability in training outcomes have largely been studied separately. This review proposes a conceptual framework for integrating these approaches. Adaptive Consolidation is introduced as an organizing concept for this intermediate transition, synthesized as a multi-filter cascade spanning post-translational modification, transcription, protein turnover, chromatin remodeling, immune-cell reprogramming, and autonomic remodeling. Sleep-Gated Adaptation (SGA) is proposed as a physiological gate for this transition; evidence indicates that sleep dependence is domain-conditional rather than uniform, strongest for protein-synthetic and motor-memory domains, and detectable in immune and autonomic domains only under specific combinations of exercise damage, sleep-loss severity, and readout timing. Adaptive Consolidation Efficiency (ACE) is proposed as an organizing label for individual-specific determinants—genetic, epigenetic, baseline-biological, environmental, and prescription-related—that jointly explain variability in training response. Neither the SGA nor the ACE is proposed as an established mechanism, validated biomarker, or quantitative index; both are conceptual constructs integrating heterogeneous but convergent evidence. The framework was translated into seven falsifiable predictions, a biomarker panel of validated readouts, and minimum design requirements, including falsification criteria, for future testing. Full article

Oxidative stress compromises intestinal barrier function and antioxidant defense in weaned piglets, causing substantial economic losses in the pig industry. Probiotic interventions to improve gut health are considered a highly promising solution; research indicates that certain Lactobacillus species can promote the proliferation of Lgr5⁺ stem cells and activate the AhR/STAT3 pathway by modulating microbiota metabolism, thereby enhancing intestinal barrier and antioxidant function. Although Limosilactobacillus mucosae (L. mucosae) has demonstrated antioxidant properties in rodent models, its involvement in modulating intestinal stem cell (ISC) fate in piglets, as well as the associated mechanisms, remains unclear. We hypothesized that L. mucosae could alleviate oxidative stress in weaned piglets by modulating intestinal microbiota and activating the aryl hydrocarbon receptor/signal transducer and activator of transcription 3 (AhR/STAT3) signaling-mediated intestinal epithelial renewal. We compared the gut microbiota composition between Hezuo pigs (a subgroup of the plateau-type Tibetan breed) and Landrace × Yorkshire (LY) pigs, and isolated L. mucosae LM410 from Hezuo pigs. The strain was evaluated for acid and bile tolerance, antioxidant activity, and inhibitory properties. Subsequently, a 14-day animal trial was conducted using Duroc × Landrace × Yorkshire (DLY) weaned piglets orally administered with 1 × 10⁹ CFU/mL L. mucosae LM410. Intestinal morphology, barrier integrity, immune responses, antioxidant capacity and cecal microbiota composition and metabolic pathways were assessed. We found that Hezuo pigs harbored a higher abundance of L. mucosae in the gut compared with LY pigs. The isolate L. mucosae LM410 from Hezuo pigs, demonstrated strong acid and bile salt tolerance, as well as antioxidant and antimicrobial activities, and effectively improved intestinal morphology, barrier integrity, immune responses, and antioxidant capacity in DLY weaned piglets. Mechanistically, L. mucosae LM410 reshaped the cecal microbiota by enriching short-chain fatty acid (SCFA)-producing bacteria and upregulating the tyrosine metabolic pathway. Concomitantly, L. mucosae LM410 activated the AhR/STAT3 signaling axis, which likely promoted ISC proliferation and differentiation into goblet cells. These findings demonstrate for the first time that L. mucosae may enhance piglet antioxidant defense through coordinated cecal microbiome remodeling, upregulation of tyrosine metabolism and AhR/STAT3-driven epithelial renewal, providing a theoretical foundation for developing L. mucosae LM410 as a candidate probiotic to improve piglet health. Full article

Colorectal cancer (CRC) arises within a complex microbial ecosystem that may influence carcinogenesis, tumor immunity, and therapeutic response. This is particularly relevant in metastatic disease, where most tumors are microsatellite-stable/mismatch repair-proficient (MSS/pMMR) and derive little meaningful benefit from immune checkpoint inhibitor (ICI) monotherapy. Specific pathobionts, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, have been implicated in genotoxic, inflammatory, and checkpoint-related mechanisms that may contribute to tumor progression and immune evasion, whereas selected commensals and microbiota-derived metabolites may support antitumor immunity in a context-dependent manner. This review integrates translational evidence linking microbial taxa and functions, metabolites, neutrophil biology, bacterial extracellular vesicles, and T-cell dysfunction with CRC progression and immunotherapy response. This review critically examines emerging microbiome-directed strategies, including fecal microbiota transplantation, next-generation probiotics, defined bacterial consortia, dietary and perioperative interventions, postbiotics, and bacteriophage-based approaches, as potential means of modifying immune resistance in MSS/pMMR CRC. Although early clinical signals from microbiota-modulating combinations are encouraging, the available evidence remains limited by small cohorts, heterogeneous interventions, and the absence of randomized CRC-specific studies. Microbiome-based biomarkers and therapeutics therefore remain investigational, and standardized sampling, prospective validation, and carefully designed trials will be required before microbiome modulation enters routine CRC care. Full article

Objective physical-function assessment may help personalize supportive care across chimeric antigen receptor (CAR) T-cell therapy, yet rehabilitation evidence remains dispersed. We narratively synthesized adult hematologic CAR T-cell reports identified through a reproducible PubMed search, targeted source verification, conference and registry surveillance, and reference tracking through 7 August 2026. Studies used the six-minute walk test, sit-to-stand tests, gait speed, Timed Up and Go, grip strength, balance testing, Section GG, and the Functional Independence Measure. Prehabilitation and ward-based rehabilitation appeared feasible. Six-minute walk distance was preserved overall in one acute cohort, although cytokine release syndrome and neurotoxicity were associated with worse change. Retrospective studies linked poor endurance, falls, balance or strength deficits, and assistive-device use with hospitalization, neurotoxicity, or mortality. Selected patients improved during inpatient rehabilitation, while recommended postacute services were not consistently received. The evidence is heterogeneous, predominantly single-center, and insufficient for causal or eligibility thresholds. Objective functional phenotyping may nevertheless provide a complementary patient-level data layer for matching assessment, mobility, referral, and recovery pathways to treatment phase and clinical context. Full article

Heart and vascular complications now rank among the leading health threats facing individuals with HIV, a reality that continues even when modern drug regimens successfully silence viral replication. Sustained immune system overdrive and persistent low-grade systemic inflammation appear central to this heightened vulnerability. This narrative review integrates current understanding of how inflammatory signaling molecules, particularly interleukins, connect to heightened cardiovascular danger in HIV-positive populations, while exploring mechanistic underpinnings, cohort-derived evidence, and prospective treatment possibilities. Elevated concentrations of proinflammatory messengers such as IL-6 and IL-18, alongside indicators of myeloid cell activation including sCD14 and sCD163, characterize the HIV-positive state and independently forecast arterial disease progression, clinical cardiac events, and shortened survival. Notably, this inflammatory signature endures despite pharmacologically induced viral quiescence. Disturbances in protective lipoprotein function, heightened clotting propensity, and leakage of gut-derived bacterial components into the bloodstream each amplify vascular injury. Inflammatory cytokines occupy a central position in HIV-associated cardiovascular pathobiology, serving dual roles as disease predictors and candidate treatment targets. Importantly, recent evidence from the REPRIEVE randomized clinical trial demonstrated that pitavastatin therapy reduced major adverse cardiovascular events by approximately 35% in people living with HIV receiving antiretroviral therapy, highlighting inflammation-modulating strategies as a new foundation of cardiovascular prevention in this population. Full article

Avian metapneumovirus (aMPV) is an emerging viral pathogen causing many outbreaks in chickens all over the world. There are several subtypes of the MPV circulating in chickens in the US. The current circulating subtypes of the virus in the US chicken are A, B, and C. Despite the availability of some aMPV vaccines in the US, most of these vaccines are based on foreign strains, particularly European aMPV-A/B strains. Their protective efficacy against contemporary U.S. aMPV isolates has not been fully established. The main goal of this study is to integrate the most recent aMPV genome sequencing data and the machine learning tools to design a novel aMPV. The machine learning tools such as epitope mapping, molecular docking, and immune simulation were used to design the multiepitope DNA vaccine based on the top-ranked epitopes of two major surface proteins of the virus (F and G). The top-ranked seventeen epitopes representing B cells, CD4 and CD8 epitopes were linked using linkers, with IL-18 added as an adjuvant. The selected epitopes showed high antigenicity, no toxicity and no allergenicity values among the screened epitopes. The molecular docking analysis of the designed vaccine construct showed a high binding affinity to the MHC class I and II epitopes to chicken alleles. The immune simulation analysis of this vaccine provides an in silico proof of concept assessment through modeling of the vaccine potential to elicit humoral and cell-mediated immunity. Further functional studies are required to test the immunogenicity and the efficacy of this novel vaccine before applications using chickens and turkey. Full article

Neutrophils are key regulators of innate immunity and, in addition to their antimicrobial function, contribute to the progression of tumors by forming extracellular traps (NETs). Within the tumor microenvironment, the NETs interact with tumor cells, immune cells, fibroblasts and endothelial cells to promote tumor growth, angiogenesis, immune suppression, metastasis and resistance to treatment. This review critically examines the molecular mechanisms underlying intercellular communication mediated by NETs in cancer and examines their impact on disease progression and response to treatment. In addition, we assess current therapeutic approaches focused on NETs, discuss the available clinical evidence and highlight the main limitations, including safety concerns, validation of biomarkers and translational challenges. We also outline unresolved issues and future research priorities, emphasizing the need for more mechanistic and clinical studies. In addition to oncology, NETs can also play a role in cardio-oncology by linking cancer-related inflammation to thrombosis and cardiotoxicity. Overall, this review provides an integrated framework for understanding the biological and clinical relevance of NETs and supports their potential as a therapeutic target and biomarker in precision medicine. Full article

Background: Traumatic brain injury (TBI) is increasingly recognized as a systemic disorder that may involve alterations in the brain–gut-microbiome (BGM) axis, a bidirectional network linking the brain, immune system, and gut microbiota. While animal studies suggest that disruption and restoration of the BGM axis influence TBI-related changes and recovery, respectively, human evidence remains fragmented. Methods: MEDLINE, Embase, Scopus, and Web of Science were searched through 2025; Global Health was additionally searched for Aim 2. This study had two aims: (1) to assess gut microbiome changes following TBI and (2) to evaluate the effects of probiotic supplementation in TBI patients. Data were synthesized using random-effects meta-analyses, and risk of bias was assessed using the Newcastle–Ottawa and Cochrane tools. Results: Five studies (Aim 1) and fifteen studies (Aim 2) met the inclusion criteria. TBI was associated with shifts in microbial composition, including reduced abundance of Prevotella (p < 0.001), and Parabacteroides merdae (p = 0.038), whereas overall alpha diversity did not differ significantly. Probiotic supplementation improved neurological outcomes [Glasgow Coma Scale (GCS): MD = 2.25, 95% CI 1.34–3.16, p < 0.001] and functional outcomes [Glasgow Outcome Scale (GOS): MD = 1.40, 95% CI 1.12–1.69, p < 0.001], and reduced inflammatory markers, including TNF-α (p = 0.006), IL-6 (p < 0.001), procalcitonin (p < 0.001), and D-lactic acid levels (p < 0.001). High heterogeneity was observed across several outcomes, with the GOS showing moderate heterogeneity. Neurocognitive outcomes were evaluated qualitatively and were not pooled in a meta-analysis because of limited available data. Conclusions: The findings of this analysis suggest that TBI is associated with alterations in the gut microbiome and that microbiota-targeted therapies involving probiotics may improve inflammatory, gut-barrier, neurological, and functional outcomes. Although substantial heterogeneity was observed across several outcomes, particularly the GCS, the available evidence supports further investigation of microbiome-directed interventions as adjunctive strategies for TBI management. Standardized multicenter trials are warranted. PROSPERO: CRD420251135998. Full article

Background/Objectives: AP-2 transcription factors are increasingly recognized as key regulators in cancer biology. The TFAP2E gene, which encodes the AP-2ε transcription factor, remains understudied in cancer compared with other AP-2 family members. The scarcity of studies examining potential AP-2ε targets and related genes limits our understanding of its functional significance. Moreover, related studies have not incorporated a screening step to select the tumor type for justified molecular investigation. Through comparison of tumor–normal expression differences in a pan-cancer spectrum, this study prioritized ovarian serous carcinoma for downstream assessment. Methods: Expression patterns were evaluated using GENT2, GEPIA2, and TNMplot. After prioritizing ovarian serous carcinoma, TFAP2E and related signatures in TCGA-OV were analyzed using transcriptomic and clinical data from GDC and CDR, followed by comparison of findings with the GSE32062 cohort. The workflow included survival and clinicopathological analyses, outcome-independent limma-voom differential expression analysis and WGCNA, MCODE clustering, gene ontology, immune subtype and stemness assessment, PCA, CancerHallmarks enrichment, clinically adjusted Cox and competing-risk survival modeling, and HPA-derived immunostaining evaluation. Additional analyses assessed WGCNA parameter stability and preservation in GSE32062, an outcome-independent MAD-based variability screen, AP-2 family coexpression, and promoter motif enrichment. Results: TFAP2E was downregulated in ovarian cancer across the three queried resources, whereas higher expression was associated with favorable survival across multiple endpoints. Differential expression and WGCNA identified a TFAP2E-associated signature; its ontology indicated GPCR, stimulus responsiveness, and KRAS enrichment for the 933-gene module. The WGCNA pink module was stable across alternative settings, moderately preserved in GSE32062 (Zsummary = 7.86), and enriched in the outcome-independent MAD screening. GSE32062 supported concordant gene expression patterns and showed an association of TFAP2E with progression-free survival. Exploratory immune analyses showed a modestly increased proportion of C5 tumors in the higher-expression groups, whereas differences in stemness were statistically insignificant. The TFAP2E group associations with PFI and DSS in TCGA-OV and with PFS in GSE32062 remained significant after clinical adjustment; Fine-Gray sensitivity analyses gave consistent results for DSS. Immunohistochemistry provided protein-level characterization; eighteen entries differed between representative normal and tumor specimens, with lower tumor staining in fifteen. The seven-gene candidate set showed a clinically adjusted DSS association in TCGA-OV, which was not supported in the GSE32062 evaluation model. Conclusions: TFAP2E expression is associated with survival and a transcriptomic cross-cohort pattern in ovarian serous carcinoma. Covariate-adjusted and competing-risk analyses supported the association but did not establish clinical utility. The highlighted genes remain exploratory candidates for mechanistic investigation. Full article

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Beyond the classical pathogenetic pathways, increasing evidence suggests that epigenetic regulation and the gut–retina axis may substantially contribute to AMD development and progression. This review synthesizes current evidence on two increasingly recognized and interconnected domains of AMD pathogenesis: epigenetic regulation and gut microbiota dysbiosis. Epigenetic processes, such as DNA methylation, histone modifications, and non-coding RNAs, can influence gene function involved in oxidative stress responses, complement regulation, angiogenesis, and inflammation, while several related markers have emerged as potential diagnostic and prognostic biomarkers. Moreover, growing evidence suggests a functional gut–retina axis, in which alterations in the gut microbiota impair intestinal barrier function and facilitate the systemic passage of bacteria and microbial metabolites, potentially affecting retinal inflammation and immune responses. Furthermore, several microbial metabolites, including short-chain fatty acids, lipopolysaccharide, bile acids, tryptophan derivatives, and trimethylamine-N-oxide, may have either protective or harmful effects on retinal and choroidal homeostasis, with altered circulating and fecal concentrations reported in patients with AMD compared with controls. These findings support AMD as a systemically and molecularly interconnected disorder, while further longitudinal, mechanistic, and multi-omics studies are required to establish causality, define interactions between epigenetic and microbiome-related pathways, and clarify their potential utility as biomarkers and therapeutic targets. Full article

Neonatal calf diarrhea caused by intestinal microbial dysbiosis severely restricts rearing efficiency, and fecal microbiota transplantation (FMT) emerges as a promising antibiotic-free strategy for regulating gut homeostasis. Nevertheless, to the best of our knowledge, the effects of colostrum-period FMT and the functional differences between colonic and colostrum delivery routes remain poorly characterized in pre-weaned dairy calves. We hypothesized that colostrum-period FMT would accelerate gut microbiota maturation, improve immune status and reduce diarrhea incidence in pre-weaned calves, with delivery-route-dependent effects. This study aimed to investigate how two colostrum-phase FMT delivery routes shape growth performance, serum immune profiles and gut microbiota in neonatal Holstein calves. Sixty newborn calves were randomly assigned to three groups (n = 20 per group): control (no FMT), colon-FMT (colonic perfusion), and colostrum-FMT (FMT mixed with colostrum). Donor feces were homogenized with sterile saline at a 1:9 ratio for FMT suspension preparation, and the trial lasted 56 days. For growth performance, the colon-FMT calves exhibited significantly higher average daily gain from D29 to D56 (p < 0.05). In terms of intestinal health, the colostrum-FMT group exhibited lower diarrhea incidence during D15-28 (p < 0.05) but markedly higher diarrhea rates during D29-56 (p < 0.01). For serum immunity, colon-FMT calves had elevated serum IgG at D14 (p < 0.05). At D56, the concentrations of IL-2 (p < 0.01) and IL-4 (p = 0.05) were significantly lower in the colostrum-FMT group than the colon-FMT group; no intergroup differences were detected for other serum cytokines and immunoglobulins. 16S rRNA gene sequencing of D28 fecal samples revealed that the colon-FMT group possessed a significantly higher relative abundance of Lactobacillus compared with the other two treatments (p < 0.05). Collectively, colonic FMT is associated with remodeling intestinal microbiota by enriching beneficial Lactobacillus, improved late-stage growth and sustained long-term intestinal health in pre-weaned calves, whereas colostrum-mediated FMT only provides transient protection against early diarrhea. Full article

Fungal infections cause substantial morbidity and mortality, particularly in immunocompromised individuals, yet the immune mechanisms that distinguish protective inflammation from tissue-damaging responses remain incompletely understood. Monocyte chemoattractant protein-1, also known as C-C motif chemokine ligand 2 (MCP-1/CCL2), is frequently induced during fungal infection and regulates the recruitment of CCR2-expressing monocytes and other immune-cell populations. This review synthesizes experimental and clinical evidence concerning MCP-1/CCL2 across infections caused by Cryptococcus, Candida, Aspergillus, Pneumocystis, dimorphic fungi, Mucorales, environmental molds, and other fungal species. The available literature shows that MCP-1/CCL2 is neither uniformly protective nor pathogenic. Early and localized production often supports antifungal defense by recruiting functionally competent immune cells, particularly in the lung and at some mucosal surfaces. In contrast, delayed or persistent expression may accompany uncontrolled fungal growth, ineffective chemotaxis, immune reconstitution, and tissue injury, especially in the central nervous system, kidney, cornea, and chronically inflamed airways. Its biological and clinical significance therefore depends on the infected tissue, timing of expression, host immune status, fungal traits, CCR2 function, and the identity and competence of recruited cells. MCP-1/CCL2 is unlikely to serve as a stand-alone biomarker or universal therapeutic target but may be useful in stage-specific therapeutic strategies and biomarker panels. Full article

Childhood adversity is a major risk factor for the development of numerous psychiatric and medical disorders later in life. Individuals exposed to early adversity also tend to experience more severe, treatment-resistant, and highly comorbid conditions, suggesting that childhood adversity represents a distinct pathophysiological entity requiring specialized diagnostic and therapeutic approaches. However, the biological mechanisms underlying these diverse long-term outcomes remain poorly understood. Recent studies have implicated disruptions of the gut–immune–brain axis and persistent low-grade inflammation in mediating the long-term consequences of childhood adversity. Here, we propose a complementary and novel, but still speculative, hypothesis that shifts the focus away from chronic low-grade neuroinflammation and instead emphasizes the direct crosstalk between the gut microbiome and glia-mediated synaptic pruning during critical periods of brain development. Specifically, we hypothesize that alterations in microbiome-derived signals disrupt the normal maturation and function of glial cells, leading to aberrant synaptic pruning, long-lasting changes in neural circuit connectivity, and persistent deficits in cognition and emotional regulation. Although several lines of evidence are consistent with individual components of this model, direct evidence linking these processes into a causal pathway is currently limited. We therefore discuss the experimental findings that provide a rationale for this hypothesis, identify important gaps in the current literature, and propose specific experimental strategies to rigorously test its central predictions. If validated, this framework could transform our understanding of how childhood adversity becomes biologically embedded and provide a foundation for the development of novel diagnostic biomarkers and targeted therapeutic interventions. Full article

Cardiovascular disease is shaped not only by cardiomyocyte excitability but also by electrophysiological and membrane-signaling programs in cardiac fibroblasts, endothelial cells, mural cells, immune cells, and adipocytes. Recent single-cell RNA sequencing, spatial transcriptomic, and disease-atlas studies have revealed broad expression of ion-channel transcripts across these non-excitable cardiac cell populations. However, transcript detection alone does not establish functional channel activity, cell-state specificity, or therapeutic relevance. This narrative Review therefore focuses on mechanistically supported channel–cell–disease axes rather than providing an exhaustive catalogue of ion channels detected in cardiac non-myocytes. We synthesize evidence for mechanosensitive channels, transient receptor potential channels, calcium-entry pathways, acid-sensing channels, and potassium, sodium, and chloride channels, as well as connexin hemichannels and pannexin channels. We emphasize studies in which omics-based channel nomination is supported by functional validation through electrophysiology, Ca²⁺ imaging, mechanostimulation, pharmacological intervention, or cell-selective genetic perturbation. Particular attention is given to mechanisms linking mechanical stress, Ca²⁺ entry, membrane potential, cell-volume regulation, ATP release, immune activation, vascular tone, fibrosis, and metabolic dysfunction. We also identify key evidence gaps where expression-based observations require direct functional testing in human tissues and disease-relevant cardiac models. By distinguishing atlas-level association from causal channel function, this Review provides a framework for prioritizing non-myocyte ion-channel mechanisms as therapeutic targets in cardiovascular diseases. Full article