Search Results (24,100)

The gut microbiota, acting as a critical extrinsic endocrine organ, is profoundly involved in the pathological evolution and therapeutic response of hormone-dependent malignancies. This review elucidates the core mechanisms governing the microbiota, endocrine, and immune triple-axis. Multi-omic and biochemical evidence demonstrates that microbial metabolic networks, comprising the estrobolome, androbolome, and progestobolome/corticobolome, rely on enzymatic systems such as β-glucuronidases (GUS) and steroid-17,20-desmolases to execute hormone deconjugation and structural modification, thereby modulating systemic steroid exposure. Concurrently, microbe-derived metabolites, such as secondary bile acids and purine derivatives, act as inter-kingdom messengers. These metabolites remodel the tumor immune microenvironment by antagonizing hormone receptors and activating specific signaling axes, such as the Inosine-A2AR pathway. By modulating localized immune cells like effector T cells and myeloid cells, they play a pivotal role in tumor immune evasion. Furthermore, pharmacomicrobiomics reveals a bidirectional regulation between anti-tumor agents and the gut microbiota, where endocrine and immunotherapeutic drugs can induce microbial dysbiosis, while specific gut taxa contribute to primary or acquired resistance by enzymatically inactivating drugs (e.g., reductive inactivation of Enzalutamide) or providing hormonal precursors through bypass pathways. Facing translational challenges, such as real-world microbiome complexity and the colonization resistance of indigenous flora, we propose treating the human body as a unified host–microbe holobiont system. Future research should leverage gnotobiotic models and genetic causal inference to establish functional causality. These efforts will facilitate the development of precision tools, including ubiquitin–proteasome system (UPS) modulators, microbial enzyme inhibitors, and engineered live biotherapeutics. Collectively, these systems biology strategies offer a robust framework for overcoming therapeutic resistance in hormone-dependent malignancies. Full article

Lyme disease (LD) is classically defined as a tick-borne infection caused by Borrelia burgdorferi sensu lato (Bbsl). However, accumulating evidence indicates that, beyond microbial persistence, Bbsl infection can initiate sustained immune dysregulation and post-infectious inflammatory phenotypes in a subset of patients. This narrative review integrates open-access experimental, translational, and clinical data and discusses LD within the spectrum of infection-triggered, immune-mediated processes. We review key immunopathogenic mechanisms, including dysregulated innate immune activation, type I interferon (IFN-I) signaling, T helper 1 and T helper 17 (Th1/Th17) polarization with regulatory T-cell (Treg) insufficiency, antigen persistence (notably borrelial peptidoglycan), and pathways linking infection to autoimmunity such as molecular mimicry, epitope spreading, and human leukocyte antigen (HLA)-restricted susceptibility. These mechanisms are integrated with immune-mediated clinical manifestations affecting the central nervous system (CNS), peripheral nervous system (PNS), musculoskeletal system, heart, skin, and hematologic compartment. Finally, we discuss translational implications for diagnosis, biomarker-guided stratification, and emerging therapeutic strategies that extend beyond antimicrobial therapy, while addressing current controversies and limitations. This framework supports a mechanistic model in which Lyme disease-associated morbidity in selected patients reflects persistent immune activation and dysregulated host responses triggered by infection. Full article

Background/Objectives: People with HIV (PWH) remain at high risk for cardiovascular and metabolic complications despite effective antiretroviral therapy (ART). Diet quality is an important modifiable factor that may influence these complications. Diets high in ultra-processed foods (UPF) have been linked to adverse metabolic and inflammatory profiles in the general population, but their impact on PWH remains poorly understood. The NOVA 4 classification categorizes foods by degree of processing, from unprocessed/minimally processed (NOVA 1) to UPF (NOVA 4). Methods: We conducted a cross-sectional study of adults with virologically suppressed HIV on stable ART. Assessments included dietary intake consisting of 24 h recalls analyzed with Nutrition Data System for Research software (NDSR) and classified into NOVA categories by a registered dietitian and the following characteristics: body composition (total and regional fat by DEXA and CT scan abdomen), cardiometabolic variables (glucose, HbA1C, HOMA-IR, lipids, blood pressure), and biomarkers of inflammation, immune activation, and gut integrity quantified by ELISA. Patients were stratified into NOVA 4 groups based on the median and quartile proportions of total energy intake from NOVA 4 foods. Associations between dietary NOVA and outcomes were analyzed using generalized additive models (GAMs) adjusted for age, sex, race, and CD4 count. Results: Among 222 PWH (mean age 45.4 ± 14.2 years; 31% female; 66% non-white; BMI 30.61 ± 7.91 kg/m²), median NOVA 4 intake was 45.6% of total energy intake. Participants with higher vs. lower NOVA 4 intake showed differences in diet quality, but in GAMs, higher NOVA 4 intake was not associated with higher levels of inflammatory, cardiometabolic, gut integrity, and body composition variables. Conclusions: In PWH, UPF consumption was high but not associated with markers of cardiometabolic health, systemic inflammation, or gut integrity. This may reflect the multifactorial nature of the heightened inflammation in PWH, potentially obscuring the effect of diet. Full article

Tuberculosis–diabetes mellitus (TB-DM) is increasingly recognized as a syndemic in which chronic metabolic dysregulation amplifies tuberculosis severity, delays treatment response, and increases relapse and mortality. However, conventional systemic correlates soluble cytokines and bulk whole-blood transcriptomic signatures often appear broadly similar between TB and TB-DM. This highlights a key gap: clinically meaningful immune dysfunction in TB-DM likely resides in specific lung and blood cell states that are poorly resolved by bulk assays. Small extracellular vesicles (EVs) in plasma and bronchoalveolar lavage (BAL) provide a tractable “liquid biopsy” layer because their RNA and protein cargo can integrate information from infected macrophages, neutrophils, and epithelial/endothelial compartments, and may also include pathogen-derived components. Yet most EV studies remain bulk and cell-agnostic, and interpretation is constrained by heterogeneous vesicle mixtures, selective cargo packaging, and co-isolated non-vesicular contaminants, issues that are especially problematic for nucleic-acid claims without rigorous controls. In this targeted narrative review (2010–2026), we argue that single-cell and multimodal immune reference atlases, including scRNA-seq/CITE-seq, provide a needed scaffold to link EV cargo patterns to specific immune cell states, pathways, and anatomic compartments in TB-DM, enabling prioritized candidates and testable hypotheses. We outline three complementary frameworks: reference-atlas anchoring to project EV cargo modules onto atlas-defined immune states; orthogonal triangulation combining computational inference with immunoaffinity enrichment, targeted validation, and functional assays; and cautious use of “droplet-era” extracellular signals as hypothesis-generating priors for EV-producing states. Implemented in longitudinal, clinically annotated cohorts with standardized EV workflows, atlas-guided EV profiling could yield cell-of-origin–resolved biomarkers of TB-DM immunopathology and treatment response, while prioritizing mechanistically plausible targets for host-directed intervention. Full article

Larix olgensis, a keystone timber species in Northeast China, is increasingly threatened by Neofusicoccum laricinum-induced shoot blight, a devastating disease that compromises forest health and necessitates sustainable management strategies. Here, we demonstrate that the endophytic bacterium Bacillus amyloliquefaciens JL54 elicits multifaceted defense responses in L. olgensis, enhancing resistance to pathogen infection. Greenhouse assays revealed that JL54 pretreatment reduced disease incidence by 12.5% and achieved 43.75% control efficacy while maintaining host vigor. Histochemical analyses identified JL54-induced rapid hydrogen peroxide (H₂O₂) accumulation, extensive lignin deposition, and localized programmed cell death (PCD), indicative of a primed immune response. Transcriptomic analyses uncovered distinct temporal defense patterns: early-stage responses (0 h post-inoculation) were characterized by upregulation of cutin, suberin, and wax biosynthesis pathways, reinforcing physical barriers, whereas late-stage responses (12 h post-inoculation) were dominated by ribosome- and proteostasis-related pathways (e.g., heat shock proteins [HSPs], glutathione S-transferases [GSTs]) to mitigate cellular damage. Biochemical assays corroborated these findings, with JL54 colonization reducing membrane lipid peroxidation (27.2% decrease in malondialdehyde content) and significantly elevating the activity of key defense enzymes, including peroxidase (POD), phenylalanine ammonia-lyase (PAL), and GST. Phytohormone profiling implicated jasmonic acid (JA) as the central mediator of induced systemic resistance (ISR), with JL54-potentiated JA signaling preceding pathogen containment. Collectively, these results demonstrate that JL54 contributes to a coordinated defense strategy in L. olgensis, integrating structural reinforcement (cuticle/lignin), oxidative stress management, and JA-mediated immune priming. These insights advance the understanding of endophyte-conferred resistance in conifers and highlight JL54’s potential as a biocontrol agent for sustainable forestry. Full article

Background/Objectives: This study aimed to compare hematological and inflammatory markers among patients with dry and wet age-related macular degeneration (AMD) and healthy controls, and to evaluate the influence of geographic atrophy (GA) in dry AMD and treatment response (TR) in wet AMD on these markers. Methods: The study included patients with dry AMD (n = 54), wet AMD (n = 53), and age- and sex-matched controls (n = 55). Hematological parameters, serum albumin, and systemic inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), systemic inflammation response index (SIRI), pan-immune–inflammation value (PIV), and hemoglobin, albumin, lymphocyte, and platelet index (HALP), were compared among the groups. Results: Age and sex distributions did not differ significantly between groups. Compared to controls, the wet AMD group had significantly higher neutrophil counts (p = 0.013), red cell distribution width (RDW) (p = 0.033), and inflammatory indices, including NLR, PLR, SII, SIRI, and PIV (all p < 0.01). HALP levels were significantly lower in wet AMD (p < 0.001). Dry AMD patients also had higher PLR (p = 0.045) and RDW (p = 0.005) than controls. When comparing wet and dry AMD groups directly, SIRI (p = 0.041) and PIV (p = 0.029) were significantly elevated in wet AMD, indicating stronger systemic inflammatory burden. In the dry AMD subgroup, patients with GA had significantly lower hemoglobin (p = 0.002) and erythrocyte counts (p = 0.039) than those without GA. No significant differences were observed between TR-positive and TR-negative wet AMD patients. Conclusions: Patients with wet AMD exhibit a more pronounced systemic inflammatory profile than both dry AMD patients and healthy controls. These findings support the hypothesis that systemic inflammation may contribute to AMD pathogenesis. Geographic atrophy in dry AMD may also be associated with additional hematologic alterations, whereas treatment response in wet AMD is not reflected in systemic markers. Full article

Pseudomonas plecoglossicida causes bacterial hemorrhagic ascites in ayu (Plecoglossus altivelis), a lethal disease characterized by abdominal distension with hemorrhagic ascites, multifocal organ hemorrhages, and histopathologically evident hepatocellular necrosis and inflammatory infiltration. The lack of effective treatments exacerbates mass mortalities, posing a significant threat to aquaculture. Given the severe pathogenesis of P. plecoglossicida infection—which involves bacterial colonization, tissue necrosis, and host immune dysregulation—effective therapeutic strategies are urgently needed. Through a screen of traditional Chinese medicine monomers, we identified harmine, an indole alkaloid derived from Peganum harmala seeds, as a potent agent against this pathogen. In vivo, harmine exhibited direct bactericidal activity by disrupting membrane integrity, as evidenced by increasing membrane permeability, and inhibiting biofilm formation. In an ayu infection model, harmine significantly increased host survival, reduced tissue bacterial load, and enhanced innate immunity by augmenting monocyte/macrophage phagocytosis and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis. Mechanistically, the Drug Affinity Responsive Target Stability assay was used to identify the molecular target of harmine, followed by functional validation through PRDX6−knockdown experiments. Harmine exhibited direct bactericidal activity by disrupting membrane integrity and inhibiting biofilm formation. In the ayu infection model, harmine significantly increased host survival, reduced tissue bacteria1 load, and enhanced innate immunity by augmenting monocyte/macrophage system and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis, the latter likely through modulation of PRDX6−mediated oxidative stress and downstream caspase signaling. Mechanistically, DARTS revealed that harmine binds to peroxiredoxin 6 (PRDX6), a multifunctional enzyme possessing peroxidase, phospholipase A₂, and lysophosphatidylcholine acyltransferase activities. This binding liberates TNF receptor-associated factor 6 (TRAF6), facilitating its mitochondrial translocation and association with the ECSIT signaling integrator complex, thereby amplifying mitochondrial reactive oxygen species (mROS) production and potentiating macrophage-mediated bacterial killing. These findings establish harmine as a promising therapeutic candidate for controlling P. plecoglossicida infections and underscore the value of host-directed immunomodulation derived from natural products in aquaculture medicine. Full article

Advances in pediatric oncology have markedly improved survival, shifting attention toward long-term treatment-related morbidity. Targeted agents and immune-based therapies are now widely used across pediatric malignancies and selected non-malignant conditions, often for prolonged periods and during critical windows of growth and development. Because many therapeutic targets regulate physiological pathways involved in growth, pubertal maturation, gonadal function, bone metabolism, and energy homeostasis, clinically relevant endocrine toxicity may emerge during treatment or become apparent only with extended follow-up. This narrative review summarizes pediatric evidence on endocrine and metabolic effects associated with major classes of targeted and immune-based therapies, including tyrosine kinase inhibitors, mTOR inhibitors, MAPK-pathway inhibitors (BRAF/MEK), TRK inhibitors, ALK inhibitors, immune checkpoint inhibitors, and immune effector therapies. Distinct patterns of endocrine vulnerability emerge across drug classes: growth impairment and bone–mineral alterations are most consistently reported with tyrosine kinase inhibitors; weight gain and metabolic changes predominate with MAPK-, TRK-, and ALK-targeted agents; immune checkpoint inhibitors are characterized by early, multi-axis immune-related endocrinopathies with a high likelihood of permanent hormone deficiency once established. In contrast, endocrine abnormalities observed after immune effector therapies largely reflect indirect effects of systemic inflammation, corticosteroid exposure, and prior hematopoietic stem cell transplantation rather than direct endocrine toxicity. Given the limited pediatric-specific data, frequent confounding by multimodal therapy, and the potential for delayed or irreversible endocrine sequelae, structured endocrine monitoring and long-term survivorship care are essential for children exposed to modern anticancer therapies. Full article

Chronic exposure to artificial light at night (ALAN) is increasingly recognized as an environmental risk factor that disrupts circadian regulation of endocrine and metabolic systems. In this study, we investigated the effects of extreme ALAN on oxidative stress and gut microbiota composition in mice using two complementary experiments. In Experiment 1, adult female mice were maintained under either as a standard 12 h light/12 h dark cycle (12 h group) or continuous 24 h light exposure (24 h group) throughout pregnancy and lactation. In Experiment 2, the offspring from the 12 h group were maintained under the same photoperiod, whereas offspring from the 24 h group were divided into a 12 h light/12 h dark group or a continuous 24 h light group, with treatments initiated on postnatal day 19 and continued until 2 months of age. For all 12 h groups, light exposure occurred from 8:00 to 20:00. Compared with dams in the 12 h group, dams exposed to continuous light exhibited significantly increased catalase activity, while their offspring maintained under the 12 h photoperiod showed elevated glutathione levels. No significant changes were detected in immune organ indices. These results suggest that extreme ALAN modulates antioxidant defenses, potentially reflecting adaptive responses to oxidative stress. Moreover, offspring exposed early to extreme ALAN showed significantly reduced gut microbial α-diversity, accompanied by decreased abundances of Firmicutes, Bacteroidota, Campylobacterota, and Desulfobacterota, and an increase in Proteobacteria. Notably, Verrucomicrobiota and Akkermansia failed to recover following photoperiod normalization, indicating persistent microbiota dysbiosis. Overall, these findings demonstrate that extreme ALAN induces oxidative stress and long-lasting alterations in gut microbiota composition, highlighting potential health risks associated with night-time light pollution. Full article

Two-pore channels (TPCs) are evolutionarily conserved intracellular cation channels found in both plants and animals, where they mediate ion fluxes across endomembrane compartments. While historically the plant channel was among the first plant ion channels to be characterized, thanks to the relative ease of applying the patch-clamp technique to isolated plant vacuoles, where it is localized, the functional properties of the two main human isoforms, HsTPC1 and HsTPC2, expressed in endosomal and lysosomal membranes, were elucidated much later. In plants, TPCs are typically represented by a single isoform, exemplified by AtTPC1 in the model plant Arabidopsis thaliana, which functions as a voltage-dependent, Ca²⁺-regulated channel. The physiological role of plant TPCs is not yet fully clarified, although evidence suggests that they may contribute to systemic signaling and stress responses. In humans, two main isoforms, HsTPC1 and HsTPC2, are expressed in endosomal and lysosomal membranes. Human TPCs are primarily regulated by the phosphoinositide PI(3,5)P₂ and display a high selectivity for Na⁺. However, these channels also appear as a non-selective cationic conductance when activated by the potent Ca²⁺-mobilizing messenger NAADP, likely through interaction with an accessory protein. Functionally, human TPCs are involved in endolysosomal trafficking, membrane fusion, and intracellular signaling, with emerging roles in immunity, metabolism, and disease. Overall, TPCs represent key components of intracellular ion homeostasis and cellular physiology; however, their precise regulatory mechanisms and integrated physiological roles remain only partially understood and, in several respects, are still elusive. Full article

Objectives: Lupus nephritis (LN) is a severe manifestation of pediatric systemic lupus erythematosus (SLE) requiring accurate disease activity assessment. This study evaluated the association of the Systemic Inflammation Response Index (SIRI) and the Systemic Immune-Inflammation Index (SII) with disease activity in children with LN. Methods: In this cross-sectional study, 52 children with LN aged 1 month to 18 years treated at Dr. Hasan Sadikin General Hospital, Indonesia, were included. SIRI and SII were calculated from complete blood counts, and disease activity was assessed using the Mexican Modification of the SLE Disease Activity Index (Mex-SLEDAI). Correlations were analyzed using Spearman’s test. Results: Median SIRI and SII values were 1511 and 789,544, respectively, with a median Mex-SLEDAI score of 7. SIRI showed a moderate positive correlation with disease activity (r = 0.443; p < 0.001), and SII also showed a significant positive correlation (r = 0.390; p = 0.004). Both indices increased with higher LN activity. Conclusions: SIRI and SII were significantly associated with disease activity in pediatric LN, with SIRI yielding a numerically higher correlation coefficient, though this difference was not formally compared. These indices may serve as simple, non-invasive biomarkers for assessing inflammatory activity in children with lupus nephritis. Full article

Biliverdin (BV) and bilirubin (BR) are established endogenous antioxidants and immune modulators in other organ systems; however, their roles in the male genital tract remain undefined. The aim of this study was to quantify both bile pigments in human seminal plasma using a fluorescent protein biosensor and to examine their associations with basic semen parameters. We analyzed forty-two semen samples from men undergoing infertility evaluation. Biliverdin predominated over bilirubin in 88.1% of samples. Biliverdin concentration ranged from 51.8 to 611.2 nM, whereas bilirubin ranged from 19.7 to 240.7 nM. The mean total amounts per ejaculate were 1054 pmol for biliverdin and 280 pmol for bilirubin. The total amount of bilirubin in the ejaculate was positively correlated with total sperm count (Rs = 0.47; p = 0.028), whereas biliverdin showed no significant association (Rs = 0.21; p = 0.723). Oligozoospermic samples had significantly lower bilirubin concentrations (p < 0.001) and lower total bilirubin amounts (p < 0.005). Teratozoospermic samples exhibited significantly higher biliverdin concentrations (p < 0.05). This study provides the first simultaneous quantification of biliverdin and unconjugated bilirubin in human seminal plasma and identifies distinct associations with sperm quality. These findings suggest that bile pigments may reflect localized redox-related processes in the male genital tract and may influence male fertility potential. Full article

Solid-organ transplant (SOT) recipients have an increased risk of malignancies and poor oncological prognosis compared to the general population. A central reason for both is that various factors unique to transplantation coalesce to dampen anti-tumor immunity. These include graft or immunosuppressive therapy-related T-cell dysfunction, microenvironmental changes in grafts due to ischemic/reperfusion injuries peri-transplant and comorbidities such as metabolic syndrome. Both innate and adaptive immunity are heavily implicated in cytotoxicity effected by systemic therapeutic agents, not just immune checkpoint inhibitors (ICIs) but also conventional chemotherapy and targeted therapies. Hence, impaired anti-tumor immunity may also affect the treatment efficacy of these agents. Generally, clinical data for systemic therapies in transplant recipients is constrained to retrospective and heterogenous case reports and series only, with a low level of evidence and significant risk of bias. For ICIs, the efficacy in SOT recipients is relatively well preserved in cutaneous squamous cell carcinomas but seems diminished in other tumor types compared to non-transplant recipients. Data for other agents are limited, but the efficacies of chemotherapy in SOT recipients with colorectal cancer and sorafenib/lenvatinib in LT recipients with recurrent hepatocellular carcinoma seem preserved. Given the prevailing trend of broadening the use of transplantation in patients with cancer, further clinical and translational studies to develop strategies to enhance anti-tumor immunity while ensuring graft preservation are urgently needed. Full article

Environmental exposure to particulate matter, including PM_2.5 and engineered nanomaterials, is a major global health concern. Although acute toxic effects have been widely documented, new evidence suggests that the retained particle burden arising from incomplete clearance, tissue retention, and redistribution plays a key role in long-term health outcomes. This review synthesizes knowledge on particle accumulation at multiple biological levels. It examines how particles are retained in pulmonary and lymphoid tissues, their uptake by immune cells, and their sequestration within organelles, particularly the endo-lysosomal system. The mechanisms by which lysosomal dysfunction can cause mitochondrial stress, redox and metabolic disturbances, and impaired autophagy are also discussed. These disruptions can alter the status of immune cells and disturb immune homeostasis. This review also examines how immune perturbation from accumulation may contribute to chronic lung diseases. Understanding these mechanisms explains the persistent health effects associated with low-dose exposure and supports more effective risk assessment and prevention. Full article

Long COVID (LC), also referred to as post-acute sequelae of SARS-CoV-2 infection, is characterized by persistent symptoms originating 3 months following acute COVID-19, lasting for at least two months and frequently affecting individuals who initially experienced mild to moderate disease. The clinical spectrum is heterogeneous, involving respiratory, cardiovascular, neurological, renal, gastrointestinal, and endocrine systems, thereby posing substantial diagnostic and therapeutic challenges. Despite extensive investigation, the precise immunopathogenic mechanisms underlying LC remain incompletely defined. Accumulating evidence suggests that LC is driven by a multifactorial interplay of persistent viral antigen reservoirs, chronic immune activation, dysregulated innate and adaptive immune responses, autoimmunity, endothelial dysfunction, microvascular injury, and aberrant tissue repair. These systemic immune perturbations manifest variably across different organs, contributing to the diverse clinical phenotypes observed. However, mechanistic clarity is hindered by heterogeneity in study designs, limited longitudinal data, and the absence of standardized immunological profiling. This narrative review provides integrative insights into the immunopathogenesis of LC, synthesizing current evidence on systemic immune dysregulation and organ-specific immunological mechanisms. A conceptual framework is proposed to facilitate a structured understanding of this complex syndrome and to guide future research toward targeted immunomodulatory strategies. Full article