Search Results (2,708)

Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4⁺ and CD8⁺ T cells, regulatory T cells, and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings suggest that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, Bruton’s tyrosine kinase (BTK)-, and cyclooxygenase 2 (COX2)-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including semenogelin 1 (SEMG1), intercellular adhesion molecule-4 (ICAM4), tripartite motif69 (TRIM69), amphiregulin (AREG), oncostatin (OSM), and transducer of ERBB2-1 (TOB1), suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity. Full article

Background: Ganoderma lucidum triterpenes are bioactive compounds with recognized anti-inflammatory, antitumor, and immunomodulatory properties. This systematic review synthesizes evidence regarding the anti-inflammatory activity of these triterpenes based on studies from the last two decades. Methods: A systematic search was performed in PubMed, Medline, and Embase (2003–2025) for original in vitro and in vivo (non-clinical) studies evaluating G. lucidum triterpene extracts or isolated compounds. Clinical trials, reviews, and multi-species extracts were excluded. The review is registered on PROSPERO (CRD42024510982), and animal study quality was assessed using the SYRCLE Risk of Bias tool. Findings: From over 3000 records, 23 articles were included. Studies utilized diverse models, including macrophages, human PBMCs, and various animal strains (mice, rats, chickens). All studies reported significant anti-inflammatory effects via reduction in pro-inflammatory markers (TNF-α, IL-1β, IL-6), primarily through downregulation of MAPK and TLR-4/NF-κB signaling pathways. Meta-analysis of in vitro data confirmed significant reductions in NO levels (−3.29 [95% CI: −5.21, −1.37]; p = 0.0008), IL-6 (−3.51 [−4.73, −2.29]; p < 0.00001), and TNF-α (−2.20 [−2.93, −1.48]; p < 0.00001). Similar anti-inflammatory profiles were observed in vivo across hepatic and splenic tissues. Interpretation: Evidence consistently demonstrates the potent anti-inflammatory activity of G. lucidum triterpenes, highlighting their potential as therapeutic candidates for inflammatory diseases. However, the structural complexity and isomer diversity of these compounds remain significant barriers to pharmacological standardization. Future research must prioritize clinical translation by investigating compound synergism, bioavailability, and long-term toxicity profiles, which were notably absent in current non-clinical literature. Full article

Animal-derived E. faecium poses a public health risk due to its capacity to acquire antimicrobial resistance (AMR) and virulence genes. However, the pathogenicity and cross-host transmission potential of strains originating from unique environments, such as the Qinghai–Tibet Plateau, remain poorly understood. In this study, a strain of E. faecium was isolated from yak feces. We constructed a phylogenetic tree and identified AMR and virulence genes via whole-genome sequencing. Antimicrobial susceptibility testing was performed to determine its resistance phenotype. An in vivo mouse infection model was established to assess pathogenicity, and transcriptomic analysis was utilized to investigate the host’s molecular response mechanisms in infected intestinal tissue. The results indicated that this yak-derived strain is closely related to human clinical isolates, suggesting a risk of cross-host transmission. The strain harbored the AMR genes AAC(6′)-Ii, msrC, and eatAv and exhibited resistance to penicillin, kanamycin, erythromycin, and clindamycin. The strain harbored key virulence genes, such as bopD, Acm, and ClpP. Infection with this strain caused characteristic inflammatory damage in mouse intestinal tissue, as revealed by histopathological examination, including epithelial necrosis, vascular congestion, and inflammatory cell infiltration. Transcriptomics further delineated a complete “Recognition–Response–Damage” signaling axis: pathogen recognition through Toll-like receptors and NOD-like receptors activates the NF-κB and MAPK signaling pathways. This activation is accompanied by significant upregulation of various inflammatory factors and recruits immune cells via chemokine signaling, ultimately leading to tissue damage. Our findings provide insights into the pathogenic pathway of this strain from genetic determinants to phenotypic manifestations, providing a theoretical foundation for assessing the public health risk posed by animal-derived E. faecium and for developing targeted intervention strategies. Full article

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq/PLC-MAPK, cAMP-CREB, G12/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1β-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment. Full article

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

The biological effects of radiofrequency electromagnetic fields (RF-EMFs) remain an unresolved scientific issue with important societal relevance, particularly in the context of the global deployment of fifth-generation (5G) wireless technologies. The skin is continuously exposed to both RF-EMFs and ultraviolet (UV) radiation, a well-established inducer of oxidative stress and DNA damage, making it a relevant model for assessing combined environmental exposures. In this study, we investigated whether post-exposure to 5G RF-EMFs (3.5 and 28 GHz) modulates ultraviolet A (UVA)-induced genotoxic stress in human keratinocytes (HaCaT) and murine melanoma (B16) cells. Post-UV RF-EMF exposure significantly reduced DNA damage markers, including phosphorylated histone H2AX (γH2AX) foci formation (by approximately 30–50%) and comet tail moments (by 60–80%), and suppressed intracellular reactive oxygen species (ROS) accumulation (by 56–93%). These effects were accompanied by selective attenuation of p38 mitogen-activated protein kinase (MAPK) phosphorylation (reduced by 55–85%). The magnitude of molecular protection was comparable to that observed with N-acetylcysteine treatment or pharmacological inhibition of p38 MAPK. In contrast, RF-EMF exposure did not reverse UV-induced reductions in cell viability or alterations in cell cycle distribution, indicating that its protective effects are confined to early molecular stress-response pathways rather than downstream survival outcomes. Together, these findings demonstrate that 5G RF-EMFs can facilitate recovery from UVA-induced molecular damage via redox-sensitive and p38-dependent mechanisms, providing mechanistic insight into the interaction between modern telecommunication frequencies and UV-induced skin stress. Full article

Brain-derived growth factor, BDNF, has critical roles in a wide variety of neuronal aspects, including cell survival, differentiation, and synaptic function after their maturation. TrkB, a high-affinity receptor for BDNF, is a major contributor in these neuronal aspects, and its functions are exerted via stimulating intracellular signaling pathways including the mitogen-activated protein kinase (MAPK) pathways. As a family of MAPKs, the functions of ERK1/2, p38MAPK, and JNKs have been extensively studied using in vivo and in vitro neuronal systems. ERK 1/2, a major serine-threonine kinase and belonging to the MAPK family, also works as a downstream molecule after activation of the BDNF/TrkB system. Interestingly, growing evidence has demonstrated that ERK1/2 signaling exerts a positive or negative influence on neurons in both healthy and pathological conditions in the central nervous system (CNS). Indeed, activation of ERK 1/2 stimulated by the BDNF/TrkB system is involved in the regulation of synaptic plasticity. On the other hand, overactivation of ERK1/2 signaling under pathological conditions is closely related to neurodegeneration. Furthermore, cell stress activates p38MAPKs and JNK signaling, contributing to the progression of neurodegeneration. In this review, we show how MAPK pathway signaling affects neuronal fate, including cell survival or cell death, in the CNS. Moreover, we discuss the involvement of overactivation of MAPK signaling in the neurodegeneration observed in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Full article

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and many patients cannot undergo curative surgery due to frailty. Multimodal prehabilitation: combining exercise, nutrition, and psychological support improves functional readiness, but its biological impact on the PDAC tumor microenvironment (TME) is unclear. In this exploratory pilot study, we profiled resected PDAC tissues from prehabilitation-treated patients and matched controls using NanoString GeoMx Digital Spatial Profiling across immune, tumor, and stromal compartments (n = 4). Transcriptomic signatures were analyzed via differential expression, pathway enrichment, and MCP-counter deconvolution; protein-level validation used multiplex immunofluorescence (n = 8). Ligand–receptor modeling assessed cell–cell communication, and prognostic relevance was evaluated in TCGA-PDAC (n = 178). Prehabilitation was associated with increased NK-cell cytotoxicity, interferon response, and chemokine recruitment, as well as higher neutrophil signatures (p < 0.01) and reduced fibroblast signatures (p < 0.05). Tumor regions showed lower MAPK and PI3K/AKT activity, while stroma exhibited decreased TGF-β and Wnt signaling. Immunofluorescence confirmed neutrophil infiltration and reduced fibroblast density. TCGA analysis linked neutrophil-high/fibroblast-low profiles to longer survival (1044.6 vs. 458.7 days, p = 0.0052). These findings suggest prehabilitation may promote a more immune-active, less fibrotic TME in PDAC, resembling transcriptional states associated with improved survival. Prospective studies integrating biological and clinical endpoints are warranted. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and abnormal α-synuclein aggregation. Circulating microRNAs (miRNAs) have emerged as promising biomarkers and potential modulators of PD-related molecular pathways. In this study, we investigated the expression levels of four candidate miRNAs—miR-15a-5p, miR-16-5p, miR-139-5p, and miR-34a-3p—in patients with PD compared with healthy controls. A total of 47 PD patients and 45 age- and sex-matched controls were enrolled. Plasma miRNA levels were quantified using standardized RNA extraction, cDNA synthesis, and qPCR protocols. We observed marked upregulation of miR-15a-5p and robust downregulation of both miR-139-5p and miR-34a-3p in PD patients, whereas miR-16-5p showed no significant difference between groups. Target gene prediction and functional enrichment analysis identified 432 unique genes, with enrichment in biological processes related to protein ubiquitination and catabolic pathways, and signaling cascades such as mTOR, PI3K-Akt, MAPK, and Hippo pathways, all of which are implicated in neurodegeneration. Elevated miR-15a-5p may contribute to pro-apoptotic mechanisms, while reduced miR-139-5p and miR-34a-3p expression may reflect impaired mitochondrial function, diminished neuroprotection, or compensatory regulatory responses. Together, these dysregulated circulating miRNAs provide novel insight into PD pathophysiology and highlight their potential as accessible, non-invasive biomarkers. Further longitudinal studies in larger and more diverse cohorts are warranted to validate their diagnostic and prognostic value and to explore their utility as therapeutic targets. Full article

Cataracts remain the leading cause of blindness worldwide, and surgery is currently the only effective clinical treatment, as no pharmacological therapy has yet been validated. Here, we explore Fullerenol, a hydroxylated fullerene derivative formulated as eye drops, as a potential nanomedicine for delaying cataract onset and progression. In UVB-induced mouse cataract models, topical Fullerenol preserved the lens transparency and histological structure. In human lens epithelial cells, Fullerenol reduced the oxidative stress, restored the mitochondrial function, alleviated the DNA damage, and suppressed the cellular senescence. RNA sequencing and pathway enrichment analyses further indicated that Fullerenol modulated the oxidative stress- and senescence-associated signaling pathways, including MAPK and TGF-β cascades, while downregulating the p53–CDKN1A (p21) axis. These findings provide new evidence that Fullerenol can mitigate photo-oxidative damage and age-related cellular dysfunction, highlighting its promise as a non-invasive and clinically translatable nanomedicine strategy for cataract management. Full article

Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are chronic inflammatory diseases that share immune dysregulation and mitochondrial dysfunction. Understanding the molecular mechanisms linking these diseases to mitochondrial dysfunction is crucial for developing novel diagnostic and therapeutic strategies. Datasets related to IBD and RA were obtained from the Gene Expression Omnibus database. Differentially expressed mitochondrial dysfunction-related genes (MDRGs) were identified using differential expression analysis. Weighted gene co-expression network analysis was performed to identify crosstalk genes (CGs). Logistic regression and support vector machine (SVM) models were constructed using least absolute shrinkage and selection operator regression to identify hub genes. Additionally, the differential expression and diagnostic value of the hub genes were verified using quantitative reverse transcriptase–polymerase chain reaction and validation sets. Finally, immune infiltration analysis was conducted to assess the role of immune cells in IBD and RA. A total of 87 CGs associated with mitochondrial dysfunction were identified between IBD and RA, among which PDIA4 and DUSP6 were identified as hub genes. Twenty proteins, including ERO1A, MAPK7, and P4HB, were identified as key proteins that interacted with PDIA4 and DUSP6. The area under the curve (AUC) of the ROC curves for IBD and RA based on the DUSP6 and PDIA4 diagnostic models were 0.664 and 0.856, respectively. The qRT-PCR results indicated that PDIA4 and DUSP6 were overexpressed in IBD and RA. Seven immune cell types, including activated B cells, activated dendritic cells, and eosinophils showed significant differences in the IBD and RA groups. Our findings highlight the close association between IBD, RA, and mitochondrial dysfunction. PDIA4 and DUSP6 may serve as potential biomarkers of mitochondrial dysfunction in patients with IBD and RA. Full article

Obesity, an escalating global health crisis, is characterized by adipose tissue hypertrophy and chronic low-grade inflammation. Although anti-obesity drugs can induce weight loss, their use is limited by adverse effects, underscoring the need for safer therapeutic strategies. In this study, we generated a recombinant form of Trichinella spiralis-derived macrophage migration inhibitory factor (rTs-MIF) and investigated its anti-inflammatory and anti-obesity effects via immunometabolic regulation. Male C57BL/6 mice fed a 45% high-fat diet were orally administered rTs-MIF, and its effects were evaluated by measuring fat mass, glucose metabolism, serum cytokines, liver histology, and adipose tissue parameters. In 3T3-L1 cells, we examined the effects of rTs-MIF on adipocyte differentiation, obesity-related gene expression, and intracellular signaling pathways. Oral rTs-MIF suppressed body weight gain, reduced fat mass, improved glucose levels, and decreased the food efficiency ratio. It also lowered pro-inflammatory cytokines and increased markers associated with M2 macrophages. In 3T3-L1 cells, rTs-MIF inhibited adipocyte differentiation and reduced the expression of lipogenic transcription factors and mouse Mif while modulating AKT and p44/42 MAPK signaling. These findings identify rTs-MIF as a potential bioactive candidate that ameliorates obesity by regulating the immune–metabolic axis. Full article

Background: Chronic kidney disease (CKD) represents a state of persistent, sterile low-grade inflammation in which sustained innate immune activation accelerates renal decline and cardiovascular complications. Diet-induced gut dysbiosis and intestinal barrier dysfunction lower mucosal immune tolerance, promote metabolic endotoxemia, and position the gut as an upstream modulator of systemic inflammatory signaling along the gut–kidney axis. Scope: Most studies address microbiota-derived metabolites, food-derived bioactive peptides, or omega-3 fatty acids separately. This review integrates evidence across these domains and examines their convergent actions on epithelial barrier integrity, immune polarization, oxidative-inflammatory stress, and inflammasome-dependent pathways relevant to CKD progression. Key mechanisms: CKD-associated dysbiosis is characterized by reduced short-chain fatty acid (SCFA) production and increased generation and accumulation of uremic toxins and co-metabolites, including indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, and altered bile acids. Reduced SCFA availability weakens tight junction-dependent barrier function and regulatory immune programs, favoring Th17-skewed inflammation and endotoxin translocation. Bioactive peptides modulate inflammatory mediator networks and barrier-related pathways through effects on NF-κB/MAPK signaling and redox balance, while omega-3 fatty acids and specialized pro-resolving mediators support resolution-phase immune responses. Across these modalities, shared control points include barrier integrity, metabolic endotoxemia, oxidative stress, and NLRP3 inflammasome activation. Conclusions: Although evidence remains heterogeneous and largely preclinical, combined nutritional modulation targeting these convergent pathways may offer greater immunomodulatory benefit than isolated interventions. Future multi-omics-guided, factorial trials are required to define responder phenotypes and translate precision immunonutrition strategies into clinical CKD care. Full article

Ziziphus jujuba is an important source of polysaccharides in food supply, and studies have demonstrated that polysaccharides serve as the principal active constituents responsible for immunomodulatory effects. The results indicated that “Huizao” polysaccharides (HP2-1) increased the viability and phagocytic activity of RAW264.7 cells and triggered immune responses by promoting cytokines TNF-α, IL-6, and IL-1β secretion, as well as NO and ROS production. In addition, HP2-1 also stimulated cytokine production, elevated immunoglobulin levels, and alleviated oxidative stress via increasing antioxidant enzyme activities and reducing MDA production in immunosuppressed mice. Furthermore, HP2-1 potentiated immune responses both in vitro and in vivo by modulating the TLR4/MAPK/NF-κB pathway due to upregulating TLR4 expression, leading to phosphorylation of ERK, JNK, and p38 MAPKs, thereby activating NF-κB and subsequent cytokine secretion. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC; diagnosed before age 50) is rising at an accelerated rate, with a disproportionate impact on underserved populations. While alterations in the receptor tyrosine kinase–RAS (RTK–RAS) signaling pathway play a fundamental role in colorectal cancer (CRC) biology, their prognostic significance in the setting of FOLFOX chemotherapy—particularly across different age groups and ancestral backgrounds—remains insufficiently characterized. We sought to characterize age-, ancestry-, and treatment-specific associations between RTK–RAS alterations and clinical outcomes using an AI-enabled precision oncology framework. Methods: We analyzed 2515 CRC cases, including 266 Hispanic/Latino (H/L) and 2249 non-Hispanic White (NHW) patients, stratified by age at onset, ancestry, and FOLFOX treatment status. Mutation frequencies were assessed using Fisher’s exact and chi-square tests, while overall survival was analyzed with Kaplan–Meier methods. The AI-HOPE and AI-HOPE–RTK–RAS conversational artificial intelligence platforms were used to integrate clinical, genomic, and treatment data via multi-parameter, natural language–based queries. Results: In early-onset Hispanic/Latino patients, ERBB2 and NF1 mutations occurred at significantly lower frequencies in FOLFOX-treated cases compared with untreated cases (p = 0.01 for both). In late-onset H/L patients, NTRK2 mutations were depleted in FOLFOX-treated tumors (p = 0.04). In untreated early-onset H/L patients, MAPK3 and NF1 mutations were enriched relative to NHW counterparts. Among early-onset NHW patients, IGF1R and ERRFI1 mutations were less frequent with FOLFOX exposure, while multiple RTK–RAS genes were reduced in FOLFOX-treated late-onset NHW patients. Survival analyses revealed worse overall survival in FOLFOX-untreated early-onset NHW patients with RTK–RAS alterations (p = 0.029), but improved survival in FOLFOX-treated late-onset NHW patients (p = 0.048). Conclusions: RTK–RAS pathway alterations demonstrate strong age-, ancestry-, and treatment-specific prognostic effects and may serve as precision biomarkers of differential chemotherapy response. AI-enabled analytics substantially accelerated integrative biomarker discovery, supporting their utility for advancing precision oncology in EOCRC. Full article