Search Results (1,295)

Glatiramer acetate (GA) is a first-line disease-modifying therapy for multiple sclerosis (MS) with well-established moderate efficacy and high safety, yet its mechanisms of action remain incompletely understood. DNA methylation plays a significant role in MS development and is modulated by various environmental factors, including therapeutic drugs. In this pilot study, we report the first prospective analysis of genome-wide DNA methylation changes in peripheral blood mononuclear cells (PBMCs) from four female relapsing-remitting MS patients before GA initiation and after approximately four and eight months of therapy. We identified 365 loci that are characterized by differential methylation, distinguishing post-treatment time points from baseline, with significant enrichment in CpG islands, shores, and promoter regions. Two distinct temporal patterns emerged: (1) non-monotonic DNA methylation changes peaking at four months and associated with response to foreign antigenic stimuli, and monotonic changes progressively increasing by eight months and related to mTOR-associated pathways relevant to chronic inflammation and neurodegeneration. Integration of DNA methylation and transcriptomic data revealed significant methylation-expression correlations for eight genes, including HLA-DMA, PDE4A, and SMOX—genes with established roles in MS-associated antigen presentation, immunoregulation, and neuroinflammation. Cell composition of PBMCs remained stable throughout treatment. In general, GA therapy for MS appears to induce dynamic, locus-specific DNA methylation changes in PBMCs, with distinct temporal patterns suggesting a biphasic response of the immune system. However, given that none of the individual DMPs reached genome-wide significance, the results presented in this pilot study strongly require validation in larger independent cohorts. Nevertheless, we believe that our findings provide insights into the immunomodulatory effects of GA and lay the foundation for future hypothesis-driven studies to develop epigenetic biomarkers for therapeutic monitoring and generic GA product assessment. Full article

Background/Objectives: Gliomas are among the most aggressive primary brain tumors in adults, characterized by profound molecular heterogeneity and poor response to conventional therapies. Immunotherapy has transformed outcomes in several cancers, yet glioma remains largely refractory, due in part to an immunosuppressive tumor microenvironment. Post-transcriptional regulation of gene expression is increasingly recognized as a key mechanism controlling immune cell function in tumors. Regnase-1, an endoribonuclease regulating the stability of inflammation- and immunity-related mRNAs, is a central modulator of immune responses; however, its role in glioma progression and immune modulation remains poorly understood. This study aimed to evaluate Regnase-1 expression in glioma and investigate its association with tumor grade, prognosis, and immune microenvironment characteristics. Methods: Regnase-1 transcript levels were evaluated by RT-PCR in tumor samples from 40 Moroccan glioma patients and validated using transcriptomic data from The Cancer Genome Atlas (TCGA, n = 672) and the Chinese Glioma Genome Atlas (CGGA, n = 959). Bioinformatic analyses and statistical assessments were performed using established pipelines. Results: Regnase-1 expression was significantly elevated in glioblastoma, IDH-wildtype tumors, and higher tumor grades, correlating with poorer overall survival, and emerging as an independent prognostic factor in the CGGA cohort. High Regnase-1 expression was associated with enrichment of pathways related to angiogenesis, hypoxia, invasion, and immune evasion. Tumors with elevated Regnase-1 showed reduced infiltration of effector immune cells (CD8⁺ T cells, Th1 cells) and increased presence of immunosuppressive populations, including regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages. Single-cell analyses further highlighted exhausted CD8⁺ T cells and regulatory T cells as major populations linked to Regnase-1 expression. Notably, Regnase-1 expression also exhibited strong positive correlations with multiple inhibitory immune checkpoint pathways. Conclusions: Elevated Regnase-1 expression defines an aggressive, immunosuppressive glioma phenotype and is associated with poor prognosis, supporting its potential as a prognostic biomarker and a target for immunomodulatory strategies. Full article

In recent years, the rapid rise of antimicrobial resistance has intensified the search for alternative agents to treat drug-resistant infections. Antimicrobial peptides (AMPs) are promising therapeutic candidates due to their broad-spectrum activity, diverse mechanisms of action, relatively low risk of resistance development, and potential for use in combination therapies. This review outlines current knowledge on the properties and mechanisms of action of AMPs compared to conventional antibiotics. Furthermore, it discusses synergistic interactions between antimicrobial peptides and antibiotics, focusing on the underlying mechanisms, therapeutic implications, and translational challenges. It also summarizes key in vitro and in vivo studies, demonstrating enhanced antimicrobial efficacy of AMP–antibiotic combinations, including mechanisms such as increased membrane permeability, disruption of intracellular pathways, inhibition of biofilm formation, and efflux pump inhibition. The immunomodulatory and wound-healing properties of AMPs are also highlighted as factors that further strengthen their therapeutic potential in vivo. The review concludes with an overview of the main limitations hindering clinical translation and highlights ongoing research efforts aimed at optimizing AMP-based combination therapies against multidrug-resistant pathogens. Full article

Acute non-typhoidal salmonellosis (NTS) from non-typhoidal Salmonella remains a major cause of foodborne bacterial gastroenteritis, and non-antibiotic interventions are needed to combat multidrug-resistant NTS. Bioactive compounds from edible mushroom extracts have shown both direct and indirect antimicrobial activities on Salmonella. However, the variation in their antimicrobial activity could be due to several factors, including the extract’s form and strain. This study investigated the ability of crude exopolysaccharides (EPs) produced by Schizophyllum commune CMU-01 to limit Salmonella infection in vitro. Agar well diffusion and liquid culture were used to determine the direct anti-Salmonella activity of S. commune EPs, while the gentamicin protection assay and qPCR in human gut epithelium (T84 cells) and murine macrophages (RAW264.7 cells) were used to investigate its indirect (immunomodulatory) activity. Our data reveal that S. commune EPs do not confer the direct antimicrobial property against Salmonella. However, its immunomodulatory activity in two important components of the gut innate defense (the gut epithelium and macrophages) against Salmonella infection has been demonstrated. S. commune EPs reduce Salmonella gut epithelial cell invasion and activate macrophages toward M1 (inflammatory phenotype) polarization, resulting in the reduction in intracellular Salmonella burdens. Alterations in proinflammatory and anti-inflammatory cytokine gene expressions were also detected in S. commune EPs-treated cells. These findings suggest that the host innate immune response to fungal exopolysaccharides derived from S. commune CMU-01 favors reducing Salmonella proliferation within host cells by altering the expression levels of proinflammatory cytokines. Full article

Mesenchymal stromal cells (MSCs) are multipotent cells characterized by their regenerative capacity and strong immunomodulatory properties. In recent years, MSC-based therapy has attracted significant attention as a potential treatment for a wide range of immune-mediated and degenerative diseases. The therapeutic effects of MSCs are primarily mediated through paracrine signaling and secretion of cytokines that regulate immune responses and promote tissue repair. This review focuses on five key cytokines involved in MSC immunomodulation: interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). These cytokines interact within a complex signaling network that allows MSCs to suppress excessive inflammation and restore immune balance. The role of MSC therapy is examined in several clinically relevant conditions, including systemic lupus erythematosus, systemic sclerosis, ischemic stroke, spinal cord injury, diabetes mellitus, and female infertility. Across these diseases, MSCs demonstrate the ability to inhibit pro-inflammatory immune cell activity, promote regulatory immune phenotypes, reduce oxidative stress, and stimulate regeneration through the secretion of growth factors and extracellular vesicles. Despite promising experimental and early clinical findings, several limitations remain, including variability in MSC sources, limited cell survival after transplantation, and the need for optimized dosing strategies. Overall, MSC therapy represents a multifunctional therapeutic approach combining immunomodulation, anti-inflammatory activity, and regenerative support. Further research is required to better understand cytokine interactions, improve standardization of MSC-based treatments, and enhance clinical efficacy across diverse pathological conditions. Full article

Capsaicin has been investigated as a phytogenic feed additive in animal production due to reported growth-promoting and immunomodulatory properties; however, its pungency limits practical application. Capsiate, a naturally occurring non-pungent capsaicin analog present in specific Capsicum annuum accessions, conserves many of its bioactive properties without inducing sensory irritation and has not been studied as a potential growth-promoting alternative. The present study evaluated whether dietary exposure to a capsiate-producing chili pepper influences growth and assessed associated intestinal responses using a murine model. A capsiate-producing Capsicum annuum accession (509-45-1) was characterized and incorporated into experimental diets providing 30 or 50 mg/kg capsiate to male C57BL/6J mice for 12 weeks. The dietary intervention was associated with dose-dependent increases in body weight and longitudinal femoral growth without altering body composition. Femoral elongation was accompanied by increased growth plate area and higher osteocyte number and area. At the intestinal level, the intervention was associated with downregulation of colonic transient receptor potential vanilloid 1 (TRPV1) gene expression, modulation of redox-associated responses, including catalase (CAT) and superoxide dismutase (SOD) expression, and differential modulation of innate immune signaling, including upregulation of Toll-like receptor 2 (TLR2) and downregulation of Toll-like receptor 4 (TLR4), together with reduced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) expression. Collectively, these findings indicate that dietary supplementation with a capsiate-producing chili is associated with increased somatic growth and enhanced femoral development in mice, accompanied by intestinal transcriptional changes consistent with immunometabolic responses, while preserving body composition. Full article

Post-infectious bronchiolitis obliterans (PIBO) is a severe chronic airway disease in children following lower respiratory tract infections. Human adenovirus (HAdV) and Mycoplasma pneumoniae (MP) are the major associated pathogens, with geographic variations in their relative importance. This review analytically compares the mechanistic divergence and convergence between HAdV and MP. Both pathogens converge on MyD88/NF-κB/MAPK signaling and neutrophil-driven inflammation, but diverge in initial host engagement (CAR/integrins vs. TLR2/6 and CARDS toxin) and inflammasome activation (TLR9-related vs. NLRP3-related). This review aims to propose an integrative model linking acute immune activation to fibrotic bronchiolar narrowing and to evaluate the risk factors for PIBO. Genetic susceptibility and epigenetic regulation help explain population differences in PIBO risk and geographic distribution. Despite progress, significant knowledge gaps remain, including the lack of single-cell resolution studies, the absence of co-infection animal models, and uncertainty regarding the long-term efficacy of targeted immunomodulatory therapies. Addressing these gaps is essential for improving early diagnosis and clinical outcomes. Full article

Cardiovascular diseases remain the leading cause of mortality in developed countries. Among these conditions, acute myocardial infarction (AMI) is associated with particularly high rates of cardiac morbidity and mortality. Cardiac development in mammals is primarily dependent on cardiomyocyte (CM) proliferation during embryonic and early postnatal stages. However, following birth, the proliferative capacity of CMs declines markedly, with only limited cellular renewal occurring during adult life in response to pathological injury. Consequently, the irreversible loss of functional cardiomyocytes and the subsequent formation of fibrotic scar tissue frequently lead to persistent cardiac dysfunction and progressive impairment of cardiac physiology. Cardiomyocyte self-renewal is a tightly regulated process involving multiple molecular pathways. Among factors implicated in this regulation, microRNAs (miRNAs) have emerged as key modulators coordinating both cardiac development and tissue repair mechanisms. In this context, extracellular vesicles (EVs) have attracted considerable interest as potential modulators of these regenerative processes. In particular, mesenchymal stromal cells (MSCs) represent a promising therapeutic platform due to their immunomodulatory and anti-fibrotic properties demonstrated across multiple in vitro and in vivo models. Furthermore, the therapeutic potential of MSC-derived EVs can be enhanced through bioengineering approaches aimed at improving targeted molecular delivery. In this review, we summarize recent advances in the development and application of EV-based therapeutic strategies, with particular emphasis on their potential use as advanced therapy medicinal products (ATMPs) for cardiovascular regeneration and repair. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, which ultimately leads to hepatic fibrosis and cirrhosis. The current first-line therapy, ursodeoxycholic acid, is associated with a high rate of non-response. Moreover, second-line treatments are constrained by variable efficacy and safety concerns. Mesenchymal stem cells (MSCs), owing to their potent immunomodulatory and tissue-repairing capabilities, represent a promising new therapeutic strategy for PBC patients with poor response to conventional therapies. This review systematically outlines the pathogenesis of PBC, focusing on factors including genetics, environment, and immune dysregulation. Furthermore, it examines recent evidence on the mechanisms by which MSCs and their derivatives, such as exosomes, may intervene in PBC progression through immunomodulation, anti-fibrotic effects, and potential hepatic differentiation. This paper also reviews the current status and challenges of the clinical translation of MSCs therapy, and proposes that engineered modification and standardized preparation are the key directions to promote its application. In conclusion, this review provides a theoretical foundation and future directions for deepening the understanding of PBC pathogenesis and developing novel MSC-based therapeutic strategies. Full article

Mesenchymal stromal cells (MSCs), also known as multipotent stromal cells or mesenchymal stromal cells, support cell growth and viability through the secretion of trophic factors and immunomodulatory molecules. Their secretome exerts cytoprotective effects in the brain, although the mechanisms underlying MSC-mediated neurological recovery remain poorly understood. A substantial portion of the MSC secretome is delivered via extracellular vesicles (EVs), membrane-bound particles that facilitate intercellular communication. EVs derived from MSCs of various origins exhibit therapeutic potential, and numerous studies are examining the miRNA and protein cargo contained within MSC-EVs. Despite these efforts, methodological differences across the literature and the inherent variability associated with MSC sources have limited data interpretation and identification of EV-factors which may be responsible for neuroprotection. In this study, we have reviewed proteomic, transcriptomic and lipidomic datasets from a selection of recent MSC-EV studies, to identify shared cargo components that may contribute to promoting cell repair and plasticity in brain, counteracting neurodegeneration. Full article

Immunotherapy has emerged as an established clinical approach for lung cancer; however, both intrinsic and adaptive resistance mechanisms substantially constrain its therapeutic efficacy. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) serve as pivotal stromal mediators of this resistance. These fibroblasts manifest their immunomodulatory effects, in part, through the secretion of small extracellular vesicles (sEVs). While multiple lines of evidence strongly implicate CAF-sEVs in immunotherapy resistance, establishing a direct causal link remains an active area of investigation. Clinically, elevated levels of specific CAF-sEV cargoes correlate with poor response in lung cancer patients. Functionally, CAF-sEVs can directly suppress T-cell activity and drive pro-resistance phenotypes via defined molecular pathways, and pharmacological inhibition of sEV secretion has been shown to attenuate resistance in preclinical models. However, the extent to which these effects are independent of other CAF-derived factors remains to be fully elucidated in vivo. This review comprehensively synthesizes the biophysical properties of CAF-derived sEVs, delineates the molecular mechanisms underpinning their role in immunotherapy resistance, critically evaluates the existing causal evidence and its limitations, and assesses their translational potential as diagnostic biomarkers and therapeutic targets—ultimately providing a conceptual framework to overcome resistance barriers in lung cancer immunotherapy. Full article

Platelet-rich gel supernatants (PRGS) are increasingly used in veterinary medicine due to their regenerative and immunomodulatory properties; however, most studies focus on individual mediators and provide limited insight into their coordinated biological behavior. This study aimed to characterize the integrated inflammatory–regenerative signatures of bovine PRGS stored under different temperature conditions using a multivariate approach. Concentrations of transforming growth factor beta-1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), and interleukin-6 (IL-6) were evaluated in PRGS samples from six clinically healthy cows stored at −80, −20, 4, 21, and 37 °C for up to 326 h. Data were standardized and explored using hierarchical clustering and heatmaps, and principal component analysis (PCA) based on area under the concentration–time curve (AUC) was used to integrate temporal behavior. Temperature-dependent multivariate signatures were identified, with frozen PRGS clustering separately from samples stored at moderate temperatures. The first two principal components explained 43.0% and 28.9% of the variance and defined an inflammatory–regenerative gradient contrasting TGF-β1/IL-2 versus TNF-α/IL-6 profiles. Linear mixed-effects modeling showed that PC1 was significantly affected by temperature and time (p < 0.001), whereas PC2 was influenced by temperature, time, and their interaction (p ≤ 0.048). Differences among temperatures were minimal at early time points but became more pronounced from 48 to 96 h onward, following a temperature gradient with higher values at moderate temperatures and lower values under frozen conditions. These findings indicate that storage temperature reshapes the integrated biological profile of PRGS, rather than merely preserving mediator composition. Full article

Background: Tumor-associated macrophages (TAMs) are key components of the hepatocellular carcinoma (HCC) microenvironment, but their spatial heterogeneity remains incompletely characterized. We aimed to assess the biological and prognostic relevance of a BAG3-associated TAM program in HCC. Methods: Public single-cell RNA sequencing (scRNA-seq) datasets were analyzed to characterize TAM heterogeneity, and an integrated validation scRNA-seq dataset was used to assess reproducibility. Spatial transcriptomics was used to provide spatial context in a small treatment-exposed cohort. Pseudotime, regulatory network, and cell–cell communication analyses were performed to characterize state transitions and microenvironmental interactions. Survival modeling evaluated the prognostic relevance of the BAG3-associated program. Results: Five TAM subsets were identified, including MARCO⁺, MT⁺ RTM−, MMP9⁺, UBE2C⁺, and BAG3⁺ TAMs. Among them, BAG3⁺ TAMs, a less well-characterized subset, exhibited coordinated stress-adaptive, proteostasis-related, and matrix-remodeling programs that were reproduced in the validation dataset. Pseudotime analysis suggested a continuum of TAM states, with BAG3⁺ TAM stress-remodeling features enriched toward late pseudotime. Communication analysis centered on BAG3⁺ TAMs suggested crosstalk between inflammatory stress cues and angiogenic, stromal-remodeling, and immunomodulatory programs; this pattern was primarily supported by HBV-derived samples and recurrently involved the MIF–CD74 axis. Spatial mapping further supported BAG3⁺ TAM-enriched niches with elevated AP-1, EGR1, and NFKB1 activity. A BAG3-associated risk score derived from a 10-gene signature remained an independent prognostic factor for overall survival after clinical adjustment. Conclusions: These findings characterize a BAG3-associated TAM program with spatial, immunoregulatory, and prognostic relevance in HCC, and support its further evaluation in biomarker and mechanistic studies. Full article

Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disorder marked by progressive cardiomyocyte loss, fibro-fatty replacement, ventricular arrhythmias, and risk of sudden cardiac death. Traditionally considered a structural and electrical disease driven by desmosomal dysfunction, emerging evidence redefines ACM as an inflammatory cardiomyopathy in which immune activation plays a central role. This review integrates genetic, molecular, experimental, and clinical data to highlight inflammation as a unifying feature of ACM. Desmosomal gene variants impair cell adhesion and also activate cardiomyocyte-intrinsic inflammatory pathways, including nuclear factor of kappa B (NFκB) and glycogen synthase kinase 3β (GSK3β) signaling, promoting cytokine release, immune cell recruitment, and fibrotic remodeling. Preclinical studies suggest inflammation precedes structural changes, indicating it may be an initiating event rather than a secondary response. Clinical and pathological findings support this model, with inflammatory infiltrates, circulating cytokines, and autoantibodies observed across disease stages. These processes often present as episodic “hot phases” resembling myocarditis, thus complicating diagnosis. The inflammatory landscape involves both innate and adaptive immunity, along with stromal and neuronal remodeling, contributing to arrhythmogenesis through gap junction disruption, calcium-handling abnormalities, and fibrosis. Environmental factors such as exercise, stress, and metabolic disturbances further modulate inflammatory pathways and disease expression. Therapeutically, this evolving perspective supports immunomodulatory approaches, including inhibition of NFκB, GSK3β, and cytokine signaling. Early clinical data on immunosuppressive and cytokine-directed therapies are promising, especially during active inflammatory phases, while gene-based strategies specifically address the underlying genetic defects. In conclusion, ACM should be recognized as an inflammatory cardiomyopathy shaped by interactions between genetic susceptibility and immune dysregulation. Integrating genetic and immunologic profiling may improve diagnosis, risk stratification, and treatment, ultimately leading to refined personalized therapeutic strategies. Full article

Aging is associated with chronic, low-grade inflammation (“inflammaging”), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer’s disease, and Parkinson’s disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug–drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT_2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT_2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin’s neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research. Full article