Search Results (5,489)

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and surgical repair primarily address symptoms or structural deficits without correcting the underlying biological limitations of tendon healing. Cell-based therapies have emerged as a promising regenerative approach aimed at restoring tissue homeostasis through modulation of angiogenesis, collagen synthesis, immune responses, and tenogenic differentiation. Mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), tendon-derived stem cells (TDSCs), induced pluripotent stem cells (iPSCs), differentiated tenocytes, and extracellular vesicle (EV)-based products have demonstrated the ability to enhance vascularization, promote type I collagen remodeling, suppress excessive inflammation, and stimulate tenocyte lineage commitment. These effects are mediated through paracrine signaling, growth factor secretion, and activation of key pathways, including HIF-1α, TGF-β/SMAD, NF-κB, and PI3K/Akt signaling. Despite promising preclinical data, significant translational challenges remain, including limited cell survival at the injury site, variability in cell sources and dosing, immunogenicity, risk of misdifferentiation, and lack of standardization across clinical protocols. Emerging strategies such as genetic modification, hypoxic preconditioning, scaffold-based delivery systems, and extracellular vesicle engineering aim to enhance therapeutic efficacy and reproducibility. This review synthesizes current evidence on cell-based tendon repair, critically evaluates mechanistic insights, clinical trials, and translational barriers, and outlines future directions toward biologically informed regenerative therapies. Full article

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions: DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy. Full article

Chronic diseases and aging-related disorders are driven by interconnected mechanisms, including oxidative stress, low-grade inflammation, metabolic dysregulation, and glycation. Targeting these overlapping pathways remains a major challenge for conventional single-target therapeutics. In this context, endophytic fungi have emerged as a promising source of bioactive metabolites with multi-target pharmacological potential. This review provides a mechanistic overview of endophyte-derived metabolites, including alkaloids, terpenoids, polyketides, and phenolic compounds, with a focus on their ability to modulate key signaling pathways such as NF-κB, Nrf2, PI3K/Akt, AMPK, and the AGE–RAGE axis. Evidence from experimental studies suggests that these metabolites exhibit anticancer, anti-inflammatory, antioxidant, and metabolic regulatory effects through coordinated modulation of cellular signaling networks. Several endophyte-derived metabolites also possess antimicrobial activity against bacterial and fungal pathogens and may represent a promising source of novel anti-infective agents. Their ability to modulate host immune responses and microbial-associated signaling pathways further highlights their relevance for antimicrobial discovery and microbiome-based therapeutic strategies. Particular attention is given to pathway-level convergence in chronic diseases, including cancer, diabetes, and inflammation-associated disorders, as well as their relevance to aging and health span. The pharmacological potential of these compounds is discussed alongside key limitations, including issues related to bioavailability, reproducibility, and translation into clinical applications. Overall, endophytic fungal metabolites represent a structurally diverse and mechanistically rich resource for the development of multi-target therapeutic strategies. Future integration of metabolomics, genome mining, and advanced disease models will be essential to bridge the gap between experimental findings and clinical application. Full article

Immune cells possess an intrinsic covalent signalling system in which endogenous electrophilic species function as molecular regulators of cellular state that integrate metabolic activity, oxidative stress, and inflammatory signals. Lipid peroxidation-derived electrophiles, enzymatically generated electrophilic lipid mediators, nitro-fatty acids, and metabolite-derived electrophiles selectively modify reactive amino acid residues within signalling proteins to regulate immune cell differentiation, metabolic adaptation, stress responses, and tissue responses. This perspective highlights that endogenous electrophilic signalling provides a biological blueprint for the development of next-generation precision covalent immunotherapeutics. Beyond exploiting electrophilic chemistry as a reactive pharmacological strategy, emerging insights reveal that immune cells naturally employ regulated covalent modifications to achieve stimulus-dependent control of signalling networks. Advances in chemoproteomics, structural biology, systems immunology, computational chemistry, and targeted delivery technologies are enabling the identification of electrophile-sensitive regulatory targets and the rational design of selective covalent modulators. The discussion includes how the principles derived from endogenous electrophilic signalling can guide therapeutic innovation across major immunotherapeutic areas, including chronic inflammatory diseases, cancer immunology, inflammasome-driven disorders, fibrotic disease, neuroinflammation, and vascular immunometabolic disorders. By translating endogenous covalent regulatory mechanisms into precision drug design strategies, electrophile-guided pharmacology offers an emerging strategy for developing therapies that reprogramme immune cell states, restore immune homeostasis, and achieve stimulus-dependent modulation of disease-associated immune responses. Full article

At present, there is no cure for the human genetic disorder ataxia-telangiectasia (A-T), which is managed by supportive care. This disorder arises due to mutations in the ATM (ataxia-telangiectasia mutated) gene and is characterised by a defect in the response to DNA damage, oxidative stress, mitochondrial dysfunction and immune deficiency. The ATM protein is activated by DNA damage, reactive oxygen species (ROS), and a variety of other stimuli, which leads to the phosphorylation or altered cellular localisation of multiple protein substrates that participate in cellular defence pathways. ATM plays a central role in orchestrating cellular defence against stress, which forms a focal point for approaches to treating the symptoms in this disorder. These strategies involve boosting mitochondrial function and dampening the inflammatory response. A more direct approach to treatment is gene therapy, yet the leading method using Adeno-Associated Virus (AAV) is hampered by the large size of the ATM gene itself. The use of antisense oligonucleotides (ASO) as an alternative gene therapeutic approach to treat patients has been increasingly utilised. However, only certain mutations fit the criteria for ASO-based intervention, which encourages rescue through readthrough of premature truncation mutations. For this reason, small-molecule-based therapies addressing the multi-system nature of the disease are urgently required. We address these different approaches to therapy and the outcome of numerous recent clinical trials with A-T patients, as well as ongoing research that has potential to lead to therapy. Full article

Skeletal muscle retains adaptive information from previous mechanical loading, enabling faster responses to subsequent training and regenerative challenges. This review synthesizes current evidence on the cellular and epigenetic mechanisms underlying skeletal muscle memory and examines how these mechanisms are modified by aging and post-injury regeneration. Muscle memory emerges from complementary structural and molecular components, including myonuclear retention, persistent DNA methylation changes, chromatin remodeling, transcriptional priming, non-coding RNA regulation, and mitochondrial epigenetic adaptations. These mechanisms interact with muscle satellite cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and extracellular matrix remodeling to maintain regenerative competence. During aging, epigenetic drift, chronic low-grade inflammation, altered macrophage states, MuSC dysfunction, persistent FAP activity, fibrosis, mitochondrial impairment, and anabolic resistance progressively reduce this plasticity, thereby contributing to sarcopenia. Training–detraining–retraining studies indicate that parts of the exercise-induced epigenetic landscape remain detectable after training cessation and can be reactivated during renewed loading, although the persistence and functional importance of individual molecular signatures remain incompletely defined. Physical exercise remains the most established intervention for preserving muscle function and epigenetic responsiveness, whereas caloric restriction, modulation of nutrient-sensing pathways, senolytic strategies, and direct targeting of epigenetic regulators remain promising but translationally less mature approaches. Overall, the preservation of epigenetic plasticity may be a key determinant of healthy skeletal muscle aging and effective regeneration. Full article

Calcium ions (Ca²⁺) function as ubiquitous second messengers that translate environmental and developmental cues into spatially and temporally defined cellular responses in plants. This review summarizes the cellular architecture and molecular mechanisms that generate, shape, and terminate Ca²⁺ signals, with emphasis on plasma-membrane channels, intracellular stores, pumps, exchangers, and organelle-associated transport systems. We also examine the development of live Ca²⁺ indicators, from chemical dyes and aequorin to ratiometric and single-fluorophore genetically encoded calcium indicators, and discuss principles for selecting sensors for different tissues and subcellular compartments. Recent studies have applied these tools to abiotic stress, plant immunity, polar growth, development, symbiosis, and systemic signaling. Accurate quantitative imaging nevertheless requires careful matching of sensor properties to the target cellular environment and rigorous control of motion, spectral interference, and analytical procedures. Combining improved indicators with advanced microscopy, genetic validation, and standardized data analysis should help connect distinct Ca²⁺ signatures with their molecular origins and physiological roles. Full article

Rainbow trout (Oncorhynchus mykiss) is an important cold-water aquaculture species and a tractable salmonid model for functional genomics. Rapid advances in chromosome-level genome assemblies, genetic variation resources, regulatory annotations, tissue and cell models, controlled challenge systems, and genome-editing technologies have established an increasingly integrated framework for linking genomic variation with measurable phenotypes. Evidence from studies of mucosal immunity, disease-resistance genetics, and environmental stress responses indicates that these resources can improve candidate-gene prioritization and mechanistic interpretation across molecular, cellular, tissue, and whole-fish levels. However, differential gene expression, quantitative trait locus and genome-wide association signals, genomic predictions, and cell-type localization remain largely associative and rarely provide direct evidence of causality. Interpretation is further complicated by salmonid-specific whole-genome duplication, because retained paralogues may exhibit tissue-specific divergence, functional redundancy, and compensatory responses. Further progress will require the integration of pangenomics, regulatory annotation, single-cell and spatial analyses, and paralogue-aware functional perturbation in both cell-based and whole-fish systems. Such integration will strengthen causal inference, clarify genotype–phenotype relationships, and support disease-resistant breeding, healthy aquaculture, and environmental risk assessment. Full article

Klebsiella pneumoniae infection following H9N2 Influenza A virus (IAV) infection causes severe pneumonia. But the underlying pathogenic mechanisms of H9N2 IAV and K. pneumoniae co-infection are complex and need to be further explored. In this study, the lung transcriptomes of mice with H9N2 IAV and K. pneumoniae co-infection were characterized by transcriptomic profiling. As a result, GO enrichment analysis revealed that the differential genes were primarily involved in the activation of immune responses, cellular components of membranes and extracellular spaces, and defense responses against pathogen infections. According to KEGG enrichment, the differentially expressed genes (DEGs) were concentrated in TLR signaling pathways, RLR signaling pathways, TNF signaling pathways and NLRP3 signaling pathways. Furthermore, in vitro cell models were established to investigate the innate immune responses induced by H9N2 IAV and K. pneumoniae CPS co-stimulation. K. pneumoniae CPS stimulation influenced the cytokine profiles of mink lung epithelial cells infected with H9N2 IAV, worsened cell viability, and aggravated apoptosis, indirectly inhibiting H9N2 IAV replication. The findings demonstrated that K. pneumoniae superinfection modulated the innate immune responses induced by H9N2 IAV infection, contributing to its pathogenesis. Full article

Prostate cancer is formed of a heterogeneous population of cancer cells with different biological properties. They initially form a small part of the normal stromal microenvironment but are able, through cell-to-cell contact and via exosomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, and chemokines and cytokines, to transform the normal stromal cells into tumour-associated cells to create an immunosuppressive environment as well as inhibit the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement membrane but also the extracellular matrix, allowing the exosomes to disseminate via the circulation. Exosomes are organotrophic, homing in to specific tissues such as bone. Here, they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environment, as well as induce changes in the host cells and produce myeloid-derived suppressor cells, of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response, they are able to implant in the premetastatic niche, transforming it into the metastatic niche. Here, they enter a latent state or dormancy period, which may last for months or years but later can “awake” to form metastasis. This review critically analyses the cellular and molecular mechanisms, which produce this process from cellular aspects to the signalling pathways responsible for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells, from cellular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNAs and long non-coding RNAs in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survival at 10 years. Therefore, a precision medical approach may improve the biochemical free survival rate without affecting the role of the signalling pathways in normal cells. This includes the modulation of interleukin expression, elimination of exosomes, or the inhibition of important enzymes, such as MMP-2, thus mitigating the residual recurrence risk that persists with conventional therapy. Full article

Primary membranous nephropathy (pMN) is an antibody-mediated podocytopathy, most commonly caused by autoantibodies against the M-type phospholipase A2 receptor (PLA2R1). Rituximab (RTX), an anti-CD20 monoclonal antibody, is a first-line treatment for moderate-to-high-risk pMN, inducing partial or complete remission in about 60% of patients within 24 months. However, treatment response varies considerably, and current biomarkers, including anti-PLA2R1 titers and peripheral B cell counts, have limited predictive value for non-response or relapse. Beyond B cell depletion, RTX exerts broader immunomodulatory effects by influencing T cell subsets, monocytes, and natural killer (NK) cells involved in antibody-dependent cellular cytotoxicity. This review examines the peripheral immune cell changes that accompany anti-CD20 therapy and their value as candidate biomarkers. Total CD19+ B cell depletion is the standard pharmacodynamic measure of drug effect but correlates only loosely with clinical outcome. A specific B cell reconstitution profile was associated with pending relapse. Class-switched memory B cells remain depleted during sustained remission, and their premature re-expansion has been associated with subsequent relapse. Regulatory T cells are reduced in active disease and rise within days of infusion in patients who later respond. The systemic inflammation response index, derived from the routine differential count, has been associated with both 6- and 12-month remission. These observations derive from small, mostly single-center cohorts using heterogeneous panels and different RTX regimens. On the available evidence, immune cell profiling cannot yet be recommended for routine disease monitoring, and larger prospective studies with standardized panels are required. Full article

Colorectal cancer progression and therapeutic response are determined not only by tumor-intrinsic programs but also by neural, stromal, and immune components of the tumor microenvironment. However, biologically interpretable transcriptomic scores that jointly capture neural/stromal remodeling and immune activation remain limited. We developed a neuro-immune score (NIS), defined as the neural/stromal module score minus the immune activation module score. NIS was constructed using the combined TCGA-COAD/READ colorectal cancer cohort and externally evaluated in independent Gene Expression Omnibus (GEO) datasets. Single-cell RNA sequencing, focused ligand–receptor analysis, and spatial transcriptomics were further integrated to characterize the cellular origins, spatial organization, and potential mechanisms underlying NIS-associated biology. A high NIS (NIS-high) was associated with adverse prognosis in bulk transcriptomic cohorts. External validation demonstrated that a high NIS was significantly associated with worse disease-free survival/relapse-free survival (DFS/RFS) in GSE39582 and worse overall survival in GSE17536. A multi-cohort meta-analysis further supported a consistent association between NIS-high and poor clinical outcomes. Single-cell analysis localized the NIS-high signal mainly to glial-like cells, fibroblasts, pericytes, endothelial cells, and malignant epithelial cells, whereas CD8+ T cells and natural killer cells exhibited low NIS. Focused ligand–receptor analysis suggested that NIS-high cellular compartments may communicate with immune and tumor compartments through MIF-CD74/CXCR4, SPP1-CD44, extracellular matrix (ECM)–integrin, TGF-β, and immune checkpoint-related axes. Spatial transcriptomics further demonstrated that NIS-high regions were enriched in stromal, neural/glial-like, vascular/pericyte, and tumor–stromal niches, whereas NIS-low regions were associated with immune-activated and cytotoxic T/NK cell-rich areas. NIS captures a spatially organized state of the colorectal cancer microenvironment characterized by neural/stromal remodeling, activation of ECM and vascular/pericyte niches, and relatively reduced or spatially segregated immune activation. NIS may serve as a biologically interpretable microenvironment stratification score associated with adverse outcomes. It also provides a framework for future studies targeting stromal remodeling, myeloid-mediated immune regulation, neural-associated signaling, and antitumor immunity. Full article

Gyrovirus homsa1 (GyH1) causes immunosuppression and multi-organ damage in young poultry. The VP1 capsid protein (VP1) is a key target for subunit vaccine development; however, recombinant VP1 alone elicits limited immunogenicity and requires an efficient delivery system. Here, we developed a liposomal formulation associated with the GyH1 VP1 protein (LNP-VP1) and evaluated its immunogenicity and preliminary safety in specific-pathogen-free chickens. The prepared LNP-VP1 had a mean particle size of 230.11 ± 5.95 nm, a polydispersity index of 0.204 ± 0.023, a zeta potential of −36.55 ± 0.99 mV, and an apparent encapsulation efficiency of 84.03% ± 2.10%. In addition, immunization of chicks with LNP-VP1 induced robust antigen-specific IgG responses and significantly enhanced the infiltration of CD4⁺ and CD8⁺ T cells in the spleen. Furthermore, cytokine analysis revealed upregulation of IFN-γ, IL-4, and IL-17 levels following vaccination. Importantly, no vaccine-associated histopathological changes were observed in major immune or metabolic organs after immunization. Overall, LNP-VP1 effectively elicited both humoral and cellular immune responses with a favorable safety profile, indicating its potential as a candidate vaccine against GyH1 and providing experimental evidence supporting lipid nanoparticles as a delivery platform for avian subunit vaccines. Full article

Despite substantial progress in biomarker discovery and multi-omics profiling, several features of Alzheimer’s disease (AD), including prolonged compensated states, heterogeneous clinical trajectories, and marked stage-dependent therapeutic responses, remain difficult to integrate into a single mechanistic framework. In this review, we propose an integrative and testable conceptual framework that reframes AD as a single, progressive multi-layer network disorder whose dynamics arise from hierarchical constraint propagation and progressive loss of cross-scale coordination. Integrating evidence from human genetics, epigenomics, transcriptomics, proteomics, metabolomics, spatial biology, connectomics, and longitudinal biomarker studies, we examine how molecular, cellular, and circuit-level processes interact over time to shape disease progression. Within this framework, different omics measurements are interpreted as complementary representations of disease-related changes, rather than as independent molecular signatures. Disease progression reflects the gradual convergence of immune, metabolic, proteostatic, cytoskeletal, and synaptic stress, with overt cognitive impairment emerging when compensatory capacity is exceeded, producing threshold-like network destabilization. By explicitly linking biological scale, temporal hierarchy, and network structure, this synthesis extends prior network-medicine, connectomic, and multi-omics approaches into a testable framework for state-aware stratification, integrative analysis, and stage-appropriate therapeutic investigation in AD. Full article

Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), remains a major global health challenge. The prolonged duration of treatment and the emergence of multidrug-resistant strains have highlighted the need for alternative therapeutic strategies. This study investigated the therapeutic potential of Ag85A aptamer-conjugated PEGylated niosomes encapsulating ethanolic extract of propolis (Ag85A-PEGNio/EEP) using Mtb-infected macrophage model. Ag85A-PEGNio/EEP exhibited efficient cellular uptake, with more than 99.8% internalization by macrophages, and trafficked host phagolysosome, facilitating targeted delivery of EEP to intracellular Mtb. Ag85A-PEGNio/EEP treatment showed an anti-mycobacterium efficacy by reducing intracellular Mtb viability by approximately 51.2% compared with untreated controls. Moreover, Ag85A-PEGNio/EEP modulated macrophage immune responses by significantly increasing the expression of the pro-inflammatory cytokines IL-12 (8.4-fold) and IL-6 (3.8-fold), while markedly decreasing the expression of the anti-inflammatory cytokine IL-10 (6.4-fold). Protein–protein interaction (PPI) network analysis further revealed the association of proteins with immune regulation and antioxidant responses in treated cells. These findings suggest that Ag85A-PEGNio/EEP functions as a dual-action therapeutic platform by enhancing intracellular anti-mycobacterial activity while balancing host immune responses. This targeted nano-delivery system represents a promising candidate for host-directed TB therapy and further investigations are needed to validate these outcomes and explore their potential applications against TB treatment challenges. Full article