Search Results (379)

The pathogenic fungus Mycocentrospora acerina, responsible for Panax notoginseng round spot disease, poses a serious threat to the development of the P. notoginseng industry. To investigate its genetic information and potential pathogenic mechanisms, this study employed nanopore third-generation sequencing technology to conduct de novo genome sequencing and analysis of M. acerina, followed by an assessment of its plant cell wall-degrading enzyme activities. The sequencing results revealed that the M. acerina genome has a total length of 37.03 Mb, a GC content of 47.68%, an N50 value of 1.66 Mb, and a repeat sequence proportion of 9.37%. A total of 9989 protein-coding genes were predicted. Genome annotation identified 499 carbohydrate-active enzyme (CAZyme) family genes—more than those found in Botrytis cinerea (469), Phanerochaete chrysosporium (381), and Erysiphe necator (136). Moreover, M. acerina harbors a relatively large number of genes encoding plant cell wall-degrading enzymes. Experimental measurements of cell wall-degrading enzyme activities were consistent with the genomic predictions, demonstrating that M. acerina exhibits strong abilities to degrade cellulose, pectin, and lignin. This study provides new insights into the pathogenic mechanisms of M. acerina and establishes a theoretical foundation for developing potential control strategies for P. notoginseng round spot disease. Full article

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, a central innate immune sensor of cytosolic DNA, plays a dual role in immunoregulation within pulmonary diseases. Recent studies demonstrate its critical role in sensing microbial infections and tissue injury in the lung, allowing it to drive the production of type I interferons (IFN-I) and pro-inflammatory cytokines. While this pathway is essential for anti-viral defense and anti-tumor immunity, its dysregulation can exacerbate pathologies such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer, mainly through sustained inflammation and fibroblast proliferation. Nowadays, many cGAS-STING agonists and inhibitors are available to treat different diseases. This review comprehensively summarizes the basic mechanism of the cGAS-STING pathway, its diverse roles across various pulmonary diseases, and the current landscape of potential therapeutic strategies targeting this pathway. Notably, the critical role of the cGAS-STING signaling pathway in various lung diseases offers new avenues for therapeutic research. Full article

Tenascin-C (TNC) is a complex extracellular matrix (ECM) protein that plays a critical role in regulating cellular adhesion, motility, proliferation, and inflammation through its interaction with Toll-like receptor 4 (TLR4) and other receptors. The upregulation of TNC is associated with inflammatory responses, autoimmune disorders, and neoplastic conditions during both physiological and pathological tissue remodeling. In the central nervous system (CNS), TNC contributes to neuroinflammatory processes by modulating the function of immune cells and the secretion of pro-inflammatory mediators, thereby playing a pivotal role in the initiation and progression of neuroinflammatory diseases. TNC is expressed in astrocytes, neural progenitor cells, and various neuronal populations within both developing and mature CNS regions. It regulates neuronal migration and axonal guidance during neurogenesis, facilitating synaptic plasticity and CNS regeneration. Furthermore, TNC enhances neuroplasticity through interactions with receptor families, such as integrins, to establish the molecular connections necessary for cell communication and signal transduction. This review investigates the mechanistic properties of TNC, focusing on its spatiotemporal expression, molecular interactions with receptors, and its role in neurological disorders, in addition to its modulatory capacity in neuroplastic processes. Additionally, this review delves into recent research advancements with respect to neuroinflammation involving TNC, along with therapeutic strategies targeting TNC. Full article

The immunosuppressive and anti-inflammatory potential of mesenchymal stromal cells (MSCs) underpins their therapeutic value in musculoskeletal disorders. However, the underlying mechanisms remain ill-defined. Traditionally associated with immune cells, immunometabolism (the cellular metabolism–immune system interplay) is now recognized as central in a broader range of processes, including tissue homeostasis, repair, and chronic inflammation. Depending on the context and cell type, distinct metabolic pathways (e.g., fatty acid oxidation, lipid mediator biosynthesis) can drive pro-inflammatory/pro-resolving immune phenotypes. This dynamic is salient in musculoskeletal tissues: macrophage polarization, T-cell activation, and MSC immunomodulation are governed by metabolic cues. Emerging evidence highlights lipid-driven immunometabolism as a key player in MSC function, particularly in post-traumatic osteoarthritis (PTOA) and osteoporosis (OP). Unlike immune cells, MSCs rely on distinct metabolic programs (e.g., lipid sensing, uptake, and signaling) to exert context-dependent immunoregulation. In PTOA, persistent inflammation triggers lipid-centric metabolic pathways, enhancing MSC-driven immunomodulation and therapeutic outcomes. In OP, low-grade inflammation and altered lipid metabolism impair bone regeneration, modulating lipid-driven routes that can restore MSC osteogenic function and influence osteoclast precursors. This review explores how lipid-derived mediators and signaling contribute to MSCs’ immunosuppressive capacity, positioning lipid immunometabolism as a novel axis for rebalancing the inflamed joint microenvironment and encouraging musculoskeletal regeneration. Full article

Mesenchymal stromal cells (MSCs) exert their immunoregulatory properties after licensing by inflammatory signaling cues, e.g., interferon (IFN)-γ. However, MSCs licensing by IFN-γ may result in increased expression of human leukocyte antigen (HLA) class II, which is related to rapid cell elimination, impairment of their immunosuppressive properties, and patient sensitization. The aim of this study was to evaluate the impact of IFN-γ on mediated immunoregulation and HLA class II expression. In this study, Wharton’s jelly (WJ) MSCs were isolated from human umbilical cords. Well-defined WJ-MSCs were submitted to IFN-γ exposure, and after 96 h, evaluation of biomolecule secretion and HLA class II expression was performed. Typing of HLA alleles using a next-generation sequencing (NGS) platform was performed. IFN-γ-primed WJ-MSCs secreted a high amount of immunoregulatory biomolecules, while elevated expression of HLA-DRB1 was observed. Analyses the NGS results showed the possibility of WJ-MSCs cluster formation based on their frequency of detected HLA alleles and immunoregulatory potential. Taking into consideration that IFN-γ-primed WJ-MSCs express HLA class II alleles, it is suggested that the HLA histocompatibility between allogeneic donor and recipient should be strongly considered to acquire the most beneficial outcome for the MSCs therapeutic strategy. Full article

The early secreted antigenic target of 6 kDa (ESAT-6), a main effector molecule of the ESX-1 secretion system, is identified as a virulence determinant and immunoregulatory protein of Mycobacterium tuberculosis (Mtb), affecting the interaction between host immune cells and pathogens. ESAT-6 facilitates the survival of mycobacteria and their cell-to-cell spreading through membrane-permeabilizing activity and the regulation of host immune cell functions. In this review, we first summarize the recent knowledge of the roles of ESAT-6 in the survival of bacteria, phagosomal escape, and pathogenicity during Mtb infection. Then, we focused on its complex immunomodulatory effects on different immune cells, such as macrophages, dendritic cells, neutrophils, and T cells, accentuating its capability to either facilitate or inhibit immune responses through different signaling pathways. While our review has summarized its main roles in immunopathology in the context of tuberculosis, we additionally search for emerging evidence indicating that ESAT-6 has anti-inflammatory and immunosuppressive properties. Particularly, we discuss recent preclinical studies showing its capability to suppress transplant rejection and alloimmunity, probably via the induction of regulatory T cells. Nevertheless, the potential clinical use of ESAT-6 remains uncertain and needs further verification by comprehensive preclinical and clinical studies. Thus, we propose that ESAT-6 may be exploited to ameliorate immunopathology in TB infection and to suppress immune-mediated inflammation or transplant rejection as well. Full article

Immunoregulation is an emerging treatment strategy to promote wound healing by modulating the local immune system at the wound site. In this study, an extracellular matrix biomimetic and polysaccharide-based hydrogel was engineered to regulate the wound immune environment through Michael-type addition between maleimidyl pullulan and chitosan modified with hydroxyproline. The proposed hydrogel exhibited favorable injectable and self-healing properties, which facilitated the full coverage of irregularly shaped wounds. A natural polyphenol, epigallocatechin-3-gallate (EGCG), was incorporated into hydrogels, which thereby exhibited excellent biocompatibility, good reactive oxygen species (ROS) scavenging ability, anti-inflammatory activity, and antibacterial properties against S. aureus and E. coli. Furthermore, evaluations of a full-thickness skin defect mice model showed that the hydrogel with EGCG effectively alleviated the inflammatory response by reducing pro-inflammatory cellular infiltration and down-regulating the inflammatory cytokine TNF-α, while up-regulating anti-inflammatory cytokine IL-10. Notably, a faster wound healing rate was also achieved by the better promotion effect of the hydrogel on increasing the formation of re-epithelialization, granulation tissue generation, collagen deposition, and angiogenesis. Therefore, our immunoregulatory strategy showed great potential in the design of biomaterials for wound management. Full article

Breast cancer is one of the most frequently diagnosed malignancies and remains the leading cause of cancer-related death among women worldwide. Emerging evidence implicates the microbiota to be a potential contributor to its pathogenesis and progression. This review summarizes emerging evidence of microbial alterations across various body niches in breast cancer patients, including gut, breast tissue, nipple aspirate fluid (NAF), oral cavity, skin, urinary and reproductive tracts, and blood. Reductions in commensal taxa such as Faecalibacterium, Bifidobacterium, Lachnospira, Akkermansia, and Sphingomonas, along with an increase in pro-inflammatory genera like Prevotella, Fusobacterium, and Desulfovibrio, may promote breast tumor development and progression through multiple pathways including modulation of estrogen metabolism, production of microbial metabolites, and immunoregulation. The presence of cross-niche overlaps and possible translocation of microbiota between niches through the bloodstream suggests the existence of a complex interconnected oral–gut–breast microbiota axis. Progress in the field will depend on integrative multi-omics, translational approaches, and longitudinal studies to give a clearer mechanistic understanding of microbiota–host interactions to develop feasible microbiota-based biomarkers and therapeutic strategies in breast cancer. Full article

Artemisinin and its derivatives are widely recognized for their exceptional antimalarial efficacy. Recently, accumulating evidence indicates therapeutic potential beyond malaria. Despite these advances, detailed mechanisms and pharmacological limitations remain incompletely defined. This review summarizes their pharmacological activities and molecular mechanisms associated with oncology, immunoregulation, and metabolic disorders. Mechanistically, these compounds exert potent antitumor effects by inducing oxidative stress, arresting the cell cycle, triggering apoptosis, and inhibiting angiogenesis. They likewise modulate immune responses, re-establishing immune homeostasis and enhancing the effectiveness of immunotherapeutic strategies. Preliminary evidence also suggests involvement in metabolic regulation, pointing to promising avenues for treating metabolic disorders. Given alternative mechanisms of artemisinin and its derivatives, we also discuss the trinity modulation network among antitumor activity, immunoregulation, and metabolic homeostasis. We anticipate that future research will address these knowledge gaps, thereby enhancing the clinical utility of artemisinin and its derivatives and improving patient outcomes across diverse pathologies. Full article

Insect pests impose major economic, agricultural, and public health burdens, damaging crops and transmitting pathogens such as dengue, malaria, and Zika. Conventional chemical control is increasingly ineffective due to insecticide resistance and environmental concerns, prompting a search for innovative strategies. The insect microbiome—comprising both obligate symbionts and environmentally acquired microbes—emerges as a key driver of host physiology and behavior. Microbes influence nutrient acquisition, immunity, reproduction, and chemosensory processing, often to promote their own transmission. By modulating olfactory and gustatory pathways, microbiota can alter host-seeking, mate choice, foraging, and oviposition patterns, reshaping ecological interactions and vector dynamics. These effects are shaped by microbial acquisition routes, habitat conditions, and anthropogenic pressures such as pesticide use, pollution, and climate change. Understanding these multi-directional interactions offers opportunities to design highly specific, microbe-based insect control strategies, from deploying microbial metabolites that disrupt host sensory systems to restoring beneficial symbionts in threatened pollinators. Integrating microbiome ecology with insect physiology and behavior not only deepens our understanding of host–microbe coevolution but also enables the development of sustainable, targeted alternatives to chemical insecticides. This review synthesizes current evidence linking microbiomes to insect biology and explores their potential as tools for pest and vector management. Full article

Identifying effective adjuvants to prevent and alleviate the adverse effects of chemotherapy remains a critical challenge in cancer therapy. This study investigated the protective effects of longan polysaccharide (LP) against cyclophosphamide-induced immunosuppression and oxidative stress in mice. Our findings revealed that LP administration significantly improved systemic immune function, as evidenced by marked increases in serum immunoglobulin levels (IgG2a: 1.82-fold, IgG2b: 1.46-fold, IgM: 1.26-fold, and IgG1: 1.22-fold) and key cytokines (IL-10: 1.53-fold, IL-12: 1.22-fold, and IFN-γ: 1.20-fold), accompanied by substantial reductions in pro-inflammatory mediators (TGF-β1: 28.72% decrease and IL-21: 36.28% decrease). Concurrently, LP restored oxidative balance by increasing SOD, GSH, and NO levels in multiple organs (liver, kidneys, and small intestine) and serum. Mechanistic studies using an in vitro Caco-2/RAW264.7 coculture system revealed that four purified LP fractions (LPIa-LPIVa) effectively suppressed NF-κB pathway activation through downregulation of TLR4 expression, reduction of the p-IκB-α/IκB-α ratio, and inhibition of nuclear NF-κB translocation. These molecular effects correlated with decreased production of inflammatory mediators (TNF-α, IL-6, IL-8, iNOS, and NO). Collectively, these findings provide compelling evidence that LP possesses dual immunomodulatory and antioxidant capabilities, highlighting its potential as a natural adjuvant for alleviating chemotherapy-induced side effects. Full article

N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increases the secretion of pro-inflammatory cytokines in C2C12 skeletal muscle cells and markedly impairs mitochondrial respiration in HepG2 liver cells and rat brain-derived synaptosomes, but not in isolated mitochondria. These findings highlight potential adverse metabolic effects of Lac-Phe, especially when administered at high concentrations, and underscore the necessity of conducting a comprehensive risk assessment and dose optimization before considering Lac-Phe or related Lac-AAs as therapeutic agents. Our work provides important insights into the molecular liabilities associated with Lac-Phe and calls for further studies to balance its therapeutic promise against possible metabolic risks. Full article

This study investigated the expression of immune checkpoint molecules on CD4⁺ and CD4⁻ NKT cell subpopulations throughout healthy pregnancy trimesters and in non-pregnant condition to understand their role in maternal–fetal immunotolerance. Using flow cytometry, we found that CD4⁻ NKT cells significantly outnumbered CD4⁺ NKT cells in all investigated groups. In the case of the immune checkpoint molecules, PD-1 receptor expression was significantly lower in CD4⁻ NKT cells compared to CD4⁺ counterpart cells only in non-pregnant women, while the PD-L1 ligand expression on CD4⁺ NKT cells significantly decreased in the third trimester. In contrast, LAG-3 and Galectin-3 expressions remained stable across all subsets and trimesters. For the TIGIT/CD226 axis, CD226 expression was significantly higher in CD4⁺ NKT cells in the third trimester and in non-pregnant women. The two ligands CD112 and CD155 were consistently lower on CD4⁻ NKT cells across all groups. The activating receptor NKG2D was significantly higher on CD4⁻ NKT cells in all examined cohorts. These findings suggest that CD4⁺ NKT cells tend towards a more tolerogenic phenotype, while CD4⁻ NKT cells maintain a balanced cytotoxic potential with reduced immunoregulation function. The dynamic regulation of immune checkpoints on NKT cell subsets, particularly the downregulation of PD-L1 and CD226 in late pregnancy, highlights their fine-tuned role in balancing maternal–fetal immune tolerance with readiness for parturition. Full article

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Ischemic stroke is a primary cause of cerebrovascular diseases and continues to be one of the leading causes of death and disability among patients worldwide. Pathological processes caused by vascular damage due to stroke occur in a time-dependent manner and are classified into three categories: acute, subacute, and chronic. Current treatments for ischemic stroke are limited to effectiveness in the early stages. In this study, we investigated the therapeutic effect of an oriental medicine, Gosha-jinki-gan (TJ107), on improving chronic ischemic stroke using the mouse model with middle cerebral artery occlusion (MCAO). The changes in the intracerebral inflammatory response (macrophages (F4/80), TLR2•4, IL-23, IL-17, TNF-α, and IL-1β) were examined using real-time RT-PCR. The MCAO mice showed the increased expression of glial fibrillary acidic protein (GFAP) and of F4/80, TLR2, TLR4, IL-1β, TNF-α, and IL-17 in the brain tissue from the MCAO region. This suggests that they contribute to the expansion of the ischemic stroke infarct area and to the worsening of the neurological symptoms of the MCAO mice in the chronic phase. On the other hand, the administration of TJ107 was proven to reduce the infarct area, with decreased GFAP expression, suppressed macrophage infiltration in the brain, and reduced TNF-α, IL-1β, and IL-17 production compared with the MCAO mice. This study first demonstrated Gosha-jinki-gan’s therapeutic effects on the chronic ischemic stroke. Full article