Search Results (366)

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

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, characterized by an initial hyperinflammatory phase frequently followed by compensatory immunosuppression (CARS). Regulatory T cells (Tregs) play a critical, biphasic role: inadequate suppression during early hyperinflammation fails to control cytokine storms, while excessive/persistent activity in late-phase immunosuppression drives immune paralysis and secondary infection susceptibility. This review explores advances in targeting Treg immunoregulation across bacterial, viral, and fungal sepsis, where pathogenic type critically influenced the types of immunoresponses, shaping Treg heterogeneity in terms of phenotype, survival, and function. Understanding this multifaceted Treg biology offers novel therapeutic avenues, highlighting the need to decipher functional heterogeneity and develop precisely timed, pathogen-tailored immunomodulation to safely harness beneficial Treg roles while mitigating detrimental immunosuppression. Full article

Although Brassica rapa (B. rapa) is vital in agricultural production and vulnerable to the pathogen Plasmodiophora, the intracellular water–nutrient metabolism and immunoregulation of Plasmodiophora infection in B. rapa leaves remain unclear. This study aimed to analyze the responsive mechanisms of Plasmodiophora-infected B. rapa using rapid detection technology. Six soil groups planted with Yangtze No. 5 B. rapa were inoculated with varying Plasmodiophora concentrations (from 0 to 10 × 10⁹ spores/mL). The results showed that at the highest infection concentration (PWB5, 10 × 10⁹ spores/mL) of B. rapa leaves, the plant electrophysiological parameters showed the intracellular water-holding capacity (IWHC), the intracellular water use efficiency (IWUE), and the intracellular water translocation rate (IWTR) declined by 41.99–68.86%. The unit for translocation of nutrients (UNF) increased by 52.83%, whereas the nutrient translocation rate (NTR), the nutrient translocation capacity (NTC), the nutrient active translocation (NAT) value, and the nutrient active translocation capacity (NAC) decreased by 52.40–77.68%. The cellular energy metabolism decreased with worsening Plasmodiophora infection, in which the units for cellular energy metabolism (∆G_E) and cellular energy metabolism (∆G) of the leaves decreased by 44.21% and 78.14% in PWB5, respectively. Typically, based on distribution of B-type dielectric substance transfer percentage (BPn), we found PWB4 (8 × 10⁹ spores/mL) was the maximal immune response concentration, as evidenced by a maximal BPn_R (B-type dielectric substance transfer percentage based on resistance), with increasing lignin and cork deposition to enhance immunity, and a minimum BPn_Xc (B-type dielectric substance transfer percentage based on capacitive reactance), with a decreasing quantity of surface proteins in the B. rapa leaves. This study suggests plant electrophysiological parameters could characterize intracellular water–nutrient metabolism and immunoregulation of B. rapa leaves under various Plasmodiophora infection concentrations, offering a dynamic detection method for agricultural disease management. Full article

Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of IL-35 in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding IL-35 gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on IL-35 levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating IL-35 dynamics in correlation with periodontal parameters, as well as genetic association studies investigating IL-12A and EBI3 gene polymorphisms. IL-35 levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, IL-35 levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between IL-35 polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. IL-35 appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supports its role in promoting tissue stabilization. The integration of cytokine profiling and genetic screening may enhance personalized risk assessment and targeted interventions in periodontal care. Full article

Fever is a frequent complication in children receiving chemotherapy, primarily caused by bloodstream infections and non-infectious inflammation. Yet, the pathophysiological mechanisms remain unclear, and diagnostics are insufficient, which often results in continued antibiotic treatment despite negative blood cultures. In a nationwide study, we collected whole blood in PAXgene tubes from 168 febrile episodes in children with hematological malignancies, including 37 episodes with bacteremia, and performed single-cell RNA sequencing. We compared transcriptomic profiles between febrile children with and without bacteremia. In children with bacteremia, differentially expressed genes were related to immunoregulation and cardiac and vascular function. Children without bacteremia had distinct gene expression patterns, suggesting a viral or other inflammatory cause of fever. Several differentially expressed genes overlapped with previously published transcriptomics-based diagnostic signatures developed in immunocompetent children. In conclusion, blood transcriptomics provided novel insights into the pathophysiological mechanisms of febrile children with hematological malignancies. We found differentially expressed genes suggesting viral infections or non-bacterial inflammation as causes of fever in children with negative blood cultures, supporting early antibiotic discontinuation in children with cancer. Full article

Sepsis acts as the leading cause of mortality in intensive care units, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection. Vitamin D (VD) pleiotropic functions were demonstrated in different biological processes, including inflammation and immunity. VD receptor (VDR) is a member of the nuclear receptor superfamily, involved in immunoregulation and resistance to infections. Previous studies have demonstrated that VD deficiency is a potential risk factor for sepsis development, which may be regulated by VDR-related physiological processes. In this review, we present a comprehensive overview of the roles of VD and VDR in sepsis, focusing on immune modulation, anti-inflammatory and anti-infective responses, oxidative stress regulation, gut microbiome enhancement, vascular endothelial cell modulation, and antiplatelet activity. We also discuss recent advances in clinical research on VD/VDR in sepsis, considering the clinical implications and potential interventions of VD analogs and VDR ligands in treatment. Despite its challenges, VD holds potential for personalized sepsis interventions. Additionally, VD/VDR may serve as a promising bidirectional immunomodulator, capable of addressing both hyperinflammatory and immunosuppressive phases of sepsis, yet require systematic investigations into its dynamic states and functions across different sepsis phases. Ongoing study and evidence-based guidelines are crucial to maximize its therapeutic benefits and improve clinical outcomes. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells that play a central role in regulating host immune responses during fungal infections. Their recruitment is mediated by pathogen recognition receptors, particularly Dectin-1 and CARD9 signaling, which promote the production of reactive oxygen species (ROS) and IL-1β. Once activated, MDSCs suppress T-cell and natural killer cell functions through immunosuppressive cytokines like IL-10 and TGF-β, as well as enzymes such as arginase-1 and indoleamine 2,3-dioxygenase 1 (IDO-1). This review explores the role of MDSCs in fungal infections caused by Candida spp., Paracoccidioides brasiliensis, Aspergillus spp., and Cryptococcus neoformans, emphasizing their impact on immune modulation and disease progression. The emerging evidence suggests that fungal bioactive compounds, such as polysaccharides, can influence MDSC activity and restore immune balance. Notably, therapies targeting MDSCs have demonstrated promise in both fungal infections. In particular, infections with P. brasiliensis and C. neoformans show improved T-cell responses following MDSC-targeted interventions. Additionally, polysaccharides from Grifola frondosa and exposure to Aspergillus sydowii affect MDSC behavior, supporting the potential of modulating these cells therapeutically. Together, these findings highlight the relevance of MDSCs in fungal pathogenesis and underscore their potential as targets for immunotherapeutic strategies in infectious diseases. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely impacts patients’ quality of life. Although current therapies have improved symptom management, they often fail to alter disease progression and are associated with immunosuppressive side effects. This study evaluated the immunomodulatory potential of resolvin D2 (RvD2), a pro-resolving lipid mediator, using a murine model of colitis and the ex vivo treatment of intestinal mucosal biopsies from CD patients, comparing its effects to those of conventional anti-TNFα therapy. To determine the optimal concentration of RvD2 for application in human tissue explant cultures, an initial in vitro assay was conducted using intestinal biopsies from mice with experimentally induced colitis. The explants were treated in vitro with varying concentrations of RvD2, and 0.1 μM emerged as an effective dose. This concentration significantly reduced the transcriptional levels of TNF-α (p = 0.004) and IL-6 (p = 0.026). Intestinal mucosal biopsies from fifteen patients with CD and seven control individuals were analyzed to validate RNA-sequencing data, which revealed dysregulation in the RvD2 biosynthetic and signaling pathways. The real-time PCR confirmed an increased expression of PLA2G7 (p = 0.02) and ALOX15 (p = 0.02), while the immunohistochemical analysis demonstrated the reduced expression of the RvD2 receptor GPR18 (p = 0.04) in intestinal tissues from CD patients. Subsequently, samples from eight patients with active Crohn’s disease, eight patients in remission, and six healthy controls were used for the serum analysis of RvD2 by ELISA, in vitro treatment of intestinal biopsies with RvD2 or anti-TNF, followed by transcriptional analysis, and a multiplex assay of the explant culture supernatants. The serum analysis demonstrated elevated RvD2 levels in CD patients both with active disease (p = 0.02) and in remission (p = 0.002) compared to healthy controls. The ex vivo treatment of intestinal biopsies with RvD2 decreased IL1β (p = 0.04) and TNFα (p = 0.02) transcriptional levels, comparable to anti-TNFα therapy. Additionally, multiplex cytokine profiling confirmed a reduction in pro-inflammatory cytokines, including IL-6 (p = 0.01), IL-21 (p = 0.04), and IL-22 (p = 0.009), in the supernatant of samples treated with RvD2. Altogether, these findings suggest that RvD2 promotes the resolution of inflammation in CD and supports its potential as a promising therapeutic strategy. Full article

Kala-azar is a protracted disease caused by the protozoan Leishmania infantum (zoonotic) or L. donovani (anthroponotic), transmitted by sandflies. Patients present with fever, anemia, and hepatosplenomegaly, potentially progressing to hemorrhaging, secondary infections, and death. Its pathogenesis is linked to an exaggerated cytokine response. We studied 72 hospitalized patients, analyzing clinical data and outcomes in relation to L. infantum DNA loads in blood and bone marrow, and plasma concentrations of IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α, and TGF-β. Cytokine levels were found to be elevated. L. infantum kDNA loads in blood and bone marrow were strongly correlated and increased with disease duration. Higher parasite loads were observed in men, adults, and HIV-infected patients, and they were significantly associated with mortality. IL-6 was independently linked to sepsis. In multivariate analysis, IL-12 was the only cytokine inversely associated with blood parasite load. Parasite load, but not cytokine levels, correlated with disease severity, suggesting additional mechanisms drive progression. IL-12 appears to limit parasitemia, indicating a weak, persistent adaptive immune response that is ultimately overwhelmed by a progressive, inefficient, and inflammatory innate response. Full article

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko japonicus. The peptide Gj-CATH5, from G. japonicus, shows promise against Pseudomonas aeruginosa through various mechanisms. This study examined Gj-CATH5’s protective effects using in vitro and in vivo models, finding that it significantly reduced bacterial load in a mouse infection model when administered before or shortly after infection. Flow cytometry and the plate counting method showed that Gj-CATH5 boosts neutrophil and macrophage activity, enhancing chemotaxis, phagocytosis, and bactericidal functions. Gj-CATH5 increases ROS production, MPO activity, and NET formation, aiding pathogen clearance. Its amphipathic α-helical structure supports broad-spectrum bactericidal activity (MBC: 4–8 μg/mL) against Gram-negative and antibiotic-resistant bacteria. Gj-CATH5 is minimally cytotoxic (<8% hemolysis at 200 μg/mL) and preserves cell viability at therapeutic levels. These results highlight Gj-CATH5’s dual role in pathogen elimination and immune modulation, offering a promising approach to combat multidrug-resistant infections while reducing inflammation. This study enhances the understanding of reptilian cathelicidins and lays the groundwork for peptide-based immune therapies against difficult bacterial infections. Full article

Systemic cancer progression culminating in metastatic disease is implicitly dependent on tumour cell interactions with the vascular system. Indeed, different facets of the micro- and macro-vasculature can be regarded as rate-limiting ‘vascular checkpoints’ in the process of cancer dissemination. The underlying complex communication networks drive tumour neovascularization, angiogenesis, immunoregulation, activation of the coagulation system, angiocrine interactions, and non-angiogenic vascular responses across multiple cancer types. Yet, each cancer may represent a unique vascular interaction scenario raising a prospect of targeted modulation of blood and lymphatic vessels for therapeutic purposes, beyond the traditional notion of tumour anti-angiogenesis. While the emphasis of studies aiming to understand this circuitry has traditionally been on soluble, or ‘mono-molecular’ mediators, the rise of the particulate secretome encompassing heterogeneous subpopulations of extracellular vesicles (EVs; including exosomes) and particles (EPs) brings another dimension into the tumour–vascular communication web during the process of metastasis. EVs and EPs are nanosized cellular fragments, the unique nature of which lies in their ability to encapsulate, protect and deliver to target cells a range of bioactive molecular entities (proteins, RNA, DNA) assembled in ways that enable them to exert a wide spectrum of biological activities. EVs and EPs penetrate through biological barriers and are capable of intracellular uptake. Their emerging vascular functions in metastatic or infiltrative cancers are exemplified by their roles in pre-metastatic niche formation, thrombosis, vasectasia or angiocrine regulation of cancer stem cells. Here, we survey some of the related evidence supporting the biological, diagnostic and interventional significance of EVs/EPs (EVPs) in disseminated neoplastic disease. Full article

Background/Objectives: Ivy leaf extract has been shown to alleviate bronchial infection symptoms through various mechanisms, including anti-inflammatory effects. However, its impact on adaptive immunity, particularly dendritic cell (DC)/T-cell interactions, remains unexplored. This study investigated the immunomodulatory potential of ivy leaf extract (EA 575^®) using human monocyte-derived DCs (MoDCs). Methods: Immature MoDCs (imMoDCs) were differentiated with IL-4/GM-CSF and matured with LPS/IFN-γ (mMoDCs). MoDCs, treated with EA 575^® during differentiation, were co-cultured with purified T cells. Results: EA 575^® (non-cytotoxic up to 100 µg/mL) inhibited MoDC differentiation and maturation by reducing the expression of CD1a, CD83, CD40, CD86, HLA-DR, Dectin-1, CD206, CD209, HIF-1α, and proinflammatory cytokines (IL-12, IL-23, IL-27, IL-1β, IL-6, TNF-α). EA 575^®-treated mMoDCs suppressed allogeneic T-cell proliferation and reduced Th1 (IFN-γ), Th17 (IL-17A, IL-22), Th9 (IL-9), Th21 (IL-21), TNF-α, and IL-6 responses. Effects were dose-dependent, with higher concentrations (100 µg/mL) showing stronger inhibition. At lower concentrations (20 µg/mL), EA 575^® increased Th2 (IL-4, IL-5) and IL-10 responses, and the frequencies of CD4+ T cells with Treg properties, such as CD25hiFoxp3+, Tr1 (IL-10+Foxp3−), and IL-35+ Foxp3+ cells. Immunoregulatory mechanisms mediated by EA 575^®-treated mMoDCs correlated with the upregulation of tolerogenic markers (PD-L1, ILT3, ILT4, IDO1) on mMoDCs and the increased frequency of exhausted CD4+ T cells (PD-1+CD69+) and cytotoxic T cells (Granzyme B+PD-1+). Conclusions: EA 575^® induces tolerogenic DCs with significant anti-inflammatory and immunoregulatory properties, a previously undescribed phenomenon. Lower concentrations primarily enhance immunoregulatory responses, while higher concentrations exert more pronounced anti-inflammatory effects. Full article

Background: The retina plays a vital role in vision, and its impairment can cause significant visual deficits. Current retinal disease treatments range from conventional anti-inflammatory drugs to advanced anti-VEGF therapies and monoclonal antibodies. TnP, a novel synthetic peptide in preclinical development, has demonstrated therapeutic potential in chronic inflammatory conditions such as multiple sclerosis and asthma due to its immunomodulatory properties. Using zebrafish—which share significant genetic homology with humans—we investigated TnP’s effects on retinopathy models mimicking diabetic retinopathy (DR) through either cobalt chloride (CoCl₂)-induced hypoxia or light-induced retinal damage (LIRD). Methods: We employed two retinal injury models (CoCl₂-induced hypoxia and LIRD) and subjected them to TnP treatment, assessing the outcomes through visual–motor response testing and histological examination. Results: CoCl₂ exposure impaired swimming activity, while light damage reduced the movement distance. Both models induced distinct retinal morphological changes. Although TnP failed to reverse most injury effects, it specifically restored the inner plexiform layer (IPL)’s thickness. Conclusions: Our findings suggest that TnP may enhance neuronal plasticity by promoting cell proliferation and synaptic connectivity. While showing promise as a therapeutic candidate for retinal and neurodegenerative disorders, TnP might achieve optimal efficacy when combined with complementary treatments. Full article

Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease. Full article