Search Results (3,525)

Feline leishmaniasis is an emerging zoonotic disease, yet the cellular and immunological mechanisms underlying Leishmania infection in cats remain poorly understood. In this study, we established and characterized Fcwf-4 feline macrophages as an in vitro model of Leishmania amazonensis infection and investigated the immunomodulatory effects of glucuronoxylomannan (GXM), the major capsular polysaccharide of Cryptococcus neoformans. Fcwf-4 macrophages were infected with L. amazonensis promastigotes and evaluated at 2, 24, and 48 h post-infection. Parasite burden, macrophage viability, nitric oxide (NO), and reactive oxygen species (ROS) production were assessed in the presence or absence of GXM. Fcwf-4 macrophages supported L. amazonensis infection throughout the experimental period, with a progressive decrease in the infection index, indicating partial control of parasite burden over time. Notably, the presence of GXM increased the infection index without compromising macrophage viability, suggesting that enhanced parasite persistence resulted from immunomodulation rather than cytotoxicity. LPS stimulation enhanced NO and ROS production, whereas L. amazonensis infection selectively reduced NO production, indicating impairment of macrophage effector responses. Further, GXM suppressed ROS production, including basal ROS levels, suggesting an additional inhibitory effect on macrophage oxidative responses. Collectively, these findings provide experimental evidence that Fcwf-4 could be useful as a tool to study feline macrophage–Leishmania interactions in vitro and co-infection-associated immunomodulation. Full article

This study investigated the phytochemical profile, antioxidant capacity, and immunomodulatory properties of Pinus sylvestris xylem sap harvested from the Kastamonu region of Türkiye during the early spring active sap-flow period. Quantitative screening demonstrated significant polyphenolic density, with total phenolic (39.65 ± 2.12 mg GAE/g) and flavonoid contents (21.48 ± 3.11 mg Catechin/g) reflecting a high relative accumulation of mobile, hydrophilic flavonoids. Targeted LC-MS/MS analysis further revealed the presence of several phenolic and flavonoid-related compounds, with catechin as the predominant compound in the directly extracted sample, while epicatechin and epigallocatechin were among the major compounds detected following acid hydrolysis. The sap exhibited consistent, robust antioxidant activity across DPPH (43.52 ± 2.76 mg TE/g), ABTS (41.64 ± 2.17 mg TE/g), and FRAP (39.21 ± 1.95 mg TE/g) assays, indicating multi-pathway radical scavenging and electron-donating capacities in cell-free chemical models. While direct exposure yielded concentration-dependent cytotoxicity against tumor lines (IC50 values: 7.6–12.5 µg/mL), subtoxic conditioning (1 µg/mL) and substantially enhanced NK-92-mediated lysis of target cancer cells, most prominently against MCF-7 breast carcinoma. Flow cytometric analysis revealed that xylem sap treatment selectively upregulated surface expression of CD16 (from 0.00% to 15.93%) and CD57 on NK-92 cells without altering baseline CD56. Furthermore, sap stimulation triggered a concentration-dependent surge in IFN-γ production and elevated cytotoxic responses in lymphocytes isolated from both healthy controls (n = 5) and breast cancer patients (n = 5). These findings indicate that conifer xylem sap represents in vitro immunomodulatory properties and enhances NK-92 cell-mediated cytotoxic responses in cell culture models. Full article

Polysaccharides have emerged as versatile building blocks for the design of advanced biomaterials owing to their biocompatibility, biodegradability, structural diversity, and broad chemical tunability. Over the past decade, numerous engineering strategies have been developed to tailor their physicochemical properties and expand their use in biomedical applications. Although several comprehensive reviews have summarized chemical modification methods, specific classes of polysaccharides, or individual biomedical applications, fewer studies have examined how different engineering strategies collectively influence the biological performance of polysaccharide biomaterials. This review provides an integrated overview of the principal approaches used to engineer polysaccharide-based biomaterials, including chemical functionalization, surface modification, biofunctionalization, and combined engineering strategies. Particular attention is given to the relationship between material design and biological response, discussing how these strategies influence key interactions such as protein adsorption, cell adhesion and proliferation, antimicrobial activity, immunomodulation, and tissue integration. Representative examples from hydrogels, films, coatings, nanoparticles, and scaffolds are presented to illustrate how engineering approaches can be adapted to achieve specific biological functions across different biomedical applications. Full article

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent nodules, abscesses, and sinus tract formation, driven by dysregulated innate immunity and microbial dysbiosis. Intravenous ertapenem has emerged as a therapeutic option for severe, refractory HS, with clinical studies consistently demonstrating meaningful improvements in pain, drainage, inflammatory markers, and quality of life. While these benefits have traditionally been attributed to ertapenem’s broad-spectrum antimicrobial activity against the polymicrobial anaerobic flora of HS lesions, the rapid onset of clinical improvement and inconsistent anaerobic suppression observed during treatment suggest that additional mechanisms may be at play. Emerging mechanistic evidence from studies of carbapenems in non-HS experimental systems suggests that this drug class may influence host inflammatory pathways through effects on cytokine signaling, endotoxin release, neutrophil and macrophage activation, and NF-κB inhibition. Additionally, ertapenem’s unusually high plasma protein binding, particularly to acute-phase reactants elevated in HS such as haptoglobin and fibrinogen, may further influence drug distribution and immune signaling within inflamed tissues. This review examines the antimicrobial and emerging immunomodulatory properties of ertapenem and explores how these convergent mechanisms may explain its clinical efficacy in severe HS, while highlighting stewardship considerations and directions for future research. Methods: A structured search of PubMed/MEDLINE was conducted from database inception through 1 May 2026 using terms related to hidradenitis suppurativa, ertapenem, carbapenems, antimicrobial activity, immunomodulation, inflammatory signaling, innate immune cells, and pharmacokinetics. During revision, a targeted literature update through 1 September 2026 was performed to incorporate newly published and reviewer-requested studies. Eligible clinical, microbiologic, pharmacologic, and mechanistic studies were screened by title, abstract, and full text and synthesized narratively. Full article

Hashimoto’s thyroiditis (HT) is a chronic autoimmune thyroid disease in which natural product-derived compounds may influence both immune-mediated injury and thyroid-specific physiology. This critical narrative review integrated molecular, cellular, animal, and human evidence using a dual-axis framework: H1, covering anti-inflammatory, immunomodulatory, antioxidant, and cytoprotective effects; and H2, covering direct effects on thyroid peroxidase, sodium–iodide symporter activity, thyroglobulin, thyroid-specific gene expression, and hormone synthesis. PubMed/MEDLINE, Scopus, and Web of Science searches identified 687 records; after deduplication, 356 unique publications were screened and 79 were retained for final synthesis. Human evidence was limited to three independent HT trials evaluating curcumin, Nigella sativa, and genistein. These studies reported preliminary immunological and/or biochemical thyroid-function signals, including changes in thyroid autoantibodies, inflammatory markers, TSH, or thyroid hormones. Reductions in TPOAb or TgAb are surrogate immunological outcomes and should not be interpreted as evidence of disease modification. None of the available trials established preservation of thyroid functional reserve, prevention or delay of hypothyroidism, reduced levothyroxine requirements, or improvement in patient-important outcomes. Preclinical studies supported biological plausibility but also identified direct thyroid modulation whose clinical relevance depends on exposure and context. Natural products should currently be regarded as investigational adjuncts rather than established disease-modifying therapies. Full article

Antibiotic use in marine ornamental fish farming has raised concerns about resistance and tissue damage, motivating the search for safe probiotic alternatives. In this study, three Bacillus strains—B. subtilis (BS), B. megaterium (BM), and B. velezensis (BV)—that were isolated from healthy clownfish intestines were evaluated as dietary supplements for Amphiprion frenatus over a four-week feeding trial. The growth performance of the fish, the antioxidant enzyme activity in the liver and intestine, and the expression of pro-inflammatory and antimicrobial peptide genes in four tissues were examined. The intestinal barrier genes and intestinal morphology were also measured. The obtained data indicate that BM elicited the broadest immune activation, upregulated antimicrobial peptides and all four barrier genes, and increased the hepatosomatic index and MDA. BV has the best promotional effects on growth without elevating the hepatosomatic index; it selectively induced lyz and leap2 while suppressing gill il1b, and it reduced intestinal MDA. BS showed comparatively mild effects. These findings demonstrate strain-specific probiotic actions in clownfish, with B. velezensis offering the most favorable balance of growth promotion and immunomodulation for aquaculture applications. Full article

White Spot Syndrome Virus (WSSV) remains a major factor limiting the sustainable development of crustacean aquaculture, creating an urgent need to develop comprehensive antiviral strategies with multiple protective functions. Natural bioactive compounds with antiviral, immunomodulatory, and antioxidant activities hold great potential for application; however, their poor stability and low bioavailability limit their practical use. In this study, self-assembled nanosystem (CE SA) composed of epigallocatechin gallate (EGCG) and curcumin (Cur) was constructed based on noncovalent interactions, and its protective effects against WSSV-infected Procambarus clarkii were systematically evaluated. The results indicate that CE SA exhibits good stability, sustained-release properties, and biosafety. Compared with Cur, EGCG, and their physical mixture (CE), CE SA significantly improved the survival rate of infected shrimp and reduced viral copy numbers as well as the expression levels of key viral genes such as IE1, DNApol, and VP28. At the same time, CE SA significantly promoted the expression of relevant genes such as Dorsal, Relish, SOD, and CAT, increased SOD and CAT enzyme activities and hematopoietic cell viability, and effectively alleviated damage to the hepatopancreas and intestinal tissues. Furthermore, metabolomic analysis indicated that CE SA regulates key metabolic processes such as amino acid metabolism, inflammation-related metabolism, nucleotide metabolism, and redox homeostasis, further elucidating its potential mechanism for enhancing the host’s antiviral capacity. In summary, by enhancing the stability and utilization efficiency of natural bioactive components, CE SA achieves superior anti-WSSV efficacy compared to individual components. Its protective effects are closely related to the inhibition of viral replication, enhancement of the immune response, improvement of antioxidant defenses, and regulation of host metabolic homeostasis. This study provides a promising, self-assembling nanostructure strategy for the green prevention and control of viral diseases in aquatic animals. Full article

Neutrophils play a central role in the innate immune response. However, in inflammatory and autoimmune diseases, the exacerbated activation of these cells can result in excessive release of reactive oxygen species (ROS), proteases, and inflammatory mediators, contributing to tissue damage. In this context, natural compounds derived from amphibian venoms have attracted interest due to their pharmacological and immunomodulatory potential. This study aimed to evaluate in vitro the effects of the crude methanolic extract (CME) of Rhinella marina on the effector functions of human neutrophils. For this purpose, peripheral blood neutrophils from healthy individuals were treated with CME (0.5, 5, and 50 µg/mL) or untreated controls. Cytotoxicity, total ROS production, superoxide anion production, myeloperoxidase (MPO) activity, elastase degranulation, NET (Neutrophil Extracellular Trap) formation, and parameters related to cellular redox status, including antioxidant enzymes and markers of oxidative damage, were evaluated. CME showed concentration-dependent cytotoxicity. There were no changes in ROS production by luminol-dependent chemiluminescence after stimulation with myristoylphorbol acetate (PMA). However, it reduced superoxide anion production in neutrophils in both stimuli in the NBT assay. CME did not significantly modulate MPO activity or NET formation, but it reduced elastase release, suggesting modulation of neutrophil degranulation. Additionally, it increased glutathione-S-transferase (GST) activity and reduced glutathione (GSH) levels. It can be concluded that CME partially modulated neutrophil effector functions, such as superoxide anion production and degranulation, in addition to exhibiting partial protective effects on cellular redox state parameters. These findings suggest the extract’s immunomodulatory potential and reinforce the need for further studies to clarify its mechanisms of action and possible applicability in neutrophil-mediated inflammatory conditions. Full article

Salicylic acid is widely used in dermatological and cosmetic formulations, yet the influence of its production route on solid-state structure and biological behaviour remains underexplored. This study compares a naturally derived salicylic acid (NSA), obtained from wintergreen oil through green chemistry, with a synthetic form (SSA) produced via the Kolbe–Schmitt reaction, integrating physicochemical characterization with antioxidant and immunomodulatory profiling. Crystal morphology, crystallinity (XRD, FTIR), melting point, solubility, dissolution and Franz-cell skin permeation were determined, alongside intrinsic radical scavenging (DPPH), intracellular reactive oxygen species (DCFH-DA), cytoprotection (MTT), CD9⁺ extracellular-vesicle (EV) release and cytokine transcription in RAW 264.7 macrophages. SSA formed uniform, needle-like crystals of higher crystallinity, comparable equilibrium solubility (2.239 vs. 2.115 mg/mL; not significant) and faster dissolution, whereas the less-ordered NSA showed a numerically higher steady-state flux (39.94 ± 16.43 µg cm⁻² h⁻¹) and a shorter lag time (2.47 ± 1.71 h). SSA was the stronger radical scavenger (DPPH 20.7% vs. 8.7%) and reduced intracellular ROS more effectively, while NSA afforded greater cytoprotection. Both forms were associated with a lower CD9⁺ EV concentration in the conditioned medium following LPS stimulation, with SSA consistently more active across radical scavenging, ROS and vesicle endpoints. These findings show that the synthesis route, through its effect on solid-state properties, influences the physical performance, while the biological behaviour is discussed separately from the anti-inflammatory behaviour of salicylic acid, informing the rational selection of natural versus synthetic material for topical applications. Full article

Rheumatoid arthritis (RA) arises from interactions among immune, stromal, and osteoimmune compartments, supporting interest in agents with multilevel activity, such as celastrol. This narrative review critically integrates evidence on its chemical–pharmacological basis, immunomodulatory mechanisms, cellular effects, and translational potential in RA. Preclinical data show inhibition of inflammatory programs in macrophages and neutrophils, modulation of T- and B-cell responses, suppression of pathogenic fibroblast-like synoviocyte (FLS) functions, and reduced osteoclastogenesis and structural damage. COMM domain-containing proteins 3 and 8 (COMMD3/8) provide the strongest causal validation, while insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has biophysical and functional support; numerous inflammatory and metabolic nodes primarily represent downstream signaling. Multicellular models support functional convergence, but intercellular causation in RA remains limited; directional functional evidence for dendritic cell–T-cell modulation comes from non-rheumatoid models, and no persistent synovial reprogramming has been demonstrated. Low bioavailability, multitarget covalent pharmacology, a narrow therapeutic window, and contributions from delivery carriers constrain translational interpretation. Addressing these translational challenges explicitly can help guide future research to improve celastrol's safety and efficacy, which is essential for clinical application. Full article

Acidity, hypoxia, redox imbalance, and altered enzyme activity in the tumor microenvironment (TME) can be used to regulate nanocarrier structure and drug release. However, these conditions vary among tumors and across regions within individual tumors and overlap with certain normal physiological and inflammatory processes. This review examines TME-responsive nanomedicines for chemotherapy, phototherapy, immunomodulation, and theranostics in terms of their triggering conditions, response mechanisms, and carrier materials. Particular attention is given to matching activation thresholds to biological compartments, the relationship between delivery and release, and the biological interpretation of imaging signals. By comparing representative original studies, we examine the benefits of multiresponsive designs, potential off-target activation, and manufacturing complexity, while distinguishing the clinical use of conventional nanoformulations from clinical validation of TME-responsive mechanisms. Current studies demonstrate the feasibility of conditional drug release and local microenvironment modulation, but their clinical value remains to be established through consistent product quality, evidence of in vivo activation, and comparative efficacy studies. Full article

Osteonecrosis of the femoral head (ONFH) is a progressive ischemic bone disorder that may lead to subchondral fracture, femoral-head collapse, and total hip arthroplasty. Impaired regeneration reflects persistent ischemia, endothelial dysfunction, defective angiogenesis and bone remodeling, inflammation, oxidative stress, and dysfunction of endogenous mesenchymal stromal cells (MSCs). Although MSC therapy, particularly with core decompression in precollapse ONFH, is a promising joint-preserving approach, conventional two-dimensional (2D)-expanded MSCs are limited by poor survival and retention, anoikis, disrupted cell–cell and cell–extracellular matrix interactions, and loss of potency during ex vivo expansion. Three-dimensional MSC spheroids may overcome several of these limitations by preserving intercellular and matrix interactions and enhancing resistance to ischemic stress, paracrine signaling, angiogenic activity, immunomodulation, and osteogenic competence. Hypoxia-responsive signaling, autophagy, trophic-factor secretion, and extracellular vesicle-mediated communication may promote angiogenesis–osteogenesis coupling and the restoration of the ischemic bone–vascular niche. This review summarizes the pathophysiological barriers to ONFH regeneration, current evidence and limitations of conventional MSC therapy, biological mechanisms underlying MSC-spheroid activity, and emerging strategies for therapeutic optimization. Importantly, direct evidence demonstrating the superiority of MSC spheroids over conventional MSC preparations specifically in ONFH remains limited. Future translation will require disease-specific comparative studies, standardized GMP-compatible manufacturing, validated potency assays and clinically practical delivery systems. Full article

Sudachitin, a polymethoxyflavone found in the peel of the Japanese citrus sudachi, has been reported to possess anti-cancer activity and the ability to modulate immune responses. Given its diverse pharmacological properties, expanding its application to malignant tumors of the central nervous system (CNS) represents a compelling therapeutic strategy. Furthermore, it has been suggested that sudachitin can cross the blood–brain barrier. Given these diverse pharmacological properties, extending its application to malignant tumors of the CNS represents an attractive therapeutic strategy. In various types of cancer, the expression of PD-L1 (programmed death-ligand 1) promotes immune evasion. In this study, we evaluated the effect of sudachitin on PD-L1 expression in human A172 glioblastoma cells. Sudachitin significantly suppressed PD-L1 levels. Although the major signaling pathways regulating PD-L1 include MEK, JAK, and NF-κB, pharmacological inhibition of these pathways failed to rescue the suppression of PD-L1 expression induced by sudachitin. In contrast, the broad-spectrum HDAC inhibitor trichostatin A moderately attenuated this suppression. Notably, the Class I-selective inhibitor mocetinostat (predominantly targeting HDAC1/2) fully restored PD-L1 expression to control levels. However, sirtuin modulators had no impact. These results show that sudachitin suppresses PD-L1 expression through a Class I HDAC-dependent mechanism. Overall, sudachitin represents a promising plant-derived immunomodulator for targeting immune checkpoints in brain tumors. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder characterized by complex interactions among genetic susceptibility, environmental factors, dysregulated immune responses, and alterations of the intestinal microbiota. Although corticosteroids, immunomodulators, biologics, and advanced small-molecule therapies remain central to disease management, a substantial proportion of patients experience primary non-response, loss of response, or treatment-related adverse effects. This has stimulated interest in complementary therapeutic strategies targeting host–microbe interactions and intestinal microbial homeostasis. This review critically examines emerging microbiome-directed approaches for CD, with particular emphasis on pathobionts such as adherent-invasive Escherichia coli (AIEC). We discuss the available evidence for antibiotics, antimicrobial peptides (AMP), gut bacteriophages, fecal microbiota transplantation (FMT), and selected nutraceutical and dietary interventions. While some approaches show promising biological or clinical signals, the strength of evidence varies considerably, ranging from in vitro and animal studies to randomized clinical trials and meta-analyses. Antibiotic therapies targeting intestinal pathogens have shown heterogeneous results, suggesting the need for pathogen-guided and intracellularly active antimicrobial strategies. Novel approaches, including AIEC-specific phages and AMP-based interventions, represent promising microbiome-sparing alternatives capable of selectively modulating disease-associated microorganisms. Furthermore, FMT and nutraceuticals may contribute to restoring microbial balance and strengthening intestinal homeostasis, although their efficacy requires further validation in controlled clinical trials. Overall, these strategies support a transition toward precision medicine approaches integrating microbial profiling, host immune characterization, and targeted antimicrobial interventions to improve therapeutic outcomes in CD. Full article

Paricalcitol (19-nor-1,25-dihydroxyvitamin D₂) is a synthetic vitamin D receptor (VDR) agonist used for the treatment of secondary hyperparathyroidism mainly in chronic kidney disease (CKD), with a 10-times lower calcemic potential and 3-times less potent to the VDR than calcitriol. This narrative review examines the available preclinical and clinical evidence on the immunomodulatory actions of paricalcitol beyond mineral metabolism. Experimental studies show that paricalcitol can modulate immune-cell function, inflammatory signaling, oxidative stress and fibrosis through VDR-dependent pathways. Human evidence is derived mainly from patients with CKD and kidney transplantation, where reductions in inflammatory and oxidative stress markers have been reported; however, findings are not consistent across all studies. Evidence in other immune-mediated conditions, including IgA nephropathy, psoriasis, atopic dermatitis, autoimmune alopecia, and type 1 diabetes (T1D), remains limited and is based largely on case series and reports and non-RCTs. The PRECAL study (ISRCTN17354692) provides preliminary evidence that timely VDR activation may influence the course of T1D, requiring controlled confirmation. No dosing regimen has yet been established for immunomodulatory use, while the calcitriol replacement daily dose × 3/day (given the relevant potency) has been proven reasonably safe and effective in the PRECAL study. Predictive biomarkers of response are lacking, warranting further basic research. Full article