Search Results (589)

Chronic sleep restriction (SR) impairs multiple organs. Although exogenous melatonin counteracts SR-induced gut microbiota disruption, its role in protecting renal function and the involvement of gut microbiota remain unclear. To this end, we subjected mice to a 28-day SR paradigm with exogenous melatonin treatment or antibiotic-induced microbiota depletion. SR mice demonstrated significant renal dysfunction evidenced by elevated serum creatinine, blood urea nitrogen, and uric acid levels compared to controls. Histopathological analysis revealed characteristic tubular abnormalities in SR mice, including epithelial degeneration and lumen dilation, with reduced expression of key renal filtration markers (Nephrin, Podocin, CD2-associated protein, and α-Actinin-4). All of these could be mitigated by melatonin treatment, and all changes were statistically significant (p < 0.05 or p < 0.01). Intriguingly, microbiota depletion significantly reversed the protective effect of exogenous melatonin on kidney injury in SR mice, while propionic acid supplementation mitigated SR-induced kidney injury. Furthermore, we found that gut microbiota and the metabolite propionic acid mediated the role of exogenous melatonin probably through attenuating SR-induced renal oxidative damage, including regulating renal superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA) level. These findings collectively indicated that melatonin may ameliorate SR-associated kidney injury through gut microbiota-derived propionic acid. Our finding highlights a novel gut–kidney axis in SR-related pathophysiology. Full article

African swine fever virus (ASFV) is an important transboundary animal pathogen with significant impacts on the global swine industry. Overwhelming proinflammatory responses are a major virulence mechanism for ASFV, but the dynamics of these changes during clinical disease are not completely understood. We constructed a detailed portrait of the innate immune responses during acute African swine fever (ASF) at the cellular, transcriptomic, and cytokine levels. Samples serially obtained from infected piglets show that progression of acute ASF is characterized by rapid increases in plasma type I interferons, TNF-α, IL-12p40, and IL-10, which coincide with the manifestation of clinical disease and viral DNAemia. Lymphocytes and natural killer (NK) cells progressively declined, with fluctuations in B cell, CD8+ T cell, and CD4+/CD8+ T cell populations. Blood monocytes and macrophages were highly variable throughout infection, with an abrupt spike in CD203+ mature macrophages immediately prior to death. Transcriptomic analysis of blood showed downregulation of cellular translation as early as 1 day post-challenge (DPC) and significant upregulation of antiviral immune processes at 5 DPC and 7 DPC, which overlapped with the onset of clinical disease. Together, these results present a detailed delineation of fatal ASF which involves an initial infection and damage of susceptible myeloid cells prior to symptomatic disease characterized by pro-inflammatory immune responses, lymphoid depletion, and clinical deterioration. Full article

Background/Objectives: CD38-targeting monoclonal antibodies isatuximab and daratumumab have revolutionized multiple myeloma (MM) treatment, but a deeper understanding of their distinct mechanisms is crucial for therapeutic optimization. Methods: We used flow cytometry to assess isatuximab and daratumumab binding competition in MM cell lines and patient-derived bone marrow cells. The dynamics of CD38 expression were evaluated at different time points before and after antibody-mediated removal. The effects of IMiDs (pomalidomide, lenalidomide) on CD38 expression and isatuximab-induced apoptosis, either alone or in combination with IMiDs, were also examined. Moreover, MM cell migration was assessed through CXCR4-mediated assays, and cell adhesion was evaluated via CD49d-dependent assays. Results: Isatuximab and daratumumab did not compete for CD38 binding, confirming distinct epitope recognition. Following depletion with either antibody, CD38 expression on the MM cell surface began to recover within 2 h, suggesting a dynamic regulation of CD38 availability. While daratumumab lacked direct apoptosis, isatuximab induced significant direct cell death. Pomalidomide enhanced isatuximab-induced apoptosis by increasing CD38 expression, whereas lenalidomide had no significant effect. Additionally, both antibodies effectively inhibited MM cell migration and significantly reduced cell adhesion. Conclusions: Their non-competitive binding and shared impact on cell dynamics suggest opportunities for optimizing treatment strategies through combinatorial or sequential approaches in MM therapy. Full article

In this study, the applicability of carbon dots (CDs) for the treatment of oral cancer cells in vitro was assessed under laser irradiation. For the study, CDs were synthesized using an amino acid via heat treatment and then combined with a photosensitizer. The absorbance and photoluminescence of CDs were measured. The production of reactive oxygen species (ROS) was evaluated using assay agents. The glutathione (GSH) content of the test solutions was evaluated. The viability of normal and cancer cells was evaluated using CDs at different concentrations under laser irradiation. Live/dead cells and intracellular lipid peroxidation (LPO) were observed after treatment. According to the assays, the production of •OH, •O₂⁻, and ¹O₂ was spectroscopically observed, which was reflected by the change in their peak absorbance. GSH was depleted mostly during light irradiation. Cancer cells were eliminated without leaving visible live cells, whereas normal cells were minimally affected. Intracellular LPO was confirmed in cells by green fluorescence, which was emitted from an oxidized assay dye. Conclusively, the amino acid-based photosensitizer-combined CDs eliminated approximately 70% of the cancer cells in vitro under laser irradiation, with no visible live cells. Based on these assays, ROS production may induce cell death via synergistic apoptosis–ferroptosis therapy. Full article

Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer’s disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson’s disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety. Full article

Background: Respiratory syncytial virus (RSV) remains a leading cause of respiratory illness globally, with limited vaccine options, particularly for infants and high-risk populations. This study investigates Cyclosporin A (CsA), traditionally an immunosuppressant, as a novel adjuvant to enhance RSV-specific immunity. Methods: BALB/c mice were subcutaneously immunized with RSV G protein co-administered with varying Cyclosporin A doses, challenged intranasally with RSV, and analyzed for RSV-specific humoral immunity and mechanistic Treg-dependent B-cell responses. Results: We demonstrate that co-administration of CsA with the RSV G protein (G+CsA) dose-dependently boosts RSV-specific IgG and neutralizing antibodies, with selective augmentation of IgG1 and IgG2 subclasses. Mechanistically, G+CsA induces regulatory T cells (Tregs) expressing CD40L and IL-10, which directly promote B-cell activation, proliferation, and plasma cell differentiation. Depletion of Tregs or neutralization of IL-10/CD40L abrogated antibody production, confirming these pathways as critical mediators. Notably, G+CsA-induced Tregs adopt a helper phenotype distinct from conventional Tregs, balancing immune enhancement and homeostasis. Conclusions: CsA demonstrates dual adjuvant properties by enhancing RSV-specific neutralizing IgG titers through Treg-driven B-cell activation, offering a potential strategy to optimize vaccine-induced humoral immunity. Full article

Background/Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is a rare peripheral T-cell lymphoma of follicular helper T-cell (TFH) origin, often associated with immune dysregulation and EBV-positive B-cell proliferation. Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus 8 (HHV-8), typically arising in immunocompromised individuals. The synchronous occurrence of AITL and KS in HIV-negative patients is exceptionally rare, with only three cases previously reported worldwide. Case Presentation: We describe an 81-year-old HIV-negative Korean woman presenting with progressive generalized edema and dyspnea. Imaging revealed multifocal lymphadenopathy. Excisional biopsy of the inguinal lymph node showed two distinct but adjacent neoplastic processes. The AITL component demonstrated a polymorphous infiltrate of atypical TFH cells expressing CD3, CD4, CD10, PD-1, and Bcl-6, with monoclonal TCR-γ rearrangement and TET2 and RHOA mutations. The KS component comprised spindle cells with slit-like vascular spaces, red blood cell extravasation, and immunoreactivity for HHV-8, CD31, CD34, and ERG. The findings were consistent with a collision tumor. Despite supportive care, the patient’s condition deteriorated, and she was discharged with palliative care. Discussion: The coexistence of AITL and KS in an HIV-negative setting raises important pathogenetic considerations. AITL is characterized by profound immune dysregulation, with depletion of normal T-cell subsets, abnormal B-cell activation, and cytokine milieu changes that may favor latent viral reactivation. This immunologic environment may permit HHV-8 reactivation, thereby facilitating the development of KS even in the absence of overt immunodeficiency due to HIV infection. Our findings support the hypothesis that AITL-related immune dysfunction may create a permissive niche for HHV-8-driven neoplasia. Conclusions: This is the first reported case in Asia and the fourth worldwide of a collision tumor comprising AITL and KS in an HIV-negative patI dient. The case suggests that AITL-associated immune dysregulation may facilitate HHV-8 reactivation and KS development even in the absence of HIV infection. Awareness of this association is critical for accurate diagnosis and optimal patient management. Full article

Background: Human Immunodeficiency Virus (HIV) is a virus that progressively impairs immune function by depleting CD4 + T-lymphocytes, ultimately leading to acquired immunodeficiency syndrome (AIDS). People living with HIV face a higher risk of developing various bone disorders, such as osteopenia, osteoporosis, and osteonecrosis. The aim of this study was to evaluate the bone mineral density (BMD) status, to determine the prevalence of osteopenia/osteoporosis and to identify the risk factors for low BMD in patients living with HIV undergoing antiretroviral treatment (ART), registered in Craiova Regional Center. Methods: A retrospective study was conducted between June 2024 and January 2025, including HIV-infected subjects aged over 18 years. Results: The study group included 106 patients. Dual-energy X-ray absorptiometry (DEXA) showed that 87 patients had low BMD, 51% having osteopenia and 31.1% having osteoporosis. We found a statistically significant correlation between low BMD and older age, higher levels HIV viremia, CD4 nadir < 200 cells/mm³, prolonged ART exposure and tenofovir disoproxil fumarate containing regimens. Conclusions: These findings support the inclusion of routine bone health monitoring in the standard care of patients with HIV, as well as the need for reevaluation. Full article

The STAT (Signal Transducer and Activator of Transcription) signaling pathway plays a central role in immune regulation by mediating cytokine responses and orchestrating both innate and adaptive immunity. Although CD4+ T cell depletion is the main driver of HIV-1–induced immunodeficiency, the virus also exerts a significant and often underestimated impact by disrupting the function of STAT family members, thereby exacerbating immune imbalance and accelerating disease progression. Specifically, HIV-1 suppresses STAT1 activation, impairing the induction of antiviral genes; inhibits IL-23–driven STAT3 activation in CD4+ Th17 cells with a reduction in IL-17; alters STAT3-dependent functions in antigen-presenting cells; and imposes profound—and at times opposing—dysregulations of STAT5, including the induction of a truncated isoform that contributes to latency. Notably, pharmacological inhibition of the JAK/STAT axis, particularly with JAK2 inhibitors, has been shown to reduce integrated proviral DNA and viral replication in vitro and in early clinical studies. This review provides an updated overview of the roles of individual STAT proteins in HIV-1 infection and pathogenesis, emphasizing the intricate interplay between viral factors and host signaling, highlighting the potential therapeutic implications, and suggesting that immunological assessment in HIV-1 patients should extend beyond CD4+ T cell counts and the CD4/CD8 ratio to include functional analysis of STAT signaling for deeper insights into immune dysfunction and chronic inflammation. Full article

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM’s heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers. Full article

Background: End-stage renal disease (ESRD) is a growing global health concern, and hemodialysis (HD) remains the most common life-sustaining therapy for patients with advanced kidney failure. Both humoral and cellular immunity are impaired post hemodialysis, leading to immune system dysfunction. Methods: We utilized flow cytometry to quantify cell populations based on surface markers, including CD3 (total T lymphocytes), CD4 (helper T-cells), CD8 (cytotoxic T-cells), CD19 (B lymphocytes), and CD16/CD56 (natural killer (NK) cells). EDTA-blood samples were collected intravenously immediately before and after dialysis. Results: A consistent decline in CD3⁺ T lymphocytes was observed post hemodialysis. This reduction occurred across both male and female cohorts: p = 0.0342 and p = 0.0002, respectively. CD8⁺ cytotoxic T-cells decreased significantly post HD, p = 0.0003. Conversely, CD4⁺ helper T-cells exhibited a paradoxical increase, p = 0.0321. The divergent trends in CD4⁺ and CD8⁺ cells led to a statistically significant increase in the CD4/CD8 ratio post dialysis, p = 0.0005. Notably, stratification by gender uncovered that the post-HD changes in CD4⁺ and CD8⁺ T-cells were exclusive to female patients. Females demonstrated a pronounced increase in CD4⁺ cells and a sharper decline in CD8⁺ cells compared to males. CD19⁺ B lymphocytes showed a statistically significant decline post hemodialysis (p < 0.0001). While both genders exhibited reduced B-cell percentages, female patients experienced a more pronounced reduction than males. NK cells were severely depleted post dialysis in both male and female cohorts. Conclusions: Overall, the immune alterations observed in HD patients, including T-cell reduction, B-cell lymphopenia, and changes in NK cell populations, contribute to the increased risk of infections, malignancy, and cardiovascular disease in this population. Full article

Celiac disease (CD) is a chronic autoimmune disorder triggered by gluten in genetically susceptible individuals. While gluten-free diet (GFD) remains the primary treatment, the molecular mechanisms underlying immune reconstitution remain poorly understood in pediatric populations. This study aimed to characterize T cell receptor (TCR) repertoire remodeling in pediatric CD patients following short-term GFD. We conducted a longitudinal observational study analyzing peripheral blood circulating T cells from five pediatric CD patients at two time points: pre-GFD (at diagnosis) and post-GFD (after 9–10 months of strict dietary adherence). Single-cell TCR sequencing was performed to analyze clonotype diversity, gene usage patterns and TRAV-TRBV pairing combinations. Analysis of 9661 T cells revealed significant TCR repertoire remodeling post-GFD. Expanded clones, predominantly cytotoxic CD8+ T cells, contracted post-GFD (p = 0.02), while increasing clonotype diversity. Notably, specific αβ chain pairings underwent clear reorganization in the complete T cell compartment. Pathogenic combinations were depleted post-GFD, especially in CD4+ T cells, while beneficial pairings became enriched. GFD induced comprehensive TCR repertoire remodeling, revealing that changes occur at the level of specific TCR pairings rather than individual gene usage. Our findings highlight the precision of single-cell approaches in capturing functionally relevant immune changes for monitoring treatment response in pediatric CD. Full article

Background: Various studies have demonstrated fucoidan’s immunomodulatory effects. A previous study reported the anticancer effects of Durvillaea antarctica fucoidan (DAF) via immune activation in mice. Methods: In this study, we confirmed the DAF’s pulmonary immune activation ability by nasal administration of the dendritic cells (DCs) and T cells. Furthermore, we examined its ability to enhance the efficacy of lung cancer treatment by combining it with anti-PD-L1 antibodies to activate the lung immune response. Results: Nasal DAF administration increased C-C chemokine receptor type 7 expression in DCs and promoted DC migration to the mediastinal lymph nodes (mLN). Specifically, DAF increased conventional DC type 1 (cDC1) and cDC2 numbers in mLN and potently activated cDC1. Furthermore, the nasal administration of DAF increased the production of inflammatory cytokines in the lungs and peripheral blood. Repeated intranasal administration of DAF induced T-cell activation, resulting in the enhanced production of interferon-gamma and tumor necrosis factor-alpha in CD4 T and CD8 T cells. CD8 T cells also showed increased secretion of cytotoxic mediators after DAF treatment, and the proportion of Tregs expressing FoxP3 decreased in the mLN. DAF inhibited lung cancer growth in Lewis lung carcinoma 2 cells, which was enhanced by combining it with an anti-programmed death-ligand 1 antibody. Finally, the anticancer effects of DAF were not observed in mice with depleted CD4-positive and CD8-positive cells. Conclusions: Nasal administration of DAF may inhibit lung cancer growth by inducing lung immune activation and is expected to be helpful as an immune activator for nasal administration. Full article

IgG4-related disease (IgG4-RD) is a subacute, progressive, multisystemic autoinflammatory condition which presents with nonspecific symptoms like weight loss, fatigue and myalgia, and is marked by lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells. IgG4-RD can involve various organs including the pancreas, bile ducts, thyroid, salivary and lacrimal glands, retroperitoneum, kidneys, lungs and CNS, often mimicking malignancy. A rigorous literature review was conducted. Articles on IgG4 disease, CD-19 and the MITIGATE trials were studied and included in the review. Glucocorticoids remain first-line therapy, but adverse effects and relapses are common. Rituximab, an anti-CD20 agent, is effective but may leave CD20-negative plasmablasts intact, contributing to relapse. In contrast, CD19-targeting therapies like inebilizumab offer more comprehensive B-cell depletion, including plasmablasts, potentially reducing relapses, fibrosis progression and long-term organ damage. MITIGATE trials showed promise in the use of an anti-CD-19 agent in preventing IgG4 disease flares and prolonging the time to first flare. Full article

Background: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), remains a major public health concern in Latin America. No licensed vaccine exists to prevent or treat T. cruzi infection. Identifying correlates of protection (CoPs) could provide substitute endpoints to guide and accelerate vaccine development. Although most CoPs established to date are antibody-based, their utility has not been demonstrated in T. cruzi vaccine reports. Thus, this study aimed to explore alternative strategies considering the use of immune cells as potential CoPs. Methods: Mice were immunized with a vaccine candidate based on the T. cruzi trans-sialidase protein (TSf) and potentiated with 5-fluorouracil (5FU) to deplete myeloid-derived suppressor cells (MDSCs). Percentages of CD4⁺, CD8⁺, and CD11b⁺Gr-1⁺ cellular biomarkers were assessed by flow cytometry from the peripheral blood of immunized mice, which were subsequently challenged with a high dose of T. cruzi. A machine-learning (ML) model based on decision trees was applied to identify potential CoPs to predict survival by day 25 post-infection. Results: Individual biomarkers obtained from flow cytometry did not show strong predictive performance. In contrast, biomarker engineering led to a combination that integrated biomarkers rationally: summing the percentages of CD8⁺ and CD4⁺ cells and subtracting the percentage of CD11b⁺Gr-1⁺ MDSC-like cells (REB), enhanced the predictive capacity. Subsequent computational analysis and ML application led to the identification of a better and even improved potential Integrative CoP: $2 \ast \%CD{8}^{+}+ {\%CD4}^{+} - {\%CD11b}^{+}{ Gr1}^{+}$(pICoP), which significantly improved the performance of a simple one-level decision-tree model, achieving an average accuracy of 0.86 and an average AUC-ROC of 0.87 for predicting survival in immunized and infected mice. Conclusions: Results presented herein provide evidence that integrating cellular immune biomarkers through rational biomarker engineering, together with ML analysis, could lead to the identification of potential CoPs for a T. cruzi vaccine. Full article