Search Results (35,581)

Adjuvants, which enhance the effectiveness of antigens, are essential for vaccines against infectious or malignant diseases. Currently, the development of adjuvants encounters challenges as highly effective adjuvants tend to be highly toxic, whereas those with lower toxicity often lack efficacy. Polysaccharides have unique advantages as adjuvants due to their multiple immunomodulatory activities and favorable safety profiles. In this study, longan polysaccharide (LP) was characterized physicochemically and identified as an effective adjuvant. LP, consisting of 96.44% glucose, was mainly linked by the α-1,6-glycosidic bond. In vitro experiments revealed that LP could induce the secretion of pro-inflammatory cytokines (TNF-α, IL12, and IL1β) and expression of co-stimulatory molecules (CD80 and CD86) through toll-like receptor 4 (TLR4) activation. More importantly, LP could promote antigen cross-presentation when formulated with a model antigen—ovalbumin (OVA). In vivo experiments indicated that the LP+OVA formulation could boost both humoral and cellular immune responses in immunized C57BL/6J mice. The histopathological evaluation of the major organs showed that LP+OVA was non-toxic. Therefore, our findings suggested that LP is an effective and safe adjuvant for vaccine development. Full article

Glucose oxidase (GOD) is a natural enzyme with antioxidant and antimicrobial properties but its effects on sows remain insufficient. This study investigated the effects of dietary GOD supplementation during gestation on inflammatory response, antioxidant capacity, immune function, and gut microbiota of farrowing sows. Twenty-four primiparous sows were randomly assigned to two groups and fed a basal diet or a basal diet supplemented with GOD (300 mg/kg diet) from gestation day 30 to farrowing. GOD supplementation significantly increased triglyceride, superoxide dismutase, and immunoglobulin M levels (p < 0.05), and significantly decreased alanine aminotransferase and interleukin-6 levels in serum (p < 0.05); significantly reduced placental interleukin-1β, malondialdehyde and tumor necrosis factor-α concentrations and NF-κB gene expression (p < 0.05), and elevated glutathione peroxidase activity and relative mRNA expressions of Nrf2, HO-1, GPX1 and SOD2 (p < 0.05). Moreover, GOD supplementation altered the fecal microbial community structure (p < 0.05), significantly reducing Clostridium, dgaA-11_gut_group, Bacteroides, and Prevotellaceae_NK3B31_group abundance (p < 0.05), while enriching Lachnospira, unclassified_f_Erysipelotrichiaceae, and Anaerostipes (p < 0.05). Collectively, 300 mg/kg glucose oxidase supplementation during mid-to-late gestation improved the health status of farrowing sows by improving nutrient utilization, immune function and antioxidant capacity, and altering fecal microbial structure and relative abundances. Full article

Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy–neuroinflammation axis in neurodegenerative disorders. Full article

Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments. Full article

(1) Background: Despite the success of combination antiretroviral therapy (cART), immune recovery in treated HIV infection remains heterogeneous, and discordant immune–virologic responses persist in a substantial proportion of people living with HIV (PLWH). These patterns may reflect ongoing immune dysregulation despite effective viral suppression. This study aimed to characterize discordant treatment classifications, evaluate immune imbalance using the CD4/CD8 ratio, identify associated clinical predictors, and assess opportunistic infection burden in a Romanian cohort of people living with HIV receiving long-term cART. (2) Methods: A retrospective cross-sectional study was conducted in 462 adults with HIV-1 infection receiving cART at the “Prof. Dr. Matei Balș” National Institute of Infectious Diseases, Bucharest (2018–2021). PLWH were classified as concordant responders (CR), immunological discordant responders (ID), or virological discordant responders (VD) based on plasma HIV-1 RNA and CD4+ T-cell count thresholds. Immune dysregulation was assessed using the CD4/CD8 ratio. Multinomial logistic, logistic, and negative binomial regression models were used to identify predictors of discordant responses, severe CD4/CD8 ratio inversion, and opportunistic infection burden. (3) Results: Discordant responses were observed in 30.7% of PLWH (14.5% ID, 16.2% VD). CD4/CD8 ratio inversion occurred in 71.2% and severe inversion in 40.0%. Significant differences across clinical classification groups were found for CD4+T-cell counts (H = 153.62, p < 0.001, ε² = 0.33) and CD4/CD8 ratio (H = 115.10, p < 0.001, ε² = 0.25), while CD8+ counts were similar (p = 0.571). Male sex was associated with both ID and VD, and severe CD4/CD8 inversion was strongly associated with ID. Opportunistic infection burden was associated with duration of HIV infection and CDC stage. (4) Conclusions: Discordant immune–virologic responses remain frequent during long-term cART and are characterized by persistent immune imbalance reflected by CD4/CD8 ratio inversion. The CD4/CD8 ratio may provide clinically relevant information on immune recovery beyond CD4+ T-cell counts. Full article

Background/Objectives: The emergence of SARS-CoV-2 variants and breakthrough infections underscores the need for next-generation vaccines capable of protecting from natural infection and/or preventing virus transmission. Intranasal vaccination offers a promising approach by eliciting local immune responses in the nasal mucosa, the primary site of infection and reservoir for transmissible virus. We evaluated two live-attenuated, respiratory syncytial virus-vectored vaccines in which the RSV F and G surface glycoproteins were replaced with a chimeric SARS-CoV-2 Spike protein from the ancestral USA/WA-1/2020 strain (MV-014-212) or the Delta variant (MV-014-212-delta). Methods: K18-hACE2 mice and LVG Syrian hamsters were vaccinated with a single intranasal dose of MV-014-212 or MV-014-212-delta. Systemic and mucosal immunity were assessed following vaccination, and protection was evaluated following Delta SARS-CoV-2 challenge. In vaccinated hamsters, morbidity, viral shedding, and lung inflammation and injury were also assessed following natural exposure to infected cagemates. Results: A single intranasal dose of either vaccine elicited systemic and mucosal immunity in K18-hACE2 mice, including serum neutralizing antibodies, Spike-specific memory B cells and plasmablasts, and Spike-specific CD8⁺ lung-resident memory T cells. Although MV-014-212-delta vaccination provided the best protection against the Delta variant virus challenge, both vaccines decreased viral loads in nasal discharge, lung, and brain, and reduced weight loss and mortality. In naturally acquired infection studies, vaccinated hamsters exposed to infected cagemates exhibited minimal weight loss, limited viral replication within the nasal mucosa, and attenuated lung pathology. Conclusions: Intranasal RSV-vectored vaccines can elicit broad protective respiratory immunity, suggesting that this platform could be leveraged for other respiratory pathogens. Full article

Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (≥50%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression. Full article

Melanoma-associated antigen (MAGE) is a promising immunotherapeutic target for cancer vaccines. Heat shock protein 110 (HSP110), expressed in various tumors, including canine mammary tumors, serves as a molecular marker. This study aimed to develop a recombinant fusion protein by linking HSP110 with MAGE-B10 to target MAGE-B10-expressed tumors and assess immune response efficacy. The recombinant MAGE-B10-HSP110 (rMAGE-B10-HSP110) fusion protein was constructed, and separate recombinant MAGE-B10 (rMAGE-B10) and recombinant HSP110 (rHSP110) proteins were also prepared for comparison. Our study on mice is distributed across five treatment groups: the rMAGE-B10-HSP110 fusion protein, rMAGE-B10, rHSP110, a protein mixture, and a PBS control. Antibody responses specific to canine MAGE-B10 were measured using ELISA, while splenocyte activation, proliferation, and cytokine production were analyzed using flow cytometry. The results showed significantly higher antibody responses in mice immunized with the rMAGE-B10-HSP110 fusion protein compared to those receiving PBS or rHSP110 on days 7, 14, and 21. The proportion of CD3+ and CD4+ lymphocytes were significantly higher in these mice (p < 0.05). rMAGE-B10-HSP110 fusion protein immunization also resulted in increased CD69+ lymphocytes and higher IFN-γ levels in stimulated lymphocytes (p < 0.05). In conclusion, the rMAGE-B10-HSP110 fusion protein effectively stimulates both innate and adaptive immune responses. Further in vivo investigation is recommended. Full article

The rectal mucosa houses a large number of viruses with important roles in shaping the local microbial communities and modulating immune responses, which could influence host susceptibility to infection and other diseases. Unique composition of the gut microbiome, including the predominance of clinically significant eukaryotic viruses like herpesviruses, cytomegalovirus, and human papillomavirus, has been described in both people with HIV (PWH) and men who have sex with men (MSM) vulnerable to HIV. Despite these insights, the rectal virome and the clinical implications of virome–bacteriome–immune interactions in the rectal mucosa remain poorly understood. In this review, we synthesize existing data on the composition of the rectal virome, its interactions with the bacteriome and the immune system, and implications on clinical outcomes in people living with or vulnerable to HIV. We also highlight the gaps and research needed to further explore and unravel these relationships. Full article

Gray mold caused by Botrytis cinerea poses a severe threat to tomato production. In this study, physiological, biochemical, transcriptomic, and proteomic analyses were integrated to characterize the dynamic responses of tomato ‘Ailsa Craig’ to B. cinerea infection. During B. cinerea infection, peroxidase (POD) activity showed a progressive increase, while catalase (CAT) activity was significantly upregulated at 24 hpi and remained stable through 48 hpi. Malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) contents showed a delayed response, increasing significantly only at 48 hpi, whereas SOD activity exhibited a biphasic pattern. Transcriptome and proteome profiling identified 5824 differentially expressed genes and 124 differentially expressed proteins. Functional enrichment analysis highlighted defense-related pathways, including plant–pathogen interaction, flavonoid biosynthesis, and inositol phosphate metabolism. Notably, the chlorophyll a/b-binding protein SlLhcb13 exhibited post-transcriptional upregulation despite transcriptional suppression. Functional validation demonstrated that overexpression of SlLhcb13 enhanced resistance, whereas silencing increased susceptibility. These findings identify SlLhcb13 as a positive regulator linking photosynthesis to immunity and provide new insights into the defense mechanisms of tomato. Full article

As a probiotic lactic acid bacterium, E. faecalis regulates intestinal flora, strengthens the intestinal barrier, and enhances immunity in the host. However, as a new strain isolated from healthy feline gut, E. faecalis HHP003 has an unclear effect on feline intestinal health. Twenty cats with mild diarrhea were randomly assigned to two groups: one group received the standard diet (MD), while the other group received supplemental E. faecalis HHP003 (EF). Meanwhile, 10 healthy cats were enrolled as a healthy control group (CON). After 42 days of intervention, the EF group exhibited significantly reduced serum inflammatory markers (TNF-α and IL-1β), as well as decreased levels of calprotectin and lipopolysaccharide, compared with the MD group (p < 0.05). The intestinal microbial diversity was altered in the EF group, with increased Chao and Shannon indices (p < 0.05). Specifically, the relative abundances of Bacillota, Bacteroidota, and Ruminococcaceae were significantly higher in the EF group than those in the MD group (p < 0.05). Metabolomic analysis identified 697 differential metabolites and nine KEGG metabolic pathways (p < 0.05) between the EF and MD groups. Furthermore, the study identified significant associations between the gut microbiota and selected serum metabolites. In summary, E. faecalis HHP003 supplementation was associated with reduced serum inflammatory responses, improved intestinal inflammation and barrier markers, and altered gut microbiota and serum metabolite levels in cats with mild diarrhea. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe hepatic steatosis, lobular inflammation, and fibrosis. Although hesperidin, a citrus-derived flavanone, has been reported to exert metabolic and anti-inflammatory effects, its role in severe inflammatory and fibrotic conditions such as MASH remains incompletely understood. This study aimed to evaluate the effects of hesperidin in MASH using integrated in silico and in vivo approaches. Methods: Potential targets of hesperidin were identified using network pharmacology and molecular docking. For in vivo validation, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for five weeks, with oral administration of hesperidin (150 or 300 mg/kg/day) starting from week two. The MCD model induces severe hepatic inflammation and fibrosis but does not fully reflect metabolic features such as obesity and insulin resistance. Hepatic histology, serum transaminases, immune cell populations, and hypothalamic neuroinflammatory markers were assessed. Results: In silico analyses suggested that hesperidin interacts with key regulators associated with MASH, including PPARG, TGFB1, and TNF. In the in vivo MCD-induced model, hesperidin treatment reduced hepatic lipid accumulation and collagen deposition, accompanied by significant decreases in serum ALT and AST levels (by approximately 30–34% and 42–53%, respectively, depending on dose). These effects were associated with downregulation of pro-inflammatory and pro-fibrogenic gene expression and increased expression of antioxidant markers. In addition, hesperidin decreased circulating Ly6C^high monocytes and hepatic Kupffer cells, along with reduced hypothalamic microglial and astrocyte activation. Conclusions: Hesperidin attenuated key pathological features of MASH, including steatosis, inflammation, and fibrosis, and was associated with modulation of peripheral immune responses and central neuroinflammatory markers. These findings suggest that hesperidin may influence the liver–immune–brain axis and warrant further investigation in models that more closely reflect human metabolic conditions. Full article

Background: Responses to atezolizumab plus bevacizumab (Atezo+Bev) in hepatocellular carcinoma (HCC) are heterogeneous, and response determinants remain unclear. We investigated whether spatial proximity between PD-L1(+) tumor-associated macrophages (TAMs) and CD8(+) T cells represents an immune niche associated with Atezo+Bev responsiveness. Methods: Multiplex immunohistochemistry was performed on biopsies from patients treated with Atezo+Bev (n = 23) or lenvatinib (n = 20). An interaction variable was defined via nearest-neighbor analysis as CD8(+) T cells within 25 µm of PD-L1(+) TAMs, normalized to cell counts. Associations with tumor shrinkage and progression-free survival (PFS) were examined. CD8(+) T cell phenotypes were evaluated via GZMB and TIM3. Transcriptomic profiling of resected HCCs (n = 8) was conducted using next-generation sequencing and gene set enrichment analysis (GSEA). Results: In a patient with responsive and non-responsive lesions, the responsive lesion showed closer PD-L1(+) TAM-CD8(+) T cell proximity. In cohort analyses, the interaction variable was associated with tumor shrinkage and prolonged PFS in the Atezo+Bev group, whereas PD-L1(+) TAM or CD8(+) T cell density alone was not predictive. This association was absent in the lenvatinib cohort. High-interaction tumors showed increased GZMB(+) and TIM3(+) CD8(+) T cells. Transcriptomic analysis revealed the upregulation of inflammatory, cytotoxic, chemotactic, and immunoregulatory genes, with enrichment of the chemokine, IFN-gamma, and IL-10 signaling pathways. Conclusions: Spatial proximity between PD-L1(+) TAMs and CD8(+) T cells defines an immune niche characterized by coexisting immune activation and regulatory programs and is strongly associated with Atezo+Bev responsiveness in HCC. Quantification of this spatial interaction may serve as a biopsy-based biomarker for immunotherapy stratification. Full article

An essential multiprotein complex in the innate immune system is the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. Through the coordination of upstream sensors and the adaptor protein ASC, which converge on the inflammasome complex in response to pathogens and cellular homeostatic disruptions, a broad range of metabolic danger signals activate the NLRP3 inflammasome. New research demonstrates the anti-inflammatory qualities of natural products, suggesting that they could be used as supplemental treatments for a number of chronic inflammatory conditions, such as diabetes mellitus and cardiovascular disorders. The literature related to inhibition of the NLRP3 inflammasome was compiled using keywords such as “NLRP3 Inflammasome”, “Natural products”, and “Inhibitor” from scientific databases, including “China Knowledge Resource Integrated Databases (CNKI)”, “Google Scholar”, “PubMed”, and “Web of Science” and so on, covering the period from 1997 to 2025. Herbal remedies have shown protection against the activation of the NLRP3 inflammasome. For the treatment of chronic inflammatory illnesses, natural products’ capacity to prevent NLRP3 inflammasome activation offers a novel and practical therapeutic approach. The impact of natural compounds made from medicinal plants on NLRP3 inflammasome activation and their underlying mechanisms of action are the main topics of this review. Full article

Stress has been prevalent and has become an epidemic health burden, loaded with chronic disorders. The stress response is an adaptive mechanism that prepares an individual to respond to threats or other stressors in a fight-or-flight situation. The stress response involves the induction of neurological and hormonal networks and is usually resolved when stress subsides; however, persistent stress leads to permanent and detrimental impacts on health. With the rise of advanced single-cell analysis technologies, a wave of basic and translational research aimed at elucidating stress has shed light on the underlying mechanisms. Among 80 studies in this review, stressors are classified into acute/chronic physical, physiological, and psychological groups, whereas some studies have more than one stress source. Single-cell RNA-seq was the dominant technology utilized in these studies. This advanced technique systematically reveals cellular heterogeneity in gene expression patterns and the differential transcriptomic landscape of stress response in a wide array of tissues and organ systems, e.g., the nervous system, the endocrine system, the immune system, and others. Bioinformatics identified a single-cell atlas of stress-specific cell subtypes, cell-to-cell interactions, and enriched pathways, showing promise for stress syndrome biomarkers, attenuation, and targeted therapy. The limits of these stress studies were mainly focused on transcriptomics, so future studies using multi-omics approaches across multiple organ systems will yield insights into stress disorders and novel therapeutic strategies. Full article