Immune Function Research Articles

Research Progress of PD 1/PD L1 Inhibitors in the Treatment of Urological Tumors.

Immune checkpoint inhibitors (ICIs) offer significant advantages for the treatment of urologic tumors, enhancing the immune function of anti-tumor T cells by inhibiting PD-1 and PDL1 binding. They have been shown to be well tolerated and remarkably effective in clinical practice, offering hope to many patients who are not well treated with conventional drugs. Clinical trials in recent years have shown that anti-PD-1 and PD-L1 antibodies have good efficacy and safety in the treatment of urologic tumors. These antibodies can be applied to a variety of urologic tumors, such as bladder cancer, renal cell carcinoma, and prostate cancer. They have been approved for the first-line treatment or as an option for follow-up therapy. By blocking the PD-1/PD-L1 signaling pathway, ICIs can release immune functions that are suppressed by tumor cells and enhance T-cell killing, thereby inhibiting tumor growth and metastasis. This therapeutic approach has achieved encouraging efficacy and improved survival for many patients. Although ICIs have shown remarkable results in the treatment of urologic tumors, some problems remain, such as drug resistance and adverse effects in some patients. Therefore, further studies remain important to optimize treatment strategies and improve clinical response in patients. In conclusion, PD-1/PD-L1 signaling pathway blockers have important research advances for the treatment of urologic tumors. Their emergence brings new hope for patients who have poor outcomes with traditional drug therapy and provides new options for immunotherapy of urologic tumors. The purpose of this article is to review the research progress of PD-1 and PD-L1 signaling pathway blockers in urologic tumors in recent years.

A critical role for microglia in regulating metabolic homeostasis and neural repair after spinal cord injury

Traumatic spinal cord injury (SCI) often results in severe immune and metabolic disorders, aggravating neurological damage and inhibiting locomotor functional recovery. Microglia, as resident immune cells of the spinal cord, play crucial roles in maintaining neural homeostasis under physiological conditions. However, the precise role of microglia in regulating immune and metabolic functions in SCI is still unclear and is easily confused with that of macrophages. In this study, we pharmacologically depleted microglia to explore the role of microglia after SCI. We found that microglia are beneficial for the recovery of locomotor function. Depleting microglia disrupted glial scar formation, reducing neurogenesis and angiogenesis. Using liquid chromatography tandem mass spectrometry (LC‒MS/MS), we discovered that depleting microglia significantly inhibits lipid metabolism processes such as fatty acid degradation, unsaturated fatty acid biosynthesis, glycophospholipid metabolism, and sphingolipid metabolism, accompanied by the accumulation of multiple organic acids. Subsequent studies demonstrated that microglial depletion increased the inhibition of FASN after SCI. FASN inhibition exacerbated malonyl-CoA accumulation and significantly impeded the activity of mTORC1. Moreover, microglial depletion exacerbated the oxidative stress of neurons. In summary, our results indicate that microglia alleviate neural damage and metabolic disorders after SCI, which is beneficial for achieving optimal neuroprotection and neural repair.

Potential mechanism of CARD16 protein action and susceptibility to sepsis in the elderly infected population: Through transcriptome analysis of blood

As global aging accelerates, the super-elderly population is at higher risk of infectious diseases, especially sepsis, a condition that may be associated with declining immune system function and abnormal inflammatory responses. The aim of this study was to investigate the role of CARD16 protein in sepsis susceptibility in the elderly population and its potential mechanism, and to reveal the expression characteristics of CARD16-related genes through blood transcriptomic analysis. Transcriptome sequencing was conducted on peripheral blood samples obtained from patients suffering from senile sepsis, along with samples from a healthy elderly control group. To examine the differences in gene expression, bioinformatics techniques were employed to compare the expression levels of CARD16-related genes between the two groups. Additionally, a comprehensive analysis was performed on the downstream inflammatory pathways and cytokines that are regulated by CARD16.The findings from the transcriptome analysis indicated that the expression of CARD16 was markedly upregulated in the cohort of patients experiencing hypersenile sepsis. This upregulation was associated with an increase in a variety of pro-inflammatory factors. Further network analysis suggested that CARD16 may potentiate the inflammatory response by modulating the NF-κB signaling pathway, which could consequently heighten the patients' vulnerability to sepsis.In comparison to the healthy elderly control group, the levels of anti-inflammatory genes in the super-elderly cohort were found to be significantly diminished. This observation points to a notable imbalance in immune regulation, further emphasizing the altered immune response in individuals with senile sepsis.

Construction a novel osteoporosis model in immune-deficient mice with natural ageing

Osteoporosis (OP) predominantly affects elderly individuals. Stem cells show potential for treating OP. However, animal models with normal immune function can eliminate implanted human cells. This study utilized naturally aging NOD/SCID mice, which exhibit immunodeficiency, to create a human osteoporosis model. This approach helps to minimize the premature immune clearance of transplanted allogeneic or xenogeneic cells in preclinical studies, allowing for a more accurate replication of the clinical pharmacological and pharmacokinetic processes involved in stem cell interventions for osteoporosis. NOD/SCID mice were fed until 12, 32, and 43 weeks of age, respectively, and then euthanized. We harvested lumbar vertebra for Micro‐Computed Tomography (Micro-CT) scanning and pathological examination. Additionally, we performed biomechanical testing of lumbar vertebra to assess the severity of osteoporosis. We utilized real-time RT-PCR to assess gene expression changes associated with bone metabolism, aging, inflammation, oxidative stress, and the Tgf-β1/Smad3 signaling pathway. In addition, the protein expression levels of P16, Tgf-β1 and Smad3 were detected using Western Blotting (WB). In comparison to 12-week-old mice, the 32-week-old and 43-week-old mice displayed significantly sparser and fractured trabeculae in their lumbar vertebra, lower bone mineral density (BMD), and changes in bone microstructural parameters (**P<0.01, ***P<0.001). Additionally, compared to 12-week-old mice, the 32-week-old and 43-week-old mice exhibited decreased expression of osteogenic genes (Alp, Opg, Sp7, Col1a1), increased expression of osteoclastic gene (Rankl), the number of TRAP-positive osteoclasts significantly increased in 32-week-old and 43-week-old mice compared to 12-week-old mice. The expression of genes related to aging and inflammatory (P16, Il-1β, Tnf-α) increases with advancing age (*P<0.05, **P<0.01, ***P<0.001). The expression of oxidative stress-related genes (Sod1, Sod2, Foxo3, Nrf2), as well as Tgf-β1 and Smad3 decreased with age (*P<0.05, **P<0.01, ***P<0.001). As age increases, the levels of P16 protein increase, Tgf-β1 and Smad3 proteins decrease. Our study successfully replicated osteoporosis models in NOD/SCID mice at both 32 and 43 weeks, with the latter exhibiting more severe osteoporosis. This condition seems to be driven by factors such as aging, inflammation, oxidative stress, and the Tgf-β1/Smad3 signaling pathway.

Vaccinations in older adults: Optimization, strategies, and latest guidelines.

This article is a summary of the first AGS Symposium entitled "Update on Vaccination Strategies for Older Adults: Matching the Approach to the Individual and the Care Setting." Given declines in host defenses and immune function with aging, vaccinations play a pivotal role in fortifying older adults against preventable infections, resulting diseases, disability, and death. Current guidelines generally list recommendations applicable for an average older adult of a given chronological age. However, growing evidence indicates that heterogeneity in terms of factors as varied as biological sex, frailty, functional status, and multimorbidity may impact vaccine responses and clinical outcomes. As a result, clinicians will increasingly need to take these additional factors into consideration as they seek to improve outcomes through improved targeting of such aging-related heterogeneity. Moreover, efforts at protecting older citizens through vaccination must also include strategies to overcome barriers to the adoption of vaccine recommendations in varied settings including long-term care. This 2023 AGS Plenary Symposium sought to commence a broader dialogue across AGS and beyond on optimizing vaccinations for older adults, ensuring not only extended lifespans but also healthier and more active lives. This report is not a systematic review, and thus should not be considered comprehensive.

Identification and Experimental Verification of PDK4 as a Potential Biomarker for Diagnosis and Treatment in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by sustained joint inflammation, with an etiology that remains elusive. Achieving an early and precise diagnosis poses significant challenges. This study aims to elucidate the molecular pathways involved in RA pathogenesis by screening genes associated with its occurrence, analyzing the related molecular activities, and ultimately developing more effective molecular-level treatments for RA. Microarray expression profiling datasets GSE1919, GSE10500, GSE15573, GSE77298, GSE206848, and GSE236924 were sourced from the Gene Expression Omnibus (GEO) database. Samples were divided into experimental (RA) and control (normal) groups. Differentially expressed genes (DEGs) were identified using R software packages such as limma, glmnet, e1071 as well as randomForest. Cross-validation of DEGs was conducted using lasso regression and the random forest (RF) algorithm in R software to pinpoint intersecting genes that met the criteria. Among these, one gene was selected as the target for correlation analysis to identify DEGs related to the target gene. Enrichment analysis utilized the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases and Gene Ontology (GO) data. Gene Set Enrichment Analysis (GSEA) was performed to compare the expression levels of the target gene (PDK4) across various biological pathways and functions in groups with high and low expression. The relationship between target gene expression levels and cellular immune function was assessed using the immune function score technique. The discrepancy in immune cell distribution between the control and experimental groups, as well as their correlation with target gene expression levels, was elucidated using CIBERSORT. The relationships between mRNA, lncRNA, and miRNA were depicted in the ceRNA regulation network. The expression levels of the target gene were validated using Western blot and qRT-PCR. In this study, six intersecting genes meeting the criteria were identified through cross-validation, and PDK4 was chosen as the target gene for further investigation. Functional analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that PDK4-associated DEGs are primarily enriched in the PPAR signaling pathway, thereby regulating synovial cell proliferation and migration, ultimately influencing the onset and progression of rheumatoid arthritis (RA). Immune infiltration analysis suggested that eosinophil quantity may influence the progression of RA. Experimental results from PCR and Western blot confirmed the downregulation of PDK4 in the RA group. The significant downregulation of PDK4 expression in patients diagnosed with rheumatoid arthritis (RA) was confirmed. PDK4 may function as a novel regulatory factor in the onset and progression of RA, with potential applications as a diagnostic biomarker for the condition.

Profiling the L-arginine/arginase 1 metabolism in early and advanced atherosclerosis

Abstract Background Atherosclerosis is a chronic inflammatory disease and the primary underlying cause of cardiovascular disease (CVD). Recently, intracellular metabolic pathways have been identified as master switches of immune cell function and thus seem promising targets for therapeutic interventions aimed at lowering inflammation and thereby atherogenesis. Decades of research have demonstrated the importance of the amino acid (AA) L-arginine (Arg) in CVD. Although most research has focused on endothelium-dependent effects of Arg by the nitric oxide synthase (NOS), Arg metabolism - mainly through its metabolizing enzyme arginase 1 (Arg1) - has also been shown to regulate immune cell responses independent of its endothelial functions. Despite these findings, the cell-specific contribution of Arg/Arg1 metabolism on atherogenesis is still largely unknown. Purpose Profiling the Arg metabolism in endothelial and immune cells to identify cell-specific changes during athero-progression. Methods To investigate Arg metabolism in atherogenesis, we fed apolipoprotein E deficient (Apoe-­/­-) mice a Western diet (WD) for 6 and 12 weeks. Chow diet-fed aged-matched Apoe-­/-­ mice were used as littermate controls and C57BL/6 mice as steady-state controls. Systemic and local Arg concentrations were measured by mass-spectrometry. Arg metabolism in organs was studied by qPCR. Arg1 expression in atherosclerotic lesions was examined by immunohistochemistry (IHC). To assess cell-specific expression of Arg-related enzymes, aortic leukocytes from WD-fed Apoe-­/-­ mice were subjected to CITE-seq analysis. The role of T cell Arg1 was determined by nor-NOHA inhibition in Jurkat cells. Results AA measurements showed that systemic Arg was reduced in early and advanced atherogenesis (p&amp;lt;0.02), and splenic Arg was reduced in advanced atherogenesis (p=0.006) compared with steady state. In advanced atherosclerosis, Arg1 was decreased in the liver but increased in the spleen and aorta, whereas Nos2 was increased in the liver and aorta compared with steady state. To identify the cell types driving these local changes, we performed IHC on atherosclerotic lesions. Arg1+ lesional macrophages accumulated in advanced compared to early lesions (p=0.03), whereas Arg1+ endothelial cells tended to decrease (p=0.2). Surprisingly, we also found an accumulation of Arg1+ CD4+ T cells in lesions and a further upward trend with athero-progression. CITE-seq confirmed a constitutive expression of Arg1 in lymphoid clusters. In vitro experiments with Jurkat cells showed that arginase inhibition suppressed T cell proliferation and promoted apoptosis and migration (all p&amp;lt;0.0001). Conclusion Our data indicate that Arg metabolism is strongly regulated during athero-progression and suggest a so far unknown role of T cell-intrinsic Arg/Arg1 metabolism in the disease. Murine atherosclerosis studies are now being performed to decipher the cell-specific contribution of Arg/Arg1 metabolism in atherosclerosis.

Evaluating off-target drug effects seen in RCTs using proteomics and mendelian randomisation

Abstract Introduction Serious adverse drug effects are often not detected until late in drug development after thousands of patients have been exposed to an investigational drug in long and costly clinical trials. More efficient approaches are desirable. Proteomics-informed Mendelian randomisation (MR) can identify potential molecular mechanisms underlying off-target effects of pharmaceuticals and drug repurposing opportunities. Purpose As a demonstration of this approach, we used findings from a previous plasma proteomics study nested within a clinical trial of torcetrapib, which was terminated early because of an increased risk of cardiac events and mortality, in which 200 plasma proteins significantly increased (n=68) or decreased (n=132) after three months of torcetrapib use. We surveyed potential plasma protein-mediated causal effecs of torcetrapib on a wide array of relevant phenotypes in three broad domains: cardiovascular(n=10), immunological(n=9) and cancer(n=4), representing major categories of adverse outcomes that were more common in the treatment arm. Methods We performed three-sample MR on torcetrapib-associated proteins. First, we identified independent cis-pQTL instruments for these proteins in the Atherosclerosis Risk in Communities (ARIC) Study. Then, we used pQTL effect estimates from the deCODE study, to reduce the potential for bias due to winner’s curse and to increase precision. Lastly, we conducted MR analyses on disease-relevant phenotypes using a debiased-IVW estimator and summary results from the largest available GWAS on these phenotypes: coronary artery disease, ischaemic stroke, blood pressure, lipids, heart rate, QT interval, eGFR, serious infections, blood cell counts, immune cell fractions, and several cancers. The significance level for causal protein-phenotype associations was p=1.85E-5 (0.05/(104*26)), correcting for the 104 proteins with valid instruments and the 26 tested outcomes. Results Thirty-three proteins had evidence of a causal association with at least one phenotype. Seventeen proteins were associated with cardiovascular outcomes, including 8 for blood pressure and 9 for lipid levels. We identified more proteins, 25, associated with immune-related phenotypes. One protein was associated with cancer. Of note, 9 proteins had pleiotropic effects across several domains. Conclusions Our approach of using Mendelian randomisation to investigate the causal effects of plasma proteins impacted by medication with known off-target adverse effects revealed several novel causal relationships, highlighting the role of immune function in the development of cardiovascular disease. These results support the use of intermediate omics evaluation to identify potential biomarkers for safety monitoring for drug development and reveal avenues of investigation for drug repurposing.

Ginsenoside Rg3 activates the immune function of CD8+ T cells via circFOXP1-miR-4477a-PD-L1 axis to induce ferroptosis in gallbladder cancer.

Gallbladder cancer (GBC) is the most common and leading cause of cancer-associated mortality among biliary tract carcinomas worldwide and there is no specific drug for treatment. Activation of CD8+ T cell immune activity is one of the strategies to improve GBC treatment. This study is aimed to investigate the role of Ginsenoside Rg3 on CD8+ T cell activation and pathogenesis of GBC. In GBC cells, Rg3 administration led to the significant reduction of circFOXP1 and PD-L1 as measured by Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting. Mechanistically, circFOXP1 acted as the sponge of miR-4477a to regulate PD-L1 expression as demonstrated by RNA pull-down assay and dual luciferase reporter assay. Rg3 treatment enhanced the activity of CD8+ T cells by inhibiting thecircFOXP1/miR-4477a/PD-L1 signaling axis. Besides, Rg3 administration induced lipid oxidation and ROS reduction as detected by Flow cytometry, resulting in ferroptosis via theinactivation of circFOXP1/miR-4477a/PD-L1 axis. Ferroptosis inhibitor Fer-1 administration could reverse the beneficial effects caused by Rg3 treatment while ferroptosis inducer Erastin treatment enhanced the effects. Moreover, Rg3 gavage alleviated tumor growth and elevated ferroptosis and apoptosis in tumor tissues, which were prevented by PD-L1 overexpression. Furthermore, Rg3 was demonstrated to activate the function of CD8+ T cells via regulating thecircFOXP1-miR-4477a-PD-L1 signaling axis in vivo. Rg3 inactivated thecircFOXP1-miR-4477a-PD-L1 signaling axis to activate the immune function of CD8+ T cells, thereby inducing ferroptosis and apoptosis in GBC cells. This research recognizes the mechanism of Rg3-mediated anti-cancer effect and offers evidence for the potentiality of Rg3 in clinical application for GBC therapy.

Exploring the Vital Role of Vitamins in Disease Prevention and Health Maintenance

The human body relies on vitamins to carry out fundamental functions, yet it is unable to produce them on its own. Certain nutrients, like phytochemicals, are considered essential as the body cannot produce them in sufficient quantities. While ideally vitamins are obtained through a healthy diet, supplements are often necessary. Vitamins are crucial for growth, metabolism, and overall health, with vitamin D being the only one the body can produce. Vitamers, related molecules with similar vitamin activity, make up the bulk of vitamins. Vitamin C is a potent antioxidant drug used in dermatology to treat photoageing and hyperpigmentation. L-ascorbic acid is the active form, with limited oral absorption, making topical application more effective. Its electron-donating ability is crucial for various physiological processes, and its deficiency can lead to scurvy. Vitamin E (tocopherols and tocotrienols) has demonstrated significant biological effects on enhancing human health and play a promising role in food systems Supplementation of α-tocopherol up to 0.2% in oils provides higher oxidative stability, making vitamin E a valuable functional ingredient for food preservation and nutritional quality enhancement.This study investigates the roles of vitamins C and E in disease prevention and management, highlighting their antioxidant properties and physiological functions. Both vitamins are crucial for neutralizing free radicals, thereby reducing oxidative stress linked to various diseases, including cardiovascular conditions, cancer, and neurodegenerative disorders. Vitamin C supports immune function and collagen synthesis, while Vitamin E contributes to cellular integrity and skin health. The research underscores the synergistic effects of these vitamins, which enhance each other's antioxidant capabilities and may improve overall health outcomes. By addressing their roles in disease processes, the study emphasizes the importance of adequate vitamin intake for promoting health and preventing illness

Evidence of honey-processed Astragalus polysaccharides improving intestinal immune function in spleen Qi deficiency mice integrated with microbiomics and metabolomics analysis.

Radix Astragali, commonly known as Astragalus, is a traditional medicinal and edible plant valued for its Qi-tonifying properties. The dosage form of Radix Astragali processed with honey, known as honey-processed Astragalus (HPA), shows improved Qi-tonifying efficacy as compared to the raw product. Polysaccharides are the main bioactive ingredients in its aqueous extract. This study used a multiomics approach integrating microbiomics and metabolomics to elucidate the Qi-tonifying mechanisms of honey-processed Astragalus polysaccharides (HAPS). HAPS-treated mice showed improved symptom scores, spleen and thymus indices, serum cytokines (tumor necrosis factor α, interleukin 1β) and intestinal mucosa secretory immunoglobulin A (SIgA) compared to the mice with spleen Qi deficiency. The analysis of gut microbiota indicated that HAPS regulated the relative abundance of Bacteroidetes, Bacteroides, Proteobacteria and Helicobacter, thereby improving intestinal flora dysbiosis in mice with spleen Qi deficiency. Eleven biomarkers in fecal metabolomics analysis were screened and identified, primarily associated with linoleic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and biosynthesis of unsaturated fatty acids. Furthermore, comprehensive analyses demonstrated that HAPS regulates palmitic acid and sphingolipid metabolism by modulating the abundance of Bacteroidetes, which in turn increased the levels of intestinal mucosal SIgA and restored intestinal mucosal immune function in mice with spleen Qi deficiency. Our findings revealed that HAPS is an essential active ingredient of HPA, and its Qi-tonifying mechanism is closely related to the improvement of intestinal immune function. These findings lay the foundation for the application of HAPS as an immunomodulatory agent in health and dietary foods. © 2024 Society of Chemical Industry.

Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation

Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4+ and CD8+ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4+ and CD8+ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.

The Impact of Acute Ammonia Nitrogen Stress on Serum Biochemical Indicators and Spleen Gene Expression in Juvenile Yellowfin Tuna (Thunnus albacares)

The presence of ammonia nitrogen in water has a significant impact on the serum and spleen of fish, potentially leading to changes in substances such as proteins in the serum while also causing damage to the immune function of the spleen. To investigate the effects of ammonia nitrogen (NH3-N) stress on juvenile yellowfin tuna (Thunnus albacares), this study established three NH3-N concentrations, 0, 5, and 10 mg/L, denoted as L0, L1, and L2, respectively. Serum and spleen samples were collected at 6, 24, and 36 h. The effects of different NH3-N concentrations and exposure times on the physiological status of juvenile fish were investigated by analyzing serum biochemical indices and splenic gene expression. The results indicate that in the L1 group, the serum high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), complement 3 (C3) and complement 4 (C4) levels, and acid phosphatase (ACP) activity showed a trend of initially increasing and then decreasing. In the L2 group, the serum low-density lipoprotein cholesterol (LDL-C), HDL-C, and C4 levels and ACP activity also displayed an initially rising and then declining trend, while TG, C3, and creatinine (CRE) levels and alkaline phosphatase (AKP) activity showed an upward trend. In the L1 group, glutathione peroxidase 1b (GPX1b), interleukin 10 (IL-10), interleukin 6 receptor (IL-6r), and tumor necrosis factor alpha (TNF-α) gene expression levels in the spleen exhibited a trend of first increasing and then decreasing. In the L2 group, IL-10, IL-6r, tumor necrosis factor beta (TNF-β), caspase 2 (casp2), and caspase 9 (casp9) gene expression levels in the spleen also showed an initial increase followed by a decrease. When NH3-N levels are below 5 mg/L, it is recommended to limit stress exposure to no more than 36 h for the juvenile fish. For concentrations ranging from 5 to 10 mg/L, stress should be strictly controlled to within 24 h. Exposure to high NH3-N levels may affect biochemical indicators such as serum lipid metabolism, immunity, and metabolism in juvenile fish, and may damage the expression of antioxidant, immune gene, and apoptosis factors in the spleen. This study aims to deepen our understanding of the effects of NH3-N on juvenile tuna, with the goal of establishing effective water quality monitoring and management strategies. This will ensure the quality of aquaculture water, reduce the harm caused by NH3-N to juvenile yellowfin tuna, and enhance aquaculture efficiency and product quality.

Pathogen-specific social immunity is associated with erosion of individual immune function in an ant

Contagious diseases are a major threat to societies in which individuals live in close contact. Social insects have evolved collective defense behaviors, such as social care or isolation of infected workers, that prevent outbreaks of pathogens. It has thus been suggested that individual immunity is reduced in species with such ‘social immunity’. However, this hypothesis has not been tested functionally. Here, we characterize the immune response of the ant Lasius niger using a combination of genomic analysis, experimental infections, gene expression quantification, behavioural observations and pathogen quantifications. We uncover a striking specialization of immune responses towards different pathogens. Systemic individual immunity is effective against opportunistic bacterial infections, which are not covered by social immunity, but is not elicited upon fungal infections, which are effectively controlled by social immunity. This specialization suggests that immune layers have evolved complementary functions predicted to ensure the most cost-effective response against a wide range of pathogens.

Recombinant leptins affect lipid metabolism in hepatocytes of Cynoglossus semilaevis

Leptin is a peptide hormone primarily produced by adipose tissue, which plays a crucial role in regulating energy balance by controlling appetite and energy expenditure. To better understand the intricate physiological functions of leptin in hepatocytes in tongue sole (Cynoglossus semilaevis), this study presents an integrated transcriptomic and metabolomic analysis of tongue sole hepatocytes following stimulation with lepA and lepB. Comparative analysis identified 2971 and 2900 upregulated differentially expressed genes (DEGs) and 1895 and 1821 downregulated DEGs in response to lepA and lepB stimulation, respectively. Notably, 5706 genes were commonly regulated by both stimulations, suggesting overlapping functional roles of these two leptin proteins. GO and KEGG enrichment analysis indicated significant enrichment in immune response (JAK-STAT signaling pathway, NF-κB signaling pathway, etc.) and lipid metabolism pathways, such as fatty acid synthesis, with similar findings for lepB. Metabolomic analysis demonstrated clear separation between treatment and control groups, with 34 medium- to long-chain fatty acids and numerous differentially expressed metabolites (DEMs) identified. KEGG analysis of the metabolome paralleled the transcriptomic findings, with shared pathways in lipid metabolism and immune function. Finally, joint analysis highlighted co-enrichment in linoleic acid metabolism and leishmaniasis pathways. Detailed mechanistic insights revealed the activation of JAK-STAT and NF-κB signaling pathways, modulation of arachidonic acid metabolism, and the influence on the MAPK signaling pathway. Additionally, lepA uniquely co-enriched in the fatty acid synthesis pathway, with specific gene regulation affecting the synthesis of various fatty acids. The study concluded that lepA and lepB exerted significant regulatory effects on lipid metabolism and immune responses in tongue sole hepatocytes through complex molecular networks. To our current knowledge, this represents the first direct evidence of leptin's role in immune function within teleost fish and offers valuable insights into the molecular mechanisms of lipid metabolism underlying the actions of lepA and lepB.

Relationships Among COVID-19-Related Service Uptake, HIV Status, Drug Use, and COVID-19 Antibody Status Among HIV Testing Intervention Participants in KwaZulu-Natal, South Africa

People living with HIV (PLWH) and people who use drugs are vulnerable populations who may face barriers to accessing health services and may have irregularities in immune function. People with undiagnosed HIV infection may be particularly likely to have compromised immune function. However, research about whether/how HIV status is related to COVID-19-related health outcomes has been equivocal, and research on the predictors of COVID-19-related health service access/uptake has been limited in Sub-Saharan African settings. Among 470 participants of a peer-recruitment-based HIV-testing intervention in KwaZulu-Natal, we examined whether HIV status and/or hard drug use were associated with uptake of COVID-19 testing and vaccination, and whether they moderated the relationship between COVID-19 vaccination status and COVID-19 IgG antibody status. Women were significantly more likely than men to report testing for COVID-19 (OR = 1.84; p = 0.002) and being vaccinated (OR = 1.79; p = 0.002). Neither HIV status nor drug use was associated with likelihood of getting tested or vaccinated. Vaccinated participants (90% of whom obtained vaccines more than 6 months before the study) were significantly more likely to test positive for COVID-19 IgG antibodies (OR = 6.86; p &lt; 0.0005). This relationship held true for subgroups of PLWH and participants with previously undiagnosed/uncontrolled HIV infection, and was not moderated by HIV status or hard drug use. These findings may suggest that both people who use drugs and PLWH were served as well as other people by KwaZulu-Natal’s COVID-19 response. However, gender-based disparities in COVID-19 service uptake suggest that special care should be taken during future COVID-19 outbreaks or other new epidemics to improve access to related healthcare services among men in this region.

Expression of key molecules of the classical inflammation activation pathway in blood leukocytes of autistic children

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders, whose causes are currently not fully understood. Research suggests that inflammation and changes in immune functions may play an important role in the development of autism. Increased levels of proinflammatory cytokines in the brains of autistic children lead to negative regulation of synaptic plasticity, as well as impaired proliferation and differentiation of neurons through activation of the nuclear factor kappa B (NF-κB) signaling pathway. The purpose of the work is to analyze the levels of mRNA: TLR2, TLR4, MyD88, IκBα, NF-κB p50, NF-κB p65 in peripheral blood leukocytes of children in comparison with the severity of autism spectrum disorders. The study included 126 children aged from 3 to 13 years (the ratio of boys to girls was 4:1): 45 children with typical neurodevelopment, and 81 children with a clinically confirmed diagnosis of autism. According to the Childhood Autism Rating Scale, 51 children had mild to moderate ASD (CARS score: 29-36), and 30 children had severe autism (CARS score: 36-60). The expression of inflammatory signal transduction pathway molecules was determined in peripheral blood leukocytes using real-time polymerase chain reaction with SYBRGreen. To compare the samples, one-way ANOVA and Tukey’s test were used. It was found that in leukocytes of children with severe ASD, the expression of the adapter protein MyD88 and the p65 subunit of the nuclear transcription factor NF-κB was significantly reduced, and the expression of the NF-κB inhibitor, IκBα, was significantly increased, compared to the control group. In leukocytes of children with mild ASD, a decrease in NF-κB p65 expression was found at a trend level. When comparing groups of children with different severity of autism symptoms (mild/severe), no significant differences were found in the levels of mRNA of key signaling molecules of the classical inflammation activation pathway in blood leukocytes. Thus, in the blood leukocytes of children with severe ASD, suppression of the expression of key molecules of the classical inflammation activation pathway (NF-κB) is observed, which leads to a decrease in the expression of pro-inflammatory cytokines: IL-1β, IL-18 and IL-2, against the background of increased expression of key cytokine of Th1 cells – IFNγ.

Consumption of a Probiotic Blend with Vitamin D Improves Immunity, Redox, and Inflammatory State, Decreasing the Rate of Aging—A Pilot Study

There is evidence of the effect of probiotic intake on the immune system. However, the effect probiotics may have on the rate of aging is unknown. The aim of this study is to determine the effect of a probiotic blend on immunity, redox state, inflammation, and the rate of aging or biological age. A group of 10 men and 14 women took, daily for 2 months, a sachet with three probiotics (Bifidobacterium animalis subsp. lactis BSO1, Lactobacillus reuteri LRE02, Lactobacillus plantarum LP14) and vitamin D. Before starting the treatment and after 2 months, peripheral blood was collected. Immune functions were assessed in isolated immune cells, and cytokine concentrations were also measured both in mononuclear cell cultures and plasma. Redox state parameters were also analyzed in whole blood cells. Finally, the Immunity Clock was applied to determine the biological age. Results show that the intake of this probiotic blend in general, in both men and women, improves immunity and decreases the oxidative and inflammatory state. In addition, it rejuvenates the biological age by 10 years on average. It can be concluded that this probiotic blend could be proposed as a good strategy to slow down the aging process, and to achieve healthy aging.

Clinical characteristics and nomogram model for predicting the risk of recurrence of complicated urinary tract infection in pediatric patients

Complicated urinary tract infection (cUTI) has higher incidences of antibiotic resistance, recurrence, chronicity, and progression. There exist differences in the immune functions, anatomical structures and physiological functions of urinary tract system between children and adults. In addition, the immature stage of hygiene habit development and the inability to express discomfort accurately all contribute to cUTI recurrence in pediatric patients. cUTI recurrence in children can lead to serious consequences such as growth and development delay, renal scars, and progression to end-stage kidney diseases. Despite the high incidence of cUTI recurrence, no predictive model currently exists to guide targeted intervention in pediatric patients. This study aimed to establish a nomogram to predict the risk of cUTI recurrence in children, thereby facilitating targeted prevention and treatment strategies in pediatric patients. The nomogram was developed based on a retrospective cohort that included 421 pediatric patients with cUTI at West China Second University Hospital from January 2020 to August 2023. The patients were randomly divided into a training set and a validation set in a 3:1 ratio. Logistic regression analysis was used to identify risk factors and construct the nomogram for predicting the risk of cUTI recurrence, followed by validation and performance analysis. Of the 421 children with cUTI, the recurrence rate of cUTI was 68.4% (288 cases) during an average follow-up duration of 22.9 months. The nomogram comprised female gender, history of urinary tract surgery, Escherichia coli in urine culture, renal dysfunction, and vesicoureteral reflux as predictors of cUTI recurrence in pediatric patients. The model showed favorable performance with C-index values of 0.735 and 0.750 in the training dataset and the validation dataset, respectively. The decision curve analysis revealed that the nomogram might be clinically useful. The reliable nomogram would be beneficial for clinicians to identify children with high risks of cUTI recurrence for targeted intervention.

Interactions between the human milk oligosaccharide 2′-fucosyllactose and Bifidobacterium longum subspecies infantis in influencing systemic immune development and function in piglets

IntroductionThe oligosaccharide 2′-fucosyllactose (2′-FL) is a predominant component of human milk, serving as a prebiotic for gut microbiota and influencing immune development in infants. Bifidobacterium longum subspecies infantis (B. infantis) is a commensal bacterium found in breastfed infants. Both 2′-FL and a specific strain of B. infantis, Bi-26™, are commercially available. This study investigates the potential synbiotic relationship between 2′-FL and Bi-26™ on immune development.MethodsTwo-day-old piglets (n = 53) were randomized in a 2 × 2 design, receiving either a commercial milk replacer ad libitum without (CON) or with 1.0 g/L 2′-FL (FL). Piglets in each diet were further randomized to receive either glycerol stock alone or Bi-26™ (109 CFU) (BI and FLBI) orally once daily. On postnatal day (PND) 34/35, animals were euthanized, and blood was collected for serum cytokine analysis. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated for ex vivo stimulation and flow cytometry analysis. Serum and ex vivo cytokines were analyzed using a multivariate model. All other outcomes were analyzed using a two-way ANOVA, considering prebiotic and probiotic fixed effects. The significance level was set at a p value &amp;lt;0.05, with trends reported for 0.05 &amp;lt; p &amp;lt; 0.1.ResultsImmune cell populations in PBMCs were unaffected by the experimental treatment. However, serum interleukin (IL)-1RA, IL-1β, IL-12, and IL-18 were all higher (p &amp;lt; 0.05) in the FL group than in the CON group. In isolated PBMCs, lipopolysaccharide (LPS) stimulation resulted in higher IL-1RA and a trend for higher IFN-γ secretion in the FL group vs. the CON group.Conclusion2′-FL stimulates a balanced cytokine profile in healthy piglets without changing immune cell populations. When immune cells are stimulated ex vivo with LPS, 2′-FL primes T-cells for a proinflammatory response, which is moderated by co-administration of Bi-26™.