Changes In Immune Function Research Articles

Fluoride-Mediated Immune Damage Through Cytokine Network Regulation of Tregs

Long-term fluoride exposure can induce inflammatory responses in various tissues of the body, thereby affecting the inflammatory microenvironment. To explore how fluoride induces changes in immune function within this microenvironment, this study collected baseline information and biological samples from participants in areas with the drinking water type of fluorosis, and simultaneously established Wistar rat models with a 12-week and 24-week fluoride exposure, as well as a 12-week fluoride exposure followed by 12-week pure water feeding regimen. Luminex multiplex assays and enzyme-linked immunosorbent assays (ELISAs) were used to measure cytokine expression levels. Subsequently, correlation analysis, multiple linear regression, and mediation analysis were employed to explore the long-term effects induced by the complex cytokine network during fluoride exposure. The population survey results indicated that fluoride suppressed the expression of pro-inflammatory factors such as Interleukin-2 (IL-2), Interleukin-12 (IL-12), Interferon-γ (IFN-γ), Tumor necrosis factor-α (TNF-α), and anti-inflammatory factors such as Interleukin-4 (IL-4), Interleukin-13 (IL-13), and Interleukin-37 (IL-37), while promoting an increase in the proportion of regulatory T cells (Tregs) in peripheral blood. Among these, IL-2 and IFN-γ mediated the fluoride-induced peripheral Tregs expansion. Animal experiments indicate that the proportion of Tregs in peripheral blood and immune organs increases in a time-dependent manner with fluoride exposure. After reducing the fluoride concentration in the drinking water of rats, the number of Tregs remained significantly elevated. The changes in Treg numbers in the 12-week fluoride feeding group, 24-week fluoride feeding group, and 12-week fluoride feeding followed by 12-week water improvement group were related to the cytokine levels. Therefore, the impact of fluoride on the immune homeostasis has cumulative and long-term effects, and may be related to the accumulation and migration of Tregs induced by fluoride in an inflammatory environment, mediated by cytokines.

Effect of circadian rhythm disruption induced by ‍time-restricted feeding and exercise on ‍oxidative stress and immune in mice

Frequent or long-term circadian disorders can lead to a range of health problems, including chronic insomnia, depression, chronic diseases, and cancer. It has also been shown that altering the feeding time of mice from night to day can result in circadian disorder. Recent studies have revealed complex interactions between circadian rhythm and oxidative stress. However, little is known about the impact of circadian rhythm disorders caused by time-restricted feeding on mental state, immune function, and oxidative DNA damage. In this study, we investigated the effects of circadian rhythm disruption by controlling the timing of feeding and exercise on oxidative DNA damage and immune responses in 8-week-old mice for 14 days. Body weight, daytime running wheel activity, serum interleukin-6 levels, urinary 8-hydroxy-2'-deoxyguanosine levels, and nuclear DNA (liver, lung, testes, and pancreas) were significantly increased in the night-restricted group compared with the control group. Additionally, the mice in the night-restricted group exhibited anxiety-like behavior. These results indicated that the circadian rhythm disruption due to abnormal dietary timing can lead to obesity, mental state dysregulation, immune function changes and oxidative DNA damage in mice. This oxidative DNA damage may contribute to the initiation and increased risk of cancer.

Lower Serum IL-10 Linked to Oral Manifestations in Diabetes Patients.

Diabetes mellitus (DM) is a chronic disease that remains a global health problem with increasing prevalence, particularly in Indonesia. The presence of oral manifestations in patients with DM is influenced by changes in immune system function. Interleukin-10 (IL-10) is an inflammatory marker implicated in DM. However, no studies have investigated the differences in IL-10 levels between non-DM and DM patients with and without oral manifestations. This study aimed to compare the serum levels of IL-10 between non-DM and DM patients with and without oral manifestations at Dr. Hasan Sadikin Hospital Bandung. This observational study used a cross-sectional design. A total of 88 serum samples that met the inclusion criteria were selected, consisting of 37 (42%) samples from non-DM patients, 35 (39.8%) samples from DM patients with oral manifestations, and 16 (18.2%) samples from DM patients without oral manifestations. Serum levels of IL-10 were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Among the 35 DM patients with oral manifestations, xerostomia was the most common (80%). The mean serum IL-10 level was 0.93 pg/mL in non-DM patients, 0.80 pg/mL in DM patients with oral manifestations, and 1.08 pg/mL in DM patients without oral manifestations. Statistical analysis using the Kruskal-Wallis test showed a p-value of 0.008 (p ≤ 0.05), indicating a significant difference in serum levels of IL-10 between non-DM and DM patients with and without oral manifestations. DM patients with oral manifestations had lower IL-10 serum levels compared to non-DM patients and DM patients without oral manifestations. These findings suggest that monitoring IL-10 levels could help identify diabetic patients at higher risk for oral complications.

International Symposium on Ruminant Physiology: The involvement of the endocannabinoid system in metabolic and inflammatory responses in dairy cows during negative energy balance.

The endocannabinoid system (ECS) is involved in the regulation of energy metabolism, immune function and reproduction in mammals. The ECS is consisted of the endocannabinoid (eCB) ligands, enzymes, and cannabinoid receptors. In mammals, the cannabinoid-1 receptor (CB1/CNR1) is expressed in the central nervous system and in peripheral tissues; and its activation increases anabolic processes. The cannabinoid-2 receptor (CB2/CNR2) is most highly expressed in immune cells, and its activation exerts mainly anti-inflammatory effects. Until recently, little was known about the involvement of the ECS in physiological responses in dairy cows. As peripartum dairy cows undergo vast changes in energy metabolism and immune function, processes that are regulated by the ECS, several studies characterized ECS components in transition cows. Concentrations of eCB in the adipose tissue were higher postpartum (PP), and levels of the eCB N-arachidonoylethanolamide (AEA) were increased PP compared with prepartum. Exogenous injections of AEA to transition cows may increase adipose deposition, but did not affect feed intake. In vitro models showed that bovine adipocyte metabolism was differentially affected by CB1 agonists and antagonists in nonlactating non-gestating compared with PP cows. Thus, the responses of the PP dairy cows to ECS modulations may be related to the physiological and reproductive stage of the cow. Currently, whole-body ECS activation via agonists is mostly not feasible in vivo in livestock. Alternatively, downregulation of ECS activation can be achieved by supplementation of omega-3 (n-3) fatty acids. Indeed, in vivo studies with transition cows supplemented with n-3 showed a moderate downregulation of ECS components in the blood, adipose and liver, improved systemic insulin sensitivity, but evidently reduced insulin sensitivity in the adipose tissue PP. The abundance of CB1 was lower in immune cells, and anti-inflammatory effects were found in PP cows supplemented with n-3; possibly associating ECS downregulation with immune function. The physiological impact of ECS activation is an exciting and complex area of research, that could influence the physiology of dairy cows during metabolic and inflammatory challenges. Dairy cows may be an experimental model for ECS modulations, with broader relevance to female mammals. More research is required on how selective ECS activation/downregulation in tissues could affect immune-metabolic function in dairy cows.

SQLE-mediated squalene metabolism promotes tumor immune evasion in pancreatic cancer

BackgroundSqualene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and has been shown to negatively affect tumor immunity and is associated with poor outcomes of immunotherapy in various cancers. While most research in this area has focused on the impact of cholesterol on immune functions, the influence of SQLE-mediated squalene metabolism within the tumor immune microenvironment (TIME) remains unexplored.MethodsWe established an immune-competent mouse model (C57BL/6) bearing mouse pancreatic cancer xenografts (KPC cells) with or without stable SQLE-knockdown (SQLE-KD) to evaluate the impact of SQLE-mediated metabolism on pancreatic cancer growth and immune functions. The effect of squalene on tumor growth and immune cells was tested by direct administration of squalene to C57BL/6 mice bearing KPC tumors. Flow cytometry analysis and immunohistochemical (IHC) staining of immune cells from the tumor tissues were performed to evaluate changes in immune function. We also employed RNA-sequencing to analyze the gene expression profiles in pancreatic cancer cells (PANC-1) treated with or without squalene. RT-PCR and Western blot analyses were used to investigate the relevant molecular mechanisms.ResultsWe show that SQLE is significantly overexpressed in pancreatic cancer, and abrogation of SQLE results in a significant increase in squalene accumulation within tumor cells. The elevated squalene inhibits CXCL1 transcription through its impact on the NF-κB pathway via p65, and thus reduces the recruitment of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into the tumor microenvironment. Silencing of SQLE also leads to an increased proportion of CD8+ T cells in the tumor tissues and suppresses tumor growth in vivo. Importantly, direct administration of squalene, the metabolic substrate of SQLE, to immune-competent mice bearing KPC pancreatic cancer tumors causes a substantial decrease in CD206+ TAMs and MDSCs, thus releasing immune suppression and inhibiting tumor growth.ConclusionOur study shows that squalene is an important immune-modulating metabolite that inhibits the infiltration of immune-suppressive cells in TIME, and that SQLE exerts its tumor immune evasion effect by metabolic removal of squalene. Thus, SQLE-mediated squalene metabolic pathway could be a potential target to enhance antitumor immunity in pancreatic cancer.

Identification of pyroptosis-associated miRNAs in the immunoscape and prognosis of hepatocellular carcinoma

BackgroundHepatocellular carcinoma is one of the most prevalent types of liver malignancy and poses a severe threat to global health. Despite recent improvements in therapeutic approaches, treatment options for patients with advanced or recurrent HCC are still limited.Materials and methodsOur study analyzed miRNA differential expression using data from hepatocellular carcinoma patients in the Cancer Genome Atlas. Pyroptosis-related genes were identified from gene cards. Differential expression of miRNAs was analyzed using DESeq2 and visualized using ggplot2 and pheatmap. A prognostic risk model for pyroptosis-associated miRNAs was constructed using LASSO regression and validated by principal component analysis, Kaplan-Meier survival and ROC curve analysis. We also performed gene and pathway enrichment analysis. Immune cell infiltration and function in HCC were assessed using single-sample genomic enrichment analysis, and correlations with immune cells and function were explored. Also, CCK-8 assay as well as migration and invasion assays were performed after knockdown of miR-6844.ResultsWe have established and validated a prognostic risk model based on ten DEmiRNAs, which is important for the survival of HCC patients. Significant changes in immune cell infiltration and immune function were also found in high-risk patients. It also demonstrated that knockdown of miR-6844 inhibited HCC cell proliferation, migration and invasion, highlighting its role in HCC progression.ConclusionOur study reveals the implications of pyroptosis-associated differential miRNAs on the prognosis of patients with hepatocellular carcinoma and provides a foundation for novel HCC therapies, especially immunotherapy.

Insights into the paradoxical effect of smoking on vasculitis: a comprehensive review.

Vasculitis is a group of uncommon diseases characterized by inflammation of blood vessels, which contributes to the organ ischemia and damage. Cigarette smoke contains a high concentration of various toxins, which have the potential to affect the immune response and development of autoimmune/autoinflammatory rheumatic diseases including vasculitis. Smoking influences both innate and adaptive immune systems and plays binary functions in modulating immunity by either aggravating pathogenic immune responses or attenuating defensive immunity. Smoking contributes to the pathogenesis of autoimmune diseases by various mechanisms including induction of tissue damage and apoptosis, changes in innate immune function and production of proinflammatory cytokines, changes in humoral immunity and T cell responses and anti-estrogen effects. In this review, we considered the available evidence on the association between smoking with the risk, clinical manifestations, response to treatment and outcomes of vasculitis, and the effect of smoking cessation on these parameters. In conclusion, despite inconclusive evidence of an increased risk of giant cell arthritis and anti-neutrophil cytoplasmic autoantibody associated vasculitis (AAV) in smokers, there is strong evidence that smokers have a lower risk of Behcet's disease (BD). Furthermore, smoking changes the clinical picture and outcomes of BD and AAV.

Exploratory analysis of the key role of immune function changes in BPD

AbstractBronchopulmonary dysplasia (BPD) is one of the most prevalent and severe chronic lung diseases in premature infants. The objective of the current study was to screen for key BPD‐associated genes and pathways by transcriptomic analysis from clinical patients and animal models. In our study, the differentially expressed genes were screened from 58 children with 14‐day BPD and 40 normal children in the GSE32472 dataset of the Gene Expression Omnibus database. Then, we identified four hub genes (Cd3e, Cd3g, Cd247, and Itk) and a signaling pathway (T cell receptor signaling pathway) by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and protein‐protein interaction analysis. The differential expression of the relevant pathways and gene sets among the groups was verified via GSEA analysis. Subsequently, a rat model of BPD with hyperoxia‐induced lung injury was established, and the transcriptome sequencing of the whole lung tissue was performed. A similar analysis was done on the sequencing data of the hub genes and associated pathway screening to verify the accuracy. Ultimately, quantitative polymerase chain reaction was performed to validate the transcriptomics data of core gene expression in the rat model. Our study revealed that the downregulation of the expression of the above four key genes in the course of BPD leads to a decrease in the function of T cell receptor signaling pathways, it causes immune dysfunction and increases the severity of lung inflammation as well as susceptibility to other respiratory infectious diseases.

Effects of a Saccharomyces cerevisiae-Derived Postbiotic in Adult Labrador Retrievers Undergoing Exercise and Transport Stress

Postbiotics are emerging as potential functional ingredients for companion animal diets. This study aimed to determine if a Saccharomyces cerevisiae-based postbiotic can alter cytokine and stress responses to exercise and transport stress in adult Labrador Retrievers. Dogs received 15 g ground corn germ (Control, n = 12), 7.5 g postbiotic (Low, n = 12), or 15 g postbiotic (High, n = 12), daily for 63 days. Exercise was twice weekly for 7 weeks, and a single transport per dog occurred in week 8. Fecal inflammatory biomarkers, serum chemistries, and complete blood counts were assessed at the beginning and end of the study. Serum cytokines were quantified before and 18–20 h after the first and last exercise runs. Gait analysis was assessed before and 24 h after the first and final runs. Saliva cortisol was measured before and after transportation. Treatment did not affect blood chemistries, gait, fecal biomarkers, or saliva cortisol (p ≥ 0.19). Eosinophils increased slightly in Controls (p = 0.01), though remained below 0.80 × 109 cells/L. Most cytokines were unaffected by treatment (p ≥ 0.15), but there were minor changes in circulating monocyte chemoattractant protein-1 (p = 0.01) and IL-8 over time at the initial run (p = 0.03) and IL-10 in males (p = 0.02) in the Low dose dogs. The High dose decreased Blautia (p = 0.04) slightly and tended to decrease Fusobacterium abundances (p = 0.07). The Low dose tended to increase Clostridium hiranonis (p = 0.07) slightly. The tested S. cerevisiae postbiotic produced small changes in immune function and gut microbial species in dogs.

Changes of immune function mediated by Gasdermin-E in the immune microenvironment of primary oral squamous cell carcinoma

In primary oral squamous cell carcinoma (OSCC), the tumor microenvironment (TME) constitutes a highly intricate ecosystem comprised of cellular and acellular elements. The tumor immune microenvironment (TIME) is characterized by the presence of a broad of immune cells, while there is a scarcity of cytotoxic lymphocytes (CTLs) intratumorally. Consequently, the recruitment of a larger cohort of CTLs to infiltrate the tumor core has emerged as a pressing scientific challenge. Gasdermin E (GSDME), as a pivotal effector protein in pyroptosis, plays a significant role in anti-tumor therapy. Here, primary OSCC was induced by Gsdme knockout (KO) mice and wild type (WT) mice of the same strain respectively, using the chemical mutagen 4-Nitroquinoline N-oxide (4-NQO). Through comparative analysis of immune function between the two kinds of mice, intriguing observations have been elucidated, the presence of GSDME was instrumental in augmenting the infiltration of lymphocytes towards the neoplastic site, effectively ameliorating the TIME. Our findings elucidated that the absence of GSDME promotes the development of primary OSCC, accompanied by a notable increase in malignancy. Furthermore, our data delineated a positive inter-relationship between the presence of GSDME and the host organism’s immunological reactivity, which enhances the TIME in primary OSCC.

Dietary supplementation with Rehmannia glutinosa catalpol improves broiler performance by regulating intestinal immune microenvironment

Plant extracts have been widely considered as a feed additive. Rehmannia glutinosa catalpol can promote the growth performance of the host, improve the immune response, and strengthen the intestinal barrier function of the host. The broilers were fed with Rehmannia glutinosa catalpol (0.01%), and the composition of caecum microbiota in broilers was explored by 16S rRNA gene sequencing. Finally, the changes of intestinal mucosa morphology and immune function were analysed by tissue staining and RT-qPCR. The proportion of thick-walled bacteria in the treatment group was higher than that in the control group. At the genus level, the relative abundance of Faecalibacterium, Paraacteroides and Barnesiella increased after the addition of Rehmannia glutinosa catalpol. The function prediction results of PICRUSt2 showed that the microbiota mainly participated in the biosynthesis and degradation/utilization/association pathway. The results of tissue staining and RT-qPCR showed that the caecum tissue morphology and immune barrier function of broilers were significantly improved after the addition of catalpol. The results of this study show that Rehmannia glutinosa catalpol in the diet may be beneficial to the intestinal health of broilers, which may be achieved by regulating the intestinal microbiota and enhancing the immune function of broilers.

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.

Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas unknown_T cells were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift- myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). The shift- myeloid signature was also found to be associated with KD treatment resistance, and effective therapies improve treatment outcomes by reducing this signaling. Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model PHARE (https://xiazlab.org/phare/), which can apply to both scRNA-seq and bulk RNA-seq data. Using this model, we found patients with coronary artery disease (CAD) also exhibit accelerated aging compared to healthy individuals. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

How lactate affects immune strategies in lymphoma.

Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.

Evaluation of the safety of PD-1/PD-L1 inhibitors for immunotherapy in patients with malignant tumors after COVID-19 infection: A single-center cohort study.

An increasing body of evidence suggests a close association between COVID-19 infection and the safety of PD-1/PD-L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. We conducted a retrospective analysis of cancer patients who received PD-1/PD-L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune-related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter-subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi-squared, and Mann-Whitney U-tests. The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD-1/PD-L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). Our findings suggest that infection with COVID-19 does not significantly impact the safety of PD-1/PD-L1 inhibitors in cancer patients. Most cancer patients used PD-1/PD-L1 inhibitors during COVID-19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.

Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.

Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging andmuscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Extrachromosomal circular DNAs in prostate adenocarcinoma: global characterizations and a novel prediction model.

The role of focal amplifications and extrachromosomal circular DNA (eccDNA) is still uncertain in prostate adenocarcinoma (PRAD). Here, we first mapped the global characterizations of eccDNA and then investigate the characterization of eccDNA-amplified key differentially expressed encoded genes (eKDEGs) in the progression, immune response and immunotherapy of PRAD. Circular_seq was used in conjunction with the TCGA-PRAD transcriptome dataset to sequence, annotate, and filter for eccDNA-amplified differentially expressed coding genes (eDEGs) in PRAD and para-cancerous normal prostate tissues. Afterwards, risk models were created and eKDEGs linked to the PRAD prognosis were identified using Cox and Lasso regression analysis. The immune microenvironment of the risk model was quantified using a variety of immunological algorithms, which also identified its characteristics with regard to immunotherapy, immune response, and immune infiltration. In this research, there was no significant difference in the size, type, and chromosomal distribution of eccDNA in PRAD and para-cancerous normal prostate tissues. However, 4,290 differentially expressed eccDNAs were identified and 1,981 coding genes were amplified. Following that, 499 eDEGs were tested in conjunction with the transcriptome dataset from TCGA-PRAD. By using Cox and Lasso regression techniques, ZNF330 and PITPNM3 were identified as eKDEGs of PRAD, and a new PRAD risk model was conducted based on this. Survival analysis showed that the high-risk group of this model was associated with poor prognosis and validated in external data. Immune infiltration analysis showed that the model risks affected immune cell infiltration in PRAD, not only mediating changes in immune cell function, but also correlating with immunophenotyping. Furthermore, the high-risk group was negatively associated with anti-CTLA-4/anti-PD-1 response and mutational burden. In addition, Tumor Immune Dysfunction and Exclusion analyses showed that high-risk group was more prone to immune escape. Drug sensitivity analyses identified 10 drugs, which were instructive for PRAD treatment. ZNF330 and PITPNM are the eKDEGs for PRAD, which can be used as potential new prognostic markers. The two-factor combined risk model can effectively assess the survival and prognosis of PRAD patients, but also can predict the different responses of immunotherapy to PRAD patients, which may provide new ideas for PRAD immunotherapy.

Bone Marrow and Peripheral Blood Mononuclear Cell Phenotype Changes after Cultivation and Autologous Infusion in Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a condition affecting the liver and immune system. In this study, the impact of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation on PBC patients was investigated. Sixteen eligible PBC patients participated at the National Scientific Medical Center in Astana, Kazakhstan, between 2017 and 2022, and BM-MNCs were harvested from their anterior iliac crest. After isolating and cultivating the BM-MNCs, they were infused back into the patient's peripheral veins. Changes in BM-MNC and peripheral blood mononuclear cell (PB-MNC) phenotypes were assessed before and after a 24-hour cultivation period and 72 hours post-transplantation. We monitored liver function parameters over 6-month intervals and conducted flow cytometry analysis to assess CD markers on BM-MNCs before and after cultivation and PB-MNCs before and after transplantation. Statistical analysis included the Friedman test for liver parameters and the Wilcoxon signed-rank test for BM-MNC and PB-MNC comparisons. Our findings revealed significant reductions in liver function tests after multiple transplantations. Flow cytometry analysis before and after a 24-hour culture and autologous BM-MNC infusion revealed the expansion of specific cell populations, with significant increases in CD3+, CD4+, CD16+, CD20+, CD25+, CD34+, CD105+, CD73+, СD117+, and CD34+populations, while CD4+25+, CD34+105+, and CD4+FOXP3+ populations decreased. Interestingly, a contradictory finding was observed with a decrease in bone marrow CD34+105+ cell lines (P=0.03) alongside an increase in peripheral CD34+105+ population (P=0.03). In summary, our study shows that BM-MNC transplantation in PBC patients leads to changes in immune cell populations and liver function. These findings suggest potential therapeutic applications of BM-MNC transplantation in managing PBC and offer insights into the dynamics of immune cells associated with this treatment approach.

The interplay between aging and inflammation and its role in chronic disease development

This paper explores the complex relationship between aging and inflammation and its impact on the development of chronic diseases. Aging is an important contributor to elevated levels of inflammation, with mechanisms including changes in immune regulatory function, chronic low-grade inflammation, cellular aging and tissue damage, changes in gene expression, and increased oxidative stress. These inflammatory processes not only accelerate aging itself, but also promote the development of chronic diseases such as cardiovascular disease (CVD) and Alzheimers disease (AD). The article goes on to address other modern anti-inflammatory treatment approaches, such as biologics, JAK inhibitors, and nonsteroidal anti-inflammatory medications. These treatments help manage and mitigate aging-related pathologies by targeting key molecules and pathways of inflammation. A better comprehension of the relationship between inflammation and aging may serve as the foundation for the creation of novel therapeutic approaches that, in addition to reducing inflammatory reactions, may also prevent or slow the advancement of illnesses associated with age. This article aims to improve medical and scientific understanding of the relationship between inflammation and aging and to encourage the development and use of more potent therapies to lessen the burden of chronic illnesses and enhance the quality of life for the aged.

Characterization of Immune Aging in the Japanese Medaka (Oryzias latipes)

The prevalence of chronic inflammation increases with age and may be aggravated by environmental exposures. Similarly, during immune aging, inflammatory disease incidence increases as protective immunity decreases. To better understand disease and exposure risks, an immune aging model outlining key changes in immune function is crucial. Utilizing the lowest possible vertebrate class, we propose the Japanese medaka (Oryzias latipes) as a model to investigate sex-specific immune aging including changes in immune gene expression, leukocyte profiles, and organismal level immune response. Evaluating the expression of immune initiators (CRP, TLR5-s, TLR5-m, TCRb, and MHCII), immune mediators (MYD88, Nf-kß, C3, and IL1b), and immune effectors (LYZ and C8) in concomitance with alterations in leukocyte populations and host resistance to pathogens will inform about immune competence across ages. The data presented here demonstrate a critical decrease in the expression of immune initiators (CRP, TLR5-soluble, TCRb, and MHCII), mediators (MYD88, Nf-kß, C3, and IL1b), and effector (LYZ) in both females and males after 11 months post hatching (mph). Interestingly, both sexes displayed an upregulation for the immune effector, C8, during this older life stage (11–13 mph). Gene expression profiles for both sexes at the most elderly age (20 or 23 mph) appear to revert to a younger profile of expression indicating a second change in immune function during aging rather than a steady decline. Significant changes in leukocyte populations were observed in both male and female medaka after peaking sexual maturation at 3 mph. Organismal level immune competence data revealed male medaka at the elderly age to be more vulnerable than their female and younger male counterparts while no differences were observed in females based on age. Together, these data provide a holistic profile for immune aging in medaka, a useful tool for future immunological studies considering age as a factor influencing disease susceptibility.