IL-10 Levels Research Articles

APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.

The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

Effects of continuous negative pressure suction combined with autologous platelet-rich gel on the levels of CRP, IL-6, wound healing and length of stay in clients with diabetic foot

ObjectiveContinuous passive pressure suction and APG gel therapy effect diabetic foot IL-6, CRP, wound healing, and hospitalization. MethodsClinicopathological data from 102 diabetic foot ulcer patients treated at our institution between March 2018 and May 2022 was examined. Tables generated 51 joint and controlling teams randomly. The observation team received passive pressure suction and APG gel whereas the controlled team received conventional treatment. Teams monitored therapy outcomes, adverse responses, wound healing, hospital stay, and costs. Both teams compared blood uric acid, cystatin C, homocysteine, and serum IL-6, IL-10, and CRP before and after medication. ResultsThe joint team had higher hospitalization costs, shorter stays, and faster wound healing than the controlled team. Diaparity was significant (P < 0.05). The united team worked 100 %, unlike the controlling team. This difference was significant (P < 0.05). Both teams showed significant decreases in CRP, IL-6, and IL-10 levels after therapy (P < 0.05). After therapy, both the combined and controlled teams had substantial differences in blood CRP, IL-6, and IL-10 levels (P < 0.05). Both teams had significantly decreased uric acid, cystatin C, and homocysteine after treatment. The combined team showed significantly decreased uric acid, cystatin C, homocysteine levels following therapy compared to the control team (P < 0.05). ConclusionThe joint team experienced considerably fewer adverse events (3.92 % vs. 17.65 %) than the controls team (P < 0.05). Permanent passive pressure suction and APG gel therapy lower inflammatory response, blood uric acid, cystatin C, and homocysteine, speeding wound healing, reducing side effects.

Gastroprotective role of a flavonoid-rich subfraction from Fridericia chica (Bonpl.) L. G. Lohmann: a medicinal plant used in the Amazon region.

Fridericia chica is an Amazonian plant used to treat stomach disorders. However, the pharmacological activity of flavonoids in the extract has yet to be investigated. Therefore, we considered that a flavonoid-rich F. chica subfraction (FRS) has gastroprotective functions. For this, before the induction of gastric ulcers with ethanol or piroxicam, the rats received vehicle (water), omeprazole (30mg/kg), or FRS (30mg/kg), and the ulcer area was measured macro and microscopically, and the antisecretory action was investigated in pylorus-ligated rats. In addition, the roles of nitric oxide (NO) and nonprotein sulfhydryl compounds (NP-SH) in the gastroprotective effects of FRS were studied. FRS reduced ethanol- and piroxicam-induced ulcerations by 81% and 77%, respectively, as confirmed histologically. Antioxidant effects were observed for FRS through the maintenance of GSH and LPO levels, and the SOD and CAT activity similar to those found in the nonulcerated group. Moreover, FRS avoided the increase in MPO activity and TNF, IL-6, IL-4 and IL-10 levels. Moreover, mucin staining increased in ulcerated rats receiving FRS, and the pharmacological mechanism gastroprotective seems to involve the NO and NP-SH in addition to antisecretory actions. The chemical study by mass spectrometry confirmed the presence of flavonoids in FRS, and molecular docking studies have shown that these compounds interact with cyclooxygenase-1 and NO synthase. Furthermore, there was no indication that FRS had cytotoxic effects. Our results support the popular use of F. chica, and we conclude that the gastroprotection effect promoted by FRS can be attributed to the combined effect of the flavonoids.

Immune and inflammation features of severe and critical Omicron infected patients during Omicron wave in China

ObjectiveThe current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred.MethodA cross‐sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared.ResultPatients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO.ConclusionThis present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

Endoplasmic Reticulum Stress Differently Modulates the Release of IL-6 and IL-8 Cytokines in Human Glial Cells.

Endoplasmic reticulum (ER) stress is a significant player in the pathophysiology of various neurodegenerative and neuropsychiatric disorders. Despite the established link between ER stress and inflammatory pathways, there remains a need for deeper exploration of the specific cellular mechanisms underlying ER stress-mediated neuroinflammation. This study aimed to investigate how the severity of ER stress (triggered by different concentrations of tunicamycin) can impact the release of proinflammatory cytokines IL-6 and IL-8 from astrocytes and microglia, comparing the effects with those induced by well-known immunostimulants-tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Mild ER stress has a distinct effect on the cytokine release compared to more intense stress levels, i.e., diminished IL-6 production was accompanied by an increase in IL-8 level, which was significantly more pronounced in astrocytes than in microglia. On the contrary, prolonged or more severe ER stress induced inflammation in glial cells, leading to a time- and concentration-dependent buildup of proinflammatory IL-6, but unlike inflammatory agents, an ER stress inducer diminished IL-8 secretions by glial cells. The differences could hold importance in identifying ER stress markers as potential drug targets for the treatment of neurodegenerative diseases or mood disorders, yet this requires confirmation in more complex animal studies.

Therapeutic Potential of Lactiplantibacillus plantarum FB091 in Alleviating Alcohol-Induced Liver Disease through Gut-Liver Axis.

Alcoholic liver disease (ALD) poses a significant global health burden, often requiring liver transplantation and resulting in fatalities. Current treatments, like corticosteroids, effectively reduce inflammation but carry significant immunosuppressive risks. This study evaluates Lactiplantibacillus plantarum FB091, a newly isolated probiotic strain, as a safer alternative for ALD treatment. Using an in vivo mouse model, we assessed the effects of L. plantarum FB091 on alcohol-induced liver damage and gut microbiota composition. Alcohol and probiotics administration did not significantly impact water/feed intake or body weight. Histopathological analysis showed that L. plantarum FB091 reduced hepatocellular ballooning and inflammatory cell infiltration in liver tissues and mitigated structural damage in colon tissues, demonstrating protective effects against alcohol-induced damage. Biomarker analysis indicated that L. plantarum FB091 decreased aspartate aminotransferase levels, suggesting reduced liver damage, and increased alcohol dehydrogenase activity, indicating enhanced alcohol metabolism. Additionally, cytokine assays revealed a reduction in pro-inflammatory TNF-α and an increase in anti-inflammatory IL-10 levels in colon tissues of the L. plantarum FB091 group, suggesting an anti-inflammatory effect. Gut microbiota analysis showed changes in the L. plantarum FB091 group, including a reduction in Cyanobacteria and an increase in beneficial bacteria such as Akkermansia and Lactobacillus. These changes correlated with the recovery and protection of liver and colon health. Overall, L. plantarum FB091 shows potential as a therapeutic probiotic for managing ALD through its protective effects on liver and colon tissues, enhancement of alcohol metabolism, and beneficial modulation of gut microbiota. Further clinical studies are warranted to confirm these findings in humans.

Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang inhibits the progression of triple negative breast cancer though the activation inhibition of NF-κB triggered by CAFs-derived IL6

Ethnopharmacological relevanceThe treatment options for triple-negative breast cancer (TNBC) are limited. Traditional Chinese Medicine (TCM) plays an important role in the treatment of TNBC. The herb pair Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang (SH) is commonly used in clinical practice for its anti-tumor properties. It has been proven to have good therapeutic effects on tumor-related diseases, but the underlying molecular mechanisms are not yet fully explained. Aim of studyThrough bioinformatics, it was validated that IL6, primarily derived from cancer-associated fibroblasts (CAFs), is associated with poor prognosis. Additionally, cell and animal experiments confirmed that SH inhibits tumor proliferation, migration, and growth in an orthotopic tumor model by suppressing the IL6/NF-κB pathway. Materials and methodsGEO, TCGA and HPA databases were used to analyze the prognostic value of CAFs and IL6, then IL6 resource was detected. After the bioinformatics, the influence of CAFs and CAFs-derived IL6 on TNBC was verified by experiments both in vitro and in vivo. Cell clone formation assay, wound-Healing assay, and Transwell assay were used to detect the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vitro. TNBC model in mice was used to prove the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vivo. The biological pathway of NF-κB was explored by western blotting through detecting unique molecules. ResultsBioinformatics analysis revealed that higher proportion of CAFs and elevated level of IL6 were significantly associated with poor prognosis in TNBC. At the same time, IL6 was proved predominantly derived from CAFs. After the indication of bioinformatics, experiments in vitro demonstrated that both CAFs and IL6 could enhance the clone formation and migration ability of MDA-MD-231 cells (231), furthermore, the promotion of CAFs was related with the level of IL6. Based on these data, mechanism was detected that CAFs-derived IL6 enhancement was closely related to the activation of NF-κB signaling pathway, while the activation can be reduced by SH. In the end, the promotion of CAFs/CAFs-derived IL6/NF-κB and the efficacy of SH inhibition were both confirmed by experiments in vivo. ConclusionsBioinformatics data indicates that higher proportion of CAFs and higher level of CAFs-derived IL6 are significantly related to poorer survival of TNBC. CAFs and CAFs-derived IL6 were proved to promote the progression of TNBC both in vitro and in vivo, and the process of which was significantly related to the activation of NF-κB. SH inhibited the progress of TNBC, which was proved to be closely related to CAFs/CAFs-derived IL6/NF-κB.

Integrating 16S rRNA Sequencing, Microflora Metabolism, and Network Pharmacology to Investigate the Mechanism of SBL in Alleviating HDM-Induced Allergic Rhinitis.

Allergic rhinitis (AR) is a series of allergic reactions to allergens in the nasal mucosa and is one of the most common allergic diseases that affect both children and adults. Shi-Bi-Lin (SBL) is the modified formula of Cang Er Zi San (CEZS), a traditional Chinese herbal formula used for treating AR. Our study aims to elucidate the anti-inflammatory effects and mechanisms of SBL in house dust mite-induced AR by regulating gut microflora metabolism. In vivo studies showed that nasal allergies and the infiltration of inflammatory cells in the nasal epithelium were significantly suppressed by SBL. Moreover, SBL restored the impaired nasal epithelial barrier function with an increased tight junction protein expression and reduced the endothelial nitric oxide synthase (eNOS). Interestingly, SBL significantly reconstituted the abundance and composition of gut microbiota in AR mice; it increased the relative abundance of potentially beneficial genera and decreased the relative abundance of harmful genera. SBL also restored immune-related metabolisms, which were significantly increased and correlated with suppressing inflammatory cytokines. Furthermore, a network analysis and molecular docking indicated IL-6 was a possible target drug candidate for the SBL treatment. SBL dramatically reduced the IL-6 level in the nasal lavage fluid (NALF), suppressing the IL-6 downstream Erk1/2 and AKT/PI3K signaling pathways. In conclusion, our study integrates 16S rRNA sequencing, microflora metabolism, and network pharmacology to explain the immune mechanism of SBL in alleviating HDM-induced allergic rhinitis.

Interleukin-10 contrasts inflammatory synaptopathy and central neurodegenerative damage in multiple sclerosis.

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS.

Development of a highly sensitive platform for protein–protein interaction detection and regulation of T cell function

We developed a highly sensitive assay for detecting protein-protein interaction using chimeric receptors comprising two molecules of interest in the extracellular domain and interferon alpha and beta receptor subunit 1 or 2 (IFNAR1/2) in the intracellular domain. This intracellular IFNAR1/2 reconstitution system (IFNARRS) proved markedly more sensitive than the NanoBiT system, currently considered one of the best detection systems for protein interaction. Employing chimeric receptors with extracellular domains from the IFNγ or IL-2 receptor and the intracellular domains of IFNAR1/2, the IFNARRS system effectively identifies low IFNγ or IL-2 levels. Cells stably expressing these chimeric receptors responded to IFNγ secreted by activated T cells following various stimuli, including a specific peptide-antigen. The activation signals were further enhanced by the expression of relevant genes, such as costimulators, via IFN-stimulated response elements in the promoters. Besides IFNγ or IL-2, the IFNARRS system demonstrated the capability to detect other cytokines by using the corresponding extracellular domains from these target cytokine receptors.

Efficacy and prognostic analysis of carbon nanotracers combined with the da Vinci robot in the treatment of esophageal cancer.

Traditional methods cannot clearly visualize esophageal cancer (EC) tumor contours and metastases, which limits the clinical application of da Vinci robot-assisted surgery. To investigate the efficacy of the da Vinci robot in combination with nanocarbon lymph node tracers in radical surgery of EC. In total, 104 patients with early-stage EC who were admitted to Liuzhou worker's Hospital from January 2020 to June 2023 were enrolled. The patients were assigned to an observation group (n = 52), which underwent da Vinci robot-assisted minimally invasive esophagectomy (RAMIE) with the intraoperative use of nanocarbon tracers, and a control group (n = 52), which underwent traditional surgery treatment. The operation time, intraoperative blood loss, postoperative drainage tube indwelling time, hospital stay, number of lymph nodes dissected, incidence of complications, and long-term curative effects were comparatively analyzed. The postoperative stress response C-reactive protein (CRP), cortisol, epinephrine (E) and inflammatory response interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) were evaluated. Compared with the control group, the observation group had significantly lower postoperative CRP, cortisol, and E levels (P < 0.05) with a milder inflammatory response, as indicated by lower IL-6, IL-10, and TNF-α levels (P < 0.05). Patients who underwent RAMIE had less intraoperative blood loss and shorter operation times and hospital stays than those who underwent traditional surgery. The average number of dissected lymph nodes, time of lymph node dissection, and mean smallest lymph node diameter were all significantly lower in the observation group (P < 0.05). The rate of postoperative complications was 5.77% in the observation group, significantly lower than the 15.38% observed in the control group. Furthermore, the lymphatic metastasis rate, reoperation rate, and 12- and 24-month cumulative mortality in the observation group were 1.92%, 0%, 0%, and 0%, respectively, all of which were significantly lower than those in the control group (P < 0.05). The treatment of EC using the da Vinci robot combined with nanocarbon lymph node tracers can achieve good surgical outcomes and demonstrates promising clinical applications.

72 Impact of microbiome modulation on serum cytokine profile in a randomized, phase I trial of cabozantinib/nivolumab (cabo/nivo) with or without CBM588 in pts with metastatic renal cell carcinoma (mRCC)

Abstract Background We have previously demonstrated that the orally administered, live bacterial product CBM588 can augment clinical outcomes with cabo/nivo in pts with mRCC (Ebrahimi et al ASCO 2023). As it is postulated this effect may be mediated through changes in systemic immunity, we sought to characterize changes in serum cytokine profile induced by CBM588. Methods Pts with previously untreated mRCC with clear cell, papillary or sarcomatoid histology were enrolled. Key eligibility criteria included Karnofsky performance status ≥ 70% and measurable disease. Pts were randomized to receive cabo/nivo on a standard schedule alone or the same regimen with CBM588 at 80 mg bid. Pts had blood collection performed at baseline and at weeks 9, 13, 17 and 25. Samples underwent processing within 4-6 hrs of collection, and a total of 30 cytokines and growth factors were assessed using the Luminex Flexmap 3D system (Biotechne). Changes in circulating cytokine levels between baseline and week 13 (± 7 days) were examined across the treatment arms to investigate the impact of CBM588 on the immune system. The Wilcoxon matched-pairs test was used to compare the levels of cytokines at the two timepoints. Results A total of 30 pts were enrolled; the majority were male (67%) and had intermediate- or poor-risk disease (60%). Most pts had clear cell histology (87%); 5 pts (17%) had sarcomatoid features. As previously reported, pts receiving cabo/nivo/CBM588 had a significantly higher response rate as compared to pts receiving cabo/nivo alone (74% vs 20%; P=0.01). Across baseline and week 13, a total of 53 samples were available for assessment. In pts receiving cabo/nivo/CBM588, there was a significant change in the level of IL-12, IL-13, eotaxin, interferon-γ, and granulocyte-macrophage colony stimulating factor (GM-CSF); this was not observed in the cabo/nivo alone arm. Additional flow cytometric analyses characterizing relevant CD4- and CD8-positive subsets will be presented. Conclusions Taken together with our previous study evaluating nivolumab/ipilimumab with CBM588 (Dizman et al Nat Med 2022), these results suggest that the augmented clinical outcome seen with the addition of CBM588 to cabo/nivo may be related to systemic immunomodulation. Combined analyses of the cohorts across studies are planned.

Assessing molecular genetic and immunological predictors of COVID-19 course in healthcare worker risk group

Relevance. Studying features of innate and adaptive mechanisms of immune response in medical workers (MW), the most vulnerable social group with a high risk of infection, is an urgent research task. The aim of the study: Comprehensive study of innate and adaptive immune mechanisms and analyzing relationships between clinically significant polymorphisms (SNPs) in TLR2, TLR4 genes, TLR2 expression level on peripheral blood monocytes, peripheral blood cytokine profile (IL-1β, IL-10, IL-6, IFNγ, platelet activation marker) and SARS-CoV-2-specific humoral immune response in medical workers (MW) at a temporary infectious disease hospital in early and late COVID-19 convalescence. Materials and methods. immunologic, cytofluorimetric and molecular-genetic research methods were applied. Adaptive immune response in medical workers — COVID-19 convalescent subjects. Results. Early post-COVID-19 convalescence period in MW was linked to higher TLR2 monocyte expression; the mean fluorescence intensity was significantly elevated by 1.5-fold compared to control group. Late convalescence period (7 months post-COVID-19) was characterized by lowered serum IFNγ level. A decline in IFNγ production was significant: decreased by 82-fold in MR that was markedly stronger compared to control group (59 times). The imbalance of cytokines controlling antiviral innate and adaptive immune response was revealed in MW with identified combination of polymorphisms rs5743708 and rs4986790 in TLR2, TLR4 genes with the rate not exceeding 6.7%. It was found that 7 months after COVID-19 there was a markedly decreased IFNγ, IL-1β and IL-10 levels. The studies indicate both altered innate and adaptive immune mechanisms and a need to optimize therapeutic and prophylactic measures aimed at increasing patient-intrinsic resistance, protection of respiratory tract mucosal barriers and identification of genetic predictors of defects in innate and adaptive immune response in medical workers — COVID-19 convalescent subjects.

Diagnostic utility of sortilin & other biomarkers in the diagnosis of carotid & coronary atherosclerosis in individuals with arterial hypertension.

Background & objectives Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. The aim of this investigation was to study the role of biological markers in predicting the risk of carotid and coronary artery atherosclerosis. Methods A total of 161 males in the age group of 30-65 yr were included in this study. All participants underwent biochemical analyses [cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides, glucose, (interleukin) IL-8, IL-10, (proprotein convertase inhibitors subtilisin/kexin type 9) PCSK9, sortilin, creatinine]; ECG; echocardiography; coronary angiography; ultrasound doppler of brachiocephalic arteries. Based on PCSK9 levels, participants were divided into four groups: group 1, n=41 individuals with PCSK9 level of 100-250 ng/ml; group 2, n=37 individuals with PCSK9 level of 251-400 ng/ml; group 3, n=51 individuals with PCSK9 level of 401-600 ng/ml and group 4, n=32 individuals with PCSK9 level of 601-900 ng/ml. Results Sortilin level was the highest in group 2. Group 3 individuals had the highest level of IL-8. Correlation analysis of the entire data set revealed the relationship of relative left ventricular thickness index with age, cardiovascular risk, body mass index, intima-media thickness and left ventricular mass index; sortilin had a negative relationship of weak strength with age and smoking, a direct relationship between the risk of cardiovascular complications and with IL-10. Interpretation & conclusions Sortilin is the innovative marker of CVDs. In the present investigation, we demonstrated the clear increase in the inflammatory markers (IL-8) in individuals with subclinical atherosclerosis. This fact can be explained by the oxygen stress activation. In individuals with coronary artery stenosis (50% and more), the increase in IL-10 levels demonstrates, to our opinion, the activation of antioxidant protection activation.

Abstract We059: Age-associated Alterations in T cell Output and Functions

The elderly have a higher risk for a wide range of diseases, including infection, tumor, and cardiovascular disease. This could be, at least partially, attributed to T lymphocyte changes during aging. The goal of this project was to characterize age-related changes in T cell output and functions. In this study, young (3-6 months old) and aged (18-24 months old) male and female C57BL/6J mice were utilized. Our data showed that compared to young mice, aged mice demonstrated significantly smaller thymus and fewer developing thymocytes, including double negative CD4 - CD8 - , double positive CD4 + CD8 + , as well as single positive CD4 + and CD8 + thymocytes, which implies that aged mice generate less T cells. Accordingly, circulating T cell count was significantly lower in aged mice than young controls. To investigate how aging affects T cell functions, we isolated splenic T cells and stimulated them with PMA (100 nM) + ionomycin (1 µM) (P+I) or vehicle for 4 hours. At the steady state, aged T cells expressed higher levels of Ifng , Tnfα , granzyme b , and perforin than young T cells, suggesting that aged T cells show a senescence-associated secretory phenotype (SASP). After stimulation with P+I, both young and aged T cells expressed dramatically higher levels of Ifng , Tnfα , Il2 , Il4 , Il17 , and granzyme b , indicative of T cell activation. Interestingly, aged T cells had higher expression of Ifng, Il17, and granzyme b, but lower Tnfα and Il2 levels. Moreover, aged T cells expressed higher levels of exhaustion markers, such as Pd1 , Ctla4 , Lag3 , and Tigit , indicating that aged T cells exhibit an exhaustion phenotype. In conclusion, our study demonstrates that aged mice show smaller thymus and fewer thymocytes and blood T cells than young mice. In addition, aged T cells exhibit a SASP and exhaustion phenotype. Upon activation, aged T cells might be more cytotoxic by secreting higher levels of IFN-γ, IL-17, and granzyme B.

Variation in Interleukin-4, -6, and -10 in Mastitis Milk: Associations with Infections, Pathogens, Somatic Cell Counts, and Oxidative Stress.

Poor mastitis control favors intramammary infection (IMI), which always involves CNS. This study aimed to determine the relationships of IL-4, IL-6, and IL-10 in mastitis milk with concurrent infection, bacterial pathogens, SCC, and MDA, an oxidative stress marker. All mastitis quarters from five smallholder dairy farms were sampled aseptically before morning milking and again before afternoon milking for bacteriological identification using MALDI-TOF mass spectrometry. The samples with the concomitant infection between streptococci and CNS and their pairs of another sample from the quarters were selected. In addition, samples were randomly chosen to have a controlled single infection. IL-4, IL-6, and IL-10 were measured with ELISA kits. MDA was measured using HPLC, while SCC was measured using Fossomatic™ FC. The results from a repeated measure analysis showed that IL-4 positively correlated with SCC, while IL-6 showed a negative trend. IL-4 levels were highest in CNS infections and significantly higher than in non-infected or mixed infections (p < 0.05). The IL-6 level of the mixed bacteria was highest and showed a different trend from non-infection, and the quarter was infected with streptococcal bacteria. In conclusion, from a single infection, the streptococci and CNS quarter showed varied immune responses, including trendily higher IL-6 and IL-4.

Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-β and IL-10 in Hemophilia A Patients with FⅧ Inhibitor

To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-β and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-β and IL-10 in serum, and their differences between different groups were compared. Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-β, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). The decrease of Tregs, IL-35, TGF-β, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Efficiency of Cysticidal Therapy Impacted by the Host's Immune Response in Neurocysticercosis Patients.

Neurocysticercosis (NCC) is a neurological condition caused by the presence of cysts ofTaenia solium in the brain, which manifests with a range of clinical symptoms. The severity of NCC and its prognosis following anti-helminth drug (AHD) treatment are closely linked to peripheral and local inflammation. The study aimed to analyse the efficiency of cysticidal therapy impacted by the host's immune response in NCC patients. A total of 104 patients were screened in thisstudy, and blood samples were collected from 30 patients. The follow-up samples within 3 to 6months of treatment were collected. Patients were categorised as Responder (R) and Non-Responder (NR). Cytokines IL-6, IL-10, IFN-γ and TNF-α were estimated using ELISA kits in PBMC cells. T0 is the time point before the AHD treatment begins, and T1 is between 3 to 6months after the treatment starts. The responder patients showed significantly lower IL-10 and IL-6 levels in the supernatants at T0 as compared to T1, while in non-responder patients, IL-10 and IL-6 levels were higher at T0 as compared to T1. The IFN-γ and TNF-α levels were found to be higher in the supernatants at T0 as compared to T1 in both the responder and non-responder patients. These observations imply that these cytokines might have an impact on the efficacy of AHD treatment in NCCpatients.

Expression of MAF bZIP transcription factor B protects against ulcerative colitis through the inhibition of the NF-κB pathway.

The aim of this study was to explore whether MAF bZIP transcription factor B (MAFB) might alleviate ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced mice and LPS-induced IEC-6 cells. UC in vivo and in vitro model was established by using DSS and LPS, respectively. The mice body weight and disease activity index (DAI) score were recorded daily, and colon length was measured. Moreover, the permeability was evaluated utilizing a fluorescein isothiocyanate dextran (FITC-Dextran) probe. Histopathological changes of DSS-induced colitis mice was assessed utilizing H&E staining. Next, qRT-PCR was performed to detect IL-1β, IL-6, TNF-α, and IL-10 level in in vivo and in vitro. Furthermore, the level of MDA, SOD, CAT, and GSH were evaluated in colon tissues. Besides, the expressions of tight junction proteins and NF-κB pathway relative proteins were examined in colitis mice and IEC-6 cells using western blot, immunohistochemistry and immunofluorescence. MAFB level was downregulated in DSS-induced colitis mice. Moreover, the upregulation of MAFB protected mice from DSS-induced colitis by suppressing DSS-induced inflammation, oxidative stress, and intestinal barrier impairment. We also demonstrated that the upregulation of MAFB inactivated NF-κB pathway in DSS-caused colitis mice. Subsequently, we observed that MAFB upregulation could inhibit LPS-caused epithelial barrier impairment and inflammation in IEC-6 cells. Additionally, MAFB overexpression could suppress the activation of NF-κB pathway in IEC-6 cells. The upregulation of MAFB could protect against UC via the suppression of inflammation and the intestinal barrier impairment through inhibiting the NF-κB pathway.

Exploring the mechanism of action of Vanda tessellata extract for the treatment of osteoarthritis through network pharmacology, molecular modelling and experimental assays

The present study employed a comprehensive approach of network pharmacology, molecular dynamic simulation and in-vitro assays to investigate the underlying mechanism of the anti-osteoarthritic potential of Vanda tessellata extract (VTE). Thirteen active compounds of VTE were retrieved from the literature and the IMPPAT database. All of these passed the drug likeness and oral bioavailability parameters. A total of 535 VTE targets and 2577 osteoarthritis related targets were obtained. The compound-target-disease network analysis revealed vanillin, daucosterol, gigantol and syringaldehyde as the core key components. Protein-protein interaction analysis revealed BCL2, FGF2, ICAM 1, MAPK1, MMP1, MMP2, MMP9, COX2, STAT3 and ESR1 as the hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed AGE-RAGE signalling pathway, HIF-1 signalling pathway and ESR signalling pathway as the major signalling pathway of VTE involved in treating osteoarthritis. Molecular docking analysis showed daucosterol and gigantol to have good binding affinity with BCL2, ESR1 and MMP9, and the results were further confirmed through molecular dynamics simulation analysis. The mechanism predicted by network pharmacology was validated in vitro on IL-1β-induced SW982 synovial cells. VTE did not show any cytotoxicity and inhibited the migration of SW982 cells. VTE inhibited the expression level of IL-6, IL-8, TNF-α, PGE-2, MMP-2 and MMP-9 in a dose-dependent manner. VTE inhibited nuclear translocation of NF- κβ and suppressed phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) signalling pathway. The results showed that VTE exerted an anti-osteoarthritic effect by a multi-target, multi-component and multi-signalling pathway approach.