Tumor Necrosis Factor-related Protein Research Articles

Adipocytokine expression, platelet-to-lymphocyte ratio and TGF-β1/Smad signaling activity in diabetic patients complicated with pulmonary infection.

ObjectiveTo investigate adipocytokine expression levels, platelet-to-lymphocyte ratio (PLR) and transforming growth factor (TGF)-β1/Smad signaling activity in diabetic patients with pulmonary infection.MethodsEighty-two type 2 diabetic patients with pulmonary infection were included in the observation group and 75 patients with simple type 2 diabetes were recruited into the control group. The fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and PLR in the two groups were compared. Complement-C1q/tumor necrosis factor related protein 3 (CTRP-3), complement-C1q/tumor necrosis factor related protein 9 (CTRP-9), leptin, adiponectin, and TGF-β1/Smad signaling pathway activity in peripheral blood mononuclear cells (PBMCs) was detected.ResultsCompared with patients in the control group, patients in the observation group presented with increased levels of FGB, HbA1c, and leptin, an increase in the PLR, and decreased serum CTRP-3, CTRP-9, and adiponectin levels. TGF-β1, p-Smad2, and p-Smad3 protein expression levels were up-regulated in PBMCs from patients in the observation group compared with the control group.ConclusionsThese results show that in type 2 diabetic patients with pulmonary infection, adipocytokine expression is altered, PLR is disturbed, and the TGF-β1/Smad signaling pathways in PBMCs are significantly activated.

Methylation of CpG sites in C1QTNF1 (C1q and tumor necrosis factor related protein 1) differs by gender in acute coronary syndrome in Han population: a case-control study.

ACS (acute coronary syndrome), a subgroup of coronary artery disease (CHD), is a leading cause of death worldwide. Reports shown the association between methylation and CHD, while the abnormal expression of C1QTNF1 (C1q and tumor necrosis factor related protein 1) in CHD patients, but the underlying mechanisms are still unclear. To analyze the methylation of CpG sites of C1QTNF1 in ACS patients. Peripheral blood samples were collected from healthy controls and ACS patients. The methylation of total C1QTNF1, promoter sequence and CpG sites of C1QTNF1 were measured using methylation detection kits. The outcomes were compared between patients and controls based on gender, clinical classification and clinical stages. The promoter sequences from 37 ACS patients and 20 controls indicate that the methylation rate of C1QTNF1 was significantly lower in male patients compared to healthy controls at + 63 CpG sites (p = 0.03). Whereas, the methylation rate of C1QTNF1 in female patients was significantly lower than female health controls at - 89, + 39 and + 167 CpG sites (p = 0.021, 0.042, 0.021). In addition, the methylation rate of C1QTNF1 was significantly higher in male patients than female patients at - 89, - 41 and + 39 CpG sites (p = 0.011, 0.043, 0.006). Moreover, the methylation rate significantly decreased at - 24 sites (p = 0.021), but it significantly increased at - 14 site (p = 0.048) in patients with UA, compared to patients with STEMI (ST-segment elevation myocardial infarction). There were significant differences in the methylation rate + 63 CpG sites between controls and male ACS patients. The - 14 site methylation increased in patients with UA, compared to patients with STEMI.

C1q/TNF-related protein-9 alleviates airway inflammation in asthma

BackgroundsAsthma is characterized as inflammatory disorder in the respiratory system with increasing tendency. Most of the asthma patients suffered from the disease since childhood. Thus, developing novel therapeutic targets of childhood asthma is necessary. Here, we conducted the present study to investigate the effects of CTRP9 (C1q tumor necrosis factor-related protein 9), a newly identified anti-inflammatory factor, on asthma. MethodsSixty asthmatic children (30 moderate and 30 mild) were recruited. The mRNA level of CTRP9 in peripheral blood mononuclear cells (PBMCs) and protein level of CTRP9 in serum and induced sputum (IS) samples from asthma patients and healthy controls (HCs) were measured by qPCR and ELISA, respectively. The anti-inflammatory effects of CTRP9 was determined in vitro and potential therapeutic effect on asthma was evaluated in mouse model. ResultsThe mRNA and protein levels of CTRP9 was significantly down-regulated in asthmatics than HCs. Furthermore, the expression level of CTRP9 was negatively correlated with the expression of TNF-α, IL-1β, and IL-6 in PBMCs. The CTRP9 significantly suppressed the expression of pro-inflammatory factors in PBMCs and sputum cells from asthma patients in vitro. And delivering CTRP9 into mouse model of asthma showed disease alleviation. ConclusionOur data here indicated that CTRP9 may alleviate airway inflammation and remodeling in asthma.

Serum C1q/TNF-Related Protein-2 (CTRP2) Levels are Associated with Coronary Artery Disease

Recent studies have shown that complement C1q tumor necrosis factor related proteins (CTRPs) such as adiponectin, have different regulatory roles on the cardiovascular system. CTRP2 is the most similar to adiponectin and one of the best characterized beneficial adipokines important in the regulation of whole body metabolism. However, there were no studies about the relationship between CTRP2 and Coronary artery disease (CAD). This study aimed to evaluate the serum CTRP2 levels in patient with Coronary artery disease. In this study, a total of 82 participants who underwent vascular angiography were included. All of subjects were male. According to their coronary angiography results, all participants were divided into CAD group (n=42) and control group (n=40). Serum CTRP2 levels were determined quantitatively with enzyme-linked immunosorbent assay (ELISA). Our study for the first time showed that the CTRP2 levels were higher in CAD patients (1.79±1.46ng/mL) compared to control subjects (1.08±0.78ng/mL; p=0.001). The levels of CTRP2 also were positively correlated with severity of CAD (r=0.356, p=0.001). In addition, logistic regression analysis indicated that CTRP2 had an independent association with the risk of CAD (OR [CI]=3.366 [1.605-7.060]; p=0.001). Increased levels of CTRP2 in CAD patients were independently associated with the progression of the CAD, it might be regarded as a novel biomarker for assessing the risk of CAD; however, more study is required in this regard.

MiR-29b-3p promotes particulate matter-induced inflammatory responses by regulating the C1QTNF6/AMPK pathway.

Inflammatory responses are considered to be the critical mechanism underlying particulate matter (PM)-induced development and exacerbation of chronic respiratory diseases. MiR-29b-3p has been found to participate in various biological processes, but its role in PM-induced inflammatory responses was previously unknown. Here, we constructed a miRNA PCR array to find that miR-29b-3p was the most highly expressed in human bronchial epithelial cells (HBECs) exposed to PM. MiR-29b-3p promoted PM-induced pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) expression via inhibiting the AMPK signaling pathway in HBECs. RNA sequencing and luciferase reporter assay identified that miR-29b-3p targeted complement C1q tumor necrosis factor-related protein 6 (C1QTNF6), a protein that protected from PM-induced inflammatory responses via activating the AMPK signaling pathway. In vivo, miR-29b-3p antagomirs delivered via the tail vein prior to PM exposure significantly counteracted PM-induced miR-29b-3p upregulation and C1QTNF6 downregulation in lung tissues. Furthermore, miR-29b-3p inhibition alleviated inflammatory cells infiltration and pro-inflammatory cytokines secretion in the lung of PM-exposed mice. These findings firstly revealed that miR-29b-3p acted as a novel modulator of PM-induced inflammatory responses by targeting the C1QTNF6/AMPK signaling pathway, which contributes to a better understanding of the biological mechanisms underlying adverse PM-induced respiratory health effects.

Protective Role of CTRP3 and CTRP9 in the Development of Gestational Diabetes Mellitus.

The current study aims to detect the expression of C1q tumor necrosis factor related protein 3 (CTRP3) and CTRP9 in serum of patients with gestational diabetes mellitus (GDM), so as to provide basis for the prevention and treatment of GDM. A total of 129 pregnant women with GDM were selected, and 130 pregnant women with normal glucose metabolism were selected as the control group. The serum levels of CTRP3 and CTRP9 were detected by enzyme-linked immunosorbent assay (ELISA). Pearson's correlation assay was used to compare the correlation between the level of serum CTRP3 and CTRP9 and clinical indicators. ROC analysis was performed to evaluate the diagnostic value of serum CTRP3 and CTRP9. Our data showed that the levels of CTRP3 and CTRP9 in the GDM group were lower than those in the control group, while body mass index (BMI), hemoglobin A1C (HbA1c), hypersensitive C-reactive protein (hs-CRP), IL-6, TNF-α, fasting plasma glucose (FPG), fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) were higher than those in the control group. Pearson's correlation assay showed that serum CTRP3 and CTRP9 was negatively correlated with FPG, FINS, and HOMA-IR. The AUC of the combined diagnosis of GDM was better than that of the single index (0.936 (0.868 - 0.996)), including CTRP3, CTPR9 and FPG. Altogether, low expression of serum CTRP3 and CTRP9 in patients with GDM was negatively correlated with IR and may shed light on revealing the pathogenesis of GDM.

C1q/TNF-related protein-9 attenuates atherosclerosis through AMPK-NLRP3 inflammasome singling pathway

BackgroundsC1q tumor necrosis factor-related protein 9 (CTRP9) has been suggested to exert an atheroprotective effect by modulating the inflammation, foam cell formation, endothelia and smooth muscle cell function via Adenosine Monophosphate Activated Protein Kinase (AMPK) pathway. On the other hand, the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome plays an critical role in the atherosclerosis development, which is regulated by the AMPK. However, whether the CTRP9 affects the activity of NLRP3 inflammasome during the atherosclerosis development remains unclear, which would be elucidated in the current study. MethodsThe macrophage cells were stimulated with the oxidized low-density lipoprotein (ox-LDL) and also treated with the recombinant CTRP9 in the meantime. The activation of NLRP3 inflammasome was determined by measuring the releasing of IL-1β and caspase-1 p10 via ELISA and western blot, respectively. Then the AMPK was inhibited in macrophages by Dorsomorphin. Finally, the CTRP9-AMPK-NLRP3 inflammasome pathway was validated in the mouse model of atherosclerosis. ResultsThe CTRP9 could down-regulate the expression of NLRP3 protein and also the activity of NLRP3 inflammasome in the ox-LDL activated macrophages. Inhibiting the AMPK significantly restored the activities of NLRP3 inflammasome. In the apolipoprotein E-deficient mice, lentiviral expression of CTRP9 could suppress the atherosclerosis development, which could be abolished by AMPK inhibition. ConclusionOur data here indicated that the CTRP9 showed atheroprotective function via CTRP9-AMPK- NLRP3 inflammasome pathway.

Relationship between serum CTRP6 level and insulin resistance in patients with newly diagnosed type 2 diabetes mellitus

Objective To explore the relationship between serum C1q and tumor necrosis factor related protein 6(CTRP6) level and insulin resistance in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Methods A total of 167 patients with newly diagnosed T2DM in the outpatient department of our hospital were recruited from April 2016 to March 2017 and 165 subjects with normal glucose tolerance were used as the control group. The concentrations of CTRP6, interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNF-α) were determined by ELISA. Results Circulating CTRP6 level was significantly higher in T2DM group than that in control group [(652.54±132.57) vs (521.28±119.93)μg/L, P<0.01] after adjusting age and body mass index (BMI). Overweight/obese subjects revealed higher CTRP6 levels compared with those in lean individuals. In addition, circulating CTRP6 level was positively correlated with BMI, waist circumference, fasting plasma glucose, postprandial 2h plasma glucose, HbA1C, fasting insulin, homeostasis model assessment insulin resistance index (HOMA-IR), triglyceride (TG), IL-6, MCP-1, highly sensitive C-reactive protein (hs-CRP), and TNF-α, while it was inversely correlated with high-density lipoprotein-cholesterol(P<0.01). Multivariate linear regression analysis showed that TG, HOMA-IR, and IL-6 were independent factors for CTRP6 level. After adjusting for potential confounders, CTRP6 remained an independent risk factor for T2DM. Trend test showed that the increase in CTRP6 level was significantly linear with the occurrence of T2DM. The analysis of receiver operating characteristic curves revealed that the area under the curve for circulating CTRP6 to predict T2DM was 0.730. Conclusions CTRP6 may be associated with insulin resistance. Key words: C1q/TNF-related protein-6; Diabetes mellitus, type 2; Inflammation; Insulin resistance

The Novel Adipokine C1Qtnf1 Significantly Predicts The Incidence Of Future Major Cardiovascular Events In Patients With Type 2 Diabetes

Background and Aims: Increased serum levels of the novel adipokine C1q and tumor necrosis factor related protein 1 (C1QTNF1) have been linked with type 2 diabetes (T2DM) and ischemic heart disease. The impact of circulating C1QTNF1 on the incidence of future major cardiovascular events (MACE) is unclear and is addressed in the present study.

Circulating CTRP1 Levels Are Increased and Associated with the STOD in Essential Hypertension in Chinese Patients.

This study aimed to investigate the correlation between complement C1q tumor necrosis factor-related protein 1 (CTRP1) and subclinical target organ damage (STOD) in essential hypertension (EH). 720 patients were enrolled in this study, including 360 healthy subjects and 360 patients with EH. The EH group included 183 patients complicated with STOD and 177 patients without STOD. In the STOD group, there were 87 patients with left ventricular hypertrophy (LVH), 32 patients with microalbuminuria (MAU), and 58 patients with complication of LVH and MAU. Enzyme-linked immunosorbent assay (ELISA) was used to detect the CTRP1, adiponectin (APN), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). We found that CTRP1 levels were higher in patients with EH than those in healthy subjects; moreover, the level of CTRP1 of patients in the group complicated with EH and STOD was increased compared with EH patients without STOD. CTRP1 levels in the group complicated with LVH and MAU were significantly higher than those in the LVH group and the MAU group. Furthermore, APN, CTRP1, and IL-6 were three factors that influenced the STOD of EH patients, among which CTRP1 and IL6 were positively related with the complication of hypertension and STOD. In conclusion, CTRP1 levels are increased and associated with the STOD (heart and kidney) in essential hypertension, which can be regarded as a novel biomarker in the prediction of prognosis for patients with essential hypertension.

Predicting the survival of patients with lung adenocarcinoma using a four-gene prognosis risk model.

Lung adenocarcinoma (LAD) is difficult to diagnose as it tends to be small in size and metastasize early. The aim of the present study was to investigate prognostic factors for patients with LAD and establish a prognosis risk model. A training set consisting of clinical and RNA sequencing data from 503 patients with LAD, as well as expression data from a further 59 LAD and adjacent tissues, was obtained from The Cancer Genome Atlas. Additionally, a validation dataset was acquired from the Gene Expression Omnibus database (GSE26939), which included clinical and gene expression data from 115 patients. Using the DESeq2 package to compare expression between LAD and adjacent tissues, differentially expressed genes (DEGs) were identified. On the basis of survival and the random forests for survival, regression and classification package, genes for constructing the prognosis risk model were selected. The prognosis risk model was constructed and validated using the survival package. Subsequently, high- and low-risk groups were compared using the Limma package to identify DEGs, and enrichment analysis was performed using the web-based gene set analysis toolkit. A protein-protein interaction network was visualized using Cytoscape software. There were 18,567 DEGs between the LAD samples and the adjacent tissues, and 363 DEGs between the high- and low-risk groups. Of these, four genes were selected for constructing the prognosis risk model, myosin IE (MYO1E), endoplasmic reticulum oxidoreductase 1α (ERO1L), C1q and tumor necrosis factor-related protein 6 (C1QTNF6) and family with sequence similarity 83, member A (FAM83A). The survival time of high- and low-risk groups in the validation set were significantly different. Functional enrichment revealed that the genes that interacted with MYO1E, ERO1L, C1QTNF6 and FAM83A separately were enriched in ‘cell cycle regulation’, ‘synthesis and assembly of nucleic acids’, ‘histone modification and cell cycle progression’ and ‘cell secretion process’. The four-gene prognosis risk model could potentially be used for predicting the survival of patients with LAD.

Association of C1q/TNF-related protein-1 (CTRP1) serum levels with coronary artery disease.

ObjectiveComplement C1q tumor necrosis factor-related proteins (CTRPs), belonging to the CTRP superfamily, are extensively involved in regulating metabolism and the immune-inflammatory response. The inflammatory process is linked to the pathogenesis of coronary artery disease (CAD). Here, we investigated the association of serum levels of CTRP1 with CAD.MethodsStudy participants were divided into two groups according to the results of coronary angiography: a control group (n = 63) and a CAD group (n = 76). The concentrations of serum CTRP1 and inflammatory cytokines were determined by enzyme-linked immunosorbent assay. Further analysis of CTRP1 levels in individuals with different severities of CAD was conducted. The CAD severity was assessed by Gensini score.ResultsSerum levels of CTRP1 were significantly higher in CAD patients than in controls (17.24 ± 1.07 versus 9.31 ± 0.56 ng/mL), and CTRP1 levels increased with increasing severity of CAD. CTRP1 levels were positively correlated with concentrations of tumor necrosis factor-α and interleukin-6. Multiple logistic regression analysis showed that CTRP1 was significantly associated with CAD.ConclusionsOur data showed close associations of serum CTRP1 levels with the prevalence and severity of CAD, indicating that CTRP1 can be regarded as a novel and valuable biomarker for CAD.

The novel adipokine CTRP1 is significantly associated with the incidence of major adverse cardiovascular events

Background and aimsThe recently identified adiponectin paralogue C1q and tumor necrosis factor-related protein 1 (CTRP1) has been associated with obesity-linked disorders and coronary atherosclerosis. So far, the impact of circulating CTRP1 on the incidence of future cardiovascular events is unclear. Therefore, we aimed at investigating the association between CTRP1 and future cardiovascular risk. MethodsWe measured CTRP1 serum levels in 539 patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Prospectively, we recorded major adverse cardiovascular events (MACE), defined as the incidence of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke over a follow-up period of 8 years. ResultsAt baseline, obesity, the metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease were significantly associated with increased CTRP1 (all p-values ≤0.001). Prospectively, MACE rates were lowest in the first quartile (15.3%) and increased over the second (23.7%) to the third and fourth quartile (each 29.0%; ptrend = 0.008). Moreover, after multivariable adjustment, CTRP1 was significantly associated with future MACE, with adjusted HRs of 1.83 [1.04–3.23]; p=0.037, 2.16 [1.25–3.75]; p=0.006, and 1.80 [1.03–3.15]; p=0.038, for CTRP1 quartiles two, three and four, respectively, when compared to quartile one. ConclusionsWe conclude that high serum levels of CTRP1 are significantly associated with future MACE.

Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease mainly involving the formation of a synovial pannus, for which no effective treatment is available. In order to study the molecular biological mechanisms underlying the inhibition of RA synovial pannus by triptolide, differentially expressed genes in synovial tissues from an adjuvant arthritis (AA) rat model with and without triptolide treatment were detected in an mRNA microarray profile produced by Agilent Technologies and verified by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR). An AA model was established by subcutaneously injecting 0.1 ml Freund's complete adjuvant daily for 18 days and scored by arthritis index assessment. Subsequently, triptolide (0.4 mg/kg) or an equivalent amount of saline was administered daily for 14 days. At the end of the experiment, synovial tissues were obtained from the ankle joints of the rats' hind legs. Total RNA was extracted and purified, and microarray hybridization was used to obtain the gene expression profile for RA with and without triptolide treatment. A total of 48 genes were identified to be differentially expressed between the treatment and model groups, including 32 upregulated and 16 downregulated genes. The possible signaling pathways associated with the effect of triptolide were investigated by Gene Ontology and pathway analysis, revealing that the phosphoinositide-3 kinase (PI3K)/AKT signaling pathway has a key role in the proliferation and apoptosis of synovial cells in RA joints. Reverse transcription-quantitative polymerase chain reaction analysis was applied to confirm the aberrant expression of key mRNAs and revealed that vascular endothelial growth factor (VEGF) A and C1q and tumor necrosis factor related protein 3 (C1QTNF3) were downregulated in the treatment group compared with the model group (P<0.05). In conclusion, triptolide may exert its effects against RA via the PI3K/AKT pathway and has an inhibitory effect on the expression of VEGFA and C1QTNF3, thus are potentially associated with the occurrence and development of RA.

Autoantibodies Against β1-Adrenoceptor Exaggerated Ventricular Remodeling by Inhibiting CTRP9 Expression.

BackgroundAutoantibodies against the second extracellular loop of the β1‐adrenoceptor (β1‐AA) act similarly to agonist of β1‐adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor–related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP9 in ventricular remodeling induced by β1‐AA.Methods and ResultsBlood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of β1‐AA and CTRP9 were detected using ELISA. The results revealed that CTRP9 levels in β1‐AA–positive patients were lower than those in β1‐AA–negative patients, and serum CTRP9 concentrations were inversely correlated with β1‐AA. β1‐AA monoclonal antibodies (β1‐AAmAbs) were administered in mice with and without rAAV9‐cTnT‐Full Ctrp9‐FLAG virus for 8 weeks. Reverse transcription–polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP9 expression was significantly reduced in β1‐AAmAb–treated mice. Moreover, compared with the β1‐AAmAb alone group, cardiac‐specific CTRP9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP9 overexpression decreased the levels of G‐protein–coupled receptor kinase 2 and promoted the activation of AMP‐dependent kinase pathway. However, cardiac‐specific overexpression of CTRP9 had no effect on the levels of cAMP and protein kinase A activity elevated by β1‐AAmAb.ConclusionsThis study provides the first evidence that the long‐term existence of β1‐AAmAb suppresses cardiac CTRP9 expression and exaggerates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in β1‐AA–positive patients with coronary heart disease.

Adiponectin deficiency has no effect in murine autoimmune myocarditis

BackgroundAdiponectin is a hormone that together with its receptors modulates a number of metabolic processes including gluconeogenesis and lipid catabolism. It belongs to the C1QTNF (complement C1q tumor necrosis factor-related protein) family, which has a variety of members with high amino acid sequence homology and overlapping functions. Concentration of adiponectin in blood is inversely correlated with body fat percentage and cardiac risk factors like blood pressure and CRP (C-reactive protein) level. Studies have identified the existence of a cardiac adiponectin system. However, little is known about the role of this system in the pathogenesis of autoimmune myocarditis. Thus, we have studied the involvement of adiponectin in the development of this autoimmune disorder in a mouse model of experimental autoimmune myocarditis (EAM). MethodsAdiponectin knockout (ko) and wild type (wt) mice were immunized with cardiac troponin I (cTnI) to induce an EAM. To determine the severity of myocardial damage, inflammation and fibrosis were scored after HE and Afog staining and high sensitivity troponin T (hsTnT) level was measured. To detect if changes in specific inflammatory cell numbers could be observed between the genotypes, we performed immunohistochemical staining to detect T lymphocytes, B lymphocytes and macrophages. The level of the humoral immune response was determined through the measurement of cTnI-specific serum IgG autoantibodies. Relative mRNA expression of different cytokines, C1QTNF family members and adiponectin receptors in the heart tissue was analyzed with qPCR. ResultsAnimals immunized with cTnI developed autoimmune myocarditis with a significant deterioration of cardiac parameters compared to the corresponding control group. The adiponectin ko group immunized with cTnI showed a tendency towards increased inflammation, fibrosis, heart-to-body-weight ratio, infiltration pattern of T lymphocytes, B lymphocytes and macrophages, hsTnT concentration, humoral immune response and mRNA expression of interleukin 6 in the heart tissue and decreased weight gain compared to the wt group immunized with cTnI. However, the difference to the wt group treated with cTnI was not significant. The analysis of cardiac mRNA expression of adiponectin receptors and four C1QTNF family members, most suitable for fulfilling the functions of adiponectin in adiponectin ko mice, did not show any significant differences between adiponectin ko and wt group at all. ConclusionOur study reveals that the absence of adiponectin did not lead to a significantly increased impairment of cardiac function and was also unlikely to be compensated by its receptors or other C1QTNF family members in the murine model of EAM. Here, other synergistic or redundant effects might play a role and must be investigated in further studies to understand the role and function of adiponectin in autoimmune myocarditis.

Complement c1q tumor necrosis factor-related protein 3 a novel adipokine, protect against diabetes mellitus in young adult Egyptians

C1q/TNF-related protein-3 (CTRP3) is a novel adipokine with anti-inflammatory and a multitude of biological effects on glucose and lipid metabolism however, the influence of CTRP3 on incidence of diabetes mellitus remain unclear. This study investigated the effects of CTRP3 levels in obese and normal body weight young adults on insulin resistance and occurrence of diabetes mellitus. Subjects and methodsIn this case control study, Serum levels of CTRP3, HbA1c, Lipid profile, glucose and insulin levels were determined in 75 obese and 68 normal body weight individuals. ResultsIn obese young adults CTRP3 concentrations were decreased compared to normal body weight young adults (NBW). The association between reduction of CTRP3 concentrations and the presence of diabetes is statistically significant. CTRP3 showed significant negative correlation with BMI, HOMA-IR and triglycerides as well as positive correlations with HDL – cholesterol while there is no association between CTRP3 and BMI within the NBW group. Higher HbA1C, HOMA-IR, and risk of diabetes development within obese subjects were related to lower CTRP3 concentration. ConclusionsThis study shows that reduction of CTRP3 concentrations is likely to bring a concomitant increase in risk of diabetes in obese and normal body weight young adults. Decrease in CTRP3 concentration may have an essential role in the pathophysiology of metabolic disorders concomitant to obesity.

Anti-glucocorticoid-induced Tumor Necrosis Factor-Related Protein (GITR) Therapy Overcomes Radiation-Induced Treg Immunosuppression and Drives Abscopal Effects.

Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono- or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.

Detoxification- and Immune-Related Transcriptomic Analysis of Gills from Bay Scallops (Argopectenirradians) in Response to Algal Toxin Okadaic Acid.

To reveal the molecular mechanisms triggered by okadaic acid (OA)-exposure in the detoxification and immune system of bay scallops, we studied differentially-expressed genes (DEGs) and the transcriptomic profile in bay scallop gill tissue after 48 h exposure to 500 nM of OA using the Illumina HiSeq 4000 deep-sequencing platform. De novo assembly of paired-end reads yielded 55,876 unigenes, of which 3204 and 2620 genes were found to be significantly up- or down-regulated, respectively. Gene ontology classification and enrichment analysis of the DEGs detected in bay scallops exposed to OA revealed four ontologies with particularly high functional enrichment, which were ‘cellular process’ (cellular component), ‘metabolic process’ (biological process), ‘immune system process’ (biological process), and ‘catalytic process’ (molecular function). The DEGs revealed that cyclic AMP-responsive element-binding proteins, acid phosphatase, toll-like receptors, nuclear erythroid 2-related factor, and the NADPH2 quinone reductase-related gene were upregulated. In contrast, the expression of some genes related to glutathione S-transferase 1, C-type lectin, complement C1q tumor necrosis factor-related protein, Superoxide dismutase 2 and fibrinogen C domain-containing protein, decreased. The outcomes of this study will be a valuable resource for the study of gene expression induced by marine toxins, and will help understanding of the molecular mechanisms underlying the scallops’ response to OA exposure.

The Novel Adipokine C1QTNF1 Significantly Predicts the Incidence of Future Major Cardiovascular Events in Patients with Type 2 Diabetes

Increased serum levels of the novel adipokine C1q and tumor necrosis factor related protein 1 (C1QTNF1) have been linked with type 2 diabetes (T2DM) and ischemic heart disease. The impact of circulating C1QTNF1 on the incidence of future major cardiovascular events (MACE) is unclear and is addressed in the present study. We measured C1QTNF1 serum levels in 542 patients undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD) using an enzyme-linked immunosorbent assay. Prospectively, MACE were recorded over a mean follow-up period of 6.3 years. C1QTNF1 serum levels at baseline were significantly increased in patients with T2DM (n=160) compared to those without diabetes (521.4 ± 224.8 vs. 429.5 ± 130.3 ng/ml; p&amp;lt;0.001). Prospectively, the incidence of MACE increased significantly through tertiles of C1QTNF1 (17.8%, 24.7%, and 29.7% in the 1st, 2nd and 3rd tertiles, respectively; ptrend=0.010). Also after adjustment for age, sex, and T2DM as well as after additional adjustment for body mass index, hypertension, LDL cholesterol, HDL cholesterol, triglycerides, and angiographically determined baseline CAD, C1QTNF1 significantly predicted MACE, with adjusted HRs of 1.30 [1.04-1.61]; p=0.019 and 1.36 [1.09-1.70]; p=0.007, respectively. Patients with T2DM were at a significantly higher risk of MACE than those who did not have diabetes (48% vs. 26%; p=0.003). C1QTNF1 in subgroup analyses also in T2DM patients proved to be a strong predictor of MACE (adjusted HR 1.57 [1.10-2.24]; p=0.013). We conclude that high serum levels of C1QTNF1 significantly predict MACE, in particular in patients with T2DM. Disclosure A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. K. Geiger: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.