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Growing evidence shows that there is an increased risk of cardiovascular diseases among gout patients, especially coronary heart disease (CHD). Screening for CHD in gout patients based on simple clinical factors is still challenging. Here we aim to build a diagnostic model based on machine learning so as to avoid missed diagnoses or over exaggerated examinations as much as possible. Over 300 patient samples collected from Jiangxi Provincial People's Hospital were divided into two groups (gout and gout+CHD). The prediction of CHD in gout patients has thus been modeled as a binary classification problem. A total of eight clinical indicators were selected as features for machine learning classifiers. A combined sampling technique was used to overcome the imbalanced problem in the training dataset. Eight machine learning models were used including logistic regression, decision tree, ensemble learning models (random forest, XGBoost, LightGBM, GBDT), support vector machine (SVM) and neural networks. Our results showed that stepwise logistic regression and SVM achieved more excellent AUC values, while the random forest and XGBoost models achieved more excellent performances in terms of recall and accuracy. Furthermore, several high-risk factors were found to be effective indices in predicting CHD in gout patients, which provide insights into the clinical diagnosis.

Abstract Background As important enzymes regulating acetylation, histone deacetylases (HDACs) participate in a series of cell physiological process. However, the mechanisms responsible for individual HDAC family members in regulating innate immunity remained to be elucidated. Here we sought to reveal the mechanism of HDAC3 in regulating the inflammatory response of macrophages. Methods RNAseq was done to detect the transcriptional influence of HDAC3 on macrophages. Kyoto Encyclopedia of Genes and Genomes was used to reveal the change of signaling pathways after HDAC3 knockout. CHIPseq was done to detect the deacetylation modification of HDAC3 on chromosome. Western blot, immunofluorescence, and real-time quantitative PCR were used to measure the change of genes and proteins’ levels. Mice were intratracheal instillation with lipopolysaccharide or Pseudomonas aeruginosa to determine the influence of HDAC3 on inflammatory response in vivo. Results HDAC3-deficient macrophages had increased expression of cathepsins resulting from elevated histone acetylation. Over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which reduced TNFα mediated NF-κB activation and inflammatory response. Consistently, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and thereby susceptible to Pseudomonas aeruginosa infection. Conclusion HDAC3 was required for protecting RIP1 from degrading by CTSB in macrophages. Decreased RIP1 in HDAC3 knockout macrophages impaired TNFα mediated NF-κB activation. Our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.

Flat peach, a predominant fruit consumed in China, is highly susceptible to softening and perishable. The impact of 1-methylcycloproene (1-MCP) fumigation combined with ε-poly-L-lysine (ε-PL) on softening and postharvest reactive oxygen species (ROS) and phenylpropanoid pathway metabolisms in peaches and its relationship to disease resistance were investigated. Findings revealed that a combination of 1 µL L−1 1-MCP and 300 mg L−1 ε-PL effectively suppressed the activity of cell-wall-degrading enzymes and the disassembly of cell wall structure, thus maintaining higher firmness and lower decay incidence. Compared to the control group, the synergistic approach bolstered enzymatic responses linked to disease resistance and ROS-scavenge system, consistently preserving total phenolics, flavonoids, ascorbic acid, and glutathione levels. Concurrently, the accumulation of hydrogen peroxide and malondialdehyde was significantly diminished post-treatment. These results show that there is good synergistic effect between 1-MCP and ε-PL, which could effectively maintain the quality of flat peach fruit by modulating cell wall metabolism and enhancing the resistance.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by multi-articular, symmetrical and invasive arthritis resulting from immune system abnormalities involving T and B lymphocytes. Although significant progress has been made in the understanding of RA pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest that NLRP3 inflammasome, a regulator of inflammation, might play an important role in the development of RA. There have been increasing clinical and pre-clinical evidence showing the treatment of NLRP3/IL-1β in inflammatory diseases. To provide a foundation for the development of therapeutic strategies, we will briefly summarize the roles of NLRP3 inflammasome in RA and explore its potential clinical treatment.

Background: Systemic Sclerosis (SSc) is an autoimmune disease that is characterized by vasculopathy, digital ulcers, Raynaud’s phenomenon, renal failure, pulmonary arterial hypertension, and fibrosis. Regulatory T (Treg) cell subsets have recently been found to play crucial roles in SSc with interstitial lung disease (ILD) pathogenesis. This study investigates the molecular mechanism of Treg-related genes in SSc patients through bioinformatic analyses. Methods: The GSE181228 dataset of SSc was used in this study. CIBERSORT was used for assessing the category and proportions of immune cells in SSc. Random forest and least absolute shrinkage and selection operator (LASSO) regression analysis were used to select the hub Treg-related genes. Results: Through bioinformatic analyses, LIPN and CLEC4D were selected as hub Treg-regulated genes. The diagnostic power of the two genes separately for SSc was 0.824 and 0.826. LIPN was associated with the pathway of aminoacyl−tRNA biosynthesis, Primary immunodeficiency, DNA replication, etc. The expression of CLEC4D was associated with the pathway of Neutrophil extracellular trap formation, PPAR signaling pathway, Staphylococcus aureus infection, Systemic lupus erythematosus, TNF signaling pathway, and Toll−like receptor signaling pathway. Conclusion: Through bioinformatic analyses, we identified two Treg-related hub genes (LIPN, CLEC4D) that are mainly involved in the immune response and metabolism of Tregs in SSc with ILD. Moreover, our findings may provide the potential for studying the molecular mechanism of SSc with ILD.

Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune activation and multi-immunologic phenotypes. Interleukin-33 (IL-33) has been shown to be a critical and pleiotropic immunoregulatory mediator in the pathogenesis of many autoimmune diseases. At present, there are conflicting findings in the research of IL-33 in SLE. The purpose of this study was to investigate whether and how IL-33 is involved in the occurrence and development of SLE. Methods 43 SLE patients and 43 healthy volunteers were recruited for this study. Serum levels of IL-33, IL-4, IL-6, IL-10 and IL-21 were measured by ELISA. The expression of IL-33 was investigated in kidney sections by immunohistochemistry in lupus nephritis patients ( n = 5) and controls ( n = 3). The mRNA expressions of Toll like receptor 4 (TLR4), TLR2, and tumorigenicity 2 (ST2)L were quantified in peripheral blood mononuclear cells (PBMCs) by real-time PCR. The surface expression of TLR4 on T cells, B cells, monocytes, and neutrophils was assessed by flow cytometry ( n = 22). Mann–Whitney U-test and Spearman’s test were used for statistical analysis. Results Serum concentrations of IL-33 were significantly higher in SLE patients than in healthy controls ( p < 0.0001). IL-33 expressions were positively correlated with IL-4 and IL-6 levels in SLE patients, which play pivotal roles in the autoantibody production. In addition, TLR4 and TLR2 mRNA were markedly increased in PBMCs from SLE patients ( p < 0.05). TLR4 was positively associated with IL-33, while TLR2 was not. Conclusions These results imply that upregulated expression of serum IL-33 together with increased TLR4 in PBMCs may contribute to the pathogenesis of SLE via promotion of inflammatory cytokines production.

Background:Depressive disorder is the leading cause of disability and suicidality worldwide. Metabolites are considered indicators and regulators of depression. However, the pathophysiology of the prefrontal cortex (PFC) in depression remains unclear.MethodsA chronic unpredictable mild stress (CUMS) model and a maturation rodent model of depression was used to investigate metabolic changes in the PFC. Eighteen male Sprague-Dawley rats were randomly divided into CUMS and control groups. The sucrose preference test (SPT) and forced swimming test (FST) were employed to evaluate and record depression-associated behaviors and changes in body weight (BW). High-performance liquid chromatography–tandem mass spectrometry was applied to test metabolites in rat PFC. Furthermore, principal component analysis and orthogonal partial least-squares discriminant analysis were employed to identify differentially abundant metabolites. Metabolic pathways were analyzed using MetaboAnalyst. Finally, a metabolite-protein interaction network was established to illustrate the function of differential metabolites.ResultsSPT and FST results confirmed successful establishment of the CUMS-induced depression-like behavior model in rats. Five metabolites, including 1-methylnicotinamide, 3-methylhistidine, acetylcholine, glycerophospho-N-palmitoyl ethanolamine, α-D-mannose 1-phosphate, were identified as potential biomarkers of depression. Four pathways changed in the CUMS group. Metabolite-protein interaction analysis revealed that 10 pathways play roles in the metabolism of depression.ConclusionFive potential biomarkers were identified in the PFC and metabolite-protein interactions associated with metabolic pathophysiological processes were explored using the CUMS model. The results of this study will assist physicians and scientists in discovering potential diagnostic markers and novel therapeutic targets for depression.

ObjectivesTo evaluate the role of C-reactive protein/albumin ratio (CAR), neutrophil/lymphocyte ratio (NLR), and mean platelet volume (MPV) in newly diagnosed AAV patients and examine their clinical significance.MethodsData from 79 untreated newly diagnosed AAV patients were collected and 76 health examination subjects were included in the healthy control group. All clinical characteristics of AAV patients were extracted from their medical records. The NLR, CAR, and MPV levels of AAV patients and the healthy controls were compared and the correlation between these markers and clinical characteristics was analyzed. Patients were then divided into two groups based on the 2003 Birmingham Vasculitis Activity Score (BVAS). The correlation between NLR, CAR, and MPV and disease activity was analyzed and their effects on the cumulative survival rate were analyzed.ResultsCompared with the healthy control group, elevated CAR, NLR, and MPV were observed in AAV patients. CAR (r = 0.701, P < 0.0001) and NLR (r = 0.369, P < 0.05) were positively correlated with the BVAS while MPV did not show any significant correlation (P = 0.85). The optimal cutoff value for disease activity evaluation using CAR was 0.80 (sensitivity: 85% and specificity: 82%, P < 0.05). The optimal cutoff value for disease activity evaluation using NLR was 5.15 (sensitivity: 66% and specificity: 72%, P < 0.05). Kaplan–Meier survival analysis revealed that the all-cause mortality rate was higher in patients with CAR ≥ 0.8 than in patients with CAR < 0.8 (P < 0.05). Patients with low NLR also showed a lower cumulative survival rate (P < 0.05).ConclusionsNLR and CAR can reflect the inflammatory response and disease activity in AAV patients, while MPV is not significantly correlated with disease activity in AAV patients. The all-cause mortality rate was higher in patients with high CAR and NLR than in patients with low CAR and NLR.

BackgroundThe association between the triglyceride–glucose (TyG) index and type 2 diabetes mellitus (T2DM) in older adults has not been fully understood. This research aims to explore the association between the TyG index and the incidence of T2DM in an older Chinese population aged over 75 years.MethodsThis longitudinal analysis study was performed based on a database from a health check screening program in China. The participants were stratified based on the quintile ranges of the TyG index (Q1 to Q5 groups). T2DM was defined as fasting plasma glucose (FPG) ≥ 7.00 mmol/L and/or self-reported T2DM. The cumulative incidences of T2DM in various quintile groups were estimated by the Kaplan–Meier method. The Cox proportional hazard model was used to examine the independent impact of the TyG index on the risk of T2DM during the follow-up period. Subgroup analysis was performed by gender and BMI to further validate the credibility of the results.ResultsDuring the follow-up period, a total of 231 new-onset T2DM cases were recorded among the 2,571 individuals aged over 75 years. After adjusting confounding factors, elevated TyG index independently indicated a higher risk of T2DM (HR = 1.89; 95% CI, 1.47–2.44; p < 0.01). Higher TyG index quintile groups (Q3 to Q5) also presented with a higher risk of T2DM (hazard ratio (HR) = 1.36, 1.44, and 2.12, respectively) as compared with the lowest quintile group (Q1). Subgroup analysis showed that increased TyG index led to a higher risk of T2DM with HR = 2.35 (95% CI, 1.73–3.19), 1.90 (95% CI, 1.27–2.83), 2.95 (95% CI, 1.94–4.50), and 1.72 (95% CI, 1.25–2.35) in male subgroup, female subgroup, BMI < 24 kg/m2 subgroup, and BMI ≥ 24 kg/m2 subgroup, respectively.ConclusionsTriglyceride–glucose index independently correlated with the risk of incident T2DM in Chinese adults aged over 75 years. The TyG index might be useful in monitoring T2DM in the older populations.

Bag-of-Visual-Words (BoVW) is still a useful image classification model when there is not enough data to use Deep Learning. In BoVW model, the practice of reducing the reconstruction errors of local features can improve the classification accuracy owing to the decrease of information loss. Many reconstruction-based coding methods are proposed to learn a visual dictionary and encode local features via minimizing the reconstruction errors of local features with constraints. Besides this, the accuracy can also be improved by learning the category-specific dictionaries and then encoding features based on these dictionaries. By considering the two practices together, we propose a simple category-specific dictionary learning method tailored for reconstruction-based feature coding. Our method can be used as a universal one to improve the classification accuracies of many reconstruction-based coding methods, which is the highlight of our method. Concretely, a universal dictionary is learned by employing a reconstruction-based coding method and then refined for each category to obtain the category-specific dictionary of this category. When encoding a feature by a category-specific dictionary, the visual words for encoding it are decided in advance by the indices, which correspond to the non-zero elements of its coding vector obtained with the universal dictionary. The effectiveness of our method is validated by observing whether there is an accuracy improvement after applying our method. Our results on Scene-15, Caltech-101, and UIUC-Sports datasets show that the accuracies of four representative coding methods are improved by about 0.3% to 2.7%, which experimentally demonstrates the universality and effectiveness of our method.

Background: Chaihu-Shugan-San is a classical prescription to treat depression. According to the traditional Chinese medicine (TCM) principle, the 2 decomposed recipes in Chaihu-Shugan-San exert synergistic effects, including Shu Gan (stagnated Gan-Qi dispersion) and Rou Gan (Gan nourishment to alleviate pain). However, the specific mechanism of Chaihu-Shugan-San on depression and its compatibility rule remain to be explored.Objective: We aimed to explore the anti-depression mechanisms and analyze the advantage of TCM compatibility of Chaihu-Shugan-San.Methods: The chronic unpredictable mild stress (CUMS) rat model was established. Antidepressant effects were evaluated by sucrose preference test (SPT), and forced swimming test (FST). Tandem Mass Tag (TMT)-based quantitative proteomics of the hippocampus was used to obtain differentially expressed proteins (DEPs). Bioinformatics analysis including Gene Ontology (GO), pathway enrichment, and protein-protein interaction (PPI) networks was utilized to study the DEPs connections. At last, the achieved key targets were verified by western blotting.Results: Chaihu-Shugan-San increased weight gain and food intake, as well as exhibited better therapeutic effects including enhanced sucrose preference and extended immobility time when compared with its decomposed recipes. Proteomics showed Chaihu-Shugan-San, Shu Gan, and Rou Gan regulated 110, 12, and 407 DEPs, respectively. Compared with Shu Gan or Rou Gan alone, the expression of 22 proteins was additionally changed by Chaihu-Shugan-San treatment, whereas the expression of 323 proteins whose expression was changed by Shu Gan or Rou Gan alone were not changed by Chaihu-Shugan-San treatment. Bioinformatics analysis demonstrated that Chaihu-Shugan-San affected neurotransmitter’s release and transmission cycle (e.g., γ-aminobutyric acid (GABA), glutamate, serotonin, norepinephrine, dopamine, and acetylcholine). GABA release pathway is also targeted by the 22 DEPs. Unexpectedly, only 2 pathways were enriched by the 323 DEPs: Metabolism and Cellular responses to external stimuli. Lastly, the expression of Gad2, Vamp2, and Pde2a was verified by western blotting.Conclusions: Chaihu-Shugan-San treats depression via multiple targets and pathways, which may include regulations of 110 DEPs and some neurotransmitter’s transmission cycle. Compared with Shu Gan and Rou Gan, the 22 Chaihu-Shugan-San advanced proteins and the affected GABA pathway may be the advantages of Chaihu-Shugan-San compatibility. This research offers data and theory support for the clinical application of Chaihu-Shugan-San.

Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide that signals through the GLP-1 receptor (GLP-1R). GLP-1R, therefore, plays a critical role in diabetes and cardiovascular disease. Whether GLP-1R is involved in inflammatory disease such as gout remains unclear. Macrophages are critical effector cells in the pathogenesis of gout, a common form of inflammatory arthritis caused by the deposition of uric acid in joints. The expression of GLP-1R at the protein level is controversial due to the lack of specificity of existing antibodies against GLP-1R. Using a transgenic mouse model expressing enhanced green fluorescent protein (EGFP) under the control of GLP-1R promoter, here we confirmed the expression of GLP-1R by macrophages. M2 type macrophages and Ly6C+ macrophages expressed higher levels of GLP-1R, compared to their counterparts. GLP-1R deficient macrophages displayed a reduced the migratory ability and an enhanced expression of interleukin (IL)-6, while the expression of IL-1β was not affected. In monosodium urate (MSU) crystal-induced peritonitis, an experimental model of gout, the recruitment of macrophages, especially M2 macrophages, was significantly suppressed in GLP-1R knockout mice compared to wild-type mice. In conclusion, our data suggests that GLP-1R plays a critical role in macrophage migration in MSU-induced inflammation.

Background: We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages. Methods: Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit. Findings: Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI

The CCN proteins are a family of extracellular matrix- (ECM-) associated proteins which currently consist of six secreted proteins (CCN1-6). CCN3 protein, also known as nephroblastoma overexpressed protein (NOV), is a member of the CCN family with multiple biological functions, implicated in major cellular processes such as cell growth, migration, and differentiation. Recently, CCN3 has emerged as a critical regulator in a variety of diseases, including immune-related diseases, including rheumatology arthritis, osteoarthritis, and systemic sclerosis. In this review, we will briefly introduce the structure and function of the CCN3 protein and summarize the roles of CCN3 in immune-related diseases, which is essential to understand the functions of the CCN3 in immune-related diseases.

Background. Although the relationship between gout and cardiovascular has been well demonstrated, there is little information about the difference between gout with cerebrovascular disease and cardiovascular disease. In this study, the differences between gout with cerebral infarction (gout+CI) and gout with coronary heart disease (gout+CHD) and related factors that affect serum uric acid (sUA) levels in gout+CI were investigated by a cross-sectional study. Method. The patients from Jiangxi Provincial People’s Hospital with gout+CHD, gout+CI, and gout with coronary heart disease and cerebral infarction (gout+CHD+CI) between 2016 and 2020 were included in this study, and the medical record data were collected and analyzed. Results. We observed significant differences in age, drinking, hypertension, long-term use of diuretics and NSAIDs, sUA, CRE, and blood glucose in patients with gout+CHD and gout+CI. The sUA level was significantly positively correlated with smoking, CRE, and TG in the gout+CI group and was only positively correlated with CRE in the gout+CHD group and the gout+CHD+CI group (p

Background Heterozygous mutation in BMP (bone morphogenetic protein) receptor 2 is rare, but BMP cascade suppression is common in congenital heart disease–associated pulmonary arterial hypertension (CHD‐PAH); however, the underling mechanism of BMP cascade suppression independent of BMP receptor 2 mutation is unknown. Methods and Results Pulmonary hypertensive status observed in CHD‐PAH was surgically reproduced in rats. Gremlin‐1 expression was increased, but BMP cascade was suppressed, in lungs from CHD‐PAH patients and shunted rats, whereas shunt correction retarded these trends in rats. Immunostaining demonstrated increased gremlin‐1 was mainly in the endothelium and media of remodeled pulmonary arteries. However, mechanical stretch time‐ and amplitude‐dependently stimulated gremlin‐1 secretion and suppressed BMP cascade in distal pulmonary arterial smooth muscle cells from healthy rats. Under static condition, gremlin‐1 significantly promoted the proliferation and inhibited the apoptosis of distal pulmonary arterial smooth muscle cells from healthy rats via BMP cascade. Furthermore, plasma gremlin‐1 closely correlated with hemodynamic parameters in CHD‐PAH patients and shunted rats. Conclusions Serving as an endogenous antagonist of BMP cascade, the increase of gremlin‐1 in CHD‐PAH may present a reasonable mechanism explanation for BMP cascade suppression independent of BMP receptor 2 mutation.

Nephroblastoma overexpressed protein (NOV/CCN3), the early discovered member of the CCN family, has recently been suggested to be involved in a number of inflammatory processes, including wound healing, alveolar epithelial cell inflammation, cancer metastasis, and macrophage foam cell formation. However, the role of CCN3 in rheumatoid arthritis (RA), a classic autoimmune and inflammatory disease, remains elusive. RA is a chronic systemic autoimmune disease that eventually leads to cartilage and bone destruction and joint dysfunction. In this study, we investigated the potential of serum CCN3 as a biomarker for RA. The serum levels of CCN3 were measured by ELISA. The clinical and laboratory parameters were collected from a clinical record system, and disease activity was determined by joint disease activity score 28 (DAS28). Our results showed that the serum levels of CCN3 were significantly increased in RA patients compared to healthy controls. Furthermore, the CCN3 level was positively correlated with DAS28 (CRP), DAS28 (ESR), and the level of anti-CCP Ab, an autoantibody highly specific for RA. Furthermore, CCN3 showed a positive correlation with inflammatory cytokine IL-6, while no significant correlation with TNF-α was observed. These data suggest that CCN3 plays an important role in the development of RA and might be a potential disease activity biomarker for RA.

Interleukin-33 (IL-33) is a member of the IL-1 family of proteins that are produced by a variety of cell types in multiple tissues. Under conditions of cell injury or death, IL-33 is passively released from the nucleus and acts as an “alarmin” upon binding to its specific receptor ST2, which leads to proinflammatory or anti-inflammatory effects depending on the pathological environment. To date, numerous studies have investigated the roles of IL-33 in human and murine models of diseases of the nervous system, digestive system, pulmonary system, as well as other organs and systems, including solid organ transplantation. With graft rejection and ischemia-reperfusion injury being the most common causes of grafted organ failure or dysfunction, researchers have begun to investigate the role of IL-33 in the immune-related mechanisms of graft tolerance and rejection using heart transplantation models. In the present review, we summarize the identified roles of IL-33 as well as the corresponding mechanisms by which IL-33 acts within the progression of graft rejection after heart transplantation in animal models.

Abstract Background Recent studies have shown a crucial role of Gαq in immune regulation, but how Gαq modulates regulatory B-cell (Breg) function is still unclear. We address this here. Methods CD19+IL-10+ Bregs of wild-type (WT) and Gnaq −/− mice were analyzed by flow cytometry after stimulation by lipopolysaccharide. The WT and Gnaq −/− Bregs were isolated and cocultured with WT CD4+CD25− T cells in the presence of T-activator, and the proliferation of T cells and differentiation of regulatory T cells (Tregs) were analyzed by flow cytometry. We used inhibitors of PI3 kinase (PI3K), extracellular regulated protein kinases 1/2 (Erk1/2), and p38 mitogen-activated protein kinase (p38 MAPK) to detect the pathways involved in the regulation of Gαq on Breg differentiation, which were confirmed by western blot analysis. Furthermore, the expression level of Gαq was assessed by quantitative real-time PCR in peripheral blood mononuclear cells (PBMCs) from healthy controls and rheumatoid arthritis patients. The frequency of CD19+CD24hiCD38hi B cells in PBMCs was detected by flow cytometry, and the association of the Gαq mRNA expression level and the frequency of CD19+CD24hiCD38hi B cells was analyzed by Spearman test. Results The differentiation of CD19+IL-10+ Bregs was inhibited in the Gnaq −/− mice. In addition, Gαq depletion showed an impaired suppressive function of Bregs on T-cell proliferation, which might be due to the decreased Treg expansion. Mechanically, our data demonstrated that the PI3K, Erk1/2, and p38 MAPK signaling pathways were required for regulation of Gαq on Bregs, and blockage of these signaling pathways impaired Breg differentiation. Consistent with our previous studies, we also found a decreased frequency of CD19+CD24hiCD38hi Bregs in rheumatoid arthritis patients. As expected, a significantly positive correlation was investigated between CD19+CD24hiCD38hi Bregs with Gαq mRNA expression. Conclusions Our results indicate that Gαq plays a critical role in the differentiation and immunosuppression of Bregs, and it may provide a new therapeutic target for autoimmune diseases.

Abstract The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4-incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis.

Gout is one of the most common metabolic disorders in human. Previous studies have shown that the disease activity is closely associated with sympathetic nervous system (SNS). α2B-adrenergic receptor (α2BAR), a subtype of α2 adrenergic receptor, plays a critical role in many diseases. However, the role of α2BAR in the pathogenesis of gout remains unclear. Here, we assessed the role of α2BAR in the monosodium urate (MSU) crystals-induced peritonitis that mimics human gout by using the α2BAR-overexpressing mice (α2BAR-Tg). We found that the number of recruited neutrophils was significantly increased in the α2BAR-Tg mice after MSU treatment, when compared with wild type mice. In contrast, the number of macrophages was not changed. Importantly, there is no difference in the IL-1β levels and caspase-1 activity between wild type and α2BAR-Tg mice in the gout animal model. Notably, the enhanced neutrophil migration in α2BAR-Tg mice was dependent on the α2BAR overexpression in neutrophils, but not resulted from other tissues or cells with α2BAR overexpression. In conclusion, our data provide a direct evidence that α2BAR plays a critical role in neutrophil migration and MSU-induced inflammation.

Interleukin-33 (IL-33), a member of the IL-1 superfamily, has been shown to play a critical role in many diseases through regulating the immune cell responses, including myeloid-derived suppressor cells (MDSCs). Our previous study demonstrated that IL-33 might play a protective role in kidney injury in gout patients by regulating the lipid metabolism. However, the role of IL-33in the development of MSU-induced inflammation remains elusive. In this study, an increased IL-33 expression was observed in gout patients, which was positively correlated with inflammatory marker CRP. To explore the effects and mechanisms of the increased IL-33 expression in the gout patients, the anti-ST2 antibody and exogenous recombinant IL-33 were used in MSU-induced peritonitis animal model that mimics human gout. Compared with control group, mice with exogenous recombinant IL-33 significantly ameliorated the inflammatory cells infiltration, while blockage of IL-33 signaling by anti-ST2 had no effect on the development of MSU-induced peritonitis. Furthermore, the crucial inflammatory cytokine IL-1β was markedly decreased in IL-33-treated mice. Besides that, a large number of anti-inflammatory MDSCs with CD11b+Gr1intF4/80+ phenotype was observed in the IL-33-treated mice, and adoptive transfer of IL-33-induced MDSCs (CD11b+Gr1intF4/80+) markedly inhibited the IL-1β production in MSU-induced peritonitis. In conclusion, our data provide clear evidences that the increased expression of IL-33 in the gout patients might be due to a cause of self-negative regulation, which inhibits the development of MSU-induced inflammation through expanding MDSCs. Thus, IL-33 might serve as a promising therapeutic target for gout.

Gout is a common metabolic disease in humans, and it is due to persistently elevated levels of uric acid in the blood. At high levels, uric acid crystallizes and the crystals deposit in joints and surrounding tissues, resulting in an attack of gout. Interestingly, the gout attack can spontaneously resolve within a few days. However, the self-limited mechanism of gout remains elusive. It has been demonstrated that CD14 plays an important role in self-remission of gout. In this study, we found that the proportion of CD14-positive PBMCs was decreased in gout patients when compared with healthy controls and the serum sCD14 level was also considerably decreased in gout patients in comparison to healthy controls. In addition, sCD14 levels were positively correlated with CRP levels. Furthermore, the effect of MSU on the levels of CD14 in healthy volunteer’s PBMC was explored in in vitro experiment. The results showed that CD14 expression on macrophage and sCD14 levels in the culture supernatants were significantly decreased after MSU treatment. However, there was no significance in the levels of membrane CD14 and sCD14 in healthy volunteer’s PBMC stimulated by LPS. Taken together, these results suggest that CD14 might play an important role in self-remission of gout.

The inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract and involve a complicated reciprocity of environmental, genetic, and immunologic factors. Despite substantial advances in the foundational understanding of the immunological pathogenesis of IBD, the detailed mechanism of the pathological progression in IBD remains unknown. In addition to Th1/Th2 cells, whose role in IBD has been previously well defined, recent evidence indicates that Th17 cells and Tregs also play a crucial role in the development of IBD. Diets which contain excess sugars, salt, and fat may also be important actors in the pathogenesis of IBD, which may be the cause of high IBD incidence in western developed and industrialized countries. Up until now, the reason for the variance in prevalence of IBD between developed and developing countries has been unknown. This is partly due to the increasing popularity of western diets in developing countries, which makes the data harder to interpret. The enterocrinins glucagon-like peptides (GLPs), including GLP-1 and GLP-2, exhibit notable benefits on lipid metabolism, atherosclerosis formation, plasma glucose levels, and maintenance of gastric mucosa integrity. In addition to the regulation of nutrient metabolism, the emerging role of GLPs and their degrading enzyme dipeptidyl peptidase-4 (DPP-4) in gastrointestinal diseases has gained increasing attention. Therefore, here we review the function of the DPP-4/GLP axis in IBD.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant T cell immune response. Diffuse proliferative lupus nephritis (LN-IV) is the most common, severe, and active form of lupus nephritis. In this study, we investigated the production of Th1, Th2, and Th17 cytokines in prediction of active form of LN-IV. ProcartaPlex multiplex immunoassays panels were used for detection of serum Th1, Th2, and Th17 cytokines profiling. Th1 and Th17 cytokines (IL-18, IFN-γ, IL-12p70, IL-6, and IL-17A) were considerably expressed in the serum of lupus nephritis IV patients in comparison to the healthy control. However, only IL18 and IL6 were higher in class IV versus class III lupus nephritis. Importantly, the ratios of Th1/Th2 (IL-18/IL-4) and Th17/Th2 (IL-17A/IL-4) were significantly elevated in LN-IV when compared with LN-III, LN-V, and healthy controls. Consistently, the serum cytokines IL-18, IL-17A, and IFN-γ were markedly expressed in LN-IV patient glomeruli and interstitial tissue compared to other classes of LN by IHC. ROC further suggests that IL-18 was a potential marker for LN-IV. The data from our study suggests that the early detection and quantification of these cytokines may help in prediction of active form of LN-IV.

Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout.

The long noncoding RNAs (lncRNAs) are RNA transcripts more than 200 nucleotides in length, which do not encode proteins. The lncRNAs are emerging as an important regulator of biological process, such as chromatin remodeling, gene transcription, protein transport, and trafficking through diverse mechanisms. The lncRNAs play crucial role in various multigenetics human diseases including cancers and neurological diseases and currently its role in autoimmune diseases is attracting many researchers. Recent studies have reported that differentiation and activation of immune cells, T cells, B cells, macrophages, and NK cells have correlation with lncRNAs, which have also an essential role in autoimmune diseases such as rheumatoid arthritis and SLE. Therefore, elucidation of the roles of lncRNAs in autoimmunity could be beneficial to understand the pathogenesis of autoimmune diseases. In this review article we attempt to highlight the recent progress regarding lncRNAs studies and summarize its role in autoimmune diseases.

To study the serum Procalcitonin (PCT) level in inflammatory arthritis including gouty arthritis (GA), Rheumatoid arthritis (RA), and ankylosing spondylitis (AS) without any evidence of infection were evaluated the possible discriminative role of PCT in gouty arthritis susceptibility in southern Chinese Han Population.From Feb, 2012 to Feb, 2015, 51 patients with GA, 37 patients with RA, 41 patients with AS and 33 healthy control were enrolled in this study with no evidence of infections. The serum level of PCT (normal range < 0.05 ng/ml) was measured by electrochemiluminescence immunoassay (ECLIA). Disease activity was determined by scores of VAS (4.07 ± 1.15), DAS28 (4.97 ± 1.12), and ASDAS (2.97 ± 0.81) in GA, RA and AS groups respectively. Other laboratory parameters such as, serum creatinine (CRE), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), uric acid (UA) and white blood cells (WBC) were extracted from medical record system.Serum PCT level was predominantly higher in gouty arthritis than in RA and AS patients, especially in the GA patients with tophi. PCT was significantly positively correlated with VAS, CRP and ESR in gouty arthritis and CRP in AS. PCT also had positive correlation-ship with ESR, DAS28 and ASDAS in RA and AS patients respectively, but significant differences were not observed.These data suggested that PCT is not solely a biomarker for infection, but also an indicator in inflammatory arthritis, especially in gouty arthritis.

Bullous systemic lupus erythematosus (BSLE) is an autoantibody-mediated vesiculobullous disease in patients with SLE. Autoimmunity in BSLE is characterized by the presence of circulating anti-type VII collagen antibodies. BSLE patients often present with multiple, tense, clear fluid-filled vesicles and bullae overlying erythematous edematous plaques. Skin biopsy from BSLE patients shows subepidermal bullae with numerous neutrophils and only occasional eosinophils. Furthermore, immunofluorescence examination showed linear deposition of lgG, lgA, C3, and C1q along the basement membrane zone. BSLE patients with corticosteroids treatment constantly do not receive a marked improvement, while dapsone generally dramatically improved the skin condition. Recently, it has been reported that quite a few cases of BSLE were successfully treated with other immune suppressive drugs. Therefore, a comprehensive review of the treatment of BSLE would be beneficial to cure the disease.

Regulatory B cells (Bregs), a newly described subset of B cells, have been proved to play a suppressive role in immune system. Bregs can inhibit other immune cells through cytokines secretion and antigen presentation, which give them the role in the pathogenesis of autoimmune diseases and cancers. There are no clear criteria to identify Bregs; different markers were used in the different experimental conditions. Massive researches had described the functions of immune cells such as regulatory T cells (Tregs), dendritic cells (DCs), and B cells in the autoimmune disorder diseases and cancers. More and more researches focused on the roles of Bregs and the cytokines such as Interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) secreted by Bregs. The aim of this review is to summarize the characteristics of Bregs and the roles of Bregs in cancer.

Interleukin-33 (IL-33), a novel member of IL-1 family, has been recently implicated in several inflammatory and autoimmune diseases. IL-33 can be produced by various types of tissues and cells and induce gene expression of Th2-associated cytokines via binding to the orphan receptor ST2. By promoting Th2 type immune response, IL-33 plays important roles in the allergy, whereas its function in autoimmune diseases attracts more attention. Recent studies reported the correlation of IL-33 with rheumatic diseases, and most of them found that the IL-33 expression levels were consistent with disease activity and development. Furthermore, evidence has indicated that IL-33-related treatment may ameliorate the pathogenic conditions and attenuate disease progression of those rheumatic diseases. Therefore, elucidation of the roles of IL-33 in rheumatic diseases would be beneficial to understand the pathogenesis and therapy of these diseases. In this paper, we will summarize the roles of IL-33 in the rheumatic diseases.