Mechanism of neutrophil extracellular traps in the pathogenesis of gout.

Gout is a self-limited inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and surrounding tissues due to abnormal purine metabolism. Neutrophil extracellular traps (NETs) are formed by neutrophils in response to pathogen attack. During gout, NETs induced by MSU crystals exacerbate inflammation, and aggregated NETs (aggNETs) promote the resolution of gout-associated inflammation by encapsulating MSU crystals, degrading cytokines and chemokines, and blocking the recruitment and activation of neutrophils. With disease progression, NETs participate in the formation of tophi. Therefore, aggNETs are a possible mechanism of spontaneous gout regression. Studying the specific mechanism by which NETs affect inflammatory bursts and spontaneous regression in gout patients is important. This review summarises the role of NETs in different stages of gout and the specific pathogenesis of NETs in gout to provide new ideas for the diagnosis and treatment of gout.

Corrigendum: Analysis of risk factors for changes of left ventricular function indexes in Chinese patients with gout by echocardiography.

[This corrects the article DOI: 10.3389/fphys.2023.1280178.].

Association Between Family History in Patients with Primary Gout and Left Ventricular Diastolic Function: A Cross-Sectional Study.

Objective: This study aimed to employ echocardiography for measuring the markers of left ventricular (LV) diastolic function to investigate the effects of family history of gout on the LV diastolic function in patients with primary gout. Methods: Two hundred and eighty-four patients with primary gout who visited the Department of Rheumatology and Immunology of the First Affiliated Hospital of Chengdu Medical College from September 2020 to July 2022 were selected and their family history of gout, general information, and laboratory markers were recorded. Parameters of LV diastolic function were measured via echocardiography. The correlation between family history and LV diastolic function markers was analyzed using univariate and multivariate regression and the receiver operating characteristic (ROC) curve analyses. Results: LV diastolic function parameters, peak early mitral diastolic velocity (E)/peak late mitral diastolic velocity (A), and early septal mitral annulus diastolic motion velocity (Sepe'), early lateral mitral annulus diastolic motion velocity (Late') and their mean (e'), were significantly lower in patients with familial primary gout, while left atrial volume index (LAVI) and E/e' were markedly elevated in patients with sporadic primary gout. In patients with family history, the proportion of grade ≥2 LV diastolic insufficiency was distinctly higher than that in patients without family history (41.6% vs 12.3%). Even after adjusting for confounding variables, LAVI, E/A, Sepe', Late', e', E/e' were obviously associated with family history of gout. The area under ROC of family history combined with SUA level for identifying grade ≥2 LV diastolic insufficiency in patients with primary gout was 0.872 (P<0.05). Conclusion: Family history of gout was closely related to echocardiographic LV diastolic function parameters in patients with gout, what is more, family history of gout combined with SUA level was found to be a valuable indicator for discriminating grade ≥2 LV diastolic insufficiency in patients with primary gout.

Deficits in brain default mode network connectivity mediate the relationship between poor sleep quality and anxiety severity.

STUDY OBJECTIVES: Chronic insomnia disorder (CID) is a prevalent sleep disorder that frequently cooccurs with anxiety. The association between insomnia and anxiety has been established; however, the neurobiological basis of this relationship remains unclear. This study aimed to investigate the neural markers of CID patients with and without anxiety and to determine whether specific neural connectivity mediates the relationship between insomnia and anxiety. METHODS: This study included 180 participants, comprising CID patients with anxiety (CID-A), CID patients without anxiety (CID-NA), and good sleep controls. All participants completed self-reported measures of sleep quality and anxiety severity and underwent functional magnetic resonance imaging. Brain functional integration was measured using functional connectivity density (FCD) and resting-state functional connectivity (rsFC). Correlation and mediation analyses were used to examine the relationships among brain connectivity, sleep quality, and anxiety severity. RESULTS: The CID-NA and CID-A groups showed decreased local FCD in the medial prefrontal cortex (mPFC) and disrupted rsFC between the precuneus and other brain regions. Only the CID-A group exhibited altered long-range FCD in the precuneus and the rsFC between the anterior default mode network (DMN, e.g. mPFC) and posterior DMN (e.g. precuneus). Mediation analysis revealed DMN dysconnectivity underlying the association between poor sleep quality and anxiety symptoms. CONCLUSIONS: This study identified shared and distinct brain circuit disruptions in the CID-NA and CID-A groups, with deficits in DMN connectivity as a potential neural mechanism through which disrupted sleep augments anxiety. These findings may facilitate the development of personalized therapies for insomnia and associated anxiety problems.

The prevalence and independent risk factors of elevated common carotid artery intima-media thickness and carotid plaque in patients with gout.

OBJECTIVES: Gout patients are at high risk of carotid atherosclerosis, which could be convincingly reflected by common carotid artery intima-media thickness (CCAIMT) and carotid plaque. The current study aimed to investigate the prevalence and risk factors of thick CCAIMT and carotid plaque in gout patients. METHODS: Comprehensive demographic characteristics, chronic comorbidities, disease features, and biochemical indexes (42 parameters) were obtained from 237 gout patients. CCAIMT and carotid plaque were evaluated by bilateral carotid artery ultrasound in gout patients and 80 healthy controls. RESULTS: The CCAIMT and carotid plaque percentage were increased in gout patients compared to healthy controls (both p<0.001). In detail, the prevalence of thick CCAIMT (>0.9 mm) and carotid plaque was 22.4% and 34.6% in gout patients, respectively. Forward-stepwise multivariate logistic regression model revealed that age (p<0.001, odds ratio (OR)=1.143], disease duration (p=0.001, OR=1.176), alkaline phosphatase (ALP) (p=0.002, OR=1.037), and low-density lipoprotein cholesterol (LDLC) (p=0.039, OR=2.144) were independently associated with elevated thick CCAIMT risk, while serum uric acid (SUA) (p=0.002, OR=0.992) exhibited an opposite trend; their combination well-identified thick CCAIMT risk [area under the curve (AUC)=0.910] by receiver operator characteristic (ROC) curve. Meanwhile, age (p<0001, OR=1.116), tophus (p=0.009, OR=3.523), and triglycerides (TG) (p=0.014, OR=1.323) were independently associated with a higher risk of carotid plaque, while SUA (p=0.008, OR=0.995) showed an opposite trend; their combination also well-identified carotid plaque risk (AUC=0.886) by ROC curve. CONCLUSIONS: Thick CCAIMT and carotid plaque are prevalent in gout patients, whose occurrence relates to age, disease duration, ALP, LDLC, SUA, TG, and tophus.

Analysis of risk factors for changes of left ventricular function indexes in Chinese patients with gout by echocardiography.

Background: Echocardiographic data investigating the association between left ventricular (LV) function and gout is still limited. Purpose: To analyze the association of echocardiographic parameters based on two-dimentional speckle tracking analysis with clinically related indicators in patients with gout, and to provide a clinical basis for the early diagnosis and treatment of cardiovascular disease in patients with gout. Methods: This study collected gout patients who visited the outpatient and inpatient departments of the first affiliated hospital of chengdu medical college from November 2019 to December 2020. Spearman correlation test was performed to analyze the correlation coefficients between the laboratorial indicators with echocardiographic parameters. And the logistic regression analysis was performed to evaluate the independent effects. Results: The results of multivariate logistic regression showed that fasting plasma glucose (FPG) was a risk factor for the decrease in absolute value of global longitudinal strain [GLS (OR = 2.34; 95% CI, 1.01-5.39; p = 0.04)], Urea was a risk factor for absolute reduction in GCS (OR = 1.40; 95% CI, 1.07-1.85; p = 0.02), age (OR = 1.09, 95% CI, 1.04-1.16; p = 0.001), and hypertension (OR = 8.35; 95% CI, 1.83-38.02; p = 0.006) were risk factors for increased E/Em. High urea levels were significantly related with high risks of LVH (OR = 1.59, 95% CI, 1.04-2.43; p = 0.03) and enlargement of LAVI (OR = 1.68, 95% CI, 1.01-2.80; p = 0.04). Conclusion: Our study found that elevated urea and FPG were risk factors for subclinical LV myocardial dysfunction in patients with gout, which might provide a theoretical basis for the early diagnosis and treatment of heart disease in clinical practice.

Telenursing needs and influencing factors in patients with type 2 diabetes mellitus: A cross-sectional study.

AIMS AND OBJECTIVES: This study aimed to determine the relationship between the demand for telenursing and the chronic illness resources available to patients with type 2 diabetes mellitus (T2DM), as well as the factors that affect this requirement. DESIGN: Cross-sectional. METHODS: This study included 586 participants with T2DM. A telenursing needs questionnaire developed by the research team was used to assess the telenursing needs of patients with T2DM, and the Chinese version of the Chronic Illness Resources Survey was used to assess the participants' community chronic disease resources. A one-way ANOVA and multiple regression analysis were used to determine the factors influencing the demand for telenursing and to estimate the relationship between chronic illness resources and the need for telenursing. The STROBE checklist was followed. RESULTS: The patients' telenursing needs, ranked from high to low, are as follows: individualized skills and safety; basic disease care; psychological and spiritual needs; respect and social support; and high-level health management. The chronic disease resource score was 3.47 ± .02, which suggested that patients with T2DM have relatively rich disease resources. Multiple regression analyses showed that resources for chronic diseases, the course of diabetes and complications, family income and other chronic diseases accounted for 79.6% of the variance in T2DM patients' telenursing needs. CONCLUSIONS: The telenursing needs of patients with T2DM are prominent, and primarily focus on basic nursing needs for the disease. To some extent, chronic disease resources affect the telenursing needs of patients with T2DM. RELEVANCE TO CLINICAL PRACTICE: It is crucial to pay attention to research on telenursing for T2DM patients from the patients' perspective. Enhancing resources for chronic diseases may help meet the telenursing needs of T2DM patients. PATIENT OR PUBLIC CONTRIBUTION: Parents and diabetes management specialists participated in designing the telenursing needs questionnaire.

Association between serum uric acid levels of patients with gout and their complications and examination fees: A cross-sectional analysis.

OBJECTIVE: Correlation influence factor analysis of gout patients' serum uric acid (SUA) levels, their examination fees, and various complications were explored. METHODS: From January 2017 to December 2021, 17 666 patients with gout were obtained. Conduct quartile grouping according to gout patients' SUA levels was used to compare the differences between groups in terms of examination fees and complications. Kernel density estimation method was adopted to analyze the data distribution, Spearman and Mantel-Haenszel χ2 tests were used to analyze the correlation between SUA levels and examination fees and complications. Binary logistic regression analysis was used to analyze the correlation influence factor between SUA levels and complications. RESULTS: Of the 17 666 gout cases, 85.46% were male. Among them, 7637 (43.23%) were inpatients and 10 029 (56.77%) were outpatients. Compared with outpatients, age, SUA levels, and examination fees were significantly higher, and there were more complications among inpatients (P < 0.05). Correlation analysis revealed that outpatients and SUA levels of patients with gout were positively correlated with examination fees, cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases (P < 0.01). Binary logistic regression analysis showed that SUA level is an independent influence factor for cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases (odds ratio [95% confidence interval]: 1.002 [1.002-1.002], 1.001 [1.000-1.001], 1.003 [1.002-1.003], and 1.001 [1.001-1.002], respectively). CONCLUSIONS: As SUA levels increased, examination fees, cardiovascular disease, pulmonary disease, liver disease, and kidney disease complications increased. SUA level is an independent influence factor for the combination of gout with cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases.

Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout.

OBJECTIVE: To determine the effects of berberine (BBR) on the activation of toll-like receptor 4 (TLR4), nuclear factor (NF)κB (NF-κB) signaling and NLRP3 inflammasome in patients with gout. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 24 acute (AP) and 41 non-acute (NAP) phases of primary gout patients, respectively, as well as 30 healthy controls (HC). TLR4, NF-κB (p65), NLRP3, apoptosis-associated specklike protein containing a CARD (PYCARD), cysteinyl aspartate specific proteinase-1 (CASP1), and interleukin-1ß (IL-1ß) mRNA expression levels in PBMCs were measured by quantitative reverse transcriptase polymerase chain reaction. The protein levels of TLR4, myeloid differentiation factor 88 (MyD88), NF-κB (p50/65), inhibitor of kappa B kinase α/ß (IKKα/ß), NF-κB inhibitor α (IKBα), phospho-IKKα/ß (p-IKKα/ß), NLRP3, PYCARD, and CASP1 were monitored by Western blotting. Serum IL-1ß protein level was measured using enzyme-linked immunosorbent assay (ELISA). In addition, PBMCs from HC and macrophages derived from a spontaneously immortalized monocyte-like cell line (THP-1) were stimulated using monosodium urate (MSU, 100 µg/mL), 0.1% dimethyl sulfoxide, 25 µmol/L BBR, and 10, 25, and 50 µmol/L BBR+100 µg/mL MSU for different time periods. The protein levels of IL-1ß and IL-18 in cell culture supernatants was measured by ELISA, and the protein expressions of TLR4, MyD88, NF-κB (p50/p65), IKKα/ß, I κBß, p-IKKα/ß, NLRP3, PYCARD, and CASP1 in macrophages were analyzed by Western blotting. RESULTS: (1) TLR4, NF-κB (p65), PYCARD, CASP1, and IL-1ß mRNA levels in PBMCs were significantly higher in the AP group than in the HC group (P<0.05). The NLRP3 mRNA expression levels in PBMCs were found to be significantly lower in the AP and NAP groups than in the HC group (P<0.05, P<0.01). (2) The protein levels of TLR4, IKKß, MyD88, NF-κB, p-IKKα/ß, PYCARD, and CASP1 in PBMCs were significantly higher, and those of IκBα, IKKα, and NLRP3 were found to be significantly lower in the AP group than in the HC group (P<0.05 or P<0.01). (3) The serum IL-1ß protein levels were significantly higher in the AP and NAP groups than in the HC group (P<0.01). (4) The IL-1ß protein level was significantly lower in the culture supernatants of the PBMCs stimulated with MSU for 3 and 6 h in the 25 and 50 µmoL/L BBR groups compared with that in the MSU group (P<0.01). (5) The protein levels of IL-1ß and IL-18 were also significantly lower in the culture supernatants of macrophages stimulated with MSU for 3 and 6 h in BBR groups compared with those in the MSU group (P<0.01). (6) The protein levels of TLR4, MyD88, NF-κB (p50, p65, p105), IKKα/ß, p-IκBα, p-IKKα/ß, PYCARD, and CASP1 were significantly differed between the macrophages stimulated with MSU for 0.5 and 6 h in BBR groups compared with those in the MSU group (P<0.05 or P<0.01). CONCLUSIONS: Activation of TLR4-NFκB signaling and NLRP3 inflammasome by MSU crystals drives the progression of gout inflammation. BBR ameliorates gouty inflammation, which is mechanistically associated with its regulation of TLR4-NF-κB signaling and NLRP3 inflammasome expression.

Safety and efficacy of SHR4640 combined with febuxostat for primary hyperuricemia: a multicenter, randomized, double-blind, phase II study.

BACKGROUND: To evaluate the safety, tolerability, and efficacy of SHR4640, a highly selective urate transporter-1 inhibitor, in combination with febuxostat, in patients with primary hyperuricemia. METHODS: In this randomized, double-blind, parallel-controlled phase II study, patients whose fasting serum uric acid (sUA) levels were ⩾ 480 µmol/L at screening with gout or sUA levels were ⩾ 420 µmol/L lasting for at least 3 months without gout, either with sUA levels ⩾ 540 µmol/L at screening or sUA levels ⩾ 480 µmol/L with comorbidities at screening, were enrolled. Patients were randomized (1:1:1) to receive SHR4640 10 mg plus febuxostat 80 mg, SHR4640 10 mg plus febuxostat 40 mg, and SHR4640 5 mg plus febuxostat 20 mg orally once daily. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). RESULTS: A total of 93 patients were randomized and received treatment. TEAEs occurred in 55.9% of patients. The incidence of TEAEs was comparable among all the groups. Serious TEAEs occurred in one patient (1.1%), with no deaths observed. The proportion of patients who achieved the target sUA levels by week 4 was 79.3%, 96.6%, and 75.0% in the SHR4640 10 mg plus febuxostat 80 mg, SHR4640 10 mg plus febuxostat 40 mg, and SHR4640 5 mg plus febuxostat 20 mg groups, respectively. The mean percent reduction of sUA was 59.7%, 63.7%, and 41.8%, respectively. CONCLUSION: SHR4640 plus febuxostat exhibited a tolerable safety profile and substantial sUA lowering activity in patients with primary hyperuricemia. REGISTRATION: www.chinadrugtrials.org.cn; CTR 20192429.

Analysis of Risk Factors for Changes in the Renal Two-Dimensional Image in Gout Patients.

OBJECTIVE: To explore the effects of different blood uric acid levels in gout patients on the two-dimensional image of the kidney and the risk factors for gout-related kidney damage for providing clinical evidence to enable early prevention and treatment of gout-related kidney damage. METHODS: We obtained information of 227 patients with primary gout and estimated the association between two-dimensional kidney images and clinical indicators using binary logistic regression. RESULTS: Our study showed that different uric acid levels, age, disease course, cystatin C (CysC) level, and γ-glutamyl transpeptidase level were correlated with echo of the renal medulla (P < 0.05). CysC level was correlated with the renal cortex thickness and kidney stones in different uric acid-level groups (P < 0.05). Disease course, aspartate transaminase (AST) level, creatinine (CREA) level, and tophi were risk factors for renal cortex thinning in gout patients (P = 0.045, 0.026, 0.004, 0.006, respectively). The disease course, platelet (PLT) count, and high-density lipoprotein (HDL-C) level were risk factors for kidney stone formation in gout patients (P = 0.037, 0.022, 0.023, respectively), while CysC level and C-reactive protein (CRP) level were risk factors for increased renal medulla echo in these patients (P = 0.022, 0.028, respectively). CONCLUSION: Our study revealed disease course, AST level, CREA level, tophi, PLT count, HDL-C level, CysC level and CRP level may be important predictors of renal image changes.

Differential Diagnosis of Acute and Chronic Gouty Arthritis by Multijoint Ultrasound.

To investigate whether multi-joint ultrasound (US) findings in patients with gouty arthritis could be used to distinguish between acute and chronic stages, we performed a retrospective study with 129 enrolled patients from the Rheumatology Department of the First Affiliated Hospital of Chengdu Medical College from September 1, 2018 to June 12, 2019. Patients with acute or non-acute gout were categorized using clinical data, and US imaging findings of the knees, ankles and first metatarsophalangeal joints were analyzed and compared between groups. Notably, we found that the most prevalent sign detected by US was the hyperechoic spot in the synovium, followed by arthrosynovitis, aggregates, double contour signs and tophi; meanwhile, bone erosions were the least common. Additionally, synovitis was more frequently detected in the acute joints of gouty arthritis (49%) compared with the non-acute joints (35%), whereas grade 1 or 2 blood flow classifications (97%), tophi and bone lesions were more often seen in the latter. Overall, our data suggest that multi-joint US scanning might be used to evaluate disease severity and discriminate between stages of gouty arthritis.

An optimal prognostic model based on gene expression for clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of RCC; however, prognostic prediction tools for ccRCC are scant. Developing mRNA or long non-coding RNA (lncRNA)-based risk assessment tools may improve the prognosis in patients with ccRCC. RNA-sequencing and prognostic data from patients with ccRCC were downloaded from The Cancer Genome Atlas and the European Bioinformatics Institute Array database at the National Center for Biotechnology Information. Differentially expressed (DE) RNAs (DERs) and prognostic DERs were screened between less favorable and favorable prognoses using the limma package in R 3.4.1, and analyzed using univariate and multivariate Cox regression analyses, respectively. Risk score models were constructed using optimal combinations of DEmRNAs and DElncRNAs identified using the Least Absolute Shrinkage And Selection Operator Cox regression model of the penalized package. Associations between risk score models and overall survival time were evaluated. Independent prognostic clinical factors were screened using univariate and multivariate Cox regression analyses, and nomogram models were constructed. Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the clusterProfiler package in R3.4.1. A total of 451 DERs were identified, including 404 mRNAs and 47 lncRNAs, between less favorable and favorable prognoses, and 269 DERs, including 233 mRNAs and 36 lncRNAs, were identified as independent prognostic factors. Optimal combinations including 10 DEmRNAs or 10 DElncRNAs were screened using four risk score models based on the status or expression levels of the 10 DEmRNAs or 10 DElncRNAs. The model based on the expression levels of the 10 DEmRNAs had the highest prognostic power. These prognostic DEmRNAs may be involved in biological processes associated with the inflammatory response, complement and coagulation cascades and neuroactive ligand-receptor interaction pathways. The present validated risk assessment tool based on the expression levels of these 10 DEmRNAs may help to identify patients with ccRCC at a high risk of mortality. These 10 DEmRNAs in optimal combinations may serve as prognostic biomarkers and help to elucidate the pathogenesis of ccRCC.

Study on the expressions of NLRP3 gene transcript variants in peripheral blood monocytes of primary gout patients.

It is well-known that NLRP3 is closely related to the onset of primary gout (PG). However, the relation between NLRP3 gene transcript variants and the occurrence of PG remains unclear. This study was undertaken to evaluate whether NLRP3 gene transcript variants are involved in the occurrence of PG. A total of 44 acute phase PG (APPG), 52 non-acute phase PG (NAPPG) male patients, and 30 male health control (HC) were involved in this study. We measured NLRP3 and its transcript variants 2, 3, 4, 5, and 1 + 6 expressions in the PBMCs, together with the level of IL-1ß in the serum. Further, PBMCs of HC were stimulated with MSU crystals. The levels of NLRP3, NLRP3 gene transcript variants 2, 3, 4 mRNA, and protein expressions were significantly lower in the APPG and NAPPG groups than in the HC group (P < 0.05, respectively), and IL-1ß expression was significantly higher in the APPG group than in the HC and NAPPG groups (P < 0.05, respectively). Levels of IL-1ß and NLRP3-4 mRNA expressions were negatively correlated with APPG group (r = - 0.2828, P = 0.0252). After stimulating PBMCs of HC with MSU crystals, levels of NLRP3, NLRP3-4 mRNA, and NLRP3 protein expressions were reduced significantly (P < 0.05, respectively), and the level of IL-1ß in MSU group was increased significantly (P < 0.05). Here, we show that NLRP3-4 transcript variant may be closely related to the occurrence of PG. Thus, NLRP3-4 gene transcript variant may provide a novel target for the diagnosis and therapy of PG.

Expression of PYCARD gene transcript variant mRNA in peripheral blood mononuclear cells of primary gout patients with different Chinese medicine syndromes.

OBJECTIVE: To study the expression level and role of apoptosis-associated speck-like protein containing a caspase recruitment domain (PYCARD) gene transcript variant mRNA in peripheral blood mononuclear cells (PBMCs) of primary gout (PG) patients with different Chinese medicine (CM) syndromes. METHODS: The expressions of PYCARD gene transcript variant mRNA and interleukin-1ß (IL-1ß) mRNA in PBMCs were investigated in 96 PG patients with acute phase (APPG, 44 cases) and non-acute phase (NAPPG, 52 cases) and 30 healthy controls (HCs) by reverse transcription-polymerase chain reaction (PCR) and/or realtime quantitative PCR. PYCARD and nuclear factor-κB (p50) [NF-κB (p50)] protein was detected by Western blot in PBMCs respectively. IL-1ß, IL-4 and IL-10 protein levels in plasma of HCs and PG patients were measured by enzyme-linked immuno sorbent assay. RESULTS: The main CM syndromes in APPG patients were obstruction of dampness and heat syndrome (ODHS, 36.36%) and intermingled phlegm-blood stasis syndrome (IPBSS, 27.27%), while in NAPPG patients were Pi (Spleen)-deficiency induced dampness syndrome (PDIDS, 40.38%) and qi-blood deficiency syndrome (QBDS, 26.92%). It showed statistical significances of the expressions of PYCARD gene and its transcript variant mRNA, the protein of PYCARD and NF-κB (p50) and the plasma IL-1ß, IL-4 and IL-10 in APPG, NAPPG, ODHS, IPBSS, PDIDS and QBDS groups, compared with the HC group respectively (P<0.05 or P<0.01). There were also significant differences of mRNA expressions of PYCARD-1 and PYCARD-2 as well as protein expressions of IL-1ß, IL-4 and IL-10 among the 4 CM syndromes groups (P<0.05 or P<0.01). Correlation analysis showed positive correlation between the mRNA expressions of PYCARD-1 gene transcript variant and IL-1ß in APPG patients (r=0.3088, P=0.0183). CONCLUSION: PYCARD gene and its transcript variant may play a critical and regulative role in the inflflammatory response of PG patients with different phases and CM syndromes.

IL-37 inhibits the production of pro-inflammatory cytokines in MSU crystal-induced inflammatory response.

Acute gouty arthritis (AGA) is an auto-inflammatory disease characterized by resolving spontaneously, which suggests that negative feedback loops control inflammatory and immunological responses to monosodium urate (MSU) crystals. By now, the molecular mechanism for spontaneous resolution of acute GA remains unclear; this study was undertaken to evaluate whether IL-37 is involved in spontaneous resolution of AGA. A total of 45 acute GA (AGA),29 non-acute GA (NAGA) male patients and 82 male health control (HC) were involved in this study, we measured IL-7 expression in the peripheral blood mononuclear cells (PBMCs), together with levels of IL-1ß, IL-6, IL-10, TNF-α and TGF-ß1 in the serum. Further, we either inhibited IL-37 expression in human PBMCs with siRNA or over-expressed the cytokine in human macrophages. Pro-inflammatory cytokine IL-1ß, IL-6, and TNF-α expressions were significantly higher in the AGA group than in the NAGA or HC group (P < 0.05, respectively). However, anti-inflammatory IL-37, TGF-ß1, and IL-10 were greater in the NAGA group than in the AGA and HC groups (P < 0.05, respectively). Expression of IL-37 in MSU crystal-treated macrophages inhibited the expression of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. However, anti-inflammatory TGF-ß1 and IL-10 expressions in these supernatants were unaffected by over-expression or knockdown of IL-37. Our study indicates that IL-37 is an important anti-inflammatory cytokine in AGA by suppressing the production of pro-inflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of GA.

Expression of Caspase-1 Gene Transcript Variant mRNA in Peripheral Blood Mononuclear Cells of Patients with Primary Gout in Different TCM Syndromes.

A large number of studies have shown that cysteinyl aspartate specific protease-1 (CASP1) played an important role in the inflammatory response of primary gout, but the decreased expression of different CASP1 transcript variant could inhibit the activation of IL-1ß. Our study mainly analyzed the expression level and function of CASP1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with gout in different TCM syndromes. The expression of CASP1 gene transcript variant and IL-1ß mRNA in PBMCs were detected in patients with PG [acute phase (AP: 44 cases); nonacute phase (NAP: 52 cases)] and healthy controls (HC: 30 cases) by reverse transcription-polymerase chain reaction and/or real-time quantitative polymerase chain reaction. The expressions of plasma IL-1ß in patients with PG and HC were detected by enzyme-linked immunosorbent assay. Dysregulated expression of the CASP1 gene and its transcript variant, plasma proinflammatory cytokines in all patients with primary gout in different TCM syndromes, correlation analysis showed that there was negative correlation between the expression of CASP1-gamma gene transcript variant mRNA and IL-1ß protein in APPG group. The study suggested that CASP1 gene and its transcript variant may play a critical role in the inflammatory response of patients with PG in different phases and TCM syndromes.

[Changes in expression of PYCARD gene and its transcript variant mRNA in peripheral blood mononuclear cells of patients with primary gout].

OBJECTIVE: To determine the expression level and role of PYCARD [PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase recruitment domain (CARD), PYCARD] gene and its transcript variant mRNA in peripheral blood mononuclear cells (PBMCs) of patients with primary gout (PG). METHODS: PYCARD gene and its transcript variant mRNA were measured using reverse transcription-polymerase chain reaction (RT-PCR) in PBMCs. The expression of PYCARD gene and PYCARD-1,-2 mRNA in PBMCs was compared between the patients with acute phase PG (APPG) (n=44), non-acute phase PG (NAPPG) (n= 51) and healthy controls (HC) (n=87). PYCARD and NF-kappaB (p105/p50) protein expressions were measured using Western blot in the PBMCs of participants in the PG and HC groups. Routine blood tests and blood uric acid test were undertaken in all participants. Differences in the indicators were examined among the three groups. Correlations between the expression of PYCARD gene and PYCARD-1,-2 mRNA and other indicators were analyzed. RESULTS: The expression level of PYCARD gene, PYCARD-1,-2 mRNA was significantly higher in the APPG and NAPPG group than in the HC group (P<0.01). The NAPPG group had significantly higher levels of PYCARD gene transcript variant 2x mRNA and 2y mRNA in the HC and APPG groups (P<0.05). The expression of PYCARD and NF-kappaB (p105/p50) protein was significantly higher in the PG group compared with the HC group [(4.900 +/- 1.324) vs. (3.975 +/- 0.210) and (0.263 +/- 0.106) vs. (0.127 +/- 0.008), respectively P<0.05]. The expression level of PYCARD-2 mRNA and granulocyte were positively correlated in the NAPPG group. CONCLUSION: Abnormal expression of PYCARD gene and its transcript variant and PYCARD protein in PG patients suggests that PYCARD gene and its transcript variant may play an important role in regulating the inflammatory response of PG patients.

Estrogen receptor ß signaling induces autophagy and downregulates Glut9 expression.

Glut9 is highly expressed in the human kidney proximal convoluted tubular and plays a crucial role in the regulation of plasma urate levels. The gene effects were stronger among women. Our results show that 17-ß-estradiol (E2) through ER (estrogen receptor) ß downregulates Glut9 protein expression on human renal tubular epithelial cell line (HK2). Intriguingly, E2 does not affect the expression of Glut9 mRNA. ERß is linked to PTEN, the PTEN gene negatively regulates the PI3K/AKT pathway, and the PI3K/AKT pathway inhibition may lead to autophagy. Further study indicates that ERß may affect the expression of Glut9 though autophagy.

[Comparative analysis of clinical indicators of gout patients of different syndrome types and its significance].

OBJECTIVE: To understand the difference in clinical indicators of gout patients of different Chinese medical syndromes and its clinical significance. METHODS: Form November 2011 to December 2012, syndrome typed were 257 male gout in-/outpatients from Affiliated Hospital of Chuanbei Medical College. Another 50 healthy male subjects were recruited as the control. Their clinical and laboratory data were collected. All were excluded from infections and other inflammatory diseases. RESULTS: Four syndrome types existed in gout patients, i.e., intermingled phlegm-stasis blood syndrome (IPSBS), obstruction of dampness and heat syndrome (ODHS), Pi-deficiency induced dampness syndrome (PDIDS), qi-blood deficiency syndrome (QBDS). Of them, 53 acute phase gout patients suffered from IPSBS, 41 from ODHS, 25 from QBDS, and 17 from PDIDS; 41 non-acute phase gout patients suffered from QBDS, 40 from PDIDS, 24 from ODHS, and 16 from IPSBS. Statistical analysis of clinical data showed that, when compared with the normal control group, there was statistical difference in blood routines (WBC, GR, LY, MO) and blood biochemical indices (UA, Ur, Cr, ALT, AST, ALB, GLOB, TG, HDL-C, VLDL-C, apoA, apoB100) of gout patients of different syndromes (P < 0.05, P < 0.01). There was also statistical difference or correlation among different syndromes (P < 0.05). CONCLUSIONS: In the acute phase gout patients, IPSBS and ODHS were dominated, while in the non-acute phase gout patients, QBDS and PDIDS were often seen. In patients of IPSBS and ODHS, inflammation and immune response were more obvious, indicating that better efficacy might be achieved by clearing heat and removing blood stasis associated anti-inflammatory and immune regulation therapies. In patients of QBDS and PDIDS, impaired renal functions were more significant, indicating that better efficacy might be achieved by invigorating Pi and tonifying Shen dominated treatment.