Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.

Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing.

OBJECTIVE: To investigate the prevalence of eight common rheumatic diseases in a large Chinese population. METHODS: A population-based epidemiological investigation of the prevalence of eight common rheumatic diseases in a suburb of Beijing was conducted in 14 642 individuals. A community-based survey was carried out using a screening questionnaire. Positive responders were included in a clinical and laboratory examination. Diagnosis was based on the criteria of ACR or those used widely in literature. RESULTS: A total of 10 556 inhabitants were interviewed. Forty-three cases of RA were identified with an age-adjusted prevalence of 0.28% (95% CI 0.19%, 0.41%). Gout was diagnosed with a crude prevalence of 0.09% (95% CI 0.05%, 0.17%). Psoriasis was reported in 28 individuals with a prevalence of 0.27% (95% CI 0.18%, 0.38%). This included two cases diagnosed with PsA, resulting in a prevalence of 7.14% (95% CI 0.88%, 23.5%) in psoriasis patients and 0.02% (95% CI 0%, 0.07%) in the general population. Three individuals were identified with SLE, with a prevalence of 0.03% (95% CI 0%, 0.06%). One individual was identified with SSc and the calculated prevalence was 0.01% (95% CI 0%, 0.05%). One case of Behçet's disease was identified, giving a prevalence of 0.01% (95% CI 0%, 0.05%). CONCLUSION: This large-scale epidemiological survey provides an estimate of the burden of rheumatic diseases in China.

Diagnostic significance of measuring antibodies to cyclic type 3 muscarinic acetylcholine receptor peptides in primary Sjogren's syndrome.

OBJECTIVE: SS is an autoimmune disease characterized by salivary and lacrimal gland dysfunction leading to dry mouth (xerostomia) and dry eyes (xerophthalmia). Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been shown to be a good serum marker in primary SS (pSS). The aim of this study was to assess the clinical correlations of anti-M3R-derived peptide antibodies in patients with pSS. METHODS: Sequences of the first to fourth cycle-M3R (c1M3R-c4M3R)-derived peptide was synthesized by a solid-phase technique on an Applied Biosytems Peptide Synthesizer. Synthesized cM3R peptide (cM3RP) was used as substrate in an ELISA to detect IgG anti-cM3RP antibodies in serum samples of patients and controls. The clinical and biological parameters of the diseases were also evaluated. The EULAR SS disease activity index (ESSDAI) score was used to measure disease activity in patients with primary SS. RESULTS: (i) Anti-c2M3RP antibodies were highly prevalent in pSS patients, and the titre is much higher than anti-c1,3,4M3RP antibodies. (ii) The prevalence of anti-c2M3RP antibodies in pSS, SLE, RA and healthy controls was 62.2, 7.1, 5.3 and 1.6%, respectively. The prevalence of anti-linear-2-M3RP antibodies in pSS, SLE and RA patients and healthy controls were 56.1, 20.0, 14.7 and 9.4%. (iii) The specificity of anti-c2M3RP antibodies was 95.1%, much higher than that of linear polypeptide (84.7%) for pSS diagnosis. (iv) In pSS patients, anti-c2M3RP positivity had significantly increased frequency in patients who were RF or ANA positive, and had several haematological abnormalities, such as leucopenia, anaemia and thrombocytopenia. Furthermore, the ESSDAI score was significantly higher in anti-c2M3RP-positive pSS patients (P < 0.05). CONCLUSION: Anti-c2M3RP antibody was highly specific for patients with pSS. The presence of anti-c2M3RP antibody in pSS indicates that c2M3RP may act as an autoantigen that may play a role in the pathogenesis of pSS.

Variation in STAT4 is associated with systemic lupus erythematosus in Chinese Northern Han population.

BACKGROUND: Recent studies have identified signal transducer and activator of transcription 4 (STAT4) as a susceptibility gene for systemic lupus erythematosus (SLE) in different populations. In order to examine whether the allele distribution of the single nucleotide polymorphism (SNP) in gene STAT4 rs7574865 in patients with SLE is different from those of healthy controls in Chinese Northern Han population, we investigated whether the variants of STAT4 rs7574865 were associated with any specific clinical features of SLE. METHODS: We genotyped SNPs in STAT4 rs7574865 in 252 patients with SLE and 497 healthy controls. All subjects were from the Northern part of Chinese Han population. The genotypes in rs7574865 were determined by polymerase chain reaction (PCR) and consequence direct sequencing of PCR products in the DNA samples. RESULTS: There was a significant difference in distribution of the SNPs in rs7574865 between the SLE patients and healthy controls. Compared with healthy controls, there was a significant correlation between TT genotypes in rs7574865 and the risk of SLE when GG genotype was used as a reference genotype after adjusting for gender and age. The frequency of T allele in the SLE patients was strongly significantly higher than that of healthy controls. Furthermore, there was a significant difference in the distribution of SNP in rs7574865 between male and female SLE patients, when compared with healthy controls. The frequency of T allele in rs7574865 in male patients was significantly higher than that of male healthy controls or female patients. There was no significant correlation between the frequencies of T allele in STAT4 rs7574865 and the clinical features of SLE. CONCLUSIONS: The SNP rs7574865 in STAT4 is strongly associated with risk of SLE in the Chinese Northern Han population. The TT genotype and T allele in STAT4 rs7574869 are susceptibility factors for SLE, especially for male SLE patients.