Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

BACKGROUND: Reduced application of percutaneous coronary intervention (PCI) is associated with higher mortality rates after ST-segment elevation myocardial infarction (STEMI). We aimed to evaluate potential factors contributing to the refusal of PCI in STEMI patients in China. METHODS: We studied 957 patients diagnosed with STEMI in the emergency departments (EDs) of six public hospitals in China. The differences in baseline characteristics and 30-day outcome were investigated between patients who refused PCI and those who underwent PCI. Multivariable logistic regression was used to evaluate the potential factors associated with refusing PCI. RESULTS: The potential factors contributing to refusing PCI were older than 65 years (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.56-4.52, P < 0.001), low body mass index (BMI) (OR 0.91, 95% CI 0.84-0.98, P = 0.013), not being married (OR 0.29, 95% CI 0.17-0.49, P < 0.001), history of myocardial infarction (MI) (OR 2.59, 95% CI 1.33-5.04, P = 0.005), higher heart rate (HR) (OR 1.02, 95% CI 1.01-1.03, P = 0.002), cardiac shock in the ED (OR 5.03, 95% CI 1.48-17.08, P = 0.010), pre-hospital delay (>12 h) (OR 3.31, 95% CI 1.83-6.02, P < 0.001) and not being hospitalized in a tertiary hospital (OR 0.45, 95% CI 0.27-0.75, P = 0.002). Compared to men, women were older, were less often married, had a lower BMI and were less often hospitalized in tertiary hospitals. CONCLUSIONS Patients who were older, had lower economic or social status, and had poorer health status were more likely to refuse PCI after STEMI. There was a sex difference in the potential predictors of refusing PCI. Targeted efforts should be made to improve the acceptance of PCI among patients with STEMI in China.
China ; Female ; Humans ; Male ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Risk Factors ; ST Elevation Myocardial Infarction/surgery* ; Time Factors ; Treatment Outcome

Objective: To explore the protective effect and mechanisms of Renshen Sinitang and its active ingredients on cardiomyocyte injury induced by pentobarbital sodium. Method: H9C2 cells were sub-cultured with ginsenoside Rb₂ 0.01, 0.1, 1 μmol ·L^-1, Re 0.01, 0.1, 1 μmol·L^-1, isoliquiritigenin 20, 40, 80 μmol·L^-1, glycyrrhetinic acid 10, 20, 40 μmol·L^-1, Renshen Sinitang, 10, 100, 400 mg·L^-1, for 4 h. After treatment with 0.1% of sodium pentobarbital for 30 min, cell viability, lactate dehydrogenase (LDH), lipid peroxide malondialdehyde (MDA), Na⁺-K⁺-adenosine triphosphate(ATP) ase, Ca²⁺-ATPase activity, and real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) were used to detect the expressions of peroxisome proliferative activated receptor-1α (PGC-1α), B-cell lymphoma-2 associated X protein(Bax) and cysteine aspartate-specific protease-3(Caspase-3) mRNA. Result: Renshen Sinitang and its active ingredients have a protective effect on heart failure cell model. Compared with the normal group, the cell survival rate of the model group decreased significantly, while the LDH and MDA contents increased significantly, and the Na⁺-K⁺-ATPase activity increased. Ca²⁺-ATPase activity was significantly decreased, PGC-1α mRNA expression was down-regulated, Bax and Caspase-3 mRNA expressions indicates the modeling(P<0.01). Compared with the model group, each administration group showed a significantly increased cell viability, decreased LDH, MDA content, inhibited Na⁺-K⁺-ATPase activity, increased Ca²⁺-ATPase activity, up-regulated PGC-1α mRNA expression, and inhibited Bax and Caspase-3 mRNA expression (P<0.05, P<0.01). Conclusion: Renshen Sinitang and its active ingredients have a significant protective effect on heart failure cell model, and its mechanisms of action are related to anti-oxidation, improvement of mitochondrial energy metabolism and inhibition of mitochondrial apoptosis pathway.

The aim of this paper was to observe the effect of triptolide( TP) on cardiovascular function and its possible mechanism by intraperitoneal injection of bacterial lipopolysaccharide in rats with endotoxemia. Sixty male Sprague-Dawley rats were randomly divided intonormal group( NC group),endotoxemia model group( LPS group),TP low concentration intervention group( LPS + TP-L group,25 μg·kg~(-1)),TP middle concentration intervention group( LPS+TP-M group,50 μg·kg~(-1)),TP high concentration intervention group( LPS+TP-H group,100 μg·kg~(-1)) and polymyxin B group( LPS+PMX-B group,0. 2 mg·kg~(-1)). 10 mg·kg~(-1) LPS was injected intraperitoneally for 6 h to replicate the endotoxemia rat model. The rats in TP intervention groups were pre-treated 15 min before intraperitoneal injection of LPS. Rats in each group underwent total arterial intubation to measure hemodynamic parameters: heart rate( HR),left ventricular diastolic pressure( LVDP),the maximum rate of the increase/decrease of left ventricular pressure( ±dp/dtmax). The levels of BNP,CK-MB and c Tn-Ⅰ in serum and levels of TNF-α and IL-6 in plasma were detected by ELISA. The contents of p65 protein in myocardium and contents of p65,TLR4,i NOS and e NOS protein in thoracic aorta were detected by Western blot. As compared with NC group,the hemodynamic indexes in LPS group were significantly decreased; the contents of BNP,CK-MB and c Tn-Ⅰ in serum,TNF-α and IL-6 in plasma,p65 in myocardium,i NOS,e NOS,TLR4 and p65 in vascular tissues were significantly increased. As compared with LPS group,the hemodynamic indexes were significantly improved in LPS+TP-M group,LPS+TP-H group and LPS+PMX-B group; the contents of BNP,CK-MB and c Tn-Ⅰ in serum,TNF-α and IL-6 in plasma,p65 in myocardium,i NOS,e NOS,TLR4 and p65 in vascular tissues were significantly decreased in each treatment group. Triptolide has a protective effect on cardiovascular damage in a dose-dependent manner in endotoxemia rats,probably through TLR4/NF-κB p65 signaling pathway to improve endothelial function.
Animals ; Diterpenes/pharmacology* ; Endothelium ; Endotoxemia ; Epoxy Compounds/pharmacology* ; Lipopolysaccharides ; Male ; NF-kappa B ; Phenanthrenes/pharmacology* ; Protective Agents/pharmacology* ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Toll-Like Receptor 4/metabolism* ; Tumor Necrosis Factor-alpha

Objective To analyze the incidence of lung cancer in Qidong , Jiangsu Province of China from 1993 to 2012 . Methods The clinical data of lung cancer from 1993 to 2012 for patients with census registration in Qidong were sorted out from the cancer registration center in Qidong .The annual percent change ( APC) model was used to analyze the trend over time for the incidence of lung cancer .The SAS 9.4 software and the Joinpoint Regression Program 4.3.1.0 were used to implement data analyses . Results A total of 11 895 new cases of lung cancer were diagnosed in Qidong , Jiangsu province from 1993 to 2012 .Among them , 8 629 were male cases and 3 266 were female cases and the median age for these patients was 68 .41 .The crude incidence rate for lung cancer for males was 90 .06/100 000 , which was significantly higher than that for females, i.e., 29.94/100 000(Poisson distribution test, P<0.01). The standardized incidence rate of lung cancer for male was 52 .92/100 000 , which was significantly higher than that for females, i.e.18.52/100 000(Poisson distribution test, P<0.01).The APC for the crude incidence rate for lung cancer was 6 .1 from 1993 to 2012 and the APC for the standardized incidence rate for lung cancer was 5 .5 . Conclusion The incidence of lung cancer increases in Qidong on a yearly basis from 1993 to 2012, with the incidence thereof for males being significantly higher than that for females .

Adult ; Cerebrospinal Fluid Rhinorrhea ; diagnosis ; surgery ; Humans ; Magnetic Resonance Imaging ; methods ; Male ; Skull Base ; pathology ; surgery ; Tomography, X-Ray Computed ; methods