阿托伐他汀预处理对心肌保护作用的实验研究

目的观察阿托伐他汀（ATV）预处理的心肌保护效应,探讨诱导型一氧化氮合酶（iNOS）和线粒体膜ATP敏感性钾通道（KATP）在其中的作用以及这两个环节的相互关系。方法将兔随机分成缺血再灌注模型对照组（对照组）、ATV组、ATV复合iNOS阻断剂S-甲基异琉脲硫酸盐组（ATV＋SMT组）、S-甲基异琉脲硫酸盐组（SMT组）、ATV复合线粒体膜KATP通道阻断剂5-羟癸酸组（ATV＋5-HD组）、5-羟癸酸组（5-HD）组。进行40min局部缺血和240min再灌注,观察各组心肌梗死范围、血液生物化学、一氧化氮合酶、线粒体ATP合成能力。结果3天阿托伐他汀预处理（10mg·kg^-1·d^-1）使心肌梗死范围、肌酸激酶同工酶（CK—MB）、乳酸脱氢酶同工酶（LDH-1）分别下降26．3％、31．4％、19．1％,使iNOS、线粒体ATP合成能力分别提高102．6％和46．8％。ATV＋SMT组心肌梗死范围、CK-MB、LDH-1、iNOS、线粒体ATP合成能力和对照组无明显差异。ATV＋5-HD组心肌梗死范围、CK-MB、LDH-1、线粒体ATP合成能力和对照组无明显差异,ATV＋5-HD组iNOS和ATV组相似,均明显高于对照组（P〈0．01）。结论阿托伐他汀预处理通过上调iNOS和激活线粒体膜KATP产生心肌保护作用,且iNOS是线粒体膜KATP的上游途径。     

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). In this study, we examined the mechanisms by which CRP decreases eNOS activity in HAECs. To this end, we explored different strategies such as availability of tetrahydrobiopterin (BH4)-a critical cofactor for eNOS, superoxide (O(2)(-)) production resulting in uncoupling of eNOS and phosphorylation/dephosphorylation of eNOS. CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. Pretreatment with sepiapterin, a BH4 precursor, prevented CRP-mediated effects on BH(4) levels, superoxide production as well as eNOS activity. The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. Furthermore, CRP-induced O(2)(-) production was reversed by pharmacologic inhibition and siRNAs to p47 phox and p22 phox. Additionally, CRP treatment significantly decreased the eNOS dimer: monomer ratio confirming CRP-mediated eNOS uncoupling. The pretreatment of cells with NO synthase inhibitor (N-nitro-l-arginine methyl ester [l-NAME]) also prevented CRP-mediated O(2)(-) production further strengthening CRP-mediated eNOS uncoupling. Additionally, CRP decreased eNOS phosphorylation at Ser1177 as well as increased phosphorylation at Thr495. CRP appears to mediate these effects through the Fcgamma receptors, CD32 and CD64. To conclude, CRP uncouples eNOS resulting in increased superoxide production, decreased NO production and altered eNOS phosphorylation.     

Nitric oxide production in PCD: possible evidence for differential nitric oxide synthase function

Primary cilliary dyskinesia (PCD) is characterized by decreased levels of fractional exhaled nitric oxide (FeNO), thought to reflect low activity of airway inducible nitric oxide synthase (iNOS) levels. Alveolar NO (Calv) concentration and bronchial NO (JNO) flux can be calculated from FeNO measured at multiple exhalation flow rates. We hypothesised that whereas bronchial NO would be reduced in PCD due to reduced iNOS function, alveolar NO would reflect endothelial NOS (eNOS) function and be normal. We recorded the medical history; measured FeNO at multiple flow rates (50, 100, 200, 260 ml/sec); and performed spirometry in 24 children (aged 8-16 years). FeNO50 of the PCD children was significantly lower than normal mean (+/-SD) 8.1 +/- 1.3 ppb versus 12.5 +/- 1.6 ppb, P = 0.033. The mean +/- SD values of PCD (n = 24) and normal (n = 20) subjects were respectively: JNO: 383.5 +/- 307.9 versus 650.1 +/- 489 pl/s, P = 0.033, Calv: 1.60 +/- 0.78 versus 1.60 +/- 0.75 ppb, P = NS. We show that Calv is normal in PCD, demonstrating that there is no generalized disorder of NO handling in this condition. This differs from a previous report. Furthermore, we speculate that these data may provide supportive evidence that variable flow NO measurements can assess the relative activity of iNOS and eNOS.     

Diagnostic and prognostic value of secreted protein acidic and rich in cysteine in the diffuse large B-cell lymphoma

BACKGROUNDSecreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix-associated protein. Studies have revealed that SPARC is involved in the cell interaction and function including proliferation, differentiation, and apoptosis. However, the role of SPARC in cancer is controversial, as it was reported as the promoter or suppressor in different cancers. Further, the role of SPARC in lymphoma is unclear.AIMTo identify the expression and significance of SPARC in lymphoma, especially in diffuse large B-cell lymphoma (DLBCL).METHODSThe expression analysis of SPARC in different cancers was evaluated with Oncomine. The Brune, Eckerle, Piccaluga, Basso, Compagno, Alizadeh, and Rosenwald datasets were included to evaluate the mRNA expression of SPARC in lymphoma. The Cancer Genome Atlas (TCGA)-DLBCL was used to analyze the diagnostic value of SPARC in DLBCL. The Compagno and Brune DLBCL datasets were used for validation. Then, the diagnostic value was evaluated with the receiver operating characteristic (ROC) curve. The Kaplan-Meier plot was conducted with TCGA-DLBCL, and the ROC analysis was performed based on the survival time. Further, the overall survival analysis based on the level of SPARC expression was performed with the {"type":"entrez-geo","attrs":{"text":"GSE4475","term_id":"4475"}}GSE4475 and E-TABM-346. The Gene Set Enrichment Analyses (GSEA) was performed to make the underlying mechanism-regulatory networks.RESULTSThe pan-cancer analysis of SPARC showed that SPARC was highly expressed in the brain and central nervous system, breast, colon, esophagus, stomach, head and neck, pancreas, and sarcoma, especially in lymphoma. The overexpression of SPARC in lymphoma, especially DLBCL, was confirmed in several datasets. The ROC analysis revealed that SPARC was a valuable diagnostic biomarker. More importantly, compared with DLBCL patients with low SPARC expression, those with higher SPARC expression represented a higher overall survival rate. The ROC analysis showed that SPARC was a favorable prognostic biomarker for DLBCL. Results of the GSEA confirmed that the high expression of SPARC was closely associated with focal adhesion, extracellular matrix receptor interaction, and leukocyte transendothelial migration, which suggested that SPARC may be involved in the regulation of epithelial-mesenchymal transition, KRAS, and myogenesis in DLBCL.CONCLUSIONSPARC was highly expressed in DLBCL, and the overexpression of SPARC showed sound diagnostic value. More interestingly, the overexpression of SPARC might be a favorable prognostic biomarker for DLBCL, suggesting that SPARC might be an inducible factor in the development of DLBCL, and inducible SPARC was negative in some oncogenic pathways. All the evidence suggested that inducible SPARC might be a good diagnostic and prognostic biomarker for DLBCL.     

Statins: Mechanisms of neuroprotection

Clinical trials report that the class of drugs known as statins may be neuroprotective in Alzheimer's and Parkinson's disease, and further trials are currently underway to test whether these drugs are also beneficial in multiple sclerosis and acute stroke treatment. Since statins are well tolerated and have relatively few side effects, they may be considered as viable drugs to ameliorate neurodegenerative diseases. However, the mechanism of their neuroprotective effects is only partly understood. In this article, we review the current data on the neuroprotective effects of statins and their underlying mechanisms.