Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC₅₀ of 0.88?µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH₃O group or CF₃O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.     

Vascular dysfunction in type 2 diabetic TallyHo mice: role for an increase in the contribution of PGH2/TxA2 receptor activation and cytochrome p450 products

In this study, we tested the hypothesis that spontaneously diabetic TallyHo (TH) mice, a novel polygenic model for type 2 diabetes, will exhibit endothelial dysfunction associated with an increased contribution from endothelium-derived contractile factors (EDCF). The cellular mechanisms underlying the increased contribution of EDCF were explored in 16 and 30-week-old male TH and age-matched male C57BL/6J mice (n=4-9). Blood glucose and serum lipid profiles were markedly increased in the TH mice. Superoxide generation, assessed with a lucigenin chemiluminescence assay, was markedly increased in the aortae of TH mice. Endothelium-dependent vascular relaxations and contractions to acetylcholine (ACh), but not endothelium-independent relaxations to sodium nitroprusside, were impaired and vascular contractions to phenylephrine were significantly enhanced in aortae from TH mice. Nomega-nitro-L-arginine methyl ester markedly increased the ACh-induced contractions in TH mice, whereas SQ29548, a thromboxane receptor antagonist, and cytochrome P450 (CYP) inhibitors 17-octadecynoic acid and sulfaphenazole, the latter being specific for CYP2C6 and 2C9, decreased and (or) normalized the contractile response to ACh in TH mice. The present study indicates that enhanced contribution of prostaglandin H2/thromboxane A2 receptor and CYP, likely CYP2C6 and 2C9, play a critical role in the pathogenesis of increased EDCF in the aortae of type 2 diabetic TH mice.     

Expression of chemokine-like factor 1 is upregulated during T lymphocyte activation

Chemokine-like factor 1 (CKLF1) is a cytokine with chemotactic effects on leukocytes and a functional ligand of CCR4. This cytokine is widely expressed and the level of expression is reported to be upregulated in asthma and rheumatoid arthritis (RA), disease conditions in which T lymphocytes are over-activated. In order to determine the expression profile of CKLF1 in activated T lymphocytes, we first employed a PCR-based method on human blood fractions cDNA panels and found that CKLF1 was upregulated in activated CD4+ and CD8+ cells, with no obvious changes in CD19+ cells. We further performed kinetic analyses of CKLF1 expression in phytohemagglutinin (PHA)-stimulated human peripheral blood lymphocytes (PBL) at both the mRNA and protein levels. In resting PBL, the constitutive expression of CKLF1 was low at mRNA level and barely detectable at the protein level; however, both were remarkably upregulated by PHA, appearing at 8h after PHA-stimulation and persisting up to 72h. These results suggest that CKLF1 may be involved in T lymphocyte activation and further study of CKLF1 function will prove valuable.     

菱纹叶蝉属中国种类记要(同翅目,叶蝉科,殃叶蝉亚科)

记述中国菱纹叶蝉属Hishimonus Ishihara 17种,其中有2新种,即长突菱纹叶蝉H.prolongatus sp.nov.和褐斑菱纹叶蝉H.fuscomaculatus sp.nov..新种模式标本保存在贵州大学昆虫研究所.     

急性缺血性脑卒中患者血清GAL3、CXCL12水平与病情严重程度和预后的关系研究

目的:探讨急性缺血性脑卒中(AIS)患者血清半乳糖凝集素3(GAL3)、血清趋化因子12(CXCL12)水平与病情严重程度和预后的关系。方法:选取成都市第五人民医院于2016年2月～2018年9月期间接收的AIS患者138例为观察组,另选取同期来该院行健康体检的志愿者60例为对照组。其中观察组根据美国国立卫生研究所中风量表(NIHSS)评分分为轻症组(n=42,4分),中症组(n=61,4～15分),重症组(n=35,15分),根据改良RABKIN量表(m RS)评分分为预后良好组(n=82)和预后不良组(n=56)。比较对照组、观察组的血清GAL3、CXCL12水平,分析不同NIHSS得分、不同预后的血清GAL3、CXCL12水平,采用Pearson相关性分析血清GAL3、CXCL12水平与NIHSS评分、m RS评分的相关性。结果:观察组血清GAL3、CXCL12水平均显著高于对照组,差异有统计学意义(P0.05)。重症组、中症组AIS患者血清GAL3、CXCL12水平高于轻症组,且重症组高于中症组,差异有统计学意义(P0.05)。预后不良组的AIS患者血清GAL3、CXCL12水平均高于预后良好组,差异有统计学意义(P0.05)。Pearson相关性分析结果可知,血清GAL3、CXCL12水平与NIHSS评分、m RS评分均呈正相关(P0.05)。结论:AIS患者的血清GAL3、CXCL12水平均异常升高,且其升高程度与AIS患者病情严重程度及预后息息相关。     

人降钙素基因相关肽转基因马铃薯的RT-PCR分析

报道经过农杆菌介导将人降钙素基因相关肽(calcitoningenerelatedpeptide,CGRP)基因由马铃薯块茎专一表达classIpatatin基因5′侧翼区和CaMV35S启动子驱动构建的马铃薯表达载体导入马铃薯,PCR鉴定获得了转基因植株。RTPCR分析证实classIpatatin基因5′侧翼区驱动的CGRPmRNA在转基因马铃薯中的表达。研究结果在开发转基因马铃薯生物反应器表达医用多肽中具有重要意义。