Structure-activity relationship studies on chalcone derivatives. the potent inhibition of chemical mediators release

Some chalcones exert potent anti-inflammatory activities. 2',5'-Dialkoxychalcones and 2',5'-dihydroxy-4-chloro-dihydrochalcone inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-activated N9 microglial cells and in LPS-activated RAW 264.7 macrophage-like cells have been demonstrated in our previous reports. These compounds also suppressed the inducible NO synthase (iNOS) expression and cyclooxygenase-2 (COX-2) activity in RAW 264.7 cells. In an effort to continually develop potent anti-inflammatory agent, a series of chalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and then evaluated their inhibitory effects on the activation of mast cells, neutrophils, macrophages, and microglial cells. Most of the 2',5'-dihydroxychaclone derivatives exhibited potent inhibitory effects on the release of beta-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Some chalcones showed potent inhibitory effects on superoxide anion generation in rat neutrophils in response to fMLP/CB. Compounds 1 and 5 exhibited potent inhibitory effects on NO production in macrophages and microglial cells. Compound 11 showed inhibitory effect on NO production and iNOS protein expression in RAW 264.7 cells. The present results demonstrated that most of the 2',5'-dihydroxychaclones have anti-inflammatory effects. The potent inhibitory effect of 2',5'-dihydroxy-dihydrochaclones on NO production in LPS-activated macrophage, probably through the suppression of iNOS protein expression, is proposed to be useful for the relief of septic shock.     

Reappraisal of the Therapeutic Role of Celecoxib in Cholangiocarcinoma

Cholangiocarcinoma (CCA), a lethal disease, affects many thousands worldwide yearly. Surgical resection provides the best chance for a cure; however, only one-third of CCA patients present with a resectable tumour at the time of diagnosis. Currently, no effective chemotherapy is available for advanced CCA. Cyclooxygenase-2 (COX-2) is a potential oncogene expressing in human CCA tissues and represents a candidate target for treatment; however, COX-2 inhibitors increase the risk of negative cardiovascular events as application for chemoprevention aim. Here, we re-evaluated the effectiveness and safety of celecoxib, one widely used COX-2 inhibitor, in treating CCA. We demonstrated that celecoxib exhibited an anti-proliferative effect on CGCCA cells via cell cycle arrest at G2 phase and apoptosis induction. Treatment for 5 weeks high dose celecoxib (160 mg/kg) significantly repressed thioacetamide-induced CCA tumour growth in rats as monitored by animal positron emission tomography through apoptosis induction. No obviously observable side effects were noted during the therapeutic period. As retrospectively reviewing 78 intrahepatic mass-forming CCA patients, their survival was strongly and negatively associated with a positive resection margin and high COX-2 expression. Based on our result, we concluded that short-term high dose celecoxib may be a promising therapeutic regimen for CCA. Yet its clinical application still needs more studies to prove its safety.     

Anthraquinone derivatives induce G2/M cell cycle arrest and apoptosis in NTUB1 cells

Thirteen anthraquinone derivatives 5-17 including two 3-(3-alkylaminopropoxy)-9,10-anthraquinone (NHA) derivatives 5 and 6, and 11 1-hydroxy-3-(3-alkylaminopropoxy)-9,10-anthraquinone (MHA) derivatives 7-17 were synthesized, evaluated for cytotoxicities against two cancer cell lines, and assayed the generation of reactive oxygen species (ROS) in NTUB1 cells (a human bladder carcinoma cell line). Compound 9 bearing a pyrrolidinyl group induced the stronger cytotoxic effect than those of other synthesized NHA and MHA derivatives. Exposure of NTUB1 cells to 9, 13, and 17 for 24h significantly increased the production of ROS, respectively. Flow cytometric analysis exhibited that the exposure of NTUB1 cells to the selective 9 led to the G2/M phase arrest accompanied by an increase of apoptotic cell death after the incubation for 24h. Compound 9 induced up-regulation of cyclinB1 and p21 expressions. Biological results suggested that the induction of G2/M arrest, apoptosis, and cell death by 9 may associate with increased expression of p21 and cyclin B1, elevation of Bax and p53 levels, and generation of ROS in the cell. In conclusion, these series of compounds may be used as anticancer agents.     

Fractioned Dose Regimen of Sunitinib for Patients with Gastrointestinal Stromal Tumor: A Pharmacokinetic and Treatment Efficacy Study

AIM: Sunitinib has shown benefit in patients with imatinib (IM)–resistant gastrointestinal stromal tumor (GIST). However, its advantages are somewhat diminished because of associated toxicities. Herein, we clarify the efficacy and safety of fractioned dose regimen of sunitinib by a pharmacokinetic and efficacy study. MATERIALS AND METHODS: Between 2001 and March 2013, a total of 214 patients with metastatic GIST was treated at Chang Gung Memorial Hospital. Among them, 55 (11.6%) patients who received sunitinib were investigated. One group of patients was administered with standard dose of once-daily sunitinib (standard dose group) and the other group was administered with standard total daily dose of sunitinib in fractioned doses (fractioned dose group). RESULTS: Thirty-two male and 23 female patients with a median age of 55 years received sunitinib. The median duration of sunitinib administration was 9.2 months. The clinical benefit was 65.2%. The mean peak blood level of sunitinib in patients with fractioned doses was significantly lower than that in those with once-daily dose (83.4 vs 50.1 ng/ml, P = .01). The rates of adverse effects of hand-foot syndrome, mucositis, and yellow skin were significantly decreased by fractioned doses of sunitinib. However, the progression-free and overall survival did not differ between patients with different treatment regimens. CONCLUSION: The fractioned dose regimen of sunitinib appears to be a safe and effective treatment for patients with IM-resistant/intolerant GISTs. Significantly decreased toxicity of this regimen could be explained by significantly lower peak sunitinib blood level. However, the treatment efficacy is not reduced by this regimen.     

吉林省森林植被固碳现状与速率

通过对吉林省森林植被的普遍调查、典型调查以及植被样品含碳率测定, 结合吉林省2009年和2014年森林清查数据, 估算了区域森林植被的碳储量、碳密度及固碳速率。研究结果表明: 林下植被的生物量在不同林分和同类林分中存在较大的差异, 整体不足乔木层生物量的3%, 灌木植物的生物量略高于草本植物和幼树。不同林分类型的乔木含碳率介于45.80%-52.97%之间, 整体表现为针叶林高于阔叶林; 灌木和草本植物分别为39.79%-47.25%和40%左右。吉林省森林植被碳转换系数以0.47或0.48更为准确, 若以0.50或0.45作为植被的碳转换系数计算碳储量, 会造成±5.26%的偏差。吉林省森林植被不仅维持着较高的碳库水平, 而且极具碳汇能力; 2009年和2014年碳储量分别为471.29 Tg C和505.76 Tg C, 累计碳增量34.47 Tg C, 平均每年碳增量6.89 Tg C·a^-1; 碳密度由64.58 t·hm^-2增至66.68 t·hm^-2, 平均增加2.10 t·hm^-2, 固碳速率0.92 t·hm^-2·a^-1。森林植被碳储量的增长主体是蒙古栎(Quercus mongolica)林和阔叶混交林, 合计碳增量占总体的90.34%。受植被发育引起的生物量增长、林分龄组晋级以及森林经营所引起的面积变化影响, 各龄组植被碳增量为幼龄林>过熟林>近熟林>中龄林, 成熟林表现为负增长; 固碳速率为过熟林>幼龄林>近熟林>中龄林>成熟林。森林植被碳储量和碳密度的市/区分布整体表现为自东向西明显的降低变化; 碳增量以东北和中东部地区较高, 西部地区较低; 固碳速率整体以南部的通化地区和白山地区相对较高, 中部的吉林地区和东部的延边地区次之, 西部的白城地区、松原地区等地呈负增长。     

基于特定时间调查数据组建的白蜡窄吉丁种群生命表

为了探明影响白蜡窄吉丁Agrilus planipennis Fairmaire自然种群变化的关键因子, 本研究于2010-2011年采用当年秋季和翌年春季两个特定时间调查取样的方法, 组建了天津、 北京和辽宁3个地区白蜡窄吉丁的自然种群生命表。结果显示, 这3个地区白蜡窄吉丁的自然种群数量在今后几年均将呈增长趋势, 但不同地区的增长速率存在较大差异。北京地区白蜡窄吉丁的种群数量增长速率最快（种群趋势指数I=12.9997）, 其次是天津地区（I=12.4388）, 这两个地区的寄主植物相同, 均为绒毛白蜡。增长最慢的是辽宁地区（I=3.6394）, 其寄主植物为水曲柳。另外, 通过3个地区白蜡窄吉丁生命表和排除控制指数可以看出, 天津地区白蜡窄吉丁最主要的致死因子是白蜡吉丁柄腹茧蜂Spathius agrili Yang（种群数量排除控制指数EIPC=1.5382）, 对种群数量变动的贡献最大; 北京地区的是啄木鸟（EIPC=1.4515）, 而辽宁地区白蜡窄吉丁最主要的致死因子是白蜡吉丁卵跳小蜂Oobius agrili Zhang et Huang的寄生作用（EIPC=1.4701）。这些研究结果表明, 寄主植物的差异是影响白蜡窄吉丁自然种群数量变动的主要因素, 同时寄生性天敌白蜡吉丁柄腹茧蜂对种群数量的影响作用也比较大。因此, 实际应用中可以通过培育抗性树种和人工繁育优势天敌等方法对该虫进行有效防治。