Isomeric acetoxy analogs of celecoxib and their evaluation as cyclooxygenase inhibitors

A group of celecoxib analogs having a SO(2)NH(2) (9a-f), or SO(2)Me (12a-f), COX-2 pharmacophore at the para-position of the N-1 phenyl ring in conjunction with a C-5 phenyl ring having a variety of substituents (4-, 3-, 2-OAc; 4-Me,2-OAc, 4-Me,3-OAc, 4-F,2-OAc) was synthesized for evaluation as cyclooxygenase (COX) inhibitors of the COX-1/COX-2 isozymes. Within this group of compounds, 1-(4-aminosulfonylphenyl)-3-trifluoromethyl-5-(2-acetoxy-4-fluorophenyl)pyrazole (9f) emerged as the most potent (COX-1 IC(50)=0.7 μM; COX-2 IC(50)=0.015 μM) and selective (COX-2 selectivity index=47) inhibitor agent that exhibited good anti-inflammatory activity (ED(50)=42.3mg/kg) which was lower than the reference drug celecoxib (ED(50)=10.8 mg/kg), but greater than ibuprofen (ED(50)=67.4 mg/kg) and aspirin (ED(50)=128.7 mg/kg). Molecular modeling studies for 9f showed that the SO(2)NH(2) group assumes a position within the secondary pocket of the COX-2 active site wherein the SO(2)NH(2) oxygen atom is hydrogen bonded to the H90 residue (2.90?), the SO(2)NH(2) nitrogen atom forms a hydrogen bond with L352 (N?O=2.80?), and the acetyl group is positioned in the vicinity of the S530 residue where the acetyl oxygen atom undergoes hydrogen bonding to L531 (2.99?).     

COX-2和P-STAT_3、P-STAT_5在肝癌细胞株SMMC-7721中的表达及意义

目的观察COX-2和P-STAT3、P-STAT5在人肝癌细胞株SMMC-7721中的表达及其相互关系,探讨环氧合酶2表达与JAK/STAT信号转导通路之间的关系。方法培养人肝癌SMMC-7721细胞,应用免疫组化法检测COX-2抑制剂塞来昔布处理人肝癌细胞株SMMC-7721前后COX-2、P-STAT3、P-STAT5表达的变化。结果COX-2、P-STAT3、P-STAT5在人肝癌细胞株SMMC-7721均呈高表达,并且COX-2与P-STAT3、P-STAT5的表达呈显著正相关;应用COX-2抑制剂塞来昔布后COX-2、P-STAT3、P-STAT5的表达均显著降低,用药前后相比差异有显著性(P<0.01);但用药后COX-2与P-STAT3、P-STAT5的表达无显著相关性。结论COX-2和JAK/STAT通路有密切联系,抑制COX-2的过度表达可能影响JAK/STAT细胞信号转导通路的活性。     

思他宁联合美常安治疗重症急性胰腺炎的临床研究

目的 探讨思他宁联合美常安治疗重症急性胰腺炎(SAP)的疗效.方法 将2005年至2009年SAP患者35例设为A组,按照SAP常规处理原则予监护、止痛、禁食、胃肠减压、抑酸、抗生素、纠正水电解质酸碱平衡治疗及给予静脉持续滴注思他宁(250 μg/h),连用5～10 d;另将SAP患者45例设为B组,B组在A组治疗方案...     

Effect of Celecoxib on Ca2+ Fluxes and Proliferation in MDCK Renal Tubular Cells

The effect of celecoxib on renal tubular cells is largely unexplored. In Madin Darby canine kidney (MDCK) cells, the effect of celecoxib on intracellular Ca^{2 +} concentration ([Ca^{2 +}]_i) and proliferation was examined by using the Ca^{2 +}-sensitive fluorescent dye fura-2 and the viability detecting fluorescent dye tetrazolium, respectively. Celecoxib (≥1 μ M) caused an increase of [Ca^{2 +}]_i in a concentration-dependent manner. Celecoxib-induced [Ca^{2 +}]_i increase was partly reduced by removal of extracellular Ca^{2 +}. Celecoxib-induced Ca^{2 +} influx was independently suggested by Mn^{2 +} influx-induced fura-2 fluorescence quench. In Ca^{2 +}-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca^{2 +}-ATPase, caused a monophasic [Ca^{2 +}]_i increase, after which celecoxib only induced a tiny [Ca^{2 +}]_iincrease; conversely, pretreatment with celecoxib completely inhibited thapsigargin-induced [Ca^{2 +}]_i increases. U73122, an inhibitor of phospholipase C, abolished ATP (but not celecoxib)-induced [Ca^{2 +}]_i increases. Overnight incubation with 1 or 10 μ M celecoxib decreased cell viability by 80% and 100%, respectively. These data indicate that celecoxib evokes a [Ca^{2 +}]_i increase in renal tubular cells by stimulating both extracellular Ca^{2 +} influx and intracellular Ca^{2 +} release and is highly toxic to renal tubular cells in vitro.     

Visualization of capsule formation by Erwinia amylovora and assays to determine amylovoran synthesis

Exopolysaccharide (EPS) synthesis by Erwinia amylovora depends on environmental and genetic predispositions. To measure the amount of the acidic EPS amylovoran synthesized by E. amylovora cell cultures, a turbidity assay using cetylpyridinium salt was developed. The EPS produced by bacteria grown on solid media was additionally characterized by its water content. The amylovoran capsules were visualized in situ by staining with fluorescein isothiocyanate (FITC)-labelled lectin from Abrus precatorius, which reacts with the galactose residue of the EPS side chain. The staining and the turbidity assays were applied to suspension cell cultures or to cells from colonies and did not require any purification steps. Lectin staining was superior to electron microscopic (EM) techniques for visualization of capsules. For EM, the capsule was stabilized with polycationic ferritin. In contrast to lectin staining, only a small fraction of the cells was found to be EPS-coated in the EM assay. An increase in capsulation and in amylovoran production was found in conjunction with mutations in a ribosomal protein conferring resistance to streptomycin. Furthermore, the presence of sorbitol in the growth environment resulted in high synthesis of amylovoran. Cells in the stationary growth phase continued to produce amylovoran. Apparently, the strong dependence of the fireblight pathogen on capsules requires the capacity for EPS synthesis in all growth stages in order to escape plant defence reactions.     

Regulation of expression of group IA capsular polysaccharides inEscherichia coli and related extracellular polysaccharides in other bacteria

Bacterial surface polysaccharides fulfill a number of important roles in cell-cell interactions, survival in natural environments, and formation of biofilms. Consequently, the mechanisms involved in regulation of extracellular polysaccharides are predicted to have a significant impact on microbial adaptation. Strains ofEscherichia coli, Klebsiella spp, andErwinia spp produce extracellular polysaccharides which share structural features. There are also similarities in the organization of genes required for synthesis of these cell surface polymers and, in some cases, the mechanism of synthesis may be related. Despite the diverse habitats of these bacteria, the systems which regulate expression of their extracellular polysaccharides appear to share components and mechanisms. Understanding these regulatory processes may lead to novel therapeutic approaches for pathogens, or for control of unwanted biofilm formation in industrial settings.     

松龄血脉康胶囊联合立普妥对老年高血压患者血清Fibulin-3、Lp(a)、MCP-1水平的影响

目的:研究松龄血脉康胶囊联合立普妥对老年高血压患者血清细胞外基质蛋白-3 (Fibulin-3)、脂蛋白a (Lipoprotein(a),Lp(a))、单核细胞趋化蛋白-1 (monocyte chemoattractant protein-1,MCP-1)水平的影响。方法:选择2015年04月至2017年12月在我院治疗的老年高血压患者72例,按照随机数字表法为观察组和对照组,对照组采用立普妥口服治疗,观察组在对照组的基础上联用松龄血脉康胶囊口服治疗,观察和比较两组临床治疗效果,治疗前后血脂、动态血压及Fibulin-3、Lp(a)、MCP-1水平的变化情况。结果:治疗后,观察组总有效率为88.89%,明显高于对照组(69.44%,P0.05);观察组血清血清总胆固醇(Serum total cholesterol,TC)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)、甘油三酯(triglyceride,TG)、游离脂肪酸(nonesterified fatty acid,FFA)、Lp(a)、MCP-1等水平均显著低于对照组(P0.05),而血清HDL-C、Fibulin-3水平明显高于对照组(P0.05);治疗后,观察组动态血压水平降低范围较对照组更明显(P0.05);观察组患者生活愉快、心理健康及认知功能等方面评分均显著高于对照组(P0.05)。结论:松龄血脉康胶囊联合立普妥治疗老年高血压患者的临床疗效显著优于单用立普妥口服治疗,其能更有效维持动态血压的正常水平,且显著改善Fibulin-3、Lp(a)、MCP-1水平,降脂效果良好。     

COX-1/COX-2 inhibition assays and histopathological study of the new designed anti-inflammatory agent with a pyrazolopyrimidine core

Four pyrazolopyrimidine series were prepared with a substitution at position- 4 by Schiff base, triazole, oxadiazole and pyrazole moieties (7a-f, 8a,b, 9a-f, 10a,b and 13a,b), respectively. All the synthesized compounds were evaluated in vitro against COX-2 and in vivo against carrageenan-induced rat paw edema as anti-inflammatory agents. Regarding the anti-inflammatory activity (AI) compounds 7c, 7f, 8a, and 9a showed higher activity with respect to celecoxib. Compounds 9a, 7d, and 7f were closely selective to celecoxib. Also, 7c and 7d were safer than indomethacin and similar to celecoxib as resulted from the histopathological study. In addition, the docking study that showed the binding mode of prominent pyrazolopyrimidine compounds inside the COX-2 receptor. Formation of unexpected pyrazole 13a and 13b was briefly discussed using 2D NMR.