Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors

The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pK_a and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC₅₀ 7.4 nM) and submicromolar cellular target engagement activity (EC₅₀ 0.5 μM).     

Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X₇ receptor

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.     

Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility

Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.     

口源性口臭指示菌的筛选

目的从口源性口臭(Oral Malodor)相关菌种中筛选主要代表菌,用以建立口臭细菌学(Oral Bacteri-ology)临床辅助诊断的指示菌(Indicator bacteria)。方法用感官检测(鼻闻法)(Organoleptic test)、气相色谱(Gas Chromatography)、硫化物检测仪(Halimeter)和硫化氢检测仪(Easicult S)等4种方法,在实验室检测常见的8种牙周及龋病致病菌,通过检测鼻闻臭味程度、硫化物(Volatile sulfur compounds,VSCs)、硫化氢(Hydrogen sulfide,H2S)及有异味的短链脂肪酸(Short Chain Fatlf acid)含量来确定指示菌。结果鼻闻:牙龈卟啉单胞菌(P.gingivalis,P.g)、中间普雷沃菌(P.intermedius,P.i)和具核梭杆菌具核梭亚种(F.subsp nucleatum,F.n)恶臭明显,其他菌有微臭或无味。气相色谱检测:P.g、P.i、F.n和伴放线聚生杆菌(Aggregatibscter actinomycetemcomitans,A.a)中有异味的丁酸(Butyric acid)含量在40%～66%,其他菌,其他产物含量较低。硫化物检测:P.g、P.i和F.n的VSCs量在1 000ppb以上,硫化氢检测:P.g、P.i和F.n的H2S在600 ppb以上,其他菌两项检测均在36 ppb以下。结论 P.g、P.i和F,n是主要产臭菌种,可作为临床口臭的细菌学辅助诊断的指示菌,供临床进一步研究。     

人类微生物组测序与比较研究

人体微生物群系影响人类的健康,与人类的各种疾病,如肥胖、糖尿病、冠心病、结肠癌等的发生具有密切的关系.近年来,人类微生物组研究日益受到重视.综述人类微生物组的测序和比较研究进展.     

Teleost intestinal immunology

Teleosts clearly have a more diffuse gut associated lymphoid system, which is morphological and functional clearly different from the mammalian GALT. All immune cells necessary for a local immune response are abundantly present in the gut mucosa of the species studied and local immune responses can be monitored after intestinal immunization. Fish do not produce IgA, but a special mucosal IgM isotype seems to be secreted and may (partly) be the recently described IgZ/IgT. Fish produce a pIgR in their mucosal tissues but it is smaller (2 ILD) than the 4–5 ILD pIgR of higher vertebrates. Whether teleost pIgR is transcytosed and cleaved off in the same way needs further investigation, especially because a secretory component (SC) is only reported in one species. Teleosts also have high numbers of IEL, most of them are CD3-?⁺/CD8-α⁺ and have cytotoxic and/or regulatory function. Possibly many of these cells are TCRγδ cells and they may be involved in the oral tolerance induction observed in fish. Innate immune cells can be observed in the teleost gut from first feeding onwards, but B cells appear much later in mucosal compartments compared to systemic sites. Conspicuous is the very early presence of putative T cells or their precursors in the fish gut, which together with the rag-1 expression of intestinal lymphoid cells may be an indication for an extra-thymic development of certain T cells. Teleosts can develop enteritis in their antigen transporting second gut segment and epithelial cells, IEL and eosinophils/basophils seem to play a crucial role in this intestinal inflammation model. Teleost intestine can be exploited for oral vaccination strategies and probiotic immune stimulation. A variety of encapsulation methods, to protect vaccines against degradation in the foregut, are reported with promising results but in most cases they appear not to be cost effective yet. Microbiota in fish are clearly different from terrestrial animals. In the past decade a fast increasing number of papers is dedicated to the oral administration of a variety of probiotics that can have a strong health beneficial effect, but much more attention has to be paid to the immune mechanisms behind these effects. The recent development of gnotobiotic fish models may be very helpful to study the immune effects of microbiota and probiotics in teleosts.     

埃索美拉唑治疗幽门螺杆菌阳性十二指肠球部溃疡疗效观察

目的：比较埃索关拉唑与兰索拉唑、奥美拉唑三联疗法治疗幽门螺杆菌（Hp）阳性十二指肠球部渍疡疗效观察。方法：将84例Hp阳性的十二指肠球部溃疡随机分为三组。埃索美拉唑组（28例）：埃索美拉唑20mg＋阿莫西林1g＋呋喃唑酮100mg,每日2次,共7日,后服用埃索美拉唑20mg,每日一次,共21天;兰索拉唑组（28例）：兰索拉唑15mg＋阿莫西林1g＋呋喃唑酮100mg,每日2次,共7日,后服用兰索拉唑15mg,每日一次,共21天;奥美拉唑组（28例）：奥美拉唑20mg＋阿莫西林1g＋呋喃唑酮100mg,每日2次,共7日,后服用奥美拉唑20mg,每日一次,共21天。疗效结束4周后复查胃镜并检测Hp,观察腹痛缓解率、溃疡愈合率,Hp根治率及药物不良反应。结果：埃索美拉唑组、兰索拉唑组和奥关拉唑组溃疡愈合率分别为100％,85．7％,82．1％,HP根治率为85．7％,60．7％,64.3％,埃索美拉唑组溃疡愈合率及Hp根除率高于兰索拉唑组及奥美拉唑组,差异具有统计学意义（P〈0．05）。兰索拉唑组及奥美拉唑组溃疡愈合率及Hp根除率无明显差异（P〉0．05）。三组用药后不良反应少,具较好的安全性。结论：埃索关拉唑三联疗法治疗Hp阳性的消化性溃疡疗效优于兰索拉唑及奥美拉唑三联疗法,值得临床广泛应用。     

骨形成蛋白Ⅱ型突变受体基因转染对口腔鳞癌细胞增殖和凋亡的影响

目的探讨骨形成蛋白（BMPs）与口腔鳞癌的发生、发展的可能关系。方法将含有BMP-Ⅱ突变受体的真核表达载体转染入Tea8113舌癌细胞,筛选和鉴定后,构建稳定表达BMP-Ⅱ突变受体的细胞株tBRⅡ-Tea8113。对tBRⅡ—Tca8113细胞和Tca8113细胞分别进行MTT检测,流式细胞仪（FCM）分析、BrdU标记检测细胞的增殖活性及DNA合成;检测tBRⅡ-Tca8113细胞和Tea8113细胞的凋亡及细胞周期相关因子（CyclinD1,CDK-4,p27,p57）的表达。结果Tea8113细胞和tBRⅡ-Tea8113细胞的增殖指数MTT检测为0．47±0．01和0．35±0．008（t=22．953,P=0．000）,BrdU检测为12．0±3．4和23．0±1．9（f=6．918,P=0．000）,FCM检测为6.3和7．9;两组的凋亡指数为3．7±1．2和8．7±1．6（t=29．583,P=0．000）;细胞周期因子在Tca8113和tBRⅡ-ca8113细胞中的平均灰度测量值为CyclinD1（186．5±2．4和145．6±3．9,t=28．244,P=0．000）,CDK4（169．9±2．9和129．5±3．2,t=29．583,P=0．000）,p27（110．1±1．1和167．34-1．8,f=85．754,P=0．000）,p57（107．9±2．1和156．8±2．2,t=50．844,P=0．000）。结论BMPs及其受体可能在口腔上皮组织的恶变过程中有重要作用,研究结果为探讨BMPs信号在上皮性肿瘤中的作用提供了重要依据。tBRⅡ-Tea8113细胞的建立,进一步表明了BMPs及其受体在口腔上皮组织的恶变过程中有重要作用,并为进一步探讨BMP信号在上皮性肿瘤的恶变过程中的作用奠定了基础。     

拔除阻生智齿患者牙科焦虑的调查及分析

目的:了解综合医院口腔科拔除阻生智齿患者牙科焦虑的患病情况并进行相关因素分析。方法:采用牙科焦虑一般因素调查表、改良牙科焦虑量表(MDAS)及状态焦虑量表(S-AI)对300例口腔颌面外科门诊的拔除阻生智齿患者进行调查及评定,同时对引起牙科焦虑的相关因素进行分析。结果:拔除阻生智齿患者牙科焦虑的发生率为56.00%,有6项因素对牙科焦虑症的患病率有影响,差异有统计学意义(P<0.05),其中5项因素对MDAS得分影响较大。结论:牙科焦虑在拔除阻生智齿的患者中较普遍,有多种因素影响患者牙科焦虑的程度。     

埃索美拉唑治疗幽门螺杆菌阳性十二指肠球部溃疡疗效观察

目的:比较埃索美拉唑与兰索拉唑、奥美拉唑三联疗法治疗幽门螺杆菌(Hp)阳性十二指肠球部溃疡疗效观察。方法:将84例Hp阳性的十二指肠球部溃疡随机分为三组。埃索美拉唑组(28例):埃索美拉唑20mg+阿莫西林1g+呋喃唑酮100mg,每日2次,共7日,后服用埃索美拉唑20mg,每日一次,共21天;兰索拉唑组(28例):兰索拉唑15mg+阿莫西林1g+呋喃唑酮100mg,每日2次,共7日,后服用兰索拉唑15mg,每日一次,共21天;奥美拉唑组(28例):奥美拉唑20mg+阿莫西林1g+呋喃唑酮100mg,每日2次,共7日,后服用奥美拉唑20mg,每日一次,共21天。疗效结束4周后复查胃镜并检测Hp,观察腹痛缓解率、溃疡愈合率,Hp根治率及药物不良反应。结果:埃索美拉唑组、兰索拉唑组和奥美拉唑组溃疡愈合率分别为100%,85.7%,82.1%,HP根治率为85.7%,60.7%,64.3%,埃索美拉唑组溃疡愈合率及Hp根除率高于兰索拉唑组及奥美拉唑组,差异具有统计学意义(P<0.05)。兰索拉唑组及奥美拉唑组溃疡愈合率及Hp根除率无明显差异(P>0.05)。三组用药后不良反应少,具较好的安全性。结论:埃索美拉唑三联疗法治疗Hp阳性的消化性溃疡疗效优于兰索拉唑及奥美拉唑三联疗法,值得临床广泛应用。