Evaluation of the Mycobacterium smegmatis and BCG models for the discovery of Mycobacterium tuberculosis inhibitors

The objective of this study was to measure the efficacy of Mycobacterium smegmatis as a surrogate in vitro model for the detection of compounds which are inhibitory to the growth of Mycobacterium tuberculosis. A chemical screen of the LOPAC library for anti-mycobacterial compounds was performed using M. smegmatis. Parallel screens were conducted with another tuberculosis model, Mycobacterium bovis BCG, and with M. tuberculosis under identical growth conditions and the inhibitors detected across the three species were compared. 50% of compounds that were detected as active against M.?tuberculosis were not detected using M. smegmatis compared to 21% of compounds using M. bovis BCG. To examine whether these findings were unique to LOPAC, screens were performed with the NIH Diversity Set and Spectrum Collection. An even higher proportion of M. tuberculosis inhibitors were not detected from the NIH Diversity Set and Spectrum Collection using M. smegmatis compared to M. bovis BCG. These data reveal that a significant proportion of M. tuberculosis inhibitors are missed in library screening with M.?smegmatis. The basis of the variation in the inhibitory profiles of M. smegmatis and M. tuberculosis has yet to be fully determined, however, our genomic comparisons indicate that approximately 30% of M.?tuberculosis proteins lack conserved orthologues in M. smegmatis compared to 3% being absent in M.?bovis BCG. In conclusion, although M. smegmatis offers some technical benefits such as a shorter generation time and negligible risk to laboratory workers, it is significantly less effective in the detection of anti-M. tuberculosis compounds relative to M. bovis BCG. This limitation needs to be taken into consideration when selecting an in vitro screening model for tuberculosis drug discovery.     

Changes in olfactory inputs modify the energy balance response to short days in male gray mouse lemurs

The role of olfaction/olfactory cues on photoperiodic responses was assessed in Malagasy primate, the gray mouse lemur. When exposed to short photoperiod (SP), this primate demonstrates rapid changes in energy balance as adaptive anticipatory response for winter survival. To follow early changes induced by SP exposure, body mass, food intake, resting metabolism (RMR) and free thyroxin levels in plasma (T4) were measured in males abruptly transferred to SP: six intact males (controls), eight males that underwent bilateral olfactory removal (BOX) and eight males exposed to male urinary cues (U-exposed). To assess the effect of SP exposure, two other groups were maintained for 6 weeks under LP: six controls and six BOX males. Whereas all studied parameters remained constant in controls and BOX males maintained under LP, exposure to SP led to different responses according to groups. In controls, SP exposure led to a regular increase in body mass and after 4 weeks under SP, plasma T4 levels, food consumption and RMR significantly decreased. Even if BOX males demonstrated hyperphagic patterns regardless of the photoperiod, an increase in body mass was also induced by SP exposure but without changes in RMR or food intake that were body mass-dependent. In U-exposed males, body mass gain was significantly reduced while food intake and RMR remained high. In both BOX and U-exposed males, SP exposure led to a transient but high increase in T4 levels compared to controls. These results suggest that olfaction/olfactory cues may delay the SP-mediated changes in energy balance.     

四君子汤抗胃癌活性部位配伍作用及其对细胞周期的影响

[目的]研究四君子汤抗胃癌活性部位的配伍作用及其对细胞周期的影响.[方法]以SGC-7901胃癌细胞为细胞模型,以接种SGC-7901细胞的裸鼠为动物模型,通过体内、体外方法筛选四君子汤抗胃癌活性部位的最佳配伍;流式细胞仪观察四君子汤活性部位配伍对SGC-7901细胞周期的影响.[结果]四君子汤挥发油部位、萜类部位、黄酮部位在体内、体外均体现出配伍协同作用,活性部位配伍组对SGC-7901细胞的药物半数抑制浓度(IC50)为1.574mg/ml,其高、低剂量组体内抑瘤率分别为55.48％和44.52％;四君子汤活性部位配伍组处理后G2/M期SGC-7901细胞显著增加,为12.84％.[结论]四君子汤挥发油部位、萜类部位、黄酮部位具有协同配伍作用,能将SGC-7901细胞阻滞于G2/M期.     

Protein tyrosine phosphatase conjugated with a novel transdermal delivery peptide,astrotactin 1–derived peptide recombinant protein tyrosine phosphatase (AP-rPTP), alleviates both atopic dermatitis–like and psoriasis-like dermatitis

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与抗寄生虫药物阿苯达唑相关的中国发明专利

本文对在中国已授权的阿苯达唑药物发明专利进行综述,从专利角度反映抗寄生虫药物阿苯达唑的研究现状,为从事阿苯达唑药物研究或申请有关发明专利的研究人员提供资料。     

A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine

Delivery of therapeutic macromolecules is limited by the physiological limitations of the gastrointestinal tract including poor intestinal permeability, low pH and enzymatic activity. Several permeation enhancers have been proposed to enhance intestinal permeability of macromolecules; however their utility is often hindered by toxicity and limited potency. Here, we report on a novel permeation enhancer, Dimethyl palmitoyl ammonio propanesulfonate (PPS), with excellent enhancement potential and minimal toxicity. PPS was tested for dose- and time-dependent cytotoxicity, delivery of two model fluorescent molecules, sulforhodamine-B and FITC-insulin in vitro, and absorption enhancement of salmon calcitonin (sCT) in vivo. Caco-2 studies revealed that PPS is an effective enhancer of macromolecular transport while being minimally toxic. TEER measurements in Caco-2 monolayers confirmed the reversibility of the effect of PPS. Confocal microscopy studies revealed that molecules permeate via both paracellular and transcellular pathways in the presence of PPS. In vivo studies in rats showed that PPS enhanced relative bioavailability of sCT by 45-fold after intestinal administration. Histological studies showed that PPS does not induce damage to the intestine. PPS is an excellent permeation enhancer which provides new opportunities for developing efficacious oral/intestinal delivery systems for therapeutic macromolecules.     

化学修饰的茯苓β-D-葡聚糖结构与抗胃腺癌活性的关系

目的:探讨茯苓多糖及其衍生物的结构与抗胃腺癌活性之间的构效关系.方法:对从茯苓菌核中提取的(1→3)-?-D-葡聚糖PCS3-Ⅱ及其硫酸酯、羧甲基、羟乙基、羟丙基和甲基化衍生物,用粘度法、激光光散射(LLS)及尺寸排除色谱和光散射仪联用(SEC-LLS)表征了他们在磷酸缓冲液(PBS)中37℃下的[?]、Mw及z1/2等分子参数.然后用MTT法研究了PCS3-Ⅱ和几种衍生物对不同分化程度的胃腺癌细胞株MKN-45、SGC-7901和MKN-28生长的抑制作用.结果:S-PCS3-Ⅱ、C-PCS3-Ⅱ、M-PCS3-Ⅱ、HE-PCS3-Ⅱ和HP-PCS3-Ⅱ衍生物在PBS溶液中Mw值分别为3.8×104、18.9×104、16.0×104、76.8×104和224.3×104,未改性?-葡聚糖PCS3-Ⅱ几乎无抗胃腺癌活性,而他的硫酸酯和羧甲基衍生物对细胞株MKN-45、SGC-7901和MKN-28却显示较高的抑制率.结论:天然茯苓菌核多糖体外没有抗胃腺癌活性;水不溶性多糖PCS3-Ⅱ链上引入羧甲基和硫酸酯基后,其衍生物溶于水,且链刚性增大,同时其抗胃腺癌活性增强;良好的水溶性、较高的链刚性和适当大的分子量有利于茯苓多糖抗胃腺癌活性的提高.     

ANA、ds-DNA抗体联合检测自身免疫病的临床应用研究

目的 探讨ANA、ds-DNA抗体联合检测对自身免疫病的临床应用及意义.方法 应用间接免疫荧光法检测ANA、ACA、ACYA和ds-DNA抗体,并进行回顾性分析.结果 ①245例各种自身免疫病患者检测ANA、ACA、ACYA、ds-DNA抗体结果,ANA在SLE患者中最高,阳性率为97.67%;ACA抗体在SSc患者中最高,阳性率为（80%）;ACYA抗体检测在PM/DM患者中最高,阳性率为28.57%;ds-DNA抗体亦在SLE患者中最高,阳性率为62.79%;②180例ANA阳性结果分布情况为均质型以MCTD患者最多,阳性数为27例;斑点型和核周型则均以SLE患者为最多,有54例和12例阳性;核仁型则与SSc患者为最多,阳性3例;③13例ACYA抗体阳性结果以均质型为主,均质型阳性有9例,并且均是SLE患者.结论 应用ANA、ACA、ACYA和ds-DNA抗体联合检测在自身免疫病患者诊断中具有互补性,并能提高阳性检出率.对自身免疫病的诊断分型、治疗预后均有重要的临床价值.