Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.     

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.     

蛇伤凉血合剂治疗蝰蛇咬伤的疗效观察

目的观察蛇伤凉血合剂对蝰蛇咬伤的临床疗效。方法将62例病人分为治疗组和对照组,两组均给予常规治疗,治疗组加服蛇伤凉血合剂。观察比较两组预后,局部组织坏死发生率,肢体功能受限发生率,肾损害发生率和血液透析率,住院时间等指标。结果两组病人的临床疗效、肿胀消退时间、疼痛缓解时间、局部坏死发生率、致残率、肾损害发生率和血液透析率、住院时间均有显著性差异（P〈0.05）。结论蛇伤凉血合剂对蝰蛇咬伤有显著疗效。     

模拟胃酸条件下的幽门螺杆菌CAT特异性抗体活性研究

幽门螺杆菌是常见的感染性病原菌,人类多种疾病发生与此菌感染有关。预防和治疗菌体感染及引发的相关疾病仍是现代医学面临的课题。实验利用原核表达的幽门螺杆菌过氧化氢酶(1~380 aa)免疫家兔,获得效价为1∶6 000的特异性抗血清,经硫酸铵沉淀法得到初步纯化的抗体。在体外模拟胃酸环境下(pH3.4)将抗体进行水解。SDS-PAGE结果显示,抗体的重链能被水解。水解后的抗体产物经ELISA方法检测,仍然具有与抗原特异性结合的能力。实验结论证实,在体外环境下特异性幽门螺杆菌抗体保护作用不会被胃蛋白酶的水解而破坏,提示口服特异性抗体预防和治疗幽门螺杆菌感染可能是一条可行的途径。     

肥大细胞介导的ADCC效应在抗旋毛虫病免疫机理中的作用

检测旋毛虫感染大鼠血清中的总IgE、特异性IgE和观察IgE介导的肥大细胞脱颗粒,并进一步探讨抗体依赖的(肥大)细胞介导的细胞毒性(Antibody dependent cell mediated cytotoxicity,ADCC)在旋毛虫病免疫机理中的作用。采用雄性Wistar大鼠为旋毛虫感染的动物模型,将90只大鼠随机分为10组。试验时,以ELISA双抗体夹心法和间接法分别动态检测总IgE和特异性IgE;肥大细胞脱颗粒试验采用直接法;然后采用细胞培养法观察免疫血清对肥大细胞杀伤旋毛虫肌幼虫作用的影响。在免疫血清存在时,无论感染鼠还是正常鼠的肥大细胞对旋毛虫幼虫均有杀伤作用,但以感染鼠的作用更强。肥大细胞在ADCC效应机制中对杀伤旋毛虫肌幼虫发挥了重要的作用。     

Molecular characterization and mRNA expression of catalase from pearl oyster Pinctada fucata

Catalase (EC 1.11.1.6) is an important antioxidant enzyme that protects aerobic organisms against oxidative damage by degrading hydrogen peroxide to water and oxygen. In the present study, a catalase cDNA of peal oyster Pincatada fucata (designated as PoCAT) is cloned and characterized by expressed sequence tag (EST) and rapid amplification of cDNA ends (RACE) methods. PoCAT is 2428 bp long and consists of a 5′-UTR of 140 bp, an unusually long 3′-UTR of 749 bp, and an open reading frame (ORF) of 1539 bp. The ORF of PoCAT encodes a polypeptide of 512 amino acids with molecular weight of 58.1 kDa and the theoretical isoelectric point of 8.4. PoCAT shares 62.3–82.2% identity and 73.0–92.0% similarity to other catalase amino acid sequences. Sequence alignment indicates that PoCAT contains the proximal heme-ligand signature sequence (R³⁵¹LFSYSDT³⁵⁸), the proximal active site signature (F⁶¹NRERIPERVVHAKGGGA⁷⁸), and the three catalytic amino acid residues (His⁷², Asn¹⁴⁵, and Tyr ³⁵⁵). PoCAT has two potential glycosylation sites (N⁴³⁶YS⁴³⁸ and N⁴⁷⁸FS⁴⁸⁰) and a peroxisome targeting signal (ASL). PoCAT mRNA was ubiquitously expressed in all detected tissues, and the expression level of PoCAT mRNA was higher in intestine and mantle. The expression profile analysis showed that the expression level of PoCAT mRNA in intestine was significantly up-regulated at 2, 4 and 12 h after Vibrio alginolyticus stimulation. These results demonstrated that PoCAT is a typical member of catalase family and might be involved in innate immune responses of pearl oyster.     

Tumor-derived interleukin (IL)-6 induced anti-tumor effect in immune-compromised hosts

Tumor-derived cytokines, such as interleukin (IL)-6, function in the context of tumor-to-host interactions, and their functions in immune-compromised hosts need to be addressed in the light of ever- increasing number of patients under immunosuppression. We studied the effects, in immune-comprised animals, of tumor-derived IL-6 on tumor growth using an experimental tumor vaccination model. Murine mammary carcinoma FM3A clone 25 (CL25) cells, which neither produce IL-6 nor express IL-6 receptors, were used. cDNA for murine IL-6 (mIL-6) was introduced to the CL25 cells, resulting in a high-producer (mIL-6H) clone. In the severe combined immune-deficient (SCID) mice, the inoculation 3 weeks earlier of mIL-6H to a dorsal flank site suppressed the growth of the CL25 cells at the opposite flank site; a tumor-derived IL-6-mediated vaccination effect occurred. In the T-cell-deficient nude mice, the inoculations 4 weeks earlier of mIL-6H suppressed the growth of CL25, but the simultaneous inoculation of these transfectants did not affect the growth of CL25. Reducing the number of inoculated transfectants or a shorter vaccination period obscured the suppressive effect. The amounts of circulating tumor-reactive immunoglobulin did not correlate with the suppressive effect. The subcutaneous injection of the anti-CD40 antibody generated a further suppression of tumor growth in the mIL-6H-inoculated, but not in the mock-inoculated, T-cell-deficient mice. In the immune-competent hosts, a suppressive effect was not observed. Natural killer (NK) activity was augmented in the spleen of mIL-6H-inoculated scid mice. This study indicated a possible vaccination effect with tumor-derived IL-6 in immune-compromised hosts.     

Agent-based modeling of the context dependency in T cell recognition

Antigen recognition by T cells is a key event in the adaptive immune response. T cells scan the surface of antigen-presenting cells (APCs) or target cells for specific peptides bound to MHC molecules. In the physiological setting, a typical APC presents tens of thousands of diverse endogenous self-derived peptides complexed to MHC (pMHC complexes). When 'foreign' peptides are presented, they constitute a small fraction of the total surface peptide repertoire. As T cells seem to be capable of discerning minute amounts of 'foreign' peptides among a complex background of self-peptides, endogenous peptides are generally assumed to play no role in recognition. However, recent results suggest that these background peptides may alter the sensitivity of T cells to foreign peptides. Current experimental limitations preclude analysis of peptide mixtures approaching physiological complexity, making it difficult to further address the role of complex background peptides. In this paper, we present a computational model to test how complex, varied peptide populations on an APC could potentially modulate a T cell's ability to detect the presence of small numbers of agonist peptides among a diverse population. We use the model to investigate the notion that under physiological conditions, T cell recognition of foreign peptides is context dependent, that is, T cells process signals gathered from all pMHC interactions, not just from a few agonist peptides while ignoring all others.     

免疫活性细胞中的非神经元型胆碱能系统

本文对淋巴细胞、巨噬细胞、粒细胞、肥大细胞及胶质细胞等免疫活性细胞中非神经元型胆碱能系统的特点、药理学和病理生理学意义进行了综述。免疫活性细胞,尤其是淋巴细胞中存在完整、独立的胆碱能系统。与神经元型胆碱能系统相比,该系统具有不同特点,如乙酰胆碱(ACh)的合成存在于整个细胞内;ACh可能储存于细胞中某种储存结构,也可能不需储存,而是按需合成并直接释放。免疫活性细胞中的非神经元型胆碱能系统对机体免疫功能及炎症过程可能发挥重要的调控作用。对该系统的深入研究将有助于进一步阐明免疫性疾病、炎症/感染性疾病和神经退行性疾病等的病理生理和发现药物治疗的新靶标。     

Epidemiological evaluations of the efficacy of slow-released praziquantel-medicated bars for dogs in the prevention and control of cystic echinococcosis in man and animals

To assess the epidemiological efficacy of type SRP III slow-released praziquantel-medicated bars for dogs in the prevention and control of cystic echinococcosis in man and livestock, praziquantel-medicated bars were implanted subcutaneously in over 90% of dogs in villages in north Xinjiang, China, where cystic echinococcosis is highly endemic. After implantation, infection rate of Echinococcus granulosus in dogs, specific antibodies in children and prevalence of echinococcosis in one-year-old lambs were observed for 3 years. Coproantigen of E. granulosus was positive in 41.2% of the dogs at the start of experiment. In the second and third year after medicated-bar implantation, coproantigen was undetectable in any dogs examined, while 3.0% of dogs were positive at the end of the fourth year. The antibody positive rate in 7-year-old pupils, that was 41.2% before the experiment, declined gradually and it was 5.4% in the fourth year, while children in the non-intervention control area showed 30.6% seropositivity. The prevalence of hydatid disease in children aged 7–16 years also declined significantly. The prevalence of hydatidosis in lambs one year of age was 44.8% in the first year, dropping to 10.7% in the fourth year, while in the non-intervention control area the level of infection was 46.4%. These results demonstrated not only that the slow released praziquantel-medicated bars efficiently blocked reinfection in dogs at least for 2 years, but also the measure was effective in preventing transmission of cystic echinococcosis to both man and livestock.