活菌药物在肿瘤免疫治疗中的应用进展和未来展望

肠道微生物是人体重要的器官,在人类健康和疾病中发挥重要作用。很多疾病被证实与肠道微生物的组成和功能改变相关。肿瘤免疫治疗作为一种新兴的肿瘤治疗手段,具有特异性强、疗效显著等特点,免疫检查点抑制剂是目前应用较为广泛的方法之一。免疫检测点抑制剂的疗效与肠道菌群有直接联系。本文对近年来肿瘤免疫治疗相关肠道微生物的研究进展进行总结,阐述了肠道菌群在肿瘤治疗中的功能和作用机制,如通过代谢产物或表面蛋白直接或间接抑制肿瘤生长或诱导肿瘤细胞凋亡,调节免疫系统特别是肿瘤微环境发挥抗肿瘤功能等。随着HUMAnN2流程、DADA2流程、metaWRAP等生物信息工具和统计方法在肠道菌群方面的应用,肠道菌群在肿瘤免疫方面的研究得到进一步发展。目前,各研究机构和生物制药公司均已在肠道微生物领域进行规划,并已注册多项临床试验。本文还就免疫治疗相关肠道微生物的发现方法以及用于肿瘤免疫治疗的活菌药物开发进展情况进行介绍,并在此基础上探讨了目前的缺陷和未来的发展趋势。

微妙的活菌药物——双歧杆菌

1989年法国巴斯德研究的一位科研人员在观察人体肠粘膜切片的时候,看到一个奇特的不知名的杆菌,形态与其它杆菌不同,尾部成两岔,于是命名为双歧杆菌。用中国话形容可称“人字形杆菌”。1960年日本用双歧杆菌制成药品,1968年第一个报道了在食品上的应用。西德把双歧菌加入奶粉里面,用于肝硬化患者。

碳青霉烯类抗菌药物灭活试验筛查产碳青霉烯酶肠杆菌科细菌的效能评价

目的评估碳青霉烯类抗菌药物灭活试验(CIM)快速筛查产碳青霉烯酶肠杆菌科细菌的应用价值。方法以碳青霉烯酶基因聚合酶链反应(PCR)及测序结果为金标准,用CIM在154株肠杆菌科细菌(分离于临床样本)中筛查产碳青霉烯酶的细菌,并与改良Hodge试验结果进行比较。结果 CIM的符合率、特异性和敏感性分别为99.4%、96.6%和100.0%,改良Hodge试验的符合率、特异性和敏感性分别为98.7%、93.1%和100.0%。结论与改良Hodge试验相比,CIM具有符合率和特异性高、结果易于观察等优势,适合在各级医院的微生物实验室中推广使用。

赖氨葡锌联合肠道活菌药物治疗肠炎的观察疗效

目的:观察分析赖氨葡锌联合肠道活菌药物治疗肠炎的疗效。方法:将我院2018年1月-6月收治的90例肠炎患儿随机分为两组(各45例),2组均进行止泻、止痛、纠正水电解质平衡,对照组应用常道活菌药物等对症治疗,在此基础上对观察组患儿联合赖氨葡锌,对比2组患儿症状持续时间、疗效。结果:观察组患儿治疗后发热持续时间[(2.2±0.5)d]短于对照组[(3.3±1.0)d],差异有统计学意义(P<0.05,t=-6.033);腹泻持续时间[(3.0±1.3)d]短于对照组[(4.1±1.8)d],差异有统计学意义(P<0.05,t=-3.323);呕吐持续时间[(1.0±0.2)d]明显短于对照组[(1.8±0.7)d],差异有统计学意义(P<0.05,t=-6.025)。观察组患儿治疗总有效率为88.89%,明显高于对照组的68.89%(χ^2=5.402,P<0.05)。结论:赖氨葡锌联合肠道活菌药物治疗肠炎起效迅速,疗效确切。

活体菌药物产业化

肠道微生物组通常被认为与胃肠道疾病,如传染性腹泻相关。然而,肠道细菌也可以通过调节人体免疫系统、新陈代谢,甚至神经功能来影响身体远端部位的功能。这是一种进化的功能,允许细菌与身体系统相互作用,并调节身体系统。活体菌药物通过多种机制与人类生物系统相互作用。尽管宿主和微生物相互作用通常在肠道中启动,但产生的下游通路变化是多种多样的,影响身体的肠道和肺部,甚至中枢神经系统。过去10来年基因组学的发展带动人体微生物组学的繁荣,逐步阐明了人体微生物与人体健康、疾病的关系,也促进了微生物组学产业化的进程。活体菌药物提供了一种治疗广泛范围疾病的新方法,如从癌症到哮喘和中枢神经系统疾病。在临床治疗上,活体菌药物产品也逐渐从研究、发现进入到后期临床阶段。

Synthesis and Antibacterial Effect of New Alkylenedibiguanides

Seven new alkylenedibiguanides were synthesized and comfirmed by 1H NMR, MS and elemental analyses. The preliminary test in vitro showed that some of them had potential antibacterial activities.

A Bioactive Diterpene from the Chinese Herb Aster souliei

Aster souliei Franch, (Compositae) is a. herbaceous plant distributed innorth China. It has been used in folk medicine as antipyretic, detoxicant, expectorant andantitussive. In an effort to find biologically active components from Chinese medicinal plants ' ,we have examined the aerial parts of this herb, leading to the isolation of a clerodane-typediterpene, 18, 19-dihydroxy-5α, 10β-neo-cleroda-3, 13 (l4)-dien-16, 15-butenolide (1). In thispaper we report the structural elucidation, and the antitumor and antibacterial activities of thiscompound. It was found that 1 possesses moderate cytotoxicity against human leukemia cells (HL-60)and activity against microorganisms.

Synthesis and Antifungal Activity of 1-(1H-1,2,4-Triazole)-2-(2,4-diflurophenyl)-3-(N-methyl-N-substituted benzylamino)-2-propanols

Eleven 1-(1H-1,2,4-triazole)-2-(2,4-diflurophenyl)-3-(N-methyl-N-substituted benzylamino)-2-propanols were designed and synthesized, on the basis of the crystal structure of P450 cytochrome 14α-sterol demethylase(CYP51) and the docking results of inhibitors to the active site of the enzyme. All title compounds were first by reported. Results of preliminary biological tests showed that most of title compounds exhibited activity against the seven common pathogenic fungi. Compound 11 showed best antifungal activity with broad antifungal spectrum and proved to be more active against Cryptococcus neoformans, Candida albicans, Microsporum lanosum and Trichophyton rubrum than ketoconazole. Compounds 3, 10 and 4 also had high activities.

谷氨酰胺联合双歧杆菌四联活菌治疗急性肠炎临床疗效观察

目的观察评估谷氨酰胺联合双歧杆菌四联活菌治疗急性肠炎的临床疗效。方法 2015年10月-2018年10月,某医院收治的急性肠炎患者80例,行血常规超敏C反应蛋白(CRP)、粪常规及潜血5项检验,随机将患者分为对照组与实验组,每组40人,对照组采用口服双歧杆菌四联活菌,实验组在对照组基础上加用谷氨酰胺。结果经过5 d治疗后,实验组病情改善情况:腹泻、大便潜血或白细胞、血象或CRP有效率分别为:77.5%、82.5%、67.5%;与对照组与之对应有效率分别为:35.0%、35.0%、42.5%,差异有统计学意义(P<0.05)。结论谷氨酰胺联合双歧杆菌四联活菌治疗急性肠炎优于双歧杆菌四联活菌单药治疗急性肠炎效果,值得推广。

Isolation and characterization of bioactive fungi from shark Carcharodon carcharias' gill with biopharmaceutical prospects

Until recently, little was known about the fungi found in shark gills and their biomedicinal potential. In this article, we described the isolation, bioactivity, diversity, and secondary metabolites of bioactive fungi from the gill of a shark （Carcharodon carcharias）. A total of 115 isolates were obtained and grown in 12 culture media. Fifty-eight of these isolates demonstrated significant activity in four antimicrobial, pesticidal, and cytotoxic bioassay models. Four randomly selected bioactive isolates inhibited human cancer cell proliferation during re-screening. These active isolates were segregated into 6 genera using the internal transcribed spacer-large subunit （ITS-LSU） rDNA-sequence BLAST comparison. Four genera, Penicillium, Aspergillus, Mucor, and Chaetomium were the dominant taxa. A phylogenic tree illustrated their intergenera and intragenera genetic diversity. HPLC-DAD-HRMS analysis and subsequent database searching revealed that nine representative strains produced diverse bioactive compound profiles. These results detail the broad range of bioactive fimgi found in a shark＇s gills, revealing their biopharmaceutical potential. To the best of our knowledge, this is the first study characterizing shark gill fungi and their bioactivity.

Antibacterial activity of panipenem/betamipron in vitro and its pharmacokinetics and therapeutic efficacy in patients with pulmonary infection

Objective: To investigate the in vitro antimicrobial activity of panipenem/betamipron to common clinical isolates, determine its pharmacokinetics in patients with pulmonary infection and evaluate its effectiveness and safety in treatment of pulmonary infection. Methods: (1) The minimal inhibition concentrations of panipenem/betamipron were determined in 247 clinical isolates by agar dilution method. The minimal bactericidal concentrations of panipenem/betamipron for some clinical isolates were also determined. (2) Twenty cases of pulmonary infection were treated with intravenous dripping of panipenem/betamipron at 500/500 mg every 12 h for 3-7 d. Panipenem/betamipron concentration in the plasma was consecutively measured, and bacterial culture was conducted and the efficacy was evaluated. Results: (1) The in vitro antimicrobial activity of panipenem/betamipron was almost the same as that of panipenem, indicating that panipenem played the major role in antimicrobial reaction. Panipenem/betamipron had a strong antimicrobial activity against Staphylococcus aureus including methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, β-Streptococcus hemolytic, Streptococcus pneumonia, micrococcus, Escherichia coli and Klebsiea pneumonia. The drug also showed a potent effect against Haemophilus influenzae,Enterobacter cloacae, Proteus and Pseudomonas aeruginosa (2) The peak value of panipenem/betamipron in plasma was (30.25±5.43) mg/L and the level decreased to (0.66±0.34) mg/L 6 h later. The half-life of distribution and elimination of panipenem in the plasma was (0.34±0.18) h and (1.42±0.31) h, respectively. (3) The eradication rate of bacteria was 77.8% and the effective healing rate was 75%. No adverse drug reaction was found. Conclusion: Panipenem/betamipron has a strong antimicrobial activity against clinical isolates and is effective and safe for treatment of pulmonary infection.

Screening and Preservation of Douchi Fibrinolytic Enzyme Producing Strain

[Objective] To isolate and preserve a high-activity Douchi fibrinolytic enzyme producing strain from Douchi products. [Method] The Douchi flbrinolytic enzyme producing strain was screened on the selected medium prepared with self-made pork blood powder, the strain with the highest activity was screened out according to the size of hydrolysis cycle, and then preserved in LB medium. [ Rebait] A Douchi fibrinolytic enzyme producing strain with high thrombolytic activity was successfully screened out from the Douchi produced in Hunan, Guangdong and Jiangxi Prov- inces. [ Ceadusioe] The study lays foundation for the development of new-type thrombolytic drugs.

A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents

A series of naphthalimide azoles as potential antibacterial and antifungal agents were conveniently and efficiently synthesized starting from commercially available 6-bromobenzo[de]isochromene-l,3-dione. All the new compounds were characterized by NMR, IR, MS and HRMS spectra. Their antimicrobial activities were evaluated against four Gram-positive bacteria, four Gram-negative bacteria and two fungi using two-fold serial dilution technique. The biological assay indicated that most of the prepared compounds exhibited inhibition to the tested strains. In particular, the triazolium derivatives not only gave higher ef- ficacy than their corresponding precursory azoles, but also demonstrated comparable or even better potency than the reference drugs Chloromycin, Orbifloxacin and Fluconazole. Some factors including structural fragments, pH and ClogP values of the target molecules were also preliminarily discussed.