Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure

Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC₅₀ 1–50 μm ) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC₅₀ 10–200 μm ). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC₅₀ 10–30 μm ). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.     

腰痛宁胶囊治疗寒湿瘀阻型坐骨神经痛临床疗效观察

目的以安慰剂为对照评价腰痛宁胶囊治疗坐骨神经痛(寒湿瘀阻证)的临床有效性及安全性。方法对2008年10月—2009年5月符合试验纳入标准的144例坐骨神经痛患者采用随机双盲安慰剂对照试验进行研究。随机分为两组,治疗组(腰痛宁胶囊组)72例,对照组(腰痛宁胶囊安慰剂组)72例;治疗方法:两组患者分别服用相应药物,每次5粒,黄酒兑少量温开水送服,每日1次,睡前半小时服。连续用药14 d为1个疗程。结果入选受试者144例,主要疗效指标治疗组疾病控显率明显优于对照组(U=4.138,P0.001);疼痛改善方面:治疗组的疾病(中医证候)控显率明显优于对照组(U=6.330,P0.001)。安全性评价方面:试验过程中无不良事件发生;其他生命体征、实验室及辅助检查项目的组间差异无统计学意义。结论腰痛宁胶囊治疗坐骨神经痛(寒湿瘀阻证)具有较好的疗效,明显优于安慰剂,试验期间未发现严重不良反应,安全性较好。     

基于肝细胞毒价检测的雷公藤质量评价方法研究

目的建立基于肝细胞毒价检测的雷公藤药材质量评价方法。方法以正常人肝细胞(L02细胞系)为研究载体,以细胞抑制率为检测指标,优化建立肝细胞毒价检测方法 ,评价不同产地雷公藤及其地方习用品昆明山海棠药材的质量。结果以对乙酰氨基酚(毒价定义为400 U/g)为阳性对照品,50%乙醇超声提取雷公藤后真空干燥为干膏,用培养基配制生药量3 mg/m L的供试液,稀释比1∶0.65,量反应平行线法检测,18份雷公藤样品肝细胞毒价17.78~4 131.4 U/g(相差超过200倍),5份昆明山海棠样品肝细胞毒价209.42~7 422.2 U/g(相差超过30倍),不同产地雷公藤及昆明山海棠药材的肝细胞毒价差异显著;并且所检测样品鲜品较市售干品毒性大。结论初步建立了基于肝细胞毒价检测的雷公藤质量评价方法 ,直接关联其临床肝脏毒副反应,对从质量控制角度提高雷公藤临床用药安全具有参考价值,也为雷公藤肝毒性成分筛选提供准确定量的方法 。     

基于胃寒证模型的吴茱萸挥发油功效及伴随毒副作用研究

目的 :对吴茱萸挥发油在胃寒证小鼠模型上镇痛作用的药效剂量范围及机制进行初步研究,并探讨其伴随毒性与氧化损伤机制的相关性,为阐明其"功效-证候-毒性"相关性提供实验依据。 方法 :制备胃寒证小鼠模型,采用经典的小鼠热板法,灌胃不同剂量吴茱萸挥发油,观察其镇痛及伴随毒副作用,检测血清ALT,AST,PGE₂,NO,NOS,MDA,SOD,GSH,GSH-Px,BUN,CR及肝脏ALT,AST;并通过相关的毒性反应积分表,记录小鼠的伴随毒性症状。 结果 :吴茱萸挥发油在给药后30 min有明显的镇痛作用,60 min达到峰效应,呈现一定的"量-效"和"时-效"关系,血中和肝内ALT和AST水平升高,血中PGE₂,MDA,NO,NOS水平增高,SOD,GSH,GSH-Px水平下降,BUN,CR水平无明显变化,肝脏指数增加,肾脏比值无明显变化。 结论 :吴茱萸挥发油发挥镇痛效应的机制与抑制疼痛介质释放、过氧化损伤及NO损伤有关;在发挥镇痛效果的同时还会伴随着对肝脏产生一定的毒性,毒性机制主要为氧化损伤,呈现与肝毒性损伤相并行的"量-时-毒"关系。     

乌鲁木齐市住宅室内潮湿表征与儿童哮喘及过敏性疾病的相关性

[目的]研究乌鲁木齐市儿童哮喘及过敏性疾病与住宅室内潮湿的关系,为进一步提出有效预防儿童哮喘及过敏性疾病的措施提供科学依据。[方法]2011年10—12月,采取多阶段整群抽样的方法,对乌鲁木齐市7个行政区的5 650名1~8岁儿童进行问卷调查。调查问卷包括基本信息,儿童及家长的健康情况,住宅和建筑特征以及室内潮湿表征4个部分。应用卡方检验和非条件logistic回归方法估计室内潮湿表征与儿童哮喘及过敏性疾病的关联。[结果]有效问卷共4 618份,应答率81.7%,男童占53.7%。共有20.8%的住户报告"窗户凝结水",其次是"水损"(15.1%),"湿斑"(14.1%)和"霉点"(8.6%)。在所调查的疾病中,46.4%的儿童报告曾经出现鼻炎;近12个月里,42.7%的儿童出现鼻炎,25.3%出现喘息;医生诊断哮喘和鼻炎的报告率分别为3.7%和8.7%。室内潮湿与儿童哮喘及过敏性疾病显著相关,其中,"湿斑"与近12个月喘息症状显著相关[OR=1.57;95%置信区间(CI):1.27~1.95];"霉点"与医生诊断哮喘(OR=2.18;95%CI:1.30~3.67);"窗户凝结水"(OR=1.62;95%CI:1.09~2.40)和"水损"(OR=1.93;95%CI:1.35~2.76)与近12个月湿疹等均呈现正相关;且近12个月里出现的喘息、鼻炎和湿疹症状,其OR值随着潮湿表征评分的升高而增大。[结论]乌鲁木齐市住宅室内潮湿可能是儿童哮喘及过敏性疾病的潜在危险因素。     

Toxic optic neuropathies: an updated review

Toxic optic neuropathy (TON) is caused by the damage to the optic nerve through different toxins, including drugs, metals, organic solvents, methanol and carbon dioxide. A similar clinical picture may also be caused by nutritional deficits, including B vitamins, folic acid and proteins with sulphur‐containing amino acids. This review summarizes the present knowledge on disease‐causing factors, clinical presentation, diagnostics and treatment in TON. It discusses in detail known and hypothesized relations between drugs, including tuberculostatic drugs, antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfiram, halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodiesterase type 5 inhibitors and optic neuropathy.     

Acute toxicity of 50 metals to Daphnia magna

Metals are essential for human life and physiological functions but may sometimes cause disorders. Therefore, we conducted acute toxicity testing of 50 metals in Daphnia magna: EC50s of seven elements (Be, Cu, Ag, Cd, Os, Au and Hg) were < 100 µg l^?1; EC50s of 13 elements (Al, Sc, Cr, Co, Ni, Zn, Se, Rb, Y, Rh, Pt, Tl and Pb) were between 100 and 1000 µg l^?1; EC50s of 14 elements (Li, V, Mn, Fe, Ge, As, In, Sn, Sb, Te, Cs, Ba, W and Ir) were between 1,001 and 100,000 µg l^?1; EC50s of six elements (Na, Mg, K, Ca, Sr and Mo) were > 100,000 µg l^?1; and. 7 elements (Ti, Zr, Bi, Nb, Hf, Re and Ta) did not show EC50 at the upper limit of respective aqueous solubility, and EC50s were not obtained. Ga, Ru and Pd adhered to the body of D. magna and physically retarded the movement of D. magna. These metals formed hydroxides after adjusting the pH. Therefore, here, we distinguished this physical effect from the physiological toxic effect. The acute toxicity results of 40 elements obtained in this study were not correlated with electronegativity. Similarly, the acute toxicity results of metals including the rare metals were also not correlated with first ionization energy, atomic weight, atomic number, covalent radius, atomic radius or ionic radius. Copyright © 2014 John Wiley & Sons, Ltd.     

Optimal adjuvant therapy for resected hepatocellular carcinoma: a systematic review with network meta-analysis

Objectives

Major adjuvant therapies (ATs) for resected hepatocellular carcinoma (HCC) include chemotherapy, internal radiation therapy (IRT), interferon therapy (IFNT) and immunotherapy but the optimum regimen remains inconclusive. We aim to compare these therapies in terms of patient survival and recurrence rates.

Methods

We searched PubMed, EMBASE and Cochrane library databases for randomized trials comparing the above four therapies until 31 March 2014. We estimated the HRs for survival and ORs for overall recurrence among different therapies. Toxic effects were also evaluated.

Results

Fourteen eligible articles were included. IFNT improved 5-year survival greatly (HR 1.81, 95% CI 1.01–3.81, P = 0.034), whereas chemotherapy (HR 0.33, 95% CI 0.03–2.02), IRT (HR 0.31, 95% CI 0.02–3.33) and immunotherapy (HR 0.73, 95% CI 0.05–9.12) all provided a poorer survival outcome after 1-year. Similarly, for 5-year survival rates, although differing, IRT did not provide a significant improvement in survival (HR 1.38, 95% CI 0.34–5.19) compared with IFNT. Chemotherapy (HR 0.49, 95% CI 0.18–1.14) and immunotherapy (HR 0.56, 95% CI 0.17–1.59) did not appear to provide benefit over IFNT. Chemotherapy was ranked the worst in overall recurrence (OR 0.99, 95% CI 0.18–5.38) and most likely to cause toxic effects.

Conclusions

IFNT was the most efficacious AT regimen both for short and long term survivals. Immunotherapy and IFNT were the most two effective in preventing overall relapse for resected HCC.