Synergistic interaction of diclofenac,benfotiamine, and resveratrol in experimental acute pain

This study was designed to evaluate the possible synergistic antinociceptive interactions between diclofenac, benfotiamine, and resveratrol on acetic acid‐induced nociception in mice. Isobolographic analyses were used to define the nature of the interactions between drugs. Diclofenac, benfotiamine, or resveratrol, as well as their combinations, produced a dose‐dependent antinociceptive effect. ED₃₀ values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED₃₀ values for the combinations estimated from the isobolograms were 170.9±23.4, 4.9±1.0, and 173.3±11.8 mg/kg for the diclofenac+benfotiamine, diclofenac+resveratrol, or benfotiamine+resveratrol combination, respectively. These values were significantly higher than the actually observed ED₃₀ values, which were 10.2±1.9, 0.3±0.1, and 5.3±0.8 mg/kg, respectively, indicating a synergistic interaction in the three combinations. Data indicate that low doses of the diclofenac+benfotiamine, diclofenac+resveratrol, or benfotiamine+resveratrol combination can interact synergistically to reverse acetic acid‐induced nociception and they may represent a therapeutic advantage for clinical treatment of inflammatory pain. Drug Dev Res 72: 397–404, 2011. © 2011 Wiley‐Liss, Inc.     

迷迭香中鼠尾草酸的抗MRSA活性研究

目的对迷迭香中鼠尾草酸的抗MRSA(耐甲氧西林金黄色葡萄球菌)活性进行研究。方法采用硅胶柱层析法对迷迭香提取物(鼠尾草酸含量72.4%)进行分离精制获得鼠尾草酸,然后以标准菌株MRSA ATCC 33592和临床分离菌株MRSA 01~08为指示菌,采用微量肉汤稀释法测定鼠尾草酸对MRSA菌株的最低抑菌浓度和最低杀菌浓度;运用棋盘格法设计试验,采用微量肉汤稀释法,分别测定鼠尾草酸与苯唑西林钠或氨苄西林钠的联合抗MRSA作用。结果分离精制获得含量为98.6%的鼠尾草酸,其对指示菌MRSAATCC33592和MRSA 01~08的最低抑菌浓度的范围为8~16μg.mL 1,最低杀菌浓度均为32μg.mL 1;与苯唑西林钠或氨苄西林钠合用对MRSA指示菌的部分抑菌浓度指数(FICIs):0.5≤FICIs<1.0。结论鼠尾草酸具有明显的抗MRSA活性,与苯唑西林钠或氨苄西林钠合用时呈现抗MRSA的相加或协同作用。     

海桐皮汤治疗骨性关节炎的化学空间及多靶点效应分析

目的：从化学空间角度探讨海桐皮汤治疗骨性关节炎的多靶点作用。方法：运用计算机方法对海桐皮汤中分子组成的数据库及药物分子／类药分子数据库进行化学空间分析,对一些特征描述符的分布进行了描述,同时采用主成分分析方法将多维化学空间映射到二维空间以得到更直观的图像。结果：海桐皮汤中分子有良好的多样性,既有类药性质,也是天然产物化合物的一个特殊的子集。结论：本方法直观地揭示了复方海桐皮汤的多靶点效应,对于解释复方的协同效应有重要意义。     

Conceptual importance of identifying alcoholic liver disease as a lifestyle disease

The concept that alcoholic liver disease (ALD) is as a toxic disease does not mirror the exact nature of the disease. ALD should be defined as an alcohol-associated lifestyle disease, the predisposition to which is largely governed by gene–environment interactions, much like other chronic diseases such as diabetes, atherosclerosis, and neurodegenerative diseases. The epidemiology and pathogenesis of ALD need to be re-addressed from this viewpoint. Specifically, the interactions between alcohol and secondary risk factors (high-fat diet, iron, tobacco, medications, female gender) and comorbidities (viral hepatitis, diabetes) are of urgent epidemiological importance. Molecular characterization of the interfaces of these interactions is essential for revelation or acquisition of new pathogenetic, preventive, and therapeutic insights.     

Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat

The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter's reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.     

羟基喜树碱联合奥沙利铂诱导人大肠癌耐药细胞株LoVo/5-FU的凋亡机制

目的:体外观察羟基喜树碱(HCPT)联合奥沙利铂(L-OHP)对人大肠癌耐药细胞株LoVo/5-FU增殖抑制及诱导凋亡作用,并初步探讨其诱导凋亡方面机制.方法:MTT法测定HCPT联合L-OHP对LoVo/5-FU细胞增殖抑制作用,并根据中效原理判断两药合用时的效应.流式细胞仪观察两药对LoVo/5-FU细胞的凋亡诱导作用.半定量RT-PCR方法检测单药及联合作用后X染色体连锁的凋亡抑制蛋白(XIAP) mRNA表达变化.结果:HCPT联合L-OHP对LoVo/5-FU细胞有明显的抑制增殖作用,细胞增殖的抑制率与药物浓度呈正相关.在抑制率(fa)>0.18时合用指数(CI)<1,两药表现为协同作用.HCPT浓度分别为0.02、0.04和0.08 mg/L.作用48 h后,LoVo/5-FU细胞凋亡率分别为5.92±0.58、9.93±0.62和3.76±0.45.当0.04 mg/L HCPT联合L-OHP作用48 h后,其凋亡率为18.44±0.57,联合组与单药组比较差异有统计学意义,P<0.05.耐药细胞LoVo/5-FU较亲本细胞LoVo高表达XIAP mRNA(0.88±0.03 vs 0.11±0.02,P<0.01),两药联合作用后XIAP mRNA降低明显为0.21±0.03,P<0.01.结论:HCPT联合L-OHP能够协同抑制LoVo/5-FU细胞增殖,其机制可能与诱导细胞凋亡有关,抑制XIAP表达发挥作用.     

人支气管上皮细胞5-脂氧合酶介导4-氨基联苯的活化及DNA损伤

目的探讨人支气管上皮(HBE)细胞内5-脂氧合酶(5-LOX)对4-氨基联苯(4-ABP)的氧化活化及所致DNA损伤,为LOX作为前致癌物氧化活化的代谢途径提供依据。方法①体外酶系统实验:4-ABP在含有大豆脂氧合酶(SLO)的体外酶体系中反应,用分光光度法检测体系中反应产物生成。②细胞实验:4-ABP 100～800μmol.L-1染毒HBE细胞,MTT法检测HBE细胞存活率;Western印迹法检测5-LOX蛋白表达;单细胞凝胶电泳检测DNA损伤。同时,检测特异性5-LOX抑制剂AA861对5-LOX蛋白表达和多种酶抑制剂对细胞存活率和DNA损伤的影响。结果在过氧化氢参与下,SLO可以协同氧化4-ABP,LOX抑制剂去甲二氢愈创木酸可抑制该协同氧化作用。4-ABP可以使HBE细胞内5-LOX蛋白表达增加,AA861对5-LOX蛋白表达没有影响;4-ABP 400μmol.L-1可以使HBE细胞产生明显的DNA损伤,彗星细胞的阳性率达47.7%(P<0.01),AA861和萘普生可以抑制该浓度4-ABP所致的DNA损伤,最大保护率分别为58.1%和21.7%。结论 4-ABP上调HBE的5-LOX蛋白表达。5-LOX可能通过介导4-ABP协同氧化,导致DNA损伤,这可能是4-ABP致癌的机制之一。     

Protective role of tea polyphenols in combination against radiation-induced haematopoietic and biochemical alterations in mice

The purpose of this study was to investigate the radioprotective effects of tea polyphenols (TPs) in various combinations against radiation‐induced damage in mice. Mice were divided into different groups: non‐irradiated control, irradiated control, amifostine (43.6 mg/kg, i.v. 30 min before irradiation; positive control) and various combinations of tea polyphenols in different doses. The radioprotective effect on the haematopoietic system, serum cytokines and endogenous antioxidant enzymes were studied. TP50, containing approximately 50% of (‐)‐epigallochatechin‐3‐gallate in addition to other catechins, showed the greatest radioprotective effect against radiation‐induced changes in haematological parameters (red blood cell count, white blood cell count and haemoglobin), and maintained the spleen and thymus indices unchanged (spleen or thymus weight/body weight × 1000). Tea polyphenols also significantly decreased radiation‐induced lipid peroxidation (malondialdehyde levels), elevated endogenous antioxidant enzymes (superoxide dismutase) and reduced the serum cytokines which were elevated in radiation‐induced toxicity. This evidence shows the potential of tea polyphenols, particularly in the combination found in TP50, as radioprotectors in mice, especially regarding recovery of the haematopoietic system, antioxidant potential activity and reduction of inflammatory cytokines. Copyright © 2011 John Wiley & Sons, Ltd.     

柘树黄酮体内外抗肿瘤作用研究

目的评价柘树黄酮的抗肿瘤活性。方法采用甲基噻唑基四唑比色法体外检测柘树黄酮对15种肿瘤细胞株的生长抑制作用;建立B16黑色素瘤小鼠肿瘤模型和SKOV-3卵巢癌裸小鼠移植瘤模型,评价柘树黄酮的体内抗肿瘤活性：建立S180肉瘤小鼠肿瘤模型,考察柘树黄酮与环磷酰胺、顺铂及5-氟尿嘧啶等化疗药物的协同作用。结果柘树黄酮对人胃癌细胞（BGC-823）株、人肺癌细胞（A549）株及小鼠淋巴细胞白血病细胞（L1210）株较敏感,半数抑制浓度（IC50）分别为611、12．20和12．73ug／mL,对其他12种细胞株的细胞毒作用较小。体内试验表明,柘树黄酮能有效抑制B16黑色素瘤（250mg／kg时抑瘤率为50．54％）,并对SKOV-3卵巢癌裸小鼠移植肿瘤的生长有很好的抑制作用（250mg／kg时抑瘤率为46．38％）;柘树黄酮与化疗药物有明显的协同作用。结论体内体外试验均表明柘树黄酮有较好的抗肿瘤作用,并且与环磷酰胺、顺铂及5-氟尿嘧啶等化疗药物具有协同效应。     

Lethal interaction between heat and methylene blue in Escherichia coli

Hyperthermia treatment is shown to act synergistically with methylene blue (MB), from the end point of lethality in Gram-negative Escherichia coli bacteria. That this lethality is correlated to the damage produced in DNA by the dye is deduced from the fact that bacteria differing in capacity for repair are almost equally sensitive to heat, but differ considerably in sensitivity to concomitant heat and dye treatment. It is demonstrated that the damage is repairable by the excision-repair system. The role of temperature seems to be that of facilitating the incorporation of the dye, which enables the latter to intercalate into the DNA. Ability of the outer membrane of E. coli AB1157 bacteria to act as a barrier to the penetration of MB remains almost intact up to 46°C, but above this temperature it seems to disrupt abruptly (but reversibly), leading to inactivation of the cells by the dye. Since hyperthermia is in current use for the treatment of cancer, it is suggested that if this synergism also exists in mammalian cells, MB could eventually be used independently of its photodynamic action as an adjuvant in cancer therapy.