凤尾草对雷公藤甲素的减毒作用

目的:研究凤尾草对雷公藤甲素的减毒作用以及免疫抑制和抗炎镇痛活性的影响。方法:通过比较雷公藤甲素单用及与凤尾草联用对小鼠急性毒性、肝组织形态和大鼠肝功能的影响来评价凤尾草对雷公藤甲素的减毒作用;采用噻唑兰(MTT)法测定雷公藤甲素单用及与凤尾草联用对小鼠T、B淋巴细胞增殖的影响;采用二甲苯致小鼠耳廓肿胀实验研究凤尾草对雷公藤甲素抗炎作用的影响;采用热板法和扭体法研究凤尾草对雷公藤甲素镇痛作用的影响。结果:雷公藤甲素联用凤尾草后LD50增大了约1倍,肝细胞损伤明显减轻,ALT和AST明显降低;雷公藤甲素单用及与凤尾草联用均能显著抑制小鼠T、B淋巴细胞的增殖和二甲苯致小鼠耳廓肿胀,并均有明显的镇痛作用,但两者作用效果差异无显著性。结论:联合运用凤尾草可降低雷公藤甲素毒性并基本保持其免疫抑制和抗炎镇痛活性。     

雷公藤甲素抗类风湿性关节炎的分子机制概述

以雷公藤甲素为主要活性成分的多种雷公藤提取物在临床治疗类风湿性关节炎（RA）疗效确切，已得到广泛认可。为了有利于临床的合理应用和进一步开发，本复习了近十年来国内外的最新研究资料，从如下几方面对雷公藤甲素抗PLA作用的分子机制进行概述：     

雷公藤甲素对Caspase诱导人肝细胞L-02凋亡机制的研究

目的：研究雷公藤甲素诱导正常人肝细胞株L-02细胞凋亡的机制。方法：体外培养L-02细胞。MTT法检测雷公藤甲素的细胞毒性作用;Annexin V-FITC/PI双染法检测雷公藤甲素对L-02细胞的凋亡诱导作用;测定细胞基质中半胱天冬氨酸酶（Caspase）8、Caspase9与Caspase3活性的变化及加入Caspase抑制剂Z-DEVD-FMK后对细胞凋亡的影响。结果：雷公藤甲素能显著诱导L-02细胞的凋亡,其作用呈明显的量效关系与时间依赖性;120nmol·L-1雷公藤甲素作用L-02细胞24h使Caspase3的活性显著增强;加入Z-DEVD-FMK后,能有效抑制雷公藤甲素诱导的细胞凋亡。结论：雷公藤甲素体外诱导正常人肝细胞株L-02细胞凋亡可能与上调Caspase3、9的活性有关。     

雷公藤甲素对生殖系统毒性的研究进展

雷公藤甲素为雷公藤的主要活性成分之一,也是雷公藤片、雷公藤多苷片等制剂的主要有效成分。它具有抗炎、抗肿瘤、免疫调节等药理作用,是热点研究的天然活性化合物。但是,雷公藤甲素的副作用在很大程度上影响了其在临床上的应用,其中对生殖系统的毒性及抗生育作用尤为明显,特别是对雄性生殖系统的影响。综述了雷公藤甲素对男性睾丸、附睾和精子等,以及对女性生殖系统的损害及作用机制,并建议系统开展配伍减毒增效的研究,实现对配伍雷公藤甲素安全窗口的拓宽优化,为安全有效地应用于临床提供有力依据。     

雷公藤甲素脂质体制备及体内抗肿瘤实验研究

目的注入法制备雷公藤甲素脂质体,观察其形态特征和包封率,并对其体内抗H22疗效进行初步研究。方法用注入法制备雷公藤甲素脂质体,通过普通光学显微镜和动态光散色粒度分析仪测定其形态、粒径,用HPLC测定其包封率;并建立H22荷瘤模型观察其抗肿瘤活性。结果该法所得脂质体形态规则、粒度均匀,平均直径约为45.6 nm,但包封率不是很高约为46.7%;体内抗肿瘤实验结果表明,雷公藤甲素脂质体具有较强的抗H22活性,且与浓度呈正相关,而且相对“游离”雷公藤甲素毒性较小。结论雷公藤甲素脂质体具有较强的抗肿瘤活性,且不良反应较小。     

雷公藤甲素脂质体制备及体内抗肿瘤实验研究

目的注入法制备雷公藤甲素脂质体,观察其形态特征和包封率,并对其体内抗H22疗效进行初步研究。方法用注入法制备雷公藤甲素脂质体,通过普通光学显微镜和动态光散色粒度分析仪测定其形态、粒径,用HPLC测定其包封率;并建立H22荷瘤模型观察其抗肿瘤活性。结果该法所得脂质体形态规则、粒度均匀,平均直径约为45.6 nm,但包封率不是很高约为46.7%;体内抗肿瘤实验结果表明,雷公藤甲素脂质体具有较强的抗H22活性,且与浓度呈正相关,而且相对"游离"雷公藤甲素毒性较小。结论雷公藤甲素脂质体具有较强的抗肿瘤活性,且不良反应较小。     

雷公藤甲素对人肺腺癌A549细胞增殖和凋亡的影响

目的：研究雷公藤甲素对人肺腺癌‰细胞增殖和凋亡的影响。方法：采用MTT实验检测雷公藤甲素对体外培养的人肺腺癌A谢细胞增殖的影响，运用流式细胞术、基因组DNA电泳观察凋亡特征性“梯状”条带检测细胞凋亡，采用caspase活性定量检测试剂盒分析caspase-9，3的活化。结果：雷公藤甲素对体外培养的A谢细胞具有明显的抑制作用。流式细胞仪检测显示雷公藤甲素可以显著诱导‰细胞凋亡，DNA电泳显示雷公藤甲素作用于A谢细胞后出现凋亡细胞特有的DNA阶梯状条带。雷公藤甲素作用后‰细胞caspase-9，caspase-3活性明显升高。结论：雷公藤甲素可能通过线粒体信号通路抑制肺腺癌A谢细胞的生长并诱导其凋亡。     

雷公藤甲素提取分离工艺研究现状

雷公藤甲素属二萜类化合物,是雷公藤中具有抗炎、抗肿瘤和免疫抑制活性的有效部位。1972年文献首次报道雷公藤甲素、雷公藤乙素和雷公藤内酯酮具有明显抑制白血病瘤株L1210,P388的效果,此后国内外形成一股雷公藤甲素药理学、毒理学研究的高潮。但雷公藤甲素在雷公藤植物中的含量不高,传统的提取工艺比较复杂,因此对雷公藤甲素进行提取、分离、富集、精制的系统研究显得很有必要。本文对近年来较新的几种制备雷公藤甲素的方法进行了介绍,包括醇提氯仿萃取法、醇提氯仿萃取法、醇提乙酸乙酯萃取法、英国专利提取法等,希望通过对这些方法的研究获得好的思路,为雷公藤甲素的工业化生产提供简单、重复性好、可靠性高的最佳提取工艺。     

雷公藤甲素防治卵巢癌的作用机制研究进展

卵巢癌是第2大普遍存在的妇科恶性肿瘤,具有较高的死亡率。化疗是卵巢癌主要的治疗手段,但大多数患者会发生化疗耐药性。雷公藤甲素是从雷公藤中提取的天然活性二萜类化合物,具有多种药理活性。雷公藤甲素可以通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、降低卵巢癌侵袭力、降低卵巢癌对顺铂耐药性、调节卵巢癌细胞周期、增强抗肿瘤免疫应答、改变肿瘤微环境发挥多途径防治卵巢癌。归纳了雷公藤甲素防治卵巢癌的作用机制,为卵巢癌的临床治疗提供依据。     

雷公藤甲素对人肝细胞L-02肝药酶活性的影响

目的:研究雷公藤甲素对正常人肝细胞株L-02细胞的损伤作用及其对肝CYP3A及CYP2E1蛋白表达量的影响。方法:体外培养L-02细胞,MTT法检测雷公藤甲素对L-02细胞的损伤,试剂盒测定培养基上清液中AST、ALT及AKP活性,Western-blot测定细胞中CYP3A及CYP2E1蛋白的含量。结果:雷公藤甲素对L-02细胞有损伤作用,且随雷公藤甲素浓度的增加或孵育时间的延长,其损伤作用增强,同时,培养基中AST、ALT及AKP的活性增强;雷公藤甲素诱导细胞中CYP3A蛋白表达减弱,CYP2E1蛋白表达增强。结论:雷公藤甲素体外对人正常肝细胞L-02细胞有损伤作用,且能影响肝CYP450酶系的表达。     

Elucidation of anti-allergic activities of curcumin-related compounds with a special reference to their anti-oxidative activities

The anti-allergic and anti-oxidative activities of curcumin-related compounds (glycosides, reductants and bis-demethoxy analogs) were investigated to elucidate the underlying active mechanisms and structural features of curcumin in exerting these activities. The anti-allergic activities were assessed by measurement of histamine release from rat basophilic leukemia cells, RBL-2H3. Curcumin and tetrahydrocurcumin (THC) caused a marked decrease in histamine release. Glycosides of curcumin, bis-demethoxycurcumin and THC also inhibited the release of histamine, though less potently than curcumin did. The anti-oxidative activities were assessed by measurement of cell-free or cellular radical scavenging. All compounds but diglycosides or bis-demethoxycurcumin analogs distinctly exerted anti-oxidative effects. The relationship between both of these activities revealed that all compounds with potent radical scavenging activities caused a definite decrease in histamine release, but some compounds with non-potent radical scavenging activities also inhibited the histamine release. These results suggest that the hydroxy groups of curcumin play a significant role in exerting both the anti-oxidative and anti-allergic activities, and that most of the compounds develop the anti-allergic activities through mechanisms related to anti-oxidative activities, but some through mechanisms unrelated to anti-oxidation activity.     

土木香中纯化的五种倍半萜类化合物抑制肿瘤增殖活性的研究

目的检测土木香中纯化的五种倍半萜化合物抑制肿瘤增殖的活性,并探讨化合物结构与活性之间的关系。方法应用MTT法测定五种倍半萜类化合物对体外培养人肿瘤细胞增殖的影响;应用小鼠移植性肝癌模型测定了异土木香内酯的抗肿瘤活性。结果化合物1(异土木香内酯)对U251SP细胞、HLE细胞和MM1-CB细胞的增殖显示较强的抑制活性;化合物2～5对各种实验用肿瘤细胞的增殖不显示抑制活性;化合物1对移植性肿瘤(肝癌H22)具有明显的抑制作用,并呈现较好的剂量依赖关系。结论异土木香内酯具有较强的肿瘤抑制活性;化合物2～5对肿瘤细胞增殖抑制活性丧失可能由于A-环和B-环之间的键裂开,形成一个大10元环,改变了原来的构象所致。     

Relationships between plasma and tissue transaminase activities in rats maintained under different feeding conditions

In order to verify the nutritional aspect of alterations of the plasma and tissue transaminase activities, rats were fed 4 hr per day for 35 days (the spaced-fed (SF) rats) and the time course of the alterations in plasma and tissue transaminase activity was compared with those in the ad libitum fed (ALF) rats. Plasma transaminase activities were stable throughout the experiment period in the ALF rats. In the SF rats there were alterations in the plasma alanine aminotransferase (ALT) activities, the direction of which was different between the early phase and late phase of the experiment period; plasma ALT activities decreased in the early phase and gradually increased in the late phase. Plasma aspartate aminotransferase (AST) activities were stable in the SF rats throughout the experiment period as well as the ALF rats. The decreases in plasma ALT activities in the early phase were considered to be related to decreases in ALT activities in the small intestinal mucosa (SI mucosa). On the other hand, the increases in plasma ALT activities in the late phase were considered to be related to increases in ALT activities in the liver. Multiple regression analyses (MRAs) revealed that plasma ALT activities in the SF rats could be estimated by the ALT activities in the SI mucosa and liver. From these results, the alterations of the plasma ALT activities in the SF rats could be explained by those in the SI mucosa and liver under the conditions in our study.     

Daily fluctuation of hepatic P450 monooxygenase activities in male rats is controlled by the suprachiasmatic nucleus but remains unaffected by adrenal hormones

Hepatic P450 monooxygenase activities, which strongly influence the efficacy and/or toxicity of drugs, are known to fluctuate daily. We also know that the P450 activities assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities fluctuate daily, with apparently high values during the dark period in male rats. However, there is little knowledge about the factors that regulate daily fluctuation of P450 monooxygenase activities. In the present study using rats, we induced lesions in the suprachiasmatic nucleus (SCN) of the brain, the known site of the body's internal clock, and examined the effects on the daily fluctuation of the ACD activities to clarify the relationship between the SCN and the daily fluctuation of P450 monooxygenase activities. In addition, adrenalectomy was performed to re-evaluate the influence of adrenal hormones on the P450 activities. Our results indicated that daily fluctuations of the hepatic ACD activities were completely eliminated in the SCN-lesioned rats. However, the ACD activities in the adrenalectomized rats showed apparent daily fluctuations with high values during the dark period and low values during the light period. Therefore, this study demonstrated that the daily fluctuation of the hepatic P450 monooxygenase activities in male rats is controlled by the SCN but remains unaffected by the adrenal hormones. Received: 11 May 1999 / Accepted: 19 July 1999     

Daily fluctuation of 7-alkoxycoumarin O-dealkylase activities in the liver of male F344 rats under ad libitum-feeding or fasting condition.

It has been reported that drug metabolizing enzyme activities in the liver fluctuate daily, though the daily fluctuation of 7-alkoxycoumarin O-dealkylase (ACD) activities catalyzed by P450 has not been examined. The ACD activities are known to be useful to clarify the extensive induction of P450-dependent oxygenases. In the present study, the hepatic ACD activities, as well as P450 content, were investigated periodically in male F344 rats under ad libitum-feeding or fasting condition. The ACD activities in ad libitum-fed rats were found to follow obvious daily fluctuations with high values during dark periods and with low values during light periods. This agreed with the other previous results of drug metabolizing enzyme activities measured with other substrates. Because the daily fluctuation was also observed in fasted rats, the fluctuation in ACD activities was clearly not affected by feeding, an external factor. P450 content, however, showed different fluctuation patterns from the ACD activities. This suggests that the fluctuation of ACD activities might not be related to the quantitative variation of P450 proteins.     

Synergistic action of cefodizime and other antimicrobial agents on clinically isolated microorganisms. III. Synergistic action with gentamicin]

An in vitro investigation was done on antimicrobial activities of cefodizime (CDZM) in combination with gentamicin (GM) against clinically isolated Gram-negative rods. The results are summarized as follows. 1. Combined antimicrobial activities were dependent on antimicrobial activities of GM, similar to the CDZM + sisomicin (SISO) combination. The combined activities were concentration dependent, and they were more strongly dependent on GM concentrations than on CDZM concentrations. The obtained results suggested that synergistic or cooperative antimicrobial activities of the combination would be expected when GM concentrations in blood are at or somewhat lower than 1 MIC, and clinical activities would be exerted regardless of the presence of CDZM resistant organisms, similarly to CDZM+SISO combination. 2. It seems possible that, with regard to combinations of beta-lactam antibiotics and aminoglycoside antibiotics, there exist universal rules that combined activities are dependent on activities of aminoglycoside antibiotics, and that stronger concentration dependencies on aminoglycosides would be observed than those on beta-lactams.     

Microsomal lauric acid hydroxylase activities after treatment of rats with three classical cytochrome P450 inducers and peroxisome proliferating compounds.

In order to investigate a proposed relationship between induction of hepatic microsomal lauric acid hydroxylase activity and peroxisome proliferation in the liver, male Wistar rats were treated with peroxisome proliferating compounds, and the lauric acid hydroxylase activity, the immunochemical detectable levels of cytochrome P450 4A1 and the activities of peroxisomal enzymes were determined. In addition, the levels of cytochrome P450 4A1 and lauric acid hydroxylase activities were studied after treatment of rats with three cytochrome P450 inducers. After treatment with aroclor-1254, phenobarbital or 3-methylcholanthrene total cytochrome P450 was 1.7-2.7 times induced. However, no induction of lauric acid omega-hydroxylase activities or P450 4A1 levels were found. After treatment of rats with di(2-ethylhexyl)phthalate (DEHP) a dose-dependent induction of lauric acid omega-hydroxylase activities, levels of cytochrome P450 4A1 and peroxisomal fatty acid beta-oxidation was found. Even at a dose-level of 100 mg DEPH/kg body weight per day a significant induction of these activities was observed. The main metabolites of DEHP, mono(2-ethylhexyl)phthalate and 2-ethyl-1-hexanol, also caused an induction of levels of P450 4A1, lauric acid omega-hydroxylase activities and the activity of peroxisomal palmitoyl-CoA oxidase. 2-Ethyl-1-hexanoic acid did not influence lauric acid omega-hydroxylase activities, but did induce levels of P450 4A1 and palmitoyl-CoA oxidase activities. Three other compounds (perfluoro-octanoic acid, valproate and nafenopin) induced both lauric acid omega-hydroxylase activity and peroxisomal palmitoyl-CoA oxidase activity. The plasticizer, di(2-ethylhexyl)adipate, did not induce levels of P450 4A1, lauric acid omega-hydroxylase activities or palmitoyl-CoA oxidase activities. With the compounds tested a close association between the induction of lauric acid omega-hydroxylase activities and peroxisomal palmitoyl-CoA oxidase activity was found. These data support the theory that peroxisome proliferating compounds do induce lauric acid omega-hydroxylase activities and that there might be a mechanistic inter-relationship between peroxisome proliferation and induction of lauric acid omega-hydroxylase activities.     

阿司匹林衍生物药理活性研究概述

阿司匹林具有多种药理活性,是老药新用的典型药物之一。近年来,人们为开发阿司匹林,对其结构进行修饰及改造,以期得到副作用更小、活性更好的衍生物。本文总结了30种阿司匹林衍生物的合成路线及药理活性。其药理活性主要集中在解热镇痛、抗炎、抗骨质疏松、防治心脑血管疾病及抗肿瘤活性等方面,可为相关研究和应用提供参考。     

Neonatal exposure to Aroclor 1254: effects on adult hepatic testosterone hydroxylase activities

1. The effects of neonatal exposure to Aroclor 1254 (100 mumol/kg) on the metabolism of testosterone by adult male and female rats were determined by comparing their hepatic microsomal testosterone hydroxylase activities at 60, 90 and 120 days after the initial exposure. 2. The most pronounced effects in male rats were observed 90 days after treatment with Aroclor 1254, whereas in female rats the major changes in testosterone hydroxylase activities were observed after 60 days. 3. Ninety-day-old male rats neonatally treated with Aroclor 1254 exhibited decreased basal testosterone 7 alpha-hydroxylase and increased basal testosterone 16 alpha-, 2 alpha- and 15 beta-hydroxylase activities and androstenedione formation. In addition, the Aroclor 1254-mediated induction of testosterone 7 alpha- and 6 alpha-hydroxylase activities and androstenedione formation was decreased, and that of testosterone 2 beta- and 15 beta-hydroxylase activities was increased. 4. Sixty-day-old female rats exposed neonatally to Aroclor 1254 exhibited increased basal testosterone 16 alpha-, 2 beta-, 6 alpha- and 15 beta-hydroxylase activities and androstenedione formation, and increased Aroclor 1254-induced metabolism of testosterone at all positions except 16 alpha and 2 alpha. 5. Changes in testosterone hydroxylase activities indicative of permanent damage (or imprinting) in androgen metabolism, i.e. altered activities in 120-day-old animals, were observed only in male rats. These activities included basal testosterone 6 beta-, 16 alpha- and 2 alpha-hydroxylase activities and androstenedione formation.