紫花牡荆素药理作用的研究进展

 紫花牡荆素,即5,3'-二羟基-3,6,7,4'-四甲氧基黄酮（5, 3′-dihydroxy-3, 6, 7, 4′-tetram thoxyflavone;casticin,CAS）,是一种从蔓荆子（Vitex trifolia L）中提取的具有广泛药理活性的多甲基黄酮类化合物,是蔓荆子的主要成分,其药理作用近年来成为研究热点。CAS通过抑制细胞信号通路,阻滞细胞有丝分裂,激活细胞凋亡通路,阻滞周期相关蛋白等途径使肿瘤细胞阻滞在G2/M期,进而引起细胞凋亡发挥其抗肿瘤作用;CAS阻滞组胺释放发挥其抗炎作用;CAS直接作用于脑垂体,引起催乳素抑制因子分泌增多而降低血清催乳素水平;CAS可以清除体内的氧自由基而发挥抗氧化作用。文中对CAS的药理作用进行综述。     

颈动脉粥样硬化斑块的高分辨MRI与超声成像特征

目的 探讨高分辨MRI和超声成像诊断动脉粥样硬化斑块的价值.方法 24例拟诊颈动脉粥样硬化患者同时行高分辨MRI及超声成像检查.结果 24例中,共发现17例25个颈动脉粥样硬化斑块.MRI清晰显示17例患者的25处颈动脉粥样硬化病变:劲总动脉6处,颈动脉分叉14处,颈内动脉5处;且MRI在19处复杂斑块的成分显示中,可明确显示钙化、脂质核心、纤维帽及出血.超声成像检出17例患者的23处颈动脉粥样硬化:软斑块13例,硬斑块4例.超声成像对于显示贴壁小斑块较MRI清晰.结论 高分辨MRI与超声成像诊断颈动脉粥样硬化斑块各具优势,超声易于检出早期小斑块,MRI对斑块成分及活动性判定优于超声成像,两者联合应用有助于颈动脉粥样硬化斑块的诊断及稳定性评估.     

基于网络药理学探索复方生地合剂治疗系统性红斑狼疮的作用机制

目的：利用网络药理学研究复方生地合剂治疗系统性红斑狼疮的关键靶标和潜在分子机制。方法：通过中国科学院化学数据库和文献搜索构建药材化合物成分数据库,以分子类药性DL、口服生物利用度OB、Lipinski规则和Veber规则筛选活性化合物,并以TCMSP和STITCH数据库预测活性成分靶点,GeneCards、TTD数据库获取系统性红斑狼疮相关靶点,两者相互映射得到复方生地合剂作用系统性红斑狼疮的交集靶点,STRING数据库构建蛋白质相互作用网络,DAVID数据库进行GO和KEGG分析,Cytoscape 3.7.1软件构建成分-靶点-通路网络,分析主要通路。结果：经筛选共获得复方生地合剂20个活性成分,对应285个靶点,46个为交集靶点,复方生地合剂的潜在活性成分为槲皮素、木犀草素等12个化合物,治疗关键靶点有肿瘤坏死因子、白介素6、白介素2等,主要作用于6条通路。结论：复方生地合剂可能通过细胞因子-细胞因子受体相互作用、丝裂原活化蛋白激酶信号通路等途径和基因表达、炎症反应、RNA聚合酶II启动子转录的正调控等生物过程发挥作用。     

Suppressive effects of peptide antibiotics against proliferation and cytokine production in mitogen-activated human peripheral-blood mononuclear cells

Certain kinds of peptide antibiotics are suggested to have immunomodulatory effects; however, few studies have been carried out systemically to evaluate the antiproliferative effects of peptide antibiotics in human lymphoid cells. The suppressive efficacies of nine peptide antibiotics and seven non-antibiotic peptides against proliferation of human peripheral-blood mononuclear cells (PBMCs) stimulated with T cell mitogen were examined in vitro. Nigericin (CAS 28643-80-3), valinomycin (CAS 2001-95-8), gramicidin D (CAS 1405-97-6), and tyrothricin (CAS 1404-88-2) strongly inhibited the proliferation of concanavalin A-stimulated PBMCs with IC50 values of 0.15-11.2 ng/ml, while these antibiotics did not show cytotoxicity at 10 000 ng/ml. The IC50 value of the immunosuppressant cyclosporine (CAS 59865-13-3) was 5.2 ng/ml. Virginiamycin (CAS 11006-76-1) and gramicidin S (CAS 113-73-5) moderately inhibited PBMC-proliferation with IC50 values of 1000 and 1900 ng/ml, respectively. On the other hand, bacitracin (CAS 1405-87-4), capreomycin (CAS 11003-38-6), polymyxin B (1404-26-8), angiotensin II antipeptide (CAS 121379-63-3), angiotensin III antipeptide (CAS 133605-55-7), fibrinogen binding inhibitor peptide (CAS 89105-94-2), LH-RH (CAS 71447-49-9), pepstatin A (CAS 26305-03-3), oxytocin (CAS 50-56-6), and vasopressin (CAS 16679-58-6) showed little or no suppressive effect on PBMC-proliferation. Nigericin and valinomycin decreased the concentrations of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and IL-17 in the culture medium with IC50 values less than 0.01 ng/ml. Nigericin also decreased the concentrations of IL-4 and IL-6 with IC50 values of less than 1 ng/ml. The results show that peptide antibiotics such as nigericin and valinomycin efficiently suppress the production of several cytokines and proliferation in mitogen-stimulated human PBMCs.     

CAS 936, a novel syndnonimine with direct vasodilating and nitric oxide-donating properties: effects on isolated blood vessels.

Organic nitrates and sydnonimines exert their vasorelaxant activity by a common mechanism of action, i.e., release of nitric oxide (NO) and stimulation of the soluble guanylate cyclase of vascular smooth muscle cells. We wished to investigate the vasodilating activity of the novel sydnonimine CAS 936 in guinea pig isolated pulmonary arteries without endothelium. CAS 936 had no effect on contractions induced by norepinephrine (NE) or by the PGF2 alpha-analogue U46 619, but induced a longlasting relaxation of potassium depolarized arteries and of A23 187-contracted vessels. This effect was concentration-dependent (IC50 approximately 16 microM). Oxyhemoglobin and methylene blue had no inhibitory effect on CAS 936, whereas they inhibited the relaxations induced by SIN-1, a sydnonimine which acts by releasing NO. These results suggest that the vasodilating activity of CAS 936 is not related to NO. On the other hand, in vivo metabolites of CAS 936 inhibited NE- and U46 619-induced contractions. Oxyhemoglobin inhibited this effect. Therefore, we conclude that the CAS 936 molecule possesses a vasodilating activity of its own, whereas the metabolites may function as NO donors. The primary target of the intrinsic vasodilating activity of CAS 936 is very likely the vascular smooth muscle cell membrane. To determine which mechanism of action (NO unrelated or NO related) contributes mainly to the in vivo effects of CAS 936, studies of the metabolic fate of CAS 936 may be crucial.     

Prediction of the efficacy of cutaneously applied nonsteroidal anti-inflammatory drugs from a lipophilic vehicle

The maximum cutaneous fluxes of 12 nonsteroidal anti-inflammatory drugs (NSAIDs), determined in a preceding study from the lipophilic vehicle light mineral oil in vivo on 24 healthy volunteers, were related to data concerning their intrinsic activities. From the multiplication of the relative intrinsic activities with the relative maximum fluxes, both related to indometacin (CAS 53-86-1) as standard, the percutaneous activities result as parameters for the prediction of the efficacy of cutaneous preparations with NSAIDs. According to the results of the calculations, the percutaneous activities of ibuprofen (CAS 15687-27-1) and nabumetone (CAS 42924-53-8) from lipophilic vehicles are remarkable because of their very high maximum fluxes. NSAIDs with still high percutaneous activities are ketoprofen (CAS 22071-15-4), naproxen (CAS 22204-53-1), piroxicam (CAS 36322-90-4) and diclofenac (CAS 15307-86-5). In contrast, the systemically highly effective NSAIDs indometacin and acemetacin (CAS 53164-05-9) show rather low percutaneous activities, when applied in lipophilic vehicles. Especially nabumeton and also tenoxicam (CAS 59804-37-4), both not yet commercially used cutaneously, can be recommended for lipophilic skin preparations.     

Drug-drug interactions evaluated by a highly active reconstituted native human cytochrome P4503A4 and human NADPH-cytochrome P450 reductase system

Catalytic activities of native human CYP3A4-mediated reactions as well as drug interactions were directly evaluated by isolated reconstituted human CYP3A4: NADPH-cytochrome P450 reductase systems. The SDS-PAGE pure CYP3A4 and human NADPH-cytochrome P450 reductase had been incorporated into a binary vesicular phospholipid system of dilauroyl-phosphatidyl-choline and phosphatidyl-serine which had proven to achieve optimal nifedipine oxidase activity (19.6 nmol nifedipine oxidized x min(-1) x nmol CYP3A4(-1)). The IC50 values of ketoconazole (CAS 65 277-42-1) (approximately 3 micromol/l), quinidine (CAS 56-54-2) (approximately 5 micromol/l), mifepristone (CAS 84 371-65-3) (-8 micromol/l), 17alpha-ethinylestradiol (CAS 57-63-6) (approximately 17 micromol/l), cimetidine (CAS 51 481-61-9) (approximately 46 micromol/l), FK 506 (tacrolimus) (CAS 104 987-11-3) (approximately 53 micromol/l), naringenin (CAS 480-41-1) (approximately 87 micromol/l), and cyclosporine A (CAS 59 865-13-3) (approximately 90 micromol/l) indicate that all these drugs have an inhibitory effect on nifedipine (CAS 21 829-25-4) metabolism, whereas the drug quinine (CAS 130-95-0) did not elicit any significant inhibition.     

Crk-associated substrate, vascular smooth muscle and hypertension

Hypertension is characterized by vascular smooth muscle constriction and vascular remodeling involving cell migration, hypertrophy and growth. Crk-associated substrate (CAS), the first discovered member of the adapter protein CAS family, has been shown to be a critical cellular component that regulates various smooth muscle functions. In this review, the molecular structure and protein interactions of the CAS family members are summarized. Evidence for the role of CAS in the regulation of vascular smooth muscle contractility is presented. Contraction stimulation induces CAS phosphorylation on Tyr-410 in arterial smooth muscle, creating the binding site for the Src homology (SH) 2/SH3 protein CrkII, which activates neuronal Wiskott-Aldrich syndrome protein (N-WASP)-mediated actin assembly and force development. The functions of CAS in cell migration, hypertrophy and growth are also summarized. Abelson tyrosine kinase (Abl), c-Src, focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (PYK2), protein tyrosine phosphatase-proline, glutamate, serine and threonine sequence protein (PTP-PEST) and SHP-2 have been documented to coordinate the phosphorylation and dephosphorylation of CAS. The downstream signaling partners of CAS in the context of cell motility, hypertrophy, survival and growth are also discussed. These new findings establish the important role of CAS in the modulation of vascular smooth muscle functions. Furthermore, the upstream regulators of CAS may be new biologic targets for the development of more effective and specific treatment of cardiovascular diseases such as hypertension.     

板栗中蛋白质的分离鉴定及活性研究

目的探讨板栗中蛋白质的分离纯化及其促肾细胞生长作用和抗肿瘤作用及机制。方法从板栗中提取出的水溶性蛋白质,经鉴定是欧栗球蛋白(CAS)。利用MTT法检测该蛋白对正常肾细胞和肝癌细胞HepS,小鼠肉瘤S180腹水型肿瘤细胞增殖的影响;检验其对小鼠T细胞和B细胞增殖作用的影响;用DNA电泳方法检测该蛋白诱导HepS细胞凋亡的作用。结果 CAS在体外对正常肾细胞的增殖有促进作用,对试验的肿瘤细胞的增殖均有抑制作用,对T细胞和B细胞的增殖有促进作用,对HepS细胞具有诱导凋亡的作用。结论 CAS具有促肾细胞生长和抗肿瘤作用,其抗肿瘤作用机制可能通过提高机体免疫力和诱导细胞凋亡来实现。     

紫花牡荆素诱导人肺腺癌A549细胞凋亡及其机制的探讨

目的探讨紫花牡荆素（CAS）诱导人肺腺癌A549细胞凋亡及其机制。方法平皿集落法测定CAS对A549细胞生长的抑制作用;碘化丙啶（PI）染色流式细胞术（FCM）分析细胞凋亡率;丫啶橙／溴乙啶（AO／EB）荧光染色观察细胞凋亡形态;Westernblot检测FoxMl（forkhead box protein M1）表达水平。结果CAS能抑制人肺腺癌A549细胞生长,呈浓度依赖性,半数抑制浓度（IC50）值为7．26p．mol·L^-1;CAS处理后A549细胞呈典型凋亡细胞形态学改变,诱导细胞凋亡呈浓度依赖性;CAS诱导A549细胞FoxM1蛋白表达下调,呈浓度和时间依赖性。结论CAS抑制人肺腺癌A549细胞的生长并诱导其凋亡,其作用机制可能与FoxM1表达下调有关。     

Suppressive efficacies of antimicrobial agents against human peripheral-blood mononuclear cells stimulated with T cell mitogen and bacterial superantigen

The immunomodulatory efficacies of 12 antimicrobial agents clinically used were examined against T cell mitogen- or bacterial superantigen-induced proliferation of peripheral-blood mononuclear cells of healthy subjects. Minocycline (CAS 13614-98-7), rifampicin (CAS 13292-46-1), trimethoprim (CAS 738-70-5), and ribavirin (CAS 36791-04-5) significantly inhibited the proliferation of mitogen-stimulated mononuclear cells at 1-100 microg/ ml (p < 0.001), whereas ofloxacin (CAS 82419-36-1) enhanced the proliferation (p < 0.001). Ampicillin (CAS 69- 53-4), lincomycin (CAS 859-18-7), vancomycin (CAS 1404-93-9), sulfamethoxazole (CAS 723-46-6), fosfomycin (CAS 26016-99-9), colistin (CAS 1264-72-8), and polymyxin B (CAS 1405-20-5) showed no significant effect. Minocycline, rifampicin, trimethoprim, and ribavirin also inhibited the proliferation of superantigen-stimulated peripheral-blood mononuclear cells at 1-100 microg/ml (<0.001), whereas ofloxacin stimulated the proliferation (p < 0.001). Rifampicin and minocycline at 10-100 microg/ml significantly inhibited interleukin-2 production from mitogen- or superantigen-stimulated peripheral-blood mononuclear cells (p < 0.025). These results suggest that certain kinds of antimicrobial agents inhibited the proliferation of mitogen- and superantigen-stimulated human peripheral-blood mononuclear cells and suppressed interleukin-2 production from these cells. The ofloxacin effect is immunostimulative, while the drug did not influence the interleukin-2 production.     

Prevention of sodium valproate-induced hepatotoxicity by curcumin, rosiglitazone and N-acetylcysteine in rats

The present study was designed to examine the potential preventive effect of curcumin (CMN; CAS 458-37-7), rosiglitazone (RGN; CAS 155141-29-0), N-acetylcysteine (NAC; CAS 616-91-1), resveratrol (RSV; CAS 501-36-0), and losartan (LOS; CAS 114798-26-4) on sodium valproate-induced hepatotoxicity. Sodium valproate (SVP; CAS 1069-66-5) was given at a dose of 250 mg/kg i. p. 3 times daily for one week. The tested compounds were given simultaneously with SVP for one week. The results demonstrate that CMN, RGN and NAC treatment can confer protection from SVP-induced hepatotoxicity. The second part of the study includes an evaluation of the effect of CMN, RGN and NAC on the anticonvulsant activity of SVP against pentetrazole-induced seizures in mice. The results demonstrate that CMN, RGN and NAC do not affect the anticonvulsant activity of SVP. Combined administration of either of CMN, RGN and NAC with valproate appears to be beneficial in reducing valproate-induced hepatotoxicity.     

Synthesis of DL-hydroxybenzenamides as anticonvulsants

The anticonvulsant activity of some DL-hydroxybenzenamides is described. The following compounds from this series were prepared and tested: DL-2-hydroxy-2-(3'-bromophenyl)butyramide (4, CAS 620950-12-1), DL-2-hydroxy-2-(4'-bromophenyl)butyramide (5, CAS 620950-13-2), DL-2-hydroxy-2-(3'-nitrophenyl)butyramide (6, CAS 620950-14-3), DL-2-hydroxy-2-phenyl hexanamide (7, CAS 63002-05-1), DL-2-hydroxy-2-(3',4'-dichlorophenyl)hexanamide (8, CAS 863976-06-1), DL-3-hydroxy-3-(4'-bromophenyl)pentanamide (9, CAS 620950-16-5), DL-3-hydroxy-3-phenyl-heptanamide (10, CAS 863976-08-3) and DL-4-hydroxy-4-(4'-bromophenyl)hexanamide (11,CAS 620950-18-7). Compounds 4, 5, 9 and 11 exhibited significant activity in seizures induced by pentylenetetrazol. Incorporation of bromine in the phenyl ring increased their potency. Compounds 4, 5, 9 and 11 exhibited a similar anticonvulsant activity as the reference drug phenobarbital (CAS 50-06-6).     

紫花牡荆素对人宫颈癌裸鼠移植瘤生长的影响及其机制

目的研究紫花牡荆素（CAS）对人宫颈癌HeLa细胞裸鼠移植瘤生长的影响及其机制。方法建立人宫颈癌HeLa细胞裸鼠皮下移植瘤模型,并随机分成5组,每组5只：生理盐水组、顺铂组、低剂量CAS组、中剂量CAS组和高剂量CAS组。观察和比较各组裸鼠移植瘤的体积和重量,裸鼠体重的变化,裸鼠血清乳酸脱氢酶、谷丙转氨酶、肌酐值和外周血白细胞计数的变化;FCM测定瘤组织细胞凋亡率;Westernblot分析瘤组织细胞内p21和cyclinB1的蛋白表达。结果CAS可显著抑制人宫颈癌HeLa细胞裸鼠移植瘤的体积和重量的增加,呈作用剂量和时间依赖性;而对裸鼠的体重、谷丙转氨酶、乳酸脱氢酶、肌酐值和外周血白细胞计数均无明显的影响。CAS作用16天后,裸鼠移植瘤细胞的凋亡率呈剂量依赖性增加,cyclinBl的蛋白表达降低,p21的蛋白表达增高。结论CAS具有抑制人宫颈癌裸鼠移植瘤生长的作用,可能与其降低cyclinB1的蛋白表达,增加p21的蛋白表达,促进细胞凋亡有关。     

SFINX—a drug-drug interaction database designed for clinical decision support systems

Objective  The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Methods  Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. Results  SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. Conclusion  SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.     

类风湿关节炎与颈动脉粥样硬化症的相关性研究

目的：探讨类风湿关节炎（RA）与颈动脉粥样硬化症（CAS）的相关性。方法将该院2010年6月至2013年6月诊治的RA患者130例（RA组）,根据改良的疾病活动性评分分为4个亚组（RA1、RA2、RA3、RA4）,选择同期健康体检者96例作为对照组。分析各组颈动脉内膜增厚情况及颈动脉斑块数量,并探讨CAS相关性因素。结果 RA组患者CAS发生率高于对照组,差异有统计学意义（P〈0.05）,但缓解期患者CAS检出率与对照组比较,差异无统计学意义（P＞0.05）,活动期患者发生CAS检出率明显高于对照组,差异有统计学意义（P〈0.01）。进行Logistic回归分析,发现类风湿因子滴度、年龄、红细胞沉降率、C-反应蛋白是CAS的危险因素。结论 RA与CAS的发生和发展关系密切。     

Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine oxidase inhibition

A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine (CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5-hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64-04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily for 5 days) were those known to possess anti-stress properties in other animal models. In contrast to the reference substances investigated (nialamide (CAS 51-12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did not exhibit any activity indicative of MAO inhibition. It was concluded that MAO inhibition was not the mechanism primarily responsible for EGb 761's anti-stress activity.     

新疆维吾尔族人群高甘油三酯血症与颈动脉粥样硬化的相关性研究

目的探讨新疆巴州地区维吾尔族人群高甘油三酯(triglyceride,TG)血症与颈动脉粥样硬化(carotid atherosclerotic,CAS)及CAS病变严重程度之间的相关性。方法采用病例对照研究,选择2008年1月~2011年10月在我院内科住院并行颈动脉超声检查确诊的维吾尔族CAS患者452例;对照组460例,为同期入院行颈动脉超声检查排除CAS者。对所有纳入对象测定禁食12h后静脉血清TG值及其他生物化学指标,并结合超声检查情况,探讨高TG血症与CAS及CAS病变严重程度的关系。结果 CAS组高TG血症的患病率为41.15%,明显高于对照组的14.13%(P<0.01);血TG水平(1.84±0.93)mmol/L显著高于对照组(1.53±0.95)mmol/L(P<0.01)。多因素Logistic回归分析显示,在校正了年龄、吸烟、高血压、糖尿病、血脂异常等传统危险因素作用后发现,高TG血症是CAS的独立危险因素(OR=2.865,95%CI:2.017~3.831;P=0.001)。CAS组不同病变亚组之间高TG血症患病率及血TG水平比较差异未见明显统计学意义(P>0.05)。结论高TG血症是新疆巴州地区维族人群CAS发生的独立危险因素。     

多模式影像指导下支架成形术治疗颅外颈动脉狭窄的研究

目的评估多模式影像指导下支架成形术治疗颅外颈动脉狭窄的可行性和安全性。方法从2010年1月至2013年12月,入选颅外颈动脉狭窄患者100例,随机分为常规颈动脉狭窄支架成形成术组（常规CAS组）和多模式影像指导下颈动脉狭窄支架成形成术组（个体化CAS组）,各50例,完整地评估神经专科的情况,常规CAS组和个体化CAS组年龄、性别差异无统计学意义。结果常规CAS组和个体化CAS组技术成功率均为100％。围手术期总并发症：14．0％和12．0％,差异无统计学意义（P〉0．05）,神经系统并发症：6．0％和4．0％,差异无统计学意义（P〉0．05）。随访6个月,常规CAS组和个体化CAS组脑血管事件发生率分别为：12．0％和8．0％,差异无统计学意义（P〉0．05）,血管再狭窄率分别为：24．0％和6．0％,差异有统计学意义（P〈0．05）。结论多模式影像指导颅外颈动脉狭窄支架成形术能降低远期血管再狭窄率,但尚未能降低远期脑血管事件发生率,支架成形术是治疗颅外颈动脉狭窄的可行和安全方法之一。