苦参素对佐剂性关节炎大鼠的治疗作用

目的研究苦参素(OM)对大鼠佐剂型关节炎(AA)的影响,并探讨部分作用机制。方法弗氏完全佐剂(FCA)诱导AA大鼠模型,检测大鼠足爪肿胀度、多发性关节炎指数(AI),HE染色观察关节病理学改变,放免法检测血清IL-1β、TNF-α水平。结果 OM(60、120 mg.kg-1)剂量组能明显抑制AA大鼠继发性足肿胀,改善膝关节的病理学病变,使AA大鼠血清IL-1β、TNF-α水平显著下降。结论 OM对AA大鼠有治疗作用,调节体内细胞因子IL-1β、TNF-α的水平可能是其治疗AA的作用机制之一。     

通痹胶囊对佐剂性关节炎大鼠p38MAPK/NF-κB信号通路的影响

目的观察通痹胶囊对佐剂性关节炎大鼠血清和滑膜组织中炎性因子表达及p38MAPK/NF-κB信号通路的影响。方法 48只Wistar大鼠随机分为正常组、模型组、通痹胶囊不同剂量(375、750、1500mg·kg-1)组及雷公藤多苷片(10 mg·kg-1)组,除正常组外,其余各组均于右后足跖部注射弗氏完全佐剂造模。造模第8日,各组给予相应药物灌胃治疗,每日1次,连续4周。对大鼠关节炎指数进行监测,足容积法测量致炎侧足肿胀度;灌胃结束后,采用酶联免疫吸附(ELISA)法检测大鼠血清及滑膜中白细胞介素-1(IL-1)、肿瘤坏死因子-α(TNF-α)的表达水平;蛋白免疫印迹(Western blot)法检测大鼠滑膜组织中p38MAPK、NF-κB/P65、IκBα蛋白表达的。结果与正常组相比,造模后大鼠血清及滑膜组织中IL-1、TNF-α含量明显升高,p38MAPK、NF-κB/P65、IκBα表达显著增多(P <0.01);与模型组相比,通痹胶囊能够有效降低大鼠血清及滑膜组织中IL-1、TNF-α的含量,并抑制滑膜组织中p38MAPK、NF-κB及IκBα的蛋白表达(P <0.05,P <0.01)。结论通痹胶囊具有明显的抗炎作用,其治疗类风湿关节炎的作用机制之一可能为抑制p38MAPK/NF-κB信号通路的激活。     

枫杨乙醇提物对胶原诱导性关节炎大鼠的治疗作用及其机制研究

目的观察湖北枫杨乙醇提取物对SD大鼠CIA模型的治疗作用,并对其抗炎和促凋亡的机制进行初步探索。方法构建CIA模型后,测量其体质量、足跖肿胀率、关节炎指数;通过药物灌胃治疗后,观察各组大鼠膝关节滑膜病理形态变化,血清TNF-α、IL-1β、ALT、AST、BUN、SCr变化,膝关节滑膜内NF-κB p65磷酸化(p-p65)、cleaved caspase-3、Bcl-2、Bax表达。结果不同剂量湖北枫杨乙醇提取物组及雷公藤组使大鼠体质量增加,足跖肿胀率、关节炎指数下降(P<0.05);膝关节滑膜中炎性细胞减少,凋亡滑膜细胞增多;血清TNF-α、IL-1β降低(P<0.05);滑膜内p-p65、Bcl-2表达减少,cleaved caspase-3、Bax表达增加;湖北枫杨乙醇提取物各组ALT、AST、BUN、SCr下降(P<0.05)。结论湖北枫杨乙醇提取物对SD大鼠CIA模型有很好的治疗效果,其机制可能与调控相关炎性细胞因子TNF-α和IL-1β的表达及诱导滑膜细胞凋亡有关,同时该提取物可改善CIA大鼠肝、肾损伤。     

鬼针草总黄酮对急性炎症的保护作用及可能机制研究

目的:研究鬼针草总黄酮(TFB)对急性炎症的保护作用与可能机制.方法:二甲苯诱导急性小鼠耳肿胀,检测耳肿胀度和血清TNF-α、IL-1、IL-6、IL-8含量;氟氏完全佐剂诱导佐剂性关节炎(AA)大鼠原发性炎症,检测足肿胀度和血清TNF-α、IL-1、IL-2、IL-6、IL-8含量,HE染色观察炎症关节病理学变化,免疫组织化学法检测关节软骨组织ASIC1a蛋白.结果:小鼠急性耳肿胀和AA大鼠原发性炎症中,模型组动物血清TNF-α、IL-1、IL-6和IL-8含量均明显升高,TFB(100、200mg/kg)灌胃给药能降低小鼠耳肿胀度和血清TNF-α、IL-1、IL-6、IL-8含量,TFB(67、133mg/kg)可以升高AA大鼠血清IL-2的含量.TFB灌胃给药可以使AA大鼠关节炎性细胞减少,改善病理变化.在AA大鼠原发性炎症中模型组大鼠关节软骨组织ASIC1a表达明显升高,TFB(67、133 mg/kg)组ASIC1a的表达明显降低.相关性分析结果显示,AA大鼠原发性炎症中ASIC1a与血清TNF-α、IL-1、IL-8含量呈正相关.结论:TFB对急性炎症具有保护作用,其抗炎机制可能与调节炎症介质释放有关.     

以Annexin V/PI法检测新风胶囊对AA大鼠滑膜、胸腺及胃黏膜细胞凋亡的影响

目的观察以Annexin V/PI法检测新风胶囊对佐剂性关节炎(adjuvant arthritis, AA)大鼠滑膜、胸腺及胃黏膜细胞凋亡的影响,探讨新风胶囊的作用机制.方法采用弗氏完全佐剂造成佐剂性关节炎(AA)大鼠模型,设立正常对照组、模型对照组、甲氨喋呤(MTX)对照组、雷公藤多苷(triperygium wilfordii polycoride tablet, TPT)对照组和新风胶囊(xinfeng cepsule, XFC)治疗组.记录各组大鼠的关节炎指数及体重变化,应用流式细胞仪(FCM)以Annexin V/PI法测定各组大鼠滑膜、胸腺及胃黏膜细胞凋亡率.结果与治疗前相比,XFC、TPT及MTX组治疗后大鼠的关节炎指数显著降低(P<0.05～0.01),XFC组治疗后AA大鼠体重增加(P<0.05),而TPT及MTX组体重无变化(P>0.05);模型组滑膜及胸腺细胞凋亡率低于胃黏膜细胞凋亡率,高于正常对照组(P<0.05),XFC组滑膜及胸腺细胞凋亡率高于胃黏膜细胞凋亡率,低于模型组、TPT及MTX组(P<0.05～0.01).结论XFC与MTX、TPT一样能降低AA大鼠关节炎指数,在增加AA大鼠体重、促进滑膜、胸腺细胞凋亡及抑制胃黏膜细胞凋亡方面优于MTX和TPT.新风胶囊的作用机制是促进滑膜细胞凋亡,抑制滑膜增生;促进胸腺细胞凋亡,抑制自身免疫反应以及抑制胃黏膜细胞凋亡,保护胃黏膜.     

重组人肿瘤坏死因子受体融合蛋白治疗大鼠佐剂性关节炎的作用及对巨噬细胞功能的影响

目的:研究重组人肿瘤坏死因子受体融合蛋白(RhTNFR:Fc)对佐剂性关节炎(AA)大鼠模型的治疗作用及对巨噬细胞产生细胞因子的影响。方法:完全弗氏佐剂免疫SD大鼠诱导AA模型,随机分为正常组、模型组、RhTNFR:Fc低、中、高剂量组(1,3,9 mg.kg-1)和阴性对照组(IgG-Fc 9 mg.kg-1)。记录全身评分、关节炎指数、足爪肿胀度、关节肿胀数等整体评价指标、足爪X线摄片、踝关节病理检查及评分,ELISA试剂盒测定腹腔巨噬细胞(PMφ)上清中细胞因子白细胞介素1β(IL-1β),IL-6和肿瘤坏死因子α(TNF-α)水平。结果:RhTNFR:Fc给药组能不同程度地降低AA大鼠升高的全身评分、关节炎指数、足爪肿胀度和关节肿胀数等整体评价指标,减轻AA大鼠的关节炎症,改善AA大鼠X线摄片评分和关节病理学变化,下调PMφ的IL-1β,IL-6和TNF-α的分泌水平。结论:RhTNFR:Fc对大鼠AA的关节炎症具有治疗作用,且抑制腹腔巨噬细胞促炎性细胞因子的表达。     

藏药独一味抗类风湿关节炎的作用及其药效物质基础研究

目的:研究藏药独一味抗类风湿关节炎(RA)的作用及其药效物质基础。方法:将56只SD大鼠随机分为正常对照组(0.5%羧甲基纤维素钠溶液),模型组(0.5%羧甲基纤维素钠溶液),甲氨蝶呤组(阳性对照组,3 mg/kg),独一味水提液低、中、高剂量组(0.5、1、2 g/kg,以生药量计)和独一味总黄酮组(200 mg/kg,以黄酮提取物计),每组8只。除正常对照组外,其余各组大鼠均于右后足垫注射弗氏完全佐剂(FCA)复制佐剂性关节炎模型。注射FCA次日,各组大鼠灌胃相应药物,每天给药1次(仅甲氨蝶呤组每3天给药1次),连续给药30天。给药第15、30天时,分别测定大鼠左后足的足肿胀度,计算其关节炎指数。第30天给药结束后,采用酶联免疫吸附法测定各组大鼠血清中肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、IL-6、IL-10水平,计算其胸腺指数、脾指数,并采用苏木精-伊红染色法观察各组大鼠踝关节的病理学变化。结果:与正常对照组比较,模型组大鼠给药第15、30天时的足肿胀度、关节炎指数以及给药第30天时的脾指数和血清中TNF-α、IL-1β、IL-6水平均显著升高(P<0.01);给药第30天时的胸腺指数、IL-10水平均显著降低(P<0.01);踝关节可见明显的滑膜细胞增生、浸润关节腔等病理学改变。与模型组比较,各给药组大鼠给药第15、30天时的足肿胀度、关节炎指数以及给药第30天时的脾指数和血清中TNF-α、IL-1β、IL-6水平均显著降低(P<0.01);给药第30天时的胸腺指数和血清中IL-10水平均显著升高(P<0.01);关节炎病理学变化明显改善。与独一味水提液高剂量组比较,独一味总黄酮组大鼠给药第15天时的足肿胀度以及给药第15、30天时的关节炎指数、胸腺指数、脾指数、炎症细胞因子水平、踝关节病理学变化等差异均无统计学意义(P>0.05)。结论:藏药独一味具有良好的抗RA作用,总黄酮可能是其药效物质基础。     

红花黄色素对佐剂型关节炎大鼠的抗炎作用研究

目的 观察红花黄色素对佐剂型关节炎大鼠的抗炎作用并探讨其机制。方法 用弗氏完全佐剂建立佐剂型关节炎大鼠模型,分为正常组、模型组、红花黄色素100,50,25 mg·kg^-1组,每组10只。排水法检测大鼠足趾肿胀度,Elisa法检测炎症因子IL-1β及TNF-α的水平,western blot法检测滑膜组织中IL-1β和TNF-α蛋白的表达。结果 与模型组相比,红花黄色素各组能显著降低佐剂型关节炎大鼠的足趾肿胀度（p<0.01或P<0.05）,降低血清中IL-1β及TNF-α含量水平（p<0.01或p<0.05）,还能降低滑膜组织中IL-1β及TNF-α蛋白的表达（p<0.01或p<0.05）。结论 红花黄色素能显著缓解佐剂型关节炎大鼠的关节炎症,其机制与下调炎症因子IL-1β及TNF-α的表达有关。     

雷公藤多苷纳米粒的制备及其对关节炎大鼠的治疗作用

目的 制备雷公藤多苷纳米粒,探究其对胶原诱导型(collagen-induced arthritis, CIA)关节炎大鼠的治疗作用。方法 运用薄膜分散法制备雷公藤多苷纳米粒,对其进行质量评估。构建CIA模型,进行药物干预,称量大鼠体质量、测定足趾肿胀度和关节炎指数;观察大鼠脏器、膝、踝关节滑膜的病理改变;检测大鼠血清中肝肾功能水平和炎症因子表达。结果 制备的雷公藤多苷纳米粒在电镜下呈圆粒状且分布均匀,性质稳定。相较于模型组,给药组大鼠左右足趾肿胀度均明显下降(P<0.01),关节炎指数明显降低(P<0.01)。其中TG-NPs组的疗效优于TG组。与正常组相比,大鼠心脏、脾、肾、睾丸指数均明显降低(P<0.05,P<0.01)。TG-NPs组膝踝关节软骨病理损伤明显减轻,凋亡的滑膜细胞增加;与模型组相比,TG-NPs组大鼠血清中的ALT、BUN、CRE水平均明显降低(P<0.05),IL-1β、TNF-α和IL-6含量下降明显（P<0.05）。结论 TG-NPs通过诱导滑膜细胞凋亡和降低炎性细胞因子的表达对CIA有较好的治疗作用,通过静脉注射血液循环...     

刺三甲醇提物对AA大鼠血清中炎性因子含量的影响

目的:研究彝药刺三甲醇提物对佐剂性关节炎(AA)大鼠血清中白细胞介素(IL)-1β、IL-6、IL-10、一氧化氮(NO)、肿瘤坏死因子α(TNF-α)和前列腺素E2(PGE2)含量的影响。方法:将60只大鼠随机均分为正常对照组(蒸馏水)、模型组(蒸馏水)、阳性对照(尼美舒利,0.03 g/kg)组和刺三甲高、中、低剂量[7、3.5、1.75 g(生药)/kg]组,除正常对照组外,其余各组大鼠均于右后足趾部sc弗氏完全佐剂(0.1 ml)复制AA大鼠模型,致炎后,各组大鼠ig相应药物,每天1次。30 d后测定大鼠血清中IL-1β、IL-6、IL-10、TNF-α、NO、PGE2含量,并观察大鼠踝关节病理形态学变化。结果:与正常对照组比较,模型组大鼠血清中IL-1β、IL-6、TNF-α、NO、PGE2含量升高,IL-10含量降低,差异有统计学意义(P<0.01);与模型组比较,刺三甲高剂量组大鼠血清中IL-1β、IL-6、TNF-α、NO、PGE2含量降低,IL-10含量升高,差异有统计学意义(P<0.05)。病理结果显示,刺三甲组部分切片滑膜细胞轻度增生、纤维组织轻度增生、炎细胞不同程度浸润、巨噬细胞有轻度增生;正常对照组无此变化。结论:彝药刺三甲醇提物对AA模型大鼠有明显的抗炎作用,其作用机制可能与降低炎症因子IL-1β、IL-6、TNF-α、NO、PGE2的含量,升高抗炎因子IL-10的含量有关。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.