TRPM8通道激活剂薄荷醇对肺动脉高压大鼠的治疗作用

目的 探讨瞬时受体电位M8(transient receptor potential melastatin-8,TRPM8)通道激活剂薄荷醇(menthol)对野百合碱(monocrotaline, MCT)诱导的肺动脉高压(pulmonary arterial hypertension, PAH)大鼠的治疗作用。方法 SPF级雄性Sprague-Dawley大鼠随机分为6组：正常对照组、MCT组、MCT+menthol(1 mg·kg^-1·d^-1)治疗组、MCT+menthol(2 mg·kg^-1·d^-1)治疗组、MCT+menthol(5 mg·kg^-1·d^-1)治疗组、MCT+menthol(10 mg·kg^-1·d^-1)治疗组。腹腔注射MCT(50 mg·kg^-1)构建PAH大鼠模型。造模1周后治疗组分别给予不同剂量的menthol灌胃治疗,持续2周。通过血流动力学检测、肺组织病理学...     

雷公藤-甘草配伍干预肾病综合征大鼠AVPR2/AQP2的表达

目的 探讨阿霉素诱导的肾病综合征大鼠AVPR2和AQP2的表达以及雷公藤-甘草配伍的干预机制。方法 选取成年健康雄性SD大鼠,随机选取10只作为空白组,其余大鼠均接受尾静脉注射给予6.5 mg·kg^-1的阿霉素诱导复制大鼠肾病综合征模型。并采用随机数字法将造模成功的大鼠分为4组(n=10):模型组(n=10)、阳性对照组(雷公藤多苷片80 mg·kg^-1·d^-1,n=10)、雷公藤组(雷公藤提取物240 mg·kg^-1·d^-1,n=10)及雷公藤-甘草组(雷公藤提取物240 mg·kg^-1·d^-1+甘草提取物80 mg·kg^-1·d^-1,n=10)。测定大鼠24 h尿蛋白含量、血清白蛋白、尿素、肌酐水平、肾脏中AVPR2和AQP2 mRNA表达水平。结果 大鼠经阿霉素造模后表现出大量蛋白尿、低蛋白血、高度水肿症候。相比于模型组,雷公藤及配伍给药组大鼠精神状态较好,体质量增加明显。与模型组相比...     

梓醇对T2DM大鼠大血管病变的保护作用及与oxLDL/LDL和NF-κB信号通路的关系

目的 探讨梓醇对2型糖尿病(T2DM)大鼠大血管病变的保护作用与氧化低密度脂蛋白(oxLDL)/低密度脂蛋白(LDL)和核转录因子-κB(NF-κB)信号通路的关系。方法 用高糖高脂饲料喂养和腹腔注射STZ复合因素对大鼠进行T2DM造模，将大鼠分为模型组、二甲双胍组(134 mg·kg^-1·d^-1)、梓醇组(10 mg·kg^-1·d^-1),另设对照组，每组10只，模型组和对照组给予相同体积的0.9%氯化钠溶液，干预4周。结束后，自动生化分析仪检测大鼠血清总胆固醇(TC)、三酰甘油(TG)、空腹血糖(FBG)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)水平；酶联免疫吸附法测定人巨噬细胞趋化蛋白-1(MCP-1)、oxLDL含量；RT-PCR法检测主动脉壁LOX-1、NF-κB p65、MCP-1 mRNA表达；Western blot检测主动脉壁LOX-1、NF-κB p65、MCP-1蛋白表达；透射电镜观察大鼠主动脉内皮细胞结构。结果 对照组大鼠主动脉内皮细胞形态正常，模型组细胞显著肿胀，连续性...     

芹菜素对大鼠肾损伤的保护作用及机制研究

目的:研究芹菜素(apigenin, APG)对阿霉素诱导大鼠肾损伤的保护作用并探索其机制。方法:将60只实验用SD大鼠尾静脉注射阿霉素建立大鼠阿霉素肾病(adriamycin nephropathy, AN)模型,另取10只大鼠给予等体积溶媒作为空白对照组。将AN大鼠随机分为模型组、阳性对照地塞米松组(DEX组,剂量0.1 mg·kg^-1·d^-1)、APG低剂量组(APL组,剂量50 mg·kg^-1·d^-1)、APG中剂量组(APM组,剂量100 mg·kg^-1·d^-1)、APG高剂量组(APH组,剂量200 mg·kg^-1·d^-1),每组10只。DEX及APG给药组均每日灌胃治疗,正常对照组和模型组同步灌胃APG溶剂,即0.5%CMC-Na溶液,疗程60 d。测量24 h尿蛋白总量(PRO)及血清肾功能、肝功能等监测指标;HE染色法对肾脏组织进行病理学检查;免疫组化法标记肾脏组织的CD68蛋白,检测巨噬细胞在...     

穿心莲内酯抑制IKK/IκBα/NF-κB信号通路改善抑郁症大鼠的抑郁样行为

目的 探讨穿心莲内酯(Andro)通过抑制核转录因子-κB抑制蛋白激酶(IKK)/核因子κB抑制蛋白(IκBα)/核因子-κB(NF-κB)信号通路改善抑郁症(MDD)大鼠的抑郁样行为。方法 随机取12只SD大鼠作为空白对照组(NC组),其余大鼠采用慢性不可预知轻度应激(CUMS)结合孤养模式造模,将造模成功大鼠随机平分为模型组(Mod组)、Andro组(25 mg·kg^-1·d^-1)、Res组(30 mg·kg^-1·d^-1 IKK/IκBα/NF-κB信号通路激活剂Res)、Andro+Res组(25 mg·kg^-1·d^-1Andro+30mg·kg^-1·d^-1 Res),每组12只大鼠,Mod组和NC组灌胃等量0.9%氯化钠溶液。旷场实验、糖水偏好实验、强迫游泳实验、平衡木实验评估大鼠行为;ELISA法检测血清IL-1β、IL-6、TNF-α水平;免疫荧光染色检测小胶质细胞、星形胶质细胞活性;Western ...     

芍药苷调节PI3K/AKT/NF-κB信号通路对血栓闭塞性脉管炎大鼠的治疗作用研究

目的 探讨芍药苷(PAE)对血栓闭塞性脉管炎(TAO)大鼠的治疗作用及作用机制。方法 通过月桂酸钠注射法建立TAO大鼠模型。将大鼠随机分为假手术组(腹腔注射适量0.9%NaCl)、模型组(腹腔注射适量0.9%NaCl)、低剂量实验组(腹腔内注射5 mg·kg^-1·d^-1 PAE)、高剂量实验组(腹腔内注射20 mg·kg^-1·d^-1 PAE)、高剂量+激动药剂(腹腔注射20 mg·kg^-1·d^-1 PAE+尾静脉注射10 ng·mL^-1·kg^-1·d^-1 740 Y-P)组。用磁珠凝固法检测凝血酶时间(TT);用酶联免疫吸附测定试剂盒检测白细胞介素(IL)-1β、内皮素1(ET-1)水平;用蛋白质印迹法检测磷脂酰肌醇3-激酶(PI3K)、磷酸化PI3K(p-PI3K)、蛋白激酶B(AKT)、p-AKT、核因子(NF)-κB p65、p-NF-κB p65蛋白的表达水平。结果 假手术组、模型组...     

当归红芪超滤物对H9C2心肌细胞氧糖剥夺/恢复诱导细胞凋亡的干预作用

目的 探讨当归红芪超滤物对H9C2心肌细胞氧糖剥夺/恢复损伤的影响,并探索其可能机制。方法 H9C2心肌细胞进行氧糖剥夺处理6 h,建立心肌细胞缺血再灌注损伤模型。成年Wistar大鼠口服灌胃给药制备药物血清。H9C2心肌细胞造模处理后分为4组：模型组、阳性对照组、当归红芪超滤物组和联合组。空白组为正常H9C2细胞,模型组、阳性对照组、当归红芪超滤物组、联合组分别使用完全培养基、7.5 mg·kg^-1·d^-1尼可地尔药物血清培养基、10 mg·kg^-1·d^-1当归红芪超滤物药物血清培养基和联合药物血清(7.5 mg·kg^-1·d^-1尼可地尔+10 mg·kg^-1·d^-1当归红芪超滤物)培养基在常氧条件下培养4 h。用酶联免疫吸附实验测定肌钙蛋白T、肌钙蛋白Ⅰ及C-反应蛋白含量;用实时定量-聚合酶链反应检测B淋巴细胞瘤-2（Bcl-2）和胱天蛋白酶-3（Caspase-3）的基因表达;用5-乙炔基-2′-脱氧尿苷（...     

地高辛抑制mTORC2-IRF4信号阻抑巨噬细胞M2极化改善肺纤维化

目的 探讨地高辛对博来霉素(bleomycin, BLM)诱导的肺纤维化小鼠的保护作用及机制。方法 采用气管内滴注BLM(5 mg·kg^-1)制备肺纤维化小鼠模型。造模后d 3～28,灌胃给予地高辛(1、0.2 mg·kg^-1·d^-1)、吡非尼酮(300 mg·kg^-1·d^-1)。从肺组织病理等方面探讨地高辛干预作用。采用IL-4(20μg·L^-1)诱导小鼠肺泡巨噬细胞(mouse alveolar macrophages, MHS)M2极化模型,给予地高辛(10、1μmol·L^-1)处理,采用免疫荧光、qPCR、Western blot检测地高辛对巨噬细胞M2极化相关蛋白及基因表达的作用。结果 地高辛(1、0.2 mg·kg^-1·d^-1)有效减轻肺组织炎性细胞浸润、肺泡结构破坏、纤维组织增生、肺泡间隔增厚,下调肺组织I、Ⅲ型胶原表达,降低M2型巨噬细胞标志物CD206及p-mTOR     

黄芪甲苷保护大鼠缺血/再灌注心脏的内质网应激机制研究

目的研究黄芪甲苷保护缺血/再灌注心脏的内质网应激(ERS)机制。方法建立离体心脏缺血/再灌注模型,♂Wistar大鼠结扎冠状动脉进行心肌缺血30 min/再灌注120 min,随机分成假手术组、缺血/再灌注组、ERS抑制剂牛磺熊脱氧胆酸(TUDCA)组、黄芪甲苷组;Western blot检测缺血期及再灌注期ERS分子伴侣葡萄糖调节蛋白78(GRP78)的表达;激光扫描共聚焦显微镜免疫荧光化学染色法检测GRP78的表达;TTC法测定心肌梗死面积;HE染色观察心肌组织形态学改变。结果与假手术组相比,缺血期GRP78表达没有明显增加,再灌注期GRP78表达明显增加,黄芪甲苷能够模拟TUDCA明显抑制再灌注期GRP78的表达、减少心肌梗死面积、改善心肌组织的形态,差异具有统计学意义(P<0.05)。结论 ERS发生于再灌注期而不是缺血期,黄芪甲苷通过抑制ERS保护大鼠缺血/再灌注心脏。     

雷公藤多苷调控鞘氨醇激酶信号通路改善IgA肾病大鼠肾损伤的作用研究

目的 基于鞘氨醇激酶1(Sphk1)/1-磷酸鞘氨醇受体2(S1PR2)信号通路研究雷公藤多苷片(GTW)改善免疫球蛋白A肾病(IgAN)大鼠肾损伤的作用机制。方法 通过牛血清白蛋白灌胃+蓖麻油和四氯化碳皮下注射+脂多糖尾静脉注射等手段建立IgAN大鼠模型。将造模成功大鼠随机分为模型组、对照组和实验组,每组9只;另取10只正常大鼠作为空白组。对照组灌胃给予6.25 mg·kg^-1·d^-1泼尼松;实验组灌胃给予9.375 mg·kg^-1·d^-1 GTW;空白组和模型组均灌胃给予0.5 mL·100 g^-1·d^-1 0.9%NaCl。各组大鼠每天给药1次。于15周末留尿取材,测定各组大鼠血白蛋白(ALB)、尿素氮(BUN)、24 h尿蛋白定量(24 h-UTP)、尿红细胞数,用蛋白质印迹法检测各组大鼠Sphk1/S1PR2蛋白的表达水平。结果 苏木精-伊红染色及免疫荧光见对照组与实验组肾病理损伤均较模型组明显减轻。空白组、模型组、对照组和实验组的ALB分别为(...     

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.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

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.     

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.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.