罗布麻叶水提取物对链脲佐菌素致糖尿病小鼠的治疗作用及对肠道GLP-1蛋白表达的影响

目的 探讨罗布麻叶水提取物（WEAVL）对链脲佐菌素（STZ）致糖尿病模型小鼠的治疗作用。方法 随机将ICR小鼠分为对照组和WEAVL（2.34 g/kg）组,每天ig给药1次,连续30 d,检测空腹血糖和体质量。ICR小鼠按200 mg/kg ip 2% STZ溶液制备糖尿病模型,造模成功的小鼠按血糖值随机分为模型组、盐酸二甲双胍（阳性药,130 mg/kg）组和WEAVL低、中、高剂量（0.58、1.17、2.34 g/kg）组,另设对照组,连续给药30 d,测定体质量、空腹血糖、糖耐量及血糖曲线下面积（AUC）;称取肝、肾质量,计算脏器系数;取胰腺组织进行HE染色、组织病理学检查;Western blotting检测肠道组织胰高血糖素样肽-1（GLP-1）蛋白的表达水平。结果 与对照组比较,单纯给予WEAVL对正常动物空腹血糖无明显影响,可显著降低小鼠体质量（P<0.01）。与对照组比较,模型组小鼠血糖显著升高（P<0.01）,各组小鼠体质量均显著降低（P<0.01）;与模型组比较,WEAVL高剂量组给药第2~4周体质量显著降低（P<0.05、0.01）,3个剂量组2 h血糖、血糖AUC均显著降低（P<0.01）,高剂量组肝脏系数显著降低（P<0.05）、肾脏系数显著升高（P<0.05）,中、高剂量组动物胰岛细胞空泡变性例数减少,中、高剂量组肠道组织GLP-1蛋白的表达显著上调（P<0.05）。结论 WEAVL对STZ致糖尿病小鼠有一定治疗作用,其作用机制可能与上调肠道组织中GLP-1的表达有关。     

夏黄颗粒治疗慢传输型便秘的实验研究

目的 采用吗啡致小鼠慢传输型便秘模型,评价夏黄颗粒的治疗作用,并对其通便作用进行实验研究。方法 采用连续sc 2.5 mg/kg盐酸吗啡45 d致小鼠慢传输型便秘模型,观察夏黄颗粒的通便作用;采用1次性ip 5 mg/kg盐酸吗啡致小鼠小肠推进、胃排空抑制模型,观察夏黄颗粒对胃肠抑制的拮抗作用;采用测定小鼠小肠湿、干质量法,观察夏黄颗粒对肠水分吸收的作用;采用顺铂致大鼠异嗜模型,观察夏黄颗粒的止吐作用;采用吗啡致豚鼠离体回肠、结肠痉挛模型,观察夏黄颗粒的作用及机制。结果 与模型组比较,小鼠给药5 d,夏黄颗粒14.95、7.48 g生药/kg能显著增加慢传输型便秘小鼠的24 h排便量（P<0.05、0.01）,继续给药至7 d,14.95、7.48 g生药/kg能显著增加小肠推进率、14.95 g生药/kg显著升高血清P物质含量（P<0.05、0.01）;给药1次,14.95、7.48 g生药/kg剂量组能显著增加小鼠小肠推进率、加快胃排空（P<0.01）,14.95 g生药/kg显著增加小鼠小肠含水量（P<0.01）;大鼠给药3 d,10.35 g生药/kg剂量组能显著降低大鼠异嗜高岭土质量（P<0.05）;给药1次,2.49、1.25 mg生药/mL（浴槽终浓度）能显著降低吗啡所致痉挛性回肠的肠张力（P<0.01）,2.49、1.25、0.62 mg生药/mL（浴槽终浓度）能显著降低吗啡所致痉挛性结肠的肠张力（P<0.05、0.01）。结论 夏黄颗粒对吗啡所致慢传输型便秘有显著的治疗作用,具有显著的通便、解痉、促进胃肠运动、肠吸收及止吐作用。     

淡豆豉炮制中γ-氨基丁酸含量测定及其抗抑郁作用研究

目的检测淡豆豉炮制过程中各样本γ-氨基丁酸（GABA）含量并研究其抗抑郁作用。方法应用柱前在线衍生-高效液相色谱技术测定原料黑大豆（H）、发酵第6天（F6）、再闷6 d（Z6）、再闷15 d（Z15）样本水煎液中GABA含量；将昆明种小鼠随机分成对照组、模型组、盐酸氟西汀（阳性对照，0.01 g/kg）组、GABA（0.012 8 g/kg）组、H（1.52 g/kg）组、F6（1.52 g/kg）组、Z6（1.52 g/kg）组和Z15低、中、高剂量（0.76、1.52、3.04 g/kg）组，采用单笼饲养加慢性温和不可预知性应激（CUMS）制备小鼠抑郁模型，各组在造模同时开始ig给药，每日应激前1 h给药，连续28 d。检测各组小鼠体质量、糖水偏好、敞箱、悬尾、强迫游泳等行为学指标的变化。结果 H和F6样本水煎液未检出GABA，Z6、Z15样本的GABA质量分数分别为5.559、8.421 mg/g。与对照组比较，模型组小鼠的体质量、糖水偏好、跨格数和直立数均显著减少（P<0.01），悬尾及游泳不动时间显著增加（P<0.05、0.01），表明CUMS抑郁模型制备成功。与模型组比较，盐酸氟西汀组、GABA组、Z6组和Z15高剂量组糖水偏爱度、敞箱实验跨格数和直立数均显著增加（P<0.05、0.01），Z15中剂量组糖水偏爱度和敞箱实验直立数显著增加（P<0.05、0.01）；盐酸氟西汀组、GABA组、Z6组及Z15高、中剂量组悬尾实验的不动时间均显著减少（P<0.05、0.01）；各组小鼠强迫游泳实验的不动时间均显著缩短（P<0.05、0.01）。结论发现淡豆豉炮制后期出现高含量GABA；淡豆豉显著改善小鼠的快感缺失、行为绝望等抑郁症状，具有良好的抗抑郁作用并与GABA含量可能有关。     

蝉花子实体抗疲劳作用研究

目的 研究蝉花子实体的抗疲劳、增强运动耐力作用。方法 ICR雄性小鼠随机分为对照组、人参乙醇提取物（阳性药,2.5 g/kg）组以及蝉花子实体低、中、高剂量（0.075、0.150、0.300 g/kg）组,连续ig给药15 d后,测定小鼠负重游泳力竭时间,试剂盒法检测小鼠经游泳运动后肝糖原、肌糖原、全血乳酸（LD）、血清尿素氮（BUN）、超氧化歧化酶（SOD）和乳酸脱氢酶（LDH）等与疲劳相关联的生化指标变化。结果 与对照组比较,蝉花子实体低、中剂量对小鼠力竭游泳时间有显著延长作用（P<0.05）,低剂量组LD水平显著下降（P<0.05）,高剂量LDH含量显著升高（P<0.05）,低剂量组SOD含量显著升高（P<0.05）;中、高剂量组BUN含量显著降低（P<0.05）,低剂量组肝糖原水平显著升高（P<0.05）;中剂量组肌糖原水平显著升高（P<0.05）。结论 蝉花子实体对运动后的小鼠有抗疲劳作用。     

油酰乙醇胺对东莨菪碱诱导小鼠认知功能损伤的保护作用

目的 探讨油酰乙醇胺对东莨菪碱诱导小鼠认知功能损伤的保护作用。方法 将小鼠随机分为6组：对照组、模型组、多奈哌奇组（阳性药,3 mg·kg^-1）和油酰乙醇胺低、中、高剂量（50、100、200 mg·kg^-1）组,每组6只。在ig给药4周后,除对照组外,各组ip 3 mg·kg^-1的东莨菪碱建立阿尔茨海默病（AD）模型。避暗、跳台行为学实验检测小鼠记忆功能; ELISA法检测小鼠海马和大脑皮层中乙酰胆碱（Ach）和乙酰胆碱酯酶（AChE）水平;HE染色观察小鼠大脑皮层及海马损伤。结果 与对照组比较,模型组的避暗潜伏期显著缩短、避暗错误次数显著增加（P<0.001）;大脑皮层、海马的Ach水平显著减少（P<0.01、0.001）,AChE活性显著升高（P<0.001）;模型组的小鼠脑组织形态结构不均匀,组织细胞呈弥散状,提示组织存在病变。与模型组比较,各给药组的避暗潜伏期显著升高、避暗错误次数显著减少（P<0.01）;油酰乙醇胺给药组的小鼠大脑皮层、海马组织Ach水平显著升高（P<0.05、0.01）,AChE活性显著降低（P<0.01、0.001）;小鼠脑组织形态结构病理改变减轻。结论 油酰乙醇胺对东莨菪碱诱导学习记忆障碍模型小鼠的认知功能具有改善作用,其作用机制可能与调节胆碱能系统功能、促进神经细胞存活有关。     

云树果实醋酸乙酯提取物对H22荷瘤小鼠抑瘤作用及机制研究

目的 研究云树果实醋酸乙酯提取物（EGCF）对H22实体移植瘤的抑制活性及作用机制。方法 皮下接种H22瘤株建立小鼠H22实体移植瘤模型,随机分为模型组、环磷酰胺（20 mg/kg,阳性对照,ip给药）组和EGCF高、中、低剂量（400、200、100 mg/kg,ig给药）组,连续给药10 d,另设一对照组。检测小鼠体质量变化、抑瘤率及脾脏指数,ELISA法测定血清中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）的含量,HE染色法观察肿瘤组织病理学改变,免疫组化法检测肿瘤组织p-STAT3及血管内皮生长因子（VEGF）的表达。结果 与模型组比较,EGCF高、中、低剂量组小鼠的肿瘤质量均显著降低（P<0.01、0.001）,脾脏指数均无显著性差异;高、低剂量组小鼠血清中IL-6水平显著降低（P<0.05）,各剂量组TNF-α含量显著增加（P<0.05、0.01）;各剂量组瘤组织均出现较多红染、碎片状的干酪样坏死区域,且伴有大量空泡形成;各剂量组均显著减少肿瘤组织VEGF表达,高剂量组显著抑制STAT3磷酸化（P<0.05、0.01）。结论 EGCF能够抑制H22实体移植瘤生长,其机制可能与阻断STAT3相关信号通路有关。     

芒果三芪肺纤方对博莱霉素致小鼠肺纤维化作用研究

目的 观察芒果三芪肺纤方对博莱霉素诱导小鼠肺纤维化的改善作用。方法 昆明小鼠随机分为对照组,模型组,地塞米松（阳性药,1 mg/kg）组,芒果三芪肺纤方高、中、低剂量（以生药计5.00、3.30、1.65 g/kg）组,通过鼻腔1次性滴入6 mg/kg盐酸博莱霉素制备小鼠肺纤维化模型,对照组滴入等体积的生理盐水。于造模后第14天开始ig给药,每天给药1次,连续给药14 d后处死小鼠,试剂盒法测定肺组织匀浆中的羟脯氨酸（HYP）、丙二醛（MDA）、白介素-1β（IL-1β）水平和超氧化物岐化酶（SOD）活力;HE染色观察肺组织病理切片,Masson染色观察胶原纤维的分布情况。结果 与模型组比较,芒果三芪肺纤方高、中、低剂量组小鼠HYP和IL-1β水平均显著降低（P<0.01）,SOD活力显著提高（P<0.05、0.01）,高和中剂量组小鼠MDA水平显著降低（P<0.05、0.01）;HE和Masson染色显示,芒果三芪肺纤方组肺泡炎损伤和肺纤维化病变程度明显减轻（P<0.01）,高剂量组效果最好。结论 芒果三芪肺纤方通过提高SOD活力、降低MDA水平,发挥抗自由基损伤作用;降低HYP的水平,减少纤维蛋白的形成;降低IL-1β水平,发挥抗炎作用;显著减轻肺泡炎症损伤、抑制肺纤维化病变程度,对博莱霉素诱导的小鼠肺纤维化具有很好的改善作用。     

辣木叶及其复方对便秘大鼠的通便作用和胃肠激素水平的影响

目的 观察辣木叶及其复方对便秘模型大鼠的通便作用和相关胃肠激素水平的影响。方法 按体质量随机将100只SD大鼠分为10组,即对照组、模型组、番泻叶浸液组（阳性对照,0.01 g/kg）和辣木叶水提液低、中、高剂量（0.79、1.58、3.15 g/kg）组,黄芪白术（1.05 g/kg）组,辣木叶复方水提液低、中、高剂量（1.84、2.63、4.20 g/kg）组。除对照组外,均采用盐酸洛哌丁胺（6.67 mg/kg）复制便秘模型,每日2次,连续2周。造模结束后,各给药组分别ig相应受试样品,每天1次,连续7 d。记录各组大鼠体质量、最后24 h粪便粒数,测定粪便含水量、小肠炭末推进率,ELISA试剂盒法检测血清P物质、生长抑素含量及结肠胃动素、血管活性肠肽含量。结果 与模型组比较,辣木叶水提液中、高剂量组及辣木叶复方水提液各剂量组的体质量增量显著升高（P<0.05）;各给药组大鼠的排便粒数与模型组比较均显著性增加（P<0.05）;各给药组大鼠粪便含水量与模型组比较均无显著性差异;辣木叶水提液中、高剂量组及其复方水提液中、高剂量组小肠炭末推进率显著增加（P<0.05、0.01）。辣木叶水提液中、高剂量组及其复方水提液各剂量组血清P物质含量、结肠组织胃动素含量均显著高于模型组（P<0.05、0.01）;辣木叶水提液高剂量组及辣木叶复方水提液中、高剂量组大鼠血管活性肠肽含量较模型组降低显著（P<0.05、0.01）;各给药组大鼠血清生长抑素水平均显著低于模型组（P<0.01）。辣木叶复方水提物上述作用均好于等剂量辣木叶水提液及黄芪白术水提液。结论 辣木叶及其复方具有良好的通便作用,可能与调节胃肠激素水平有关;复方的通便及调节胃肠激素的作用优于单味药辣木叶及黄芪白术,体现出复方配伍的整体优越性,其中辣木叶侧重调节P物质、胃动素及血管活性肠肽水平,而黄芪白术主要调节生长抑素水平。     

隐丹参酮对慢性不可预见应激联合脂多糖所致抑郁小鼠氧化应激和炎症反应的影响

目的 观察隐丹参酮对慢性不可预见应激（CUMS）联合脂多糖（LPS）所致抑郁小鼠氧化应激和炎症反应的影响。方法 60只清洁级ICR小鼠随机分为对照组、模型组、帕罗西汀组（20 mg/kg）及隐丹参酮低、中、高剂量（10、20、40 mg/kg）组,每组10只。采用CUMS＋LPS应激刺激14 d建立抑郁模型（除对照组）,同时ig相应药物或生理盐水,1次/d,连续14 d。通过体质量增量、糖水偏好指数、悬尾实验及新奇环境摄食测试评价抑郁行为,并测定各组血清超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）,海马和皮质白细胞介素（IL）-6、IL-1β、肿瘤坏死因子（TNF）-α变化情况。结果 隐丹参酮20、40 mg/kg组体质量增量及SOD、CAT、GSH-Px酶活性高于模型组,不动时间短于模型组（P＜0.05、0.01）,海马IL-6、海马和皮质IL-1β含量低于模型组（P＜0.05、0.01）。各治疗组糖水偏好指数高于模型组、摄食潜伏期短于模型组（P＜0.05、0.01）,血清MDA、皮质TNF-α含量低于模型组（P＜0.05、0.01）。隐丹参酮40 mg/kg组皮质IL-6、海马TNF-α含量低于模型组（P＜0.01）。结论 隐丹参酮对CUMS联合LPS致小鼠抑郁症状有改善作用,其机制可能与抑制过强的氧化应激反应与神经炎症反应,并减轻神经元损伤有关。     

山茱萸总萜对KKay糖尿病小鼠的治疗作用研究

目的 观察山茱萸总萜对KKay糖尿病小鼠的治疗作用。方法 选择KKay糖尿病小鼠模型,分别以低、中、高剂量（0.05、0.10、0.20 g/kg）的山茱萸总萜ig给药5周。每天给药前观察动物一般状况;给药前及给药期间每周测定1次小鼠体质量、空腹血糖;给药第5周,进行ip葡萄糖耐量试验（IPGTT）,采血测定胰岛素（Ins）、糖化血红蛋白（HbA1c）、糖化血清蛋白（GSP）、总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）水平,计算胰岛素抵抗指数（IR）。结果 与模型组比较,山茱萸总萜可以剂量相关性地减轻KKay小鼠体质量,高剂量组第1、2和5周差异显著（P<0.05）;各剂量组自给药第1周起即可显著降低空腹血糖水平（P<0.05、0.01）;高剂量组显著降低IPGTT中小鼠血糖-时间曲线下面积（P<0.05）;山茱萸总萜可以剂量相关性地降低Ins、HbA1c、GSP、TC、TG、LDL水平、降低IR。结论 山茱萸总萜对于KKay小鼠糖尿病相关症状和指标具有剂量相关性的改善作用,可改善脂质代谢紊乱,提示其在治疗伴有胰岛素抵抗和脂质代谢紊乱的轻、中度2型糖尿病方面具有良好的应用前景。     

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.     

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.