正极性驻极体5-氟尿嘧啶贴剂对兔耳瘢痕组织中Ⅰ、Ⅲ型胶原和TCF-β表达的影响

目的 研究+5 kV驻极体、5-氟尿嘧啶（5-FU）贴剂和+5 kV驻极体5-FU贴剂对兔耳瘢痕组织中Ⅰ、Ⅲ型胶原和转化生长因子-β（TGF-β）表达的影响。方法 将通过电晕充电系统制备的正极性聚丙烯驻极体充电面与制备的5-FU贴剂背衬层结合制成表面电位为+5 kV的驻极体5-FU贴剂,再将+5 kV驻极体、5-FU贴剂和+5 kV驻极体5-FU贴剂分别作用于兔耳创面,通过测算瘢痕增生指数,观察研究瘢痕增生状况,通过HE染色、Masson染色和免疫组织化学的方法,研究上述驻极体、5-FU贴剂和驻极体5-FU贴剂对兔耳瘢痕组织中Ⅰ、Ⅲ型胶原和TGF-β表达的影响。结果 ①兔耳创面自然愈合4周后形成增生性瘢痕组织。②正极性驻极体不会导致创面过度修复。③5-FU贴剂和正极性驻极体5-FU贴剂通过减少瘢痕组织内Ⅰ型胶原、Ⅲ型胶原和TGF-β的表达量,抑制增生性瘢痕的生长。④正极性驻极体5-FU贴剂抑制增生性瘢痕生长的效果优于5-FU贴剂。结论 正极性驻极体与5-FU联用抑制增生性瘢痕生长的效果更好。     

齐墩果酸对兔耳增生性瘢痕的治疗作用

目的研究齐墩果酸（oleanolicacid）对兔耳增生性瘢痕的治疗作用。方法用打孔器产生创面建立兔耳增生性瘢痕模型。齐墩果酸（2．5％、5％、10％）外用给药,1次／d,连续22d。给药结束后切除瘢痕组织进行组织学检测并且测定I型和Ⅲ型胶原、基质金属蛋白酶．1（MMP-1）和生长转化因子βl（TGF-βl）的水平以及瘢痕增生指数（scarelevationindex,SEI）。结果用不同质量浓度的齐墩果酸给药22d后发现其对兔耳肥厚性瘢痕有显著的治疗作用,TGF-βl、I型和Ⅲ型胶原水平显著降低,MMP-1在瘢痕组织中显著增加,SEI明显降低。组织形态观察结果显示齐墩果酸对瘢痕有明显的改善作用。结论齐墩果酸对兔耳增生性瘢痕有治疗作用,可能成为治疗人类增生性瘢痕的活性药物。     

阿利吉仑对急性心肌梗死大鼠心肌组织重构的影响

目的 探讨阿利吉仑对大鼠心肌梗死后左室重构的影响及作用机制.方法 60只Wistar大鼠随机分为假手术组、模型对照组、培哚普利组和阿利吉仑组,每组15只.除假手术组外,其他3组均制作心肌梗死模型.培哚普利组和阿利吉仑组制作心肌梗死模型后分别给予培哚普利和阿利吉仑共8周.酶联免疫吸附测定(ELISA)检测血清中高敏C-反应蛋白(hs-CRP),免疫组织化学方法 检测基质金属蛋白酶(MMP) 2、MMP-9、金属蛋白酶抑制因子(TIMP)-1和转化生长因子-β(TGF-β)的表达.逆转录聚合酶链反应(RT-PCR)检测心肌组织MMP-2、MMP-9、TIMP-1、TGF-β、CollagenⅠ和Ⅲ mRNA的表达.Western blotting检测心肌组织MMP-2、MMP-9、TIMP-1、TGF-β蛋白的表达.结果 培哚普利组和阿利吉仑组血清hs-CRP明显低于模型对照组(P<0.05).培哚普利组和阿利吉仑组MMP-2、MMP-9、TGF-β、Collagen Ⅰ和Ⅲ mRNA和蛋白的表达明显低于模型对照组(P<0.05),TIMP-1 mRNA的水平则高于模型模型对照组(P<0.05).结论 阿利吉仑通过下调MMP-2、MMP-9、TGF-β、Collagen Ⅰ和Ⅲ和hs-CRP表达、 上调TIMP-1表达发挥作用.阿利吉仑和培哚普利在减轻大鼠心肌梗死后左室重构无明显差别.     

转化生长因子-β_1对气道上皮细胞结缔组织生长因子表达的影响

目的研究转化生长因子-β1(TGF-β1)对气道上皮细胞结缔组织生长因子(CTGF)表达的影响。方法原代培养新西兰兔气道上皮细胞,采用免疫细胞化学法检测TGF-β1作用下气道上皮细胞CTGF蛋白的表达水平。结果①TGF-β1不同处理时间各组气道上皮细胞CTGF蛋白表达均较对照组显著增强,差异有统计学意义(P均<0.01);②TGF-β15ng/mL处理组、10ng/mL处理组气道上皮细胞CTGF蛋白表达均较对照组显著增强,差异有统计学意义(P均<0.01)。结论 TGF-β1可上调气道上皮细胞CTGF蛋白的表达水平,从而引起气道重塑。     

黄芪总苷液对瘢痕疙瘩成纤维细胞生长作用研究

摘 要 目的：探讨黄芪总苷液对人瘢痕疙瘩成纤维细胞的抑制作用。方法: 以正常皮肤为对照,用免疫组化检测瘢痕疙瘩组织标本中转化生长因子 β（transforming growth factor-β,TGF-β）及其转导因子(SMAD family member,Smad)的表达情况;不同浓度黄芪总苷液干预HFF-1人皮肤成纤维细胞后,MTT法检测其最适浓度;Real time PCR 测定成纤维细胞TGF-β的转导因子Smad2（SMAD family member 2）,Smad3（SMAD family member 3）,Smad4（SMAD family member 4）,Smad7（SMAD family member 7）mRNA的表达;Western blot 检测成纤维细胞TGF-βRⅡ,Smad2,Smad3,Smad4,Smad7的蛋白水平表达。结果: 与正常皮肤组织相比,瘢痕疙瘩组织Smad蛋白表达水平明显提高（P<0.05）,TGF-βRⅡ蛋白的表达水平在两组中没有明显差异（P>0.05）。MTT检测最适给药浓度为0.5 μg·mL^-1。两组细胞TGF-β/Smad信号通路相关蛋白表达量比较,给药组Smad2的表达水平明显提高,Smad3的表达水平明显降低（P<0.05）。结论:黄芪总苷液可能通过过表达Smad2以及抑制Smad3的表达来影响TGF-β/Smad 通路过程从而抑制成纤维细胞的形成。     

刺老苞根皮水提物对成骨细胞TGF-β/BMPs信号通路的影响

目的 研究刺老苞根皮水提物对成骨细胞TGF-β/BMPs信号通路的影响。方法 建立大鼠骨折模型,随机分为模型组,刺老苞根皮水提物低、中、高剂量（3.6、1.8、0.9 g/kg）组,ig给药7 d后腹主动脉取血,分离血清;培养大鼠原代成骨细胞,经碱性磷酸酶染色、茜素红染色鉴定合格后,分别以对应组别的动物血清连续培养48 h,采用实时荧光定量PCR（qRT-PCR）和Western blotting技术分别检测各组细胞中骨形态发生蛋白质-2（BMP-2）、转化生长因子-β（TGF-β）、Smad家族相关蛋白1、2（Smad-1、Smad-2）mRNA和蛋白表达。结果 与模型组比较,刺老苞根皮水提物不同浓度的含药血清组BMP-2、TGF-β、Smad-1 mRNA表达均显著升高（P<0.05、0.01）,中、高剂量含药血清组Smad-2 mRNA表达显著升高（P<0.05）;低、中、高剂量含药血清组的BMP-2、TGF-β、Smad-1、Smad-2蛋白表达均显著升高（P<0.05）。结论 刺老苞根皮水提物通过上调TGF-β/BMPs信号传导通路中的BMP-2、TGF-β、Smad-1、Smad-2表达,促进成骨细胞增殖。     

病理性瘢痕组织中TGF-β1及MMP-1的表达

目的 研究人体病理性瘢痕组织（增殖性瘢痕及瘢痕疙瘩）中转化生长因子β1（TGF-β1）及基质金属蛋白酶1（MMP-1）的表达。方法取10例病理性瘢痕切片，SP法检测TGF-β1及MMP-1，并与正常皮肤组织对照。结果免疫组化法沉淀病理性瘢痕中TGF-β1、MMP-1表达较正常皮肤组显著增高（P〈0．05）。结论病理性瘢痕组织中TGF-β1及MMP-1均呈高表达，导致胶原沉积，瘢痕形成。     

曲尼司特对兔增生性瘢痕组织的抑制作用及其机制研究

目的:研究曲尼司特对兔增生性瘢痕组织的抑制作用及其机制。方法:取兔建立增生性瘢痕模型,将建模成功的兔随机分为模型对照组(生理盐水)和曲尼司特低、中、高剂量组(0.3、0.5、0.7 mg/kg),每组6只,局部sc相应药物。各组兔分别于注射前1 h和注射后第1、3、5周测量瘢痕厚度,观察注射后第5周瘢痕病理学变化,并检测瘢痕组织中TGF-β_1、α-SMA mRNA和蛋白表达。结果:与注射前1 h比较,除模型对照组外,其余各组兔注射后各时间点瘢痕厚度均减小(P<0.05)。注射后第5周,与模型对照组比较,其余各组兔注射后第5周的瘢痕厚度均减小,病理学变化均好转,瘢痕组织中TGF-β_1、α-SMA mRNA和蛋白表达均降低(P<0.05),且与曲尼司特剂量呈正相关。结论:曲尼司特能够抑制增生性瘢痕的形成,其作用机制可能与抑制瘢痕组织中TGF-β_1、α-SMA mRNA和蛋白的表达有关。     

曲尼司特乳膏对兔耳增生性瘢痕模型的作用研究

目的考察曲尼司特乳膏外用对兔耳增生性瘢痕模型的作用。方法通过手术去皮建立兔耳增生性瘢痕动物模型,考察曲尼司特乳膏(0.5%、1%、2%)外用对瘢痕增生的影响,自造模21 d瘢痕形成后各组每日涂抹2次,连续30 d。结果与模型组相比,1%和2%曲尼司特乳膏给药对瘢痕平均厚度具有明显的改善作用,其中给药第5~20日差异具有统计学意义。曲尼司特乳膏对瘢痕组织羟脯氨酸和转化生长因子β_1水平具有浓度依赖性的抑制作用。瘢痕组织病理学检查显示,曲尼司特乳膏治疗组瘢痕修复程度优于模型组。结论曲尼司特乳膏外用对兔耳瘢痕增生具有一定的促进消退作用,主要表现为抑制瘢痕厚度和减少胶原的沉积,有良好的潜在开发价值。     

消痔丸对醋酸致肛门溃疡模型大鼠的作用机制研究

目的 探讨消痔丸对醋酸诱导大鼠肛门溃疡模型的药效作用及其可能的作用机制。方法 以醋酸诱导大鼠肛门溃疡模型,将造模成功大鼠分为模型组、消痔丸（0.81、1.62、3.24 g/kg）组、柑橘黄酮片（0.27 g/kg）组和痔炎消片（0.86 g/kg）组,另设置对照组,每组10只。对照组与模型组ig给予同等体积的0.1% CMC-Na溶液。各组连续ig给药10 d,1次/d。观察各组大鼠表观指标,并采用Image J软件计算溃疡面积;苏木素–伊红染色法观察肛门直肠组织病理学,并进行分级评分;酶联免疫吸附法（ELISA）检测大鼠肛门组织中基质金属蛋白酶-9（MMP-9）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）含量;免疫组化法检测肛门组织中诱导型一氧化氮合成酶（iNOS）、转化生长因子β1（TGFβ1）、血管内皮生长因子A（VEGFA）蛋白表达。结果 与模型组相比,消痔丸组可显著改善醋酸所致大鼠肛周溃疡、肿胀、黏液分泌等情况,加快大鼠肛周黏膜上皮修复,溃疡面积缩小,减少间质或黏膜下水肿及炎性细胞浸润和炎性渗出物;消痔丸组可抑制肛周组织中MMP-9、IL-6、TNF-α分泌和iNOS、VEGFA蛋白表达,增加TGF-β1表达（P＜0.05、0.001）。结论 消痔丸对醋酸诱导的肛门溃疡模型治疗作用显著,主要通过抑制IL-6、TNF-α、MMP-9相关细胞因子分泌和iNOS、VEGFA蛋白表达,升高TGF-β1表达,从抗炎消肿、抑制基质降解、促进组织生长因子表达等途径,起到消肿生肌作用。     

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.