氯化钆保护细菌脂多糖引发肝脏损伤及其可能机制

目的探讨氯化钆(Gadolinium Chloride,GdCl3)在细菌脂多糖(Lipopolysaccharide,LPS)引起的肝脏损伤中的作用及其机制。方法将MT基因敲除小鼠(MT-/-)及与之对应的野生型小鼠(MT / )各分为4组:生理盐水对照组、LPS染毒组、GdCl3组、GdCl3预处理 LPS染毒组。动物腹腔注射LPS(10mg/kg)或生理盐水(NS),此前24h给予GdCl3(10mg/kg,i.v.)或NS预处理。注射LPS后24h测定血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力以及一氧化氮(NO)含量,镉饱和法测定肝脏金属硫蛋白(MT)含量,进行肝组织病理学检查,判定不同处理对MT-/-小鼠及MT / 小鼠肝脏的影响的差异。结果注射LPS后,MT-/-小鼠及MT / 小鼠血ALT,AST活力,血NO含量均较对照组升高,2种小鼠肝组织均出现大量炎性细胞浸润、肝细胞浊肿、空泡变性、灶性液化坏死、星状细胞增生。LPS致MT-/-小鼠肝组织损伤程度较MT / 小鼠更为严重。氯化钆、LPS均可以诱导MT / 小鼠肝脏MT生成。GdCl3预处理可以降低LPS对MT-/-小鼠及MT / 小鼠血ALT,AST活力,血NO含量的影响,可以减轻LPS对2种小鼠肝组织病理学损伤。结论GdCl3预处理可以有效减轻LPS对MT-/-小鼠及MT / 小鼠引起的肝脏损伤,其可能机制与其对肝脏Kupffer细胞抑制作用有关。     

氯化钆保护细菌脂多糖引发肝脏损伤及其可能机制研究

目的探讨氯化钆(Gadolinium chloride,Gd Cl3)在细菌脂多糖(Lipopolysaccharide,LPS)引起肝脏损伤的影响及其机制。方法将MT基因敲除小鼠(MT-/-)及与之对应的野生型小鼠(MT+/+)各分为4组:生理盐水对照组、LPS染毒组、Gd Cl3组和Gd Cl3预处理+LPS染毒组。动物腹腔注射LPS(10 mg/kg,腹腔注射)或生理盐水(NS,腹腔注射),此前24 h给予Gd Cl3(10 mg/kg,尾静肪注射)或NS预处理。注射LPS后24 h测定血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力以及一氧化氮(NO)含量,镉饱和法测定肝脏金属硫蛋白(MT)含量,进行肝组织病理学检查,判定不同处理对MT-/-小鼠及MT+/+小鼠肝脏影响的差异。结果注射LPS后,MT-/-小鼠及MT+/+小鼠血ALT、AST活力,血NO含量均较对照组升高,两种小鼠肝组织均出现大量炎性细胞浸润、肝细胞浊肿、空泡变性、灶性液化坏死、星状细胞增生。组织病理学检查结果显示MT-/-小鼠肝组织损伤程度较MT+/+小鼠更为严重。氯化钆、LPS均可以诱导MT+/+小鼠肝脏MT生成。Gd Cl3预处理可以同时降低LPS对MT-/-小鼠及MT+/+小鼠血ALT,AST活力,血NO含量的影响,可以减轻LPS对两种小鼠肝组织病理学损伤。结论 Gd Cl3预处理可以有效减轻由LPS引起的肝脏损伤,MT通过其对Kuffer细胞的抑制作用保护LPS引起的肝脏损伤。     

NF-κB在MT对LPS致肝脏炎症损伤保护效应中的作用

目的采用NF-κB特异性抑制剂PDTC,观察NF-κB在MT保护LPS急性肝脏损伤中保护效应的作用机理。方法 MT+/+小鼠和MT-/-小鼠各分为4组,在注射LPS前30 min,腹腔注射PDTC 40 mg/kg,LPS剂量为10 mg/kg,24 h后处死动物。结果 PDTC预处理可以降低两种小鼠血清酶ALT、AST活性,减少血液中TNF-α、IL-1β、IL-6等细胞因子,血清以及肝脏组织中NO含量,降低肝组织TNF-α表达量,同时减轻两种小鼠肝脏组织病理学损伤程度,减轻肝组织内脂质过氧化产物生成量。以PDTC预处理消除MT自由基清除作用对NF-κB转录活性的影响后,不能观察到两种小鼠NF-κB转录活性间的差异,其未见两种小鼠肝脏损伤程度的差异。结论 MT可能通过其自由基清除作用调控NF-κB信号通路,从而影响整个炎症反应网络,造成了LPS致两种小鼠肝脏炎症损伤程度间的差异。     

地塞米松对二甲基甲酰胺致小鼠急性肝损伤的保护作用

目的 研究地塞米松(DEX)对二甲基甲酰胺(DMF)致小鼠急性肝损伤的保护作用.方法 采用DMF致小鼠急性肝损伤模型.染毒48 h后,测定血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)和乳酸脱氢酶(LDH)的活力.留取肝脏组织.常规石蜡包埋切片,HE染色,光学显微镜观察肝脏组织病理变化;制备肝匀浆,测定肝中金属硫蛋白(MT)的含量.结果 与正常组比较,模型组小鼠血清中ALT、AST和LDH活力明显升高,肝脏组织出现明显的肝细胞变性坏死;先给予和后给予DEX的各剂量组小鼠血清中ALT、AST和LDH活力与模型组比较显著降低,肝脏组织病理损伤明显减轻.肝脏MT的含量明显升高.结论 DEX对DMF引起的小鼠急性肝损伤具有明显的保护作用,MT可能是其保护机制的参与因子之一.     

秃疮花提取物对小鼠免疫性肝损伤的保护作用

目的　探讨秃疮花提取物 (DLF)对卡介苗 (BCG)和脂多糖 (LPS)诱导的小鼠免疫性肝损伤的影响。方法　ivBCG和LPS诱导小鼠免疫性肝损伤 ,在注射LPS前 ,小鼠ip不同剂量的DLF(0 5、1 0、2 0g·kg-1) ,连续 10d。观察血清谷丙转氨酶 (ALT)、谷草转氨酶 (AST)、乳酸脱氢酶 (LDH)的活性及血清白蛋白 (ALB)、球蛋白 (GLB)含量变化 ,测定肝组织匀浆中脂质过氧化产物丙二醛 (MDA)含量和超氧化物歧化酶(SOD)活性 ,同时进行肝组织病理学观察。结果　不同剂量的DLF治疗组小鼠血清ALT、AST、LDH活性及肝组织匀浆MDA含量均低于模型组 ,血清蛋白维持正常比例 ,且肝组织损伤不同程度地减轻。结论　秃疮花提取物对BCG和LPS诱导的小鼠免疫性肝损伤具有一定的保护作用     

口服鲨鱼肝再生因子脂质体对小鼠急性肝损伤的保护作用

为研究口服鲨鱼肝再生因子脂质体对四氯化碳(CCl4)和硫代乙酰胺(TAA)对小鼠急性肝损伤的保护作用,采用CCl4和TAA致小鼠肝损伤,观察肝组织切片,测定生化指标,检测小鼠给药后血清谷丙转氨酶(ALT)、血清谷草转氨酶(AST)活力。结果口服鲨鱼肝再生因子脂质体能明显减轻CCl4和TAA所致小鼠急性肝损伤模型的肝组织损伤作用,降低ALT、AST活力。因此口服鲨鱼肝再生因子脂质体对急性肝损伤也有明显的保护作用。     

三叶青总氨基酸对四氯化碳致小鼠肝损伤的保护作用

目的观察三叶青总氨基酸(TAART)对四氯化碳(CCl4)诱导的小鼠急性肝损伤的保护作用。方法选用CCl4致小鼠急性肝损伤模型,以测定小鼠血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)活性,肝脏系数,肝组织中超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量及对肝组织进行病理学检查等指标观察TAART对肝损伤的保护作用。结果TAART能明显降低CCl4致小鼠肝损伤血清ALT,AST值,降低肝脏系数及肝组织中MDA的含量,增加肝组织中SOD活性,减轻CCl4对肝脏细胞的病理损伤。结论三叶青总氨基酸对CCl4致小鼠急性肝损伤具有保护作用,其机制可能与其抗氧化作用相关。     

彩虹明樱蛤多糖对小鼠急性化学性肝损伤的保护作用

目的研究彩虹明樱蛤多糖(MIP)对CCl4致小鼠急性化学性肝损伤的保护作用。方法 MIP对小鼠连续腹腔注射7 d,以0.1%CCl4橄榄油溶液经腹腔注射,建立小鼠急性化学性肝损伤模型,测定给药后模型小鼠肝指数,检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)活性,测定肝组织匀浆中丙二醛(MDA)含量和超氧化物歧化酶(SOD)、谷胱甘肽(GSH)的活性及观察肝脏病理学变化。结果 MIP中、高剂量组(80,160 mg/kg)均能显著降低CCl4致急性肝损伤小鼠血清ALT、AST活性(P<0.01),降低肝脏MDA含量(P<0.01),增强SOD和GSH活力(P<0.01或0.05),并能明显改善肝组织的病理学损伤,但对肝指数无明显影响。结论 MIP对CCl4致小鼠急性化学性肝损伤有保护作用。     

番茄红素对四氯化碳致小鼠急性肝损伤的保护作用

目的 观察番茄红素对四氯化碳(CC14)引起的小鼠急性肝损伤的保护作用.方法 将小鼠分为正常组、模型组、番茄红素组和阳性药联苯双酯组.番茄红素组和联苯双酯组分别用番茄红素和联苯双酯ig进行预给药干预,正常组和模型组以溶剂0.1％羧甲基纤维素钠ig,连续给药7d后ip CCl4致小鼠急性肝损伤.计算肝脏指数,检测血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)以及肝组织中的超氧化歧化酶(SOD)、丙二醛(MDA)、乳酸脱氢酶(LDH)的水平,并观察肝组织HE染色切片的病理变化.结果 番茄红素能显著降低急性肝损伤小鼠血清ALT、AST活性;升高肝组织匀浆中SOD活力,降低MDA含量和LDH活性;病理切片表明给药组小鼠肝损伤均减轻.结论 番茄红素对CCl4致小鼠急性肝损伤具有保护作用,其机制可能与番茄红素所具有抗脂质过氧化和清除体内过多的氧自由基的作用有关.     

巴马火麻仁总木脂素酰胺类提取物对小鼠急性肝损伤的保护作用

目的研究广西巴马产火麻仁中提取分离获得的火麻仁总木脂素酰胺类提取物(LFC)对CCl4致小鼠急性肝损伤的保护作用。方法昆明种小鼠,以LFC低、中、高(60、120、180 mg·kg-1)剂量连续给药7 d后,分别采用腹腔注射0.1%CCl4的橄榄油溶液(10 mL·kg-1)建立小鼠急性肝损伤模型,16 h后,杀鼠取材,分别检测小鼠血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)活性,肝脏中丙二醛(MDA)、超氧化物歧化酶(SOD)含量,光学显微镜下观察肝组织病理学变化。结果 CCl4模型组肝功能明显异常,ALT、AST显著升高,肝组织变性、坏死严重。经LFC预防性治疗后,血清中ALT、AST活性显著降低(P<0.01)、肝组织中MDA含量显著降低(P<0.01),SOD活力增加;肝脏组织学观察证实,LFC能明显改变受损组织的病理学变化。结论 LFC对CCl4致小鼠急性肝损伤均具有较好的保护作用。     

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.     

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.

     

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.     

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.     

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.