大黄素对家兔实验性皮肤创伤的促愈合作用及其机制

目的探讨大黄素治疗皮肤创伤的可能性及其作用机制。方法采用家兔皮肤切除伤创伤模型,同时滴加绿脓杆菌或金黄色葡萄球菌。大黄素(100~200μg·g-1)敷于创面,每天1次,连续7d或14d。观察创面面积、创面细菌数量和病理组织学改变。生化测定创面组织蛋白和羟脯氨酸(OHP)含量;免疫组化S-P法检测转化生长因子(TGF-β1)含量;逆转录聚合酶链反应测定TGF-β1mRNA表达;Western印迹分析Smad2,3,4和7表达。结果大黄素(100~200μg·g-1)随药物剂量和时间的增加而提高创面愈合百分率和降低感染创面表面细菌数;创面组织蛋白和羟脯氨酸的含量也随着剂量的增加而增加。病理结果显示,大黄素200μg·g-1明显促进创面炎性渗出物吸收、肉芽组织形成和表皮增生。随大黄素浓度的增加,与基质对照组相比,TGF-β1基因和蛋白的表达逐渐增高,均有显著差异;对Smad4蛋白表达无影响,大黄素150和200μg·g-1使Smad7蛋白表达降低;大黄素200μg·g-1使Smad3和Smad2表达增加,其他剂量则无影响。与rhEGF组相比,大黄素100和(或)150μg·g-1组使Smad2和Smad3表达明显下降。结论大黄素促进实验性皮肤创面的修复,其机制可能与TGF-β1和Smads信号转导通路有关。     

Arsenic toxicity at low doses: epidemiological and mode of action considerations

Current approaches to risk assessment typically assume a linear dose-response for mutagenic compounds that directly interact with DNA or when the carcinogenic mechanism is unknown. Because the mode of action of arsenic-induced carcinogenesis is not well established, recent dose-response assessments for arsenic have assumed linearity at low doses despite evidence that arsenic is not a direct-acting mutagen. Several modes of action, including generation of oxidative stress, perturbation of DNA methylation patterns, inhibition of DNA repair, and modulation of signal transduction pathways, have been proposed to characterize arsenic's toxicity. It is probable that these mechanisms do not act in isolation, but overlap, and contribute to the complex nature of arsenic-induced carcinogenesis. All of the proposed mechanisms are likely to be nonlinear at low does. Furthermore, studies of populations outside the US exposed to arsenic in drinking water show increases in cancer only at relatively high concentrations, that is, concentrations in drinking water of several hundred micrograms per liter (microg/l). Studies in the US of populations exposed to average concentrations in drinking water up to about 190 microg/l do not provide evidence of increased cancer. Consideration of arsenic's plausible mechanisms and evidence from epidemiological studies support the use of nonlinear methods, either via biologically based modeling or use of a margin-of-exposure analysis, to characterize arsenic risks.     

烧伤变形脱细胞真皮基质用于烧伤创面修复的可行性研究

目的：评价烧伤变形脱细胞真皮基质（denatured acellular dermal matrix,DADM）用于烧伤创面修复的可行性。 方法：选取我院于2014 年9 月~2015 年2月收治的40例烧伤患者为研究对象,随机分为研究组和对照组,每组20例。实验组患者实施DADM覆盖创面移植术,对照组实施异种脱细胞真皮基质（acellular dermal matrix,ADM）覆盖创面移植术。比较两组患者的植皮成活率、瘢痕形成及治疗前后主要实验室指标。 结果：烧伤变形脱细胞真皮基质的疗效显著强于异种脱细胞真皮基质（ χ2=5.582,P=0.043）。烧伤变形脱细胞真皮基质较异种脱细胞真皮基质能够减轻瘢痕增生,研究组的瘢痕评分显著高于对照组（ χ2=9.241,P=0.002）。治疗后,两组患者的外周血血红蛋白、丙氨酸氨基转移酶（ALT）水平及尿素氮（BUN）水平均显著降低,且研究组显著低于对照组（P<0.05）。 结论：烧伤变形脱细胞真皮基质可作为真皮替代物,用于烧伤创面的修复,能够减轻瘢痕增生,值得推广应用。     

湿润烧伤膏在骨科创面修复中的应用

目的寻找一种能在骨科创面修复中抑制细菌生长,促进肉芽生长的方法。方法本组127例不能行一期修复的患者的创面,均采用湿润烧伤膏涂抹加其油纱布覆盖换药治疗后,再行植皮或皮瓣修复。结果127例患者中,124例创面的肉芽生长良好,经植皮或皮瓣修复后,创面愈合良好,治愈率97．6％。结论在骨科的创伤中不能行一期修复的创面,采用湿润烧伤膏换药治疗,促进肉芽生长后,再行创面植皮或皮瓣修复治疗,创面愈合良好。     

重组人角质细胞生长因子-2对大鼠皮肤烫伤的治疗作用及其可能机制探讨

目的：研究重组人角质细胞生长因子-2（rhKGF-2）对大鼠皮肤烫伤愈合的影响及其可能的作用机制。方法：建立大鼠深Ⅱ度烫伤模型,每天局部给药1次,连续15d,每4d测量伤口面积并计算愈合率,d16观察新生上皮面积、厚度和上皮细胞迁移距离。体外培养HaCaT细胞,MTT法检测不同浓度的rhKGF-2对HaCaT细胞增殖率的影响;划痕实验检测rhKGF-2对HaCaT细胞移行的影响。结果：rhKGF-2对大鼠皮肤深Ⅱ度烫伤的愈合有明显的促进作用,使新生上皮面积、平均厚度和上皮细胞移行距离等明显增加。rhKGF-2可刺激HaCaT细胞增殖,集落形成率增加（P〈0.05）,且细胞呈明显的增殖形态,形成的集落较大,集落内细胞多呈星状,胞内染色质丰富;rhKGF-2能显著促进创伤周围细胞向创面中央移行（P〈0.01）。结论：rhKGF-2能明显加快大鼠烫伤创面愈合,可能作用机理为通过促进表皮细胞增殖和移行,加速创面皮肤再上皮化。     

积雪草苷对小鼠胶原诱导性关节炎的抑制作用

研究积雪草苷(asiaticoside)对小鼠胶原诱导性关节炎(collagen-induced arthritis，CIA)的作用，并初步探讨其作用机制。建立CIA模型，检测小鼠足爪炎症的肿胀度，石蜡切片HE染色对关节组织进行病理检查，MTT法检测脾淋巴细胞增殖反应，Western blotting法检测关节软组织中环氧酶-2(cyclooxygenase-2，COX-2)蛋白的表达，EIA法测定关节软组织中前列腺素E₂(prostaglandin E₂，PGE₂)水平，ELISA法检测血清中炎症因子TNF-α、IL-6的水平。积雪草苷(10，20及40 mg·kg^-1)灌胃给药能剂量依赖性地减轻CIA小鼠的关节炎症状，抑制CIA小鼠C II胶原诱导的淋巴细胞增殖反应，减少CIA小鼠踝关节软组织中高水平的COX-2表达及PGE₂含量，降低血清中炎症因子TNF-α和IL-6的水平；同时病理检查发现，可以改善局部关节炎症状，抑制CIA小鼠滑膜细胞增生，减轻炎性细胞浸润。结果表明，积雪草苷对CIA具有抑制作用，其机制可能与抑制淋巴细胞增殖、减少COX-2表达及促进炎症因子TNF-α、IL-6释放等有关。     

Pyretic action of low doses of gamma-hydroxybutyrate in rats

gamma-Hydroxybutyrate (GHB) has been found to have a biphasic effect on body temperature with increased body temperature after low doses (5-10 mg/kg) and decreased body temperature after high doses (300-500 mg/kg). Brain levels of GHB between 30 and 60 min post-injection of GHB were not altered by the low doses (5-10 mg/kg), although a dose of 200 mg/kg produced a large increase in the brain concentration.     

Bioavailability of diclofenac potassium at low doses

AIM: Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K. METHODS: A randomized, three-way, cross-over study was performed in 10 subjects. Each received diclofenac-K, 22.5 mg via short-term i.v. infusion and orally at single doses of 12.5 mg and 25 mg. RESULTS: Mean (+/- SD) times to maximal plasma concentration (t(max)) of diclofenac were 0.48 +/- 0.28 h (12.5 mg) and 0.93 +/- 0.96 h (25 mg). The absolute bioavailability of diclofenac-K after oral administration did not differ significantly in the 12.5-mg and 25-mg dose group (63.1 +/- 12.6%vs. 65.1 +/- 19.4%, respectively). The 90% confidence intervals for the AUC(infinity) and AUC(t) ratios for the two oral regimes were 82.6, 103.4% (point estimate 92.4%) and 86.2, 112.9% (point estimate 98.6%), respectively. These values were within the acceptance criteria for bioequivalence (80-125%). CONCLUSIONS: Our data indicate that diclofenac-K is rapidly and well absorbed at low dose, and are consistent with a rapid onset of action of the drug. Abbreviations AUC, area under plasma concentration-time curve; C(max), peak plasma concentration; CI, confidence interval; COX, cyclooxygenase; D, dose; F, absolute bioavailability; t(max), time to reach C(max).     

Effect of lindane at repeated low doses

The relationship between brain concentration of lindane and its convulsant effect have been studied in rats after repeated low doses of lindane. The mean brain plateau concentration was achieved in 5-8 days. The doses administered (5, 12 and 20 mg/kg) and the brain concentration of lindane at the plateau were highly correlated. The incidence rate of response (percentage of rats with tonic convulsions) was also highly correlated with the log of concentration of lindane in brain for all doses and days studied. A decrease in brain concentration of lindane was observed after 12 days of daily administration at doses of 5 and 12 mg/kg but not at the highest dose (20 mg/kg).     

川芎嗪抗肿瘤转移作用及其机理

川芎嗪(TTMP)在20mg·kg~(-1)·d~(-1)剂量下,给药18d,能显著抑制B16-F10黑素瘤的人工肺转移,其肺转移结节数由134个下降到72个.放射免疫法测定TTMP能显著降低肺转移小鼠血浆TXB_2含量,而对6-keto-PGF_(1α)含量无显著影响.同位素参入法测定TTMP能增强正常及荷瘤小鼠脾脏NK细胞活性,且能拮抗环磷酰胺对NK细胞活性的抑制作用.TTMP抗肿瘤转移作用可能与降低小鼠血浆TXB_2含量和增强NK细胞活性有关     

Development of polyurethane foam dressing containing silver and asiaticoside for healing of dermal wound

 Polyurethane foam dressings for dermal wounds were formulated with natural polyols in order to improve the foam characteristics and the release of 2 active agents, silver and asiaticoside (AS) as an antimicrobial agent and an herbal wound healing agent, respectively. The foam was instantly formed by interaction of polyols and diisocyanate. Hydroxypropyl methylcellulose, chitosan and sodium alginate were individually mixed with the main polyols, polypropylene glycol, in the formulation while the active components were impregnated into the obtained foam dressing sheets. Although the type and amount of the natural polyols slightly affected the pore size, water sorption-desorption profile and compression strength of the obtained foam sheets, a prominent effect was found in the release of both active components. Among natural polyols formulations, foam sheets with alginate showed the highest silver and AS release. Non-cytotoxicity of these foam sheets to human fibroblast cells was confirmed. Antimicrobial testing on four bacteria strains showed that 1 mg/cm2 silver in formulations with 6% of natural polyols and without natural polyols had sufficient content of the silver release with comparable inhibition zone and significantly larger zone than other formulations. In pig study, the foam dressing with 6% alginate, 1 mg/cm2 silver and 5% AS could improve wound healing in both the percentage of the wound closure and histological parameters of the dermal wound without any dermatologic reactions. In conclusion, this innovative foam dressing had potential to be a good candidate for wound treatment.     

HEMA-胶原SD-Ag缓释膜的研制及促进烧伤创面愈合的实验研究

目的研制甲基丙烯酸羟乙酯穴HEMA雪-胶原抗菌药物缓释膜,考察其对烧伤创面的促愈合作用。方法制备包裹有磺胺嘧啶银穴SD-Ag雪的HEMA-胶原抗菌药物缓释膜,采用SD大鼠深Ⅱ度烧伤模型,观察测定其对创面愈合的影响。结果制备后得到乳白色半透明状、均匀有弹性的凝胶膜状物。实验组大鼠不同时间点的创面愈合率均高于对照组穴P<0.05雪,愈合时间明显缩短穴P<0.05雪。组织学观察可见实验组愈合创面上皮化程度好于对照组。结论本方法制备缓释膜简单快速,成膜性好。HEMA-胶原抗菌药物缓释膜可有效促进大鼠深Ⅱ度烧伤创面愈合,有望应用于临床。     

海兰地嗪对血小板聚集的影响及机理探讨

海兰地嗪(Her)体外对胶原,ADP,A23187和AA诱导的大鼠血小板聚集有明显抑制作用,其IC_(50)分别为14.5,41.6,44.1和48.3μg/ml。Her对AA诱导的大鼠血小板MDA生成不能抑制,但能升高兔血小板cAMP水平和抑制凝血酶诱导的人血小板胞浆内游离钙离子浓度升高。Her的抗血小板聚集作用机理可能与升高血小板内cAMP水平和抑制细胞内游离钙离子浓度升高有关。     

川芎嗪对妥布霉素肾毒性保护作用及机理的实验研究

目的：为减轻妥布霉素的肾毒性．应用川芎嗪进行预防其肾毒性的实验研究。方法：实验大鼠分三组：Ⅰ组正常对照组、Ⅱ组中毒模型组、Ⅲ组川芎嗪预防组。给大鼠腹腔注射妥布霉紊制成中毒模型。注射川芎嗪预防肾毒性。用药前、后检测大鼠的肾功能、尿酶等指标，实验结束后进行肾组织学检查。结果：发现模型组尿NAG酶（N-乙酰-β—D氨基葡萄糖苷酶）比正常组增高．血清中超氧化物歧化酶（SOD）活性低于正常组．血中的尿素氮（BUN）及肌酐（Cr）含量均比正常组增高。形态学检查可见模型组肾近曲小管上皮细胞广泛性坏死。川芎嗪预防组各项功能指标有所改善．形态学检查变性情况减轻。结论：川芎嗪对妥布霉素的肾毒性有预防保护作用。     

胡椒碱抗实验性癫痫作用及其作用机制分析

目的　研究胡椒碱的抗惊厥作用和作用机制。方法以不同的物理和化学方法引起小鼠和大鼠不同类型的惊厥 ,形成不同类型的实验性动物癫痫模型 ,预先ip不同剂量的胡椒碱 ,观察其有无抗惊厥作用。利用荧光分光光度计和氨基酸自动分析仪 ,分别测量小鼠脑内单胺类神经递质和氨基酸含量和大鼠脑片3H Glu释放实验分析其作用机制。结果　胡椒碱对多种实验性癫痫动物模型均有不同程度的对抗作用 ;对癫痫大发作动物模型MES、小发作动物模型Met和小鼠脑室注射 (icv)KA形成的颞叶性癫痫模型对抗作用较强 ,但对士的宁引起的强直性惊厥、3 巯基丙酸、荷包牡丹碱和兴奋性氨基酸引起的阵挛性惊厥均无明显的对抗作用。胡椒碱可明显增加小鼠脑内单胺类神经递质 5 HT的含量和明显降低Glu和Asp含量 ,并能降低 (Glu +Asp) /GABA的比值。 1× 10 -6 mol·L-1的胡椒碱对大鼠大脑皮层脑片预载的3H Glu的释放有明显的抑制作用。结论　胡椒碱有较强的抗惊厥作用。是一种广谱抗惊厥药。其机制可能与其增加动物脑内 5 HT和降低Glu及Asp的含量和阻断KA 受体有关     

来氟米特对佐剂性关节炎大鼠的治疗作用及部分机制研究

目的　研究来氟米特 (Lef)对佐剂关节炎 (AA)大鼠的治疗作用。方法　观察佐剂性关节炎 (AA)大鼠给药后继发性足肿胀、免疫功能及前列腺素释放水平的变化 ,并检测Lef的活性产物A77172 6体外对正常小鼠T细胞亚群的影响。结果　Lef(2 ,6与 18mg·kg-1)灌胃给药 (ig)可明显抑制AA大鼠继发性的关节肿胀 ,改善AA大鼠多发性关节炎病变症状。对AA大鼠低下的ConA诱导的增殖反应和IL 2无明显影响 ,但对AA大鼠过高的IL 1产生有明显的抑制作用。体外培养发现Lef的活性产物A77172 6(0 1,0 5 ,2 5 ,12 5 ,2 5 ,10 0 μmol·L-1)可抑制正常小鼠ConA诱导的Th 细胞 ,对ConA诱导的Ts 细胞无明显影响。而只有高浓度A77172 6(10 0 μmol·L-1)对AA大鼠PMΦ产生的过高PGE2 有明显的抑制作用。结论　Lef具免疫抑制作用 ,通过抑制细胞免疫功能 ,实现对AA大鼠的治疗作用     

Triazene compounds: mechanism of action and related DNA repair systems.

Triazene compounds of clinical interest (i.e. dacarbazine and temozolomide) are a group of alkylating agents with similar chemical, physical, antitumour and mutagenic properties. Their mechanism of action is mainly related to methylation of O(6)-guanine, mediated by methyldiazonium ion, a highly reactive derivative of the two compounds. The cytotoxic/mutagenic effects of these drugs are based on the presence of DNA O(6)-methylguanine adducts that generate base/base mismatches with cytosine and with thymine. These adducts lead to cell death, or if the cell survives, provoke somatic point mutations represented by C:G-->T:A transition in DNA helix. Triazene compounds have excellent pharmacokinetic properties and limited toxicity. Dacarbazine requires hepatic activation whereas temozolomide is spontaneously converted into active metabolite in aqueous solution at physiological pH. Moreover, temozolomide is fully active when administrated orally (100% bioavailability). The biological effects of triazene compounds and cell resistance to them depend on at least three DNA repair systems, (a) O(6)-alkylguanine-DNA-alkyltransferase, called also methyl-guanine methyl-transferase (MGMT); (b) mismatch repair (MMR), and (c) base excision repair (BER). MGMT is a small enzyme-like protein that removes small alkyl adducts from the O(6) position of DNA guanine through a stoichiometric and auto-inactivating reaction. This reaction consists in a covalent transfer of the alkyl group from the alkylated site in DNA to an internal cysteine residue of MGMT protein. High levels of MGMT are responsible for normal and tumour cell resistance to triazenes. Therefore, pre-treatment with MGMT inhibitors - i.e. O(6)-benzylguanine or O(6)-(4-bromotenyl)guanine (Lomeguatrib) - is followed by a great increase in the activity of triazenes against target cells expressing high MGMT levels. MMR is represented by a protein complex dedicated to the repair of biosynthetic errors generated during DNA replication. The MMR system recognizes base mismatches and insertion-deletion loops, cuts the nucleotide sequence containing the lesion, and restores the correct base sequence. Therefore, not only MGMT but also MMR is involved in target cell susceptibility to triazenes. However, the system does not suppress, but instead promotes the cytotoxic effects of triazenes. In fact, MMR is not able to repair the incorrect base pairing determined by treatment with triazenes and, according to a predominant hypothesis, it causes reiterated "futile" attempts of damage repair leading to the activation of cell cycle arrest and apoptosis. BER removes lesions due to cellular metabolism, or to physical or chemical agents. BER is able to repair N(7)-methylguanine and N(3)-methyladenine determined by treatment with triazenes. Therefore, triazene compounds can also kill tumour cells by a N(3)-methyladenine-mediated mechanism if BER activity is inhibited by chemical agents (i.e. PARP inhibitors). In conclusion, in selected cases, triazenes can represent a therapeutic alternative to treatment of neoplastic diseases including haematological malignancies. Moreover, the susceptibility of neoplastic cells to these compounds can be substantially increased through pharmacological modulation of the expression level and functional activity of DNA repair enzymes.     

黄芪总甙的镇痛作用及其作用机制(英文)

目的:研究黄芪总甙(astragalosides,AST)的镇痛作用及其作用机制。方法:采用小鼠福尔马林致痛模型,对痛反应进行评分。通过福尔马林试验前30min皮下注射吗啡和纳络酮或福尔马林试验前20min腹腔内注射L-精氨酸和L-NAME以研究阿片肽和一氧化氮在此疼痛模型中的作用并对AST的作用与吗啡和L-NAME进行比较。结果:AST20,40和80mg/kg可显著降低小鼠福尔马林致痛后第二时相的疼痛反应(P<0.01)。AST 40mg/kg最大镇痛作用见于给药后4h(第二时相疼痛反应的抑制率为34.4％)。吗啡5mg/kg对两个时相的疼痛反应均有明显抑制作用(P<0.01),此抑制作用能被纳络酮2mg/kg拮抗(P<0.01),而AST的镇痛作用不受纳络酮影响。L-精氨酸(400或800mg/kg)可部分抑制AST的作用(P<0.01)。结论:AST所具有的镇痛作用不是通过内源性阿片肽系统介导,而可能与抑制NO等参与疼痛反应的炎症介质的生成有关。