附子和吴茱萸对缺氧和受寒小鼠的影响

给小鼠灌服附子和吴茱萸水煎剂10和20g/kg能延长断头小鼠张口动作持续时间和KCN中毒小鼠的存活时间,对常压密闭缺氧及NaNO_2中毒小鼠的存活时间无明显延长,但吴茱萸能提高小鼠在低氧条件下的生存能力。附子和吴茱萸中所含有的拟肾上腺素成分可能干扰了它们的抗缺氧作用。附子缩短受寒小鼠的存活时间也可能与其所含的拟肾上腺素成分有关。     

糖基化三氮唑白杨素衍生物的合成与抗缺氧活性研究

以叠氮糖、炔丙基溴和白杨素为原料,利用"Click chemistry"将糖基化三氮唑药效基团巧妙的引入白杨素分子结构中得到4种糖基化三氮唑白杨素衍生物,产物结构经1H NMR、IR、ESI-MS和元素分析确认。并通过小鼠常压密闭耐缺氧模型对4个目标化合物的药理活性进行评价,均能不同程度的延长小鼠的存活时间,其中化合物1b和4b的活性优于乙酰唑胺。     

苦剌总生物碱的抗缺氧作用

给小鼠灌服苦刺总生物碱盐酸(苦碱)能增强小鼠对常压密闭缺氧的耐受力,对抗异丙肾上腺素加速整体小鼠耗氧速度和降低低氧条件下的氧利用能力,也能对抗酚妥拉明降低小鼠在缺氧条件下的氧利用能力。苦碱还能延长断头小鼠的张口动作持续时间,以及氰化钾、亚硝酸钠和利多卡因中毒时的小鼠存活时间,表现出广谱的抗缺氧作用,且呈现量效关系。     

酸柏栀油软胶囊对小鼠耐缺氧和抗疲劳的实验研究

目的:研究酸柏栀油软胶囊耐缺氧和抗疲劳作用。方法:采用常压耐缺氧实验、亚硝酸钠中毒存活实验和急性脑缺血性缺氧实验,观察软胶囊对小鼠的耐缺氧作用;采用负重游泳法记录负重游泳时存活时间,观察药物对小鼠抗疲劳作用。结果:在耐缺氧方面,酸柏栀油软胶囊可以延长小鼠在常压条件下和亚硝酸钠中毒后的存活时间(P<0.05);在抗疲劳方面,酸柏栀油软胶囊能延长小鼠在负重情况下的存活时间,增加肝糖元含量,减少乳酸水平(P<0.05)。结论:酸柏栀油软胶囊能增强小鼠耐缺氧和抗疲劳能力。     

13α—羟基苦参碱的抗整体小鼠缺氧作用

13α-羟基苦参碱(HM)是苦从刺叶中分离得到的一种新结构化合物。给小鼠isHM180和360 mg·kg~(-1)能减慢常压闭缺氧小鼠的耗氧速度并延长存活时间,能对抗异丙肾上腺素和酚妥拉明缩短小鼠存活时间的作用。HM还能延长断头小鼠的张口动作持续时间,以及氰化钾、亚硝酸钠和利多卡因中毒小鼠存活时间,表现出广谱抗缺氧能力。     

无创性肢体缺血预适应对小鼠抗应激能力的影响

目的:探讨无创性肢体缺血预适应在提高小鼠抗应激能力方面的作用。方法:小鼠分为正常组、对照组、预适应组和药物组,进行常压耐缺氧、耐疲劳负重游泳、耐高、低温实验,分别记录各种应激状态下小鼠的耐受时间,测定常压缺氧耐受后小鼠血清中SOD的活性和负重游泳后血清中乳酸的含量。结果:预适应组能显著提高小鼠常压耐缺氧时间,且SOD活性较对照组有显著的提高,但提高的程度均低于普萘洛尔组。预适应组平均游泳时间显著延长,且程度与咖啡因组相当。预适应能明显延长高温下小鼠的存活时间,且延长程度与氯丙嗪没有显著性差异。与正常组比较,预适应组能显著延长小鼠的耐低温时间。结论:无创性肢体缺血预适应能提高小鼠耐缺氧、抗疲劳、耐高温和耐低温的能力。     

花生肽对小鼠耐缺氧作用的研究

目的：探讨花生肽是否对小鼠具有耐缺氧作用。方法：将150只SPF级BALB/c雄性小鼠随机分为5组：1个空白对照组、1个乳清蛋白组（500 mg/kg BW）和3个花生肽剂量组（250、500、1 000 mg/kg BW）。连续灌胃30 d后,测定各组小鼠在常压缺氧环境下的存活时间及耗氧量,在亚硝酸钠中毒导致的缺氧状况下的存活时间以及急性脑缺血导致的缺氧状况下的存活时间,来观察花生肽对小鼠的耐缺氧作用。结果：与空白对照组相比,花生肽各剂量组小鼠在常压缺氧环境下的存活时间及耗氧量显著增加,在急性脑缺血及亚硝酸钠中毒所致的缺氧状态下的存活时间也明显延长（P<0.05）;并且与乳清蛋白组相比,花生肽中、高剂量组小鼠在三种缺氧状态下的存活时间均明显延长（P<0.05）。结论：花生肽对小鼠具有耐缺氧作用。     

吉林人参低聚肽对小鼠耐缺氧作用的研究

目的：观察吉林人参低聚肽（ginseng oligopeptides,GOP）对小鼠是否具有耐缺氧作用。方法：将BALB/C小鼠分为6个实验组：4个GOP剂量组［0.075、0.150、0.300、0.600g/（kg·BW）］、1个空白对照组和1个乳清蛋白组（0.300g/（kg·BW））,连续灌胃30d后,通过常压耐缺氧实验、亚硝酸钠中毒存活实验和急性脑缺血性缺氧实验来观察GOP的耐缺氧效果。结果：与空白对照组和乳清蛋白组相比,GOP均可明显延长小鼠常压耐缺氧存活时间、亚硝酸钠所致缺氧存活时间和急性脑缺血性缺氧存活时间。结论：GOP对小鼠具有耐缺氧作用。     

大王马先蒿苯丙素类含量测定及有效部位抗疲劳活性研究

建立了大王马先蒿中红景天苷、毛蕊花苷、异毛蕊花苷、米团花苷A、紫地黄苷D和角胡麻苷等6种苯丙素类成分的测定方法,并利用大孔吸附树脂制备有效部位,评价有效部位的抗疲劳、耐缺氧活性。采用ZORBAX-C18(4.6 mm×150 mm,5μm)色谱柱,以水(A)-甲醇(B)溶液为流动相,梯度洗脱(0~10 min,63%A;10~10.5 min,63%→58%A;10.5~40 min,58%A),流速1 m L/min,检测波长0~4 min为275 nm,4~40 min为330nm,柱温35℃,进样量10μL;利用D101大孔吸附树脂梯度洗脱方法,制备苯丙素类成分有效部位,通过小鼠负重游泳、耐缺氧模型,观察不同剂量组小鼠力竭游泳时间及密闭缺氧存活时间。结果表明6种苯丙素类成分进样量分别在2.10~8.40、13.60~54.40、0.93~3.72、0.53~2.12、1.50~6.00、0.37~1.28范围内线性关系良好,平均加样回收率(n=6)均在98%~102%范围内。有效部位制取率为0.62%,6种苯丙素类成分总含量达到65%以上。高、中、低剂量组小鼠的力竭时间和缺氧存活时间明显高于空白对照组(P0.01)。本实验分析方法准确、简便、重复性好,可作为大王马先蒿中6种苯丙素类成分的含量测定方法。苯丙素有效部位能延长小鼠游泳时间,并明显延长小鼠在常压缺氧的存活时间,增强小鼠耐缺氧能力,提示大王马先蒿具有促进恢复和消除疲劳及提高运动能力的效用。     

藏波罗花提取物对小鼠耐缺氧作用的研究

采用不同方法建立小鼠常压缺氧模型、亚硝酸钠中毒模型及急性脑缺血性缺氧模型,对藏波罗花提取物的耐缺氧活性进行研究。以0.5%羧甲基纤维素钠溶液为空白对照、盐酸普萘洛尔为阳性对照药,设置藏波罗花60%乙醇提取物、95%乙醇提取物的5g/kg、10g/kg、15g/kg三个剂量的给药组,通过观察小鼠存活时间,研究藏波罗花提取物对小鼠缺氧损伤的保护作用。结果显示,与空白对照组相比较,藏波罗花提取物各剂量组均能明显延长小鼠在常压缺氧、亚硝酸钠中毒及急性脑缺血性缺氧条件下的存活时间(P<0.05),表明藏波罗花提取物具有一定的耐缺氧活性,可提高实验小鼠的耐缺氧能力。     

Anti-hypoxic effect of glutathione depletors

The effect of various reduced glutathione (GSH) depletors on the survival time under normobaric and hypobaric hypoxia was examined in mice. The survival time was markedly prolonged in mice treated with glutathione S-transferase substrate, 2-cyclohexene-1-one (50-100 mg/kg, ip) and phorone (100-250 mg/kg, ip). The anti-hypoxic effect lasted for at least 3 hr and the maximum effect was found 0.5 hr after injection. Further, both compounds significantly elevated blood glucose levels 0.5-1 hr after treatment. The extent of the elevated blood glucose was nearly comparable to that of the mice treated with glucose (1-2 g/kg, ip), which was found to possess an anti-hypoxic effect. However, a GSH synthesis inhibitor, buthionine sulfoximine, could cause neither a prolongation of survival time of hypoxic mice nor an elevation of blood glucose. Moreover, unlike the depletion of hepatic GSH, brain GSH was markedly decreased by 2-cyclohexene-1-one and phorone, but not by buthionine sulfoximine. These findings suggest that the elevated blood glucose may involve in one of the mechanisms of the anti-hypoxic effect of 2-cyclohexene-1-one and phorone. A relationship between the anti-hypoxic effect and the depletion of brain GSH was also discussed.     

Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action

Enzyme cyclooxygenase (COX) is reported to play a significant role in neurodegeneration and may play a significant role in the pathogenesis of epilepsy. Bicuculline (4 mg/kg; ip), picrotoxin (8 mg/kg; ip) and electroshock (60 mA for 0.2 sec) significantly induced convulsions in male Laka mice. COX-inhibitors viz. nimesulide (2.5 mg/kg; ip) and rofecoxib (2 mg/kg, ip) administered 45 minutes prior to an epileptic challenge prolonged mean onset time of convulsions, decreased duration of clonus and decreased % mortality rate against bicuculline- and picrotoxin-induced convulsions in mice. COX-2 inhibitors were ineffective towards maximal electroshock-induced convulsions. Nimesulide (1 mg/kg) and rofecoxib (1 mg/kg) also enhanced the effect of subprotective dose of muscimol against picrotoxin-induced convulsions. The result of the present study strongly suggests for a possible role of cyclooxygenase isoenzymes particularly, COX-2 in the pathophysiology of epilepsy and its GABAergic modulation.     

Studies on Japanese B Encephalitis Virus Vaccines from Tissue Culture: XI. Immune Mechanism and Evaluation of the Mouse Challenge Potency Test

A study was carried out to evaluate the reliability of and to determine the mechanism involved in an antigen extinction mouse intraperitoneal (ip) challenge test for potency of a cell culture vaccine for Japanese B encephalitis, a modification of a test originated by Sabin for a mouse brain vaccine. Some comparisons were made with the official Japanese test using an intracerebral (ic) challenge after a more prolonged immunization procedure. The Japanese method of using a lyophilized reference vaccine with each test was also employed. It was found that the ip and the ic test appeared to show similar relative differences between lots. The ip test was more quickly and readily performed, gave reasonably consistent results on repetition, and, when used with a suitable reference vaccine, gave promise of being an entirely suitable and reliable test. Immunization by the intramuscular route rather than by the regular ip route appeared to offer no advantage and was less consistent in responses shown. Neutralizing antibody responses of the mice in the standard procedure were very quick to appear, about 4 days after the first dose of vaccine and had a peak titer about the seventh day, the time of challenge. This titer fell quickly unless challenge occurred. The antibody was heat stable, but it was readily inactivated by 2-mercaptoethanol (2-ME). Not until the 11th or 15th day did a small amount of immunoglobulin G appear. Challenge on day 7 significantly increased titers, but this antibody was also mostly inactivated by 2-ME. Interferon did not appear to play any significant role in the protection shown by the mice.     

Prolongation of cardiac allograft survival by pretreatment of recipient mice with donor blood or spleen cells plus cyclophosphamide.

Using six mouse strain combinations, we attempted to prolong cardiac allograft survival by pretreatment of recipients with a single iv injection of donor-specific whole blood or spleen cells plus a single ip injection of cyclophosphamide (Cy). Significant prolongation of cardiac allograft survival occurred in a small proportion of pretreated mice of some strain combinations, with some grafts surviving for periods longer than 6–9 months. Cy injected alone did not influence the normal cardiac allograft rejection time of between 1 and 2 weeks. Depending upon the strain combination, accelerated rejection of all or some of the grafts occurred in mice pretreated with blood or spleen cells or myocardial cells alone.     

High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus.

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg.kg(-1).day(-1) ip) for another 14 days. Mechanical and intracellular Ca2+ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca2+ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca2+ load, and intracellular Ca2+ decay rate (tau). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR90, reduced SR Ca2+ load, elevated resting intracellular Ca2+ level and prolonged tau associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR90, and tau, as well as reduction in SR Ca2+ load without affecting hyperglycemia and elevated resting intracellular Ca2+. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.     

The influence of 2- chlorodeoxyadenosine in combination with tumour necrosis factor-alpha or its mutein on murine leukaemias L1210 and P388

We investigated the influence of 2-chlorodeoxyadenosine (2-CdA) in combination with tumour necrosis factor-alpha (TNFalpha) or its mutein VI, which differs from the native molecule by N-terminal amino acid composition, on the survival time of mice inoculated with leukaemia L1210 or P388. Groups of mice with leukaemia L1210 and P388 receiving 2-CdA combined with TNFalpha had shorter survival times than animals treated with these agents separately. In contrast, the administration of 2-CdA in conjunction with mutein VI, prolonged the survival of mice inoculated with these leukaemias as compared with animals receiving these agents separately. The results of the present study emphasize the importance of the biological activity of the TNFalpha molecule N-terminus.     

Impact of minimal tumor burden on antibody response to vaccination

Four randomized phase III trials conducted recently in melanoma patients in the adjuvant setting have been based in part on the correlation between antibody responses in immunized patients and improved survival. Each of these randomized trials demonstrated no clinical benefit, although again there was a significant correlation between antibody response after vaccination and disease free and overall survival. To better understand this paradox, we established a surgical adjuvant model targeting GD2 ganglioside on EL4 lymphoma cells injected into the foot pad followed by amputation at variable intervals. Our findings are (1) comparable strong therapeutic benefit resulted from treatment of mice after amputation with a GD2-KLH conjugate vaccine or with anti-GD2 monoclonal antibody 3F8. (2) The strongest correlation was between antibody induction in response to vaccination and prolonged survival. (3) Antibody titers in response to vaccination in tumor challenged mice as compared to unchallenged mice were far lower despite the absence of detectable recurrences at the time. (4) The half life of administered 3F8 monoclonal antibody (but not control antibody) in challenged mice administered was significantly shorter than the half life of 3F8 antibody in unchallenged controls. The correlation between vaccine-induced antibody titers and prolonged survival may reflect, at least in part, increased tumor burden in antibody-negative mice. Absorption of vaccine-induced antibodies by increased, although not detected tumor burden may also explain the correlation between vaccine-induced antibody titers and survival in the adjuvant clinical trials described above.     

Additional evidence for the augmented induction of tumor-specific resistance in vaccinia virus-primed mice by immunization with vaccinia virus-modulated syngeneic tumor cells

The augmenting effect of vaccinia virus infection of tumor cells on induction of tumor-specific resistance was examined in mice. C3H/HeN mice were primed intraperitoneally (ip) with live vaccinia virus after whole-body irradiation with 250 rad of X-rays. Three weeks later the mice were immunized ip 3 times at weekly intervals with syngeneic murine hepatoma MH134 or spontaneous myeloma X5563 which had been infected in vitro with vaccinia virus and subsequently irradiated with 7000 rad of X-rays. One week after the third immunization, the mice were challenged with 1 X 10(5) viable cells of MH134 or X5563 ip or 1 X 10(6) tumor cells intradermally (id). On ip challenge with viable MH134 cells all mice that had not been pretreated died within 3 weeks due to ascites tumor out-growth, whereas all mice that had been vaccinia virus-primed and immunized with vaccinia virus-infected MH134 cells survived. On ip challenge with X5563 cells, the percentage survival of vaccinia virus-primed and vaccinia virus-modified tumor-immunized mice was 80%. On id challenge with MH134 and X5563 tumor cells, in un-treated mice tumors grew to more than 5 mm in diameter within 3 weeks, whereas 90% and 60%, respectively, of the mice that had been vaccinia virus-primed and immunized with vaccinia virus-infected tumor cells showed no tumor out-growth. Pretreatment by only immunization with vaccinia virus-infected cells or vaccinia virus-priming and immunization with virus non-infected tumor cells were not effective for preventing induction of tumor-resistance to either ip or id challenge with MH134 or X5563 tumor cells.(ABSTRACT TRUNCATED AT 250 WORDS)