从塞内加尔刺桐中得到的磷脂酶C抑制剂耳形鸡血藤黄素及8-prenylluteone

磷酸肌醇(PI)的转化在许多刺激物如生长因子、激素等诱导的细胞内信息传递途径中起重要作用。磷脂酶 C(PLC)则控制 PI 转化的速率,催化磷脂酰肌醇4,5-二磷酸酯(PIP_2)水解生成1,4,5-三磷酸肌醇酯(IP_3)和二酰基甘油酯(DAG)。PIP_2刺激细胞内Ca~(2+)的释放,而 DAG 则激活蛋白激酶 C。Ca~(2-)浓度的增加和蛋白激酶 C 的激活会引起一系列反应,最终导致 DNA 的合成和细     

磷脂酰肌醇激酶：肌醇磷脂代谢,肿瘤发生及其它

近年的研究已经表明,做为细胞膜结构成份的肌醇磷脂类化合物[包括磷脂酰肌醇(phosphatidylinositol,PI)、磷脂酰肌醇—4—磷酸(Phosphatidylinositol-4-Phosphate,PIP)和磷脂酰肌醇—4,5一二磷酸(Phosphatidylinositol-4,5-bisphosphate,PIP_2)]不仅代谢十分活跃,而且有许多重要的生理功能:PIP_2经肌醇磷脂特异性磷脂酶C(Phosphoinositide-specific     

川芎嗪对血小板中肌醇磷脂和2OK蛋白质磷酸化的抑制作用

在Mg~(2+)存在下.用血小板膜与(γ—~(32)P)ATP保温,以观察川芎嗪对~(32)P掺入磷脂和蛋白质的影响,结果表明:血小板膜中存在磷脂酰肌醇(PI)激酶和磷脂酰肌醇—4—磷酸(PIP)激酶,而胞浆中缺乏或极少;ATP促进肌醇磷脂磷酸化;川芎嗪抑制血小板中PIP和20K蛋白质的磷酸化.半数抑制浓度分别为40μmol·L~(-1)和110μmol·L     

5′-氯-5′-脱氧腺苷对猪血小板中肌醇磷脂和蛋白质磷酸化的抑制作用(英文)

目的:研究腺苷对血小板中肌醇磷脂和蛋白质磷酸化的影响.方法:在Mg~(2 )和/或Ca~(2 )存在下,用猪血小板膜与[γ-~(32)P]ATP在30℃下保温3 min,测定~(32)P掺入磷脂或蛋白质.结果:5′-氯-5′-脱氧腺苷减少磷脂酰肌醇-4-磷酸和磷脂酰肌醇-4,5-二磷酸的生成[IC_(50)分别为71和75(95％可信限分别为60-85和62-90)μmol·L~(-1)],抑制与ATP呈竞争性,并抑制pleckstrin(C激酶主要底物)和肌球蛋白轻链的磷酸化[IC_(50)分别为75和82(95％可信限分别为62·90和66-102)μmol·L~(-1)].结论:腺苷影响血小板中肌醇磷脂信使通路,这有助于阐明腺苷对血小板活化的抑制作用.     

磷酸肌醇代谢与新的第二信使

<正> 磷酸肌醇是一类酸性磷脂,包括磷脂酰肌醇(Phosphatidylinositol,PI),磷脂酰肌醇-4-磷酸(Phosphatidy-linostol-4-phosphate,PIP)和磷脂酰肌醇-4,5-二磷酸(Phosphalitid-ynositol-4,5-bisphosphate,PIP_2)。它们约占细胞磷脂的8％。众所周知,当激动剂作用于受体后,可激活环化酶系统而产生cAMP作为第二信使。近来发现某些受体激活后,可代谢膜的磷酸肌醇,产生肌醇三磷酸(Inositol-1,4,5trisphosphate,IP_3)和二酰基甘油     

氨基糖甙类抗生素与锂在神经肌肉节头的相互作用

氨基糖甙类抗生素除众所周知的耳毒性和肾毒性外,尚具有神经肌肉阻断作用.现已证明,氨基糖甙类抗生素与多磷脂酰肌醇相结合的能力要比生细胞膜中其他磷脂类的结合能力大得多,因而抑制三磷酸鸟苷诱导的肥大细胞分泌作用和Ca~(2+)诱导的胞泌作用(exocytosis),这两种作用均可认为是通过磷脂酰肌醇的水解作用而出现的.     

鱼油对高脂血症病人血脂、脂蛋白、血栓素、血小板及血液流变性能的影响

将262例高脂血症病人分为口服鱼油组143例和服安慰剂组119例。服药前1天、后30天分别测定总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、载脂蛋白A_1(ApoA_1)、载脂蛋白B(ApoB)、血栓素B_2(TXB_2)、6-酮-pGF_1α(6-K-pGF_1α)、血小板聚集率、血小板粘附率、血沉降(ESR)、血小板数、红细胞压积、全血粘度、血浆粘度。结果鱼油组服药后HDL 升高,HDL/LDL、ApoB、TXB_2、6-K-pGF_1α,TXB_2/6-K-pGF_1α及ESR 均下降,上述指标差数均值与安慰剂组比较有显著差异(均p<0.05)。提示鱼油胶囊具有升高高脂血症病人HDL,降低ApoB、TXB_2、ESR,改善血液流变性能,对防治冠心病、动脉粥样硬化有利。     

(一)蝙蝠葛苏林碱对兔淋巴细胞内钙含量的影响

采用钙荧光指示剂Fura—2/Am定量测试法检测了静息淋巴细胞胞浆内游离钙浓度,并以Ca~(2+)载体A23187作为阳性对照.观察了(一)蝙蝠葛苏林碱(8701)对兔淋巴细胞胞浆内Ca~(2+)浓度的影响。结果表明:8701的各种实验浓度均可显著地促进淋巴细胞内Ca~(2+)浓度增加,在浓度为10~(-4)mol·L~(-1)时,增加细胞内Ca~(2+)浓度的作用显著高于Ca~(2+)载体A23187的作用(P<0.01),提示该药有可能作为淋巴细胞的刺激剂或在高浓度时可能造成淋巴细胞的Ca~(2+)中毒作用。     

药用豆磷脂的HPLC法测定

本文报告了用HPLC法对药用豆磷脂进行定性定量分析。作者选用硅胶为固定相,以正己烷-异芮醇-醋酸盐缓冲液(pH5.8)(7.5:8:1)为流动相,紫外检测波长206nm,使得磷脂酰胆碱(PC),磷脂酰乙醇胺(PE),溶血磷脂酰胆碱(LPC),磷脂酰肌醇(PI)和磷脂酸(PA)获得满意分离,并对主成分PC进行了含量测定,平均回收率为99.8%,方法的变异系数为0.8%.     

1-烯丙基氯-3对神经纤维轴浆运输作用的机理研究

本实验结果是神经纤维MT、NF变性和数量减少,线粒体肿胀并呈变性空泡;轴浆内并为轴浆运输成分的ChE活性降低或消失;轴浆Ca~(2+)增加,Mg~(2+)无改变;cAMP增加,cGMP及游离CaM降低;神经微丝肌球蛋白ATPase活性降低,Ca~(2+)-ATPase活性无改变。表明1-烯丙基氯-3促进或加强神经膜Ca~(2+)通道磷酸化作用,或CGMP减少负反馈PIP_2信息系统增强,或内质网及线粒体扩张     

Effect of thromboxane A2 synthetase inhibition, singly and combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on inositol phospholipid turnover and on 5-HT release by washed human platelets

Differential effects on human platelet function of thromboxane A2 (TXA2) synthetase inhibition singly and of TXA2 synthetase inhibition combined with TXA2/prostaglandin endoperoxide receptor antagonism were revealed, using ridogrel as a probe. Ridogrel combines selective TXA2 synthetase inhibition with TXA2/prostaglandin receptor antagonism in one molecule: in washed human platelets, the compound reduces the production of TXB2 (IC50 = 1.3 X 10(-8) M) and increases that of PGF2 alpha, PGE2, PGD2 from [14C]arachidonic acid. Additionally, at higher concentrations (Ki = 0.52 X 10(-6) M), it selectively antagonizes the breakdown of inositol phospholipids, subsequent to stimulation of TXA2/prostaglandin endoperoxide receptors with U 46619. The latter happens in a competitive way with fast receptor association-dissociation characteristics. At low concentrations (1 X 10(-9)-1 X 10(-7) M) producing single TXA2 synthetase inhibition, ridogrel reduces the collagen-induced formation of TXB2 by washed platelets, but enhances [32P]phosphatidic acid (PA) accumulation and [3H]5-hydroxytryptamine (5-HT) release. At higher concentrations (1 X 10(-6)-1 X 10(-5) M) which additionally block U 46619-induced [32P]PA accumulation, ridogrel inhibits the [32P]PA accumulation and release of [3H]5-HT by human platelets stimulated with collagen. These observations, corroborated by results obtained with OKY 1581, sulotroban, indomethacin and human serum albumin, suggest a causal role for prostaglandin endoperoxides in the stimulation by TXA2 synthetase inhibition of platelet reactions to collagen. They reinforce the concept that TXA2 synthetase inhibition-induced reorientation of cyclic endoperoxide metabolism, away from TXA2 into inhibitory prostanoids, requires additional TXA2/prostaglandin endoperoxide receptor antagonism to achieve optimal anti-platelet effects.     

Characterization of the inhibition of U46619-mediated human platelet activation by the trimetoquinol isomers. Evidence for endoperoxide/thromboxane A2 receptor blockade

Sites of inhibition for the trimetoquinol (TMQ) isomers on 15S-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619)-, 12-O-tetradecanoylphorbol 13-acetate (TPA)- and A23187-induced human platelet activation were investigated. Experiments using washed human platelets were designed to characterize relationships among functional (aggregation, secretion) and biochemical (protein phosphorylation, metabolism of inositol phospholipids and radioligand displacement analysis) processes of platelet activation by U46619 and the specificity of inhibition by the TMQ isomers. Thromboxane A2 receptor stimulation by U46619 in human platelets resulted in a time- and concentration-dependent breakdown of inositol phospholipids [phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-monophosphate (PIP), and phosphatidylinositol (PI)], phosphatidic acid (PA) accumulation, phosphorylation of 20 and 45 kD proteins, aggregation and serotonin secretion. The TMQ isomers stereoselectively inhibited all U46619-mediated platelet activation processes. R(+)-TMQ was 40- and 22-fold more potent than S(-)-TMQ as an inhibitor of U46619-induced platelet aggregation and serotonin secretion respectively. In addition, R(+)-TMQ blocked U46619-induced 20 kD protein phosphorylation, 45 kD protein phosphorylation, PIP2, PIP and PI breakdown, and PA accumulation with a potency which was 8-, 13-, 45-, 37-, 33- and 33-fold greater than the S(-)-isomer respectively. In contrast to S(-)-TMQ, R(+)-TMQ produced a concentration-dependent inhibition of specific [3H]U46619 binding to endoperoxide/thromboxane A2 receptor sites in washed platelets. In other experiments, S(-)-TMQ was more potent than R(+)-TMQ as an inhibitor of TPA- and A23187-induced platelet aggregation and serotonin secretion, and of TPA-induced phosphorylation of 45 and 20 kD proteins. The inhibitory potencies of S(-)-TMQ against TPA- or A23187-induced responses were similar to those needed for antagonism of U46619-mediated platelet activation. In contrast, much higher concentrations of R(+)-TMQ were required for blockade of TPA or A23187 versus U46619-mediated responses in human platelets. Taken collectively, the data show that the TMQ isomers interfered with the endoperoxide/thromboxane A2 receptor-mediated phospholipase C-signal cascade of inositol phospholipid hydrolysis, calcium mobilization, and protein phosphorylation leading to platelet aggregation and secretion. R(+)-TMQ acted as a pharmacologically selective and highly stereospecific [R(+)-TMQ much greater than S(-)-TMQ] antagonist of endoperoxide/thromboxane A2 receptor sites in platelets.(ABSTRACT TRUNCATED AT 400 WORDS)     

Atherogenic lipoproteins inhibit catecholamine secretion in cultured bovine adrenal medullary cells

The effects of lipoproteins on ion channel-mediated catecholamine secretion were investigated in cultured bovine adrenal medullary cells. Low density lipoprotein (LDL; 20–80 mg/dl) and lipoprotein(a) [Lp(a); 10–80 mg/dl] inhibited catecholamine secretion induced by carbachol, an activator of nicotinic acetylcholine receptor-ion channels. LDL and Lp(a) suppressed carbachol-induced ²²Na⁺ influx as well as ⁴⁵Ca²⁺ influx in a concentration-dependent manner similar to that of catecholamine secretion. The inhibition of catecholamine secretion by Lp(a) was not overcome by increasing the concentration of carbachol. On the other hand, high density lipoprotein (HDL; <150 mg/dl) had no effect on ²²Na⁺ influx, ⁴⁵Ca²⁺ influx, and catecholamine secretion. Like LDL and Lp(a), a synthetic peptide homologous to human plasma apolipoprotein B (apoB), apoB fragment_3358–3372-amide (3–60 μM), attenuated ²²Na⁺ influx, ⁴⁵Ca²⁺ influx, and catecholamine secretion caused by carbachol. The apoB fragment also suppressed ²²Na⁺ influx induced by veratridine (an activator of voltage-dependent Na⁺ channels) and ⁴⁵Ca²⁺ influx induced by 56 mM K⁺ (an indirect activator of voltage-dependent Ca²⁺ channels). These findings suggest that atherogenic lipoproteins such as LDL and Lp(a) suppress catecholamine secretion by interfering with Na⁺ influx through nicotinic acetylcholine receptor-ion channels, in which apoB, a structural component common to both LDL and Lp(a), plays an important role. The inhibition by atherogenic lipoproteins of catecholamine secretion may influence the progression of atherosclerosis induced by these lipoproteins. Received: 5 December 1997 / Accepted: 9 June 1998     

山豆根碱对大鼠血小板摄取~（45）Ca~（2＋）的影响

用４５Ｃａ２＋摄入法测定了大鼠血小板摄取细胞外Ｃ２＋，观察山豆根碱对血小板摄取Ｃａ２＋的影响、结果表明，静息血小板可迅速摄取细胞外Ｃａ２＋，呈时间和浓度依赖性；ＡＤＰ促进血小板摄取Ｃａ２＋；山豆根碱以浓度依赖方式抑制静息的和ＡＤＰ诱导的血小板摄取细胞外Ｃａ２＋。这提示山豆根碱抑制血小板聚集的作用机制之一与阻止细胞外Ｃａ２＋内流入血小板，降低血小板胞浆内Ｃａ２＋浓度有关。     

Water-soluble cholesteryl-containing phosphorothioate monogalactosides: synthesis, properties, and use in lowering blood cholesterol by directing plasma lipoproteins to the liver

The synthesis of several monogalactoside-terminated phosphorothiolated cholesteryl derivatives is described. Monogalactosyl derivatives are coupled by phosphorothiolation to cholesterol by using ethylene glycol units as hydrophilic spacer moieties. The resulting compounds are easily soluble in water. Upon addition of such solutions to human serum (to 2 mM final concentration) the compounds are readily incorporated into lipoproteins. Isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL), preloaded with the compounds, are rapidly cleared from the circulation by the liver. The hepatic association is blocked by N-acetylgalactosamine, which indicates that galactose-specific recognition sites are responsible for the increased liver uptake. The plasma clearance and hepatic uptake of LDL loaded with the compounds is substantially higher (about 2-fold) than clearance and uptake of HDL containing the compounds. The selectivity of the effects of monogalactoside-terminated phosphorothiolated cholesteryl derivatives on the in vivo behavior of LDL as compared to that of HDL indicates that these compounds might be used to lower specifically LDL levels in patients with a high LDL-cholesterol level.     

Effect of cytoplasmic pH on Ca(2+)-stimulated eicosanoid biosynthesis in human platelets.

1. We have investigated the effect of cytoplasmic pH (pHi) on the relationship between platelet cytoplasmic Ca2+ concentration ([Ca2+]i) and eicosanoid biosynthesis. Stirred gel-filtered human platelets loaded with fluorescent indicators of Ca2+ and H+ were suspended in balanced salt solutions at 37 degrees C. [Ca2+]i was controlled by calcium ionophore (ionomycin). Increased [Ca2+]i was associated with increased production of thromboxane A2 (TXA2) as determined by radioimmunoassay of its stable hydrolysis product TXB2, and of 12-hydroxy eicosatetraenoic acid (12-HETE) measured by high performance liquid chromatography. 2. Varying pHi with a K+/H+ ionophore (nigericin) in platelets suspended in K+ rich solutions of pH 6.8, 7.4 or 7.8 with subsequent resuspension in solution of pH 7.4 containing albumin (1 g l-1) and Ca2+ (1 mM) resulted in pHi of 6.72 +/- 0.05, 7.31 +/- 0.02 and 7.71 +/- 0.04 (mean +/- s.e. mean, n = 5). Ionomycin (1.2 microM) increased [Ca2+]i by 97.1 +/- 17.6, 191.9 +/- 48.7 and 322.8 +/- 55.7 nM at the different values of pHi respectively; TXB2 production was 0.7 +/- 0.2, 2.1 +/- 0.4 and 10.7 +/- 3.3 ng micrograms-1 protein, and 12-HETE production was 150.9 +/- 68.2, 184.4 +/- 77.9 and 302.3 +/- 62.8 ng micrograms-1 protein. 3. Ammonium chloride (50 mM) caused a small reduction in pHo while increasing pHi from 7.32 +/- 0.04 to 7.89 +/- 0.05 and increasing ionomycin (1.2 microM)-induced [Ca2+]i responses from 94.1 +/- 67.3 to 721.6 +/- 288.3 nM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quin2法测定人血小板胞浆游离钙浓度

应用荧光钙指示剂Ｑｕｉｎ２测定胞装游离钙浓度的方法，研究了在不同胞外游离钙浓度［Ｃａ￣（２＋）］＿０下人血小板场急状态时及由凝血四激活后的胞装游离钙浓度［Ｃａ￣（２＋）］＿１的变化．结果显示：凝血的可使负载Ｑｕｉｎ２的人血小板［Ｃａ￣（２＋）］＿１呈现浓度依赖性的短暂升高，且这种作用对［Ｃａ￣（２＋）］＿０有明显的依赖性。该项结果提示凝血酸引起的［Ｃａ￣（２＋）］＿１升高主要来源于外钙内流，部分为内钙释放所致．     

Low-density lipoprotein nanomedicines: mechanisms of targeting,biology, and theranostic potential

Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents. While the cellular recognition of well-known HDL-based carriers occurs via interactions with an HDL receptor, the selective delivery and uptake of LDL particles by target cells are more complex. The most well-known mode of LDL-based delivery is via the interaction between apolipoprotein B (Apo-B) – the main protein of LDL – and the low-density lipoprotein receptor (LDLR). LDLR is expressed in the liver, adipocytes, and macrophages, and thus selectively delivers LDL carriers to these cells and tissues. Moreover, the elevated expression of LDLR in tumor cells indicates a role for LDL in the targeted delivery of chemotherapy drugs. In addition, chronic inflammation associated with hypercholesterolemia (i.e., high levels of endogenous LDL) can be abated by LDL carriers, which outcompete the deleterious oxidized LDL for uptake by macrophages. In this case, synthetic LDL nanocarriers act as ‘eat-me’ signals and exploit mechanisms of native LDL uptake for targeted drug delivery and imaging. Lastly, recent studies have shown that the delivery of LDL-based nanocarriers to macrophages via fluid-phase pinocytosis is a promising tool for atherosclerosis imaging. Hence, the present review summarizes the use of natural and synthetic LDL-based carriers for drug delivery and imaging and discusses various mechanisms of targeting.     

咪苯嗪酮对花生四烯酸环氧酶途径代谢产物的选择性影响

兔iv咪苯嗪酮(CI—914)20 mg/kg,用RIA法测定其血浆中TXB_2和6—kcto—PGF_(1α)含量,给药后30 min和60 min.6—keto—PGF_(1α)/TXB_2比值显著升高(p<0.05).在用放射性TLC法进行的洗涤大鼠血小板~(14)C—AA代谢实验中,CI—914在2～500 μmol/L范围内以剂量依赖方式抑制大鼠血小板TXB_2生成,IC_(50)为51.5μmol/L,对HHT生成的抑制明显弱于对TXB_2生成的抑制作用;在相同剂量范围内,CI—914同时以剂量依赖方式使PGE_2,PGF_(2α)和PGD_2生成增加.在相同实验条件下,50μmol/L的已知的TXA_2合成酶抑制剂DAZ,与大剂量CI—914的实验结果类似.上述结果提示,CI—914对血小板TXA_2合成酶可能具有选择性抑制作用.