吩噻嗪类药物潜在抗肿瘤作用机制研究

通过对3种吩噻嗪类药物进行分析,探讨3种吩噻嗪类药物潜在抗肿瘤的作用机制.首先通过预测能够与氯丙嗪、氟奋乃静和三氟拉嗪相互作用的靶蛋白,然后对3种药物的靶蛋白取交集,对交集蛋白进行细胞信号通路富集和相关疾病富集,提取属于肿瘤的富集类,进而通过蛋白相互作用网络调控分析,阐明这些靶蛋白在肿瘤中的作用机制,从而明确吩噻嗪类药物潜在抗肿瘤的作用机制.细胞信号通路富集和相关疾病富集结果均显示,得分最高的类别为肿瘤,在属于肿瘤类别的靶蛋白中,包含有Wnt,MAPK,维甲酸受体等信号通路成员.并且与靶蛋白相关的细胞信号级联传递过程中,MAPK8能够间接作用于靶蛋白CDK2,IGF1R,GSK3B,RARA,FGFR2和MAPK10进而影响肿瘤细胞的分裂与增殖.因此,吩噻嗪类药物可能具有潜在的抗肿瘤作用,其与肿瘤相关的靶蛋白在细胞信号级联转导过程中发挥着关键作用.     

新型PEI衍生物对基因沉默作用的研究

目的:构建出一种新型的高效的非病毒基因输送材料.方法:利用1,4-丁二醇二氯甲酸酯连接小分子PEI,合成新型的PEI衍生物(dPEI),通过体外COS-7和HSC细胞实验检测其对质粒和siRNA的输送情况.结果;COS-7细胞实验显示,dPEI具有高效输送质粒的能力,其转染效率是对照组PEI 25 kDa的10倍以上;同时,HSC细胞实验进一步证实dPEI包裹siRNA转染具有一定的基因沉默作用.结论:本研究合成的新型PEI衍生物既可以用于质粒基因的转染,也可用于siRNA的转染,是一种新型的高效的非毒基因输送材料.     

甘氨酸及其衍生物的抗菌作用

本文讨论甘氨酸、甘氨酸盐、甘氨酸高级脂肪醇的酯以及其它甘氨酸衍生物的抗菌作用。     

糖类及其衍生物的抗肿瘤作用

糖类不仅本身具有抗肿瘤等多种生物活性,同时发现其经过修饰后的衍生物也具有独特的作用.糖类及其衍生物抗肿瘤活性的研究已成为生物化学和医学领域的前沿,对寻找新型糖类抗肿瘤药物有重要的意义.     

血卟啉衍生物的生物学作用与制备

一、血卟啉衍生物是一种诊治癌瘤的光敏物质早在本世纪初,人们在研究血卟啉衍生物(Hematoporphyrin derjrative,简写 HPD)的光动力学过程时就发现其对人和哺乳动物癌瘤的光敏治疗作用。近年来,随着激光技术的发展,利用血卟啉加激光诊治癌瘤,在世界各国得到了广泛的应用。我国学者也在进行大量研究,还组织过攻关组来协调这方面的工作。HPD 光敏诊治癌瘤具有安全、简便、诊断率高,治疗效果好,对正常组织损伤少等优点,是一种很有前途的诊治癌瘤方法。     

壳聚糖及其衍生物抗肿瘤作用研究进展

壳聚糖为天然多糖甲壳素脱除部分乙酰基的产物,是自然界存在的唯一碱性多糖,无毒,可生物降解,具有免疫功能和良好的生物相容性。近年发现,壳聚糖具有抗肿瘤作用,却因其难溶于水及中性溶剂而影响其应用,壳聚糖衍生物改善了壳聚糖的这个缺点,也具有更广泛的药理作用。本文对壳聚糖及其壳聚糖衍生物在抗肿瘤方面的研究情况做了综述。     

新型聚乙烯亚胺衍生物体内转染活性的研究

目的:研究新型聚乙烯亚胺衍生物作为基因载体在小鼠体内的转染活性情况。方法:采用荧光素酶质粒DNA作为报告基因,与基因载体复合,对小鼠尾静脉注射,考察组织分布情况;以及对小鼠肌肉注射,应用活体成像技术考察其转染活性。结果:静脉注射后,小鼠肺组织中基因表达量最高;肌肉注射后,可以观察到活性转染结果,表达量高于对照PE(?)25KDa。结论:新型聚乙烯亚胺衍生物在体内可成功输送质粒DNA,但转染效率偏低。     

黄芩苷对嗜水气单胞菌生物膜形成的影响及体内外的抑菌作用

[目的]探讨中药单体黄芩苷对嗜水气单胞菌在体内外生长及生物膜形成的影响.[方法]体外实验中,利用牛津杯法检测抑菌圈直径,结晶紫法检测生物膜的形成,通过泳动实验检测黄芩苷对嗜水气单胞菌运动性的影响,紫外吸收法检测细胞膜完整性,用透射电镜技术观察黄芩苷对细菌形态的影响.体内实验利用草鱼为对象检测黄芩苷对嗜水气单胞菌增殖的影...     

胡椒碱及其衍生物对SH-SY5Y细胞的保护作用研究

对胡椒碱进行结构改造,合成了4个胡椒碱衍生物。以高浓度皮质酮(corticosterone)模拟抑郁及焦虑症神经细胞损伤状态。对包括胡椒碱在内的5个化合物进行了SH-SY5Y细胞保护作用的研究。结果表明:胡椒碱、5-(3,4-methylenedioxy phenyl)-2E,4E-pentadienoic acid n-propylamine amide(2)以及5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid N-methyl piperazine amide(4)对SH-SY5Y细胞有较好的保护作用。其中化合物2对SH-SY5Y细胞具有明显和持久的保护作用。     

低聚果糖体内外对肠道菌的影响

目的 :了解低聚果糖 (FOS)体内外对肠道菌双歧杆菌、类杆菌和肠杆菌科菌的增殖作用。方法 :FOS 1g/ (kg· bw· d) ,灌服 (ig)小鼠 ,连续 14 d后 ,取粪便 ,选择性培养基平板菌落计数法测各菌群。体外试验中 ,按 1%的 FOS添加到各人肠道分离菌培养液中 ,培养 2 4h后测其吸光度 A值和 p H值变化。结果 :ig FOS的小鼠肠道双歧杆菌和肠杆菌数量分别是 9.16± 0 .67和 8.3 3± 0 .70 (log10 N CFU/ g) ,高于对照组(P<0 .0 5)。 FOS体外对各肠道分离菌均有增殖作用 ,依大小分别是双歧杆菌、类杆菌和肠杆菌 ,其 A值分别增加了 0 .8～ 1.192、0 .80 2和 0 .198～ 0 .461,其 p H值分别降低了 1.5～ 1.68、1.2和 0 .2～ 0 .58。结论 :FOS体内外有相对选择性增殖双歧杆菌的作用 ,对类杆菌和肠杆菌也有调整作用     

EFFECTS OF GAMMA-HYDROXYBUTYRIC ACID AND OTHER HYPNOTICS ON GLUCOSE UPTAKE IN VIVO AND IN VITRO

Abstract— (1) The effects of gamma-hydroxybutyrate, imidazole-4-acetic acid and pento-barbitone on mouse brain glucose, glycogen and lactate levels have been studied. All the drugs significantly increased the brain glucose content, but did not significantly alter brain glycogen levels. The increase in brain glucose following imidazole-4-acetic acid or hypnotic doses of pentobarbitone was matched by corresponding decreases in the lactate level; this was not the case with gamma-hydroxybutyrate where the total glucose equivalents in the brain, expressed as the tissue level of (glucose) + (lactate/2), were significantly increased.
(2) All drugs except imidazole-4-acetic acid significantly decreased the rate of appearance of [¹⁴C]glucose into the bloodstream in vivo but had no effect on the uptake of glucose into rat diaphragm in vitro when present at 2·5 mM concentration.
(3) Only imidazole-4-acetic acid significantly inhibited glucose uptake into the brain in vivo but at 2·5 mM had no significant effect on glucose uptake into rat cerebral cortical slices in vitro.
(4) It is concluded that the very large increase in brain glucose level observed following the injection of hypnotic doses of gamma-hydroxybutyrate cannot be explained in terms of an increased net uptake of glucose into the brain.     

EFFECTS OF LITHIUM TREATMENT IN VITRO AND IN VIVO ON ACETYLCHOLINE METABOLISM IN RAT BRAIN

Abstract— The effects of LiCl on cholinergic function in rat brain in vitro and in vivo have been investigated. The high affinity transport of choline and the synthesis of acetylcholine in synaptosomes were reduced when part (25-75%) of the NaCl in the buffer was replaced with LiCl or sucrose. This appeared to be due to lack of Na⁺ rather than to Li⁺, as addition of LiCl to normal buffer had little effect. Following an injection of LiCl (10mmol/kg, i.p.) into rats the concentration of a pulsed dose of [²H₄]choline (20 μmol/kg, i.v., 1 min) and its conversion to [²H₄]acetylcholine, and the concentrations of [²H₂]acetylcholine and [²H₀]choline were measured in the striatum, cortex, hippocampus and cerebellum. The [²H₄]choline and [²H₄]acetylcholine were initially (15 min after LiCl) reduced (to ?30% in the cortex) and later (24 h after LiCl) increased (to + 50% in the striatum). There was a corresponding initial increase (to +50% in the cerebellum) and later decrease (to ?30% in the hippocampus) of the endogenous acetylcholine and choline. These results indicate an initial decrease and later increase in the utilization of acetylcholine after acute treatment with LiCl. Following 10 days of treatment with LiCl there was an increased rate of synthesis of [²H₄]acetylcholine from pulsed [²H₄]choline in the striatum, hippocampus and cortex (P < 0.05). The high affinity transport of [²H₄]choline and its conversion to [²H₄]acetylcholine was activated (131% of control; P < 0.01) in synaptosomes isolated from brains of 10-day treated rats. Investigation of synaptosomes isolated from striatum, hippocampus and cortex revealed that only striatal [²H₄]acetylcholine synthesis was significantly stimulated. Kinetic analysis demonstrated that the apparent K_T for choline was decreased by 30% in striatal synaptosomes isolated from rats treated for 10 days with LiCl. Striatal synaptosomes from 10-day treated rats compared to striatal synaptosomes from untreated rats also released acetylcholine at a stimulated rate in a medium containing 35 mM-KCl. These results indicate that LiCl treatment stimulates cholinergic activity in certain brain regions and this may play a significant role in the therapeutic effect of LiCl in neuropsychiatric disorders.     

DEVELOPMENTAL EFFECTS ON PROTEIN SYNTHESIS RATES IN REGIONS OF THE CNS IN VIVO AND IN VITRO

Abstract— Protein synthesis rates have been determined quantitatively in several regions of the nervous system of rats of various ages. The developmental changes in these regions are generally similar with a high rate maintained from several days before birth to about 4 days of age (1.9–2.1% h⁻¹). A decline in the rate ensues thereupon which continues till approx 30 days of age, whence the curve flattens though continuing slowly downward with increasing age. In the young three regions, cerebellum, pineal and pituitary, exhibit exceptionally higher rates (40–50%) than the cerebral hemispheres, pons-medulla, mid brain or cord, which all display curves of similar magnitude and shape. While the rate in the cerebellum eventually declines with age to within 10% of the rate in cerebral hemisphere, rates in the pineal and pituitary though decreasing remain far above (100%) rates in cerebral hemisphere even in adults.
The rate in vitro for slices of cerebellum follows a pattern similar to that shown previously for cerebral hemispheres: in the very young rates are 70–80% of the in vivo value but decline much more rapidly with age and in adult represent only 10–15% of the rate in vivo.
A markedly different pattern is seen in whole (unsliced) pituitaries wherein in vitro rates parallel in vivo rates with increasing age at approx 70–80% of the in vivo rate. Pineals appear to follow a similar pattern.     

ORGANIC MERCURIAL ENCEPHALOPATHY: IN VIVO AND IN VITRO EFFECTS OF METHYL MERCURY ON SYNAPTOSOMAL RESPIRATION

—A reproducible model of subacute methyl mercury (MeHg) intoxication was developed in the adult rat following the daily intragastric administration of 10 mg methyl mercury/kg body wt. Synaptosomes isolated from animals during the latent phase of mercury neurotoxicity (6-10 days) demonstrated no significant change in respiratory control, State 3, State 4, or 2,4-dinitrophenol stimulated respiration with succinate, glutamate or pyruvate plus malate. During the neurotoxic phase, a significant decline in respiratory control was evident with all substrates. Cerebellar synaptosomes revealed qualitatively similar but quantitatively greater inhibition of 2,4-dinitrophenol stimulated respiration during the latent and neurotoxic phases with glutamate. In vitro studies of synaptosome respiration, oxidative phosphorylation and respiratory control with 5-15 μm -methyl mercury revealed a stimulation of initial State 4 respiration, loss of RCI, inhibition of State 3 but no change in the gramicidin or 2,4-dinitrophenol uncoupled rate supported by pyruvate-malate. Phosphate did not relieve the State 3 inhibition. At 25 μm -methyl mercury and above, considerable inhibition of electron transfer occurred. At this concentration, cytochrome c oxidase was inhibited 50%. Isosmotic replacement of medium KC1 by mannitol reduced the MeHg stimulation of State 4 respiration but had no effect on MeHg inhibition of ADP stimulated respiration. Half-maximal stimulation of State 4 respiration by MeHg occurred at [K]⁺⋍ 6 mm . These findings are compatible with an energy-linked methyl mercury induced cation translocation across the synaptosome (mitochondrial) membrane.     

半乳糖寡糖在体内和体外对双歧杆菌生长的影响

目的:利用固定化产β-半乳糖苷酶的嗜热脂肪芽孢杆菌连续合成的产物。方法:经柱层析分离纯化得到了纯半乳糖三寡糖和半乳糖四寡糖,用于体外双歧杆菌培养和动物试验。结果:证实了半乳糖寡糖能高效、专一地促进双歧杆菌的生长繁殖。结论:半乳糖寡糖具有改善小鼠肠道内菌群分布,降低小鼠盲肠内pH值的生理功能。     

胰岛素和IGF-I对离体犊牛小肠上皮细胞增殖和吸收功能的影响

本试验选择离体犊牛小肠上皮细胞,以细胞增殖率和葡萄糖吸收率作为细胞生长发育与功能成熟的指标,研究了胰岛素与胰岛素样生长因子-I(IGF-)对细胞生长发育的影响。结果表明,胰岛素浓度为10μg/ml时,明显促进小肠上皮细胞的增殖和对葡萄糖的吸收,浓度达到50μg/ml时则抑制细胞的增殖和吸收(P<0.01)。IGF-I浓度为100ng/ml时,对促进小肠上皮细胞增殖和吸收葡萄糖的作用最强(P<0.01),但100ng/ml、500ng/ml和1000ng/ml三种不同浓度的IGF-I对刺激细胞增殖和提高吸收功能无显著差异(P>0.05)。     

α-METHYLTRYPTOPHAN: EFFECTS ON CEREBRAL MONOOXYGENASES IN VITRO AND IN VIVO

Following administration of x-methyltryptophan (AMTP) (50 mg/kg) there was a time dependent decrease of serotonin and a concomitant increase of α-methyl-5-hydroxy-tryptamine (AM-5-HT) in most cerebral areas. AMTP is hydroxylated to α-methyl-5-hydroxytryptophan (AM-5-HTP) by cerebral tryptophan hydroxylase in vitro and in vivo. Hydroxylation of AMTP in vitro and in vivo was markedly inhibited in p-chlorophenylalanine (p-CP) treated rats. After administration of AMTP, the conversion in vivo of tyrosine to norepinephrine was inhibited. This inhibition was not apparent in p-CP pretreated animals. p-Chloroamphetamine (p-CA) (10 mg/kg) lowered serotonin and AM-5-HT levels in some areas of the brain, but unlike p-CP, alone or in combination with AMTP it did not significantly inhibit hydroxylation of tryptophan (Trp). AMTP, as substrate of tryptophan hydroxylase, has a K_m of 1.08 × 10^-4 M (using 6-MPH₄, as cofactor) and as competitive inhibitor, a K₁ of 2.09 × 10^-4M with L-Trp as substrate. AMTP becomes an uncompetitive inhibitor when its concentration is equal to or exceeds that of L-Trp. D-AMTP is neither a substrate nor an inhibitor of tryptophan hydroxylase. DL-AM-5-HTP (K₁, 1.5 × 10^-5 M) and AM-5-HT (K¹ 4.0 × 10^-5 M) are competitive inhibitors.