基质相互作用蛋白分子1在肿瘤发生发展和 临床应用中的研究进展

基质相互作用蛋白分子1（STIM1）与肿瘤的发生发展密切相关,其参与多种癌症细胞凋亡、增殖、迁移和侵袭的调节过程。阻断或敲除STIM1可以显著抑制癌细胞的增殖和迁移。阐明STIM1在癌症细胞中的调节机制,将有助于新的治疗靶点的确定。本文对STIM1分子在不同肿瘤中的作用机制及临床应用前景作一综述。     

CD137/CD137L共刺激信号在自身免疫和肿瘤免疫中的应用研究进展

CD137广泛表达于人体免疫细胞或非免疫细胞中,起传递活化、增殖或凋亡信号以维持人体免疫平衡的作用。CD137配体(CD137L)是一种Ⅱ型跨膜蛋白,主要表达于抗原提呈细胞表面。该文介绍了有关CD137/CD137L的表达、功能与生物学特性及其在自身免疫性疾病及肿瘤疾病治疗中的最新研究进展。     

JNK激酶在细胞凋亡中的作用及其与癌症的关系

JNK是MAPK蛋白激酶三级激活体系最下游的关键蛋白质,位于多个信号转导通路节点位置,它在细胞的增殖与分化、细胞凋亡等重要的细胞生物过程中发挥着决定性的作用。对癌症等重大疾病的发生、发展起到重要的调控作用。然而,由于JNK激酶3种亚型在不同种类的细胞中对细胞凋亡和肿瘤的发生发展存在较大的差异,使得以JNK为靶点的抗癌药物研发遇到巨大的困难。该文对JNK介导的细胞凋亡信号通路,JNK在细胞凋亡中的调控功能以及JNK 3种亚型对癌细胞的增殖和凋亡作用进行阐述。     

JNK激酶在细胞凋亡中的作用及其与癌症的关系北大核心CSCD

JNK是MAPK蛋白激酶三级激活体系最下游的关键蛋白质,位于多个信号转导通路节点位置,它在细胞的增殖与分化、细胞凋亡等重要的细胞生物过程中发挥着决定性的作用。对癌症等重大疾病的发生、发展起到重要的调控作用。然而,由于JNK激酶3种亚型在不同种类的细胞中对细胞凋亡和肿瘤的发生发展存在较大的差异,使得以JNK为靶点的抗癌药物研发遇到巨大的困难。该文对JNK介导的细胞凋亡信号通路,JNK在细胞凋亡中的调控功能以及JNK 3种亚型对癌细胞的增殖和凋亡作用进行阐述。     

灵菌红素对人胰腺癌细胞增殖抑制的实验研究

目的 :观察从生物工程技术得到的灵菌红素对人胰腺癌 8898细胞增殖抑制的药效学作用 ,并探讨其作用的部分机理。方法 :用MTT法测定 8898细胞的存活率和抑制率 ,用流式细胞仪分析细胞的周期变化和凋亡细胞的百分比 ,用HPLC检测人胰腺癌 8898细胞内灵菌红素的浓度 ,用琼脂糖凝胶电泳对DNA段片化进行分析。结果 :灵菌红素5mg·L-1的培养液中 8898细胞出现凋亡早期的形态学特征 ,半数抑制浓度 (IC50 )为 30mg·L-1。而3T3细胞却未显示出该作用。研究表明灵菌红素抑制细胞的增殖 ,与抑制S期细胞的DNA复制及调控细胞的增殖周期相关。同时 ,细胞凋亡的产生与实验药物呈正相关。HPLC结果显示 ,灵菌红素的药理学作用与细胞内药物浓度相关。结论 :灵菌红素能有效的进入细胞内 ,抑制细胞的增殖 ,其机理与诱导细胞凋亡和调控细胞的增殖周期相关。     

葛根素对血管平滑肌细胞凋亡的影响

葛根素是中药葛根的有效成分 ,对心脑血管疾病具有广泛的药理作用[1] 。研究表明 ,经皮腔内冠状动脉成型术(ＰＴＣＡ)后最主要的并发症为再狭窄 ,其主要表现为血管平滑肌细胞 (ＶＳＭＣ)的增殖和迁移以及细胞外基质的增多 ,而ＶＳＭＣ和巨噬细胞的凋亡功能失调和 (或 )凋亡小体的清除不足是促进动脉粥样硬化发生、发展的重要因素[2 ] 。因而寻找能够促进动脉粥样硬化中ＶＳＭＣ凋亡的手段具有重要的临床意义。本实验利用体外细胞培养技术、流式细胞术、荧光显微镜观察了葛根素对ＶＳＭＣ凋亡的影响。1　材料和方法1.1　血管平滑肌原代细胞的…     

枸杞多糖对人肺癌A_(549)细胞影响的研究

目的:探讨枸杞多糖(LBP)对人肺癌A549细胞的影响及作用机制。方法:将LBP作用于肺癌A549细胞,应用M TT法、电镜和钙离子测定等技术测定LBP的抗肿瘤作用及作用机理。结果:LBP呈剂量依赖性(100m g/L~2000m g/L)地抑制人肺癌A549细胞的增殖,诱导其凋亡,并可使细胞内钙离子浓度升高。结论:LBP可诱导A549细胞凋亡,其作用机制可能与细胞内钙离子浓度升高有关。     

肝星状细胞凋亡机制研究进展

肝星状细胞(hepatic stellate cell，HSC)是肝脏产生细胞外基质的主要来源，其大量增殖和凋亡相对不足在肝纤维化(hepatic fibrosis)的发生中起桉心作用，抑制其增殖和诱导其凋亡是逆转肝纤雏化的重要对策。肝星状细胞的凋亡受到凋亡和抗凋亡基因、细胞因子等的调控。现将Fas／Fasl系统、Bcl-2、Bax、p^53、Caspase家族及p^53与肝星状细胞凋亡研究概况综述如下。     

膜联蛋白A2的结构、功能及其在疾病中的研究进展

膜联蛋白A2是一种钙离子介导的磷脂结合特性的蛋白质,属于膜联蛋白家族成员,广泛分布于各种真核细胞膜、细胞质和细胞外液,主要表达在血管内皮细胞、单核细胞、巨噬细胞、树突状细胞、滋养层细胞、上皮细胞、肿瘤细胞等细胞中。其功能主要是参与膜转运及膜表面一系列依赖于钙调蛋白的活动,包括胞吐作用中的膜融合、囊泡运输、细胞黏附、细胞增殖、凋亡、复制、信号传导以及离子通道的形成,许多疾病及体内调控都与膜联蛋白A2有关。根据最近的文献报道,对膜联蛋白A2的结构、功能及其在疾病中的研究进展作一综述。     

环核苷酸调节血管平滑肌舒张的研究进展

血管张力的调控是通过调节血管收缩与舒张之间的平衡实现的,在高血压、血管痉挛等血管类疾病的病理生理过程中具有重要作用。了解血管张力调控的分子机制,是建立预防和治疗血管疾病新途径的基础[1,2]。调节血管平滑肌(VSM)细胞张力的主要因素是细胞内钙离子浓度([Ca2+]i C)的改变。[Ca2+]i C升高,VSM收缩;反之则舒张。血管收缩剂之所以能够升高[Ca2+]i C,主要有两种途径:(1)细胞外的钙离子     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Arsenic induced changes in growth development and apoptosis in neonatal and adult brain cells in vivo and in tissue culture

Arsenic at a nonlethal level in drinking water consumed over a period of time has been reported to produce chronic toxicity and various types of health problems ranging from skin cancer to disturbance in memory. Neurotoxic effects have been reported in clinical cases with chronic exposure to arsenic. Physiological detoxication of arsenic occurs partially through methylation. Arsenic and its methylated derivatives are distributed in different organs and systems. The present study examined the possible interference in the neuronal development and differentiation due to the exposure to arsenic during gestation. The experiments were carried out to examine short and long term effects of arsenic on brain explants and cells grown and maintained in tissue culture system. The effects of arsenic exposure showed changes in brain cell membrane function indicated by generation and release of reactive oxygen-nitrogen intermediates. On the morphological aspect the explants' growth was reduced, ground matrix was lost and neural networking was inhibited. Cells showed signs of apoptotic changes. Arsenic toxicity may induce damage to brain cells prior to more visible clinical conditions. The deleterious effects also pass from the maternal to fetal tissue across the transplacental barrier.     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85–100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Circulating nucleic acids in plasma and serum: roles in diagnosis and prognosis in diabetes and cancer

The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology.     

SalB stimulates neurogenesis and angiogenesis in vitro and in vivo

Aims： Previous studies suggested that Salvianolic acid B （SalB） has strong protective effect against cerebral ischemia. Recently, Sal B has been reported to enhance angiogenesis in vitro. Based on the information above, in this study we are interested in the effect of SalB on neurogenesis and angiogenesis. Methods：In vitro study, we used embryonic mouse （El6） primary cortical neural cultures. Neuron was recognized by anti-MAP2 with immunocytochemistry. Neurogenesis was tested with BrdU incorporation by ELSA method. SalB（ 10 -6 -10 -8M） or vehicle was added to the culture medium 24 hrs before BrdU addition. In vivo, middle cerebral artery occlusion （MCAO） rats were used as focal cerebral ischemia model.     

Pharmacokinetic and pharmacogenetic determinants and considerations in chemotherapy selection and dosing in infants

INTRODUCTION: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications. AREAS COVERED: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments. EXPERT OPINION: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.     

Consistency in catecholamine and cortisol excretion in males and females

Data from a series of experiments performed on 24 female and 24 male subjects were used to evaluate the consistency in urinary catecholamine and cortisol excretion. Data were available from 8 laboratory situations of varying activity level and content, spaced at intervals of maximum 3 months. Correlational analyses showed that for cortisol, interindividual consistency was higher for measures obtained on the same day than for measures obtained on different days. Interindividual consistency was generally high in catecholamine and cortisol excretion during non-stressful situations in both sexes. During experimental stress, however, consistency was as high as during nonstress for males, while it was lower for females. Analysis of variance components confirmed these results and showed that in males variation due to interindividual differences was high during both baseline and experimental-stress situations, while in females it was high during baseline situations only. During experimental stress, variation for females was due primarily to interaction. It is suggested that the males showed a more generalized stress response over situations than the females.     

Metabolic interaction between imipramine and carbamazepine in vivo and in vitro in rats

Summary The pharmacokinetic consequences of the combination of carbamazepine with imipramine in male Wistar rats have been investigated. It was found that a 2-week treatment with the combination resulted in the increase of the concentrations of the parent compounds and a simultaneous decrease in their metabolites in blood plasma i.e. carbamazepine inhibited imipramine demethylation in the side chain while imipramine inhibited carbamazepine 10,11-epoxidation. The velocity of imipramine 2-hydroxylation and 10,11-epoxy-carbamazepine hydration did not seem to be changed by the combination. On the basis of studies in vitro it is concluded that the observed metabolic interaction between carbamazepine and imipramine is due to the competition of the drugs for the active centre of cytochrome P 450 and to a certain qualitative alteration of the enzyme by imipramine as can be deducted from the decrease of carbamazepine binding to the cytochrome. Send offprint requests to K. J. Netter     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85-100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.