BACKGROUND & AIMS: :The fumigant insecticide phosphine (PH3) is known to inhibit cytochrome c oxidase in vitro. Inhibition of the respiratory chain at this site has been shown to stimulate the generation of superoxide radicals (O2-), which dismutate to form hydrogen peroxide (H2O2). This study was performed in order to investigate the production of H2O2 by mitochondria isolated from granary weevil (Sitophilus granarius) and mouse liver on exposure to PH3. Other respiratory inhibitors, antimycin, myxothiazol, and rotenone were used with insect mitochondria. Hydrogen peroxide was measured spectrophotometrically using yeast cytochrome c peroxidase as an indicator. Insect and mouse liver mitochondria, utilizing endogenous substrate, both produced H2O2 after inhibition by PH3. Insect organelles released threefold more H2O2 than did mouse organelles, when exposed to PH3. Production of H2O2 by PH3-treated insect mitochondria was increased significantly on addition of the substrate alpha-glycerophosphate. Succinate did not enhance H2O2 production, however, indicating that the H2O2 did not result from the autoxidation of ubiquinone. NAD(+)-linked substrates, malate and pyruvate also had no effect on H2O2 production, suggesting that NADH-dehydrogenase was not the source of H2O2. Data obtained using antimycin and myxothiazol, both of which stimulated the release of H2O2 from insect mitochondria, lead to the conclusion that glycerophosphate dehydrogenase is a source of H2O2. The effect of combining PH3, antimycin, and myxothiazol on cytochrome spectra in insect mitochondria was also recorded. It was observed that PH3 reduces cytochrome c oxidase but none of the other cytochromes in the electron transport chain. There was no movement of electrons to cytochrome b when insect mitochondria are inhibited with PH3. The spectral data show that the inhibitors interact with the respiratory chain in a way that would allow the production of H2O2 from the sites proposed previously.

背景与目标： : 熏蒸剂杀虫剂磷化氢 (PH3) 已知在体外抑制细胞色素c氧化酶。已显示在此位点对呼吸链的抑制可刺激超氧化物自由基 (O2-) 的产生，其歧化形成过氧化氢 (H2O2)。进行这项研究是为了研究暴露于ph3时从粮仓象鼻虫 (Sitophilus granarius) 和小鼠肝脏中分离出的线粒体产生H2O2。其他呼吸抑制剂，抗霉素，粘噻唑和鱼藤酮与昆虫线粒体一起使用。以酵母细胞色素c过氧化物酶为指示剂，分光光度法测定过氧化氢。昆虫和小鼠肝线粒体利用内源性底物，在被ph3抑制后均产生H2O2。当暴露于ph3时，昆虫细胞器释放的H2O2比小鼠细胞器多三倍。添加底物 α-甘油磷酸后，PH3-treated昆虫线粒体产生的H2O2显着增加。琥珀酸盐并不能提高H2O2的产生，这表明H2O2不是由泛醌的自氧化产生的。NAD () 连接的底物，苹果酸和丙酮酸对H2O2的产生也没有影响，这表明NADH-脱氢酶不是H2O2的来源。使用抗霉素和粘噻唑获得的数据均刺激了昆虫线粒体中H2O2的释放，得出的结论是甘油磷酸脱氢酶是H2O2的来源。还记录了PH3，抗霉素和粘噻唑对昆虫线粒体细胞色素光谱的影响。观察到PH3减少了细胞色素c氧化酶，但没有减少电子传递链中的其他细胞色素。当ph3抑制昆虫线粒体时，电子没有向细胞色素b移动。光谱数据表明，抑制剂与呼吸链相互作用的方式将允许从先前提出的位点产生H2O2。

BACKGROUND & AIMS: :Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).

背景与目标： : 细胞周期蛋白依赖性激酶5 (CDK5) 是属于细胞周期蛋白依赖性激酶 (CDK) 家族的丝氨酸/苏氨酸激酶。CDK5参与多种神经元疾病 (包括阿尔茨海默病或帕金森氏病，中风，创伤性脑损伤)，疼痛信号传导和细胞迁移。在本信中，我们描述了新的2,6，9-三取代嘌呤的合成和生物学评估，这些嘌呤在结构上与roscovitine有关，roscovitine是目前在临床试验中有希望的CDK抑制剂 (CDK1/Cyclin B，IC(50)= 350 nM; CDK5/p25，IC(50)= 200 nM)。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的; 几种化合物 (3j，3k，3l，3e，4k，6b，6c) 显示出针对CDK5的有效激酶抑制能力 (IC(50) 值范围为17至50 nm)，并显示出显着的细胞死亡诱导活性 (IC(50) 值范围为2至9μm的SH-SY5Y)。抑制剂与CDK5催化位点的ATP结合结构域的对接突出了涉及CDK5 Lys-89的氢键的区分作用。此外，针对几种抑制剂测量的用于络合的计算的最终能量平衡与IC(50) 值的排名一致。最后，我们观察到几种化合物表现出对DYRK1A (双重特异性，酪氨酸磷酸化调节激酶1A) 的亚微摩尔活性，DYRK1A是一种与唐氏综合症和阿尔茨海默氏病有关的激酶 (3g，3h，4m; IC(50) 值范围从300到400 nM)。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： : 设计，合成和评估了一系列新型白藜芦醇衍生物，可作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，(E)-5-(4-(异丙基氨基) 苯乙烯基) 苯-1,3-二醇表现出有效的 β-淀粉样蛋白聚集抑制活性，通过ThT荧光分析 (71.65% 在20μm) 和透射电子显微镜 (TEM) 证实了这一点。化合物7l也显示出良好的抗氧化活性 (在氧自由基吸收能力分析中4.12的Trolox当量和10μm细胞中活性氧的37% 减少)。化合物的细胞毒性分析7f，7i，7j和7l表明这些化合物在60μm时的毒性比白藜芦醇低。

BACKGROUND & AIMS: :A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

背景与目标： : 已经确定了一系列新型的有效且有效的Xa因子抑制剂，该抑制剂在邻氨基苯甲酰胺化学型中具有磺胺嘧啶部分作为新型的S4结合元件。在这种新型P4组中进行铅优化可导致许多有效的Xa因子抑制剂在人血浆中具有出色的抗凝活性。将选定的化合物口服给大鼠，并检查其离体凝血酶原时间延长活性，结果鉴定了化合物5-氯-N-(5-氯吡啶-2-基)-2-(4-(N-(2-二乙基氨基) 乙酰基)-S-甲基磺酰亚胺基) 苯甲酰胺 (18f)。18f的详细药代动力学评估和随后的代谢研究表明存在活性代谢物。该化合物18f及其活性代谢物18b在大鼠动脉和静脉血栓形成模型中均表现出出色的体内功效，并被发现对相关丝氨酸蛋白酶具有高度选择性。基于这一前景，选择化合物18f进行进一步评估。

BACKGROUND & AIMS: :As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC(50) of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.

背景与目标： : 作为我们致力于从天然来源开发抗糖尿病剂的努力的继续，从Piper chaba中分离出了piplatine，并发现其IC(50) 为160 μ m抑制重组人ALR2。为了提高功效，已通过修饰该天然产物铅的苯乙烯基/芳族和杂环官能团合成了一系列类似物。测试了所有衍生物的ALR2抑制活性，结果表明，通过将哌哌丁胺与吲哚衍生物的Michael加成制备的加合物3c，3e和2j表现出有效的ARI活性，而其他化合物则表现出不同程度的抑制作用。活性化合物还能够防止山梨醇在人红细胞中的积累。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： : 表皮生长因子受体 (EGFR) 的致敏突变可预测对EGFR酪氨酸激酶抑制剂 (TKIs) 的反应，并且第一代和第二代TKIs均可作为晚期EGFR突变型非小细胞肺癌患者的一线治疗选择。在重复活检和血浆循环肿瘤DNA中，最终的耐药性可通过多种机制识别。T790M网守突变负责几乎60% 的病例。许多第三代TKIs正在临床开发中，奥希替尼已获得美国食品药品监督管理局的批准，可用于治疗EGFR T790M突变型肺癌患者的初始EGFR激酶治疗失败。这些新药物的耐药机制正在被确定，并且EGFR突变型肺癌的治疗前景继续发展。EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: :Two new families of human farnesyltransferase inhibitors 13a-m and 14a-d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC(50) values of 0.7 and 0.6 μM, respectively.

背景与目标： : 合成了基于吩噻嗪支架的两个新的人法尼基转移酶抑制剂13a-m和14a-d家族。化合物14a和14b是最有希望的人法尼基转移酶抑制剂，其IC(50) 值分别为0.7和0.6。

BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

背景与目标： : 利用x射线晶体结构分析，设计了 (3S，5R)-5-[4-(2-氯苯基)-2,2-二甲基-5-氧代哌嗪-1-基] piperidine-3-carboxamides，并鉴定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。

BACKGROUND & AIMS: :A study in mice suggests that macrophages produce resistance to checkpoint inhibitors by removing anti-PD-1 antibodies from T cells. Fcγ receptors on macrophages bind to the Fc domain on the antibodies. Blocking this interaction with other antibodies produced dramatic tumor shrinkage in mice.

背景与目标： : 一项在小鼠中的研究表明，巨噬细胞通过从T细胞中去除anti-PD-1抗体来产生对检查点抑制剂的抗性。巨噬细胞上的Fc γ 受体与抗体上的Fc结构域结合。阻断与其他抗体的这种相互作用会在小鼠中产生剧烈的肿瘤缩小。

BACKGROUND & AIMS: :Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.

背景与目标： : 人类有两个谷氨酰胺酶基因，GLS (GLS1) 和GLS2，每个基因都有两个可供选择的转录本: GLS的肾脏同工型 (KGA) 和谷氨酰胺酶C (GAC)，GLS2的肝脏同工型 (LGA) 和谷氨酰胺酶B (GAB)。初始命中化合物 (Z)-5-((1-(4-溴苯基)-2,5-二甲基-1h-吡咯-3-基) 亚甲基) thiazolidine-2，4-二酮 (thiazolidine-2，4-二酮) 是通过对40-2000个化合物的高通量筛选获得的。随后，一系列thiazolidine-2，合成了4-二酮衍生物。发现其中大多数抑制KGA和GAC的活性相当，是GAB的效力较低的抑制剂，并且对GLS1的选择性优于gls2。化学结构，活性，并研究了选择性。发现获得的铅化合物 (1) 提供体外细胞活性以抑制细胞生长，克隆性和细胞谷氨酸产生，(2) 通过药代动力学研究在血浆中表现出高浓度的暴露，(3) 减少小鼠异种移植的人胰腺癌AsPC-1细胞的肿瘤大小。

BACKGROUND & AIMS: :The present study was designed to investigate whether taxol in combination with cyclooxygenase (COX) inhibitors could be superior on inhibitory effect of ovarian cancer growth than taxol alone as drug therapy of mice implanted with human ovarian carcinoma cell line SKOV-3. The animals were treated with 100 mg/ kg celecoxib (a COX-2 selective inhibitor) alone or in combination with 3 mg/kg SC-560 (a COX-1 selective inhibitor) by gavage twice a day, 20mg/kg taxol alone by intraperitoneal (IP) once a week or in combination with celecoxib, or SC-560/celecoxib/taxol for 3 weeks. To test the mechanism of the combination treatment, the index of cell proliferation, expression of cyclin D1, and microvessel density (MVD) in tumor tissues were determined by immunohistochemistry and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Mean tumor volume in the SC-560/celecoxib/taxol group was first significantly lower than control at day 14 (p < 0.05). In the SC-560/celecoxib/taxol group, the index of cell proliferation and apoptosis and quantification of cyclin D1-postive cells were 6.93%, 69.62%, and 19.14%, respectively, which are statistically significant compared with those of the control group (29.85%, p < 0.001; 32.81% and 36.99%, both p < 0.05). Statistical significance on MVD was observed between the SC-560/celecoxib/taxol (39.57 +/- 4.98) and the control (73.2 +/- 1.96) group (p < 0.001). Our results suggest that the combined antitumor efficacy of taxol and COX inhibitors may be superior to taxol alone as drug therapy against ovarian cancer in mice, and that synergism of the combination treatment in part may be mediated through accelerated apoptosis and suppression of cell proliferation and angiogenesis.

背景与目标： 本研究旨在研究紫杉醇联合环氧合酶 (COX) 抑制剂对卵巢癌生长的抑制作用是否优于单独使用紫杉醇作为植入人卵巢癌细胞系SKOV-3的小鼠的药物治疗。分别用100 mg/kg塞来昔布 (一种COX-2选择性抑制剂) 单独或与3 mg/kg SC-560 (一种COX-1选择性抑制剂) 联合每天两次灌胃，单独用20mg/kg紫杉醇腹腔 (IP) 每周一次或与塞来昔布联合治疗，或SC-560/塞来昔布/紫杉醇3周。为了测试联合治疗的机制，采用免疫组织化学方法测定肿瘤组织中细胞增殖指数，细胞周期蛋白D1的表达和微血管密度 (MVD)，并通过末端脱氧核苷酸-转移酶介导的三磷酸脱氧尿苷缺口末端标记 (TUNEL) 方法测定凋亡细胞的指数。在第14天，SC-560/塞来昔布/紫杉醇组的平均肿瘤体积首先显着低于对照组 (p <0.05)。在SC-560/塞来昔布/紫杉醇组中，细胞增殖和凋亡指数以及细胞周期蛋白D1-postive的定量分别为6.93% 、69.62% 和19.14%，与对照组相比有统计学意义 (29.85%，p <0.001; 32.81% 和36.99%，均p <0.05)。SC-560/塞来昔布/紫杉醇 (39.57 +/- 4.98) 和对照组 (73.2 +/- 1.96) 之间的MVD有统计学意义 (p <0.001)。我们的结果表明，紫杉醇和COX抑制剂的联合抗肿瘤疗效可能优于单独的紫杉醇作为小鼠卵巢癌的药物治疗，并且联合治疗的协同作用部分可能通过加速凋亡和抑制细胞增殖和血管生成来介导。

BACKGROUND & AIMS: :The human immunodeficiency virus type-1 (HIV-1) envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. Here, we show that N(CCG)-gp41, a class 2 inhibitor, and N36(Mut(e,g)), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudo-typed virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observations for HIV-Env-mediated membrane fusion are discussed.

背景与目标： : 介导膜融合的人类免疫缺陷病毒1型 (HIV-1) 包膜 (Env) 蛋白是开发新的AIDS疗法的主要目标。已经描述了三类Env介导的膜融合抑制剂，它们专门针对gp41的发夹前中间构象。2类抑制剂与gp41的C端七药重复 (c-hr) 结合。3类抑制剂的单个实例针对gp41的三聚体N末端七位重复序列 (n-hr)，并已被假定通过形成融合无能的异三聚体来隔离发夹前中间体的n-hr。在这里，我们显示了2类抑制剂N(CCG)-gp41和3类抑制剂N36(Mut(e，g))，在细胞融合试验 (具有膜结合的CD4) 和Env-伪型病毒中和试验中，协同抑制几种代表性HIV-1菌株 (X4和R5) 的Env介导的膜融合。讨论了这些观察结果对HIV-Env介导的膜融合的机理以及潜在的治疗意义。

BACKGROUND & AIMS: :The estrogenic activity of tamoxifen on the uterus increases the risk of developing benign and malignant uterine pathologies in breast cancer patients receiving this drug. This has led to gynecological interventions specifically in symptomatic women to exclude malignant disease. Given this known side effect associated with tamoxifen therapy, newer endocrine therapies such as the third-generation aromatase inhibitors have been compared to tamoxifen also in terms of their uterine effects. To date, studies that have directly compared the uterine effects of tamoxifen with that of aromatase inhibitors generally show that aromatase inhibitors such as anastrozole, letrozole, and exemestane are associated with less uterine pathologies compared to tamoxifen. Furthermore, aromatase inhibitors may even reverse uterine abnormalities induced by tamoxifen. This implies that the absence of a stimulatory effect on the uterus would be one of the benefits gained with aromatase inhibitor therapy and may decrease or even obviate the need for gynecological interventions.

背景与目标： : 他莫昔芬对子宫的雌激素活性增加了接受这种药物的乳腺癌患者发展良性和恶性子宫病变的风险。这导致了专门针对有症状妇女的妇科干预措施，以排除恶性疾病。鉴于与他莫昔芬治疗相关的这种已知副作用，更新的内分泌疗法 (例如第三代芳香化酶抑制剂) 也已与他莫昔芬在子宫作用方面进行了比较。迄今为止，直接比较他莫昔芬与芳香化酶抑制剂的子宫效应的研究通常表明，与他莫昔芬相比，阿那曲唑，来曲唑和依西美坦等芳香化酶抑制剂与较少的子宫病变相关。此外，芳香化酶抑制剂甚至可以逆转他莫昔芬引起的子宫异常。这意味着对子宫没有刺激作用将是芳香化酶抑制剂疗法获得的好处之一，并且可能减少甚至消除对妇科干预的需求。

BACKGROUND & AIMS: Paired helical filaments (PHFs) in the neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains are composed of highly phosphorylated isoforms of tau (PHFtau) that fail to bind microtubules (MTs), and the levels of MT-binding competent tau are decreased in AD brains with abundant PHFtau. Because this loss of MT binding could compromise the viability of tangle-bearing AD neurons by destabilizing MTs, we asked whether these events could be initiated by inhibiting protein phosphatase 1 (PP1) and PP2A in cultured human neurons (NT2N cells) using okadaic acid (OK) and calyculin-A (CL-A). The treatment of NT2N cells with OK and CL-A increased tau phosphorylation, decreased the binding of tau to MTs, and selectively depolymerized the more stable detyrosinated MTs but not the more labile tyrosinated MTs. Significantly, this led to the rapid degeneration of axons, which are enriched in the more stable detyrosinated MTs, and PP2A was implicated in the initiation of this cascade of events because PP2A but not PP1 was closely associated with MTs in the NT2N cells. These studies imply that inactivation of PP2A in vulnerable neurons of the AD brain may play a mechanistic role in the conversion of normal tau into PHFtau, in the depolymerization of stable MTs, and in the degeneration of axons emanating from tangle-bearing neurons.

背景与目标： 阿尔茨海默氏病 (AD) 大脑的神经原纤维缠结 (nft) 中的成对螺旋细丝 (phf) 由高度磷酸化的tau亚型 (PHFtau) 组成，无法结合微管 (MTs)，并且MT结合的水平在具有丰富PHFtau的AD大脑中降低。因为MT结合的这种丧失可能会通过破坏MTs的稳定性而损害缠结AD神经元的生存能力，我们询问是否可以通过使用冈田酸 (OK) 和calyculin-A (cl-a) 抑制培养的人神经元 (NT2N细胞) 中的蛋白磷酸酶1 (PP1) 和PP2A来引发这些事件。用OK和CL-A处理NT2N细胞会增加tau的磷酸化，降低tau与MTs的结合，并选择性解聚更稳定的去酪氨酸化MTs，而不是更不稳定的酪氨酸化MTs。值得注意的是，这导致了轴突的快速变性，轴突在更稳定的去红细胞化MTs中富集，并且PP2A参与了该级联事件的启动，因为PP2A而不是PP1与NT2N细胞中的MTs密切相关。这些研究表明，AD大脑脆弱神经元中PP2A的失活可能在正常tau转化为PHFtau，稳定MTs的解聚以及缠结神经元产生的轴突变性中起机械作用。

BACKGROUND & AIMS: From January 1994 through May 1995, Prudential HealthCare-North Texas prospectively studied 299 member patients diagnosed with hypercholesterolemia for whom pharmacotherapy with one of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also known as statins, was prescribed. The purpose of this study was to measure the relative cost-effectiveness (CE) of these drugs in a real-world setting. This study provides information to assist decision makers in managed-care organizations (MCO) in making formulary selections. The study used a prospective, randomized, balanced cohort design, examining patients who had been prescribed initial therapy with a statin drug as monotherapy. Costs (direct medical and indirect costs) and effectiveness (percent reduction in low-density lipoprotein cholesterol levels) were based on approximately the first 6 months of initial therapy. Both the MCO and patient perspectives were considered. In the base case, mean CE ratios were significantly lower for fluvastatin compared with lovastatin, pravastatin, and simvastatin from both the managed-care perspective and the patient perspective. Sensitivity analysis did not alter the CE conclusions, even under conditions of varying cost structures. Although differences were found in the effectiveness of lovastatin, pravastatin, and simvastatin measured in this study versus efficacy measured for these drugs in controlled clinical trials, sensitivity analysis suggests that these differences alone do not determine the superior CE of fluvastatin. Finally, this study supports the idea that well-designed formularies should consider drug CE (based on safety, effectiveness, and cost) and that integration of the pharmacy benefit management with other medical management is essential. These results provide evidence that fluvastatin may represent a more cost-effective formulary choice among statin products used for initial monotherapy of hypercholesterolemia.

背景与目标： 从1994年1月到1995年5月，Prudential HealthCare-North Texas前瞻性研究了299名被诊断为高胆固醇血症的成员患者，为他们开了四种3-羟基-3-甲基戊二酰辅酶a还原酶抑制剂之一 (也称为他汀类药物) 的药物治疗。这项研究的目的是在现实环境中测量这些药物的相对成本效益 (CE)。这项研究提供了信息，以帮助管理式护理组织 (MCO) 的决策者进行处方选择。该研究使用了前瞻性，随机，平衡的队列设计，检查了使用他汀类药物作为单一疗法的初始疗法的患者。费用 (直接医疗和间接费用) 和有效性 (低密度脂蛋白胆固醇水平降低的百分比) 大约基于初始治疗的前6个月。考虑了MCO和患者的观点。在基本情况下，从管理护理的角度和患者的角度来看，氟伐他汀与洛伐他汀，普伐他汀和辛伐他汀的平均CE比显着降低。即使在成本结构不同的情况下，敏感性分析也不会改变CE的结论。尽管在本研究中发现洛伐他汀，普伐他汀和辛伐他汀的有效性与对照临床试验中这些药物的有效性存在差异，但敏感性分析表明，仅这些差异并不能确定氟伐他汀的优越CE。最后，本研究支持以下观点: 精心设计的处方应考虑药物CE (基于安全性，有效性和成本)，并且将药房效益管理与其他医疗管理相结合至关重要。这些结果提供了证据，表明氟伐他汀可能代表了用于高胆固醇血症的初始单一疗法的他汀类药物中更具成本效益的配方选择。