BACKGROUND & AIMS: :Matrix metalloproteinase (MMPs) expression has been linked to gynecological tumor aggressiveness. The objective of this study was to determine MMP-2, MMP-7, and MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 expression in endometrial malignancies and their relation to clinical and histologic parameters. Formalin-fixed, paraffin-embedded tumor samples from 50 patients with endometrial carcinoma treated between 1999 and 2004 were stained with specific monoclonal antibodies. The tumors were grouped according to the FIGO classification. The staining results were compared to histologic and clinical data. Semiquantitative analysis of MMP and TIMP expression showed a significant difference in TIMP-2 expression according to the histologic subtype (P = 0.03) and also a trend towards a difference in MMP-9 expression (P = 0.05). MMP-2 expression increased and TIMP-2 expression fell as the histologic grade increased (P = 0.0007, P < 0.0001, respectively). MMP-2 expression correlated with lymph node metastasis (P = 0.04), while TIMP-2 expression correlated with the depth of myometrial invasion (P = 0.01), vasculolymphatic space involvement (P = 0.02), and lymph node metastasis (P = 0.0003). These results support the involvement of MMPs and TIMPs in endometrial tumor growth and progression. High MMP-2 and low TIMP-2 expression were the most potent markers of endometrial tumors with a high risk of local and distant spread.

背景与目标： 基质金属蛋白酶（MMPs）的表达与妇科肿瘤的侵袭性有关。这项研究的目的是确定子宫内膜恶性肿瘤中MMP-2，MMP-7和MMP-9以及金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2的表达及其与临床和组织学参数的关系。用特异性单克隆抗体对1999年至2004年间接受治疗的50例子宫内膜癌患者的福尔马林固定，石蜡包埋的肿瘤样品进行染色。根据FIGO分类将肿瘤分组。将染色结果与组织学和临床数据进行比较。 MMP和TIMP表达的半定量分析显示，根据组织学亚型，TIMP-2表达存在显着差异（P = 0.03），并且MMP-9表达也呈现差异的趋势（P = 0.05）。随着组织学分级的升高，MMP-2表达增加而TIMP-2表达下降（分别为P = 0.0007，P <0.0001）。 MMP-2表达与淋巴结转移相关（P = 0.04），而TIMP-2表达与肌层浸润深度（P = 0.01），血管淋巴间隙受累（P = 0.02）和淋巴结转移（P = 0.0003）相关）。这些结果支持MMP和TIMP参与子宫内膜肿瘤的生长和进展。 MMP-2的高表达和TIMP-2的低表达是子宫内膜肿瘤最有效的标志物，具有局部和远处扩散的高风险。

BACKGROUND & AIMS: AIMS:Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. METHODS:In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. RESULTS:Rofecoxib increased the area under the plasma concentration-time curve (AUC(0-infinity)) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (C(max)) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t(1/2)) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC(0-25) of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). CONCLUSIONS:Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.

背景与目标： 目的：病例报告表明罗非考昔与CYP1A2底物替扎尼定之间存在相互作用。我们的目标是探索这种可能的相互作用的程度和机制，并确定罗非昔布对CYP1A2的抑制作用。
方法：在一项随机，双盲，两阶段交叉研究中，九名健康受试者每天服用25毫克罗非考昔或安慰剂，持续4天，并在第4天，每人摄入4毫克替扎尼定。在长达24小时内测量替扎尼定，其代谢产物（M）和罗非考昔的血浆浓度和尿排泄，以及药效学变量。在第3天，进行了咖啡因测试以评估CYP1A2的活性。
结果：罗非昔布将替扎尼定的血浆浓度-时间曲线下面积（AUC（0-无穷大））增加了13.6倍[95％置信区间（CI）8.0、15.6； P <0.001），峰值血药浓度（C（max））从1.6到3.0 h的6.1倍（4.8，7.3; P <0.001）和消除半衰期（t（1/2））（P <0.001） 。因此，罗非昔布显着增强了替扎尼定的降压和镇静作用（P <0.05）。罗非昔布将血浆和尿液中替扎尼定/ M-3和替扎尼定/ M-4的比例提高了几倍，尿液中替扎尼定/ M-5，替扎尼定/ M-9和替扎尼定/ M-10的比例提高了几倍（P <0.05）。此外，它使血浆咖啡因/对黄嘌呤比率增加了2.4倍（95％CI 1.4、3.4； P = 0.008），并且该比率与替扎尼定/代谢产物比率相关。最后，罗非昔布的AUC（0-25）与安慰剂相咖啡因/对黄嘌呤的比​​例相关（r = 0.80，P = 0.01）。
结论：罗非昔布是一种有效的CYP1A2抑制剂，它大大提高了血浆浓度和替扎尼定的不良反应。研究结果表明罗非考昔本身也被CYP1A2代谢，引起对罗非考昔与其他CYP1A2底物和抑制剂药物之间相互作用的担忧。

BACKGROUND & AIMS: :A new inhibitor of human immunodeficiency virus (HIV) has been isolated and purified to homogeneity from the seeds and fruits of the Momordica charantia. This compound, MAP 30 (Momordica Anti-HIV Protein), is a basic protein of about 30 kDa. It exhibits dose-dependent inhibition of cell-free HIV-1 infection and replication as measured by: (i) quantitative focal syncytium formation on CEM-ss monolayers; (ii) viral core protein p24 expression; and (iii) viral-associated reverse transcriptase (RT) activity in HIV-1 infected H9 cells. The doses required for 50% inhibition (ID50) in these assays were 0.83, 0.22 and 0.33 nM, respectively. No cytotoxic or cytostatic effects were found under the assay conditions. These data suggest that MAP 30 may be a useful therapeutic agent in the treatment of HIV-1 infections. The sequence of the N-terminal 44 amino acids of MAP 30 has been determined.

背景与目标： ：已从苦瓜种子和果实中分离出一种新的人类免疫缺陷病毒（HIV）抑制剂并将其纯化至同质。该化合物MAP 30（Momordica抗HIV蛋白）是大约30 kDa的碱性蛋白。它通过以下方式表现出对无细胞HIV-1感染和复制的剂量依赖性抑制作用：（i）在CEM-ss单层上的定量局灶性合胞体形成； （ii）病毒核心蛋白p24表达； （iii）HIV-1感染的H9细胞中的病毒相关逆转录酶（RT）活性。在这些试验中，抑制50％（ID50）所需的剂量分别为0.83、0.22和0.33 nM。在测定条件下未发现细胞毒性或细胞抑制作用。这些数据表明，MAP 30可能是治疗HIV-1感染的有用治疗剂。已经确定了MAP 30的N-末端44个氨基酸的序列。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： ：热休克蛋白90（HSP90）是结构折叠和维持各种蛋白质（包括与细胞信号相关的几种蛋白质）构象完整性的必需。利用HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向于多发性骨髓瘤（MM）患者，我们首先通过免疫荧光和流式细胞术分析了骨髓瘤细胞系（U266）和原发性骨髓瘤细胞中HSP90的表达。在证明HSP90在骨髓瘤细胞中表达后，通过免疫过氧化物酶染色分析了32例MM患者的档案样本。在所有患者中，骨髓瘤细胞在所有样品中均表现出强烈的HSP90细胞质表达，并且55％的患者还表现出并发的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266细胞和原代MM细胞可导致凋亡明显增加。分析与17-AAG孵育的MM细胞中的抗凋亡BCL2家族蛋白和akt，表明BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但是17AAG和硼替佐米治疗的组合显示出对U266细胞系的协同凋亡作用。这些数据表明，针对HSP90的靶向抑制可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: OBJECTIVE:Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS:SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS:The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION:Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.

背景与目标： 目的：大量研究结果表明，在急性髓细胞性白血病（AML）患者中，促炎性细胞因子和生长因子以自分泌和旁分泌方式在AML细胞的增殖和存活中起重要作用，从而导致AML恶化。 JTE-607是一种多细胞因子抑制剂，可有效抑制促炎细胞因子的产生。在本研究中，我们通过利用SCID小鼠急性白血病模型研究了JTE-607作为抗白血病药物的效力。
方法：将注射了抗亚洲人GM1抗体的SCID小鼠暴露于3 Gy剂量的亚致死性全身照射下，然后静脉注射AML细胞。 JTE-607使用渗透微型泵给药。研究了JTE-607对小鼠存活时间，小鼠血浆中人白介素（IL）-8水平以及骨髓中人CD45（）细胞比例的影响。
结果：小鼠的存活时间严格取决于体内增殖的U-937细胞数量。在最初的7天中施用JTE-607可以显着延长小鼠的存活期，表明JTE-607在体内对AML细胞具有杀伤活性。 JTE-607的延迟给药也延长了已确诊白血病的小鼠的存活，其作用与阿糖胞苷的最大耐受剂量相当。骨髓细胞的流式细胞仪分析显示人类CD45（）细胞数量减少。 JTE-607也降低了人IL-8水平。
结论：我们的结果表明，JTE-607有潜力成为一类新型的抗白血病药物，对AML细胞的增殖和促炎性细胞因子产生均具有抑制活性。

BACKGROUND & AIMS: :Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.

背景与目标： ：我们以前的研究表明，花生四烯酸代谢异常，尤其是5-脂氧合酶（5-Lox）途径，与口腔癌发生有关，可以作为预防癌症的靶标。为了开发用于口腔癌化学预防的有效局部用药，对来自饮食和合成来源的5种已知的5-Lox抑制剂（Zileuton，ABT-761，licofelone，姜黄素和garcinol）进行了计算机评估，以评估其潜在功效。根据理论活性指数的计算，藤黄属植物果皮中的聚异戊二烯基化的二苯甲酮藤黄醇是一种很有前途的药物。计算机模型表明，藤黄酚非常适合5-Lox的活性位点，并可能通过酚羟基与非血红素催化铁之间的相互作用而抑制酶的活性。在对7,12-二甲基苯并[a]蒽（DMBA）处理的仓鼠脸颊袋进行的一项短期研究中，局部用大蒜素抑制白三烯B4（LTB4）的生物合成，并抑制口腔上皮细胞的炎症和细胞增殖。在一项长期的致癌研究中，局部用大蒜素显着减少了可见肿瘤的大小，癌症病变的数量，细胞增殖和LTB4的生物合成。这些结果表明，局部应用5-Lox抑制剂garcinol对DMBA诱导的仓鼠脸颊袋癌变具有化学预防作用。

BACKGROUND & AIMS: AIM:To evaluate photodynamic therapy (PDT) combined with the preferential the cyclooxygenase-2 (COX-2) inhibitor, nabumetone in the treatment of the neovascular age-related macular degeneration (ARMD). METHODS:A prospective, double-blind, randomized study on 60 patients with subfoveal CNV secondary to ARMD without any previous treatment. Patients were divided into a nabumetone or placebo group. The main endpoints were the change of best-corrected visual acuity (BCVA), central macular thickness (CRT) and number of required PDT treatments. RESULTS:In the nabumetone group, 27 patients (90%) and 28 (93%) in the placebo group completed the follow-up of 12 months. In the nabumetone group, the mean CRT decreased from 332 μm (SD 68 μm) to 220 μm (SD 46 μm). In the placebo group, CRT decreased from 331 μm (SD 72 μm) to 254 μm (SD 61 μm). The mean BCVA was 0.68 log MAR (SD 0.22 log MAR) in the nabumetone group and 0.62 log MAR (SD 0.23 log MAR) in the placebo group at baseline. This stabilised in the placebo group to 0.66 log MAR (SD 0.33) but deteriorated in the nabumetone group to 0.86 log MAR (SD 0.41 log MAR). There was a significant reduction in the number of required PDTs in the nabumetone group, but significant progression of the RPE atrophy area. CONCLUSION:Combined PDT with oral intake of the COX-2 inhibitor, nabumetone reduced the number of required PDT retreatments, but worsening BCVA caused by macular atrophy progression. Therefore the combination of the PDT with the nabumetone is not recommended.

背景与目标： 目的：评估光动力疗法（PDT）结合优先的环氧合酶-2（COX-2）抑制剂萘丁美酮治疗新生血管性年龄相关性黄斑变性（ARMD）。
方法：一项前瞻性，双盲，随机对照研究，对60例继发于ARMD继发于中央凹下的CNV患者而未进行任何治疗。将患者分为萘丁美酮或安慰剂组。主要终点是最佳矫正视力（BCVA），中央黄斑厚度（CRT）和所需PDT治疗次数的改变。
结果：萘丁美通组中，安慰剂组的27例患者（90％）和28例（93％）完成了12个月的随访。在萘丁美酮组中，平均CRT从332μm（SD 68μm）降至220μm（SD 46μm）。在安慰剂组中，CRT从331μm（SD 72μm）降至254μm（SD 61μm）。萘丁美tone组的平均BCVA为0.68 log MAR（SD 0.22 log MAR），而安慰剂组的基线BCVA为0.62 log MAR（SD 0.23 log MAR）。这在安慰剂组中稳定至0.66 log MAR（SD 0.33），但在萘丁美通组中恶化至0.86 log MAR（SD 0.41 log MAR）。萘丁美通组中所需PDT的数量显着减少，但RPE萎缩区域进展明显。
结论：萘丁美酮与PDT结合口服摄入COX-2抑制剂相结合，减少了所需的PDT再治疗次数，但由于黄斑萎缩的进展而使BCVA恶化。因此，不建议将PDT与萘丁美酮组合使用。

BACKGROUND & AIMS: :The ETV6-NTRK3 (EN) fusion gene which encodes a chimeric tyrosine kinase was first identified by cloning of the t(12;15)(p13;q25) translocation in congenital fibrosarcoma (CFS). Since then, EN has been also found in congenital mesoblastic nephroma (CMN), secretory breast carcinoma (SBC) and acute myelogenous leukemia (AML). Using IMS-M2 and M0-91 cell lines harboring the EN fusion gene, and Ba/F3 cells stably transfected with EN, we demonstrated that PKC412, also known as midostaurin, is an inhibitor of EN. Inhibition of EN activity by PKC412 suppressed the activity of it downstream molecules leading to inhibition of cell proliferation and induction of apoptosis. Our data for the first time suggested that PKC412 could serve as therapeutic drug for treatment of patients with this fusion.

背景与目标： ：首先通过克隆先天性纤维肉瘤（CFS）中的t（12; 15）（p13; q25）易位，鉴定出编码嵌合酪氨酸激酶的ETV6-NTRK3（EN）融合基因。从那时起，在先天性中胚层性肾瘤（CMN），分泌性乳腺癌（SBC）和急性骨髓性白血病（AML）中也发现了EN。使用具有EN融合基因的IMS-M2和M0-91细胞系，以及用EN稳定转染的Ba / F3细胞，我们证明PKC412（也称为Midostaurin）是EN的抑制剂。 PKC412抑制EN活性会抑制其下游分子的活性，从而导致细胞增殖受到抑制并诱导凋亡。我们的数据首次表明PKC412可以作为治疗这种融合患者的药物。

BACKGROUND & AIMS: :Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.

背景与目标： ：2型糖尿病是中风的重要危险因素。 Linagliptin是临床上用于治疗2型糖尿病的二肽基肽酶4（DPP-4）抑制剂。这项研究的目的是确定利格列汀在2型糖尿病小鼠中的潜在抗中风功效。为了了解功效是否由血糖调节介导，与磺酰脲格列美脲进行了比较。为了确定利格列汀介导的功效是否取决于糖尿病背景，在非糖尿病小鼠中进行了实验。通过给小鼠喂高脂饮食32周来诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。在治疗的第4周，通过短暂性中脑动脉闭塞诱发中风。在整个实验过程中，评估了血液DPP-4活性，胰高血糖素样肽1（GLP-1）水平，葡萄糖，体重和食物摄入量。通过确定中风量和纹状体/皮层中存活的神经元的立体定量来测量缺血性脑损伤。我们在2型糖尿病和正常小鼠中显示了利格列汀的显着抗中风功效，而格列美脲仅在正常小鼠中被证明对中风有效。这些结果表明，由利格列汀介导的神经保护作用与葡萄糖无关，并且可能涉及GLP-1。这些发现可能为DPP-4抑制剂的开发提供动力，以预防和治疗糖尿病患者的中风。

BACKGROUND & AIMS: :Fluoxetine (FLX) the active pharmaceutical ingredient (API) in Prozac(®) is a widely prescribed psychoactive drug which ubiquitous occurrence in the aquatic environment is associated to a poor removal rate in waste-water treatment plant (WWTP) systems. This API acts as a selective serotonin reuptake inhibitor (SSRI) frequently reported to cause disrupting effects in non-target species. The objective of this study includes a multibiomarker response evaluation on mussel Mytilus galloprovincialis during two weeks exposure to 75 ng L(-1) FLX assessing antioxidant enzymes activities--superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); lipid peroxidation (LPO), acetylcholinesterase (AChE) neurotoxic response and endocrine disruption through alkali-labile phosphates (ALP) indirect measurement of vitellogenin-like proteins. Results show transient tissue-specific enzymatic responses and damage affecting mostly mussel gills. However, the clear ALP levels inhibition throughout time in both sex-differentiated gonads gives evidence to FLX reinforced action as an endocrine disruptor rather than an oxidative or neurotoxic inducer.

背景与目标： ：Prozac®中的活性药物成分（API）氟西汀（FLX）是一种广泛使用的精神活性药物，在水生环境中普遍存在，与废水处理厂（WWTP）系统中的去除率差有关。此API作为一种选择性血清素再摄取抑制剂（SSRI）经常报道引起非目标物种干扰作用。这项研究的目的包括在暴露于75 ng L（-1）FLX的两周期间对贻贝贻贝贻贝进行多生物标志物反应评估，以评估抗氧化酶活性-超氧化物歧化酶（SOD），过氧化氢酶（CAT）和谷胱甘肽S-转移酶（消费税）;脂质过氧化（LPO），乙酰胆碱酯酶（AChE）的神经毒性反应和通过碱不稳定的磷酸盐（ALP）间接测量卵黄蛋白原样蛋白的内分泌干扰。结果表明，短暂的组织特异性酶促反应和损害主要影响贻贝g。然而，在两个性别分化的性腺中，随着时间的推移，明显的ALP水平抑制作用为FLX作为内分泌干扰物而不是氧化或神经毒性诱导物的增强作用提供了证据。

BACKGROUND & AIMS: :The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

背景与目标： ：p38丝裂原活化蛋白激酶（MAPK）抑制剂的抗炎潜能同时扩展到了p38αMAPK和磷酸二酯酶4（PDE4）的双重抑制作用，并且两种炎症相关酶均被阻断产生了潜在的益处调查。给啮齿动物，狗和猴子施用1后，在体外实验以及离体和体内临床前研究中相继评估了最有前途的化合物CBS-3595（1）。所得数据清楚地表明有效抑制了肿瘤坏死因子α的释放。为了确认对健康的人类志愿者给药1时动物研究的结果，进行了I期临床试验。除了有关1的药代动力学和药效学特性的进一步信息外，还证明了对p38αMAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。

BACKGROUND & AIMS: PURPOSE:Many women with hormone receptor-positive breast cancer discontinue effective aromatase inhibitor (AI) treatment due to joint symptoms. METHODS:We conducted a single-arm, open-label, phase II study evaluating glucosamine-sulfate (1,500 mg/day) + chondroitin-sulfate (1,200 mg/day) for 24 weeks to treat joint pain/stiffness in postmenopausal women with early stage breast cancer who developed moderate-to-severe joint pain after initiating AIs. The primary endpoint was improvement in pain/stiffness at week 24 assessed by the Outcome Measure in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Secondary endpoints assessed changes in pain, stiffness, and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) for hands/wrists. The Brief Pain Inventory (BPI) assessed pain interference, severity, and worst pain. RESULTS:Of 53 patients enrolled, 39 were evaluable at week 24. From baseline to week 24, 46 % of patients improved according to OMERACT-OARSI criteria. At week 24, there were improvements (all P < 0.05) in pain and function as assessed by WOMAC and M-SACRAH, and in pain interference, severity, and worst pain as assessed by BPI. Estradiol levels did not change from baseline. The most commonly reported side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %). CONCLUSIONS:In this single-arm study, 24 weeks of glucosamine/chondroitin resulted in moderate improvements in AI-induced arthralgias, with minimal side effects, and no changes in estradiol levels. These results suggest a need to evaluate efficacy in a placebo-controlled trial.

背景与目标： 目的：许多患有激素受体阳性乳腺癌的妇女由于关节症状而停止有效的芳香化酶抑制剂（AI）治疗。
方法：我们进行了单臂，开放标签，II期研究，评估硫酸氨基葡萄糖（1,500毫克/天）硫酸软骨素（1200毫克/天）持续24周，以治疗绝经后早期女性的关节痛/僵硬启动AI后出现中度至重度关节痛的乳腺癌患者。主要终点是通过风湿病临床试验和国际骨关节炎研究协会（OMERACT-OARSI）标准中的结果评估标准评估的第24周疼痛/僵硬的改善。次要终点是使用西安大略省和麦克马斯特大学骨关节炎（WOMAC）指数评估臀部/膝盖的疼痛，僵硬和功能的变化，以及评估手的慢性类风湿病影响和量化的改良分数（M-SACRAH） / wrists。简短疼痛清单（BPI）评估了疼痛的干扰，严重程度和最严重的疼痛。
结果：在入组的53例患者中，有39例在第24周得到了评估。从基线到第24周，根据OMERACT-OARSI标准，有46％的患者得到了改善。在第24周时，WOMAC和M-SACRAH评估的疼痛和功能以及BPI评估的疼痛干扰，严重程度和最严重疼痛得到改善（所有P <0.05）。雌二醇水平与基线相比没有变化。最常见的副作用是头痛（28％），消化不良（15％）和恶心（17％）。
结论：在这项单臂研究中，葡萄糖胺/软骨素的24周可导致AI引起的关节痛适度改善，副作用最小，且雌二醇水平无变化。这些结果表明需要在安慰剂对照试验中评估疗效。

BACKGROUND & AIMS: :Plasminogen activator inhibitor-1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily, which inactivates tissue plasminogen activator (tPA); therefore, increased level of PAI-1 antigen counteracts the anticoagulant effect of tPA and facilitates the fibrin clot formation. Plasma PAI-1 antigen and activity levels are associated with increased body mass index and with features of the insulin resistance syndrome like obesity and diabetes. Visceral adipose tissue produces more PAI-1 than subcutaneous adipose tissue: This increased production of PAI-1 from the visceral adipose tissue is one important link between visceral obesity and cardiovascular disease. Besides visceral adipose tissue, there is mounting evidence that epicardial adipose tissue may be an important source of PAI-1, especially in patients with type 2 diabetes.

背景与目标： ：Plasminogen activator inhibitor-1（PAI-1）是丝氨酸蛋白酶抑制剂（serpin）超家族的一员，它可以使组织纤溶酶原激活物（tPA）失活。因此，PAI-1抗原水平的增加抵消了tPA的抗凝作用，并促进了纤维蛋白凝块的形成。血浆PAI-1抗原和活性水平与体重指数增加以及胰岛素抵抗综合征（如肥胖症和糖尿病）的特征有关。内脏脂肪组织比皮下脂肪组织产生更多的PAI-1：内脏脂肪组织增加的PAI-1产生是内脏肥胖与心血管疾病之间的重要联系。除内脏脂肪组织外，越来越多的证据表明心外膜脂肪组织可能是PAI-1的重要来源，尤其是在2型糖尿病患者中。

BACKGROUND & AIMS: Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

背景与目标： 前列腺素和血栓烷是花生四烯酸通过环氧合酶（CO）酶代谢的产物，它们是炎症部位常见的疼痛和肿胀的原因。非甾体类抗炎药（NSAIDs）抑制这些物质的产生，并用于治疗炎症性疾病，例如关节炎。但是，NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶（5-LO）酶促途径抑制前列腺素的产生以及白三烯形成的相关增加可能是吸引炎症细胞，引起局部炎症和产生溃疡的原因。为了确定5-LO抑制对这一假设的影响，在大鼠中进行了研究以评估替泊沙林（一种双重CO / LO抑制剂）对胃粘膜白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中，长期口服NSAID，消炎痛（2天每天2 mg / kg，共4天）可导致40％的死亡率，并在第四剂药物后24小时进行评估，并伴有肠粘连和穿孔。另外，在肠系膜小静脉中嗜中性粒细胞的粘附增加，并且在肠系膜间质中细胞浸润明显。在每天进行消炎痛治疗前30分钟，给另一组大鼠服用tepoxalin（20 mg / kg，p.o），抑制了这些胃肠道副作用。进行了进一步的研究以确定替泊沙林对与NSAID诱导的胃肠道炎症相关的早期事件的影响，包括中性粒细胞粘附，脂质过氧化物的产生和LTB4的产生。吲哚美辛（100 mg / kg，p.o.）给药90分钟后，大鼠胃黏膜中LTB4的水平升高。另外，在该剂量下并通过使用另一种NSAID萘普生，肠系膜小静脉中的中性粒细胞粘附增加。在这个时间点在胃粘膜中没有明显的脂质过氧化物的产生。 Tepoxalin（最高400 mg / kg，p.o.）对胃粘膜LTB4的产生和脂质过氧化物的水平没有影响。在最高剂量下观察到嗜中性粒细胞粘附性降低。在另一项研究中，用替泊沙林（ED50 = 7.5 mg / kg，口服）或选择性5-LO抑制剂齐留通（100 mg / kg，口服）预处理可防止由吲哚美辛（100 mg / min）引起的胃粘膜LTB4水平增加和嗜中性白细胞粘附/ kg，po）。这些数据表明，LO抑制可能在预防NSAID引起的胃部炎症中起着至关重要的作用，从而提供了对特泊沙林缺乏致溃疡性的认识，并提供了可预防胃部副作用的新的抗炎治疗方法。

BACKGROUND & AIMS: 1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

背景与目标： 1.当抑制体树突状5-HT1A自体受体时，选择性5-羟色胺（5-HT； 5-羟色胺）再摄取抑制剂（SSRIs）导致前脑细胞外5-HT的增加。在这里，我们调查了终端5-HT1B自身受体的阻断作用是否以相同的方式影响选择性5-HT再摄取抑制剂，以及是否存在阻断5-HT1A和5-HT1B自身受体的其他作用。 2.通过使用脑微透析在麻醉的大鼠的额皮质中测量细胞外5-HT。还进行了背缝核（DRN）中5-HT神经元活性的体内细胞外记录。 3.选择性5-HT再摄取抑制剂帕罗西汀（0.8mg kg-1，静脉内）在用5-HT1A受体拮抗剂WAY100635预处理的大鼠中使细胞外5-HT增加约2倍。当单独给药时，帕罗西汀（0.8 mg kg-1，i.v.）和WAY100635（0.1 mg kg-1，i.v.）均未改变细胞外5-HT水平。 4.在用5-HT1B / D受体拮抗剂GR127935（1 mg kg-1，i.v.）预处理的大鼠中，帕罗西汀（0.8 mg kg-1，i.v.）不会增加5-HT。单独给药时，GR127935（1和5 mg kg-1，静脉内）对细胞外5-HT无效。 5.有趣的是，当GR127935（1或5 mg kg-1，iv）与WAY100635（0.1 mg）联合使用时，帕罗西汀（0.8 mg kg-1，iv）引起5-HT的最大增加（最多5倍）。千克-1，iv）。不含帕罗西汀的GR127935（5 mg kg-1，i.v.）加上WAY100635（0.1 mg kg-1，i.v.）的给药对额皮质中的细胞外5-HT没有影响。 6.尽管在基本条件下GR127935对5-HT缺乏影响，但当5-HT产量提高了约3倍时（通过向灌注培养基中添加1 microM帕罗西汀），该药物引起了剂量相关（1和5 mg kg-1，iv）5-HT升高。 7.单独使用时，GR127935在较高剂量（2.0-5.0 mg kg-1，i.v。）下可轻微但显着降低DRN中5-HT细胞的发射，但不能阻止帕罗西汀诱导的5-HT细胞发射的抑制。 8.总而言之，我们的研究结果表明，当在肢体树突（5-HT1A）和神经末梢（5-HT1B）上都存在5-HT自身受体时，选择性5-HT再摄取抑制剂可能会导致额叶皮层5-HT大量增加。被阻止。该增加量大于分别封闭任一组自动受体时的增加量。在我们的实验中，单独使用5-HT1B受体拮抗剂未能增强选择性5-HT再摄取抑制剂的作用可能与由于持续抑制5-HT细胞而导致末端5-HT1B自体受体缺乏音调有关射击。这些结果与使用5-HT自身受体拮抗剂增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。