Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models

BACKGROUND: The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed. METHODS: A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed. RESULTS: The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3-Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models. CONCLUSIONS: On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment.     

AM-111 reduces hearing loss in a guinea pig model of acute labyrinthitis

OBJECTIVES/HYPOTHESIS: This study investigated the otoprotective properties of AM-111, an inhibitor of c-Jun N-terminal kinase-mediated apoptosis and inflammation. STUDY DESIGN: A controlled, prospective animal study using a guinea pig model of acute labyrinthitis. METHODS: Acute labyrinthitis was generated by injection of antigen into the scala tympani of sensitized guinea pigs. Treatment groups received 100 microL of AM-111 at concentrations of 100 micromol/L, 10 micromol/L, and 1 micromol/L in a hyaluronic acid gel formulation delivered over the round window niche within 1 hour of antigen challenge. Cochlear function was monitored over 21 days with serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements followed by histologic analysis. RESULTS: The ABR results on day 21 demonstrated that untreated control ears for acute labyrinthitis had a mean hearing loss (HL) of 68 +/- 12 dB. In contrast, ears treated with AM-111 (100 micromol/L) had a mean HL of 39 +/- 31 dB. These two groups were statistically different (one-way analysis of variance, P = .03). Secondary outcomes, including DPOAE shift, inner hair cell survival, inflammatory cell counts, and spiral ganglion density, were also statistically significant in favor of an otoprotective effect of AM-111. Lower doses of AM-111 did not produce a statistically significant reduction in HL over controls. CONCLUSION: AM-111 delivered over the round window membrane in a 100 microL hyaluronic acid formulation at a 100 micromol/L concentration immediately after induction of acute labyrinthitis in the guinea pig cochlea protects hearing, reduces hair cell loss, and reduces the number of inflammatory cells at 21 days after treatment.     

Genetic and epigenetic inactivation of T-cadherin in human hepatocellular carcinoma cells

T-cadherin is an atypical cadherin and growing evidence has indicated that T-cadherin exerts tumor-suppressive effects on cancers of epithelial cell type and also causes positive effects on tumor angiogenesis. Human hepatocellular carcinoma (HCC) is a hypervascular tumor and T-cadherin has been shown to be overexpressed in intratumoral endothelial cells of HCCs. However, the expression status and functions of T-cadherin in hepatocytes or HCC cells remain unclear. Here, we demonstrated that T-cadherin was underexpressed in HCC cells (26.5%, 13/49 cases), but was frequently (77.6%, 38/49) overexpressed in intratumoral endothelial cells immunohistochemically. Semiquantitative RT-PCR analysis also showed that the T-cadherin gene was underexpressed in 7 of 11 HCC cell lines. Loss of heterozygosity analysis revealed that 32-38% of the 42 human HCC samples had allelic losses at this locus. Upon pharmacological treatment with demethylating agent 5-aza-2'-deoxycytidine or histone deacetylase inhibitor trichostatin A, T-cadherin promoter hypermethylation and/or histone deacetylation was frequently observed in HCC samples and cell lines. Functionally, enforced expression of T-cadherin induced G(2)/M cell cycle arrest, reduced cell proliferation in low serum medium, suppressed anchorage-independent growth in soft agar and increased sensitivity to TNFalpha-mediated apoptosis in HCC cells. Intriguingly, we found that T-cadherin significantly suppressed the activity of c-Jun, a crucial oncoprotein constitutively activated in HCC cells. To conclude, T-cadherin was differentially expressed in human HCCs. The underexpression of T-cadherin in HCC cells suggests it may be another critical event in addition to T-cadherin-mediated angiogenesis during HCC development.     

SB203580对小脑颗粒神经元的保护作用

目的 :研究特异性p3 8分裂原激活的蛋白激酶 (MAPK)抑制剂SB2 0 3 580对低钾诱导的小脑颗粒神经元凋亡的作用及机制。方法 :体外神经元培养、凝胶电泳和SAPK/JNK分析盒测定JNK(c Jun氨基末端激酶 )活性。结果 :低钾 (KCl 5mmol/L)培养基诱导小脑颗粒神经元的具有典型形态学和生化特征的凋亡。但是 ,特异性的p3 8MAPK抑制剂SB2 0 3 580通过抑制凋亡 ,而促进低钾环境中培养的小脑颗粒神经元的存活。此保护作用具有浓度依赖性。培养于低钾环境中的神经元 ,其c Jun的表达和磷酸化水平升高 ,且激活了JNK的活性。当小脑颗粒神经元生长在含SB2 0 3 580 2 5μmol/L的低钾培养基中 ,c Jun的表达、磷酸化水平和JNK的活性都明显的降低。结论 :SB2 0 3 580可能通过抑制JNK的活性 ,降低c Jun的磷酸化水平而对低钾培养的小脑颗粒神经元具有保护作用。     

杨文华教授辨治慢性再生障碍性贫血经验浅析

从慢性再生障碍性贫血的中医病因病机及临证遣方用药特点等方面对杨文华教授的治疗经验进行归纳、总结,以期为临床治疗提供借鉴。杨文华教授认为慢性再生障碍性贫血发病以肾虚精亏为本,脉络瘀阻为标,“肾虚精亏、髓枯血瘀”为病机关键,治疗以“补肾生髓、祛瘀生新”为根本大法,同时注重调补阴阳,善用血肉有情之品、炭类止血药物及中药药对等治疗,临床疗效显著。     

杨进教授温病学教学艺术探讨

总结杨进教授温病学课堂教学特色。理论教学方面：为利于学生记忆与运用,在知识点的分解、类症鉴别与归纳方面的独特技巧。实践教学方面：以问题为中心,结合案例教学和专题训练学生卫气营血与三焦辨证论治临床思维体系的建立和方证结合的遣方用药能力。     

肾阳虚造型及补肾中药对大鼠免疫功能的影响

本文观察了醋酸氢化可的松肾阳虚造型对大鼠免疫功能的影响及补中药的调节作用。结果表明，造型能使大鼠脾脏重量减轻及脾细胞之白细胞介素Ⅱ（ＩＬ－２）活性降低；补肾方药肾气汤、六味地黄汤、附桂汤均能提高造型动物降低的脾细胞ＩＬ－２活性，且三组方药音的作用未见明显差别。六味地黄汤能拮抗造型引起的脾脏重量减轻，而肾气汤及附桂汤对脾重的影响不明显。结果提示免疫功能低下是肾阳虚证的重要病理变化；补肾方药具有调节肾     

电针为主治疗Bel氏面瘫的临床体会

运用电针、中药、红外线等综合治疗Ｂｅｌ氏面瘫１０２例，与单纯电针的对照组５０例比较。结果：综合治疗组临床总显效率达９８％，优于单纯电针的对照组（总显效率为８６％）。经用Ｒｉｄｉｔ方法检验，Ｐ＜０．０１，提示综合治疗组的疗效优于对照组。另外，总结１５２例患者应用电针治疗的结果，认为面瘫发展期患者可用电针。随访９０例，未见面肌痉挛或倒错现象。笔者还观察了病程与疗效的关系及面神经受损情况与疗效的关系，经用Ｍａｎｔｅｎｌ－Ｈａｅｎｓｚｅｌ卡方处理［２］，两者均Ｐ＜０．００１，提示病程短的及面神经未受损的疗效较好     

丝裂原活化蛋白激酶信号途径在热休克蛋白90基因表达？…

目的 研究丝裂原活化蛋白激酶－（ＭＡＰＫ）信号传导途径对Ｊｕｒｋａｔ细胞中热休克蛋白９０基因（ｈｓｐ９０）表达的影响。方法 用Ｗｅｓｔｅｒｎ免疫印迹－增强型化学光系统（ＥＣＬ）检测热休克前后Ｊｕｋａｔ细胞外信号调节激酶（ＥＲＫ）、ｐ３８激酶及ｃ－Ｊｕｎ Ｎ－末端蛋白激酶（ＪＮＫ）的底物ｃ－Ｊｕｎ的磷酸化程度;分别用ＪＮＤ１的显性负突变质粒ＤＮ－ＪＮＫ１、ｐ３８ｃＤＮＡ反应表达质粒ａｎｔｉ－ｐ３８及