Design of Hedgehog pathway inhibitors for cancer treatment

Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.     

在我国药物临床试验机构建设中引入国际通行管理模式

随着全球新药研发重心东移,我国医药市场和临床试验的市场迅速发展,药物临床试验机构建设任重而道远,引入以现场管理组织(SMO)管理模式为代表的国际通行管理模式,建立完善的质量管理体系,保持良好的运作机制,提高试验的综合管理水平,保证临床试验的质量,使国内药物临床试验机构完成的试验数据得到国际认可,将有利于推动中国药物临床试验与国际接轨的进程。     

Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies

Helicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host's ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease.     

卵巢和卵巢肿瘤中Hedgehog 信号通路的表达

目的探讨正常卵巢和卵巢肿瘤中Hedgehog信号通路的表达。方法采用RT—PCR和免疫组织、细胞化学染色检测26例卵巢肿瘤组织、3例卵巢癌细胞株（SKOV3、A2780和COC1）和7例正常卵巢组织中Hedgehog信号通路的信号分子SHH、IHH、PTCH、SMO和GLI1的mRNA和蛋白表达情况;通过实时定量RT—PCR对随机抽取的11例卵巢肿瘤组织和5例正常卵巢组织进行PTCH和GLI1 mRNA水平的比较。结果SHH、IHH、PTCH、SMO和GLI1的mRNA在卵巢肿瘤组织中均有表达;SHH mRNA在正常卵巢组织中不表达,而IHH、PTCH、SMO和GLI1的mRNA在正常卵巢组织中有表达;在卵巢肿瘤组织中,PTCH和GLI1的mRNA表达水平高于正常组织（P〈0．05）。SHH、IHH、PTCH、SMO和GLI1蛋白在卵巢肿瘤组织中均呈阳性表达,在正常卵巢组织中不表达。卵巢癌细胞株SKOV3、A2780和COC1均有IHH、PTCH、SMO和GLI1的mRNA和蛋白的表达;SHH仅在SKOV3和A2780中表达。结论卵巢肿瘤中存在Hedgehog信号通路,在部分卵巢肿瘤中有Hedgehog信号通路过度激活的现象。     

Hedgehog信号通路相关基因在大肠癌的表达及其临床意义

目的：研究Hedgehog信号通路相关基因SHH、SMO、GLI1在大肠癌中的表达及其临床意义。方法：用RT-PCR检测43例大肠癌切除标本的癌组织和距离癌10cm以上的癌旁组织的SHH、SMO、GLI1 mRNA表达的阳性率,并与20例非肠癌患者的正常大肠组织对照,分析其与大肠癌患者临床和病理各变量的相关性。结果：大肠癌组织SHH mRNA表达阳性率为27．9％,与癌旁组织的18．6％比较,差异无显著性（P〉0．05）,但显著高于正常组织的0％（P〈0．05）。大肠癌组织SMO、GLI1 mRNA表达阳性率分别为83．7％、34．9％,显著高于癌旁组织的58．1％、16．3％及正常组织的0％、0％（P〈0．05）。SHH、SMO、GLI1 mRNA表达阳性率之间并无相关性,阳性率与患者的年龄、性别、临床分期、肿瘤部位、肿瘤浸润深度、病理分型等变量均无相关性（P〉0．05）。结论：Hedgehog信号通路相关基因SHH、SMO、GLI1 mRNA在大肠癌组织中表达阳性率显著增高,其表达与临床和病理各变量不相关。     

永磁同步电机无传感器控制的软开关滑模观测器

针对滑模观测器估计中存在的抖振问题,采用边界层可变的正弦型饱和函数替代传统开关函数,提出了一种用于永磁同步电机无传感器控制的软开关滑模观测器。为了确定不同饱和函数的收敛速度,定义等效收敛区间,通过正弦型饱和函数边界层内的滑模状态表达式推导其等效收敛时间,并与现有初等、终端滑模型和双曲正切型饱和函数进行了对比。为扩大滑模观测器的速度适用范围,确定了开关增益的转速自适应律。利用锁相环方法提取转子位置与速度信息,解决由滤波器引起的相位误差。通过仿真分别分析了饱和函数类型和开关增益、等效收敛系数及边界层厚度等系数对估计精度与收敛时间的影响,验证了正弦型饱和函数的有效性。实验结果表明,正弦型软开关滑模观测器能够准确地观测出转子速度和位置,并很好地消除了估计结果的抖振。     

浅谈国外SMO对中国药物临床研究产业发展的启示

目的：为我国药物临床试验现场管理组织（SMO）的建立进行初步探究。方法：通过描述性手段,介绍国外SMO的建立、发展状况和运营模式,并分析SMO的职能、作用及其对我国药物临床研究产业发展的重要意义。结果与结论：SMO对于我国GCP的贯彻执行具有一定的强化作用,但需要国家对SMO的政策支持及有效监管。     

Anticancer system created by acrolein and hydroxyl radical generated in enzymatic oxidation of spermine and other biochemical reactions

A hypothesis suggesting the existence of a ubiquitous physiological anticancer system created by two highly reactive oxidative stress inducers with anticancer properties, acrolein and hydroxyl radical, is reported in this communication. Both components can originate separately or together in several biochemical interactions, among them, the enzymatic oxidation of the polyamine spermine, which appear to be their main source. The foundations of this hypothesis encompass our initial search for growth-inhibitors or anticancer compounds in biological material leading to the isolation of spermine, a polyamine that became highly cytotoxic through the generation of acrolein, when enzymatically oxidized. Findings complemented with pertinent literature data by other workers and observed anticancer activities by sources capable of producing acrolein and hydroxyl radical. This hypothesis obvious implication: spermine enzymatic oxidations or other biochemical interactions that would co-generate acrolein and hydroxyl radical, the anticancer system components, should be tried as treatments for any given cancer. The biochemical generation of acrolein observed was totally unexpected, since this aldehyde was known; as a very toxic and highly reactive xenobiotic chemical produced in the pyrolysis of fats and other organic material, found as an atmospheric pollutant, in tobacco smoke and car emissions, and mainly used as a pesticide or aquatic herbicide. Numerous studies on acrolein, considered after our work a biological product, as well, followed. In them, acrolein widespread presence, its effects on diverse cellular proteins, such as, growth factors, and its anticancer activities, were additionally reported. Regarding hydroxyl radical, the second component of the proposed anticancer system, and another cytotoxic product in normal cell metabolism, it co-generates with acrolein in several biochemical interactions, occurrences suggesting that these products might jointly fulfill some biological role. Furthermore, hydroxyl radical shares with phosphoramide mustard, anticancer activities and many similar effects against DNA, including the production of damages resulting in mutagenesis and carcinogenesis, facts that led us to consider this radical, a biological counterpart of phosphoramide mustard. A physiological system involving acrolein and hydroxyl radical, consequently, will be expected to produce effects similar to those from acrolein and phosphoramide mustard, the main anticancer metabolites from the widely used drug, cyclophosphamide.