作者机构：
[胡曼; 汪鹏; 郭静一] Hunan University of Chinese Medicine, Changsha, 410208, China;Hunan Province Pharmacy "Twelve Five" Key Disciplines, Changsha, 410208, China;[何群; 林丽美; 廖端芳] Hunan University of Chinese Medicine, Changsha, 410208, China, Hunan Province Pharmacy "Twelve Five" Key Disciplines, Changsha, 410208, China
通讯机构：
[Liao, D.-F.] H;Hunan University of Chinese Medicine, Changsha, China
作者机构：
[Gu, Hong-Feng; Tang, Xiao-Qing; Tang, Ya-Ling] Univ South China, Dept Physiol, Hengyang, Peoples R China.;[Gu, Hong-Feng; Tang, Xiao-Qing; Tang, Ya-Ling] Univ South China, Inst Neurosci, Hengyang, Peoples R China.;[Li, Hai-Zhe; Nie, Ya-Xiong] Univ South China, Affiliated Hosp 1, Dept Neurol, Hengyang, Peoples R China.;[Xie, Xue-Jiao; Liao, Duan-Fang] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha, Hunan, Peoples R China.
通讯机构：
[Nie, Ya-Xiong] U;[Liao, Duan-Fang] H;Univ South China, Affiliated Hosp 1, Dept Neurol, Hengyang, Peoples R China.;Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha, Hunan, Peoples R China.
作者机构：
[Liu, Jianghua; Zu, Xuyu] Univ South China, Affiliated Hosp 1, Inst Clin Med, Hengyang 421001, Hunan, Peoples R China.;[Yan, Ruilan; Cao, Yu; Ma, Jun; Zu, Xuyu; Zhong, Linlin; Cao, Deliang] Southern Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Simmons Canc Inst, 913 N Rutledge St, Springfield, IL 62794 USA.;[Chung, Fung-Lung; Pan, Jishen] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA.;[Cao, Deliang; Huang, Dan; Liao, Duan-Fang; Cai, Chuan] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.
通讯机构：
[Zu, Xuyu] U;[Cao, Deliang] S;Univ South China, Affiliated Hosp 1, Inst Clin Med, Hengyang 421001, Hunan, Peoples R China.;Southern Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Simmons Canc Inst, 913 N Rutledge St, Springfield, IL 62794 USA.
关键词：
AKR1B10;electrophilic carbonyl compounds;DNA damage;acrolein-deoxyguanosine adducts;colorectal cancer
摘要：
Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT). SiRNA-mediated silencing of AKR1B10 in colon cancer cells HCT-8 enhanced cytotoxicity of acrolein and HNE, whereas ectopic expression of AKR1B10 in colon cancer cells RKO prevented the host cells against carbonyl cytotoxicity. Furthermore, siRNA-mediated AKR1B10 silencing led to DNA breaks and activation of -H2AX protein, a marker of DNA double strand breaks, particularly in the exposure of HNE (10M). In the AKR1B10 silenced HCT-8 cells, hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutant frequency increased by 26.8 times at basal level and by 33.5 times in the presence of 10M HNE when compared to vector control cells. In these cells, the cyclic acrolein-deoxyguanosine adducts levels were increased by over 10 times. These findings were confirmed by pharmacological inhibition of AKR1B10 activity by Epalrestat. Taken together, these data suggest that AKR1B10 is a critical protein that protects host cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 deficiency in the colon may be an important pathogenic factor in disease progression and carcinogenesis. (c) 2016 Wiley Periodicals, Inc.
摘要：
Disease-specific markers are critical for early diagnosis, targeted therapy and prognostic prediction of diseases. Current study reports a complex microsatellite as a new prognostic marker of sporadic colorectal cancer. This microsatellite located at Chromosome 7q33 is composed of three tetranucleotide tandem repeats, (TTCC)(2)(TCCC)(5)(TCCT)(7), flanked by a CT-rich sequence. We analyzed polymorphisms of this microsatellite in 158 sporadic colorectal cancer, 143 matched normal adjacent tissues (NAT) and 150 health donors. Our results showed that this complex microsatellite was instable with polymorphic frequency of 77.2% in colorectal cancer, 52.4% in NAT and 54.7% in health donors (p<0.01) when compared to reference sequence. In the three tandem repeats, (TCCT)(7) site was most polymorphic accounting for over 70.0% of polymorphisms in this complex microsatellite, followed by (TTCC)(2) site for approximately 20%. Polymorphisms in (TCCC)(5) was rare. Polymorphisms at the (TCCT)(7) site were mainly insertions of 1 to 4 copies of TCCT (88.6%), and deletions occurred in about 6.4% of cases. The (TTCC)(2) site was featured with one copy TTCC insertions. Pair-wise analyses between colorectal tumors and NAT revealed that 88 of 121 (72.7%) tumors displayed expansion, contraction or both in these tetranucleotide tandem repeats when compared to NAT. A cross-analysis with clinicopathological data of 158 colorectal cancers revealed that polymorphic alterations of the microsatellite associated with less lymphatic metastasis (p<0.001), and the colorectal cancer patients with polymorphic changes in this microsatellite demonstrated better survival (n=112, p=0.0058). Together these data suggest that this complex microsatellite is a potential prognostic marker of sporadic colorectal cancer.
作者机构：
[林丽美; 雷思敏; 夏伯候; 林艳; 章莹; 黄杰; 吴萍; 肖榕; 廖端芳] College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China;[林丽美; 雷思敏; 夏伯候; 林艳; 章莹; 黄杰; 吴萍; 肖榕; 廖端芳] Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Changsha 410208, China;[李春] Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
摘要：
Wnt5a, a secreted glycoprotein, belongs to the noncanonical Wnt family involved in a wide range of organism development and tissue homeostasis. Wnt5a and its signaling pathway can regulate fundamental cellular processes, including specification of cell fate, proliferation, and survival. Accumulating evidence indicates that Wnt5a exhibits dual effects on angiogenesis. The formation of new blood vessels derives from pre-existing vessels via canonical and non-canonical Wnt pathways, depending on cell types, receptors, downstream effectors, and microenvironment. Given that the regulation of angiogenesis has been implicated in many diseases, such as cancer, neovascular eye diseases, and cardiovascular diseases, these findings suggest that Wnt5a may be a potential target for the treatment of angiogenesis-related diseases.
摘要：
The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. (C) 2017 Elsevier Masson SAS. All rights reserved.
