Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems

Herba Epimedii: Anti-oxidative properties and its medical implications

Herba Epimedii is a Chinese herbal medicine with proven efficacy in treating cardiovascular diseases and osteoporosis, and in improving sexual and neurological functions. This efficacy is found to be related to the potent anti-oxidative ability of Herba Epimedii and its flavonoid components, with icarrin as the main effective constituent, along with polysaccharides and vitamin C. These ingredients have been proven to be effective against oxidative-stress related pathologies (cardiovascular diseases, Alzheimer's disease and inflammation) in animal rodent models and in vitro studies. Their antioxidative properties are found to be related to an inductive effect on endogenous freeradical scavenging enzymes such as catalase and glutathione peroxidase and the inherent electron-donating ability of flavonoids. © 2010 licensee MDPI, Basel, Switzerland.published_or_final_versio

A review of the potential issues of pollution caused by the Mineral elements, Mercury, Lead and Arsenic, its possible impacts on the human beings and the suggested solutions

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Anti-metastatic mechanism of Tian-Xian Liquid (TXL) and its bioactive fractions in human colorectal cancer cells and xenograft models

Poster Session A: abstract no. 29Colorectal carcinoma is the second most prevalent cancer with an up-rising trend in Hong Kong (Hong Kong Cancer Registry). Traditional Chinese medicine acts as a complementary alternative for tumour therapy with minimal side-effects and traumatic injuries. Tian-Xian Liquid (TXL), one of the well-known natural medicinal herbal formulations, has been commercially used as an anticancer dietary supplement for a decade without known adverse effects. This study aimed to investigate the anti-metastatic property of TXL and its bioactive fractions [butanol fraction (BU), ethyl-acetate fraction (EA) and aqueous fraction (WA)] at molecular level on human colorectal cancer in vitro (HT-29 cancer cells) and in vivo (nude mice xenografts). For the cell model, TXL and its bioactive fractions have similar anti-proliferative effects by MTT assay. At 4-hour-incubation, IC50 values were obtained at 1% (V/V) TXL, 1.25% (V/V) BU, 5% (V/V) EA and 0.3125% (V/V) WA. At IC50, TXL and its bioactive fractions significantly reduced the MMP2 and MMP7 expressions at mRNA level by real-time PCR. At protein level, TXL, BU and EA correspondingly down-regulated MMP2 (active form) and MMP7 protein from 24 to 48 hours; TXL and BU also down-regulated VEGF protein expression; however, no such effect was found in WA-treated cells. Further, only TXL, EA and WA effectively inhibited the cell migration at 48 hours incubation by woundhealing assay. For the xenografts models, MMP2 and MMP7 mRNA expressions were reduced by TXL-, BU- and EA-treated xenografts; however no effects on MMP2 protein expression in all drug-treated xenografts. The VEGF protein expression was significantly down-regulated in TXL- and WA-treated xenografts. Further, TXL, BU and WA effectively inhibited the tumor growth without altering the body weight of the xenografts. In summary, the Chinese medicinal formulation, TXL, demonstrated the most effective anti-metastatic ability on human colorectal cancer in vitro and in vivo.published_or_final_versio

Evaluation of Chemical Constituents and Important Mechanism of Pharmacological Biology in Dendrobium Plants

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The use of a noninvasive and nondestructive method, microcomputed tomography, to evaluate the anti-osteoporotic activity of erxian decoction, a Chinese medicinal formula, in a rat model of menopausal osteoporosis

Aim of the study: The anti-osteoporotic activity of Erxian Decoction, a Chinese medicinal formula, in a rat model of menopausal osteoporosis was evaluated by microcomputed tomography (microCT). Materials and methods: Menopause causes a decline in both endocrine function and bone mineral density in human. In this study, 20-month-old female Sprague-Dawley-rats (SD-rats) with a low serum estradiol level and bone mineral density were employed. The anti-osteoporotic activity of EXD was assessed by the determination of trabecular material bone mineral density at the L2 mid-vertebral body after treatment. Serum estrogen levels were also determined to assess the effect of EXD on the endocrine status. Results: Results revealed a significant elevation in serum estradiol level and trabecular bone mineral density at the L2 mid-vertebral body in the EXD-treated menopausal rat model. Conclusions: The results obtained from the present investigation revealed that the EXD had anti-osteoporotic activity as evidenced by an increase of serum estradiol level and bone mineral density. ©2009 IEEE.published_or_final_versionProceedings of the 2009 2nd International Conference On Biomedical Engineering And Informatics (BMEI 2009), Tianjin, China, 17-19 October 2009, v. 1 p. 47-49, article number 530482

Network pharmacological identification of active compounds and potential actions of Erxian decoction in alleviating menopause-related symptoms

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Comparison of chemical profiles and effectiveness between Erxian decoction and mixtures of its individual herbs decoction: A novel approach for identification of the standard chemicals

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Comprehensive and Holistic Analysis of HT-29 Colorectal Cancer Cells and Tumor-Bearing Nude Mouse Model: Interactions Among Fractions Derived From the Chinese Medicine Formula Tian Xian Liquid in Effects on Human Colorectal Carcinoma

The Chinese medicine formula Tian Xian Liquid (TXL) has been used clinically for cancer therapy in China for more than 25 years. However, the comprehensive and holistic effects of its bioactive fractions for various antitumor therapeutic effects have not been unraveled. This is the first study to scientifically elucidate the holistic effect of Chinese medicine formula for treating colon cancer, hence allowing a better understanding of the essence of Chinese medicine formula, through the comparison of the actions of TXL and its functional constituent fractions, including ethyl acetate (EA), butanol (BU), and aqueous (WA) fractions. Tissue-specific proliferative/antiproliferative effects of these fractions on human colorectal carcinoma HT-29 cells and splenocytes were studied by using the MTT assay. Their modulations on the expression of markers of antiproliferation, antimetastasis, reversion of multidrug resistance in treated HT-29 cells were examined with real-time polymerase chain reaction and Western blot analysis, and their modulations in a xenografted nude mouse model were examined by Western blot analysis. Results revealed that EA fraction slightly inhibited the proliferation of HT-29 cells, but tissue-specifically exerted the most potent antiproliferative effect on splenocytes. On the contrary, only TXL and BU fraction tissue-specifically contributed to the proliferation of splenocytes, but inhibited the proliferation of HT-29 cells. WA fraction exerted the most potent antiproliferative effect on HT-29 cells and also the strongest inhibitory action on tumor size in the nude mouse model in our previous study. In the HT-29 model, TXL and WA fraction exerted the most pronounced effect on upregulation of p21 mRNA and protein; TXL, and EA and WA fractions exerted the effect on downregulation of G1 phase cell cycle protein, cyclin D1 mRNA and protein; EA and BU fractions exerted the most prominent anti-invasive effect on anti-invasion via downregulation of MMP-1 mRNA; TXL potently reversed most multidrug resistance via downregulation of MDR-1 protein. In conclusion, the comprehensive and holistic effects of TXL were demonstrated with (a) mutual accentuation and mutual enhancement, (b) mutual counteraction and mutual suppression, and (c) mutual antagonism among the 3 constituent fractions. Moreover, the design of the present study may lead to further development of more tissue-specific effective drugs with minimal side effects for clinical use in combating carcinoma.published_or_final_versio