ntubst2019EN

Anti-inflammatory medicinal plants and phytocompounds for cancer prevention and metabolomics study

Chemoprevention is now recognized as an essential approach to controlling cancer, the most life threatening human disease. We have designed and established various in vitro and in vivo cell- and genebased bioassays, a mouse skin inflammatory system, and acute liver hepatitis, orthotopic and metastatic cancer models (mammary tumor and B16 melanoma) to identify novel phytocompounds from medicinal plants. These studies attempt to explore novel natural plant resources in Taiwan for future application as botanical supplements, medicinal foods, or botanical drugs for cancer prevention or therapy. Comparative proteomics and metabolomics technologies using liquid chromatography–mass spectrometry (LC-MS) and/or gas chromatography–mass spectrometry (GC-MS) coupled with multivariate statistical analyses are employed to elucidate the pharmacological effects and modes of action of anti-cancer phytocompounds and their synergy with therapeutic drugs, or their effect on attenuating drug sideeffects in animals. A number of novel chemopreventive phytocompounds, such as galactolipids, sesquiterpene lactons, polyacetylenes, and alkamides have been identified, and their further development into nutraceuticals or pharmaceuticals is being undertaken.

Protein engineering of enzymes for agricultural biotech applications

The objective of this research is to create novel enzymes with suitable properties for applications in the biotech industries, such as bioenergy, bio-pulping and bioremediation, or in the food/feed industry. 

We have established a combinational protein engineering strategy by integrating rational design and directed evolution (DNA shuffling) approaches to improve enzyme properties and performance. Increase in thermostability, catalytic efficiency, pH-tolerance, and/or broadening of substrate specificity in the target enzymes are the main purposes of this research. Protein domain fusion/deletion, mutagenesis, enzyme kinetics, protein folding, and structural modeling and elucidation are routinely practiced in our laboratory, aiming to shed light on structure-function relationships and improve the catalytic and physio-chemical functions of the target enzymes. Laccase is a green oxidase widely applied in biotech industries. We identify novel laccases from indigenous whiterot fungi and investigate their biochemical properties and potential to degrade plant lignocellulosics and toxic compounds generated during bioenergy transformation and detoxify synthetic dyes or environmental toxic chemicals. These studies aim to increase economic benefit in various industrial processes involving laccase reactions.

1. Apaya, M. K., Hsiao, P.-W., Yang, Y.-C., and Shyur, L.-F.* (2020) Deregulating the CYP2C19/epoxyeicosatrienoic acid-associated FABP4/FABP5 signaling network as a therapeutic approach for metastatic triple negative breast cancer. Cancers 12, 199.   
2. Apaya, M. K., Shiau, J.-Y., Liao, G.-S., Liang, Y.-J., Chen, C.-W., Yang, H.-C., Yu, J.-C., and Shyur, L.-F.* (2019) Integrated omics-based pathway analyses uncover CYP epoxygenase- associated networks as theranostic targets for metastatic triple negative breast cancer. Journal of Experimental and Clinical Cancer Research 38, 187.
3. Chang, C.-T., Soo, W.-N., Chen, Y.-H., and Shyur, L.-F.* (2019)Essential oil of Mentha aquatica var. Kenting Water Mint suppresses two-stage skin carcinogenesis accelerated by BRAF inhibitor vemurafenib. Molecules 24, 2344.
4. Chao, W.-W., Cheng, Y.-W., Chen, Y.-R., Lee, S.-H., Chiou, C.-Y., and Shyur, L.-F.* (2019) Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress lung metastasis ofB16 melanoma in mice with reduced renal toxicity. Phytomedicine 56,194-206.
5. Cvetanova, B., Shen, Y.-C., and Shyur, L.-F.* (2019) Cumingianoside A, a phyto-triterpenoid saponin inhibits acquired BRAF inhibitor resistant melanoma growth via programmed cell death. Frontiers in Pharmacology 10,Article 30. (doi: 10.3389/fphar.2019.00030)　　
6. Yang, C.-C., Chang, C.-K., Chang, M.-T. , and Shyur, L.-F.* (2018) Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-a-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice. International Journal of Cancer 143, 3248–3261.
7. Hsu, S.-F., Lee, Y.-B., Lee, Y.-C., Chung, A.-L., Apaya, K. M., Shyur, L.-F., Cheng, C.-F., Ho, F.-M., and Meng, T.-C. (2018) Dual specificity phosphatase DUSP6 promotes endothelial inflammation through inducible expression of ICAM-1. The FEBS Journal doi:10.1111/febs.14425. (To be honored as the“Editor's Choice paper”in the issue for volume 285)
8. Hua, M. D., Senthil Kumar, R., Shyur, L.-F., Cheng, Y.-B., Tian, Z., Oelmuller, R. and Yeh, K.-W. (2017) Metabolomic compounds identified in Piriformospora indica-colonized Chinese cabbage roots delineate symbiotic functions of the interaction. Scientific Reports 7, 9291 (DOI:10.1038/s41598-017-08715-2)
9. Shiau, J.-Y., Nakagawa-Goto, K., Lee, K.-H., and Shyur, L.-F.*(2017) Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death. Oncotarget 25, 56942-56958.
10. Shiau, J.-Y., Chang, Y.-Q., Nakagawa-Goto, K., Lee, K.-H., and Shyur, L.-F.* (2017) Phytoagent deoxyelephantopin and its derivative inhibit triple negative breast cancer cell activity through ROS-mediated exosomal activity and protein functions. Frontiers in Pharmacology 8, Article 398 (doi.org/10.3389/fphar.2017.00398).
11. Shang, K.-M., Su, T.-H., Lee, W. L., Hsiao, W.-W., Chiou, C.-Y., Ho, B.-Y., Wang, S.-Y., and Shyur, L.-F.* (2017) Novel effect and the mechanistic insights of fruiting body extract of medicinal fungus Antrodia cinnamomea against T47D breast cancer. Phytomedicine 24, 39-48.
12. Feng, J.-H., Nakagawa-Goto, K., Lee, K.-H., and Shyur, L.-F.* (2016) A novel plant sesquiterpene lactone derivative DETD-35 suppresses BRAFV600Emutant melanoma growth and overcomes acquired vemurafenib resistance in mice. Molecular Cancer Therapeutics 15, 1163-1176. (Selected as the highlights of the issue; Selected as Significant Research Achievement of Academia Sinica, 2016)
13. Cheng, Y.-T., Yang, C.-C., and Shyur, L.-F.* (2016) Phytomedicine –Modulating oxidative stress and the tumor microenvironment for cancer therapy. Pharmacological Research 114, 128-143.
14. Apaya, M. K., Chang, M.-T., and Shyur, L.-F.* (2016) Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics. Pharmacology & Therapeutics 162, 58-68.
15. Nakagawa-Goto, K., Chen, J.-Y.,　Cheng, Y.-T., Lee, W.-L., Takeya, M., Saito, Y., Lee, K.-H., and Shyur, L.-F.* (2016) Novel sesquiterpenelactone analogues as potent anti-breast cancer agents. Molecular Oncology 10, 921-937.
16. Lee, H.-M., Patela, V., Shyur, L.-F., and Lee, W. L. (2016) Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells. Phytomedicine 23, 1535-1544.
17. Apaya, M. K., Lin, C.-Y.,Chiou, C.-Y., Yang, C.-C., Ting, C.-Y., and Shyur, L.-F.* (2015) Simvastatin and a plant galactolipid protect animals from septic shock by regulating oxylipin mediator dynamics through theMAPK-cPLA2 signaling pathway. Molecular Medicine 21, 988-1001.
18. Liu, W.-C., Maestre-Reyna, M., Jeng, W.-Y., Lee, C.-C., Hsu, C.-A., Wen, T.-N., Wang, A. H.-J.*, and Shyur, L.-F.* (2015) Structural and functional roles of glycosylation in fungal laccase from Lentinus sp. PLoS ONE 10, UNSP e0120601.
19. Shiau, J.-Y., Yin, S.-Y., Chang, S.-L., Hsu, Y.-J., Chen, K.-W., Kuo, T.-F., Feng, C.-S., Yang, N.-S., Shyur, L.-F.*, Yang, W.-C.*, and Wen, T.-N.* (2015) Mechanistic study of the phytocompound, 2-beta-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetraynein human T-Cell acute lymphocytic leukemia cells by using combined differential proteomics and bioinformatics approaches. eCAM 2015, Article ID 475610, 10 pages.
20. Cheng, Y.-B., Lo, I-W., Shyur, L.-F., Yang, C.-C., Hsu, Y.-Mi., Su, J.-H., Lu, M.-C., Chiou, S.-F., Lan, C.-C., Wu, Y.-C., Chang, F.-R. (2015) New alkaloids from Formosan zoanthid Zoanthus kuroshio. Tetrahedron 71, 8601-8606
21. Wei, W.-C., Liu, C.-P., Yang, W.-C., Shyur, L.-F., Sheu, J.-H., Chen, S.-S., and Yang, N.-S. (2015) Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS-induced expression of IL-12 and IL-23 in human dendritic cells. Journal of Leukocyte Biology 97, 1071-1080.
22. Deng, Y.-T., Lin-Shiau, S.-Y. Shyur, L.-F., and Lin, J.-K.* (2015) Pu-erh tea polysaccharides decrease blood sugar by inhibition a-glucosidase activities in vitro and in mice. Food &Function 6, 1539-1546.
23. Lee, W.-L., Huang, J.-Y., and Shyur, L.-F.* (2013) Phytoagentsfor cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms. Oxidative Medicine and Cellular Longevity 2013, doi.org/10.1155/2013/925804.
24. Chou#, T.-W., Feng#, J.-H., Huang, C.-C., Cheng, Y.-W., Chien, S.-C., Wang, S.-Y.*, and Shyur, L.-F.* (2013) A plant kavalactone desmethoxyyangonin prevents inflammation and fulminant hepatitis in mice. PLoS ONE 8, e77626.
25. Liao, G.-S., Apaya, M. K., and Shyur, L.-F.* (2013) Herbal medicine and acupuncture for breast cancer palliative care and adjuvant therapy. eCAM 2013, Article ID 437948, 17 pages.
26. Huang, C.-C., Lin, K.-J., Cheng, Y.-W., Hsu, C.-A., Yang, S.-S., and Shyur, L.-F.* (2013) Hepatoprotective effect and mechanistic insights of deoxyelephantopin, a phyto-sesquiterpene lactone, against fulminant hepatitis. Journal of Nutritional Biochemistry 24, 516-530.

• Phytochemistry and Herbal Medicien
• Protein engineering in biotechnological application
• Current R&D of plant metabolomics
• Special Topic in Nutraceuticals and Botanical Drugs Research and Development