台灣大學漁業科學研究所

研究重點：
ㄧ、海洋微生物所產活性物質之開發
1. 海洋微生物之單離、鑑種與醱酵樣品庫的建立。
2. 醱酵樣品庫的活性篩選與菌種的醱酵。
3. 活性天然物的分析、純化、解構與量產。
4. 天然抗生物質在水產養殖的開發與應用。
5. 天然活性化合物在醫藥上的開發與應用。

二、本土藥用真菌與大型藻的活性天然物開發
1. 本土藥用真菌所含活性物質的生合成與應用。 
2. 大型藻與微細藻所含活性物質的開發與應用。

目前進行的研究：
台灣海洋大型藻源真菌株之活性物質探究 (多年期，科技部)

1.研究室成員: 博士後研究員2名、博士班研究生3名和碩士班研究生4名。
2. 本研究室自2007年陸續解構本土藥用真菌牛樟芝醱酵物中所含之meroterpenoids，並命名為antroquinonols，該內容發表於Planta Medica國際期刊，之後該化合物被廣泛應用於多種疾病之治療，並已進入臨床二期研究。於2017年，我們從Antrodia cinnamomea ^#IFS006的固態醱酵物中，又發表了一系列共計20個的antroquinonol結構類似物，其中12個為新化合物，並初步推論對於A549細胞毒性的構效關係 (structure-activity relationship)，該內容已發表於J. Nat. Prod. (2017)。此外，也跟本校植微系曾顯雄教授合作，針對牛樟芝的pks63787進行基因剔除，發現菌株即失去製造antroquinonol的能力，而且菌株的外表顏色由正常的赭紅色轉變成淡黃色，因此推論pks63787這段NR-PKS基因在生合成C₇ polyketide上扮演關鍵的角色，而且證實pks63787所表現出的部分C₇ benzenoids代謝物，確實具淡黃到橘紅不等的顏色，為牛樟芝菌絲體的色素成分，這部分的內容發表在J. Nat. Prod. (2016)。最後根據PKS63787中的KS domain與其他相關菌種的資料庫 (NCBI) 所做成的親源樹進行分析，可區分成三個cluster，其中牛樟芝所在的cluster中，已知的其他菌種之NR-PKS代謝初始物已證實為苔蘚酸 (orsellinic acid, OA)，因此我們將購買的苔蘚酸標準品加入培養基中，培養先前的D pks63787突變株，結果顯現突變株的代謝物和外表型皆回復到與野生型菌株完全ㄧ致，甚至antroquinonol的產量較野生型菌株來得高，因此證實pks63787的初始產物為苔蘚酸，這部分的內容已發表於Appl. Microbiol. Biotechnol. (2017)。綜合多年來本實驗室針對於牛樟芝的研究成果，我們以傳統研究天然物的方法，找到了一系列具產業價值的antroquinonol類似物，所獲得的構效關係結論可提供後續天然物修飾的參考，另外從功能性基因體學 (functional genome) 的面向切入，證實了非還原性聚酮基因pks63787在antroquinonol的生合成上居重要的角色，而這些成果相信對於牛樟芝的應用與相關生技醫藥產業的推動，定有相當大的助益。

3. 自紅藻細翼枝菜 (Pterocladiella capillacea) 所單離出之真菌Phoma sp. NTOU4195的醱酵萃出物，分離、純化出一系列新的聚酮化合物phomaketides A‒E，在活性上具顯著的抑制血管 (anti-angiogenesis) 與淋巴管增生 (anti- lymphangiogenesis) 的活性，該內容已發表於J. Nat. Prod. (2016)，已完成雞胚胎與小鼠的動物試驗，並已獲專利 (中華民國專利第I619706號)。

4. 海芙蓉 (Atriplex maximowicziana) 為金、馬等離島重要的藥用植物，多生長於濱海高鹽貧脊的環境，刻正由金門所產海芙蓉中大量分離 (已超過2000株) 其內生真菌，並從中篩選具抗生潛力的真菌株，期能找到具應用價值的天然物。

5.已建立多種包括：Gambierdiscus sp.、Prorocentrum spp.、Amphidinium sp.和Ostreopsis sp.等近百株微細藻，目前正建構其分類、生理生態和天然物相關基礎資料。

近年重要著作 (2017- ):

*責任作者

Lin C.-Y., J.-A. Lee, P.-Y. Lin, S.-C. Hua, P.-Y. Tsai, B.-L. Chen., C.-E. Lin, T.-H. Lee,* S.‐M. Chen,* 2020, Utilizing methylglyoxal and D-lactate in urine to evaluate 1 saikosaponin C treatment in mice with accelerated 2 nephrotoxic serum nephritis. PLoS One (in press)

Chang, C.-F., C.-H. Wang, T.-H. Lee,* S.-M. Liu,* 2020, Bioactive compounds from the bark of Broussonetia papyrifera after solid fermentation with a white rot fungus Perenniporia tephropora. J. Wood Chem. Technol. 40: 317-330.

Chen, J.-J., S.-W. Wang, Y.-R. Chiang, K.-L. Pang, Y.-H. Kuo, T.-Y. Shih, T.-H. Lee,* 2020, Highly oxygenated constituents from a marine alga-derived fungus Aspergillus giganteus NTU967. Mar. Drugs 18: 303.

Chen, S.-C., S.-P. Wu, Y.-Y. Chang, T.-S. Hwang, T.-H. Lee,* C.-H. Hsu,* 2020, Crystal structure of a-galactosidase from Thermus thermophiles: insight into hexamer assembly and substrate specificity. J. Agri. Food Chem. 68: 6161-6169.

Guan, C.-Y., Chen, S.S., Lee, T.-H., Yu, C.-P., Tsang, D.C.W., 2020, Valorization of biomass from plant microbial fuel cells into levulinic acid by using liquid/solid acids and green solvents. J. Cleaner Prod. 260,121097.

G. Hsiao, S.-W. Wang, Y.-R. Chiang, W.-C. Chi, Y.-H. Kuo, D. A. Phong, C.-Y. Chen, T.-H. Lee,* 2020, Anti-inflammatory effects of peptides from a marine algicolous fungus Acremonium sp. NTU492 in BV-2 microglial cells. J. Food Drug Anal. 28: 89–97.

Wang P.-H., Y.-L. Chen, S. T.-S. Wei, K. Wu, T.-H. Lee, T.-Y. Wu, Y.-R. Chiang,* 2020, Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation. PNAS 117(3):1395-1403. 

Chou W.-L., T.-H. Lee, T.-H. Huang, P.-W. Wang, Y.-P. Chen, C.-C. Chen, Z.-Y. Chang, J.-Y. Fang, S.-C. Yang, 2019, Coenzyme Q₀ From Antrodia cinnamomea Exhibits Drug-Resistant Bacteria Eradication and Keratinocyte Inflammation Mitigation to Ameliorate Infected Atopic Dermatitis in Mouse. Front. Pharmacol. 10: 1445. 

Chang F.-P., S.-S. Huang, T.-H. Lee, C.-I Chang, T.-F. Kuo, G.-J. Huang,* Y.-H. Kuo,* 2019, Four new iridoid metabolites have been isolated from the stems of Neonauclea reticulata (Havil.) Merr. with anti-Inflammatory activities on LPS-Induced RAW264.7 cells. Molecules 24(23). pii: E4271.

Cheng M.-J., M.-D. Wu, T.-H. Lee, J.-R. Weng, J.-J. Chen, 2019, A NEW PYRROLE COMPOUND FROM Monascus ruber. Chem. Nat. Comp. 55: 1098-1100.

Liu H.-T., T.-E. Wang, Y.-T. Hsu, C.-C. Chou, K.-H. Huang, C.-C. Hsu, H.-J. Liang, H.-W. Chang, T.-H. Lee, P.-S. Tsai,* 2019, Nanoparticulated Honokiol Mitigates Cisplatin-Induced Chronic Kidney Injury by Maintaining Mitochondria Antioxidant Capacity and Reducing Caspase 3-Associated Cellular Apoptosis. Antioxidants (Basel). 8(10). Pii: E466.

Lee J.-H., H.-C. Mei, I.-C. Kuo, T.-H. Lee, Y.-H. Chen, C.-K. Lee,* 2019, Characterizing Tyrosinase Modulators from the Roots of Angelica keiskei Using Tyrosinase Inhibition Assay and UPLC-MS/MS as the Combinatorial Novel Approach. Molecules 24(18). Pii: E3297.

Jan J.-S., C.-H. Yang, M.-H. Wang, F.-L. Lin, J.-L. Yen, I Hsieh, M Khotimchenko, T.-H. Lee,^#  G. Hsiao,^#,* 2019, Hirsutanol A Attenuates Lipopolysaccharide-Mediated Matrix Metalloproteinase 9 Expression and Cytokines Production and Improves Endotoxemia-Induced Acute Sickness Behavior and Acute Lung Injury. Mar Drugs. 17(6). Pii: E360. (^#equal to corresponding author)

Lee M.-S., Y.-L. Yang, C.-Y. Wu, Y.-L. Chen, C.-K. Lee, S.-S. Tzean, T.-H. Lee,* 2019, Efficient identification of fungal antimicrobial principles by tandem MS and NMR database. J. Food Drug Anal. 27: 860-868.

Chi W.‑C., K.‑L. Pang, W.‑L. Chen, G.‑J. Wang, T.‑H. Lee,* 2019, Antimicrobial and iNOS inhibitory activities of the endophytic fungi isolated from the mangrove plant Acanthus ilicifolius var. xiamenensis. Botanical Studies 60: 4.

Tai H.-C., T.-H. Lee, C.-H. Tang, L.-P. Chen, W.-C. Chen, M.-S. Lee, P.-C. Chen, C.-Y. Lin, C.-W. Chi, Y.-J. Chen, C.-T. Lai, S.-S. Chen, K.-W. Liao, C.-H. Lee,* S.-W. Wang,* 2019, Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells. Marine Drugs 17(4). pii: E215. doi: 10.3390/md17040215.

Lin, F.-L., Y.-W. Cheng, M. Yu, J.-D. Ho, Y.-C. Kuo, G. C. Y. Chiou, H.-M. Chang, T.-H. Lee,* G. Hsiao,* 2019, The fungus-derived retinoprotectant theissenolactone C improves glaucomalike injury mediated by MMP-9 inhibition. Phytomedicine 56: 207‒214.

Chen M.-C., G.-J. Wang, Y.-H. Kuo, Y.-H. Chiang, T.-Y. Cho, Y.-M. Ju, T.-H. Lee,* 2019, Isoprenyl Phenolic Ethers from the Termite Nest-Derived Medicinal Fungus Xylaria fimbriata. J. Food Drug Anal. 27: 111-117.

Wu, K., T.-H. Lee, Y.-L. Chen, Y.-S. Wang, P.-H. Wang, C.-P. Yu, K.-H. Chu, Chiang YR, 2019, Metabolites Involved in Aerobic Degradation of the A and B Rings of Estrogen. Appl. Environ. Microbiol. 85(3). pii: e02223-18. 

Hung, C.-S., S.-C.Wang, Y.-T. Yen, T.-H. Lee,W.-C.Wen, R.-K. Lin, 2018, Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target. Int. J. Mol. Sci. 19(10). pii: E3096.

Wei, S.-T., Y.-W. Wu, T.-H. Lee, Y.-S. Huang, C.-Y. Yang, Y.-L. Chen, Y.-R. Chiang, 2018, Microbial Functional Responses to Cholesterol Catabolism in Denitrifying Sludge. mSystems. 3(5). pii: e00113-18.

Chang, Chi-I, T.-H. Lee, Y.-J. Li, C.-Y. Chao, B.-J. You, M.-J. Cheng, S.-Y. Wang, C.-C. Chen, Y.-H. Kuo, 2018, New 7-oxoabietane-type diterpenoids from the bark of Cryptomeria japonica and their xanthine oxidase inhibitory activity. Phytochem. Lett. 27: 69‒73.

Lin F.-L., J.-D. Ho, Y.-W. Cheng, G. C. Y. Chiou, J.-L. Yen, H.-M. Chang, T.-H. Lee,* G. Hsiao,* 2018, Theissenolactone C exhibited ocular protection of endotoxin-induced uveitis by attenuating ocular inflammatory responses and glial activation. Front. Pharmacol. 9:326. 

Chen Y.-L., H.-Y. Fu, T.-H. Lee, C.-J. Shih, L. Huang, Y.-S. Wang, W. Ismail, Y.-R. Chiang,* 2018, Estrogen degraders and estrogen degradation pathway identified in an activated sludge. Appl. Environ. Microbiol. 84(10). pii: e00001-18.

Cheng, M.-C.,^# T.-H. Lee ^#, Y.-T. Chu, L.-L. Syu, S.-J. Hsu, C.-H. Cheng, J. Wu *, C.-K. Lee,* 2018, Melanogenesis inhibitors from the rhizoma of Ligusticum sinense in B16-F10 melanoma cells in vitro and zebrafish in vivo. Int. J. Mol. Sci. 19(12). pii: E3994. (^#equal contribution)

Chen M.-C., T.-Y. Cho, Y.-H. Kuo, T.-H. Lee,* 2017, Bioactive meroterpenoids from a Medicinal Fungus Antrodia cinnamomea. J. Nat. Prod. 80: 2439‒2446.

Chen Y.-L., C.-P. Yu, T.-H. Lee, K.-S. Goh, K.-H. Chu, P.-H. Wang, W. Ismail, C.-J. Shih, Y. R. Chiang,* 2017, Biochemical mechanisms and catabolic enzymes involved in bacterial estrogen degradation pathways. Cell Chem. Biol. 24: 712-724.e7

Hsiao G., W.-C. Chi, K.-L. Pang, J.-J. Chen, Y.-H. Kuo, Y.-K. Wang, H.-J. Cha, S.-C. Chou, T.-H. Lee,* 2017, Hirsutane-type Sesquiterpenes with Inhibitory Activity of Microglial Nitric Oxide Production from the Red Alga-derived Chondrostereum sp. NTOU4196. J. Nat. Prod. 80: 1615-1622.

Yu P.-W., T.-Y. Cho, R.-F. Liou, S.-S. Tzean,* T.-H. Lee,* 2017, Identification of the orsellinic acid synthase PKS63787 for the biosynthesis of antroquinonols in Antrodia cinnamomea. Appl. Microbiol. Biotech. 101: 4701-4711.

Chang J.-C., G. Hsiao, R.-K. L., Y.-H. Kuo, Y.-M. Ju, T.-H. Lee,* 2017, Bioactive Constituents from the Termite Nest-Derived Medicinal Fungus Xylaria nigripes. J. Nat. Prod. 80: 38-44.

Lin H.-C., M.-H. Lin, J.-H. Liao, T.-H. Wu, T.-H. Lee, F.-L. Mi, C.-H. Wu, K.-C. Chen, C.-H. Cheng, C.-W. Lin,* 2017, Antroquinonol, a Ubiquinone Derivative from the Mushroom Antrodia camphorata, Inhibits Colon Cancer Stem Cell-like Properties: Insights into the Molecular Mechanism and Inhibitory Targets. J. Agri. Food Chem. 65:51-59.

Chien M.-H., T.-H. Lee, W.-J. Lee, Y.-H. Yeh, T.-K. Li, P.-C. Wang, J.-J. Chen, J.-M. Chow, Y.-W. Lin, M. Hsiao, S.-W. Wang, K.-T. Hua, 2017, Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and Xenografts. Cancer Lett. 388: 249-261.