葉修華

SH Yeh 2葉修華  副研究員
生技與藥物研究所
Email: bau9763@nhri.edu.tw

 

EDUCATION

  • 2000-2005 Ph.D., Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
  • 1998-2000 M.S., Pharmacology, National Cheng Kung University, Tainan, Taiwan
  • 1994-1998 B.S., Life Science, Tunghai University, Taichung, Taiwan

PROFESSIONAL EXPERIENCES

  • Associate Investigator, Institute of Biotechnology and Pharmaceutical Research, National Health research Institutes, Miaoli, Taiwan (2017/04- present)
  • Assistant Investigator, Institute of Biotechnology and Pharmaceutical Research, National Health research Institutes, Miaoli, Taiwan (2009/12- 2017/03)
  • Post-doctoral fellow, Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (2005/11- 2009/12)
  • Teaching Assistant, Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (1999-2002)

RESEARCH INTERESTS

  1. Nervous System Drug Discovery: Opioids are the most effective analgesics in the world, but long-term prescription related addiction and tolerance effects are serious clinical problems. Therefore, it is critical to develop new strategy to control pain that can avoid the adverse effects caused by opioids after prolonged use. Allosteric binding sites on GPCRs are domains topographically distinct from the orthosteric site. It is potential to develop allosteric modulators with greater receptor subtype selectivity to avoid side effects. We are interested to find a mu-opioid receptor (MOR)-specific allosteric modifier which will activate MOR without activating delta- or kappa-opioid receptors. The initial hits are selected by high-throughput screening and hit optimization is operated by medicinal chemistry group. The potential hits are further analyzed for their effects on the signaling pathway of MOR, pharmacokinetics/pharmacodynamics and animal pharmacology. Our ultimate goal is to identify a new drug allosterically activating MOR for clinical pain management without developing addiction and tolerance effects.
  2. Identifying natural compounds or clinically used drugs to reduce or treat morphine side effects.
  3. Using biochemical, molecular and animal approaches to investigate the mechanisms of pain, central nervous system injury and neurodegeneration.

HONORS & AWARDS

  • 2003 The Best Paper Award, the Pharmacological Society in Taiwan.
  • 2003 Outstanding Student Travel Grant (The Society for Neuroscience Annual Meeting), Foundation for the Advancement of Outstanding Scholarship
  • 2004 Best Effort Award, 2004 Annual Research Day, Institute of Basic Medical Sciences, National Cheng Kung University.
  • 2004 Outstanding Student Travel Grant (The Society for Neuroscience Annual Meeting), Foundation for the Advancement of Outstanding Scholarship
  • 2008 Outstanding Postdoctoral Travel Grant (6th Federation of European Neuroscience Societies Forum), Foundation for the Advancement of Outstanding Scholarship
  • 2009 Travel Fellowship (12th International Conference on Alzheimer’s Disease), the Alzheimer’s Association International Society to Advance Alzheimer Research and Treatment (ISTAART)
  • 2009 Outstanding Postdoctoral Travel Grant (12th International Conference on Alzheimer’s Disease), Foundation for the Advancement of Outstanding Scholarship
  • 2016 第13屆國家新創獎-學研新創獎
  • 2020 科技部未來科技獎

SELECTED PUBLICATIONS

  1. Lin, C.H., Yeh, S.H., Lin, C.H., Lu, K.T., Leu, T.H., Chang, W.C., Gean, P.W. (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. 31(5): 841-851
  2. Yeh, S.H., Lin, C.H., Lee, C.F., Gean, P.W. (2002) A requirement of nuclear factor-kappa B activation in fear-potentiated startle. J Biol Chem. 277(48): 46720-46729
  3. Lin, C.H., Yeh, S.H., Leu, T.H., Chang, W.C., Wang, S.T., and Gean, P.W. (2003) Identification of calcineurin as a key signal in the extinction of fear memory. J. Neurosci. 23(5): 1574-1579
  4. Lin, C.H., Yeh, S.H., Lu, H.Y., and Gean, P.W. (2003) The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J. Neurosci. 23(23): 8310-8317
  5. Yeh, S.H., Lin, C.H., Gean, P.W. (2004) Acetylation of nuclear factor-kappa B in rat amygdala improves long-term but not short-term retention of fear memory. Mol. Pharmacol. 65(5): 1286-1292
  6. Yeh, S.H., Mao, S.C., Lin, H.C., Gean, P.W. (2006) Synaptic expression of glutamate receptor after encoding of fear memory in the rat amygdala. Mol. Pharmacol. 69(1): 299-308
  7. Chuang, J.Y., Wang, Y.T., Yeh, S.H., Liu, Y.W., Chang, W.C., Hung, J.J. (2008) Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. Mol. Biol. Cell. 19(3): 1139-1151
  8. Hsiao, Y.H., Chen, P.S., Yeh, S.H., Lin, C.H., Gean, P.W. (2008) N-acetylcysteine prevents β-amyloid toxicity by a stimulatory effect on the p35/cyclin-dependent kinase 5 activity in cultured cortical neurons. J. Neurosci. Res. 86(12): 2685-2695
  9. Yeh, S.H., Hung, J.J., Gean, P.W., Chang, W.C. (2008)Hypoxia-inducible factor-1α protects cultured cortical neurons from lipopolysaccharide-induced cell death via regulation of NR1 expression.J. Neurosci. 28(52):14259-14270
  10. Wang, S.A., Chuang, J.Y., Yeh, S.H., Wang, Y.T., Liu, Y.W., Chang, W.C., Hung, J.J. (2009) Heat shock protein 90 is important for Sp1 stability during mitosis. J. Mol. Biol. 387(5): 1106-1119
  11. Ou, L.C., Yeh, S.H., Gean, P.W. (2010) A late expression of brain-derived neurotrophic factor in the amygdala is required for the maintenance of long-term fear memory. Neurobiol. Learn. Mem. 93(3): 372-382
  12. Yeh, S.H., Ou, L.C., Hung, J.J., Gean, P.W., Chang, W.C. (2011) Selective Inhibition of Early- but Not Late-Expressed HIF-1α is Neuroprotective in Rats after Focal Ischemic Brain Damage. Brain pathol. 21(3): 249-262
  13. Yeh, S.H., Gean, P.W., Yang, W.P., Hsu, C.Y., Tseng, J.T., Su, T.P., Chang, W.C., Hung, J.J. (2011) Translational and transcriptional control of Sp1 against ischemia via a hydrogen peroxide-activated IRES pathway. Nuclear Acid Research. 39(13): 5412-5423
  14. Pao, P.C., Huang, N.K., Wang, I.F., Liu, Y.W., Yeh, S.H., Hsieh, Y.T., Huang, H.S., Chang, W.C., Lee, Y.C. (2011) A novel RING finger protein, Znf179, modulates the differentiation of P19 embryonic stem cells to neurons. Cell Death and Differentiation. 18(11): 1791-1804
  15. Hsu, C.C., Lee, Y.C., Yeh, S.H., Chen, C.H., Wu, C.C., Wang, T.Y., Chen, Y.N., Hung, L.Y., Liu, Y.W., Chen, H.K., Hsiao, Y.T., Wang, W.S., Tsou, J.H., Tsou, Y.H., Wu, M.H., Chang, W.C., Lin, D.Y. (2012) MSP58, a novel Brg1-associated protein that modulates the p53-p21 senescence pathway. J Biol Chem. 287(27): 22533-22548
  16. Cheng, M.F., Ou, L.C., Chen, S.C., Chang, W.T., Law, P.W., Loh, H.H., Chao, Y.S., Shih, C., Yeh S.H.,* Ueng, S.H.* (2014) Discovery, structure–activity relationship studies, and anti-nociceptive effects of 1-phenyl-3,6,6-trimethyl-1,5,6,7- tetrahydro-4H-indazol-4-one as novel opioid receptor agonists. Bioorg Med Chem. 22(17): 4694-4703
  17. Lee, P.T., Chao, P.K., Ou, L.C., Chuang, J.Y., Lin, Y.C., Chen, S.C., Chang, H.F., Law, P.Y., Loh, H.H., Chao, Y.S., Su, T.P., Yeh, S.H.* (2014) Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling. Nucleic Acids Res. 42(21):13012-13025
  18. Wu, J.S, Lin, S.Y., Liao, F.Y., Hsiao, W.C., Lee, L.C., Peng, Y.H., Hsieh, C.L., Wu, M.H., Song, J.S., Yueh, A., Chen, C.H., Yeh, S.H., Liu, C.Y., Lin, S.Y., Yeh, T.K., Hsu, J.T., Shih, C., Ueng, S.H., Hung, M.S., Wu, S.Y. (2015) Identification of Substituted Naphthotriazolediones as Novel Tryptophan 2,3-Dioxygenase (TDO) Inhibitors through Structure-Based Virtual Screening. J Med Chem. 58(19):7807-7819.
  19. Su, T.C., Lin, S.H., Lee, P.T., Yeh, S.H., Hsieh, T.H., Chou, S.Y., Su, T.P., Hung, J.J., Chang, W.C., Lee, Y.C., Chuang, J.Y. (2016) The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury. Neuropharmacology. 105:1-9.
  20. Chen, S.R., Ke, Y.Y., Yeh, T.K., Lin, S.Y., Ou, L.C., Chen, S.C., Chang, W.T., Chang, H.F., Wu, Z,H., Hsieh, C.C., Law, P.Y., Loh, H.H., Shih, C., Lai, Y.K.,* Yeh, S.H.,* Ueng, S.H.* (2017) Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists. Eur J Med Chem. 126: 202-217.
  21. Hsu, C.C., Chang, W.C., Hsu, T.I., Liu, J.J., Yeh, S.H., Wang, J.Y., Liou, J.P., Ko, C.Y., Chang, K.Y., Chuang, J.Y. (2016) Suberoylanilide hydroxamic acid represses glioma stem-like cells. J Biomed Sci. 23: 81.
  22. Chao, P.K., Ueng, S.H., Ou, L.C., Yeh, T.K., Chang, W.T., Chang, H.F., Chen, S.C., Tao, P.L., Law, P.Y., Loh, H.H., Cheng, M.F., Chuang, J.Y., Chen, C.T., Shih, C., Yeh, S.H.* (2017) 1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one: a novel opioid receptor agonist with less accompanying gastrointestinal dysfunction than morphine. Anesthesiology. 126: 952-966.
  23. Ke, Y.Y., Huang, Y.H., Chien, W.C., Loh, H.H., Chuang, J.Y.,* Yeh, S.H.* (2017) Mapping the naloxone binding sites on the mu-opioid receptor using cell-based photocrosslinkers. Biochim Biophys Acta. 1865: 336-343.
  24. Chuang, J.Y., Kao, T.J., Lin, S.H., Wua, A.C., Lee, P.T., Su, T.P., Yeh, S.H., Lee, Y.C., Wu, C.C., Chang, W.C.* (2017). Specificity protein 1-zinc finger protein 179 pathway is involved in the attenuation of oxidative stress following brain injury. Redox Biology. 11: 135-143.
  25. Wu, C.C., Lee, P.T., Kao, T.J., Chou, S.Y., Su, R.Y., Lee, Y.C., Yeh, S.H., Liou, J.P., Hsu, T.I., Su, T.P., Chuang, C.K., Chang, W.C., Chuang, J.Y.* (2018) Upregulation of Znf179 acetylation by SAHA protects cells against oxidative stress. Redox Biology. 19: 74-80.
  26. Lin, S.Y., Kuo, Y.H., Tien, Y.W., Ke, Y.Y., Chang, W.T., Chang, H.F., Ou, L.C., Law, P.Y., Xi, J.H., Tao, P.L., Loh, H.H., Chao, Y.S., Shih, C., Chen, C.T., Yeh, S.H.,* Ueng, S.H.* (2019) The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone. Eur J Med Chem. 167: 312-323.
  27. Chao, P.K., Chang, H.F., Ou, L.C., Chuang, J.Y., Lee, P.T., Chang, W.T., Chen, S.C., Ueng, S.H., Hsu, T.A., Tao, P.L., Law, P.Y., Loh, H., Yeh. S.H.* (2019) Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Sci Rep. 9: 2405.
  28. Chao, P.K., Chang, H.F., Chang, W.T., Yeh, T.K., Ou, L.C., Chuang, J.Y., Hsu, T.A., Tao, P.L., Loh, H., Shih, C., Ueng, S.H.,* Yeh S.H.* (2019) BPR1M97, a dual mu opioid receptor/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine. Neuropharmacology. 166:107678
  29. Huang, Y.H., Chuang, J.Y., Wu, Y.W., Chang, Y.C., Chang, H.F., Tao, P.L., Loh, H., Yeh, S.H.* (2020) Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu opioid receptor splice variants. Pain. 161:1177-1190
  30. Tsou, L.K., Yeh, S.H.,1, Ueng, S.H., Chang, C.P., Song, J.S., Wu, M.H., Chang, H.F., Chen, S.R., Shih, C., Chen, C.T., Ke, Y.Y.* (2020) Comparative study between deep learning and QSAR classifications for TNBC inhibitors and novel GPCR agonist discovery. Sci Rep. 10: 16771.
  31. Yang, W.B., Hsu,C.C., Hsu, T.I., Liou, J.P., Chang, K.Y., Chen, P.Y., Liu, J.J., Yang, S.T., Wang, J.Y., Yeh, S.H., Chen, R.M., Chang, W.C.,* Chuang, J.Y.* (2020) Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma. Neuro Oncol. 22: 1439-1451.
  32. Lo, W.L., Hsu, T.I., Yang, W.B., Kao, T.J., Wu, M.H., Huang, Y.N., Yeh, S.H., Chuang, J.Y.* (2020) Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma. Cancers. 12: 981.
  33. Huang, Y.H., Chao, P.K., Loh, H., Yeh, S.H.,* Chuang. J.Y.* (2020) Using a μ-opioid receptor mutant, S198A, identifies ERK/CREB pathway as a key signaling event mediating opioid withdrawal symptoms. (submitted)
  34. Ou, L.C., Chao, P.K., Ke, Y.Y., Chang, W.T., Chang, H.F., Chuang, J.Y., Lee, P.T., Chen, S.C., Tao, P.L., Law, P.Y., Loh, H., Ueng, S.H.,* Yeh. S.H.* (2020) Small-molecule opioid antagonist produces antinociception via activating mu-opioid receptor in the presence of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid. (In preparation)
  35. Lin, S.Y., Tien, Y.W., Ke, Y.Y., Chang, Y.C., Chang, H.F., Ou, L.C., Law, P.Y., Xi, J.H., Tao, P.L., Loh, H.H., Chao, Y.S., Shih, C., Chen, C.T., Yeh, S.H.,* Ueng, S.H.* (2022) Selective and antagonist-dependent µ-opioid receptor activation by the combination of 2-{[2-(6-chloro-3,4-dihydro-1(2H)-quinolinyl)-2-oxoethyl]sulfanyl}-5-phenyl-4,6-(1H,5H)-pyrimidinedione and naloxone/naltrexone. Bioorg Chem. (In Press)

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