NTUBST2023EN

Epigenetic regulation induced by mitochondrial function:

Except for ATP production and cell death control, mitochondrial dysfunction also contributes to human pathologies including tumor formation and neurodegenerative diseases. One important aspect of our work is to investigate how mitochondrial dysfunction alters the migration and invasion ability of cancer cells. We found that mitochondrial dysfunction induced by photodynamic therapy (PDT) results in the activation of DNA methyl transferase (DNMT), which further results in the decreased expression of chloride intracellular channel 4 (CLIC4). The present study focuses on exploring the molecular mechanisms involved in the epigenetic control of the CLIC4 gene expression and the role of CLIC4 in tumorgenesis. A second important aspect is to elucidate how dysfunctional mitochondria alter the cellular genome gene expression profile by using genomic and proteomic approaches.

Translational Research in Photodynamic Therapy:

Photodynamic therapy (PDT), combining the exogenous photosensitizers and visible light, has been used as a therapeutic modality for cancer treatment. However, due to the limited light tissue penetration, PDT can only be used for the superficial tumors. One important task of our works is to develop a PDT technology platform which combines the advantages of PDT and chemotherapy for cancer therapy. To reach this goal, a dual-effect liposome has been developed and showed its efficacy in tumor treatment. Meanwhile, we also found that the combination of photodynamic inaction (PDI) and chitosan has synergistic effect in eradicating microbial infections compared to PDI or chitosan alone. Presently, different drug delivery systems have been developed in our laboratory for the translational research of tumor and infectious diseases.

1. Lee CY, Su CT, Tsai T, Hsieh CM, Hung KY, Huang JW, Chen CT. Formulation Development of Doxycycline-Loaded Lipid Nanocarriers using Microfluidics by QbD Approach. Journal of Pharmaceutical Sciences 2022; In press. (SCI)
2. Yang TL, Hsieh CM, Meng LJ, Tsai T, Chen CT. Oleic Acid-Based Self Micro-Emulsifying Delivery System for Enhancing Antifungal Activities of Clotrimazole. Pharmaceutics 2022; 14(3).(SCI)
3. Lee CY, Tsai T, Peng PC, Chen CT. Fabrication of Doxorubicin-Loaded Lipid-Based Nanocarriers by Microfluidic Rapid Mixing. Biomedicines 2022; 10(6).(SCI)
4. Pei-Chi Chiang, Pei-Tzu Li, Ming-Jen Lee and Chin-Tin Chen. DNA Hypermethylation Involves in the Down-regulation of Chloride Intracellular Channel 4 (CLIC4) Induced by Photodynamic Therapy. Biomedicines 2021; 9: 927. (Correspondence)
5. Mandy Shen, Pei-Tzu Li, Yan-Jia Wu, Ching-Hsuan Lin, Eric Chai, Ta-Chau Chang, Chin-Tin Chen. The antifungal activities and biological consequences of BMVC-12C-P, a carbazole derivative against Candida species. Medical Mycology. 2020: 58 (4): 521-529. (Correspondence)
6. Chin-Tin Chen, Po-Chun Peng, Tsuimin Tsai, Hsiung-Fei Chien, Ming-Jen Lee.  A novel treatment modality for malignant peripheral nerve sheath tumor using a dual-effect liposome to combine photodynamic therapy and chemotherapy. Pharmaceutics. 2020: 12(4), 317.
7. Po-Chun Peng, Ruey-Long Hong, Tsuimin Tsai and Chin-Tin Chen. Co-Encapsulation of Chlorin e6 and Chemotherapeutic Drugs in a PEGylated Liposome Enhance the Efficacy of Tumor Treatment: Pharmacokinetics and Therapeutic Efficacy. Pharmaceutics. 2019: 11, 617. (Correspondence)
8. Mu-Ching Huang, I-Te Chu, Zi-Fu Wang, Steven Lin, Ta-Chau Chang and Chin-Tin Chen. A G-Quadruplex Structure in the Promoter Region of CLIC4 Functions as a Regulatory Element for Gene Expression. International Journal of Molecular Sciences. 2018; 19: 2678. (Correspondence)
9. Ching-Hsuan Lin, Hsiung-Fei Chien, Ming-Hsuan Lin, Chueh-Pin Chen, Mandy Shen and Chin-Tin Chen. Chitosan Inhibits the Rehabilitation of Damaged Microbes Induced by Photodynamic Inactivation. International Journal of Molecular Sciences. 2018; 19: 2598. (Correspondence)
10. Mu-Ching Huang, Mandy Shen1, Yi-Jhen Huang, Hsiao-Chi Lin and Chin-Tin Chen. Photodynamic Inactivation Potentiates the Susceptibility of Antifungal Agents Against the Planktonic and Biofilm Cells of Candida albicans. International Journal of Molecular Sciences. 2018; 19: 434. (Correspondence)
11. Li P-T, Wang Z-F, Chu I-Te, Kuan Y-M, Li M-H, Huang M-C, Chiang P-C, Chang T-C, Chen C-T Expression of the human telomerase reverse transcriptase gene is modulated by quadruplex formation in its first exon due to DNA methylation. Journal of Biological Chemistry. 2017; 292(51): 20859-70. (Correspondence).
12. M-J Lee, S-H Hung, M-C Huang, TM Tsai, C-T Chen. Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells. PLOS One. 2017; 12(5): e0178493. (Correspondence).
13. Huang CY, Kuo WT, Huang CY, Lee TC, Chen CT, Peng WH, Lu KS, Yang CY and Yu CH. Distinct cytoprotective roles of pyruvate and ATP by glucose metabolism on epithelial necroptosis and crypt proliferation in ischaemic gut. Journal of Physiology. 2017; 595(2):505-521.
14. Peng PO, Hsieh CM, Chen CP, Tsai TM, Chen CT. Assessment of photodynamic inactivation against periodontal bacteria mediated by a chitosan hydrogel in a 3D gingival model. International Journal of Molecular Sciences. 2016; 17: 1821. (Correspondence).
15. Huang WC, Tseng, T-Y, Chen Y-T, Chang C-C, Wang Z-F, Wang C-L, Hsu T-N, Li P-T, Chen C-T, Lin, J-J, Lou P-J, Chang T-C. Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents. Nucleic Acids Research. (2015) 43: 10102-10113.
16. Chen CP, Hsieh CM, Tsai TM, Yang JC, Chen CT. Optimization and Evaluation of a Chitosan/Hydroxypropyl Methylcellulose Hydrogel Containing Toluidine Blue O for Antimicrobial Photodynamic Inactivation. International Journal of Molecular Sciences. (2015) 16: 20859-20872. (Correspondence) 
17. Tsai YJ, Tsai TM, Peng Po CP, Li PT, Chen CT. Histone acetyltransferase p300 is induced by p38MAPK after photodynamic therapy: the therapeutic response is increased by the p300HAT inhibitor anacardic acid. Free radical Biology and Medicine. 2015; 86: 118-132. (Correspondence)
18. Peng PC, Hong RL, Tsai YH, Li PT, Tsai T, Chen CT. Dual-Effect Liposomes Encapsulated with Doxorubicin and Chlorin e6 Augment the Therapeutic Effect of Tumor Treatment. Lasers in Surgery and Medicine. 2015; 47:77-87. (Correspondence)
19. Pei-Tzu Li, Yi-Jane Tsai, Ming-Jen Lee, and Chin-Tin Chen. Increased Histone Deacetylase Activity Involved in the Suppressed Invasion of Cancer Cells Survived from ALA-Mediated Photodynamic Treatment. International Journal of Molecular Sciences. 2015; 16: 23994-24010. (Correspondence)
20. Gunnar Johansson, Peng P-C, Huang P-Y, Chien H-F, Hua K-T, Kuo M-L, Chen C-T, Lee M-J. Soluble AXL: A Possible Circulating Biomarker for Neurofibromatosis Type 1 Related Tumor Burden. PLOS One. 2014; 9(12): e115916.
21. Chen CT, Chen CP, Yang JC, Tsai T. Liposome-Encapsulated Photosensitizers Against Bacteria. Recent Patents of Anti-Infective Drug Discovery. 2013; 8(2): 100-107. (Correspondence)
22. Chien H-F, Chen C-P, Chen Y-C, Chang P-H, Tsai T and Chen CT. The Use of Chitosan to Enhance Photodynamic Inactivation against Candida albicans and Its Drug-Resistant Clinical Isolates. International Journal of Molecular Sciences. 2013; 14: 7445-7456. (Correspondence)
23. Yang YT, Chien HF, Chang PH, Chen YC, Jay M, Tsai TM, Chen CT. Photodynamic Inactivation of Chlorin e6-loaded CTAB-Liposomes Against Candida albicans. Lasers in Surgery and Medicine. 2013; 45: 175-185. (Correspondence)
24. Chiang PC, Chou RH, Chien HF, Tsai T, Chen CT. Chloride Intracellular Channel 4 Involves in the Reduced Invasiveness of Cancer Cells Treated by Photodynamic Therapy. Lasers in Surgery and Medicine. 2013; 45:38-47. (Correspondence)
25. Yu-Tsai Yang, Chin-Tin Chen, Tsuimin Tsai. Absorption and fluorescence spectral properties of hematoporphyrin in liposomes, micelles, and nanoparticles. Dyes and Pigment. 2013; 96(3): 763-9.
26. Chueh-Pin Chen, Chin-Tin Chen and Tsuimin Tsai. Chitosan Nanoparticles for Antimicrobial Photodynamic Inactivation: Characterization and In Vitro Investigation. Photochemistry and Photobiology. 2012; 88: 570–576.
27. Tsuimin Tsai, HF Chien, TH Wang, CT Huang, YB Ker, Chin-Tin Chen Chitosan augments photodynamic inactivation of Gram-positive and Gram-negative bacteria. Antimicrobial Agents and Chemotherapy. 2011; 55:1883-1890. (Correspondence).
28. Yu-Tsai Yang, Chin-Tin Chen, Hsiung-Fei Chienc, and Tsuimin Tsai. Cellular Photodynamic Toxicity of Hematoporphyrin in Various Nanocarrier Systems. Current Nanoscience. 2011; 7: 850-855.
29. Hong-Tai Ji, Li-Ting Chien, Yu-Hsin Lin, Hsiung-Fei Chien, Chin-Tin Chen. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase. Molecular Cancer. 2010; 9:91 (Correspondence).
30. Yu-Tsai Yang, Chin-Tin Chen, Jen-Chang Yang, Tsuimin Tsai. Spray-dried Microparticles Containing Polymeric Micelles Encapsulating Hematoporphyrin. AAPS Journal. 2010; 12: 138-146.
31. Chih-Yu Wang, Tsuimin Tsai, Chung-Ping Chiang, Hsin-Ming Chen, Chin-Tin Chen. Improved Diagnosis of Oral Premalignant Lesions in Submucous Fibrosis Patients with 5-Aminolevulinic Acid Induced PpIX Fluorescence. Journal of Biomedical Optics. 2009; 14: 04426. (Correspondence)
32. S-P Tseng, L-J Teng, C-T Chen, T-H Lo, W-C Hung, H-J Chen, P.R. Hsueh, and J-C Tsai. Toluidine blue O photodynamic inactivation on multidrug-resistant Pseudomonas aeruginosa. Lasers in Surgery and Medicine. 2009; 41: 391-397.
33. Tsuimin Tsai, Pei-Chi Chiang, H-T Ji, R-H Chou, W-S Chang, Chin-Tin Chen. ALA-PDT results in phenotypic changes and decreased cellular invasion in surviving cancer cells. Lasers in Surgery and Medicine. 2009; 41: 305-315 (Correspondence).
34. Tsuimin Tsai, Yu-Tsai Yang, Tse-Hsien Wang, Hsiung-Fei Chien, Chin-Tin Chen. Improved Photodynamic Inactivation of Gram-positive Bacteria Using Hematoporphyrin Encapsulated in Liposomes and Micelles. Lasers in Surgery and Medicine. 2009; 41: 316-322 (Correspondence)
35. Kang CC, Chin-Tin Chen, Cho CC, Lin YC, Chang CC, Chang TC. A Dual Selective Antitumor Agent and Fluorescence Probe: the Binary BMVC–Porphyrin Photosensitizer. ChemMedChem 2008; 3:725-728.
36. Huang, F.-C., Chang, C.-C., Lou, P.-J. Kuo, I.-C., Chien, C.-W., Chen, C.-T. Shieh, F.-Y., Chang, T.-C., and Lin, J.-J. G-quadruplex stabilizer BMVC induces accelerated senescence and inhibits tumorigenic properties in cancer cells. Mole. Cancer Res. 2008; 6: 955-964. 
37. Ting-Hua Yang, Chin-Tin Chen, Cheng-Ping Wang and Pei-Jen Lou. Photodynamic therapy suppresses the migration and invasion of head and neck cancer cells in vitro. Oral Oncology. 2007; 43: 358-365.
38. Cheng-Ping Wang, Yih-Leong Chang, Chin-Tin Chen, Ting-Hua Yang, Pei-Jen Lou. Photodynamic therapy with topical 5-aminolevulinic acid as a post-operative adjuvant for an incomplete resected primary nasopharyngeal papillary adenocarcinoma: a case report. Lasers in Surgery and Medicine. 2006; 38: 435-438. 
39. Jui-Chang Tsai, Chia-Lun Wu, Hsiung-Fei Chien, Chin-Tin Chen. Reorganization of cytoskeleton induced by 5-aminolevulinic acid-mediated photodynamic therapy and its correlation with mitochondrial dysfunction. Lasers in Surgery and Medicine. 2005; 36: 398-408 (Correspondence) 
40. Hou-Yu Chiang, Chin-Tin Chen, Hsiung-Fei Chien and Sung-Tsang Hsieh. Skin degeneration, neuropathology, and neuropathic pain in a laser-induced focal neuropathy. Neurobiology of Disease. 2005; 18:40-53. 
41. Hsin-Ming Chen, Chin-Tin Chen, Hsiang Yang, Ming-I Lee, Mark Yen-Ping Kuo, Ying-Shiung Kuo, Yi-Ping Wang, Tsuimin Tsai, Chun-Pin Chiang. Successful treatment of an extensive verrucous carcinoma with topical 5-aminolevulinic acid-mediated photodynamic therapy. Journal of Oral Pathology and Medicine. 2005; 34:253-56.
42. Chang, C.-C., Kuo, I-C., Lin, J.-J., Lu, Y.-C., Chen, C.-T., Back, H.-T., Lou, P.-J., and Chang, T.-C. BMVC, a novel carbazole derivative and potential antitumor agent, as a potent telomerase inhibitor and selective fluorescence marker of cancer cells. Chem. & Biodiv. 2004; 1:1377-1384.
43. Chang, C.-C., Kuo, I.-C., Ling, I.-F., Chen, C.-T., Chen, H.-C., Lou, P.-J., Lin, J.-J., Chang, T.-C. Detection of quadruplex DNA structures in human telomeres by a fluorescent carbazole derivative. Analytical Chemistry 2004; 76:4490-4494.
44. Lee, C.-F., Lee, C.-R., Chen, C.-T. and Huang, C.-T. δ-Aminolaevulinic acid mediated photodynamic antimicrobial chemotherapy on Pseudomonas aeruginosa planktonic and biofilm cultures. Journal of Photochemistry and Photobiology B: Biology 2004; 75(1-2): 21-25. 
45. Lin, H.-Y., Chen, C.-T. and Huang, C.-T. Use of Merocyanine 540 for Photodynamic Inactivation against Staphylococcus aureus Planktonic and Biofilm cells. Applied and Environmental Microbiology. 2004; 70(11): 6453-6458.
46. Hsin-Ming Chen, Chin-Tin Chen, Hsiang Yang, Mark Yen-Ping Kuo, Ying-Shiung Kuo, Wan-Hong Lan, Yi-Ping Wang, Tsuimin Tsai, Chun-Pin Chiang. Successful treatment of oral verrucous hyperplasia with topical 5-aminolevulinic acid-mediated photodynamic therapy. Oral Oncology. 2004; 40(6): 630-637. 
47. Tsuimin Tsai, Ruey-Long Hong, Jui-Chang Tsai, Pei-Jen Lou, I-Fang Ling and Chin-Tin Chen. Effect of 5-aminolevulinic acid-mediated photodynamic therapy on MCF-7 and MCF-7/ADR cells. Lasers in Surgery and Medicine. 2004; 34:62-72. (Correspondence). 
48. Jui-Chang Tsai, Chun-Pin Chiang, Hsin-Ming Chen, Sheng Bang Huang_, Chun Wei Wang_, Ming I Lee, Yih-Chih Hsu_, Chin-Tin Chen, and Tsuimin Tsai. Photodynamic Therapy of Oral Dysplasia with Topical 5-Aminolevulinic Acid and Light-Emitting Diode Array. Lasers in Surgery and Medicine. 2004; 34:18-24. (Correspondence)
49. Jui-Chang Tsai, Lee-Jene Teng, Chin-Tin Chen, Tse-Ming Hong, Corey K Goldman and G Yancey Gillespie. Protein kinase C mediates induced secretion of vascular endothelial growth factor by human glioma cells. Biochemical and Biophysical Research Communications. 2003; 309:952-960.
50. Tsuimin Tsai, Hsin-Ming Chen, Chih-Yu Wang, Ying-Shiung Kuo, Chin-Tin Chen, Chun-Pin Chiang. In Vivo Autofluorescence Spectroscopy of Oral Premalignant and Malignant Lesions: Distortion of Fluorescence Intensity by Submucous Fibrosis. Lasers in Surgery and Medicine. 2003; 33:40-47. (Correspondence)
51. Chin-Hsiang Chien, Chin-Tin Chen, Chia-Tung Shun, Yu-Shan Lee, Song_Nan Chow. Expression of cyclin D1 and p16I^NK4 gene products in human ovarian cancer. J. Genet. Mol. Biol. 2003; 14:24-29.
52. Hsin-Ming Chen, Chih-Yu Wang, Chin-Tin Chen, Hsian Yang, Ying-Shiung Kuo, Wan-Hong Lan, Mark Yen-Ping Kuo, Chun-Pin Chiang. Autofluorescence spectra of oral submucous fibrosis. J Oral Pathol. 2003; 32:337-343.
53. Chih-Yu Wang, Tsui-min Tsai, Hsin-Ming Chen, Shu-Chen Chang, Chin-Tin Chen, Chun-Pin Chian. Autofluorescence spectroscopy for in vivo diagnosis of DMBA-induced hamster buccal pouch pre-cancers and cancers. J Oral Pathol. 2003; 32:18-24. (Correspondence)
54. Chih-Yu Wang, Tsuimin Tsai, Hui-Chun Chen, Chin-Tin Chen, Chun-Pin Chiang. A PLS-ANN Based Classification Model for Oral Submucous Fibrosis and Oral Carcinogenesis. Laser in Surgery and Medicine. 2003; 32:318-326. (Correspondence)
55. Kuan-Yu Hung, Jeng-Wen Huang, Chin-Tin Chen, Po-Huang Lee and Tun-Jun Tsai. Pentoxifylline Modulates Intracellular Signaling of TGF-β in Cultured Human Peritoneal Mesothelial Cells: Implications for Prevention of Encapsulating Peritoneal Sclerosis. Nephrology Dialysis Transplantation. 2003; 18:670-676. (Correspondence) 
56. Hung KY, Chin-Tin Chen, Huang JW, Lee PH, Tsai TJ, Hsieh BS. Dipyridamole Inhibits TGF-β-Induced Collagen Gene Expression in Human Peritoneal Mesothelial Cells Through Modulations of the Extracellular Signal-Regulated Kinase (ERK) Pathway. Kidney International. 2001; 60(4): 1249-1257.
57. Hung KY, Chin-Tin Chen, Yen CJ, Lee PH, Tsai TJ, Hsieh BS. Dipyridamole Inhibits PDGF-stimulated Human Peritoneal Mesothelial Cell Proliferation: Effects on Extracellular Signal-Regulated Protein Kinase Cascade and Cell-Cycle Progression. Kidney International. 2001; 60(3): 872-881.
58. Chin-Tin Chen, Tsuimin Tsai and Chun-Pin Chiang. Photodynamic Diagnosis and Therapy in the Management of Oral Neoplasia. New Taipei Journal of Medicine. 2001; 3(1): 1-5.
59. J-C Tsai, Y-Y Hsiao, L-J Teng, Chin-Tin Chen, Ming-Chien Kao. Comparative study on the ALA photodynamic effects of human glioma and meningioma. Laser Surg. Med. 1999; 24: 296-305.
60. C-Y Wang, Chin-Tin Chen, C-P Chiang, S-T Young, Song-Nan Chow and Huihua Kenny Chiang. A probability-based multivariate statistical algorithm for autofluorescence spectroscopic identification of oral carcinogenesis. Photochemistry and Photobiology. 1999; 69 (4): 471-477.
61. Jui-Chang Tsai, Yi-Yun Hsiao, Lee-Jene Teng, Chia-Tung Shun, Chin-Tin Chen, Corey K. Goldman, Ming-Chien Kao. Regulation of vascular endothelial growth factor secretion in human meningioma cells. J Formos Med Assoc. 1999; 98:111-7.
62. Chih-Yu Wang, Huihua Kenny Chiang, Chin-Tin Chen, Chun-Pin Chiang, Ying-Shiung Kuo, Song-Nan Chow. Diagnosis of oral cancer by light-induced autofluorescence spectroscopy using double excitation wavelengths.  European Journal of Cancer: Oral Oncology. 1999; 35: 144-150.
63. Chen, DH, Chen, CT, Zhang, Y, Liu, MA, Campos-Gonzalez, R., and Pan, BT. Characterization of p96^h2bk: immunoreaction with an anti-Erk peptide antibody and activity in Xenopus oocytes and eggs.  Biochemical J. 1998; 335:43-50.
64. Chih-Yu Wang, Chin-Tin Chen, Chun-Pin Chiang, ST Young, Song-Nan Chow and Huihua Kenny Chiang. Partial least-squares discriminant analysis on autofluorescence spectra of oral carcinogenesis.  Applied Spectroscopy. 1998; 52: 1190-1196.
65. Chin-Tin Chen, Huihua Kenny Chiang, Song-Nan Chow, Chih-Yu Wang, Yu-Shan Lee, Jui-Chang Tsai and Chun-Pin Chiang. Autofluorescence in normal and malignant human oral tissues and in DMBA-induced hamster buccal pouch carcinogenesis.  J Oral Pathol. Med. 1998; 27:470-474.
66. Chin-Tin Chen, Chien-Chu Huang, Ruey-Jien Chen, Yu-Hung Lin, Hui-Hua Chiang, Chih-Yu Wang, Yu-Shan Lee and Song-Nan Chow. Light-induced fluorescence spectroscopy to differentiate benign and malignant uterine cervical lesions. J Formos Med Assoc. 1997; 96:247-252.
67. Chin-Tin Chen, Chih-Yu Wang, Ying Shiung Kuo, Hui-Hua Chiang, Song-Nan Chow, and Chun-Pin Chiang. Light-induced fluorescence spectroscopy: A potential diagnostic tool for oral neoplasia. Proc Natl. Sci Council, ROC - Life Science 1996; 20 (4), p.123-30.
68. Song-Nan Chow, Chin Hsiang Wang, and Chin-Tin Chen. Molecular biology of human ovarian cancer.  International Surgery. 1996; 81: 152-157.
69. Chin-Tin Chen and Bin-Tao Pan. Oncogenic Ras stimulates a 96 kDa histone H2b kinase activity in activated Xenopus egg extracts: correlation with the suppression of p34^cdc2 kinase.  J Biol. Chem. 1994; 269: 28034-28043.
70. Bin-Tao Pan, Chin-Tin Chen, and Shu-Mei Lin. Oncogenic Ras blocks cell cycle progression and inhibits p34cdc2 kinase in activated Xenopus egg extracts.  J Biol. Chem. 1994; 269: 5968-5975.