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It was shown that mixed lineage kinase 1 (MLK1) regulates pancreatic cancer growth; however, its role in prostate cancer remains unclear. We showed that MLK1 is a tumor marker in prostate cancer by analyzing clinical gene expression data and identified a novel MLK1 inhibitor (NSC14465) from the compound library of the National Cancer Institute (NCI) using a MLK1 protein structure. The inhibitory effects of MLK1 were validated by an in vitro kinase assay and by monitoring phosphorylation signaling, and the anti-proliferation function was shown in several prostate and pancreatic cancer cell lines. We also demonstrated anti-tumor ability and prevention of cancer-related weight loss in a syngeneic orthotopic mouse model of pancreatic cancer that mimicked the tumor growth environment in the pancreas. Our results demonstrate that the MLK1 inhibitor is an anti-tumor agent for malignant prostate and pancreatic cancers.
Yu-Ching Fan; Kai-Chen Hsu; Tony-Eight Lin; Dietmar Zechner; Sung-Po Hsu; Yuan-Chin Tsai. Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers. Biology 2021, 10, 742 .
AMA StyleYu-Ching Fan, Kai-Chen Hsu, Tony-Eight Lin, Dietmar Zechner, Sung-Po Hsu, Yuan-Chin Tsai. Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers. Biology. 2021; 10 (8):742.
Chicago/Turabian StyleYu-Ching Fan; Kai-Chen Hsu; Tony-Eight Lin; Dietmar Zechner; Sung-Po Hsu; Yuan-Chin Tsai. 2021. "Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers." Biology 10, no. 8: 742.
Five new compounds, eupatodibenzofuran A (1), eupatodibenzofuran B (2), 6-acetyl-8-methoxy-2,2-dimethylchroman-4-one (3), eupatofortunone (4), and eupatodithiecine (5), have been isolated from the aerial part of Eupatorium fortunei, together with 11 known compounds (6‒16). Compounds 1 and 2 featured a new carbon skeleton with an unprecedented 1-(9-(4-methylphenyl)-6-methyldibe nzo[b,d]furan-2-yl)ethenone. Among the isolates, compound 1 exhibited potent inhibitory activity with IC50 values of 5.95 ± 0.89 and 5.55 ± 0.23 μM, respectively, against A549 and MCF-7 cells. The colony-formation assay demonstrated that compound 1 (5 μM) obviously decreased A549 and MCF-7 cell proliferation, and Western blot test confirmed that compound 1 markedly induced apoptosis of A549 and MCF-7 cells through mitochondrial- and caspase-3-dependent pathways.
Chun-Hao Chang; Semon Wu; Kai-Cheng Hsu; Wei-Jan Huang; Jih-Jung Chen. Dibenzofuran, 4-Chromanone, Acetophenone, and Dithiecine Derivatives: Cytotoxic Constituents from Eupatorium fortunei. International Journal of Molecular Sciences 2021, 22, 7448 .
AMA StyleChun-Hao Chang, Semon Wu, Kai-Cheng Hsu, Wei-Jan Huang, Jih-Jung Chen. Dibenzofuran, 4-Chromanone, Acetophenone, and Dithiecine Derivatives: Cytotoxic Constituents from Eupatorium fortunei. International Journal of Molecular Sciences. 2021; 22 (14):7448.
Chicago/Turabian StyleChun-Hao Chang; Semon Wu; Kai-Cheng Hsu; Wei-Jan Huang; Jih-Jung Chen. 2021. "Dibenzofuran, 4-Chromanone, Acetophenone, and Dithiecine Derivatives: Cytotoxic Constituents from Eupatorium fortunei." International Journal of Molecular Sciences 22, no. 14: 7448.
Drug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.
Shao-An Wang; Ming-Jer Young; Yi-Chang Wang; Shu-Hui Chen; Chia-Yu Liu; Yao-An Lo; Hung-Hsiang Jen; Kai-Cheng Hsu; Jan-Jong Hung. USP24 promotes drug resistance during cancer therapy. Cell Death & Differentiation 2021, 1 -18.
AMA StyleShao-An Wang, Ming-Jer Young, Yi-Chang Wang, Shu-Hui Chen, Chia-Yu Liu, Yao-An Lo, Hung-Hsiang Jen, Kai-Cheng Hsu, Jan-Jong Hung. USP24 promotes drug resistance during cancer therapy. Cell Death & Differentiation. 2021; ():1-18.
Chicago/Turabian StyleShao-An Wang; Ming-Jer Young; Yi-Chang Wang; Shu-Hui Chen; Chia-Yu Liu; Yao-An Lo; Hung-Hsiang Jen; Kai-Cheng Hsu; Jan-Jong Hung. 2021. "USP24 promotes drug resistance during cancer therapy." Cell Death & Differentiation , no. : 1-18.
Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction and insulin resistance. Islet amyloid polypeptide (IAPP) aggregation is found to induce islet β-cell death in T2DM patients. Recently, we demonstrated that yakuchinone B derivative 1 exhibited inhibitory activity against IAPP aggregation. Thus, in this study, a series of synthesized yakuchinone B-inspired compounds were tested for their anti-IAPP aggregation activity. Four of these compounds, 4e–h, showed greater activity than the lead compound 1, in the sub-μM range (IC50 = 0.7–0.8 μM). The molecular docking analysis revealed crucial hydrogen bonds between the compounds and residues S19 and N22 and important hydrophobic interactions with residue I26. Notably, compounds 4g and 4h significantly protected β-cells against IAPP-induced toxicity with EC50 values of 0.1 and 0.2 μM, respectively. In contrast, the protective activities of compounds 4e and 4f were weak. Overall, these results suggest that the compounds exhibiting IAPP aggregation-inhibiting activity have the potential to treat T2DM.
Jui-Yi Hsu; Ashish Rao Sathyan; Kai-Cheng Hsu; Liang-Chieh Chen; Cheng-Chung Yen; Hui-Ju Tseng; Kun-Chang Wu; Hui-Kang Liu; Wei-Jan Huang. Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation. Journal of Natural Products 2021, 84, 1096 -1103.
AMA StyleJui-Yi Hsu, Ashish Rao Sathyan, Kai-Cheng Hsu, Liang-Chieh Chen, Cheng-Chung Yen, Hui-Ju Tseng, Kun-Chang Wu, Hui-Kang Liu, Wei-Jan Huang. Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation. Journal of Natural Products. 2021; 84 (4):1096-1103.
Chicago/Turabian StyleJui-Yi Hsu; Ashish Rao Sathyan; Kai-Cheng Hsu; Liang-Chieh Chen; Cheng-Chung Yen; Hui-Ju Tseng; Kun-Chang Wu; Hui-Kang Liu; Wei-Jan Huang. 2021. "Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation." Journal of Natural Products 84, no. 4: 1096-1103.
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis and a high degree of relapse seen in patients. Overexpression of FMS-like tyrosine kinase 3 (FLT3) is associated with up to 70% of AML patients. Wild-type FLT3 induces proliferation and inhibits apoptosis in AML cells, while uncontrolled proliferation of FLT3 kinase activity is also associated with FLT3 mutations. Therefore, inhibiting FLT3 activity is a promising AML therapy. Flavonoids are a group of phytochemicals that can target protein kinases, suggesting their potential antitumor activities. In this study, several plant-derived flavonoids have been identified with FLT3 inhibitory activity. Among these compounds, compound 40 (5,7,4′-trihydroxy-6-methoxyflavone) exhibited the most potent inhibition against not only FLT3 (IC50 = 0.44 μM) but also FLT3-D835Y and FLT3-ITD mutants (IC50 = 0.23 and 0.39 μM, respectively). The critical interactions between the FLT3 binding site and the compounds were identified by performing a structure–activity relationship analysis. Furthermore, the results of cellular assays revealed that compounds 28, 31, 32, and 40 exhibited significant cytotoxicity against two human AML cell lines (MOLM-13 and MV-4-11), and compounds 31, 32, and 40 resulted in cell apoptosis and G0/G1 cell cycle arrest. Collectively, these flavonoids have the potential to be further optimized as FLT3 inhibitors and provide valuable chemical information for the development of new AML drugs.
Shih-Chung Yen; Liang-Chieh Chen; Han-Li Huang; Sin-Ting Ngo; Yi-Wen Wu; Tony Eight Lin; Tzu-Ying Sung; Ssu-Ting Lien; Hui-Ju Tseng; Shiow-Lin Pan; Wei-Jan Huang; Kai-Cheng Hsu. Investigation of Selected Flavonoid Derivatives as Potent FLT3 Inhibitors for the Potential Treatment of Acute Myeloid Leukemia. Journal of Natural Products 2021, 84, 1 -10.
AMA StyleShih-Chung Yen, Liang-Chieh Chen, Han-Li Huang, Sin-Ting Ngo, Yi-Wen Wu, Tony Eight Lin, Tzu-Ying Sung, Ssu-Ting Lien, Hui-Ju Tseng, Shiow-Lin Pan, Wei-Jan Huang, Kai-Cheng Hsu. Investigation of Selected Flavonoid Derivatives as Potent FLT3 Inhibitors for the Potential Treatment of Acute Myeloid Leukemia. Journal of Natural Products. 2021; 84 (1):1-10.
Chicago/Turabian StyleShih-Chung Yen; Liang-Chieh Chen; Han-Li Huang; Sin-Ting Ngo; Yi-Wen Wu; Tony Eight Lin; Tzu-Ying Sung; Ssu-Ting Lien; Hui-Ju Tseng; Shiow-Lin Pan; Wei-Jan Huang; Kai-Cheng Hsu. 2021. "Investigation of Selected Flavonoid Derivatives as Potent FLT3 Inhibitors for the Potential Treatment of Acute Myeloid Leukemia." Journal of Natural Products 84, no. 1: 1-10.
Restenosis and destructive vascular remodeling are the main reasons for treatment failure in patients undergoing percutaneous coronary intervention (PCI). In this study, we explored the efficacy of magnolol (a traditional Chinese medicine) in the treatment of restenosis. The results of this study showed that the activities of thrombin and PAR-1 (protease-activated receptor 1) were significantly decreased by the treatment of magnolol. Based on protein docking analysis, magnolol exhibits its potential to bind to the PAR-1 active site. In addition, thrombin-induced connective tissue growth factor (CTGF) expression and the upstream of CTGF such as JNK-1 (but not JNK-2), c-Jun, and AP-1 were distinctly inhibited by magnolol (50 μM) in vascular smooth muscle cells (VSMC). For the functional assay, magnolol (50 μM) significantly inhibited the migration of VSMC, and rats treated with magnolol (13 mg/kg/day) after balloon angioplasty has observed a significant reduction in the formation of common arterial neointima. In conclusion, we identified a novel mechanism by which magnolol acts as the thrombin activity inhibitor and may be the PAR-1 antagonist. In accordance with these functions, magnolol could decrease thrombin-induced CTGF expression in VSMCs via PAR-1/JNK-1/AP-1 signaling.
Wen-Chin Ko; Chia-Ti Tsai; Kai-Cheng Hsu; Yu-Che Cheng; Tony Eight Lin; Yi-Ling Chen; Chuang-Ye Hong; Wan-Jung Lu; Chun-Ming Shih; Ting-Lin Yen. Magnolol, A Novel Antagonist of Thrombin and PAR-1, Inhibits Thrombin-Induced Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorate Pathogenesis of Restenosis in Rats. Applied Sciences 2020, 10, 8729 .
AMA StyleWen-Chin Ko, Chia-Ti Tsai, Kai-Cheng Hsu, Yu-Che Cheng, Tony Eight Lin, Yi-Ling Chen, Chuang-Ye Hong, Wan-Jung Lu, Chun-Ming Shih, Ting-Lin Yen. Magnolol, A Novel Antagonist of Thrombin and PAR-1, Inhibits Thrombin-Induced Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorate Pathogenesis of Restenosis in Rats. Applied Sciences. 2020; 10 (23):8729.
Chicago/Turabian StyleWen-Chin Ko; Chia-Ti Tsai; Kai-Cheng Hsu; Yu-Che Cheng; Tony Eight Lin; Yi-Ling Chen; Chuang-Ye Hong; Wan-Jung Lu; Chun-Ming Shih; Ting-Lin Yen. 2020. "Magnolol, A Novel Antagonist of Thrombin and PAR-1, Inhibits Thrombin-Induced Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorate Pathogenesis of Restenosis in Rats." Applied Sciences 10, no. 23: 8729.
Alzheimer’s disease (AD), which is among the most prevalent neurodegenerative diseases, manifests as increasing memory loss and cognitive decline. Tau phosphorylation and aggregation are strongly linked to neurodegeneration, as well as associated with chronic neuroinflammatory processes. The anti-inflammation effects of natural products have led to wide recognition of their potential for use in treating and preventing AD. This study investigated whether eupatin, a polymethoxyflavonoid found in Artemisia species, has inhibitory effects on neuroinflammation and tau phosphorylation. We treated mouse macrophages and microglia cells with lipopolysaccharides (LPSs) to activate inflammatory signals, and we treated neuronal cells with a protein phosphatase 2A inhibitor, okadaic acid (OA), or transfection with pRK5-EGFP-Tau P301L plasmid to induce tau phosphorylation. The results indicated that eupatin significantly reduced the LPS-induced protein expression and phosphorylation of p65 and inducible nitric oxide synthase as well as downstream products interleukin 6 and nitrite, respectively. Furthermore, eupatin markedly inhibited the expression of phospho-tau in response to OA treatment and plasmid transfection. We discovered that this inhibition was achieved through the inhibition of glycogen synthase kinase 3β (GSK3β), and molecular docking results suggested that eupatin can sufficiently bind to the GSK3β active site. Our results demonstrate that eupatin has neuroprotective effects, making it suitable for AD treatment.
Ching-Hsuan Chou; Kai-Cheng Hsu; Tony Eight Lin; Chia-Ron Yang. Anti-Inflammatory and Tau Phosphorylation–Inhibitory Effects of Eupatin. Molecules 2020, 25, 5652 .
AMA StyleChing-Hsuan Chou, Kai-Cheng Hsu, Tony Eight Lin, Chia-Ron Yang. Anti-Inflammatory and Tau Phosphorylation–Inhibitory Effects of Eupatin. Molecules. 2020; 25 (23):5652.
Chicago/Turabian StyleChing-Hsuan Chou; Kai-Cheng Hsu; Tony Eight Lin; Chia-Ron Yang. 2020. "Anti-Inflammatory and Tau Phosphorylation–Inhibitory Effects of Eupatin." Molecules 25, no. 23: 5652.
Excessive eIF4E phosphorylation by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNK1 and MNK2; collectively, MNKs) has been associated with oncogenesis. The overexpression of eIF4E in acute myeloid leukemia (AML) is related to cancer cell growth and survival. Thus, the inhibition of MNKs and eIF4E phosphorylation are potential therapeutic strategies for AML. Herein, a structure-based virtual screening approach was performed to identify potential MNK inhibitors from natural products. Three flavonoids, apigenin, hispidulin, and luteolin, showed MNK2 inhibitory activity with IC50 values of 308, 252, and 579 nM, respectively. A structure–activity relationship analysis was performed to disclose the molecular interactions. Furthermore, luteolin exhibited substantial inhibitory efficacy against MNK1 (IC50 = 179 nM). Experimental results from cellular assays showed that hispidulin and luteolin inhibited the growth of MOLM-13 and MV4-11 AML cells by downregulating eIF4E phosphorylation and arresting the cell cycle at the G0/G1 phase. Therefore, hispidulin and luteolin showed promising results as lead compounds for the potential treatment for AML.
Liang-Chieh Chen; Han-Li Huang; Wei-Chun Huangfu; Shih-Chung Yen; Sin-Ting Ngo; Yi-Wen Wu; Tony Eight Lin; Tzu-Ying Sung; Ssu-Ting Lien; Hui-Ju Tseng; Shiow-Lin Pan; Wei-Jan Huang; Kai-Cheng Hsu. Biological Evaluation of Selected Flavonoids as Inhibitors of MNKs Targeting Acute Myeloid Leukemia. Journal of Natural Products 2020, 83, 2967 -2975.
AMA StyleLiang-Chieh Chen, Han-Li Huang, Wei-Chun Huangfu, Shih-Chung Yen, Sin-Ting Ngo, Yi-Wen Wu, Tony Eight Lin, Tzu-Ying Sung, Ssu-Ting Lien, Hui-Ju Tseng, Shiow-Lin Pan, Wei-Jan Huang, Kai-Cheng Hsu. Biological Evaluation of Selected Flavonoids as Inhibitors of MNKs Targeting Acute Myeloid Leukemia. Journal of Natural Products. 2020; 83 (10):2967-2975.
Chicago/Turabian StyleLiang-Chieh Chen; Han-Li Huang; Wei-Chun Huangfu; Shih-Chung Yen; Sin-Ting Ngo; Yi-Wen Wu; Tony Eight Lin; Tzu-Ying Sung; Ssu-Ting Lien; Hui-Ju Tseng; Shiow-Lin Pan; Wei-Jan Huang; Kai-Cheng Hsu. 2020. "Biological Evaluation of Selected Flavonoids as Inhibitors of MNKs Targeting Acute Myeloid Leukemia." Journal of Natural Products 83, no. 10: 2967-2975.
13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.
Yi-Chang Liu; Bo-Rong Peng; Kai-Cheng Hsu; Mohamed El-Shazly; Shou-Ping Shih; Tony Eight Lin; Fu-Wen Kuo; Yi-Cheng Chou; Hung-Yu Lin; Mei-Chin Lu. 13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity Against Oral Cancer Cells Through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts. Marine Drugs 2020, 18, 382 .
AMA StyleYi-Chang Liu, Bo-Rong Peng, Kai-Cheng Hsu, Mohamed El-Shazly, Shou-Ping Shih, Tony Eight Lin, Fu-Wen Kuo, Yi-Cheng Chou, Hung-Yu Lin, Mei-Chin Lu. 13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity Against Oral Cancer Cells Through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts. Marine Drugs. 2020; 18 (8):382.
Chicago/Turabian StyleYi-Chang Liu; Bo-Rong Peng; Kai-Cheng Hsu; Mohamed El-Shazly; Shou-Ping Shih; Tony Eight Lin; Fu-Wen Kuo; Yi-Cheng Chou; Hung-Yu Lin; Mei-Chin Lu. 2020. "13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity Against Oral Cancer Cells Through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts." Marine Drugs 18, no. 8: 382.
Uracil-DNA glycosylases (UDGs) are conserved DNA-repair enzymes that can be found in many species, including herpesviruses. Since they play crucial roles for efficient viral DNA replication in herpesviruses, they have been considered as potential antiviral targets. In our previous work, Staphylococcus aureus SAUGI was identified as a DNA mimic protein that targets UDGs from S. aureus, human, Herpes simplex virus (HSV) and Epstein-Barr virus (EBV). Interestingly, SAUGI has the strongest inhibitory effects with EBVUDG. Here, we determined complex structures of SAUGI with EBVUDG and another γ-herpesvirus UDG from Kaposi's sarcoma-associated herpesvirus (KSHVUDG), which SAUGI fails to effectively inhibit. Structural analysis of the SAUGI/EBVUDG complex suggests that the additional interaction between SAUGI and the leucine loop may explain why SAUGI shows the highest binding capacity with EBVUDG. In contrast, SAUGI appears to make only partial contacts with the key components responsible for the compression and stabilization of the DNA backbone in the leucine loop extension of KSHVUDG. The findings in this study provide a molecular explanation for the differential inhibitory effects and binding strengths that SAUGI has on these two UDGs, and the structural basis of the differences should be helpful in developing inhibitors that would interfere with viral DNA replication.
Yi-Ting Liao; Shin-Jen Lin; Tzu-Ping Ko; Chang-Yi Liu; Kai-Cheng Hsu; Hao-Ching Wang. Structural insight into the differential interactions between the DNA mimic protein SAUGI and two gamma herpesvirus uracil-DNA glycosylases. International Journal of Biological Macromolecules 2020, 160, 903 -914.
AMA StyleYi-Ting Liao, Shin-Jen Lin, Tzu-Ping Ko, Chang-Yi Liu, Kai-Cheng Hsu, Hao-Ching Wang. Structural insight into the differential interactions between the DNA mimic protein SAUGI and two gamma herpesvirus uracil-DNA glycosylases. International Journal of Biological Macromolecules. 2020; 160 ():903-914.
Chicago/Turabian StyleYi-Ting Liao; Shin-Jen Lin; Tzu-Ping Ko; Chang-Yi Liu; Kai-Cheng Hsu; Hao-Ching Wang. 2020. "Structural insight into the differential interactions between the DNA mimic protein SAUGI and two gamma herpesvirus uracil-DNA glycosylases." International Journal of Biological Macromolecules 160, no. : 903-914.
Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine–derived moiety. Some resulting compounds exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity than did the reference SAHA as a pan-HDAC inhibitor in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aβ-aggregation as well as significantly disrupted Aβ-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are multiple HDAC-Aβ-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.
Hui-Ju Tseng; Mei-Hsiang Lin; Young-Ji Shiao; Ying-Chen Yang; Jung-Chun Chu; Chun-Yung Chen; Yi-Ying Chen; Tony Eight Lin; Chih-Jou Su; Shiow-Lin Pan; Liang-Chieh Chen; Chen-Yu Wang; Kai-Cheng Hsu; Wei-Jan Huang. Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease. European Journal of Medicinal Chemistry 2020, 192, 112193 .
AMA StyleHui-Ju Tseng, Mei-Hsiang Lin, Young-Ji Shiao, Ying-Chen Yang, Jung-Chun Chu, Chun-Yung Chen, Yi-Ying Chen, Tony Eight Lin, Chih-Jou Su, Shiow-Lin Pan, Liang-Chieh Chen, Chen-Yu Wang, Kai-Cheng Hsu, Wei-Jan Huang. Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease. European Journal of Medicinal Chemistry. 2020; 192 ():112193.
Chicago/Turabian StyleHui-Ju Tseng; Mei-Hsiang Lin; Young-Ji Shiao; Ying-Chen Yang; Jung-Chun Chu; Chun-Yung Chen; Yi-Ying Chen; Tony Eight Lin; Chih-Jou Su; Shiow-Lin Pan; Liang-Chieh Chen; Chen-Yu Wang; Kai-Cheng Hsu; Wei-Jan Huang. 2020. "Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease." European Journal of Medicinal Chemistry 192, no. : 112193.
Radiotherapy is commonly used to treat patients with oral squamous cell carcinoma (OSCC), but a subpopulation of OSCC patients shows a poor response to irradiation treatment. Therefore, identifying a biomarker to predict the effectiveness of radiotherapy in OSCC patients is urgently needed. In silico analysis of public databases revealed that upregulation of CHRNA5, the gene encoding nicotinic acetylcholine receptor subunit alpha-5, is extensively detected in primary tumors compared to normal tissues and predicts poor prognosis in OSCC patients. Moreover, CHRNA5 transcript level was causally associated with the effective dose of irradiation in a panel of OSCC cell lines. Artificial silencing of CHRNA5 expression enhanced, but nicotine reduced, the radiosensitivity of OSCC cells. Gene set enrichment analysis demonstrated that the E2F signaling pathway is highly activated in OSCC tissues with high levels of CHRNA5 and in those derived from patients with cancer recurrence after radiotherapy. CHRNA5 knockdown predominantly suppressed E2F activity and decreased the phosphorylation of the Rb protein; however, nicotine treatment dramatically promoted E2F activity and increased Rb phosphorylation, which was mitigated after CHRNA5 knockdown in OSCC cells. Notably, the signature combining increased mRNA levels of CHRNA5 and the E2F signaling gene set was associated with worse recurrence-free survival probability in OSCC patients recorded to be receiving radiotherapy. Our findings suggest that CHRNA5 is not only a useful biomarker for predicting the effectiveness of radiotherapy but also a druggable target to enhance the cancericidal effect of irradiation on OSCC.
Lin; Lee; Chia-Hao Kuei; Long-Sheng Lu; Jungshan Chang; Jia-Yi Wang; Kai-Cheng Hsu; Kuei; Lu; Wang; Hsu; Che-Hsuan Lin; Hsun-Hua Lee; Hui-Yu Lin; Fei-Peng Lee; Yuan-Feng Lin. Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma. Journal of Clinical Medicine 2019, 8, 1454 .
AMA StyleLin, Lee, Chia-Hao Kuei, Long-Sheng Lu, Jungshan Chang, Jia-Yi Wang, Kai-Cheng Hsu, Kuei, Lu, Wang, Hsu, Che-Hsuan Lin, Hsun-Hua Lee, Hui-Yu Lin, Fei-Peng Lee, Yuan-Feng Lin. Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma. Journal of Clinical Medicine. 2019; 8 (9):1454.
Chicago/Turabian StyleLin; Lee; Chia-Hao Kuei; Long-Sheng Lu; Jungshan Chang; Jia-Yi Wang; Kai-Cheng Hsu; Kuei; Lu; Wang; Hsu; Che-Hsuan Lin; Hsun-Hua Lee; Hui-Yu Lin; Fei-Peng Lee; Yuan-Feng Lin. 2019. "Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma." Journal of Clinical Medicine 8, no. 9: 1454.
Protein ubiquitination is an important mechanism for regulating the activity and levels of proteins under physiological conditions. Loss of regulation by protein ubiquitination leads to various diseases, such as cancer. Two types of enzymes, namely, E1/E2/E3 ligases and deubiquitinases, are responsible for controlling protein ubiquitination. The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase family. Many studies have addressed the roles of USPs in various diseases. An increasing number of studies have indicated that USPs are critical for cancer progression, and some USPs have been used as targets to develop inhibitors for cancer prevention. Herein we collect and organize most of the recent studies on the roles of USPs in cancer progression and discuss the development of USP inhibitors for cancer therapy in the future.
Ming-Jer Young; Kai-Cheng Hsu; Tony Eight Lin; Wen-Chang Chang; Jan-Jong Hung. The role of ubiquitin-specific peptidases in cancer progression. Journal of Biomedical Science 2019, 26, 42 .
AMA StyleMing-Jer Young, Kai-Cheng Hsu, Tony Eight Lin, Wen-Chang Chang, Jan-Jong Hung. The role of ubiquitin-specific peptidases in cancer progression. Journal of Biomedical Science. 2019; 26 (1):42.
Chicago/Turabian StyleMing-Jer Young; Kai-Cheng Hsu; Tony Eight Lin; Wen-Chang Chang; Jan-Jong Hung. 2019. "The role of ubiquitin-specific peptidases in cancer progression." Journal of Biomedical Science 26, no. 1: 42.
Acute hepatopancreatic necrosis disease (AHPND) is a newly emergent penaeid shrimp disease which can cause 70–100% mortality in Penaeus vannamei and Penaeus monodon, and has resulted in enormous economic losses since its appearance. AHPND is caused by the specific strains of Vibrio parahaemolyticus that harbor the pVA1 plasmid and express PirAvp and PirBvp toxins. These two toxins have been reported to form a binary complex. When both are present, they lead to the death of shrimp epithelial cells in the hepatopancreas and cause the typical histological symptoms of AHPND. However, the binding mode of PirAvp and PirBvp has not yet been determined. Here, we used isothermal titration calorimetry (ITC) to measure the binding affinity of PirAvp and PirBvp. Since the dissociation constant (Kd = 7.33 ± 1.20 μM) was considered too low to form a sufficiently stable complex for X-ray crystallographic analysis, we used alternative methods to investigate PirAvp-PirBvp interaction, first by using gel filtration to evaluate the molecular weight of the PirAvp/PirBvp complex, and then by using cross-linking and hydrogen-deuterium exchange (HDX) mass spectrometry to further understand the interaction interface between PirAvp and PirBvp. Based on these results, we propose a heterotetrameric interaction model of this binary toxin complex. This model provides insight of how conformational changes might activate the PirBvp N-terminal pore-forming domain and should be helpful for devising effective anti-AHPND strategies in the future.
Shin-Jen Lin; Yi-Fan Chen; Kai-Cheng Hsu; Yun-Ling Chen; Tzu-Ping Ko; Chu-Fang Lo; Han-Ching Wang. Structural Insights to the Heterotetrameric Interaction between the Vibrio parahaemolyticus PirAvp and PirBvp Toxins and Activation of the Cry-Like Pore-Forming Domain. Toxins 2019, 11, 233 .
AMA StyleShin-Jen Lin, Yi-Fan Chen, Kai-Cheng Hsu, Yun-Ling Chen, Tzu-Ping Ko, Chu-Fang Lo, Han-Ching Wang. Structural Insights to the Heterotetrameric Interaction between the Vibrio parahaemolyticus PirAvp and PirBvp Toxins and Activation of the Cry-Like Pore-Forming Domain. Toxins. 2019; 11 (4):233.
Chicago/Turabian StyleShin-Jen Lin; Yi-Fan Chen; Kai-Cheng Hsu; Yun-Ling Chen; Tzu-Ping Ko; Chu-Fang Lo; Han-Ching Wang. 2019. "Structural Insights to the Heterotetrameric Interaction between the Vibrio parahaemolyticus PirAvp and PirBvp Toxins and Activation of the Cry-Like Pore-Forming Domain." Toxins 11, no. 4: 233.
This paper reports the development of a series of 5-aroylindolyl-substitued hydroxamic acids. N-hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain-barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer’s disease in the future.
Hsueh-Yun Lee; Sheng-Jun Fan; Fang-I Huang; Hsin-Yi Chao; Kai-Cheng Hsu; Tony Eight Lin; Teng-Kuang Yeh; Mei-Jung Lai; Yu-Hsuan Li; Hsiang-Ling Huang; Chia-Ron Yang; Jing-Ping Liou. 5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer’s Disease Phenotypes. Journal of Medicinal Chemistry 2018, 61, 7087 -7102.
AMA StyleHsueh-Yun Lee, Sheng-Jun Fan, Fang-I Huang, Hsin-Yi Chao, Kai-Cheng Hsu, Tony Eight Lin, Teng-Kuang Yeh, Mei-Jung Lai, Yu-Hsuan Li, Hsiang-Ling Huang, Chia-Ron Yang, Jing-Ping Liou. 5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer’s Disease Phenotypes. Journal of Medicinal Chemistry. 2018; 61 (16):7087-7102.
Chicago/Turabian StyleHsueh-Yun Lee; Sheng-Jun Fan; Fang-I Huang; Hsin-Yi Chao; Kai-Cheng Hsu; Tony Eight Lin; Teng-Kuang Yeh; Mei-Jung Lai; Yu-Hsuan Li; Hsiang-Ling Huang; Chia-Ron Yang; Jing-Ping Liou. 2018. "5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer’s Disease Phenotypes." Journal of Medicinal Chemistry 61, no. 16: 7087-7102.
In aquaculture, shrimp farming is a popular field. The benefits of shrimp farming include a relatively short grow-out time, high sale price, and good cost recovery. However, outbreaks of serious diseases inflict serious losses, and acute hepatopancreatic necrosis disease (AHPND) is an emerging challenge to this industry. In South American white shrimp (Penaeus vannamei) and grass shrimp (Penaeus monodon), this disease has a 70–100% mortality. The pathogenic agent of AHPND is a specific strain of Vibrio parahaemolyticus which contains PirAvp and PirBvp toxins encoded in the pVA1 plasmid. PirAvp and PirBvp have been shown to cause the typical histological symptoms of AHPND in infected shrimps, and in this review, we will focus on our structural understanding of these toxins. By analyzing their structures, a possible cytotoxic mechanism, as well as strategies for anti-AHPND drug design, is proposed.
Shin-Jen Lin; Kai-Cheng Hsu; Hao-Ching Wang. Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirAvp and PirBvp Toxins. Marine Drugs 2017, 15, 373 .
AMA StyleShin-Jen Lin, Kai-Cheng Hsu, Hao-Ching Wang. Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirAvp and PirBvp Toxins. Marine Drugs. 2017; 15 (12):373.
Chicago/Turabian StyleShin-Jen Lin; Kai-Cheng Hsu; Hao-Ching Wang. 2017. "Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirAvp and PirBvp Toxins." Marine Drugs 15, no. 12: 373.
Hispidulin is a naturally occurring flavone known to have various Central nervous system (CNS) activities. Proposed synthetic approaches to synthesizing hispidulin have proven unsatisfactory due to their low feasibility and poor overall yields. To solve these problems, this study developed a novel scheme for synthesizing hispidulin, which had an improved overall yield as well as more concise reaction steps compared to previous methods reported. Additionally, using the same synthetic strategy, d-labelled hispidulin was synthesized to investigate its metabolic stability against human liver microsome. This work may produce new chemical entities for enriching the library of hispidulin-derived compounds.
Liang-Chieh Chen; Kai-Cheng Hsu; Lih-Chu Chiou; Hui-Ju Tseng; Wei-Jan Huang. Total Synthesis and Metabolic Stability of Hispidulin and Its d-Labelled Derivative. Molecules 2017, 22, 1897 .
AMA StyleLiang-Chieh Chen, Kai-Cheng Hsu, Lih-Chu Chiou, Hui-Ju Tseng, Wei-Jan Huang. Total Synthesis and Metabolic Stability of Hispidulin and Its d-Labelled Derivative. Molecules. 2017; 22 (11):1897.
Chicago/Turabian StyleLiang-Chieh Chen; Kai-Cheng Hsu; Lih-Chu Chiou; Hui-Ju Tseng; Wei-Jan Huang. 2017. "Total Synthesis and Metabolic Stability of Hispidulin and Its d-Labelled Derivative." Molecules 22, no. 11: 1897.