Browsing by Author "Tsai, Kun-Hsi"

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Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation
(2014-01-01)
Hsu, Hsi-Hsien
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Cheng, Li-Hao
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Ho, Tsung-Jung
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Kuo, Wei-Wen
;
Lin, Yueh-Min
Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in apicidin-R cells, but apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients.
Association of Interleukin-16 Polymorphisms with Graves' Disease in a Taiwanese Population
(2014-04-30)
Tsai, Kun-Hsi
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Chang, Ching-Yao
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Tsai, Fuu-Jen
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Lin, Hui-Ju
;
Yang, Yuh-Shyong
Graves' disease (GD) is a complex, organ-specific autoimmune disease wherein the thyroid gland becomes enlarged and overactive. During GD progression, T cells secrete interleukin-16 (IL-16) to promote inflammation, act as chemoattractants that recruit more inflammatory cells, and activate target cells to enhance the development of GD. To investigate the role of IL-16 in GD, we genotyped 474 patients with GD at 8 single-nucleotide polymorphisms (SNPs) in the IL-16 gene. The IL-16 SNP rs8028364 was found to be associated with GD when compared with the control subjects (P = 2.93 x 10(-17); CG genotype: odds ratio [OR] = 0.2 [0.07, 0.59]; CC genotype: OR = 0.03 [0.01, 0.09]). The rs1131445 polymorphism was found to be associated with GD under the allelic model (P = 0.01; G allele: OR = 1.97 [1.17, 3.32]). Sliding-window haplotype analysis by the PLINK program showed that the most significant haplotype was provided by the 6-SNP haplotype window, consisting of rs7182786, rs8028364, rs12907134, rs4128767, rs4072111 and rs8031107 (P = 2.31 x 10(-51)). We found 2 protective haplotypes: GCAAGG (P = 8.69 x 10(-7); OR = 0.22 [0.12, 0.41]) and AGAAGG (P = 0.0012; OR = 0.26 [0.12, 0.6]). In addition, GGGGAA (P = 0.39; OR = 2.32 [1.08, 4.99]) and GGGAGA (P = 1.18 x 10(-5); OR = 5.54 [2.50, 12.31]) were found to be the two high-risk haplotypes. These results suggest that polymorphisms in IL-16 may be used as genetic markers for the diagnosis and prognosis of GD.
Dung-shen (Codonopsis pilosula) attenuated the cardiac-impaired insulin-like growth factor II receptor pathway on myocardial cells
(2013-05-15)
Tsai, Kun-Hsi
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Lee, Nien-Hung
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Chen, Guei-Ying
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Hu, Wei-Syun
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Tsai, Chen-Yen
Previous studies from our lab showed that increase in AngIl in H9c2 cells causes elevated IGFII and IGFIIR through MEK and JNK, leading to rise in intracellular calcium, calcineurin activation by PLC-beta 3 via G alpha q, insertion into mitochondrial membranes of Bad, and apoptosis via caspases 9 and 3. Codonopsis pilosula is traditionally used to lower blood pressure. The purpose of our study is to investigate if C. pilosula attenuates AngII plus Leu(27)-IGFII-induced calcium influx and apoptosis in H9c2 cardiomyoblasts. C pilosula significantly attenuated AngII induced IGFIIR promoter activity. Leu(27)-IGFII was applied to enhance the Angll effect. C pilosula also reversed Ca2+ influx, MOMP and apoptosis increased by AngIl plus Leu(27)-IGFIL Molecular markers in IGFIIR apoptotic pathway (IGFIIR, calcineurin, etc.) and IGFIIR-G alpha q association were downregulated by C pilosula. However, p-Bad(Ser136) and BcI-2 were increased. Therefore, C pilosula suppresses Angll plus Leu(27)-IGFII-induced IGFII/IGFIIR pathway in myocardial cells. (C) 2012 Elsevier Ltd. All rights reserved.
Dung-Shen Downregulates the Synergistic Apoptotic Effects of Angiotensin II Plus Leu 27-IGF II on Cardiomyoblasts
(2014-01-01)
Chang, Ko-Shih
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Lee, Nien-Hung
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Kuo, Wei-Wen
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Hu, Wei-Syun
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Chang, Mu-Hsin
Background: Insulin growth factor II (IGFII) is expressed after ischemic stress in pig hearts and after myocardial infarction in humans. However, its receptor (IGFIIR) cannot be found in normal adult hearts. Moreover, a mouse IGFII overexpression model showed a heart and kidney hypertrophy phenomenon similar to Beckwith-Wiedemann syndrome in humans. The previous studies from our lab showed that an increase in AngII in H9c2 cells causes an elevation in IGFII and IGFIIR through MEK and JNK activation, leading to a rise in intracellular Ca2+ ions, activation of calcineurin by PLC-beta 3 via Gaq, insertion into mitochondrial membranes of BAD, and apoptosis via activation of caspases 9 and 3. Codonopsis pilosula (Dung-shen) has various uses in traditional Chinese medicine, including lowering blood pressure, and increasing red and white blood cell counts. Methods: The purpose of our study is to investigate whether the addition of C. pilosula will attenuate the Angl I plus Leu27-IGF11-induced apoptosis in H9c2 cardiomyoblast cells. Results: From MTT [3-(4, 5-dimethy1-2-thiazolyI)-2, 5-dipheny1-2-tetrazolium bromide] results, it was revealed that Angll plus Leu27-IGFII significantly reduced cell viability, which was reversed by C. pilosula. Additionally, C. pilosula also reversed apoptosis (TUNEL staining) increased by Angll plus Leu27-IGFII. Up-regulation of caspase 3 by Angl I plus Leu27-IGFII was attenuated by C. pilosula treatment, as shown in western blotting assay and immunofluorescence microscopy results. Conclusions: C. pilosula is able to suppress the apoptotic pathway enhanced by Angl I plus Leu27-IGFII in myocardial cells.
NADPH oxidase-derived superoxide Anion-induced apoptosis is mediated via the JNK-dependent activation of NF-kappa B in cardiomyocytes exposed to high glucose
(2012-04-01)
Tsai, Kun-Hsi
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Wang, Wei-Jan
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Lin, Cheng-Wen
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Pai, Peiying
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Lai, Tung-Yuan
Hyperglycemia-induced generation of reactive oxygen species (ROS) can lead to cardiomyocyte apoptosis and cardiac dysfunction. However, the mechanism by which high glucose causes cardiomyocyte apoptosis is not clear. In this study, we investigated the signaling pathways involved in NADPH oxidase-derived ROS-induced apoptosis in cardiomyocytes under hyperglycemic conditions. H9c2 cells were treated with 5.5 or 33 mM glucose for 36?h. We found that 33 mM glucose resulted in a time-dependent increase in ROS generation as well as a time-dependent increase in protein expression of p22phox, p47phox, gp91phox, phosphorylated I?B, c-Jun N-terminal kinase (JNK) and p38, as well as the nuclear translocation of NF-kB. Treatment with apocynin or diphenylene iodonium (DPI), NADPH oxidase inhibitors, resulted in reduced expression of p22phox, p47phox, gp91phox, phosphorylated I?B, c-Jun N-terminal kinase (JNK) and p38. In addition, treatment with JNK and NF-kB siRNAs blocked the activity of caspase-3. Furthermore, treatment with JNK, but not p38, siRNA inhibited the glucose-induced activation of NF-?B. Similar results were obtained in neonatal cardiomyocytes exposed to high glucose concentrations. Therefore, we propose that NADPH oxidase-derived ROS-induced apoptosis is mediated via the JNK-dependent activation of NF-B in cardiomyocytes exposed to high glucose. J. Cell. Physiol. 227: 1347-1357, 2012. (C) 2011 Wiley Periodicals, Inc.
Rhubarb inhibits hepatocellular carcinoma cell metastasis via GSK-3-beta activation to enhance protein degradation and attenuate nuclear translocation of beta-catenin
(2013-05-01)
Tsai, Kun-Hsi
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Hsien, Hau-Hsueh
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Chen, Li-Mien
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Ting, Wei-Jen
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Yang, Yuh-Shyong
The aim of our study was to investigate the mechanisms by which rhubarb regulates beta-catenin as well as metastasis of hepatocellular carcinomas. Our results revealed that rhubarb extract inhibited HA22T cell migration ability in wound healing, migration and invasion assays in a dose-dependent manner. Rhubarb also reduced beta-catenin protein level, downregulated its downstream proteins, cyclin D, Tbx3 and c-Myc, and attenuated the expression of MMP9 and contactin-1 metastatic factors. Additionally, rhubarb inhibited beta-catenin nuclear accumulation and induced its degradation via proteasome-mediated pathway. Furthermore, we found that rhubarb suppressed the p-ser(9) GSK-3-beta protein level to inactivate Wnt signalling and reduce beta-catenin protein level. Taken together; we found that rhubarb blocked the metastatic process of HA22T hepatocellular carcinoma cells mediated through GSK-3-beta activation, and enhancement of protein degradation as well as reduction of the nuclear accumulation of beta-catenin. (C) 2012 Elsevier Ltd. All rights reserved.