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Wang S.-N.,Kaohsiung Medical University | Yang S.-F.,Kaohsiung Municipal Ta Tung Hospital | Tsai H.-H.,Kaohsiung Medical University | Tsai H.-H.,Fooyin University | And 2 more authors.
Journal of Gastroenterology | Year: 2014

Background Alterations of adiponectin (APN), one of the adipokines, have been associated with human cancers. However, the clinical significance and impacts of APN on hepatocellular carcinoma (HCC) remain undetermined. Methods Using immunohistochemistry, expression patterns of APN were semiquantitatively scored and further statistically correlated with clinicopathological characteristics and patient survival. Furthermore, the bioeffects and underlying mechanisms of ectopic APN overexpression were determined in Hep3B and HepG2 cells by XTT, immunoblotting, flowcytometry, and invasion assays with or without chemical inhibitors and neutralization antibody. Results We found that cytoplasmic APN staining in 85 cancerous lesions was increased and associated with a poor survival rate (P = 0.007), even when using the Cox regression model (OR = 3.590; 95 % CI = 1.240–10.394; P = 0.018). Ectopic overexpression of APN in Hep3B and HepG2 cells increased proliferation and invasion as well as the levels of p-AKT (Ser473), p-STAT3 (Tyr705), and those downstream, i.e., cyclin D1 and β-catenin. Similar results were also demonstrated in a stable APN-overexpressing clone, HepG2#136. APN neutralization anti-body and LY294002 blocked the APN-mediated effects via inhibition of activated AKT. Conclusions Our results suggest that increased APN may contribute to HCC at least in part through its activation of AKT signalling and may serve as a prognostic factor in HCC. © 2013, Springer Japan.


Hsu N.C.,Kaohsiung Medical University | Huang Y.-F.,Kaohsiung Medical University | Yokoyama K.K.,Kaohsiung Medical University | Chu P.-Y.,St Martin Of Porres Hospital | And 4 more authors.
PLoS ONE | Year: 2013

BRCA1-associated breast cancers are associated with particular features such as early onset, poor histological differentiation, and hormone receptor negativity. Previous studies conducted in Taiwanese population showed that the mutation of BRCA1 gene does not play a significant role in the occurrence of breast cancer. The present study explored methylation of BRCA1 promoter and its relationship to clinical features and outcome in Taiwanese breast cancer patients. Tumor specimens from a cohort of 139 early-stage breast cancer patients were obtained during surgery before adjuvant treatment for DNA extraction. Methylation of BRCA1 promoter region was determined by methylation-specific PCR and the results were related to clinical features and outcome of patients using statistical analysis. Methylation of the BRCA1 promoter was detected in 78 (56%) of the 139 tumors. Chi-square analysis indicated that BRCA1 promoter methylation correlated significantly with triple-negative (ER-/PR-/HER2-) status of breast cancer patients (p = 0.041). The Kaplan-Meier method showed that BRCA1 promoter methylation was significantly associated with poor overall survival (p = 0.026) and disease-free survival (p = 0.001). Multivariate analysis which incorporated variables of patients' age, tumor size, grade, and lymph node metastasis revealed that BRCA1 promoter methylation was associated with overall survival (p = 0.27; hazard ratio, 16.38) and disease-free survival (p = 0.003; hazard ratio, 12.19). Our findings underscore the clinical relevance of the methylation of BRCA1 promoter in Taiwanese patients with early-stage breast cancer. © 2013 Hsu et al.


Chuang W.-L.,Kaohsiung Medical University | Yu M.-L.,Kaohsiung Medical University | Yu M.-L.,Kaohsiung Municipal Ta Tung Hospital
Journal of Gastroenterology | Year: 2013

Combination therapy with pegylated interferon and ribavirin is the standard of care (SOC) for the treatment of chronic hepatitis C (CHC). Treating CHC with SOC may show a sustained virological response (SVR) in approximately 50-70 % of genotype 1 CHC patients and an SVR in 70-90 % of genotype 2 CHC patients. The genotype, baseline viral load, and viral kinetics (i.e., rapid virologic response and early virologic response) can be used as predictors of response-guided therapy. Nonetheless, host factors, e.g. age, ethnicity, insulin resistance, and genetic variations, may also play important roles in the SVR in CHC patients treated with SOC. Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms near the interleukin 28B gene (IL28B) were associated with SVR to treatment with SOC in CHC patients. The IL28B polymorphisms may contribute to the viral kinetics during treatment. Asian people have favorable IL28B polymorphisms. This factor may at least partly explain the high eradication rate of hepatitis C by SOC in Asia. Combination therapy with direct-acting antivirals (DAAs) and SOC can increase the SVR rates both in treatment-naïve and treatment-experienced patients. Although the IL28B polymorphisms also affect the SVR of triple therapy with SOC and first-generation protease inhibitors, pilot studies have demonstrated that potent DAAs might overcome the influence of IL28B polymorphisms. Thus, the treatment of hepatitis C virus infection could be simplified in the near future. © 2012 Springer.


Wu J.-Y.,National Cheng Kung University | Chen C.-H.,Kaohsiung Medical University | Chen C.-H.,Kaohsiung Municipal Ta Tung Hospital | Wang C.-Z.,Kaohsiung Medical University | And 3 more authors.
PLoS ONE | Year: 2013

Mesenchymal stem cell (MSC)-based tissue regeneration is a promising therapeutic strategy for treating damaged tissues. However, the inflammatory microenvironment that exists at a local injury site might restrict reconstruction. Low-power laser irradiation (LPLI) has been widely applied to retard the inflammatory reaction. The purpose of this study was to investigate the anti-inflammatory effect of LPLI on human adipose-derived stem cells (hADSCs) in an inflammatory environment. We showed that the hADSCs expressed Toll-like Receptors (TLR) 1, TLR2, TLR3, TLR4, and TLR6 and that lipopolysaccharide (LPS) significantly induced the production of pro-inflammatory cytokines (Cyclooxygenase-2 (Cox-2), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8)). LPLI markedly inhibited LPS-induced, pro-inflammatory cytokine expression at an optimal dose of 8 J/cm2. The inhibitory effect triggered by LPLI might occur through an increase in the intracellular level of cyclic AMP (cAMP), which acts to down-regulate nuclear factor kappa B (NF-κB) transcriptional activity. These data collectively provide insight for further investigations of the potential application of anti-inflammatory treatment followed by stem cell therapy. © 2013 Wu et al.


Chao A.-C.,Kaohsiung Medical University | Chao A.-C.,Kaohsiung Municipal Ta Tung Hospital | Hsu Y.-L.,Kaohsiung Medical University | Liu C.-K.,Kaohsiung Medical University | Kuo P.-L.,Kaohsiung Medical University
Journal of Agricultural and Food Chemistry | Year: 2011

This study is the first to investigate the anticancer effects of α-mangostin in human glioblastoma cells. α-Mangostin decreases cell viability by inducing autophagic cell death but not apoptosis. Pretreatment of cells with the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin or knockdown beclin-1, resulted in the suppression of α-mangostin-mediated cell death. We also found that liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling is a critical mediator of α-mangostin-induced inhibition of cell growth. Activation of AMPK induces α-mangostin-mediated phosphorylation of raptor, which subsequently associates with 14-3-3γ and results in the loss of mTORC1 activity. The phosphorylation of both downstream targets of mTORC1, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, is also diminished by activation of AMPK. Furthermore, the inhibition of AMPK expression with shRNAs or an inhibitor of AMPK reduced α-mangostin-induced autophagy and raptor phosphorylation, supporting the theory that activation of AMPK is beneficial to autophagy. A further investigation revealed that α-mangostin also induced autophagic cell death in transplanted glioblastoma in nude mice. Together, these results suggest a critical role for AMPK activation in the α-mangostin-induced autophagy of human glioblastoma cells. © 2011 American Chemical Society.


Hsieh M.-Y.,Kaohsiung Municipal Ta Tung Hospital | Lin Z.-Y.,Kaohsiung Medical University | Chuang W.-L.,Kaohsiung Medical University
Kaohsiung Journal of Medical Sciences | Year: 2011

Vascular endothelial growth factor (VEGF), angiopoietin-2, and endostatin have been reported to be related with angiogenesis of hepatocellular carcinoma (HCC). The potential feasibility of serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with HCC treated by transcatheter arterial chemoembolization (TACE) was investigated. VEGF-A, angiopoietin-2, and endostatin serum level were determined by enzyme-linked immunosorbent assay 1 day before and 7 days after TACE in 40 patients. Then they were followed up for 3 months. The results showed that TACE could cause significant increase of VEGF-A (p < 0.01) and angiopoietin-2 (p = 0.01); whereas there was no significant change of endostatin (p > 0.1). Twenty-five patients with rapid growth of HCC within 3 months after TACE had higher proportion of American Joint Committee on Cancer HCC staging >II and higher increase of VEGF-A after TACE than 15 patients without rapid growth (all p < 0.05). Stepwise logistic regression analysis revealed that VEGF-A >16.7 pg/mL 7 days after TACE selected by receiver operating characteristic curve analysis (p < 0.05) was the only independent predictor for rapid growth of HCC (odds ratio 6.33, 95% confidence interval: upper 26, lower 1.54, p < 0.05; sensitivity 76%, specificity 66.7%, accuracy 72.5%, positive predictive level 79.2%, negative predictive level 62.5%, p < 0.01). In conclusion, significant increases of serum level VEGF-A and angiopoietin-2 after TACE have been demonstrated from this study. Therefore, serial VEGF-A level 1 day before and 7 days after TACE may be used to predict rapid HCC growth. Copyright © 2011, Elsevier Taiwan LLC. All rights reserved.


Chen J.-Y.,National Health Research Institute | Li C.-F.,Chi Mei Foundation Medical Center | Kuo C.-C.,National Health Research Institute | Tsai K.K.,National Health Research Institute | And 4 more authors.
Breast Cancer Research | Year: 2014

Introduction: Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear.Methods: Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.Results: Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.Conclusion: Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival. © 2014 Chen et al.; licensee BioMed Central; licensee BioMed Central Ltd.


Tai I.-C.,Kaohsiung Medical University | Fu Y.-C.,Kaohsiung Medical University | Wang C.-K.,Kaohsiung Medical University | Chang J.-K.,Kaohsiung Medical University | And 2 more authors.
International Journal of Nanomedicine | Year: 2013

Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03-1.6 μg/day and 0.05-2.6 μg/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects.© 2013 Tai et al.


Ko C.-H.,Kaohsiung Medical University | Yen J.-Y.,Kaohsiung Medical University | Yen J.-Y.,Kaohsiung Municipal Ta Tung Hospital | Chen S.-H.,National Taiwan University | And 3 more authors.
Journal of Psychiatric Research | Year: 2014

The DSM-5 proposed the diagnostic criteria of Internet gaming disorder (IGD) and suggested that more evidence is necessary before it is included as a standard disorder in the DSM system. The aims of this study were to: 1) evaluate the diagnostic validity of individual criteria of IGD in the DSM-5 and the criteria of craving and irritability; 2) determine the optimal cut-off point for the IGD criteria in the DSM-5. We recruited 75 subjects with IGD, 75 without IGD, and 75 in remission from IGD based on the Diagnostic Criteria of Internet Addiction for College Students (DC-IA-C). All participants underwent a diagnostic interview based on the diagnostic criteria of IGD in the DSM-5 and completed the CIAS and QGU-B. Except for the "deceiving" and "escape" criteria, all criteria of IGD had diagnostic accuracy ranging from 77.3% to 94.7% to differentiate university students with IGD from remitted students. The criterion of craving had diagnostic accuracy of 88% and the criteria of irritability had an accuracy of 68.7%. Fulfilling 5 or more criteria of IGD in the DSM-5 was the best cut-off point to differentiate young adults with IGD from healthy or remitted users. © 2014 Elsevier Ltd.


Chang C.-Z.,Kaohsiung Medical University | Chang C.-Z.,Kaohsiung Municipal Ta Tung Hospital | Wu S.-C.,Kaohsiung Medical University | Lin C.-L.,Kaohsiung Medical University | Kwan A.-L.,Kaohsiung Medical University
Brain Research | Year: 2015

Background More and more evidence revealed early brain injury (EBI) may determine the final outcome in aneurismal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of nano-particle curcumin (nanocurcumin), a diarylheptanoid, on a SAH-induced EBI model. Methods A rodent double hemorrhage model was employed. Nanocurcumin (75/150/300 μg/kg/day) was administered via osmotic mini-pump post-SAH. CSF samples were collected to examine IL-1β, IL-6, IL-8 and TNF-α (rt-PCR). Cerebral cortex was harvested for NF-κB (p50/p65) (western blot), caspases (rt-PCR) measurement. Results Nanocurcumin significantly reduced the bio-expression of NF-κB (p65), when compared with the SAH groups. The levels of IL-1β and IL-6 were increased in animals subjected to SAH, compared with the healthy controls, but absent in the high dose nanocurcumin+SAH group. Moreover, the levels of TNF-α in the SAH groups were significantly elevated. Treatment with nanocurcumin (300 μg/kg) reduced the level to the healthy control. The cleaved caspase-3 and -9a was significantly reduced in 300 μg/kg nanocurcumin treatment groups (P<0.05). Conclusion Treatment with nanocurcumin exerts its neuroprotective effect through the upward regulation of NF-κB (p65) and also reduced mitochondrion related caspase-9a expression. Besides, nanocurcumin decreased CSF levels of TNF-α and IL-1β, which may contribute to the extrinsic antiapoptotic effect. This study shows promise to support curcuminin, in a nano-particle, could attenuate SAH induced EBI. © 2015 Elsevier B.V.

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