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Chun-Yu Liu,Tzu-Ting Huang,Pei-Yi Chu,Chun-Teng Huang,Chia-Han Lee,Wan-Lun Wang,Ka-Yi Lau,Wen-Chun Tsai,Tzu-I Chao,Jung-Chen Su,Ming-Huang Chen,Chung-Wai Shiau,Ling-Ming Tseng,Kuen-Feng Chen 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.
Kim, Eungseok,Liu, Ning-Chun,Yu, I-Chen,Lin, Hung-Yun,Lee, Yi-Fen,Sparks, Janet D.,Chen, Lu-Min,Chang, Chawnshang American Diabetes Association 2011 Diabetes Vol.60 No.5
<P><B>OBJECTIVE</B></P><P>TR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro.</P><P><B>RESEARCH DESIGN AND METHODS</B></P><P>TR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and <I>db/db</I> mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (<I>SCD</I>) 1 regulation.</P><P><B>RESULTS</B></P><P>TR4 transactivation is inhibited via phosphorylation by metformin-induced AMP-activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated <I>SCD1</I> promoter activity via direct binding to the TR4-responsive element located at −243 to −255 on the promoter region. The pathophysiological consequences of the metformin→AMPK→TR4→SCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of <I>SCD1</I> via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased β-oxidation and decreased lipogenic gene expression.</P><P><B>CONCLUSIONS</B></P><P>The pathway from metformin→AMPK→TR4→SCD1→insulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.</P>
( Chun-Jen Liu ),( Wan-Long Chuang ),( I-Shyan Sheen ),( Horng-Yuan Wang ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ting-Tsung Chang ),( Benede tta Massetto ),( Jenny Yang ),( Gregory Camus ),( Fangqiu Zh 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Patients co-infected with HCV and HBV have more rapid progression and worse outcomes than mono-infected patients. Taiwan has among the highest prevalence of chronic HCV/HBV coinfection in Southeast Asia. This study evaluated the safety and efficacy of an all-oral treatment with ledipasvir(LDV)/sofosbuvir(SOF) for 12 weeks in chronic HCV and HBV coinfection. Methods: Patients with or without compensated cirrhosis chronic HCV GT1/GT2 and HBV (HBsAg+) treatment naïve were enrolled into open-label, receiving LDV 90 mg/SOF 400 mg(QD) for 12 weeks. The primary efficacy endpoint is SVR12. HBV DNA was monitored at all study visits and it will be monitored for 2 years post-treatment. Results: A total of 111 patients (68[61%] with GT1 and 43[39%] with GT2) were enrolled and treated. The majority were female(62%), treatment naive(67%), and non-cirrhotic(85%), with a mean age of 55 years and mean BMI of 24.5kg/m2. All but one was HBeAg negative. Mean baseline HBV DNA was 2.1 log10IU/mL. SVR4 was 100%(111/111). The mean change in HBV DNA ranged from -0.06 log10IU/mL at week 1 to +0.49 log10IU/mL at follow-up visit 4; HBV DNA kinetics are shown in Fig 1. 60(54%) patients had an increase in HBV DNA> 10 x BL or became HBV DNA > LLOQ. No patients had ALT ≥ 2 X baseline. No patients discontinued treatment due to adverse events (AEs). Three patients had serious AEs(optic neuritis, post procedural bleeding and duodenal ulcer bleeding; none was considered drug related). Conclusions: In chronic HCV/HBV infection patients, LDV/SOF for 12 weeks resulted in an SVR4 rate of 100%. Although most patients had an increase in HBV DNA during treatment, this was not associated with ALT elevations ≥2 X baseline, and no patients started HBV therapy to date. This all-oral, interferon-free regimen was well tolerated, supporting its potential as a treatment option for HCV/HBV co-infected patients.
Liu Wen-Chung,Wu Chih-Wei,Fu Mu-Hui,Tain You-Lin,Liang Chih-Kuang,Chen I-Chun,Hung Chun-Ying,Lee Yu-Chi,Wu Kay L.H. 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.5
Inflammation alters the neural stem cell (NSC) lineage from neuronal to astrogliogenesis. However, the underlying mechanism is elusive. Autophagy contributes to the decline in adult hippocampal neurogenesis under E. coli lipopolysaccharide (LPS) stimulation. SRY-box transcription Factor 2 (SOX2) is critical for NSC self-renewal and proliferation. In this study, we investigated the role of SOX2 in induced autophagy and hippocampal adult neurogenesis under LPS stimulation. LPS (5 ng•100 g-1•hour-1 for 7 days) was intraperitoneally infused into male Sprague–Dawley rats (8 weeks old) to induce mild systemic inflammation. Beclin 1 and autophagy protein 12 (Atg12) were significantly upregulated concurrent with decreased numbers of Ki67- and doublecortin (DCX)-positive cells in the dentate gyrus. Synchronically, the levels of phospho(p)-mTOR, the p-mTOR/mTOR ratio, p-P85s6k, and the p-P85s6k/P85s6k ratio were suppressed. In contrast, SOX2 expression was increased. The fluorescence micrographs indicated that the colocalization of Beclin 1 and SOX2 was increased in the subgranular zone (SGZ) of the dentate gyrus. Moreover, increased S100β-positive astrocytes were colocalized with SOX2 in the SGZ. Intracerebroventricular infusion of 3-methyladenine (an autophagy inhibitor) effectively prevented the increases in Beclin 1, Atg12, and SOX2. The SOX2+-Beclin 1+ and SOX2+-S100β+ cells were reduced. The levels of p-mTOR and p-P85s6k were enhanced. Most importantly, the number of DCX-positive cells was preserved. Altogether, these data suggest that LPS induced autophagy to inactivate the mTOR/P85s6k pathway, resulting in a decline in neural differentiation. SOX2 was upregulated to facilitate the NSC lineage, while the autophagy milieu could switch the SOX2-induced NSC lineage from neurogenesis to astrogliogenesis.
I-Mei Lin,Sheng-Yu Fan,Cheng-Fang Yen,Yi-Chun Yeh,Tze‐Chun Tang,Mei-Feng Huang,Tai-Ling Liu,Peng-Wei Wang,Huang-Chi Lin,Hsin-Yi Tsai,Yu-Che Tsai 대한정신약물학회 2019 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.17 No.2
Objective: Autonomic imbalance is considered a psychopathological mechanism underlying major depressive disorder (MDD). Heart rate variability (HRV) is an index for autonomic activation. Poor sleep quality is common among patients with MDD. HRV biofeedback (BF) has been used for regulating autonomic balance among patients with physical illness and mental disorders. The purpose of present study was to examine the effects of HRV-BF on depressive symptoms, sleep quality, pre-sleep arousal, and HRV indices, in patients with MDD and insomnia. Methods: In this case-controlled study, patients with MDD and Pittsburgh Sleep Quality Index (PSQI) score higher than 6 were recruited. The HRV-BF group received weekly 60-minute protocol for 6 weeks, and the control group who have matched the age and sex received medical care only. All participants were assessed on Beck Depression Inventory-II, Back Anxiety Inventory, PSQI, and Pre-Sleep Arousal Scale. Breathing rates and electrocardiography were also performed under resting state at pre-testing, and post-testing conditions and for the HRV-BF group, also at 1-month follow-up. Results: In the HRV-BF group, symptoms of depression and anxiety, sleep quality, and pre-sleep arousal were significantly improved, and increased HRV indices, compared with the control group. Moreover, in the HRV-BF group, significantly improved symptoms of depression and anxiety, decreased breathing rates, and increased HRV indices were detected at post-testing and at 1-month follow-up, compared with pre-testing values. Conclusion: This study confirmed that HRV-BF is a useful psychosocial intervention for improving autonomic balance, baroreflex, and symptoms of depression and insomnia in MDD patients.
A study on pushover analyses of reinforced concrete columns
Kuang-Yen Liu,Chin-Kuo Su,I-Chau Tsai,Yu-Chi Sung,Kuo-Chun Chang 국제구조공학회 2005 Structural Engineering and Mechanics, An Int'l Jou Vol.21 No.1
This paper proposes a realistic approach to pushover analyses of reinforced concrete (RC) structures with single column type and frame type. The characteristic of plastic hinge of a single RC column subjected to fixed axial load was determined first according to column’s three distinct failure modes which were often observed in the experiments or earthquakes. By using the determined characteristic of plastic hinge, the pushover analyses of single RC columns were performed and the analytical results were investigated to be significantly consistent with those of cyclic loading tests. Furthermore, a simplified methodology considering the effect of the variation of axial force for each RC column of the frame structure during pushover process is proposed for the first time. It would be helpful in performing pushover analysis for the structures examined in this study with efficiency as well as accuracy.
A study on pushover analyses of reinforced concrete columns
Sung, Yu-Chi,Liu, Kuang-Yen,Su, Chin-Kuo,Tsai, I-Chau,Chang, Kuo-Chun Techno-Press 2005 Structural Engineering and Mechanics, An Int'l Jou Vol.21 No.1
This paper proposes a realistic approach to pushover analyses of reinforced concrete (RC) structures with single column type and frame type. The characteristic of plastic hinge of a single RC column subjected to fixed axial load was determined first according to column's three distinct failure modes which were often observed in the experiments or earthquakes. By using the determined characteristic of plastic hinge, the pushover analyses of single RC columns were performed and the analytical results were investigated to be significantly consistent with those of cyclic loading tests. Furthermore, a simplified methodology considering the effect of the variation of axial force for each RC column of the frame structure during pushover process is proposed for the first time. It would be helpful in performing pushover analysis for the structures examined in this study with efficiency as well as accuracy.
Wu, Sheng-Ju,Lin, Chun-Cheng,Liu, Tsung-Lung,Su, I-Hsuan The Society of Naval Architects of Korea 2020 International Journal of Naval Architecture and Oc Vol.12 No.1
The purpose of this study is to discuss how to improve the maneuverability of lifting and diving for underwater vehicle's vertical motion. Therefore, to solve these problems, applied the 3-D numerical simulation, Taguchi's Design of Experiment (DOE), and intelligent parameter design methods, etc. We planned four steps as follows: firstly, we applied the 2-D flow simulation with NACA series, and then through the Taguchi's dynamic method to analyze the sensitivity (β). Secondly, take the data of pitching torque and total resistance from the Taguchi orthogonal array (L9), the ignal-to-noise ratio (SNR), and analysis each factorial contribution by ANOVA. Thirdly, used Radial Basis Function Network (RBFN) method to train the non-linear meta-modeling and found out the best factorial combination by Particle Swarm Optimization (PSO) and Weighted Percentage Reduction of Quality Loss (WPRQL). Finally, the application of the above methods gives the global optimum for multi-quality characteristics and the robust design configuration, including L/D is 9.4:1, the foreplane on the hull (Bow-2), and position of the sail is 0.25 Ls from the bow. The result shows that the total quality is improved by 86.03% in comparison with the original design.