The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells

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.

Tazarotene-Induced Gene 1 Interacts with DNAJC8 and Regulates Glycolysis in Cervical Cancer Cells

Chun-Hua Wang,Rong-Yaun Shyu,Chang-Chieh Wu,Mao-Liang Chen,Ming-Cheng Lee,Yi-Yin Lin,Lu-Kai Wang,Shun-Yuan Jiang,Fu-Ming Tsai 한국분자세포생물학회 2018 Molecules and cells Vol.41 No.6

The tazarotene-induced gene 1 (TIG1) protein is a retinoid-inducible growth regulator and is considered a tumor suppressor. Here, we show that DnaJ heat shock protein family member C8 (DNAJC8) is a TIG1 target that regulates glycolysis. Ectopic DNAJC8 expression induced the translocation of pyruvate kinase M2 (PKM2) into the nucleus, subsequently inducing glucose transporter 1 (GLUT1) expression to promote glucose uptake. Silencing either DNAJC8 or PKM2 alleviated the upregulation of GLUT1 expression and glucose uptake induced by ectopic DNAJC8 expression. TIG1 interacted with DNAJC8 in the cytosol, and this interaction completely blocked DNAJC8-mediated PKM2 translocation and inhibited glucose uptake. Furthermore, increased glycose uptake was observed in cells in which TIG1 was silenced. In conclusion, TIG1 acts as a pivotal repressor of DNAJC8 to enhance glucose uptake by partially regulating PKM2 translocation.

Notch1 promotes the pericytemyofibroblast transition in idiopathic pulmonary fibrosis through the PDGFR/ ROCK1 signal pathway

Yi-Chun Wang,Qiong Chen,Jun-Ming Luo,Jing Nie,Qing-He Meng,Wei Shuai,Han Xie,Jia-Mei Xia,Hui Wang 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-

The goals of this study were to investigate the role of the Notch1/PDGFRβ/ROCK1 signaling pathway in the pathogenesis of pulmonary fibrosis and to explore the possibility of treating fibrosis by targeting Notch1. Lung tissues from patients with pulmonary fibrosis were examined for the expression of Notch1/PDGFRβ/ROCK1 using RT-qPCR, western blotting, and immunostaining. Cultured mouse lung pericytes were transfected with Notch1-overexpressed vectors or shRNA targeting PDGFRβ/ROCK1 to examine cell behaviors, including proliferation, cell cycle arrest, and differentiation toward myofibroblasts. Finally, a mouse pulmonary fibrosis model was prepared, and a Notch1 inhibitor was administered to observe tissue morphology and pericyte cell behaviors. Human pulmonary fibrotic tissues presented with overexpression of Notch1, PDGFRβ, and ROCK1, in addition to a prominent transition of pericytes into myofibroblasts. In cultured mouse lung pericytes, overexpression of Notch1 led to the accelerated proliferation and differentiation of cells, and it also increased the expression of the PDGFRβ and ROCK1 proteins. The knockdown of PDGFRβ/ROCK1 in pericytes remarkably suppressed pericyte proliferation and differentiation. As further substantiation, the administration of a Notch1 inhibitor in a mouse model of lung fibrosis inhibited the PDGFRβ/ROCK1 pathway, suppressed pericyte proliferation and differentiation, and alleviated the severity of fibrosis. Our results showed that the Notch1 signaling pathway was aberrantly activated in pulmonary fibrosis, and this pathway may facilitate disease progression via mediating pericyte proliferation and differentiation. The inhibition of the Notch1 pathway may provide one promising treatment strategy for pulmonary fibrosis.

Hyperthermia Promotes Apoptosis and Suppresses Invasion in C6 Rat Glioma Cells

Wang, Dong-Chun,Zhang, Yan,Chen, Hai-Yan,Li, Xiao-Li,Qin, Li-Juan,Li, Ya-Juan,Zhang, Hong-Yi,Wang, Shuo Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

Gliomas are a group of heterogeneous primary central nervous system tumors. Hyperthermia has proven to be a potential therapeutic tool for cancers in the clinic. However, the molecular mechanisms of hyperthermia remain unclear. The objective of this study was to investigate the effects of hyperthermia on the invasiveness in C6 glioma cells and related molecular pathways. Here our data show hyperthermia stimulated the release of tumor necrosis factor-alpha (TNF-${\alpha}$) and decreased C6 glioma cell migration and invasive capability at 30, 60, 120 and 180 min; with increased spontaneous apoptosis in C6 glioma cells at 120 min. We also found mitogen-activated protein kinase (P38 MAPK) protein expression to be increased and nuclear factor-kappa B (NF-${\kappa}B$) protein expression decreased. Based on the results, we conclude that hyperthermia alone reduced invasion of C6 glioma cells through stimulating TNF-${\alpha}$ signaling to activate apoptosis, enhancing P38 MAPK expression and inhibiting the NF-${\kappa}B$ pathway, a first report in C6 rat glioma cells.

Tazarotene-Induced Gene 1 Interacts with DNAJC8 and Regulates Glycolysis in Cervical Cancer Cells

Wang, Chun-Hua,Shyu, Rong-Yaun,Wu, Chang-Chieh,Chen, Mao-Liang,Lee, Ming-Cheng,Lin, Yi-Yin,Wang, Lu-Kai,Jiang, Shun-Yuan,Tsai, Fu-Ming Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.6

The tazarotene-induced gene 1 (TIG1) protein is a retinoidinducible growth regulator and is considered a tumor suppressor. Here, we show that DnaJ heat shock protein family member C8 (DNAJC8) is a TIG1 target that regulates glycolysis. Ectopic DNAJC8 expression induced the translocation of pyruvate kinase M2 (PKM2) into the nucleus, subsequently inducing glucose transporter 1 (GLUT1) expression to promote glucose uptake. Silencing either DNAJC8 or PKM2 alleviated the upregulation of GLUT1 expression and glucose uptake induced by ectopic DNAJC8 expression. TIG1 interacted with DNAJC8 in the cytosol, and this interaction completely blocked DNAJC8-mediated PKM2 translocation and inhibited glucose uptake. Furthermore, increased glycose uptake was observed in cells in which TIG1 was silenced. In conclusion, TIG1 acts as a pivotal repressor of DNAJC8 to enhance glucose uptake by partially regulating PKM2 translocation.

New method for rapidly estimating population densities of the concealed wood‐borer Monochamus alternatus (Coleoptera: Cerambycidae) in the field

Xiao‐Yi Wang,Zhong-qi Yang,Chun-Nan SITU,Jian WANG,Fu-Yong FU 한국곤충학회 2016 Entomological Research Vol.46 No.2

To rapidly estimate pine sawyer, Monochamus alternatus Hope, population densities in forests, the vertical distributions of M. alternatus oviposition sites and larvae on infested Masson pines (Pinus massoniana Lamb.) were studied. Results showed that the number of oviposition sites on sections of trunks between 0 and 2 m above ground was significantly greater than on sections of trunk above 2 m, and the vertical distribution had a significant logarithmic relationship with trunk height. The larval number of M. alternatus on dead infested trees had a significant difference among heights of trunks. Sections on trunks at 2–4 m usually contained the largest number of M. alternatus larvae, while the number of larvae on trunks above 10 m declined significantly, as well as in the 1 m section of trunk at the base. The vertical distribution of M. alternatus larvae on dead infested pines showed a distinct parabolic relationship with trunk height. The number of oviposition sites of M. alternatus on infested Masson pine trunks revealed a significant exponential relationship with the diameter at breast height (DBH) of trees. A significant positive linear relationship also was observed between M. alternatus larval number and DBH on the host pine trees, as well as between the numbers of larvae and oviposition sites on an individual tree. The total number of larvae in an infested tree could be calculated easily using an established equation, through counting the number of oviposition sites at 3–4 m of trunk aboveground. This study developed a practical method for rapid estimation of M. alternatus populations.

Effects of Oxygen Content on the Simultaneous Microbial Removal of SO2 and NOx in Biotrickling Towers

Xing Chun Wang,Xiao Yi Bi,Pei Shi Sun,Jin Quan Chen,Ping Zou,Xiao Ming Ma,Jing Zhang,Hai Yu Wang,Xiao Yi Xu 한국생물공학회 2015 Biotechnology and Bioprocess Engineering Vol.20 No.5

This study uses microbial methods to research the influence of oxygen (O2) content on the removal efficiency of sulfur dioxide (SO2) and nitrogen oxides (NOx) in a tandem twin-towers desulfurization and denitrification process system. Oxygen can play a significant role in biotrickling towers. Other important factors had already been optimized prior to the study, including inlet concentration, gas flow rate, and temperature. SO2 and NOx were prepared by a chemical method. A gas flow meter was used to regulate nitrogen (N2) that had been stored in steel cylinders. In this way, the O2 content was adjusted in the biotrickling towers by controlling the N2 flow rate. Five gradients of O2 content were selected for investigation, namely 4, 8, 12, 16, and 20%. Results indicated that the SO2 removal efficiency from mixed gas (SO2 and NOx) can reach 100%, from all of the five O2 gradients, in biotrickling towers. In a tandem twin-towers desulfurization and denitrification process system, the NOx removal efficiency and the inlet concentration of nitrogen dioxide (NO2) gradually increased as the O2 content increased. Specifically, the average removal efficiency of NOx increased from 49.28 to 80.85% as the O2 content changed from 4 to 20%. The oxygen levels influenced the removal of NOx but the SO2 removal efficiency in mixed gas was always stable.

Risk Factors for Anxiety in Major Depressive Disorder Patients

Li-Min Xin,Lin Chen,Zhen-Peng Ji,Suo-Yuan Zhang,Jun Wang,Yan-Hong Liu,Da-Fang Chen,Fu-De Yang,Gang Wang,Yi-Ru Fang,Zheng Lu,Hai-Chen Yang,Jian Hu,Zhi-Yu Chen,Yi Huang,Jing Sun,Xiao-Ping Wang,Hui-Chun 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.3

Objective: To analyze the sociodemographic and clinical factors related to anxiety in patients with major depressive disorder (MDD). Methods: This study involved a secondary analysis of data obtained from the Diagnostic Assessment Service for People with Bipolar Disorders in China (DASP), which was initiated by the Chinese Society of Psychiatry (CSP) and conducted from September 1, 2010 to February 28, 2011. Based on the presence or absence of anxiety-related characteristics, 1,178 MDD patients were classified as suffering from anxious depression (n=915) or non-anxious depression (n=263), respectively. Results: Compared with the non-anxious group, the anxious-depression group had an older age at onset (t=−4.39, p<0.001), were older (t=−4.69, p<0.001), reported more lifetime depressive episodes (z=−3.24, p=0.001), were more likely to experience seasonal depressive episodes (χ2=6.896, p=0.009) and depressive episodes following stressful life events (χ2=59.350, p <0.001), and were more likely to have a family history of psychiatric disorders (χ2=6.091, p=0.014). Their positive and total scores on the Mood Disorder Questionnaire (MDQ) and the 32-item Hypomania Checklist (HCL-32) (p<0.05) were also lower. The logistic regression analysis indicated that age (odds ratio [OR]=1.03, p<0.001), a lower total MDQ score (OR=0.94, p=0.011), depressive episodes following stressful life events (OR=3.04, p<0.001), and seasonal depressive episodes (OR=1.75, p=0.039) were significantly associated with anxious depression. Conclusion: These findings indicate that older age, fewer subclinical bipolar features, an increased number of depressive episodes following stressful life events, and seasonal depressive episodes may be risk factors for anxiety-related characteristics in patients with MDD.

Professionals’ experiences and attitudes toward use of Traditional Chinese Medicine in hospice palliative inpatient care units: A multicenter survey in Taiwan

Yu-Jia Lin,Hsiao-Ting Chang,Ming-Hwai Lin,Ru-Yih Chen,Ping-Jen Chen,Wen-Yuan Lin,Jyh-Gang Hsieh,Ying-Wei Wang,Chung-Chieh Hu,Yi-Sheng Liou,Tai-Yuan Chiu,Chun-Yi Tu,Yi-Jen Wang,Bo-Ren Cheng,Tzeng-Ji Ch 한국한의학연구원 2021 Integrative Medicine Research Vol.10 No.2

Background: Medical staff may have difficulties in using conventional medicine to manage symptoms among terminally ill patients, including adverse effects of the treatment. Traditional Chinese medicine (TCM) is regarded as a complementary or alternative medicine, and has been increasingly used in the field of palliative medicine in recent years. This study aimed to investigate the experiences of and attitudes toward using TCM among palliative care professionals, and to provide preliminary information about its use in palliative care. Methods: This was a cross-sectional survey study conducted in eight inpatient hospice wards in Taiwan between December 2014 and February 2016. The questionnaire was self-administered, and was analyzed with descriptive statistics including Pearson’s Chi-square test and Fisher’s exact test. Results: A total of 251 palliative care professionals responded to the questionnaire, of whom 89.7% and 88.9% believed that the use of TCM could improve the physical symptoms and quality of life in terminally ill patients, respectively. Overall, 59.8%, of respondents suggested that TCM had rare side effects, and 58.2% were worried that TCM could affect the liver and kidney function of patients. In total, 89.7% and 88.0% of professionals agreed there were no suitable clinical practice guidelines and educational programs, respectively, for TCM use in palliative care. Conclusions: Most of the respondents agreed there was insufficient knowledge, skills-training, and continuing education on the use of TCM in terminally ill patients in Taiwan. These results show that to address patient safety considerations, guidelines about use of TCM in palliative care should be established.

High Expression of Forkhead Box Protein C2 is Related to Poor Prognosis in Human Gliomas

Wang, Yao-Wu,Yin, Chun-Li,Zhang, Hong-Yi,Hao, Jin-Min,Yang, Yue-Ye,Liao, Heng,Jiao, Bao-Hua Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.24

Background: Increasing evidence has indicated that high Forkhead box protein C2 (FOXC2) level is closely associated with the development, progression, and poor prognosis of a variety of tumors. However, the relationship between FOXC2 and the progression of human gliomas remains to be clarified. The aim of present study was to assess FOXC2 expression and to explore its contribution in human gliomas. Materials and Methods: Realtime quantitative PCR was performed to examine FOXC2 expression in 85 pairs of fresh frozen glioma tissues and corresponding non-neoplastic brain tissues. Associations of FOXC2 expression with clinicopathological factors and prognosis of glioma patients were statistically analyzed. Results: The relative mRNA expression of FOXC2 was significantly higher in glioma tissues than the corresponding non-neoplastic brain tissues (p<0.001). In addition, high FOXC2 expression was significantly associated with advanced pathological grade (P=0.005) and the low Karnofsky performance score (KPS) (p=0.003), correlating with poor survival (p<0.001). Furthermore, multivariate Cox regression analysis showed that high FOXC2 expression was an independent predictor of overall survival (p=0.006). Conclusions: FOXC2 may act as an oncogenic gene and represent a potential regulator of aggressive development and a candidate prognostic marker in human gliomas.