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Journal articles on the topic 'XAV939'

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Published: 4 June 2021
Last updated: 16 February 2022

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1

Shetti, Dattatrya, Bao Zhang, Conghui Fan, Canlong Mo, Bae Hoon Lee, and Kun Wei. "Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling." Cells 8, no. 8 (August 14, 2019): 892. http://dx.doi.org/10.3390/cells8080892.

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Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.
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2

Trillsch, Fabian, Valentina Preinfalk, Martina Rahmeh, Marianne Vogel, Bastian Czogalla, Alexander Burges, Udo Jeschke, and Sven Mahner. "Inhibition of Wnt signaling as therapeutic option in platinum-resistant ovarian cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e17050-e17050. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e17050.

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e17050 Background: New therapeutic approaches for platinum-resistant ovarian cancer patients are urgently needed. In this context, Wnt signaling appears to be a promising target so that inhibition of this pathway in platinum-resistant cell lines was aim of the present study. Methods: The ovarian cancer cell line A2780 and its platinum-resistant clone A2780cis were treated with different concentrations of Wnt singaling inhibitors SB216761, XAV939, and triptolides. Metabolic activity and cell viability was estimated by MTT cell proliferation assays. Immunohistochemistry for ß-Catenin visualized activity of the Wnt pathway. Results: MTT proliferation tests revealed an impaired proliferation following treatment with all three agents. While triptolides already led to significantly reduced metabolic activity after 48h, this effect was seen for SB216761 and XAV939 not before 72h. Immunohistochemistry for ß-Catenin confirmed inhibition of Wnt signaling. Following XAV939 treatment of A2780cis, ß-Catenin signals shifted from the nucleus towards the cell membrane. Conclusions: Re-sensitizing platinum-resistant ovarian cancer cells for platinum-based chemotherapy by inhibition of Wnt signaling seems to be mechanism visualized by the translocation of ß-Catenin from the nucleus towards the cell membrane. In this context, a dose-dependent response was noted for XAV939. Inhibition of Wnt Signaling appears to be a prospective therapeutic approach for platinum-resistant ovarian cancer patients.
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3

Yu, Haixiang, Lei Xu, Zhengjia Liu, Bo Guo, Zhifeng Han, and Hua Xin. "Circ_MDM2_000139, Circ_ATF2_001418, Circ_CDC25C_002079, and Circ_BIRC6_001271 Are Involved in the Functions of XAV939 in Non-Small Cell Lung Cancer." Canadian Respiratory Journal 2019 (November 27, 2019): 1–12. http://dx.doi.org/10.1155/2019/9107806.

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Background. The small molecule inhibitor XAV939 could inhibit the proliferation and promote the apoptosis of non-small cell lung cancer (NSCLC) cells. This study was conducted to identify the key circular RNAs (circRNAs) and microRNAs (miRNAs) in XAV939-treated NSCLC cells. Methods. After grouping, the NCL-H1299 cells in the treatment group were treated by 10 μM XAV939 for 12 h. RNA-sequencing was performed, and then the differentially expressed circRNAs (DE-circRNAs) were analyzed by the edgeR package. Using the clusterprofiler package, enrichment analysis for the hosting genes of the DE-circRNAs was performed. Using Cytoscape software, the miRNA-circRNA regulatory network was built for the disease-associated miRNAs and the DE-circRNAs. The DE-circRNAs that could translate into proteins were predicted using circBank database and IRESfinder tool. Finally, the transcription factor (TF)-circRNA regulatory network was built by Cytoscape software. In addition, A549 and HCC-827 cell treatment with XAV939 were used to verify the relative expression levels of key DE-circRNAs. Results. There were 106 DE-circRNAs (including 61 upregulated circRNAs and 45 downregulated circRNAs) between treatment and control groups. Enrichment analysis for the hosting genes of the DE-circRNAs showed that ATF2 was enriched in the TNF signaling pathway. Disease association analysis indicated that 8 circRNAs (including circ_MDM2_000139, circ_ATF2_001418, circ_CDC25C_002079, and circ_BIRC6_001271) were correlated with NSCLC. In the miRNA-circRNA regulatory network, let-7 family members⟶circ_MDM2_000139, miR-16-5p/miR-134-5p⟶circ_ATF2_001418, miR-133b⟶circ_BIRC6_001271, and miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 regulatory pairs were involved. A total of 47 DE-circRNAs could translate into proteins. Additionally, circ_MDM2_000139 was targeted by the TF POLR2A. The verification test showed that the relative expression levels of circ_MDM2_000139, circ_CDC25C_002079, circ_ATF2_001418, and circ_DICER1_000834 in A549 and HCC-827 cell treatment with XAV939 were downregulated comparing with the control. Conclusions. Let-7 family members and POLR2A targeting circ_MDM2_000139, miR-16-5p/miR-134-5p targeting circ_ATF2_001418, miR-133b targeting circ_BIRC6_001271, and miR-221-3p/miR-222-3p targeting circ_CDC25C_002079 might be related to the mechanism in the treatment of NSCLC by XAV939.
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4

Fazary, Ahmed E., Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi, Mohamed E. Amer, Mohamed S. M. Nasr, Tamer M. M. Abuamara, Doaa A. Badr, Yi-Hsu Ju, and Aly F. Mohamed. "Bioactivity Studies of Hesperidin and XAV939." ACS Omega 6, no. 30 (July 26, 2021): 20042–52. http://dx.doi.org/10.1021/acsomega.1c03080.

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5

Wang, Cong, Huiming Zhu, Zhaorui Sun, Zou Xiang, Yuanyuan Ge, Can Ni, Zhaowen Luo, Weiping Qian, and Xiaodong Han. "Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury." American Journal of Physiology-Cell Physiology 307, no. 3 (August 1, 2014): C234—C244. http://dx.doi.org/10.1152/ajpcell.00366.2013.

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Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/β-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of β-catenin and suppression of the Wnt/β-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/β-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/β-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/β-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking.
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6

Kirby, Christina A., Atwood Cheung, Aleem Fazal, Michael D. Shultz, and Travis Stams. "Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939." Acta Crystallographica Section F Structural Biology and Crystallization Communications 68, no. 2 (January 21, 2012): 115–18. http://dx.doi.org/10.1107/s1744309111051219.

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The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD+donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1–PJ34 crystallization system has the NAD+donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1–PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.
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7

Renna, Cristiano, Roberta Salaroli, Claudia Cocchi, and Giovanna Cenacchi. "XAV939-Mediated ARTD Activity Inhibition in Human MB Cell Lines." PLOS ONE 10, no. 4 (April 2, 2015): e0124149. http://dx.doi.org/10.1371/journal.pone.0124149.

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8

Chen, Jing, Jizhen Li, Zhigang Miao, Xingshun Xu, and Chun-Feng Liu. "XAV939, a small molecular inhibitor, provides neuroprotective effects on oligodentrocytes." Journal of Neuroscience Research 92, no. 10 (May 26, 2014): 1252–58. http://dx.doi.org/10.1002/jnr.23415.

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9

TIAN, XIAOHONG, WEIJIAN HOU, SHULING BAI, JUN FAN, HAO TONG, and YU BAI. "XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening." Oncology Reports 32, no. 5 (September 2, 2014): 1999–2006. http://dx.doi.org/10.3892/or.2014.3460.

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10

Jung, Hyun Jun, Sang-Yeob Kim, Hyo-Jung Choi, Eui-Jung Park, Jung-Suk Lim, Jørgen Frøkiaer, Søren Nielsen, and Tae-Hwan Kwon. "Tankyrase-mediated β-catenin activity regulates vasopressin-induced AQP2 expression in kidney collecting duct mpkCCDc14 cells." American Journal of Physiology-Renal Physiology 308, no. 5 (March 1, 2015): F473—F486. http://dx.doi.org/10.1152/ajprenal.00052.2014.

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Aquaporin-2 (AQP2) mediates arginine vasopressin (AVP)-induced water reabsorption in the kidney collecting duct. AVP regulates AQP2 expression primarily via Gsα/cAMP/PKA signaling. Tankyrase, a member of the poly(ADP-ribose) polymerase family, is known to mediate Wnt/β-catenin signaling-induced gene expression. We examined whether tankyrase plays a role in AVP-induced AQP2 regulation via ADP-ribosylation of G protein-α (Gα) and/or β-catenin-mediated transcription of AQP2. RT-PCR and immunoblotting analysis revealed the mRNA and protein expression of tankyrase in mouse kidney and mouse collecting duct mpkCCDc14 cells. dDAVP-induced AQP2 upregulation was attenuated in mpkCCDc14 cells under the tankyrase inhibition by XAV939 treatment or small interfering (si) RNA knockdown. Fluorescence resonance energy transfer image analysis, however, revealed that XAV939 treatment did not affect dDAVP- or forskolin-induced PKA activation. Inhibition of tankyrase decreased dDAVP-induced phosphorylation of β-catenin (S552) and nuclear translocation of phospho-β-catenin. siRNA-mediated knockdown of β-catenin decreased forskolin-induced AQP2 transcription and dDAVP-induced AQP2 expression. Moreover, inhibition of phosphoinositide 3-kinase/Akt, which was associated with decreased nuclear translocation of β-catenin, diminished dDAVP-induced AQP2 upregulation, further indicating that β-catenin mediates AQP2 expression. Taken together, tankyrase plays a role in AVP-induced AQP2 regulation, which is likely via β-catenin-mediated transcription of AQP2, but not ADP-ribosylation of Gα. The results provide novel insights into vasopressin-mediated urine concentration and homeostasis of body water metabolism.
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11

Yang, Wei, Xiang-Ming Mu, and Xiao-Qiang Li. "XAV939 Inhibits Vascular Remodeling by Reducing Vascular Smooth Muscle Cells Proliferation in Hypertensive Rats." Journal of Biomaterials and Tissue Engineering 5, no. 12 (December 1, 2015): 967–73. http://dx.doi.org/10.1166/jbt.2015.1402.

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12

Afifi, Marwa M., Lauren A. Austin, Megan A. Mackey, and Mostafa A. El-Sayed. "XAV939: From a Small Inhibitor to a Potent Drug Bioconjugate When Delivered by Gold Nanoparticles." Bioconjugate Chemistry 25, no. 2 (January 10, 2014): 207–15. http://dx.doi.org/10.1021/bc400271x.

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13

Jang, Jaewoong, Yoonju Jung, Seyeon Chae, Taehyun Bae, Seok-Min Kim, Yae Jie Shim, Sang-In Chung, and Yoosik Yoon. "XAV939, a Wnt/β-catenin pathway modulator, has inhibitory effects on LPS-induced inflammatory response." Immunopharmacology and Immunotoxicology 41, no. 3 (November 22, 2018): 394–402. http://dx.doi.org/10.1080/08923973.2018.1536984.

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Zhang, Jinhua, Jing Si, Lu Gan, Menghuan Guo, Junfang Yan, Yuhong Chen, Fang Wang, Yi Xie, Yupei Wang, and Hong Zhang. "Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells." Artificial Cells, Nanomedicine, and Biotechnology 48, no. 1 (January 1, 2020): 479–87. http://dx.doi.org/10.1080/21691401.2020.1716779.

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15

Sun, Gangyi, Ziyi Shang, and Wenjia Liu. "SPP1 Regulates Radiotherapy Sensitivity of Gastric Adenocarcinoma via the Wnt/Beta-Catenin Pathway." Journal of Oncology 2021 (July 27, 2021): 1–10. http://dx.doi.org/10.1155/2021/1642852.

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Purpose. Radiotherapy has been widely applied for the treatment of locally advanced and metastatic gastric adenocarcinoma (GAC). The aberrant expression of secreted phosphoprotein 1 (SPP1) is involved in radiosensitivity in a variety of cancers. The present study aims to characterize the clinical significance of SPP1 expression in GAC and its role and underlying mechanism of radiosensitivity. Methods. The SPP1 expression in GAC tissues and pericarcinomatous tissues was determined by QRT-PCR and immunohistochemistry, and the SPP1 expression in GAC cell lines (BGC823, AGS, and SGC7901) and normal human gastric epithelial cell line (GES-1) was determined by western blot. T-test, one-way ANOVA, Cox regression model, and Kaplan–Meier plotter were applied to further assess the association between SPP1 expression and the prognosis of the patients with GAC. After irradiation and transfection with si-SPP1 combined with or without Wnt/β-catenin pathway inhibitor (XAV939), western blot, transwell, flow cytometry, and TOP-flash reporter assay were applied to detect DNA damage, invasion, apoptosis, cell cycle, and activation of Wnt/β-catenin pathway, respectively. Results. SPP1 mRNA and protein levels in GAC tissues were both dramatically higher than those in pericarcinomatous tissues. SPP1 overexpression was positively associated with tumor size, nodal status, and histological grade of GAC patients. SPP1 overexpression, depth of invasion, and nodal status were independent prognostic factors for the patients. High SPP1 expression was negatively related to the overall survival in patients with GAC. We found that SPP1 knockdown enhanced the radiosensitivity of GAC cell lines (AGS and SGC7901). Increasing H2AX phosphorylation, apoptosis and G2/M phase arrest, and decreasing invasion were observed after the administration of si-SPP1 and irradiation. Radiosensitivity of SPP1 was mainly dependent on the Wnt/β-catenin signal pathway. XAV939 could enhance these phenomena induced by irradiation combined with SPP1 knockdown. Conclusion. This study demonstrates that SPP1 suppresses Wnt/β-catenin signaling to enhance the radiosensitivity of GAC via inhibiting invasion and accelerating DNA damage, G2/M phase arrest, and apoptosis.
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TIAN, XIAOHONG, WEIJIAN HOU, SHULING BAI, JUN FAN, HAO TONG, and HE XU. "XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1." International Journal of Oncology 45, no. 1 (April 28, 2014): 121–28. http://dx.doi.org/10.3892/ijo.2014.2406.

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Chen, Luoman, Jianhui Zhuang, Shekhar Singh, Kai Wang, Mengting Xiong, Dachun Xu, Wei Chen, Jinjiang Pang, Yawei Xu, and Xiankai Li. "XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling." Journal of Cardiovascular Pharmacology 68, no. 6 (December 2016): 414–24. http://dx.doi.org/10.1097/fjc.0000000000000427.

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WU, XUEFANG, FENG LUO, JINBANG LI, XUEYUN ZHONG, and KUNPING LIU. "Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway." International Journal of Oncology 48, no. 4 (January 26, 2016): 1333–40. http://dx.doi.org/10.3892/ijo.2016.3360.

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Tian, Xiao-Hong, Wei-Jian Hou, Yan Fang, Jun Fan, Hao Tong, Shu-Ling Bai, Qu Chen, He Xu, and Yan Li. "XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway." Journal of Experimental & Clinical Cancer Research 32, no. 1 (2013): 100. http://dx.doi.org/10.1186/1756-9966-32-100.

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Wu, Cun-en, Yu-wen Zhuang, Jin-yong Zhou, Shen-lin Liu, Xi Zou, Jian Wu, Rui-ping Wang, and Peng Shu. "Nm23-H1 inhibits hypoxia induced epithelial-mesenchymal transition and stemness in non-small cell lung cancer cells." Biological Chemistry 400, no. 6 (June 26, 2019): 765–76. http://dx.doi.org/10.1515/hsz-2018-0351.

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Abstract The Nm23 gene has been acknowledged to play a crucial role in lung cancer metastasis inhibitory cascades controlled by multiple factors. Low expression or allelic deletion of nm23-H1 is strongly linked to widespread metastasis and poor differentiation of non-small cell lung cancer (NSCLC). In this study, nm23-H1 was down regulated in epithelial-mesenchymal transition (EMT) and stemness enhancement under cobalt chloride (CoCl2)-induced hypoxia in NSCLC cells. Moreover, knocking down of nm23-H1 by shRNA apparently promoted hypoxia induced EMT and stemness, which was entirely suppressed via over expression of nm23-H1. Mechanistically, the Wnt/β-catenin signaling pathway was found to participate in the nm23-H1-mediated process. Besides, XAV939 prohibited cell EMT and stemness which could be impaired by knocking down of nm23-H1, while stable transfection of nm23-H1 attenuated hypoxia phonotype induced by lithium chloride (LiCl). Generally, our experiment provided evidence that nm23-H1 can reverse hypoxia induced EMT and stemness through the inhibition of the Wnt/β-catenin pathway, which may furnish a deeper perspective into the better treatment or prognosis for NSCLC.
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Shen, Yehua, Litao Xu, Zhouyu Ning, Luming Liu, Junhua Lin, Hao Chen, and Zhiqiang Meng. "ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/β-catenin signaling pathway." Carcinogenesis 40, no. 11 (April 8, 2019): 1405–14. http://dx.doi.org/10.1093/carcin/bgz067.

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Abstract β-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where β-catenin is bound, negatively regulating β-catenin activation. However, the regulation of HDAC2/β-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the β-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits β-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/β-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/β-catenin pathway with a critical role in tumorigenesis.
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Fue, Misaki, Yasuhiro Miki, Kiyoshi Takagi, Chiaki Hashimoto, Nobuo Yaegashi, Takashi Suzuki, and Kiyoshi Ito. "Relaxin 2/RXFP1 Signaling Induces Cell Invasion via the β-Catenin Pathway in Endometrial Cancer." International Journal of Molecular Sciences 19, no. 8 (August 18, 2018): 2438. http://dx.doi.org/10.3390/ijms19082438.

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Relaxin is known to play an important role in animal pregnancies, including those of humans. It is suggested that relaxin induces aggressive cell growth and invasiveness in several types of cancer, including endometrial cancer. However, the mechanisms of relaxin remain largely unclear. In this study, we examined the effects of relaxin 2 (RLN2), the major circulating relaxin in humans, on human endometrial carcinoma cell lines. RLN2 treatment induced invasion in HEC-1B and Ishikawa cells. RLN2-induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs. The β-catenin inhibitor, XAV939, also significantly inhibited the RLN2-induced cell invasions. Both a decrease of cadherin expression and an increase of β-catenin phosphorylation were observed in response to the RLN2 treatment in HEC-1B and Ishikawa cells. We then examined RLN2 and RXFP1 expression in 80 human endometrioid endometrial carcinoma tissues. RLN2 immunoreactivity was detected in the human endometrial carcinoma cells and had a correlative tendency with histological grade and RXFP1. These results suggest that adherens junctions in cancer cells are weakened by the breakdown of the cadherin/catenin complex, which is induced by β-catenin phosphorylation via RLN2/RXFP1 signaling.
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Leigh, Robert S., Heikki J. Ruskoaho, and Bogac L. Kaynak. "A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior–posterior patterning of the heart." Archives of Toxicology 94, no. 2 (December 6, 2019): 631–45. http://dx.doi.org/10.1007/s00204-019-02632-1.

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AbstractReliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse embryonic stem cells (mESCs) to predict in vivo developmental toxicity, but does not take into account the stage-specific patterning of progenitor populations into anterior (ventricular) and posterior (atrial) compartments. In this study, we generated a novel dual reporter mESC line with fluorescent reporters under the control of anterior and posterior cardiac promoters. Reporter expression was observed in nascent compartments in transgenic mouse embryos, and mESCs were used to develop differentiation assays in which chemical modulators of Wnt (XAV939: 3, 10 µM), retinoic acid (all-trans retinoic acid: 0.1, 1, 10 µM; 9-cis retinoic acid: 0.1, 1, 10 µM; bexarotene 0.1, 1, 10 µM), and Tgf-β (SB431542: 3, 10 µM) pathways were tested for stage- and dose-dependent effects on in vitro anterior–posterior patterning. Our results suggest that with further development, the inclusion of anterior–posterior reporter expression could be part of a battery of high-throughput tests used to identify and characterize teratogens.
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Salcius, Michael, Andras J. Bauer, Qin Hao, Shu Li, Antonin Tutter, Jacob Raphael, Wolfgang Jahnke, et al. "SEC-TID." Journal of Biomolecular Screening 19, no. 6 (February 19, 2014): 917–27. http://dx.doi.org/10.1177/1087057114522691.

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Bioactive small molecules are an invaluable source of therapeutics and chemical probes for exploring biological pathways. Yet, significant hurdles in drug discovery often come from lacking a comprehensive view of the target(s) for both early tool molecules and even late-stage drugs. To address this challenge, a method is provided that allows for assessing the interactions of small molecules with thousands of targets without any need to modify the small molecule of interest or attach any component to a surface. We describe size-exclusion chromatography for target identification (SEC-TID), a method for accurately and reproducibly detecting ligand-macromolecular interactions for small molecules targeting nucleic acid and several protein classes. We report the use of SEC-TID, with a library consisting of approximately 1000 purified proteins derived from the protein databank (PDB), to identify the efficacy targets tankyrase 1 and 2 for the Wnt inhibitor XAV939. In addition, we report novel interactions for the tumor-vascular disrupting agent vadimezan/ASA404 (interacting with farnesyl pyrophosphate synthase) and the diuretic mefruside (interacting with carbonic anhydrase XIII). We believe this method can dramatically enhance our understanding of the mechanism of action and potential liabilities for small molecules in drug discovery pipelines through comprehensive profiling of candidate druggable targets.
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Han, Donghe, Shurui Chen, Shiqiang Fang, Shiqiong Liu, Meihua Jin, Zhanpeng Guo, Yajiang Yuan, Yansong Wang, Chang Liu, and Xifan Mei. "The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model." BioMed Research International 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/1972608.

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Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs’ transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I andβ-catenin were enhanced in the MNT group, while XAV939 (aβ-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF andβ-catenin could contribute to MDSCs’ effects.
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Iwatani, Sota, Akemi Shono, Makiko Yoshida, Keiji Yamana, Khin Kyae Mon Thwin, Jumpei Kuroda, Daisuke Kurokawa, et al. "Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation." Stem Cells International 2017 (2017): 1–16. http://dx.doi.org/10.1155/2017/8749751.

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Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation.
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Willems, Leen, Annick Daniëls, Yanick Fanton, Loes Linsen, Lize Evens, Virginie Bito, Jeroen Declercq, Jean-Luc Rummens, Karen Hensen, and Marc Hendrikx. "Differentiation of Human Cardiac Atrial Appendage Stem Cells into Adult Cardiomyocytes: A Role for the Wnt Pathway?" International Journal of Molecular Sciences 21, no. 11 (May 30, 2020): 3931. http://dx.doi.org/10.3390/ijms21113931.

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Human cardiac stem cells isolated from atrial appendages based on aldehyde dehydrogenase activity (CASCs) can be expanded in vitro and differentiate into mature cardiomyocytes. In this study, we assess whether Wnt activation stimulates human CASC proliferation, whereas Wnt inhibition induces cardiac maturation. CASCs were cultured as described before. Conventional PCR confirmed the presence of the Frizzled receptors. Small-molecule inhibitors (IWP2, C59, XAV939, and IWR1-endo) and activator (CHIR99021) of the Wnt/β -catenin signaling pathway were applied, and the effect on β-catenin and target genes for proliferation and differentiation was assessed by Western blot and RT-qPCR. CASCs express multiple early cardiac differentiation markers and are committed toward myocardial differentiation. They express several Frizzled receptors, suggesting a role for Wnt signaling in clonogenicity, proliferation, and differentiation. Wnt activation increases total and active β-catenin levels. However, this does not affect CASC proliferation or clonogenicity. Wnt inhibition upregulated early cardiac markers but could not induce mature myocardial differentiation. When CASCs are committed toward myocardial differentiation, the Wnt pathway is active and can be modulated. However, despite its role in cardiogenesis and myocardial differentiation of pluripotent stem-cell populations, our data indicate that Wnt signaling has limited effects on CASC clonogenicity, proliferation, and differentiation.
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Jeong, Myong-Ho, Hyun-Ji Kim, Jung-Hoon Pyun, Kyu-Sil Choi, Dong I. Lee, Soroosh Solhjoo, Brian O'Rourke, et al. "Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling." Proceedings of the National Academy of Sciences 114, no. 8 (February 2, 2017): E1345—E1354. http://dx.doi.org/10.1073/pnas.1615105114.

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On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon−/−hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon−/−hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon−/−cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon−/−hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.
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Xiao, Yao, Thiago F. Amaral, Pablo J. Ross, Delia A. Soto, Kenneth E. Diffenderfer, Aimee R. Pankonin, Surawich Jeensuk, Paula Tríbulo, and Peter J. Hansen. "Importance of WNT-dependent signaling for derivation and maintenance of primed pluripotent bovine embryonic stem cells." Biology of Reproduction 105, no. 1 (April 23, 2021): 52–63. http://dx.doi.org/10.1093/biolre/ioab075.

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Abstract The WNT signaling system plays an important but paradoxical role in the regulation of pluripotency. In the cow, IWR-1, which inhibits canonical WNT activation and has WNT-independent actions, promotes the derivation of primed pluripotent embryonic stem cells from the blastocyst. Here, we describe a series of experiments to determine whether derivation of embryonic stem cells could be generated by replacing IWR-1 with other inhibitors of WNT signaling. Results confirm the importance of inhibition of canonical WNT signaling for the establishment of pluripotent embryonic stem cells in cattle and indicate that the actions of IWR-1 can be mimicked by the WNT secretion inhibitor IWP2 but not by the tankyrase inhibitor XAV939 or WNT inhibitory protein dickkopf 1. The role of Janus kinase-mediated signaling pathways for the maintenance of pluripotency of embryonic stem cells was also evaluated. Maintenance of pluripotency of embryonic stem cells lines was blocked by a broad inhibitor of Janus kinase, even though the cells did not express phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Further studies with blastocysts indicated that IWR-1 blocks the activation of pSTAT3. A likely explanation is that IWR-1 blocks differentiation of embryonic stem cells into a pSTAT3+ lineage. In conclusion, results presented here indicate the importance of inhibition of WNT signaling for the derivation of pluripotent bovine embryonic stem cells, the role of Janus kinase signaling for maintenance of pluripotency, and the participation of IWR-1 in the inhibition of activation of STAT3.
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Urushihara, Maki, Shuji Kondo, Yukiko Kinoshita, Natsuko Ozaki, Ariunbold Jamba, Takashi Nagai, Keisuke Fujioka, Tomoki Hattori, and Shoji Kagami. "(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis." American Journal of Physiology-Renal Physiology 319, no. 4 (October 1, 2020): F571—F578. http://dx.doi.org/10.1152/ajprenal.00250.2020.

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(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.
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Zhang, Ye, Dan Zhao, Xutong Li, Beiyao Gao, Chengcheng Sun, Shaoting Zhou, Yanhong Ma, Xuemei Chen, and Dongsheng Xu. "The Wnt/β-Catenin Pathway Regulated Cytokines for Pathological Neuropathic Pain in Chronic Compression of Dorsal Root Ganglion Model." Neural Plasticity 2021 (April 19, 2021): 1–10. http://dx.doi.org/10.1155/2021/6680192.

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Neuropathic pain is one of the important challenges in the clinic. Although a lot of research has been done on neuropathic pain (NP), the molecular mechanism is still elusive. We aimed to investigate whether the Wnt/β-catenin pathway was involved in NP caused by sustaining dorsal root ganglion (DRG) compression with the chronic compression of dorsal root ganglion model (CCD). Our RNA sequencing results showed that several genes related to the Wnt pathway have changed in DRG and spinal cord dorsal horn (SCDH) after CCD surgery. Therefore, we detected the activation of the Wnt/β-catenin pathway in DRG and SCDH and found active β-catenin significantly upregulated in DRG and SCDH 1 day after CCD surgery and peaked on days 7-14. Immunofluorescence results also confirmed nuclear translocalization of active β-catenin in DRG and SCDH. Additionally, rats had obvious mechanical induced pain after CCD surgery and the pain was significantly alleviated after the application of the Wnt/β-catenin pathway inhibitor XAV939. Furthermore, we found that the levels of proinflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were significantly elevated in CCD rat serum, while the levels of them were correspondingly decreased after the Wnt/β-catenin pathway being inhibited. The results of Spearman correlation coefficient analysis showed that the levels of TNF-α and IL-18 were negatively correlated with the mechanical withdrawal thresholds (MWT) after CCD surgery. Collectively, our findings suggest that the Wnt/β-catenin pathway plays a critical role in the pathogenesis of NP and may be an effective target for the treatment of NP.
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Tanioka, Motomasa, Wyun Kon Park, Joohyun Park, Jong Eun Lee, and Bae Hwan Lee. "Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke." International Journal of Molecular Sciences 21, no. 19 (October 6, 2020): 7373. http://dx.doi.org/10.3390/ijms21197373.

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Stroke is a life-threatening condition that leads to the death of many people around the world. Reperfusion injury after ischemic stroke is a recurrent problem associated with various surgical procedures that involve the removal of blockages in the brain arteries. Lipid emulsion was recently shown to attenuate ischemic reperfusion injury in the heart and to protect the brain from excitotoxicity. However, investigations on the protective mechanisms of lipid emulsion against ischemia in the brain are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of ischemic reperfusion injury through middle cerebral artery occlusion (MCAO). Under sodium pentobarbital anesthesia, rats were subjected to MCAO surgery and were administered with lipid emulsion through intra-arterial injection during reperfusion. The experimental animals were assessed for neurological deficit wherein the brains were extracted at 24 h after reperfusion for triphenyltetrazolium chloride staining, immunoblotting and qPCR. Neuroprotection was found to be dosage-dependent and the rats treated with 20% lipid emulsion had significantly decreased infarction volumes and lower Bederson scores. Phosphorylation of Akt and glycogen synthase kinase 3-β (GSK3-β) were increased in the 20% lipid-emulsion treated group. The Wnt-associated signals showed a marked increase with a concomitant decrease in signals of inflammatory markers in the group treated with 20% lipid emulsion. The protective effects of lipid emulsion and survival-related expression of genes such as Akt, GSK-3β, Wnt1 and β-catenin were reversed by the intra-peritoneal administration of XAV939 through the inhibition of the Wnt/β-catenin signaling pathway. These results suggest that lipid emulsion has neuroprotective effects against ischemic reperfusion injury in the brain through the modulation of the Wnt signaling pathway and may provide potential insights for the development of therapeutic targets.
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Ahmed, Ishfaq, Badal Chandra Roy, Laxmi Uma Maheswar Rao Jakkula, Dharmalingam Subramaniam, Prasad Dandawate, Shrikant Anant, Venkatesh Sampath, and Shahid Umar. "Infection-induced signals generated at the plasma membrane epigenetically regulate Wnt signaling in vitro and in vivo." Journal of Biological Chemistry 295, no. 4 (December 13, 2019): 1021–35. http://dx.doi.org/10.1074/jbc.ra119.010285.

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Wnt signaling regulates immunomodulatory functions during infection and inflammation. Employing NCCIT and HCT116 cells, having high endogenous Wnt signaling, we observed elevated levels of low-density lipoprotein receptor–related protein 5/6 (LRP5/6) and Frizzled class receptor 10 (FZD10) and increases in β-catenin, doublecortin-like kinase 1 (DCLK1), CD44 molecule (CD44), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). siRNA-induced knockdown of these receptors antagonized TOPflash reporter activity and spheroid growth in vitro and elevated Wnt-inhibitory factor 1 (WIF1) activity. Elevated mRNA and protein levels of LRP5/6 and FZD10 paralleled expression of WNT2b and WNT4 in colonic crypts at days 6 and 12 post-infection with Citrobacter rodentium (CR) and tended to decline at days 20–34. The CR mutant escV or the tankyrase inhibitor XAV939 attenuated these responses. A three-dimensional organoid assay in colonic crypts isolated from CR-infected mice revealed elevated levels of LRP5/6 and FZD10 and β-catenin co-localization with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). Co-immunoprecipitation in the membrane fraction revealed that axin associates with LRP5/6 in CR-infected crypts, and this association was correlated with increased β-catenin. Colon tumors from either CR-infected ApcPMin/+ or azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice had high LRP5/6 or FZD10 levels, and chronic Notch blockade through the γ-secretase inhibitor dibenzazepine down-regulated LRP5/6 and FZD10 expression. In CR-responsive CT-26 cells, siRNA-induced LRP5/6 or FZD10 knockdown antagonized TOPflash reporter activity. Elevated miR-153-3p levels correlated with LRP5/6 and FZD10, and miR-153-3p sequestration via a plasmid-based miR inhibitor system attenuated Wnt signaling. We conclude that infection-induced signals from the plasma membrane epigenetically regulate Wnt signaling.
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34

Zhao, J. W., S. C. Dyson, C. Kriegel, P. Tyers, X. He, T. M. Fahmy, S. M. Metcalfe, and R. A. Barker. "Modelling of a targeted nanotherapeutic 'stroma' to deliver the cytokine LIF, or XAV939, a potent inhibitor of Wnt- -catenin signalling, for use in human fetal dopaminergic grafts in Parkinson's disease." Disease Models & Mechanisms 7, no. 10 (August 1, 2014): 1193–203. http://dx.doi.org/10.1242/dmm.015859.

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35

Ganis, Jared J., Elizabeth B. Riley, James Palis, and Leonard I. Zon. "A Screen for Regulators of Globin Switching in the Zebrafish Embryo." Blood 120, no. 21 (November 16, 2012): 826. http://dx.doi.org/10.1182/blood.v120.21.826.826.

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Abstract Abstract 826 The switching of the globin genes involves critical transcriptional regulators such as BCL11A, EKLF and SOX6, and the induction of fetal globin has been shown to ameliorate the symptoms of diseases such as sickle cell anemia. Recently, there has been interest in driving iPS cells to produce mature red cells that express adult globin genes in an attempt to make these cells therapeutically useful. Here, to understand hemoglobin switching and the molecular pathways that allow the establishment of an adult fate in embryonic tissues, we utilized a screening approach in the zebrafish model. The concept of the screen is to find transcription factors that are expressed in a stage-specific manner, and manipulate the expression of these genes to alter the cell fate of embryonic erythroid cells. In order to generate a candidate list of genes, microarray analysis was performed on murine yolk sac, fetal liver and adult derived red blood cells and red blood cell precursors, which express unique sets of globin genes. Pair-wise comparison of these populations yielded 879 unique differentially regulated genes. GO term analysis was used to narrow the list to 49 transcription factors. We focused on the transcription factors that might increase adult globin expression in the embryo based on their differential expression in the microarrays. Morpholinos were used to knock down these 24 genes by individually injecting each into one-cell stage embryos, allowing the embryos to reach 24 hpf and performing in situ hybridization for the adult globin gene αa1. The number of adult globin positive cells present in each embryo was counted for a clutch control group, which on average has 2–4 positive cells per embryo, and three doses of morpholino. We identified 4 genes, Tcf7l2, Ncoa1, Hif1al and E2F5, the knock down of which results in a significant increase in the number of adult globin positive cells in at least one dose of morpholino (control [n=53, mean=6.34], 6ng [n=56, mean=15.07], p=<0.0001; control [n=35, mean=1.543], 4ng [n=56, mean=2.75], p=<0.01; control [n=19, mean=1.368], 12ng [n=16, mean=6.188], p=<0.0001; control [n=44, mean=1.091], 4ng [n=30, mean=2.7], p=<0.05, respectively). Pair-wise knock down of these genes were also tested, and the combinations of Ncoa1 and E2F5, Tcf7l2 and E2F5 and Tcf7l2 and Ncoa1 were found to synergistically increase the number of adult globin expressing cells (control [n=49, mean=0.5306], knock down [n=38, mean=9.895], p=<0.0001; control [n=49, mean=7.633], knock down [n=54, mean=17.41], p=<0.0001; control [n=20, mean=2.95], knock down [n=28, mean=too numerous to count], p=<0.0001, respectively). The combined knock down of Tcf7l2 and Ncoa1 was both the strongest inducer of adult globin expression and had the lowest toxicity of the pair-wise combinations. Further characterization of this phenotype shows that, while many globin genes are up regulated, both of the adult globin genes, αa1 and βa1, are upregulated to a higher degree than other globin genes. In order to determine if the Wnt pathway is responsible for phenotype observed with the Tcf7l2 morpholino, we tested the Wnt pathway inhibitors IWR1 and XAV939. Both drugs phenocopied the Tcf7l2 knockdown response. In addition, XAV939 synergies with the Ncoa1 morpholino to enhance the increase in adult globin observed in a similar manner to Tcf7l2 knockdown. These results indicate that modulation of Wnt signaling, rather than a Wnt-independent function of Tcf7l2, is responsible for the phenotype and regulation of globin gene expression. Chip-Seq analysis of Ncoa1 occupancy in the erythroid cell line K562 was performed to examine potential mechanisms of action. Significant binding was observed at the enhancers of the α- and β-globin loci, indicating that the nuclear hormone receptor pathway may be acting directly on the globin loci to modulate globin expression patterns. These results indicate that Wnt signaling in combination with alterations of other pathways regulated by Ncoa1 are responsible for stage-specific globin expression. Our studies have impact on the understanding of globin switching in vertebrates, and could establish new methods to activate specific globins clinically, and to make iPS cells form adult-type tissues. Disclosures: Zon: Fate Therapeutics: Founder Other.
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36

Guo, Chun, Rui-Juan Yang, Ke Jang, Xiao-ling Zhou, and Yu-zhen Liu. "Protective Effects of Pretreatment with Quercetin Against Lipopolysaccharide-Induced Apoptosis and the Inhibition of Osteoblast Differentiation via the MAPK and Wnt/β-Catenin Pathways in MC3T3-E1 Cells." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1547–61. http://dx.doi.org/10.1159/000481978.

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Background/Aims: Quercetin, a flavonoid found in onions and other vegetables, has potential inhibitory effects on bone resorption in vivo and in vitro. In our previous study, we found that quercetin treatment reversed lipopolysaccharide (LPS)-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase (MAPK) pathway in MC3T3-E1 cells. In this study, we investigated the underlying mechanisms of pretreatment with quercetin on apoptosis and the inhibition of osteoblast differentiation in MC3T3-E1 cells induced by LPS. Methods: MC3T3-E1 osteoblasts were treated with quercetin for 2 h; cells were then incubated with LPS in the presence of quercetin for the indicated times. Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis was evaluated using Hoechst 33258 staining. The mRNA expression levels of osteoblast-specific genes, Bax and caspase-3 were determined by real-time quantitative polymerase chain reaction (qPCR). Protein levels of osteoblast-specific genes, caspase-3, Bax, cytochrome c, Bcl-2, Bcl-XL, phosphorylated MAPKs and Wnt/β-catenin were measured using Western blot assays. The MAPK and Wnt/β-catenin signalling pathways were blocked prior to pretreatment with quercetin. Results: Pretreatment with quercetin significantly restored LPS-suppressed bone mineralization and the mRNA and protein expression levels of osteoblast-specific genes such as Osterix (OSX), runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OCN) in a dose-dependent manner. Pretreatment with quercetin also inhibited osteoblast apoptosis, significantly restored the down-regulated expression of Bcl-2 and Bcl-XL and decreased the upregulated expression of caspase-3, Bax, and cytochrome c in MC3T3-E1 cells induced by LPS. Furthermore, pretreatment with quercetin not only decreased the abundance of phosphorylated p38 MAPK and increased the abundance of phosphorylated extracellular signal regulated kinase (ERK), but also triggered the Wnt/β-catenin pathway through enhancing expression of Wnt3 and β-catenin. Pretreatment with MAPK inhibitors or the Wnt/β-catenin inhibitor XAV939 blocked the protective effects of quercetin against LPS-induced apoptosis and the inhibition of osteoblast differentiation. Conclusions: Our findings suggest that pretreatment with quercetin may be a potential drug for preventing abnormal human bone loss induced by LPS in bacteria-induced bone diseases.
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37

Lafon Hughes, Laura I., Carlos J. Romeo Cardeillac, Karina B. Cal Castillo, Salomé C. Vilchez Larrea, José R. Sotelo Sosa, Gustavo A. Folle Ungo, Silvia H. Fernández Villamil, and Alejandra E. Kun González. "Poly(ADP-ribosylation) is present in murine sciatic nerve fibers and is altered in a Charcot-Marie-Tooth-1E neurodegenerative model." PeerJ 5 (May 10, 2017): e3318. http://dx.doi.org/10.7717/peerj.3318.

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BackgroundPoly-ADP-ribose (PAR) is a polymer synthesized by poly-ADP-ribose polymerases (PARPs) as a postranslational protein modification and catabolized mainly by poly-ADP-ribose glycohydrolase (PARG). In spite of the existence of cytoplasmic PARPs and PARG, research has been focused on nuclear PARPs and PAR, demonstrating roles in the maintenance of chromatin architecture and the participation in DNA damage responses and transcriptional regulation. We have recently detected non-nuclear PAR structurally and functionally associated to the E-cadherin richzonula adherensand the actin cytoskeleton of VERO epithelial cells. Myelinating Schwann cells (SC) are stabilized by E-cadherin rich autotypicadherens junctions (AJ). We wondered whether PAR would map to these regions. Besides, we have demonstrated an altered microfilament pattern in peripheral nerves of Trembler-J (Tr-J) model of CMT1-E. We hypothesized that cytoplasmic PAR would accompany such modified F-actin pattern.MethodsWild-type (WT) and Tr-J mice sciatic nerves cryosections were subjected to immunohistofluorescence with anti-PAR antibodies (including antibody validation), F-actin detection with a phalloidin probe and DAPI/DNA counterstaining. Confocal image stacks were subjected to a colocalization highlighter and to semi-quantitative image analysis.ResultsWe have shown for the first time the presence of PAR in sciatic nerves. Cytoplasmic PAR colocalized with F-actin at non-compact myelin regions in WT nerves. Moreover, in Tr-J, cytoplasmic PAR was augmented in close correlation with actin. In addition, nuclear PAR was detected in WT SC and was moderately increased in Tr-J SC.DiscussionThe presence of PAR associated to non-compact myelin regions (which constitute E-cadherin rich autotypicAJ/actin anchorage regions) and the co-alterations experienced by PAR and the actin cytoskeleton in epithelium and nerves, suggest that PAR may be a constitutive component ofAJ/actin anchorage regions. Is PAR stabilizing theAJ-actin complexes? This question has strong implications in structural cell biology and cell signaling networks. Moreover, if PAR played a stabilizing role, such stabilization could participate in the physiological control of axonal branching. PARP and PAR alterations exist in several neurodegenerative pathologies including Alzheimer’s, Parkinson’s and Hungtington’s diseases. Conversely, PARP inhibition decreases PAR and promotes neurite outgrowth in cortical neuronsin vitro. Coherently, the PARP inhibitor XAV939 improves myelinationin vitro,ex vivoandin vivo. Until now such results have been interpreted in terms of nuclear PARP activity. Our results indicate for the first time the presence of PARylation in peripheral nerve fibers, in a healthy environment. Besides, we have evidenced a PARylation increase in Tr-J, suggesting that the involvement of cytoplasmic PARPs and PARylation in normal and neurodegenerative conditions should be re-evaluated.
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38

Chien, Sylvia, Siraj U. Haq, Matthew Pawlus, Randall T. Moon, Elihu H. Estey, Frederick R. Appelbaum, Megan Othus, John L. Magnani, and Pamela S. Becker. "Adhesion Of Acute Myeloid Leukemia Blasts To E-Selectin In The Vascular Niche Enhances Their Survival By Mechanisms Such As Wnt Activation." Blood 122, no. 21 (November 15, 2013): 61. http://dx.doi.org/10.1182/blood.v122.21.61.61.

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Abstract Background Adhesion within the bone marrow microenvironment enhances leukemia survival and chemoresistance. Both normal hematopoietic stem cells and cancer cells are known to express E-selectin ligands, and adhesion of colon carcinoma cells to E selectin activates survival pathways such as NFκB (Porquet et al., BMC Cancer 11:285, 2011). E-selectin within the bone marrow vascular niche induces proliferation of normal hematopoietic stem cells (HSC), and a selectin inhibitor enhances HSC quiescence and self-renewal (Winkler et al., Nat Med 18:1651, 2012). We therefore initiated a study of E-selectin ligand expression and function by acute myeloid leukemia (AML) blasts to elucidate the potential role of E-selectin in AML biology and chemotherapy resistance. Methods Primary AML blasts and leukemia stem cells (LSCs) (CD34+CD38-CD123+) obtained with informed consent from 40 patients were analyzed for E-selectin ligands by flow cytometry for binding of E-selectin-Fc chimera or by labeling with the HECA452 antibody. Primary AML blasts were engrafted in NODscid IL2Rgc-/- mice for studies of E-selectin inhibitors in combination with chemotherapy. Human Stem Cell Signaling, Leukemia, Apoptosis, and NFκB PCR Arrays (SA Biosciences) were used to analyze gene expression by quantitative RT-PCR after adhesion of primary AML patient blasts to E-selectin coated plates, compared to bovine serum albumin (BSA) coated plates. The activation of the Wnt pathway was studied by luciferase reporter assay. Results We find that the majority of primary patient acute myeloid leukemia blasts and leukemia stem cells express an E-selectin ligand, as demonstrated by flow cytometry by binding of E-selectin-Fc chimera and by staining with HECA-452 antibody [that recognizes hematopoietic cell E-/L-selectin ligand (HCELL) and cutaneous lymphocyte antigen (CLA)], as well as by binding to E-selectin coated plates. Flow cytometry analysis reveals that the mean percent binding of E-selectin-Fc chimera is 28% ± 24% (SD) by AML blasts, the mean % staining by the HECA-452 antibody 51% ± 35% (SD). De novo patients tended to have smaller mean fluorescence intensity (MFI) values than relapsed/refractory patients, as follows: for blasts, de novo mean 1441 ± 1127 (SD) vs. relapsed/refractory 4488 ± 4920 (SD) (Wilcoxon p=0.024), and for LSCs, de novo mean 1578 ± 1560 (SD) vs. relapsed/refractory 6601 ± 8498 (SD) (Wilcoxon p=0.061), suggesting upregulation of expression of E-selectin ligand for relapsed as compared to newly diagnosed patients. The specific E-selectin small molecule inhibitor GMI-1271 is able to overcome adhesion mediated chemotherapy resistance of AML in vitro and reduce the leukemia burden of primary AML engrafted NODscid IL2Rgc-/- mice in combination with chemotherapy agents daunorubicin and cytarabine. Addition of GMI1271 to chemotherapy in this xenograft model reduced the spleen burden at 2 weeks post treatment from 17.1 ± 10.4 X 106 hCD45+ cells/spleen to 7.6 ± 5.8 (p=0.04). To assess the molecular mechanism by which adhesion to E-selectin might protect AML blasts, we first screened with quantitative RT-PCR arrays. We found that adhesion to E-selectin caused upregulation of members of the Wnt and sonic hedgehog pathways for primary AML patient blasts grown on E-selectin vs. BSA coated plates, as well as members of other pathways critical to leukemia such as GM-CSF and IL-3 receptors and Fos. We then confirmed adhesion to E-selectin by AML blasts from 4 different patients enhanced activity of Wnt target genes by Wnt reporter assays. The Wnt reporter assay demonstrated 2-3 fold enhanced activity of Wnt target genes for AML blasts on E-selectin as compared to those on BSA, which increased to 3.3-4.5 fold with addition of Wnt3a. The inhibitor GMI-1271 reduced Wnt activity to 1.4-2.5 fold, similar to XAV939, an inhibitor of the Wnt/β catenin pathway that reduced activity to 1.1-1.8 fold. Similar reduction of Wnt pathway gene expression by GMI-1271 was also observed by the quantitative RT-PCR assay. Conclusion These data support a critical role for E-selectin, likely in the vascular bone marrow niche, that promotes survival of AML, that can be targeted with therapeutic intent, and suggests that GMI-1271 should be explored as a treatment for AML in combination with chemotherapy. Disclosures: Chien: GlycoMimetics, Inc.: Research Funding. Haq:GlycoMimetics, Inc.: Research Funding. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Becker:GlycoMimetics, Inc.: Research Funding.
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Riascos-Bernal, Dario F., Jordana N. Gross, Prameladevi Chinnasamy, and Nicholas E. Sibinga. "Abstract 617: Inhibitors of Beta-Catenin Signaling Limit Growth of Vascular Smooth Muscle Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (May 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.617.

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Smooth muscle cell (SMC) growth is essential for artery formation during development and significantly contributes to neointima formation after vascular injury in adulthood. We recently showed, using a tissue-specific deletion and knock-in of mutant alleles, that beta-catenin (b-ctn) signaling function is essential for SMC growth and artery formation; moreover, protein interactions mediated by its C-terminus domain are required for assembly of the arterial wall, while b-ctn N-terminus interactions are dispensable. Inhibitors of b-ctn have been developed, but their effects on vascular SMC growth have not been fully tested. We hypothesize that inhibitors that disrupt protein interactions mediated by the b-ctn C-terminus domain will impair b-ctn signaling and limit growth of vascular SMCs. We evaluated growth of mouse aortic SMCs and human coronary artery SMCs in culture using AlamarBlue after exposure to increasing concentrations (0.01 to 10 micromolar) of several validated b-ctn inhibitors or vehicle control: PKF118-310 (disrupts the b-ctn/TCF interaction), ICG001 (disrupts the b-ctn C-terminus/CBP interaction), XAV939 (promotes the b-ctn destruction complex), and carnosic acid (disrupts the b-ctn N-terminus/BCL9 interaction). We also evaluated the effect of these inhibitors on b-ctn transcriptional activity in SMCs using a TOPflash reporter system. We found that PKF118-310 (p<0.05 vs. vehicle), ICG001 (p<0.05 vs. vehicle), and XAV939 (p<0.05 vs. vehicle), but not carnosic acid, limit mouse (n=16 independent cultures) and human (n=8 independent cultures) SMC growth in a dose-response manner. PKF118-310 exhibited the most potent inhibitory effect. We also found that PKF118-310, ICG001, and XAV939, but not carnosic acid, inhibit b-ctn transcriptional activity in arterial SMCs in culture. In conclusion, pharmacological inhibition of b-ctn signaling, particularly blocking the b-ctn C-terminus output, inhibits growth of vascular SMCs in culture, providing a rationale to test these inhibitors in models of vascular injury as they hold promise as novel therapies for cardiovascular disease.
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Zhang, Wei, Yanwei Zhang, Wensheng Zhou, Fangfei Qian, Minjuan Hu, Ya Chen, Jun Lu, Yuqing Lou, and Baohui Han. "PlGF knockdown attenuates hypoxia-induced stimulation of cell proliferation and glycolysis of lung adenocarcinoma through inhibiting Wnt/β-catenin pathway." Cancer Cell International 21, no. 1 (January 6, 2021). http://dx.doi.org/10.1186/s12935-020-01714-w.

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Abstract Background Angiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis. Here, we aimed to investigate the biological roles of PlGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms. Methods PlGF was knocked down in H358 and H1975 cells by lentiviruses, which were then cultured under hypoxia (90% N2, 5%CO2 and 5%O2) for 24 h. PlGF was overexpressed in PC9 cells treated with XAV939, inhibitor of Wnt/β-catenin signaling pathway. PlGF-silencing H1975 cells were implanted into mice, and tumor xenografts were harvested and analyzed. Results Hypoxia treatment led to up-regulation of PlGF, C-myc, lactate dehydrogenase A (LDHA), and β-catenin, promotion of cell proliferation and glycolysis in H358 and H1975 cells, which were obviously reversed by knocking down PlGF. In tumors, PlGF knockdown significantly prohibited cell proliferation and glycolysis, and decreased expression of C-myc, LDHA, and β-catenin. PlGF overexpression markedly strengthened cell proliferation, which was inhibited by β-catenin knockdown. Consistently, XAV939, inhibitor of Wnt/β-catenin pathway, also inhibited PlGF-induced cell proliferation, glycolysis, and β-catenin expression in PC9 cells. Conclusion PlGF knockdown inhibited the stimulatory effect of hypoxia on cell proliferation and glycolysis of LUAD through deactivating Wnt/β-catenin pathway.
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Telias, Michael, and Dalit Ben-Yosef. "Pharmacological Manipulation of Wnt/β-Catenin Signaling Pathway in Human Neural Precursor Cells Alters Their Differentiation Potential and Neuronal Yield." Frontiers in Molecular Neuroscience 14 (August 4, 2021). http://dx.doi.org/10.3389/fnmol.2021.680018.

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The canonical Wnt/β-catenin pathway is a master-regulator of cell fate during embryonic and adult neurogenesis and is therefore a major pharmacological target in basic and clinical research. Chemical manipulation of Wnt signaling during in vitro neuronal differentiation of stem cells can alter both the quantity and the quality of the derived neurons. Accordingly, the use of Wnt activators and blockers has become an integral part of differentiation protocols applied to stem cells in recent years. Here, we investigated the effects of the glycogen synthase kinase-3β inhibitor CHIR99021, which upregulates β-catenin agonizing Wnt; and the tankyrase-1/2 inhibitor XAV939, which downregulates β-catenin antagonizing Wnt. Both drugs and their potential neurogenic and anti-neurogenic effects were studied using stable lines human neural precursor cells (hNPCs), derived from embryonic stem cells, which can be induced to generate mature neurons by chemically-defined conditions. We found that Wnt-agonism by CHIR99021 promotes induction of neural differentiation, while also reducing cell proliferation and survival. This effect was not synergistic with those of pro-neural growth factors during long-term neuronal differentiation. Conversely, antagonism of Wnt by XAV939 consistently prevented neuronal progression of hNPCs. We show here how these two drugs can be used to manipulate cell fate and how self-renewing hNPCs can be used as reliable human in vitro drug-screening platforms.
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Quan, He, Xiaopeng Dai, Meiyan Liu, Chuanjun Wu, and Dan Wang. "Luteolin supports osteogenic differentiation of human periodontal ligament cells." BMC Oral Health 19, no. 1 (October 26, 2019). http://dx.doi.org/10.1186/s12903-019-0926-y.

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Abstract Background Previous research revealed that luteolin could improve the activation of alkaline phosphatase (ALP) and osteocalcin in mouse osteoblasts. We aimed to determine the effect of luteolin on osteogenic differentiation of periodontal ligament cells (PDLCs). Methods Cultured human PDLCs (HPDLCs) were treated by luteolin at 0.01, 0.1, 1, 10, 100 μmol/L, Wnt/β-catenin pathway inhibitor (XAV939, 5 μmol/L) alone or in combination with 1 μmol/L luteolin. Immunohistochemical staining was performed to ensure cells source. Cell activity and the ability of osteogenic differentiation in HPDLCs were determined by MTT, ALP and Alizarin Red S staining. Real-time Quantitative PCR Detecting System (qPCR) and Western blot were performed to measure the expressions of osteogenic differentiation-related genes such as bone morphogenetic protein 2 (BMP2), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), Osterix (OSX) and Wnt/β-catenin pathway proteins members cyclin D1 and β-catenin. Results Luteolin at concentrations of 0.01, 0.1, 1, 10, 100 μmol/L promoted cell viability, ALP activity and increased calcified nodules content in HPDLCs. The expressions of BMP2, OCN, OSX, RUNX2, β-catenin and cyclin D1 were increased by luteolin at concentrations of 0.01, 0.1, 1 μmol/L, noticeably, 1 μmol/L luteolin produced the strongest effects. In addition, XAV939 inhibited the expressions of calcification and osteogenic differentiation-related genes in HPDLCs, and 1 μmol/L luteolin availably decreased the inhibitory effect. Conclusion 1 μmol/L luteolin accelerated osteogenic differentiation of HPDLCs via activating the Wnt/β-catenin pathway, which could be clinically applied to treat periodontal disease.
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Li, Chong, Xu Zheng, Yanyan Han, Yan Lv, Fu Lan, and Jie Zhao. "XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway." Oncology Letters, April 13, 2018. http://dx.doi.org/10.3892/ol.2018.8491.

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"WNT-targeted compound and phytoestrogen promoted cardiogenic differentiation of human induced pluripotent stem cells (hiPSCs) in vitro." Journal of Men’s Health, 2021, 1. http://dx.doi.org/10.31083/jomh.2021.097.

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Background and objectives: Despite the advances made in the prevention and treatment of cardiovascular diseases (CVD) in the last decade, they are still the leading cause of death in males at the rate of 50% worldwide. Considering the protective role of estrogen to decrease CVD rates in young females, it was suggested that using hormone therapy can be considered to improve heart regeneration. Using in vitro induced pluripotent stem cells (iPSCs) has become one of the most significant tools in CVD treatment in both genders. We design a novel optimal protocol for the differentiation of iPSCs to cardiomyocytes which may be valuable for CVD treatment in men. Methods: Human iPSCs were initially cultivated on mouse embryonic fibroblasts and then, transferred to a specific culture medium for differentiation process. In vitro differentiation of iPSCs into cardiomyocytes was induced at three phases on RPMI-1640 medium including CHIR99021 (5 µM) on days 0–3, BMP4 (20 ng/mL), and bFGF (100 ng/mL) on days 3–5, 10 µM of XAV939 on 6–8, and phytoestrogen + ascorbic acid on days 8–13. Scanning electron microscopy and Real-time PCR using specific primers were applied to confirm produced cardiomyocytes. Results: We found that the simultaneous use of small chemical molecules such as CHIR99021 and XAV 939, growth factors, such as BMP4, bFGF, and herbal-derived phytoestrogen from red clover could efficiently differentiate hiPSCs from the mesoderm and cardiomyocytes after 13 days. Using phytoestrogen increased the induction of cardiac markers including cTnT and GATA-4 in a shorter time; consequently, the proposed formulation has the potential to be used in developing a novel approach for cardiac repair or regeneration. Conclusion: Presented data indicated that the serial use of XAV939 and phytoestrogen at different times and stages can successfully induce cardiogenesis from hiPSCs. Thus, the proposed approach can be used for improved translational strategies for cardiac regeneration with fewer side effects.
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Guo, Wenxuan, Fangzhen Shen, Wenjing Xiao, Jing Chen, and Fei Pan. "Wnt inhibitor XAV939 suppresses the viability of small cell lung cancer NCI‑H446 cells and induces apoptosis." Oncology Letters, September 28, 2017. http://dx.doi.org/10.3892/ol.2017.7100.

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46

Kim, Young Eun, Hyo Jin Jeon, Dahee Kim, Sun Young Lee, Ki Young Kim, Jongki Hong, Pil Jae Maeng, Kwang-Rok Kim, and Dukjin Kang. "Quantitative Proteomic Analysis of 2D and 3D Cultured Colorectal Cancer Cells: Profiling of Tankyrase Inhibitor XAV939-Induced Proteome." Scientific Reports 8, no. 1 (September 5, 2018). http://dx.doi.org/10.1038/s41598-018-31564-6.

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Kim, Dahee, Byumseok Koh, Kwang Kim, Ki Kim, Won Jung, Hi Kim, Sungsub Kim, and Sang Rhee. "Anticancer effect of XAV939 is observed by inhibiting lactose dehydrogenase A in a 3‑dimensional culture of colorectal cancer cells." Oncology Letters, September 5, 2019. http://dx.doi.org/10.3892/ol.2019.10813.

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48

Wu, Zhenyu, Yanli Zhu, Hongli Liu, Gongyan Liu, and Fuchang Li. "Wnt10b promotes hair follicles growth and dermal papilla cells proliferation via Wnt/β-Catenin signaling pathway in Rex rabbits." Bioscience Reports 40, no. 2 (February 2020). http://dx.doi.org/10.1042/bsr20191248.

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Abstract Wnt signaling plays an important role in the growth and development of hair follicles (HFs). Among the signaling molecules, Wnt10b was shown to promote the differentiation of primary skin epithelial cells toward the hair shaft and inner root sheath of the HF cells in mice in vitro. Whisker HFs were isolated from Rex rabbits and cultured in vitro to measure hair shaft growth. Meanwhile, dermal papilla cells (DPCs) were isolated and cultured in vitro. Treatment with AdWnt10b or the Wnt/β-Catenin Pathway inhibitor, XAV939, assessed the DPCs proliferation by CCK-8 assay. And the cell cycle was also analyzed by flow cytometry. We found that Wnt10b could promote elongation of the hair shaft, whereas XAV-939 treatment could eliminated this phenomenon. AdWnt10b treatment promoted the proliferation and induced G1/S transition of DPCs. AdWnt10b stimulation up-regulated β-Catenin protein in DPCs. Inhibition of Wnt/β-Catenin signaling by XAV-939 could decreased the basal and Wnt10b-enhanced proliferation of DPCs. And could also suppress the cell cycle progression in DPCs. In summary, our study demonstrates that Wnt10b could promote HFs growth and proliferation of DPCs via the Wnt/β-Catenin signaling pathway in Rex rabbits.
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Miyazaki, Aya, Asuna Sugimoto, Keigo Yoshizaki, Keita Kawarabayashi, Kokoro Iwata, Rika Kurogoushi, Takamasa Kitamura, et al. "Coordination of WNT signaling and ciliogenesis during odontogenesis by piezo type mechanosensitive ion channel component 1." Scientific Reports 9, no. 1 (October 14, 2019). http://dx.doi.org/10.1038/s41598-019-51381-9.

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Abstract Signal transmission from the mechanical forces to the various intracellular activities is a fundamental process during tissue development. Despite their critical role, the mechanism of mechanical forces in the biological process is poorly understood. In this study, we demonstrated that in the response to hydrostatic pressure (HP), the piezo type mechanosensitive ion channel component 1 (PIEZO1) is a primary mechanosensing receptor for odontoblast differentiation through coordination of the WNT expression and ciliogenesis. In stem cells from human exfoliated deciduous teeth (SHED), HP significantly promoted calcium deposition as well as the expression of odontogenic marker genes, PANX3 and DSPP, and WNT related-genes including WNT5b and WNT16, whereas HP inhibited cell proliferation and enhanced primary cilia expression. WNT signaling inhibitor XAV939 and primary cilia inhibitor chloral hydrate blocked the HP-induced calcium deposition. The PIEZO1 activator Yoda1 inhibited cell proliferation but induced ciliogenesis and WNT16 expression. Interestingly, HP and Yoda1 promoted nuclear translocation of RUNX2, whereas siRNA-mediated silencing of PIEZO1 decreased HP-induced nuclear translocation of RUNX2. Taken together, these results suggest that PIEZO1 functions as a mechanotransducer that connects HP signal to the intracellular signalings during odontoblast differentiation.
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Pan, Fei, Fangzhen Shen, Lijun Yang, Lijian Zhang, Wenxuan Guo, and Jinxin Tian. "Inhibitory effects of XAV939 on the proliferation of small‑cell lung cancer H446 cells and Wnt/β‑catenin signaling pathway in�vitro." Oncology Letters, May 24, 2018. http://dx.doi.org/10.3892/ol.2018.8790.

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