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Gsk3 Inhibitor

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https://www.readbyqxmd.com/read/28625976/a-genome-wide-crispr-screen-identifies-genes-critical-for-resistance-to-flt3-inhibitor-ac220
#1
Panpan Hou, Chao Wu, Yuchen Wang, Rui Qi, Dheeraj Bhavanasi, Zhixiang Zuo, Cedric Dos Santos, Shuliang Chen, Yu Chen, Hong Zheng, Hong Wang, Alexander E Perl, Deyin Guo, Jian Huang
Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD-positive and -negative AML patients and as maintenance therapy...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28606794/antifibrotic-actions-of-peroxisome-proliferator-activated-receptor-%C3%AE-ligands-in-corneal-fibroblasts-are-mediated-by-%C3%AE-catenin-regulated-pathways
#2
Kye-Im Jeon, Richard P Phipps, Patricia J Sime, Krystel R Huxlin
Wound healing after corneal injury typically involves fibrosis, with transforming growth factor β1 (TGF-β1) as one of its strongest mediators. A class of small molecules-peroxisome proliferator-activated receptor γ (PPARγ) ligands-exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPARγ ligands (rosiglitazone, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2) decrease levels of β-catenin...
June 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28602697/gsk3-inhibitor-ar-a014418-promotes-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-and-mtorc2-akt-signaling-pathway
#3
Min Zhang, Ping Zhang, Yunsong Liu, Yongsheng Zhou
Small molecule-based bone tissue engineering is emerging as a promising strategy for bone defects restoration. In this study, we intended to identify the roles and mechanisms of AR-A014418, a highly selective inhibitor of GSK3, on the osteogenic differentiation. We found that AR-A014418 exhibited a dose-dependent effect on osteogenic differentiation of human adipose-derived stem cells (hASCs). hASCs treated with AR-A014418 showed higher activity of ERK and mTORC2/Akt signaling. Administration of ERK inhibitor U0126 or knockdown of RICTOR by siRNA attenuated AR-A014418 induced osteogenic differentiation of hASCs...
June 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28577307/disrupting-interactions-between-%C3%AE-catenin-and-activating-tcfs-reconstitutes-ground-state-pluripotency-in-mouse-embryonic-stem-cells
#4
Abil Saj, Sujash S Chatterjee, Bowen Zhu, Engin Cukuroglu, Tenzin Gocha, Xiaoqian Zhang, Jonathan Göke, Ramanuj DasGupta
The 2i-media, composed of two small molecule inhibitors (PD0325901 and CHIR99021) against MEK and GSK3-kinases, respectively, is known to establish naïve ground state pluripotency in mouse embryonic stem cells (mESCs). These inhibitors block MEK-mediated differentiation, while driving β-catenin dependent de-repression of pluripotency promoting targets. However, accumulating evidence suggest that β-catenin's association with activating TCFs (TCF7 and TCF7L2) can induce expression of several lineage-specific prodifferentiation genes...
June 2, 2017: Stem Cells
https://www.readbyqxmd.com/read/28575156/consequences-of-endogenous-and-exogenous-wnt-signaling-for-development-in-the-preimplantation-bovine-embryo%C3%A2
#5
Paula Tribulo, Beatriz Caetano da Silva Leão, Khoboso C Lehloenya, Gisele Zoccal Mingoti, Peter J Hansen
Although WNT signaling regulates several developmental processes, its specific role during preimplantation development remains unclear. The present aim was to evaluate the consequences of activation and inhibition of β-catenin (CTNNB1) dependent and -independent WNT signaling in the bovine preimplantation embryo. Activation of CTNNB1 mediated WNT signaling by the agonist 2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) and a glycogen synthase kinase 3 (GSK3) inhibitor reduced development to the blastocyst stage...
May 30, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28574599/inhibition-of-glycogen-synthase-kinase-3-beta-gsk3%C3%AE-suppresses-the-progression-of-esophageal-squamous-cell-carcinoma-by-modifying-stat3-activity
#6
Shegan Gao, Shuoguo Li, Xiaoxian Duan, Zhen Gu, Zhikun Ma, Xiang Yuan, Xiaoshan Feng, Huizhi Wang
While GSK3β has been reported to have contrasting effects on the progression of different tumors, its possible functions in esophageal squamous cell carcinoma (ESCC) and the related molecular mechanisms remain unknown. Here, we investigated the expression, function, and molecular mechanism of GSK3β in the development of ESCC in vitro and in vivo. Though the expression of total GSK3β was significantly increased, the phosphorylated (inactivated) form of GSK3β (Ser9) was concurrently decreased in the cancerous tissues of patients with ESCC compared with controls, suggesting that GSK3β activity was enhanced in cancerous tissues...
June 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28566716/glycogen-synthase-kinase-3%C3%AE-inhibitors-prevent-hepatitis-c-virus-release-assembly-through-perturbation-of-lipid-metabolism
#7
Mohammed A Sarhan, Mohamed S Abdel-Hakeem, Andrew L Mason, D Lorne Tyrrell, Michael Houghton
Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-β inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses...
May 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28556462/gsk3-activity-regulates-rhythms-in-hippocampal-clock-gene-expression-and-synaptic-plasticity
#8
Rachel C Besing, Courtney O Rogers, Jodi R Paul, Lauren M Hablitz, Russell L Johnson, Lori L McMahon, Karen L Gamble
Hippocampal rhythms in clock gene expression, enzymatic activity, and long-term potentiation (LTP) are thought to underlie day-night differences in memory acquisition and recall. Glycogen synthase kinase 3-beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region-specific differences over the light-dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP)...
May 27, 2017: Hippocampus
https://www.readbyqxmd.com/read/28546219/inos-derived-nitric-oxide-induces-integrin-linked-kinase-endocytic-lysosome-mediated-degradation-in-the-vascular-endothelium
#9
Paula Reventun, Matilde Alique, Irene Cuadrado, Susana Marquez, Rocio Toro, Carlos Zaragoza, Marta Saura
OBJECTIVE: ILK (integrin-linked kinase) plays a key role in controlling vasomotor tone and is decreased in atherosclerosis. The objective of this study is to test whether nitric oxide (NO) regulates ILK in vascular remodeling. APPROACH AND RESULTS: We found a striking correlation between increased levels of inducible nitric oxide and decreased ILK levels in human atherosclerosis and in a mouse model of vascular remodeling (carotid artery ligation) comparing with inducible NO synthase knockout mice...
May 25, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28545044/differentiation-of-spontaneously-contracting-cardiomyocytes-from-non-virally-reprogrammed-human-amniotic-fluid-stem-cells
#10
Aaron J Velasquez-Mao, Christopher J M Tsao, Madeline N Monroe, Xavier Legras, Beatrice Bissig-Choisat, Karl-Dimiter Bissig, Rodrigo Ruano, Jeffrey G Jacot
Congenital heart defects are the most common birth defect. The limiting factor in tissue engineering repair strategies is an autologous source of functional cardiomyocytes. Amniotic fluid contains an ideal cell source for prenatal harvest and use in correction of congenital heart defects. This study aims to investigate the potential of amniotic fluid-derived stem cells (AFSC) to undergo non-viral reprogramming into induced pluripotent stem cells (iPSC) followed by growth-factor-free differentiation into functional cardiomyocytes...
2017: PloS One
https://www.readbyqxmd.com/read/28504720/a-clinical-drug-library-screen-identifies-clobetasol-propionate-as-an-nrf2-inhibitor-with-potential-therapeutic-efficacy-in-keap1-mutant-lung-cancer
#11
E-J Choi, B-J Jung, S-H Lee, H-S Yoo, E-A Shin, H-J Ko, S Chang, S-Y Kim, S-M Jeon
The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28499784/gsk-3-as-a-novel-prognostic-indicator-in-leukemia
#12
REVIEW
Peter P Ruvolo
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s...
May 8, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28486050/the-cdk4-6-inhibitor-palbociclib-synergizes-with-irinotecan-to-promote-colorectal-cancer-cell-death-under-hypoxia
#13
Jun Zhang, Lanlan Zhou, Shuai Zhao, David T Dicker, Wafik S El-Deiry
Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1α regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3β. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia...
May 9, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28461660/derivation-of-mouse-embryonic-stem-es-cell-lines-using-small-molecule-inhibitors-of-erk-and-gsk3-signaling-2i
#14
Jennifer Nichols, Kenneth Jones
The efficiency of embryonic stem (ES) cell derivation is very high if embryos are incubated, from the eight-cell stage, in the presence of the two inhibitors of signaling via the Erk and Gsk3 pathways (PD0325901 and CHIR99021, respectively, known as "2i"). The success rate may vary, depending on the quality of the embryos and the speed with which they are processed, but it is not unusual to obtain ES cell lines from all embryos allocated to the study, even from the least permissive strains. Furthermore, ES cells can be efficiently obtained from any complex genetic mouse model or for in vitro analysis and additional genetic manipulation in any background of choice...
May 1, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28449557/wnt-and-gsk3-signaling-pathways-in-bipolar-disorder-clinical-and-therapeutic-implications
#15
REVIEW
Ather Muneer
The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses...
May 31, 2017: Clinical Psychopharmacology and Neuroscience: the Official Scientific Journal of the Korean College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28440874/role-of-glycogen-synthase-kinase-3-in-ischemia-induced-blood-brain-barrier-disruption-in-aged-female-rats
#16
Han Xiao, Mingyang Deng, Binbin Yang, Jianguang Tang, Zhiping Hu
Estrogen receptors have protective effects against ischemic brain injury. However, the molecular mechanisms underlying this phenomenon have yet to be well studied. Given that inhibition of glycogen synthase kinase (GSK3) can reduce cerebral ischemia/reperfusion injury, we hypothesized that estrogen receptors-mediated protective effects against ischemia-induced blood brain barrier (BBB) disruption involve inhibition of GSK3. Thus, we evaluated GSK3 expression in the brain of ovariectomized female rats, and examined the effects of intracerebroventricular pre-treatments of SB216763, GSK3 inhibitor, on BBB permeability following middle cerebral artery occlusion (MCAO)...
April 25, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28431241/akt-pkb-signaling-navigating-the-network
#17
REVIEW
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28423582/parthenolide-suppresses-non-small-cell-lung-cancer-glc-82-cells-growth-via-b-raf-mapk-erk-pathway
#18
Minting Lin, Hong Bi, Yanyan Yan, Wenjing Huang, Guiping Zhang, Genshui Zhang, Sili Tang, Yun Liu, Lingling Zhang, Jinxiang Ma, Jianye Zhang
Non-small cell lung cancer (NSCLC), one type of lung cancer, owns high rates of morbidity and mortality. B-Raf is one of the promising oncogenic drivers of NSCLC. Parthenolide, a natural product, is mainly extracted from the herbal plant Tanacetum parthenium. The effect of parthenolide on NSCLC cells and its potential as B-Raf inhibitor were studied in this study. It's shown that parthenolide exhibited the strong cytotoxicity against NSCLC cells with IC50 ranging from 6.07 ± 0.45 to 15.38 ± 1.13 μM. Parthenolide was also able to induce apoptosis, suppress proliferation and invasion in NSCLC cells...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418862/niclosamide-is-a-potential-therapeutic-for-familial-adenomatosis-polyposis-by-disrupting-axin-gsk3-interaction
#19
Sung Yong Ahn, Nam Hee Kim, Kyungro Lee, Yong Hoon Cha, Ji Hye Yang, So Young Cha, Eunae Sandra Cho, Yoonmi Lee, Jeong Seok Cha, Hyun Soo Cho, Yoon Jeon, Young-Su Yuk, Suebean Cho, Kyoung Tai No, Hyun Sil Kim, Ho Lee, Jiwon Choi, Jong In Yook
The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414160/paraquat-induces-extrinsic-pathway-of-apoptosis-in-a549-cells-by-induction-of-dr5-and-repression-of-anti-apoptotic-proteins-ddx3-and-gsk3-expression
#20
Sasiphen Hathaichoti, Daranee Visitnonthachai, Pronrumpa Ngamsiri, Apichaya Niyomchan, Oyu Tsogtbayar, Churaibhon Wisessaowapak, Piyajit Watcharasit, Jutamaad Satayavivad
Paraquat (PQ) is a bipyridyl derivative herbicide known to cause lung toxicity partly through induction of apoptosis. Here we demonstrated that PQ caused apoptosis in A549 cells. PQ increased cleavage of caspase-8 and Bid, indicating caspase-8 activation and truncated Bid, the two key mediators of extrinsic apoptosis. Additionally, PQ treatment caused an increase in DR5 (death receptor-5) and caspase-8 interaction, indicating formation of DISC (death-inducing signaling complex). These results indicate that PQ induces apoptosis through extrinsic pathway in A549 cells...
April 14, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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