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Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Of the MAPKs, ERK1 and 2 (ERK1/2) were the first described in the literature (Boulton and Cobb 1991; Boulton et al. 1991a,b). These have 83% amino acid sequence identity, with a conserved Thr-Glu-Tyr (TEY) phosphorylation activation loop (Yao et al. 2000). Compared with JNK and p38, ERK1/2 responds more favorably to serum, growth factor, or phorbol ester stimulation, as opposed to stress stimuli. However, multiple other stimuli have been identified, including multiple cytokines, osmotic stress, cytoskeletal disruption, and mechanical stimulation. The current model of ERK activation is a kinase cascade initially activated almost always by an extracellular signal from a tyrosine kinase or GPCR that activates the membrane-associated GTPase Ras through interaction with the guanine nucleotide exchange factor SOS (son of sevenless) (Figure 2.20). Changing the Ras-bound GDP to GTP allows Ras to become active and to interact with and activate MAP3K, in this case a Raf family member (A-Raf, B-Raf or Raf-1). Activated Raf then phosphorylates and activates MAPKK Mek (Mek1 and 2) and then MAPK ERK (ERK1 and 2). ERK1/2 can then phosphorylate multiple substrates, including other kinases (MSK1/2 and MNK1/2), transcription factors (Elk1 and SAP1), membrane-bound proteins, nuclear proteins, and cytoskeletal proteins. Commonly, pharmacological inhibition of this pathway targets MEK, with two nonrelated compounds widely used, specifically U0126 and PD98059.
Oncological Applications of MR Spectroscopy
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Marie-France Penet, Kristine Glunde, Michael A. Jacobs, Noriko Mori, Dmitri Artemov, Zaver M. Bhujwalla
1H MRS studies of choline phospholipid metabolism in cancer cells and solid tumors have been complemented by an array of 31P MRS investigations performed in vivo and in vitro (60,114,115). Phospholipid metabolites have been monitored in cancer, using 31P MRS to determine the effects of different treatments and signaling pathways. Mutant ras-oncogene transformation (116), inhibition of hypoxia-inducible factor (HIF)-1 α (117), inhibition of mitogen-activated protein kinase (MAPK) signaling, and inhibition of phosphoinositide 3-kinase (PI3K) signaling have been shown to affect choline phospholipids (118,119). The inhibition of MAPK by the drug U0126 induced a significant drop in PC levels as shown by 31P spectra of cell extracts (119). The inhibition of PI3K with LY294002 induced a decrease in PC and an increase in GPC levels detected in 31P spectra of cell extracts (118). Several other drugs such as microtubule inhibitors (120), indomethacin, a nonsteroidal anti-inflammatory agent (121,122), and docetaxel have resulted in a decrease of PC. These data support the use of PC as a biomarker to detect the therapeutic response to several agents. Docetaxel has been tested both in MCF-7 and MDA-MB-231 cells and tumors (123). In vivo 31P spectra acquired on MCF-7 tumor before and after two days of treatment are presented in Figure 8 and demonstrated a reduction in PC levels with docetaxel treatment (123).
Molecular Targets Other than BCR-ABL: How to Incorporate them into the CML Therapy?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
V. Melo Junia, J. Barnes David
Downstream of Ras, Raf-1 activates the MAPK kinases, MEK1/2 (MAPK or ERK Kinase). MEK1/2 are dual specificity kinases, which in turn, activate Extracellular signal-Regulated Kinase 1/2 (ERK1/2). Several MEK1/2 inhibitors have been developed, including PD098059 (26), PD184352 (27) (Parke-Davis, Ann Arbor, Michigan, U.S.A.), and U0126 (28) (DuPont Merck, Wilmington, Delaware, U.S.A.). In vitro treatment of a CML cell line with PD098059 induced apoptosis (26) and PD184352, PD098059 or U0126, when combined with imatinib, caused synergistic induction of apoptosis in CML cell lines (27). Similarly, U0126 combined with imatinib was shown to significantly inhibit proliferation of CML CD34+ progenitor cells (28). In addition, the combination of PD184352 and imatinib effectively induced cell death in an imatinib-resistant cell line, which overexpressed Bcr-Abl (27). Recently, a synergistic increase in mitochondrial damage, caspase activation, and apoptosis was demonstrated in CML cell lines and CML CD34+ progenitors that were treated with the combinations of MEK1/2 inhibitors (PD184352 and U0126) and histone deacetylase inhibitors (suberanoylanilide hydroxamic acid and sodium butyrate) (29). At present, data on these compounds is limited to their activity in vitro. It remains to be seen whether MEK inhibitors will show efficacy in vivo. In addition, it should be borne in mind that MEK signaling is essential for normal cell physiology and that blocking these signals may result in unwanted toxic side-effects. These may limit the clinical usefulness of MEK inhibitors for the molecular therapy of CML.
Liraglutide Up-regulation Thioredoxin Attenuated Müller Cells Apoptosis in High Glucose by Regulating Oxidative Stress and Endoplasmic Reticulum Stress
Published in Current Eye Research, 2020
Xiang Ren, Lingmin Sun, Limin Wei, Junli Liu, Jiaxu Zhu, Quanquan Yu, Hui Kong, Li Kong
The Müller cell obtained from the college of basic medical science of Sun Yat-sen University (GuangZhou, China).29 The cells were maintained in DMEM medium (Gibco, Invitrogen, CA) with 10% fetal bovine serum (FBS, Gibco) at 37°C in a humid atmosphere containing 5% CO2. The medium was replaced every 1 or 2 days. When the cells grew to logarithmic growth, they were washed 2–3 times with PBS according to the cell growth state and digested with Trypsin-EDTA containing 0.25% for cell passage. The concentration of HG medium was 200 mmol/L for storage at 4°C. LIRA (Novo Nordisk®, Denmark) was dissolved at 1 μl/L in the DMEM medium without FBS and stored at 4°C. U0126 (Biouniquer, Nanjing, China) was dissolved in 10 mM dimethyl sulfoxide (DMSO, Sigma) for storage at −20°C. The cells were treated with a concentration of HG (50 mM) for 48 h. The cells were treated with HG (50 mM) with/without LIRA (100 nM) and U0126 in the following experiments in vitro.
Synergistic effects of a cremophor EL drug delivery system and its U0126 cargo in an ex vivo model
Published in Drug Delivery, 2019
S. T. Christensen, A. S. Grell, S. E. Johansson, C. M. Andersson, L. Edvinsson, K. A. Haanes
U0126 is an inhibitor of the MAPK/ERK kinase (MEK1/2), which is part of the mitogen-activated protein kinase (MAPK) pathway. U0126 is a specific inhibitor of phosphorylation by MEK1 and MEK2 at IC50 0.07 µM and 0.06 µM, respectively (Duncia et al., 1998; Wityak et al., 2004). The activation of the MAPK pathway in cerebrovascular tissue results in enhanced expression of contractile receptors, such as endothelin type B (ETB), 5-hydroxytryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1), and thromboxane A2 (TXA2) in the cerebral arteries (Hansen-Schwartz et al., 2003a,b; Ansar et al., 2007; 2010), as well as in intraparenchymal micro-vessels (Spray et al., 2017). Sarafotoxin (S6c), a highly specific agonist (10,000 fold selective for ETB over ETA), has been proven a particularly useful tool in regards to investigating the ETB receptors (Davenport et al., 2016). Timely treatment with U0126 prevents the upregulation of these vasoactive elements, which are believed to have a key function in the debilitating secondary cerebral vasospasm and delayed cerebral ischemia observed after subarachnoid hemorrhage (SAH) (Edvinsson et al., 2014; Macdonald, 2014; Christensen et al., 2019). It has previously been shown with western blot that an increase in contractile responses to the ETB agonist S6c coincided with an increase in ETB protein both ex vivo (Li et al., 2012) and in vivo (Povlsen et al., 2013).
The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function
Published in Experimental Lung Research, 2023
Katherine M. DiGuilio, Elizabeth Rybakovsky, Yoongyeong Baek, Mary Carmen Valenzano, James M. Mullin
The role of the ERK signaling pathway in the regulation of Calu-3 barrier function and the TNF-α induced compromise of that barrier function can be seen first in the effect of the ERK inhibitor, U0126, on dome frequency and size. As shown in Figure 6, U0126 treatment causes a substantial increase in dome size and number suggesting that ERK signaling may lead to paracellular leak and that inhibition of ERK signaling leads to Calu-3 barrier/junctional tightening. Indeed, the induction of paracellular transepithelial leak in Calu-3 cell layers by ERK signaling has already been substantiated.32,44,45 Our results expand on those earlier findings by showing the involvement of ERK signaling in both the 3 hr and the 72 hr (post-TNF-α exposure) transepithelial leak, by the U0126 reduction of TNF-α effects on both TER and 14C-D-mannitol diffusion (Figure 7). Although, at 3 hr, it is possible that the effect of U0126 alone on TER is responsible for the significant increase in resistance of the U0126 + TNF condition. The substantial increase in TER caused by U0126 on control cell layers is potentially the reason that the apparent TER decrease is less in the U0126 + TNF condition versus the TNF condition (Figure 7A). This is not the case at 72 hr given U0126 does not cause significant effects on TER on its own at this time point; however, there is still a positive effect in the U0126 + TNF condition versus the TNF condition. Furthermore, direct evidence for TNF-α activation of the ERK signaling pathway in Calu-3 cell layers is shown by the TNF-α induced increase in p-ERK levels (Figure 8).