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Onat Akyol, Prativa Sherchan, Gokce Yilmaz, Cesar Reis, Wingi Man Ho, Yuechun Wang, Lei Huang, Ihsan Solaroglu, John H Zhang
BACKGROUND: Surgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. METHODS: SBI was induced in male Sprague Dawley rats by partial right frontal lobe resection...
June 5, 2018: Experimental Neurology
Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Johan Garaude, Dang-Nghiem Vo, Sana Belkhala, Sabine Gerbal-Chaloin, Claire Gondeau, Martine Daujat-Chavanieu, Cécile Delettre, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Alberto Anel, José M Cuezva, Jose A Enriquez, Guillaume Cartron, Charles-Henri Lecellier, Javier Hernandez, Martin Villalba
Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. ROS-detoxifying enzymes are made available through the activation of their antioxidant response elements (ARE) in their gene promoters. NRF2 binds to AREs and induces this anti-oxidant response. We show that cells from multiple origins performing OXPHOS induced NRF2 expression and its transcriptional activity. The NRF2 promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression...
May 9, 2018: Scientific Reports
Scott J Cameron, Doran S Mix, Sara K Ture, Rachel A Schmidt, Amy Mohan, Daphne Pariser, Michael C Stoner, Punit Shah, Lijun Chen, Hui Zhang, David J Field, Kristina L Modjeski, Sandra Toth, Craig N Morrell
OBJECTIVE: Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions...
May 3, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Yan Deng, Tingwen Lei, Hongmei Li, Xiaochuan Mo, Zhuting Wang, Hailong Ou
Puerarin has properties of anti-oxidation and anti-inflammation, which has been demonstrated protective effects in atherosclerosis and other cardiovascular diseases. However, the detail molecular mechanism still remains unclear. Here, we determined whether the atheroprotective effect of puerarin was by reducing monocyte adhesion and explored the underlying mechanism. The results showed that puerarin dose- and time-dependently reduced oxLDL-induced monocyte THP-1 adhesion to HUVECs and the expression of adhesion-related genes such as VCAM-1, ICAM-1, MCP-1 and IL-8 in HUVECs...
August 2018: Biochimica et Biophysica Acta
Simona Pavan, Nathalie Meyer-Schaller, Maren Diepenbruck, Ravi Kiran Reddy Kalathur, Meera Saxena, Gerhard Christofori
An epithelial to mesenchymal transition (EMT) has been correlated to malignant tumor progression and metastasis by promoting cancer cell migration and invasion and chemoresistance. Hence, finding druggable EMT effectors is critical to efficiently interfere with metastasis formation and to overcome therapy resistance. We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells...
May 1, 2018: Oncogene
Behnoosh Tasharrofi, Soudeh Ghafouri-Fard
BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway contributes to regulation of many cellular functions, such as cell proliferation and differentiation, mobility and apoptosis. Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) /p38 and ERK5 construct the three main modules in this pathway. The Raf-ERK1/2 and JNK cascades contribute in cell proliferation, migration, and survival and are principal regulators of malignant phenotype. This pathway is itself regulated by several outside signals as well as lateral signals from other pathways, which construct a complex network...
2018: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Ning Ding, Bin Geng, Zhonghao Li, Quanzeng Yang, Liang Yan, Lang Wan, Bo Zhang, Cuifang Wang, Yayi Xia
PURPOSE: Extracellular-regulated kinase 5 (ERK5) is thought to regulate osteoblast proliferation. To further understand how ERK5 signaling regulates osteoblast proliferation induced by fluid shear stress (FSS), we examined some potential signaling targets associated with ERK5 in MC3T3-E1 cells. METHODS: MC3T3-E1 cells were treated with XMD8-92 (an ERK5 inhibitor) or Cyclosporin A (CsA, a nuclear factor of activated T cells (NFAT) c1 inhibitor) and/or exposed to 12 dyn/cm2 FSS...
April 16, 2018: Connective Tissue Research
Hang Thi Vu, Sivareddy Kotla, Kyung Ae Ko, Yuka Fujii, Yunting Tao, Jan Medina, Tamlyn Thomas, Megumi Hada, Anil K Sood, Pankaj Kumar Singh, Sarah A Milgrom, Sunil Krishnan, Keigi Fujiwara, Nhat-Tu Le, Jun-Ichi Abe
Adverse cardiovascular events are a leading nonmalignant cause of morbidity and mortality among cancer survivors who have been exposed to ionizing radiation (IR), but the exact mechanism of the cardiovascular complications induced by IR remains unclear. In this study we investigated the potential role of the p90RSK-ERK5 module in regulating IR-induced endothelial cell inflammation and apoptosis. Whole body radiation of mice with 2 Gy γ-ray significantly increased endothelial VCAM-1 expression; especially in the disturbed flow area in vivo ...
2018: Frontiers in Cardiovascular Medicine
X Xie, T Zhou, Y Wang, H Chen, D Lei, L Huang, Y Wang, X Jin, T Sun, J Tan, T Yin, J Huang, H Gregersen, G Wang
Vascular network formation induced by angiogenesis plays an important role in many physiological and pathological processes. However, the role of blood flow and underlying mechanisms in vascular network formation, for example for the development of the caudal vein plexus (CVP), is poorly understood. In this study on tnnt2a-MO injection and chemical blood flow modulator treatment in zebrafish embryos, we demonstrated that decreased blood flow disrupted CVP formation. The hemodynamic force was quantitatively analyzed...
March 22, 2018: Current Molecular Medicine
Shenjie Chen, Bingsheng Yang, Yifei Xu, Yiqing Rong, Yuangang Qiu
Myocardial hypertrophy is often associated with myocardial infarction. Luteolin-7-O-glucoside (LUTG) has the prosperity of preventing cardiomyocyte injury. The current study aimed to explore the potential protective effect of LUTG and its relevant mechanisms in the heart. To establish the cardiac hypertrophy model in vitro, Angiotensin II (Ang II) was used to stimuli H9c2 cells in this study. The CCK‑8 assay showed that LUTG pretreatment improved cell viability of cardiomyocytes co‑treated with Ang II and ischemia/reperfusion...
May 2018: Molecular Medicine Reports
Christian Adam, Lucia Glück, Regina Ebert, Matthias Goebeler, Franz Jakob, Marc Schmidt
Bisphosphonates play an important role in the treatment of metabolic bone diseases such as osteoporosis. In addition to their anti-resorptive activity by triggering osteoclast apoptosis, nitrogen-containing bisphosphonates (N-BP) may also influence osteogenic differentiation, which might rely on their capacity to inhibit the mevalonate pathway. In vascular endothelial cells inhibition of this pathway by cholesterol-lowering statins activates the MEK5/ERK5 mitogen-activated protein kinase cascade, which plays an important role in cellular differentiation, apoptosis or inflammatory processes...
June 2018: Bone
Yingying Liu, Yudiao Huang, Yueyue Xu, Peng Qu, Minghua Wang
Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary reperfusion. Memantine is a licensed drug providing clinically relevant efficacy in patients with Alzheimer's disease. However, little information is known regarding its effects on brain endothelial permeability. In this study, we investigated the effects of memantine on endothelial permeability and the underlying mechanisms in an ischemia-reperfusion (I/R) injury model in primary human brain microvascular endothelial cells...
April 2018: IUBMB Life
Cinzia Antognelli, Eliana Trapani, Simona Delle Monache, Andrea Perrelli, Claudia Fornelli, Francesca Retta, Paola Cassoni, Vincenzo Nicola Talesa, Saverio Francesco Retta
This article contains additional data related to the original research article entitled "KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: implication for Cerebral Cavernous Malformation disease" (Antognelli et al., 2017) [1]. Data were obtained by si-RNA-mediated gene silencing, qRT-PCR, immunoblotting, and immunohistochemistry studies, and enzymatic activity and apoptosis assays. Overall, they support, complement and extend original findings demonstrating that KRIT1 loss-of-function induces a redox-sensitive and JNK-dependent sustained upregulation of the master Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), and a drop in intracellular levels of AP-modified Hsp70 and Hsp27 proteins, leading to a chronic adaptive redox homeostasis that sensitizes cells to oxidative DNA damage and apoptosis...
February 2018: Data in Brief
Emanuele Giurisato, Qiuping Xu, Silvia Lonardi, Brian Telfer, Ilaria Russo, Adam Pearson, Katherine G Finegan, Wenbin Wang, Jinhua Wang, Nathanael S Gray, William Vermi, Zhengui Xia, Cathy Tournier
Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ignazia Tusa, Sinforosa Gagliardi, Alessandro Tubita, Silvia Pandolfi, Carmelo Urso, Lorenzo Borgognoni, Jinhua Wang, Xianming Deng, Nathanael S Gray, Barbara Stecca, Elisabetta Rovida
Malignant melanoma is among the most aggressive cancers and its incidence is increasing worldwide. Targeted therapies and immunotherapy have improved the survival of patients with metastatic melanoma in the last few years; however, available treatments are still unsatisfactory. While the role of the BRAF-MEK1/2-ERK1/2 pathway in melanoma is well established, the involvement of mitogen-activated protein kinases MEK5-ERK5 remains poorly explored. Here we investigated the function of ERK5 signaling in melanoma...
May 2018: Oncogene
Baojin Ding, Paul R Dobner, Debra Mullikin-Kilpatrick, Wei Wang, Hong Zhu, Chi-Wing Chow, John W Cave, Richard M Gronostajski, Daniel L Kilpatrick
We show that BDNF regulates the timing of neurodevelopment via a novel mechanism of extranuclear sequestration of NFATc4 in Golgi. This leads to accelerated derepression of an NFI temporal occupancy gene program in cerebellar granule cells that includes Bdnf itself, revealing an autoregulatory loop within the program driven by BDNF and NFATc4.
April 15, 2018: Molecular Biology of the Cell
Xin Sun, Tao Zhang, Qifei Deng, Qirui Zhou, Xianchao Sun, Enlai Li, Dexin Yu, Caiyun Zhong
Benzidine, a known carcinogen, is closely associated with the development of bladder cancer (BC). Epithelial-mesenchymal transition (EMT) is a critical pathophysiological process in BC progression. The underlying molecular mechanisms of mitogen-activated protein kinase (MAPK) pathway, especially extracellular regulated protein kinases 5 (ERK5), in regulating benzidine-induced EMT remains unclarified. Hence, two human bladder cell lines, T24 and EJ, were utilized in our study. Briefly, cell migration was assessed by wound healing assay, and cell invasion was determined by Transwell assay...
March 31, 2018: Molecules and Cells
Qi Zhao, Lin Wang, Yuan Sun, Xiao-Xia Wang
Diabetic retinopathy (DR) is a major complication of diabetes, and causes pathological changes in retina blood vessels, as the most common cause of vision loss. Extracellular-signal-regulated kinase 5 (ERK5) is the newest discovered member in the mitogen-activated protein kinases (MAPKs) family, and recent evidence demonstrates an essential role of ERK5 signaling in the angiogenesis. However, whether ERK5 signaling may regulate DR development is unknown. Here, we used a streptozocin (STZ)-induce mouse DR model to investigate this question...
January 2, 2018: Oncotarget
Sana Belkahla, Abrar Ul Haq Khan, Delphine Gitenay, Catherine Alexia, Claire Gondeau, Dang-Nghiem Vo, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Guillaume Cartron, Javier Hernandez, Martine Daujat-Chavanieu, Nerea Allende-Vega, Martin Villalba Gonzalez
Changes in metabolism require the efflux and influx of a diverse variety of metabolites. The ABC superfamily of transporters regulates the exchange of hundreds of substrates through the impermeable cell membrane. We show here that a metabolic switch to oxidative phosphorylation (OXPHOS), either by treating cells with dichloroacetate (DCA) or by changing the available substrates, reduced expression of ABCB1, ABCC1, ABCC5 and ABCG2 in wild-type p53-expressing cells. This metabolic change reduced histone changes associated to active promoters...
January 2, 2018: Oncotarget
Joyce K Thompson, Anurag Shukla, Alan L Leggett, Phillip B Munson, Jill M Miller, Maximilian B MacPherson, Stacie L Beuschel, Harvey I Pass, Arti Shukla
Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer...
January 2, 2018: Oncotarget
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