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https://www.readbyqxmd.com/read/29777134/zebrafish-vcap1x2-regulates-cardiac-contractility-and-proliferation-of-cardiomyocytes-and-epicardial-cells
#1
Fang-Chi Hsieh, Yu-Fen Lu, Ian Liau, Chien-Chang Chen, Chao-Min Cheng, Chung-Der Hsiao, Sheng-Ping L Hwang
Sarcomeric signaling complexes are important to sustain proper sarcomere structure and function, however, the mechanisms underlying these processes are not fully elucidated. In a gene trap experiment, we found that vascular cell adhesion protein 1 isoform X2 (VCAP1X2) mutant embryos displayed a dilated cardiomyopathy phenotype, including reduced cardiac contractility, enlarged ventricular chamber and thinned ventricular compact layer. Cardiomyocyte and epicardial cell proliferation was decreased in the mutant heart ventricle, as was the expression of pAKT and pERK...
May 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#2
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29772440/inhibition-of-nogo-b-promotes-cardiac-hypertrophy-via-endoplasmic-reticulum-stress
#3
Junli Li, Wenchao Wu, Yanguo Xin, Mingyue Zhao, Xiaojing Liu
AIMS: Nogo-B is a key endoplasmic reticulum (ER) protein that regulates ER stress signaling. However, its role in cardiac hypertrophy remains poorly understood. ER stress is interrelated with autophagy in the process of cardiac hypertrophy. Therefore, we aimed to test the hypothesis that both ER stress and autophagy signaling mediate the function of Nogo-B in cardiac hypertrophy. MAIN METHODS: Rat models of transverse aortic constriction (TAC), neonatal rat cardiomyocytes (NRCMs) stimulated with norepinephrine (Ne) and primary cardiac fibroblasts treated with transforming growth factor β1 (TGF-β1) were used in this study...
May 14, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29772059/the-orphan-g-protein-coupled-receptor-75-signaling-is-activated-by-the-chemokine-ccl5
#4
Simona Dedoni, Lee A Campbell, Brandon K Harvey, Valeria Avdoshina, Italo Mocchetti
The chemokine CCL5 prevents neuronal cell death mediated both by amyloid β, as well as the human immunodeficiency virus (HIV) viral proteins gp120 and Tat. Because CCL5 binds to CCR5, CCR3 and/or CCR1 receptors, it is unclear which of these receptors plays a role in neuroprotection. Indeed, CCL5 also has neuroprotective activity in cells lacking these receptors. CCL5 may bind to a G protein-coupled receptor 75 (GPR75), which encodes for a 540 amino-acid orphan receptor of the Gqα family. In this study, we have used SH-SY5Y human neuroblastoma cells to characterize whether CCL5 could activate a Gq signaling through GPR75...
May 17, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29771603/negative-feedback-loop-of-autophagy-and-endoplasmic-reticulum-stress-in-rapamycin-protection-against-renal-ischemia-reperfusion-injury-during-initial-reperfusion-phase
#5
Xinyuan Li, Gongmin Zhu, Xin Gou, Weiyang He, Hubin Yin, Xiaoyu Yang, Jie Li
Rapamycin, an immunosuppressant, is widely used in patients with kidney transplant. However, the therapeutic effects of rapamycin remain controversial. Additionally, previous studies have revealed deleterious effects of rapamycin predominantly when administered for ≥24 h. Few studies, however, have focused on the short-term effects of rapamycin administered only during the initial reperfusion phase. As such, we designed this study to explore the potential effects and mechanisms of rapamycin under a specific therapeutic regimen in which rapamycin is mixed in the perfusate during the initial reperfusion phase (within 24 h)...
May 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29771174/signaling-and-induction-of-chaperone-mediated-autophagy-by-the-endoplasmic-reticulum-under-stress-conditions
#6
Wenming Li, Qian Yang, Zixu Mao
Chaperone-mediated autophagy (CMA), a form of selective autophagy, maintains cellular proteostasis in response to diverse stress conditions. Whether and how endoplasmic reticulum (ER) stress triggers CMA remains elusive. In our recent study, we demonstrate that various types of ER stress activate the CMA pathway via an EIF2AK3/PERK-MAP2K4/MKK4-MAPK14/p38-dependent manner. We term this process ERICA for ER stress-induced chaperone-mediated autophagy. This pathway is activated in response to stress associated with Parkinson disease and is required for the viability of the SNc dopaminergic neurons in an animal model of Parkinson disease...
May 17, 2018: Autophagy
https://www.readbyqxmd.com/read/29769338/the-perk-arm-of-the-unfolded-protein-response-negatively-regulates-transmissible-gastroenteritis-virus-replication-by-suppressing-protein-translation-and-promoting-type-i-ifn-production
#7
Mei Xue, Fang Fu, Yanlong Ma, Xin Zhang, Liang Li, Li Feng, Pinghuang Liu
Coronavirus replication is closely associated with the endoplasmic reticulum (ER), the primary cellular organelle for protein synthesis, folding, and modification. ER stress is a common consequence in coronavirus-infected cells. However, how the virus-induced ER stress influences coronavirus replication and pathogenesis remains controversial. Here, we demonstrated that infection with the alphacoronavirus transmissible gastroenteritis virus (TGEV) induced ER stress and triggered the unfolded protein response (UPR) in vitro and in vivo , and ER stress negatively regulated TGEV replication in vitro Although TGEV infection activated all three UPR pathways (ATF6, IRE1, and PERK), the virus-triggered UPR suppressed TGEV replication in both ST and IPEC-J2 cells primarily through activation of the PERK-eIF2α axis, as shown by functional studies with overexpression, siRNA, or specific chemical inhibitors...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29764928/ovarian-steroid-dependence-of-endoplasmic-reticulum-stress-involvement-in-endometrial-cell-apoptosis-during-the-human-endometrial-cycle
#8
Jong Yeob Choi, Min Wha Jo, Eun Young Lee, Dong-Yun Lee, Doo Seok Choi
Endoplasmic reticulum (ER) stress is a common cellular stress response that enhances apoptosis to trigger cell death. However, recent studies have shown that estrogen suppresses apoptosis by inhibiting ER stress in some cell types, suggesting that ER stress-induced apoptosis is regulated by ovarian steroid hormones. In endometrial cells, ER stress may also be controlled by ovarian steroid hormones and could be involved in apoptosis induction during the menstrual cycle. To test this hypothesis, we elucidate whether ER stress is regulated by ovarian steroid hormones in human endometrial cells and if it is involved in apoptosis induction...
June 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29761862/cellular-stress-and-apoptosis-contribute-to-the-pathogenesis-of-autism-spectrum-disorder
#9
Daoyin Dong, Horst Ronald Zielke, David Yeh, Peixin Yang
The molecular pathogenesis of autism spectrum disorder, a neurodevelopmental disorder, is still elusive. In this study, we investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. This study compared the activation of ER stress signals (protein kinase R-like endoplasmic reticulum kinase [PERK], activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 alpha [IRE1α]) in different brain regions (prefrontal cortex, hippocampus, cerebellum) in subjects with autism and in age-matched controls...
May 15, 2018: Autism Research: Official Journal of the International Society for Autism Research
https://www.readbyqxmd.com/read/29754474/oxymatrine-causes-hepatotoxicity-by-promoting-the-phosphorylation-of-jnk-and-induction-of-endoplasmic-reticulum-stress-mediated-by-ros-in-lo2-cells
#10
Li-Li Gu, Zhe-Lun Shen, Yang-Lei Li, Yi-Qi Bao, Hong Lu
Oxymatrine (OMT) often used in treatment for chronic hepatitis B virus infection in clinic. However, OMT-induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of OMT-induced hepatotoxicity in human normal liver cells (L02). Exposed cells to OMT, the cell viability were decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, OMT altered apoptotic related proteins levels, including Bcl-2, Bax and pro-caspase-8/-9/-3...
May 10, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/29752433/palmitic-acid-but-not-high-glucose-induced-myocardial-apoptosis-is-alleviated-by-n%C3%A2-acetylcysteine-due-to-attenuated-mitochondrial-derived-ros-accumulation-induced-endoplasmic-reticulum-stress
#11
Yang He, Lingyun Zhou, Zhiqiang Fan, Shikun Liu, Weijin Fang
Pharmacological inhibition of reactive oxygen species (ROS) is a potential strategy to prevent diabetes-induced cardiac dysfunction. This study was designed to investigate precise effects of antioxidant N‑acetylcysteine (NAC) in alleviating diabetic cardiomyopathy (DCM). Echocardiography and histologic studies were performed 12 weeks after streptozocin injection. Protein levels involved in endoplasmic reticulum stress (ERS) and apoptosis were analyzed by western blotting in diabetic hearts or high-glucose (HG, 30 mM)- and palmitic acid (PA, 300 μM)-cultured neonatal rat cardiomyocytes (NRCMs)...
May 11, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29743975/hypothyroidism-causes-endoplasmic-reticulum-stress-in-adult-rat-hippocampus-a-mechanism-associated-with-hippocampal-damage
#12
Alejandra Paola Torres-Manzo, Margarita Franco-Colín, Vanessa Blas-Valdivia, Marisol Pineda-Reynoso, Edgar Cano-Europa
Thyroid hormones (TH) are essential for hippocampal neuronal viability in adulthood, and their deficiency causes hypothyroidism, which is related to oxidative stress events and neuronal damage. Also, it has been hypothesized that hypothyroidism causes a glucose deprivation in the neuron. This study is aimed at evaluating the temporal participation of the endoplasmic reticulum stress (ERE) in hippocampal neurons of adult hypothyroid rats and its association with the oxidative stress events. Adult Wistar male rats were divided into euthyroid and hypothyroid groups...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29743725/ufd1-contributes-to-myc-mediated-leukemia-aggressiveness-through-suppression-of-the-proapoptotic-unfolded-protein-response
#13
L N Huiting, Y Samaha, G L Zhang, J E Roderick, B Li, N M Anderson, Y W Wang, L Wang, Fjf Laroche, J W Choi, C T Liu, M A Kelliher, H Feng
Despite the pivotal role of MYC in tumorigenesis, the mechanisms by which it promotes cancer aggressiveness remain incompletely understood. Here, we show that MYC transcriptionally upregulates the ubiquitin fusion degradation 1 (UFD1) gene in T-cell acute lymphoblastic leukemia (T-ALL). Allelic loss of ufd1 in zebrafish induces tumor cell apoptosis and impairs MYC-driven T-ALL progression but does not affect general health. As the E2 component of an endoplasmic reticulum (ER)-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER...
April 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29739819/endoxifen-4-hydroxytamoxifen-and-an-estrogenic-derivative-modulate-estrogen-receptor-complex-mediated-apoptosis-in-breast-cancer
#14
Philipp Y Maximov, Balkees Abderrahman, Sean W Fanning, Surojeet Sengupta, Ping Fan, Ramona F Curpan, Daniela Maria Quintana Rincon, Jeffery A Greenland, Shyamala S Rajan, Geoffrey L Greene, V Craig Jordan
Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment for breast cancer inevitably occurs, but unexpectedly low dose estrogen can cause regression of breast cancer and increase disease free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here we describe modulation of the estrogen receptor liganded with antiestrogens (endoxifen, 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE) EthoxyTPE (EtOXTPE) on estrogen-induced apoptosis in LTED breast cancer cells...
May 8, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29734677/the-effect-of-bornyl-cis-4-hydroxycinnamate-on-melanoma-cell-apoptosis-is-associated-with-mitochondrial-dysfunction-and-endoplasmic-reticulum-stress
#15
Tzu-Yen Yang, Yu-Jen Wu, Chi-I Chang, Chien-Chih Chiu, Mei-Li Wu
Bornyl cis -4-hydroxycinnamate, an active compound isolated from Piper betle stems, was investigated in terms of its effects on A2058 and A375 melanoma cell proliferation and protein expression in this study. We used flow cytometric analysis to examine the early stages of apoptosis induced by bornyl cis -4-hydroxycinnamate in the two melanoma cell lines and employed comparative proteomic analysis to investigate the effects of this compound on protein expression in A375 cells. Master maps generated by PDQuest software from two-dimensional electrophoresis (2-DE) analysis of A375 cells showed that the expression levels of 35 proteins were significantly altered, with 18 proteins upregulated and 17 downregulated...
May 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29734211/early-versus-standard-colonoscopy-a-randomized-controlled-trial-in-patients-with-acute-lower-gastrointestinal-bleeding-results-of-the-bleed-study
#16
Inge van Rongen, Bregje J W Thomassen, Lars E Perk
GOALS: The aim of our study was to examine differences in length of hospital stay (LOHS) between patients with lower gastrointestinal bleeding who received either an early colonoscopy (within 24 h of presentation) or a standard colonoscopy (within 1 to 3 d). BACKGROUND: Diagnostic management of lower gastrointestinal bleeding has been extensively debated in recent literature, especially whether colonoscopy within 24 hours of presentation is feasible and safe...
May 4, 2018: Journal of Clinical Gastroenterology
https://www.readbyqxmd.com/read/29731995/histology-dependent-prognostic-role-of-perk-and-p53-protein-levels-in-early-stage-non-small-cell-lung-cancer
#17
Álvaro Quintanal-Villalonga, Mariló Mediano, Irene Ferrer, Ricardo Meléndez, Andrés Carranza-Carranza, Rocío Suárez, Amancio Carnero, Sonia Molina-Pinelo, Luis Paz-Ares
Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29730925/broccoli-sprout-extract-alleviates-alcohol-induced-oxidative-stress-and-endoplasmic-reticulum-stress-in-c57bl-6-mice
#18
Peng Lei, Wei Zhao, Bo Pang, Xiuli Yang, Bao-Long Li, Minghua Ren, Yu-Juan Shan
The potential efficacy of sulforaphane in protecting alcohol-induced hepatic injury in vivo and its underlying mechanism was investigated. Male C57BL/6 mice were orally administrated with broccoli sprout extract (BSE) containing sulforaphane (7.6, 25.2, 50.4 mg/kg.bw) once a day for 14 days. At the 13th day, mice were challenged with alcohol (5g/kg.bw) every 12 h for 3 times, which increased malondialdehyde (MDA) levels (4.44±1.24 nmol/mg prot, p<0.01) in liver. Our results showed that low, medium and high dose BSE markedly reversed the decrease of antioxidant capacity through enhancing glutathione (GSH) (2...
May 6, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29729927/in-vitro-toxicity-induced-by-quartz-nanoparticles-role-of-er-stress
#19
Sushma, Hridyesh Kumar, Iqbal Ahmad, Pradip Kumar Dutta
In recent years with the advancement of nanotoxicology, the scientific communities drastically increased the investigation of the potential toxicity of nanominerals which are present in all atmospheres as well as are used in a variety of applications. In this study, we reported how Quartz Nanoparticles (QNPs) depending on concentration induces different signature ER stress markers in A549 cells. QNPs induced concentration-dependent decrease in cell viability and this concentration dependent toxicity intensifies production of reactive oxygen species leading to oxidative stress and inflammation...
May 3, 2018: Toxicology
https://www.readbyqxmd.com/read/29729334/the-urgency-for-optimization-and-harmonization-of-thyroid-hormone-analyses-and-their-interpretation-in-developmental-and-reproductive-toxicology-studies
#20
REVIEW
Manon Beekhuijzen, Steffen Schneider, Narinder Barraclough, Nina Hallmark, Alan Hoberman, Sheri Lordi, Mary Moxon, Deborah Perks, Aldert H Piersma, Susan L Makris
In recent years several OECD test guidelines have been updated and some will be updated shortly with the requirement to measure thyroid hormone levels in the blood of mammalian laboratory species. There is, however, an imperative need for clarification and guidance regarding the collection, assessment, and interpretation of thyroid hormone data for regulatory toxicology and risk assessment. Clarification and guidance is needed for 1) timing and methods of blood collection, 2) standardization and validation of the analytical methods, 3) triggers for additional measurements, 4) the need for T4 measurements in postnatal day (PND) 4 pups, and 5) the interpretation of changes in thyroid hormone levels regarding adversity...
May 2, 2018: Reproductive Toxicology
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