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Andrei Golovko, Artyom Kojukhov, Bo-Jhih Guan, Benjamin Morpurgo, William C Merrick, Barsanjit Mazumder, Maria Hatzoglou, Anton A Komar
Eukaryotic initiation factor 2A (eIF2A) is a 65-kDa protein that was first identified in the early 1970s as a factor capable of stimulating initiator methionyl-tRNAi (Met-tRNA(Met)i) binding to 40S ribosomal subunits in vitro. However, in contrast to the eIF2, which stimulates Met-tRNA(Met)i binding to 40S ribosomal subunits in a GTP-dependent manner, eIF2A didn't reveal any GTP-dependence, but instead was found to direct binding of the Met-tRNA(Met)i to 40S ribosomal subunits in a codon-dependent manner. eIF2A appears to be highly conserved across eukaryotic species, suggesting conservation of function in evolution...
September 29, 2016: Cell Cycle
Yuan Lu, Jian-Ya Xu, Xiao-Hua Zhang, Xia Zhao
ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, asthma has increased dramatically in prevalence with a considerable economic burden all over the world. Long-term remission should be regarded as the promising and meaningful therapeutic goal in asthma management. However, the precise definition criteria and rational therapies for asthma remission have not been well-established. In academia, there is a consensus that even in those who develop asymptomatic remission of asthma, persistent airway inflammation is ubiquitous...
November 4, 2016: Journal of Ethnopharmacology
Gilles M Leclerc, Shuhua Zheng, Guy J Leclerc, Joanna DeSalvo, Ronan T Swords, Julio C Barredo
Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat(®), a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL...
September 5, 2016: Leukemia Research
Phaik Ju Teoh, Chonglei Bi, Chirackal Sintosebastian, Liang Seah Tay, Rafael Fonseca, Wee Joo Chng
Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its protein homeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53-reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes...
August 12, 2016: Oncotarget
Q Song, C C Han, X P Xiong, F He, W Gan, S H Wei, H H Liu, L Li, H Y Xu
PI3K-Akt-mTOR signaling pathway is associated with endoplasmic reticulum (ER) stress. However, it is not clear how this signaling pathway affects the ER stress. The present study aimed to determine whether the PI3K-Akt-mTOR signaling pathway regulates tunicamycin (TM)-induced increases in mRNA levels of genes involved in the ER stress, to help elucidate the mechanism by which this pathway affects the ER stress in primary goose hepatocytes. Primary hepatocytes were isolated from geese and cultured in vitro. After 12 h in a serum-free medium, the hepatocytes were incubated for 24 h in a medium with either no addition (control) or with supplementation of TM or TM together with PI3K-Akt-mTOR signaling pathway inhibitors (LY294002, rapamycin, NVP-BEZ235)...
2016: Genetics and Molecular Research: GMR
Qi Wang, Leng-Xin Duan, Zheng-Shun Xu, Jian-Gang Wang, Shou-Min Xi
The earthworm is a widely used Chinese herbal medicine. There are more than 40 prescriptions including earthworms in the "Compendium of Materia Medica". TCM theory holds that earthworms exert antispasmodic and antipyretic effects through the liver meridian to calm the liver. However, the clinical effect of earthworms on liver injury has not been clearly demonstrated. We have previously established a method to extract the active ingredients from earthworms (hereinafter referred to as EWAs) [1]. In the present study, we observed protective effect of the EWAs on tunicamycin-induced ERS (endoplasmic reticulum stress) model in human hepatic L02 cells...
August 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Y Liu, S Y Qi, L S Ru, C Ding, H J Wang, A Y Li, B Y Xu, G H Zhang, D M Wang
OBJECTIVE: Endoplasmic reticulum (ER) stress plays an important role in ischemia-mediated cell death. The aim of the current study is to investigate the effects of salubrinal (Sal), a selective eIF2a dephosphorylation inhibitor, on heart failure rats and related mechanisms. METHODS: Heart failure was induced by coronary artery ligation (MI) in adult male Sprague-Dawley rats. To ensure comparable MI sizes post coronary artery ligation on various groups, echocardiography examination was performed before and 30 minutes after ligation in MI groups...
June 24, 2016: Zhonghua Xin Xue Guan Bing za Zhi
Jialin Gao, Yao Zhang, Cui Yu, Fengbiao Tan, Lizhuo Wang
Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2(-/-) mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2(-/-) mice, there were obvious fat degeneration and inflammatory changes...
August 5, 2016: Biochemical and Biophysical Research Communications
Jan A Burger, Dan A Landau, Amaro Taylor-Weiner, Ivana Bozic, Huidan Zhang, Kristopher Sarosiek, Lili Wang, Chip Stewart, Jean Fan, Julia Hoellenriegel, Mariela Sivina, Adrian M Dubuc, Cameron Fraser, Yulong Han, Shuqiang Li, Kenneth J Livak, Lihua Zou, Youzhong Wan, Sergej Konoplev, Carrie Sougnez, Jennifer R Brown, Lynne V Abruzzo, Scott L Carter, Michael J Keating, Matthew S Davids, William G Wierda, Kristian Cibulskis, Thorsten Zenz, Lillian Werner, Paola Dal Cin, Peter Kharchencko, Donna Neuberg, Hagop Kantarjian, Eric Lander, Stacey Gabriel, Susan O'Brien, Anthony Letai, David A Weitz, Martin A Nowak, Gad Getz, Catherine J Wu
Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma...
2016: Nature Communications
Qian Jiang, Liuqin He, Yongqing Hou, Jiashun Chen, Yehui Duan, Dun Deng, Guoyao Wu, Yulong Yin, Kang Yao
Alpha-ketoglutarate (AKG), a key intermediate in the Krebs cycle, has been reported to promote protein synthesis through activating mechanistic targeting of rapamycin (mTOR) in enterocytes. The study tested the hypothesis that AKG may enhance growth and milk protein synthesis in porcine mammary epithelial cells (PMECs). PMECs were cultured for 96 h in Dulbecco's modified Eagle's-F12 Ham medium (DMEM-F12) containing prolactin (2 µg/ml) and AKG (0 or 1.5 mM). At the end of 96-h culture, the abundance of apoptosis-related proteins (caspase-3, caspase-9), milk-specific proteins (α-lactalbumin and β-casein), mTOR signaling proteins (mTOR, p-mTOR, PERK, p-PERK, eIF2a, P70S6K and p-P70S6K), and endoplasmic reticulum stress (ERS)-associated proteins (BiP and CHOP) in PMEC were determined...
September 2016: Amino Acids
Lili Wen, Fang Han, Yuxiu Shi, Xiaoyan Li
Previous studies revealed that patients with post-traumatic stress disorder (PTSD) have a smaller than normal medial prefrontal cortex (mPFC), and PTSD rats [single prolonged stress, (SPS)] have an increased mPFC neuron apoptosis, which are related to the severity of PTSD symptoms. Three signalling pathways [protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1)] in the endoplasmic reticulum (ER) play a critical role in resisting apoptosis...
August 2016: Journal of Molecular Neuroscience: MN
L Du, F He, L Kuang, W Tang, Y Li, D Chen
Disruption of nitric oxide pathway and endoplasmic reticulum (ER) stress had been observed in preeclampsia (PE). However, the correlation and overall detailed expression profiles of ER stress-related markers and endothelial nitric oxide synthase/inducible nitric oxide synthase (eNOS/iNOS) in patients with PE were poorly understood. In this study, placental protein expression of ER stress-related markers as well as eNOS/iNOS in normotensive control (n=32) and PE pregnancies (n=32) was examined by western blot...
March 31, 2016: Journal of Human Hypertension
Alexis Bretin, Jessica Carrière, Guillaume Dalmasso, Agnès Bergougnoux, Wafa B'chir, Anne-Catherine Maurin, Stefan Müller, Frank Seibold, Nicolas Barnich, Alain Bruhat, Arlette Darfeuille-Michaud, Hang Thi Thu Nguyen
The intestinal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC). Upon AIEC infection, autophagy is induced in host cells to restrain bacterial intracellular replication. The underlying mechanism, however, remains unknown. Here, we investigated the role of the EIF2AK4-EIF2A/eIF2α-ATF4 pathway in the autophagic response to AIEC infection. We showed that infection of human intestinal epithelial T84 cells with the AIEC reference strain LF82 activated the EIF2AK4-EIF2A-ATF4 pathway, as evidenced by increased phospho-EIF2AK4, phospho-EIF2A and ATF4 levels...
May 3, 2016: Autophagy
Hongrui Guo, Hengmin Cui, Xi Peng, Jing Fang, Zhicai Zuo, Junliang Deng, Xun Wang, Bangyuan Wu, Kejie Chen, Jie Deng
It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days...
April 5, 2016: Oncotarget
Ying Liao, Feng Gu, Xiang Mao, Qiaona Niu, Huaxia Wang, Yingjie Sun, Cuiping Song, Xusheng Qiu, Lei Tan, Chan Ding
Viral infections result in cellular stress responses, which can trigger protein translation shutoff via phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Newcastle disease virus (NDV) causes severe disease in poultry and selectively kills human tumour cells. In this report, we determined that infection of HeLa human cervical cancer cells and DF-1 chicken fibroblast cells with NDV maintained protein at early infection times, 0-12 h post-infection (p.i.), and gradually inhibited global protein translation at late infection times, 12-24 h p...
April 2016: Journal of General Virology
Ling Zhou, Lifeng Jiang, Maolei Xu, Qun Liu, Ning Gao, Ping Li, E-Hu Liu
In this study, we investigated the effects of miltirone in human leukemia cell lines, primary leukemia cells, and nude mice U937 xenograft. Treatment of cells with miltirone resulted in apoptosis, mitochondria membrane potential (MMP) collapses, increase of Bax/Bcl-2 ratio, and cytochrome c release. Miltirone triggered the endoplasmic reticulum (ER) stress identified through several key molecules of the unfolded protein response, including phosphorylated PERK, eIF2a, GRP78, GRP94, and caspase-12. Miltrone treatment also resulted in the release of Ca(2+) from the ER stores and mitochondrial Ca(2+) loading in the cells...
2016: Scientific Reports
Shelley R Starck, Jordan C Tsai, Keling Chen, Michael Shodiya, Lei Wang, Kinnosuke Yahiro, Manuela Martins-Green, Nilabh Shastri, Peter Walter
Translated regions distinct from annotated coding sequences have emerged as essential elements of the proteome. This includes upstream open reading frames (uORFs) present in mRNAs controlled by the integrated stress response (ISR) that show "privileged" translation despite inhibited eukaryotic initiation factor 2-guanosine triphosphate-initiator methionyl transfer RNA (eIF2·GTP·Met-tRNA(i )(Met)). We developed tracing translation by T cells to directly measure the translation products of uORFs during the ISR...
January 29, 2016: Science
Daoyin Dong, E Albert Reece, Peixin Yang
The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is one of the primary pathways responsible for the cellular defense system against oxidative stress. Oxidative stress-induced apoptosis is a causal event in diabetic embryopathy. Thus, the Nrf2 pathway may play an important role in the induction of diabetic embryopathy. In the present study, we investigated the potentially protective effect of the Nrf2 activator, vinylsulfone, on high glucose-induced cellular stress, apoptosis, and neural tube defects (NTDs)...
August 2016: Reproductive Sciences
Wei Ding, Bin Wang, Minmin Zhang, Yong Gu
BACKGROUND/AIMS: Uremic cardiomyopathy (UCM) is a complication in chronic kidney disease. We investigated if endoplasmic reticulum stress (ERS) is involved in UCM, and determined the efficacy of tauroursodeoxycholic acid (TUDCA) in UCM prevention. METHODS: Mice were divided randomly into three groups: sham (saline, i.p), 5/6 nephrectomized (Nx) (saline, i.p) and Nx+TUDCA (250 mg/kg/day, i.p.). Renal function was assessed by measuring serum creatinine, blood urea nitrogen and by periodic acid-Schiff reagent staining...
2016: Cellular Physiology and Biochemistry
Chiara Zucal, Vito G D'Agostino, Antonio Casini, Barbara Mantelli, Natthakan Thongon, Debora Soncini, Irene Caffa, Michele Cea, Alberto Ballestrero, Alessandro Quattrone, Stefano Indraccolo, Alessio Nencioni, Alessandro Provenzani
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide, is one of the major factors regulating cancer cells metabolism and is considered a promising target for treating cancer. The prototypical NAMPT inhibitor FK866 effectively lowers NAD(+) levels in cancer cells, reducing the activity of NAD(+)-dependent enzymes, lowering intracellular ATP, and promoting cell death. RESULTS: We show that FK866 induces a translational arrest in leukemia cells through inhibition of MTOR/4EBP1 signaling and of the initiation factors EIF4E and EIF2A...
2015: BMC Cancer
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