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Arnaud Pommier, Naishitha Anaparthy, Nicoletta Memos, Z Larkin Kelley, Alizée Gouronnec, Ran Yan, Cédric Auffray, Jean Albrengues, Mikala Egeblad, Christine A Iacobuzio-Donahue, Scott K Lyons, Douglas T Fearon
The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single, disseminated cancer cells (DCCs) lacking expression of cytokeratin-19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs that were CK19- and MHCI- The DCCs exhibited an endoplasmic reticulum (ER) stress response but, paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s)...
May 17, 2018: Science
Songhwa Choi, Justin M Snider, Nicole Olakkengil, Johana M Lambert, Andrea K Anderson, Jessica S Ross-Evans, L Ashley Cowart, Ashley J Snider
Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Theresa Kriegler, Anastasia Magoulopoulou, Rocio Amate Marchal, Tara Hessa
Secretory proteins translocate across the mammalian ER membrane co-translationally via the ribosome-sec61 translocation machinery. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient versus inefficient signal sequencing, using an assay based on Xbp1 peptide-mediated translational arrest...
May 3, 2018: Cell Chemical Biology
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
David Romeo-Guitart, Tatiana Leiva-Rodríguez, María Espinosa-Alcantud, Núria Sima, Alejandro Vaquero, Helena Domínguez-Martín, Diego Ruano, Caty Casas
Sirtuin 1 (SIRT1) activity is neuroprotective, and we have recently demonstrated its role in the retrograde degenerative process in motoneurons (MNs) in the spinal cord of rats after peripheral nerve root avulsion (RA) injury. SIRT2 has been suggested to exert effects opposite those of SIRT1; however, its roles in neurodegeneration and neuron response after nerve injury remain unclear. Here we compared the neuroprotective potentials of SIRT1 activation and SIRT2 inhibition in a mouse model of hypoglossal nerve axotomy...
May 10, 2018: Cell Death & Disease
Geeta Rao, Hailey Houson, Gregory Nkepang, Hooman Yari, Chengwen Teng, Vibhudutta Awasthi
BACKGROUND: Multi-organ failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs CLEFMA and EF24 restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. AIMS: We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock...
May 10, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Wentao Dai, Quanxue Li, Bing-Ya Liu, Yi-Xue Li, Yuan-Yuan Li
BACKGROUND: Gastric Carcinoma is one of the most lethal cancer around the world, and is also the most common cancers in Eastern Asia. A lot of differentially expressed genes have been detected as being associated with Gastric Carcinoma (GC) progression, however, little is known about the underlying dysfunctional regulation mechanisms. To address this problem, we previously developed a differential networking approach that is characterized by involving differential coexpression analysis (DCEA), stage-specific gene regulatory network (GRN) modelling and differential regulation networking (DRN) analysis...
April 24, 2018: BMC Systems Biology
Simona Martinotti, Elia Ranzato, Bruno Burlando
GRP78 is a molecular chaperone of the endoplasmic reticulum (ER) that aids proper folding of nascent polypeptides. When unfolded proteins accumulate, GRP78 triggers unfolded protein response (UPR), involving activation of transcription factors like XBP1 and CHOP that may restore cell homeostasis. Increased expression of GRP78 and mild UPR can be constitutive in cancer cells, hindering apoptosis, and promoting cell survival, for example, by GRP78 relocation to the plasma membrane that activates MAPK and PI3 K/AKT pathways...
May 10, 2018: Journal of Cellular Physiology
Yalan Huang, Yanhai Feng, Yu Wang, Pei Wang, Fengjun Wang, Hui Ren
The disruption of intestinal barrier plays a vital role in the pathophysiological changes after severe burn injury, however, the underlying mechanisms are poorly understood. Severe burn causes the disruption of intestinal tight junction (TJ) barrier. Previous studies have shown that endoplasmic reticulum (ER) stress and autophagy are closely associated with the impairment of intestinal mucosa. Thus, we hypothesize that ER stress and autophagy are likely involved in burn injury-induced intestinal epithelial barrier dysfunction...
2018: Frontiers in Physiology
Hiromi Kazama, Masaki Hiramoto, Kana Miyahara, Naoharu Takano, Keisuke Miyazawa
Excess stress caused by accumulation of misfolded proteins inside the endoplasmic reticulum (ER) lumen can cause cells to undergo apoptosis. Misfolded proteins exported from ER to cytoplasm are ubiquitinated and mostly degraded by the proteasome, but can also be destroyed by autophagy mediated by the docking proteins p62 and NBR1. When misfolded proteins accumulate beyond the capacity of these clearance systems, they are transported to the microtubule organization center to form aggresomes, which are also degraded by autophagy...
May 2, 2018: Biochemical and Biophysical Research Communications
L Montibeller, J de Belleroche
The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a crucial role in the maintenance of ER homeostasis through the transactivation of an array of transcription factors. When activated, these transcription factors induce the expression of genes involved in protein folding and degradation with pro-survival effects...
May 4, 2018: Cell Stress & Chaperones
V Palombo, J J Loor, M D'Andrea, M Vailati-Riboni, K Shahzad, U Krogh, P K Theil
BACKGROUND: Colostrum and milk are essential sources of antibodies and nutrients for the neonate, playing a key role in their survival and growth. Slight abnormalities in the timing of colostrogenesis/lactogenesis potentially threaten piglet survival. To further delineate the genes and transcription regulators implicated in the control of the transition from colostrogenesis to lactogenesis, we applied RNA-seq analysis of swine mammary gland tissue from late-gestation to farrowing. Three 2nd parity sows were used for mammary tissue biopsies on days 14, 10, 6 and 2 before (-) parturition and on day 1 after (+) parturition...
May 3, 2018: BMC Genomics
Suzanne Cole, Alice Walsh, Xuefeng Yin, Mihir D Wechalekar, Malcolm D Smith, Susanna M Proudman, Douglas J Veale, Ursula Fearon, Costantino Pitzalis, Frances Humby, Michele Bombardieri, Amy Axel, Homer Adams, Christopher Chiu, Michael Sharp, John Alvarez, Ian Anderson, Loui Madakamutil, Sunil Nagpal, Yanxia Guo
BACKGROUND: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. METHODS: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target...
May 2, 2018: Arthritis Research & Therapy
Hwa-Yeon Lee, Hyo-Kyung Bae, Bae-Dong Jung, Seunghyung Lee, Choon-Keun Park, Boo-Keun Yang, Hee-Tae Cheong
This study investigates the endoplasmic reticulum (ER) stress and subsequent apoptosis in duced during somatic cell nuclear transfer (SCNT) process of porcine SCNT embryos. Porcine SCNT and in vitro fertilization (IVF) embryos were sampled at 3 h and 20 h after SCNT or IVF and at the blastocyst stage for mRNA extraction. The x-box binding protein 1 (Xbp1) mRNA and the expressions of ER stress-associated genes were confirmed by RT-PCR or RT-qPCR. Apoptotic gene expression was analyzed by RT-PCR. Before commencing SCNT, somatic cells treated with tunicamycin (TM), an ER stress inducer, confirmed the splicing of Xbp1 mRNA and increased expressions of ER stress-associated genes...
March 2018: Balsaeng'gwa Saengsig
Yubo Liu, Yu Cao, Xiaoqing Pan, Meiyun Shi, Qiong Wu, Tianmiao Huang, Hui Jiang, Wenli Li, Jianing Zhang
Chemoresistance has become a major obstacle to the success of cancer therapy, but the mechanisms underlying chemoresistance are not yet fully understood. O-GlcNAcylation is a post-translational modification that is regulated by the hexosamine biosynthetic pathway (HBP) and has an important role in a wide range of cellular functions. Here we assessed the role of O-GlcNAcylation in chemoresistance and investigated the underlying cellular mechanisms. The results showed that the HBP has an important role in cancer cell chemoresistance by regulating O-GlcNAcylation...
April 30, 2018: Cell Death & Disease
Minji Woo, Jeong Sook Noh, Eun Ju Cho, Yeongok Song
This study investigated the inhibitory effects of kimchi bioactive compounds against endoplasmic reticulum (ER) stress-induced apoptosis in amyloid beta (Aβ)-injected mice. Mice received a single intracerebroventricular injection of Aβ25-35, except for the normal group. Mice had oral administration of 10 mg capsaicin, 50 mg (3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), 50 mg quercetin, 50 mg ascorbic acid, or 200 mg kimchi methanol extract (KME) per Kg body weight for 2 weeks, respectively (n = 7 per group)...
April 30, 2018: Journal of Agricultural and Food Chemistry
Jie Wu, Weijin Zhang, Xiaohui Liu, Lili Wu, Guangting He, Peixin Li, Xiaohua Guo, Zhongqing Chen, Qiaobing Huang
Endoplasmic reticulum (ER) stress-induced endothelial cell (EC) apoptosis has been implicated in a variety of human diseases. In addition to being regarded as an NADPH oxidase (NOX) inhibitor, apocynin (APO) exhibits an anti-apoptotic effect in various cells. The present study aimed to identify the protective role of apocynin in ER stress-mediated EC apoptosis and the underlying mechanisms. We found that ER stress resulted in a significant increase in c-Jun N-terminal kinase phosphorylation, and elicited caspase 3 cleavage and apoptosis...
April 25, 2018: Molecular and Cellular Biochemistry
Lei Liu, Lu Xu, Shaoqing Zhang, Dong Wang, Guoxia Dong, Hanwen Chen, Xinjian Li, Chi Shu, Rong Wang
Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF...
April 25, 2018: Experimental Animals
Jun Yoshino, Paloma Almeda-Valdes, Anna C Moseley, Bettina Mittendorfer, Samuel Klein
Endoplasmic reticulum (ER) stress is likely involved in the pathogenesis of metabolic dysfunction in people with obesity and diabetes. Although tissue biopsy is often used to evaluate the presence and severity of ER stress, it is not known whether acute tissue injury-induced by percutaneous muscle biopsy causes ER stress and its potential downstream effects on markers of inflammation and metabolic function. In this study, we tested the hypothesis that percutaneous biopsy-induced tissue injury causes ER stress and alters inflammatory and metabolic pathways in skeletal muscle...
April 2018: Physiological Reports
Yunhong Bai, Xingyao Wu, Kathryn M Brennan, David S Wang, Maurizio D'Antonio, John Moran, John Svaren, Michael E Shy
Objective: To determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR). Background: CMT1B is caused by >200 heterozygous mutations in MPZ , the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment...
April 2018: Annals of Clinical and Translational Neurology
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