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Sanjeev K Gotru, Wenchun Chen, Peter Kraft, Isabelle C Becker, Karen Wolf, Simon Stritt, Susanna Zierler, Heike M Hermanns, Deviyani Rao, Anne-Laure Perraud, Carsten Schmitz, René P Zahedi, Peter J Noy, Michael G Tomlinson, Thomas Dandekar, Masayuki Matsushita, Vladimir Chubanov, Thomas Gudermann, Guido Stoll, Bernhard Nieswandt, Attila Braun
OBJECTIVE: TRPM7 (transient receptor potential melastatin-like 7 channel) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic α-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg(2+) and Ca(2+) permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. APPROACH AND RESULTS: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R) ) causes a marked signaling defect in platelets...
November 16, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Fang-Wan Yang, Yu Fu, Ying Li, Yi-Huai He, Mao-Yuan Mu, Qi-Chuan Liu, Jun Long, Shi-De Lin
AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR...
October 28, 2017: World Journal of Gastroenterology: WJG
Catherine Wenhui Goh, Irene Chengjie Lee, Jeyapriya Rajameenakshi Sundaram, Simi Elizabeth George, Permeen Yusoff, Matthew Hayden Brush, Newman Siu Kwan Sze, Shirish Shenolikar
Oxidative and endoplasmic reticulum (ER) stresses are hallmarks of the pathophysiology of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In these stresses, different kinases phosphorylate eukaryotic initiation factor eIF2α enabling the translation of stress response genes, among these is GADD34, the protein product of which recruits the α-isoform of protein phosphatase 1 catalytic subunit (PP1α) and eIF2α to assemble a phosphatase complex catalyzing eIF2α dephosphorylation and resumption of protein synthesis...
November 6, 2017: Journal of Biological Chemistry
Claire Stewart, Andrea Estrada, Paul Kim, Dong Wang, Yuren Wei, Chris Gentile, Michael Pagliassotti
The unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]...
April 2017: Endoplasmic Reticulum Stress in Diseases
Toru Hosoi, Shinsuke Ino, Fumie Ohnishi, Kenichi Todoroki, Michiko Yoshii, Mai Kakimoto, Christa E Müller, Koichiro Ozawa
INTRODUCTION: Mast cells play an important role in allergic responses. METHODS: We herein demonstrated the mechanisms of inhibitory effect of adenine on IgE/antigen-induced degranulation and TNF-α release in mast cells. RESULTS: We found that these effects were dependent on the amino group of adenine because purine only weakly inhibited degranulation. Adenine also inhibited Ca(2+) ionophore- and thapsigargin-induced degranulation, however, this inhibitory effect was weaker than that of the antigen...
November 1, 2017: Immunity, Inflammation and Disease
Abdou Tchoukoua, Takuma Suzuki, Nanang Rudianto Ariefta, Takuya Koseki, Yusuke Okawa, Ken-Ichi Kimura, Yoshihito Shiono
A new eremophilane sesquiterpene, 13,13-dimethoxyintegric acid (1), together with known compound integric acid (2) have been isolated from a fungus, Xylaria sp. V-27, obtained from a dead branch. The structure of 1 was established by means of spectroscopic analyses. 1 and 2 promoted growth restoring activity against the mutant yeast strain (Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ)) and inhibited degranulation of rat basophilic leukemia RBL-2H3 cells stimulated by immnunoglobulin G + 2,4-dinitrophenylated-bovine serum albumin (IgE+DNP-BSA), thapsigargin and A23187...
October 25, 2017: Journal of Antibiotics
Moritz Schnelle, Norman Catibog, Min Zhang, Adam A Nabeebaccus, Grace Anderson, Daniel A Richards, Greta Sawyer, Xiaohong Zhang, Karl Toischer, Gerd Hasenfuss, Mark J Monaghan, Ajay M Shah
BACKGROUND: Mouse models of heart disease are extensively employed. The echocardiographic characterization of contractile function is usually focused on systolic function with fewer studies assessing diastolic function. Furthermore, the applicability of diverse echocardiographic parameters of diastolic function that are commonly used in humans has not been extensively evaluated in different pathophysiological models in mice. METHODS AND RESULTS: We used high resolution echocardiography to evaluate parameters of diastolic function in mouse models of chronic pressure overload (aortic constriction), volume overload (aorto-caval shunt), heart failure with preserved ejection fraction (HFpEF; DOCA-salt hypertension), and acute sarcoplasmic reticulum dysfunction induced by thapsigargin - all known to exhibit diastolic dysfunction...
October 19, 2017: Journal of Molecular and Cellular Cardiology
Hyun Jung Kim, Taewon Han, Yun Tai Kim, Insuk So, Byung Joo Kim
BACKGROUND: Magnolia officinalis Rehder and EH Wilson (M. officinalis) are traditional Chinese medicines widely used for gastrointestinal (GI) tract motility disorder in Asian countries. We investigated the effects of an ethanol extract of M. officinalis (MOE) on the pacemaker potentials of cultured interstitial cells of Cajal (ICCs) in vitro and its effects on GI motor functions in vivo. METHODS: We isolated ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record the pacemaker potentials in cultured ICCs in vitro...
October 19, 2017: Cellular Physiology and Biochemistry
Qun Chen, Jeremy Thompson, Ying Hu, Anindita Das, Edward J Lesnefsky
Endoplasmic reticulum (ER) stress, a disturbance of the ER function, contributes to cardiac injury. ER and mitochondria are closely connected organelles within cells. ER stress contributes to mitochondrial dysfunction, which is a key factor to increase cardiac injury. Metformin, a traditional anti-diabetic drug, decreases cardiac injury during ischemia-reperfusion. Metformin also inhibits ER stress in cultured cells. We hypothesized that metformin can attenuate the ER stress-induced mitochondrial dysfunction and subsequent cardiac injury...
September 28, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
Meng Zhang, Javier E Stern
KEY POINTS: NMDA receptor (NMDAR)-mediated Ca(2+) signalling plays a critical role in modulating hypothalamic neurosecretory function. However, whether an altered NMDAR-evoked changes in Ca(2+) (NMDAR-ΔCa(2+) ) signalling in magnocellular neurosecretory cells (MNCs) may contribute to neurohumoral activation during disease states is unknown. We show that activation of NMDARs evoked similar inward currents in MNCs of sham and renovascular hypertensive (RVH) rats. Despite this, a prolonged and larger NMDAR-ΔCa(2+) response was observed in the latter...
October 15, 2017: Journal of Physiology
Ling Xiao, Hong-Wei Liu, Hong Di, Li-Xin Chen, Qing Zhou, Xin Yu, Haiyan Jing, Shuhai Tang
A growing literature has demonstrated that the renin-angiotensin system (RAS) involves in gut function. Angiotensin II (AngII) stimulates Cl(-) secretion in intestine epithelial cells. However, the underlying signal pathway remains unexplored. Here, we explored that serosal application of Ang II (5 × 10(-8) M) significantly increased the baseline Isc compared to the control group in rat ileum. Tetrodotoxin (TTX) failed to suppress Isc evoked by Ang II. However, the Ang II-evoked Isc was significantly suppressed by the ATR1 antagonist losartan instead of ATR2 antagonist PD123319...
October 12, 2017: Biochemical and Biophysical Research Communications
Néstor Más Gómez, Wennan Lu, Jason C Lim, Kirill Kiselyov, Keith E Campagno, Yulia Grishchuk, Susan A Slaugenhaupt, Bruce A Pfeffer, Steven J Fliesler, Claire H Mitchell
The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations...
October 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Wiebe Vanhove, Kris Nys, Ingrid Arijs, Isabelle Cleynen, Manuel Noben, Sebastiaan De Schepper, Gert Van Assche, Marc Ferrante, Séverine Vermeire
Background: Endoplasmic reticulum stress was shown to be pivotal in the pathogenesis of inflammatory bowel disease. Despite progress in IBD drug development, not more than one third of patients achieve steroid-free remission and mucosal healing with current therapies. Furthermore, patient stratification tools for therapy selection are lacking. We aimed to identify and quantify epithelial ER stress in a patient-specific manner in an attempt towards personalized therapy. Methods: A biopsy-derived intestinal epithelial cell culture system was developed and characterized...
September 23, 2017: Journal of Crohn's & Colitis
Hanna Hanna, Agnese Denzi, Micaela Liberti, Franck M André, Lluis M Mir
Microsecond pulsed electric fields (μsPEF) permeabilize the plasma membrane (PM) and are widely used in research, medicine and biotechnology. For internal membranes permeabilization, nanosecond pulsed electric fields (nsPEF) are applied but this technology is complex to use. Here we report that the endoplasmic reticulum (ER) membrane can also be electropermeabilized by one 100 µs pulse without affecting the cell viability. Indeed, using Ca(2+) as a permeabilization marker, we observed cytosolic Ca(2+) peaks in two different cell types after one 100 µs pulse in a medium without Ca(2+)...
October 12, 2017: Scientific Reports
Guodong Liang, Xuedong Fang, Yubo Yang, Yan Song
Cell migration inducing hyaluronan binding protein (CEMIP) has been suggested as a contributor in the carcinogenesis of colorectal cancer (CRC). Cancer cells can adapt to endoplasmic reticulum (ER) stress by initiating unfolded protein response (UPR). This study aimed at investigating whether CEMIP affected the UPR of CRC cells, with a focus on 78 kDa glucose-regulated protein (GRP78, a major ER chaperone). We found that knockdown of CEMIP inhibited cell proliferation and induced a G1 arrest in SW480 CRC cells...
October 12, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Lauren C Burrows, Luke T Jesikiewicz, Gang Lu, Steven J Geib, Peng Liu, Kay M Brummond
The Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT)...
October 12, 2017: Journal of the American Chemical Society
Maria C Olianas, Simona Dedoni, Pierluigi Onali
The 5'-adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of the cellular energy metabolism and may induce either cell survival or death. We previously reported that in SH-SY5Y human neuroblastoma cells stimulation of muscarinic acetylcholine receptors (mAChRs) activate AMPK by triggering store-operated Ca(2+) entry (SOCE). However, whether mAChRs may control AMPK activity by regulating additional mechanisms beyond SOCE remains to be investigated. In the present study we examined the effects of mAChRs on AMPK when SOCE was induced by the sarco-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin...
October 9, 2017: Neurochemical Research
Liza Berrout, Masako Isokawa
Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity...
October 6, 2017: Brain Research
Kunkun Xia, Zegang Ma, Jianxin Shen, Menghan Li, Baoke Hou, Ming Gao, Shuijun Zhang, Jie Wu
Cellular Ca(2+) signals play a critical role in cell physiology and pathology. In most non-excitable cells, store-operated Ca(2+) entry (SOCE) is an important mechanism by which intracellular Ca(2+) signaling is regulated. However, few drugs can selectively modulate SOCE. 2-Aminoethoxydiphenyl borate (2APB) and its analogs (DPB162 and DPB163) have been reported to inhibit SOCE. Here, we examined the effects of another 2-APB analog, DPB161 on SOCE in acutely-isolated rat submandibular cells. Both patch-clamp recordings and Ca(2+) imaging showed that upon removal of extracellular Ca(2+) ([Ca(2+)]o=0), rat submandibular cells were unable to maintain ACh-induced Ca(2+) oscillations, but restoration of [Ca(2+)]o to refill Ca(2+) stores enable recovery of these Ca(2+) oscillations...
September 22, 2017: Oncotarget
Pankaj Sehgal, Paula Szalai, Claus Olesen, Helle A Praetorius, Poul Nissen, Søren Brøgger Christensen, Nikolai Engedal, Jesper Vuust Møller
Calcium (Ca2+) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA), disrupts Ca2+ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA-inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μM) concentrations of Tg and Tg analogs with various long-chain substitutions at the O(8) position extensively inhibit SERCA1a-mediated Ca2+ transport. We also found that in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca2+ stores...
September 29, 2017: Journal of Biological Chemistry
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