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Xiao-Dong Zhang, Zana A Coulibaly, Wei Chun Chen, Hannah A Ledford, Jeong Han Lee, Padmini Sirish, Gu Dai, Zhong Jian, Frank Chuang, Ingrid Brust-Mascher, Ebenezer N Yamoah, Ye Chen-Izu, Leighton T Izu, Nipavan Chiamvimonvat
Small-conductance Ca2+ -activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca2+ microdomains necessary for SK channel activation. SK currents coupled with Ca2+ influx via L-type Ca2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca2+ store, suggesting that LTCCs provide the immediate Ca2+ microdomain for the activation of SK channels in cardiomyocytes...
March 16, 2018: Scientific Reports
Z I Krutetskaya, L S Milenina, A A Naumova, S N Butov, V G Antonov, A D Nozdrachev
Using Fura-2AM microfluorimetry, we have shown for the first time that preincubation of macrophages with the calsequestrin inhibitor neuroleptic trifluoperazine leads to a significant inhibition of the store-dependent Ca2+ entry induced by endoplasmic Ca2+ -ATPase inhibitors thapsigargin or cyclopiazonic acid in rat peritoneal macrophages. The results suggest calsequestrin involvement in the regulation of the store-dependent Ca2+ entry in macrophages.
January 2018: Doklady. Biochemistry and Biophysics
Wen-Tai Chiu, Heng-Ai Chang, Yi-Hsin Lin, Yu-Shan Lin, Hsiao-Tzu Chang, Hsi-Hui Lin, Soon-Cen Huang, Ming-Jer Tang, Meng-Ru Shen
Ca2+ plays a significant role in linking the induction of apoptosis. The key anti-apoptotic protein, Bcl-2, has been reported to regulate the movement of Ca2+ across the ER membrane, but the exact effect of Bcl-2 on Ca2+ levels remains controversial. Store-operated Ca2+ entry (SOCE), a major mode of Ca2+ uptake in non-excitable cells, is activated by depletion of Ca2+ in the ER. Depletion of Ca2+ in the ER causes translocation of the SOC channel activator, STIM1, to the plasma membrane. Thereafter, STIM1 binds to Orai1 or/and TRPC1 channels, forcing them to open and thereby allow Ca2+ entry...
December 2018: Cell Death Discovery
Sei Kuriyama, Tadahiro Tsuji, Tetsushi Sakuma, Takashi Yamamoto, Masamistu Tanaka
The anti-apoptotic nature of cancer cells often impedes the effects of anti-cancer therapeutic agents. Multiple death signals influence mitochondria during apoptosis, and though many studies have attempted to elucidate these complicated pathways, Bax oligomerization, an important step in the process, remains controversial. Here we demonstrate that pleckstrin-homology N1 (PLEKHN1), also known as cardiolipin phosphatidic acid binding protein, plays pro-apoptotic roles during reactive oxygen species (ROS)-induced apoptosis...
December 2018: Cell Death Discovery
Kyoung A Jhang, Jin-Sun Park, Hee-Sun Kim, Young Hae Chong
BACKGROUND: Mer tyrosine kinase (MerTK) activity necessary for amyloid-stimulated phagocytosis strongly implicates that MerTK dysregulation might contribute to chronic inflammation implicated in Alzheimer's disease (AD) pathology. However, the precise mechanism involved in the regulation of MerTK expression by amyloid-β (Aβ) in proinflammatory environment has not yet been ascertained. METHODS: The objective of this study was to determine the underlying mechanism involved in Aβ-mediated decrease in MerTK expression through Aβ-mediated regulation of MerTK expression and its modulation by sulforaphane in human THP-1 macrophages challenged with Aβ1-42...
March 12, 2018: Journal of Neuroinflammation
Min Jae Kim, Kyung Jin Choi, Mi Na Yoon, Sang Hwan Oh, Dong Kwan Kim, Se Hoon Kim, Hyung Seo Park
Intracellular Ca2+ mobilization is closely linked with the initiation of salivary secretion in parotid acinar cells. Reactive oxygen species (ROS) are known to be related to a variety of oxidative stress-induced cellular disorders and believed to be involved in salivary impairments. In this study, we investigated the underlying mechanism of hydrogen peroxide (H2 O2 ) on cytosolic Ca2+ accumulation in mouse parotid acinar cells. Intracellular Ca2+ levels were slowly elevated when 1 mM H2 O2 was perfused in the presence of normal extracellular Ca2+ ...
March 2018: Korean Journal of Physiology & Pharmacology
Miku Maruyama, Miki Kobayashi, Takeshi Uchida, Eisaku Shimizu, Hironori Higashio, Misa Ohno, Shota Uesugi, Ken-Ichi Kimura
Amber is fossilized tree resin and several biologically active compounds were isolated from ambers using the growth-restoring activity of the mutant yeast [Saccharomyces cerevisiae (zds1∆ erg3∆ pdr1∆ pdr3∆)] involving Ca2+ -signal transduction. The aim of this study is to investigate the anti-allergic effect of both the methanol extract of Kuji amber (MEKA) and its main biologically active constituent, kujigamberol (15,20-dinor-5,7,9-labdatrien-18-ol) having activity against the mutant yeast. Both MEKA and kujigamberol inhibited the degranulation of RBL-2H3 cells by stimulation of thapsigargin (Tg) (IC50  = 15...
March 5, 2018: Fitoterapia
Moritz Horn, Virginia Kroef, Kira Allmeroth, Nicole Schuller, Stephan Miethe, Martin Peifer, Josef M Penninger, Ulrich Elling, Martin S Denzel
Forward genetic screens in haploid mammalian cells have recently emerged as powerful tools for the discovery and investigation of recessive traits. Use of the haploid system provides unique genetic tractability and resolution. Upon positive selection, these screens typically employ analysis of loss-of-function (LOF) alleles and are thus limited to non-essential genes. Many relevant compounds, including anti-cancer therapeutics, however, target essential genes, precluding positive selection of LOF alleles. Here, we asked whether the use of random and saturating chemical mutagenesis might enable screens that identify essential biological targets of toxic compounds...
February 9, 2018: Oncotarget
Jingyong Huang, Li Wan, Heping Lu, Xiaoqiang Li
Activating transcription factor 6 (ATF6), one of three sensor proteins in the endoplasmic reticulum (ER), is an important regulatory factor in the ER stress‑induced apoptosis pathway. Although recent studies have made some progress in elucidating the regulation mechanism of ATF6, the specific regulatory mechanism of ER stress‑induced vascular endothelial cell (VEC) apoptosis is still unclear. The present study was designed to investigate the role of ATF6 in VECs under thapsigargin (TG)‑induced ER stress...
March 1, 2018: Molecular Medicine Reports
Xuemei Wan, Jeffrey D Serrill, Ian R Humphreys, Michelle Tan, Kerry L McPhail, Ian G Ganley, Jane E Ishmael
Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5-/- cells relative to ATG5+/+ cells...
March 1, 2018: Marine Drugs
Antonietta Rosella Farina, Lucia Cappabianca, Luciana Gneo, Pierdomenico Ruggeri, Andrew Reay Mackay
Alternative TrkAIII splicing characterises advanced stage metastatic disease and post-therapeutic relapse in neuroblastoma (NB), and in NB models TrkAIII exhibits oncogenic activity. In this study, we report a novel role for TrkAIII in signaling ER stress to the mitochondria in SH-SY5Y NB cells that results in glycolytic metabolic adaptation. The ER stress-inducing agents DTT, A23187 and thapsigargin activated the ER stress-response in control pcDNA SH-SY5Y and TrkAIII expressing SH-SY5Y cells and in TrkAIII SH-SY5Y cells increased TrkAIII targeting to mitochondria and internalisation into inner-mitochondrial membranes...
February 2, 2018: Oncotarget
Takashi Ito, Yukiko Nakanishi, Noriko Yamaji, Shigeru Murakami, Stephen W Schaffer
It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice...
2018: Biological & Pharmaceutical Bulletin
Esther González-Almela, Hugh Williams, Miguel A Sanz, Luis Carrasco
Animal viruses have evolved a variety of strategies to ensure the efficient translation of their mRNAs. One such strategy is the use of internal ribosome entry site (IRES) elements, which circumvent the requirement for some eukaryotic initiation factors (eIFs). Much effort has been directed to unravel the precise mechanism of translation initiation by hepatitis C virus (HCV) mRNA. In the present study, we examined the involvement of several eIFs in HCV IRES-driven translation in human cells in a comparative analysis with mRNAs bearing the encephalomyocarditis virus or the Cricket paralysis virus IRES element...
2018: Frontiers in Microbiology
Stephanie R Harrison, Thomas Scambler, Lylia Oubussad, Chi Wong, Miriam Wittmann, Michael F McDermott, Sinisa Savic
Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB)...
2018: Frontiers in Immunology
Boriana K Tchernookova, Chad Heer, Marin Young, David Swygart, Ryan Kaufman, Michael Gongwer, Lexi Shepherd, Hannah Caringal, Jason Jacoby, Matthew A Kreitzer, Robert Paul Malchow
Small alterations in extracellular acidity are potentially important modulators of neuronal signaling within the vertebrate retina. Here we report a novel extracellular acidification mechanism mediated by glial cells in the retina. Using self-referencing H+-selective microelectrodes to measure extracellular H+ fluxes, we show that activation of retinal Müller (glial) cells of the tiger salamander by micromolar concentrations of extracellular ATP induces a pronounced extracellular H+ flux independent of bicarbonate transport...
2018: PloS One
Freddy Romero, Xu Hong, Dilip Shah, Caleb B Kallen, Ivan Rosas, Zhi Guo, DeLeila Schriner, Julie Barta, Hoora Shaghaghi, Jan B Hoek, Clementina Mesaros, Augustine M Choi, Nathaniel W Snyder, Ross Summer
RATIONALE: Endoplasmic reticulum stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis but neither the mechanisms causing ER stress nor its contribution to fibrosis are understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. OBJECTIVES: To determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung...
February 21, 2018: American Journal of Respiratory Cell and Molecular Biology
Patrycja Kaczara, Bartosz Proniewski, Christopher Lovejoy, Kamil Kuś, Roberto Motterlini, Andrey Y Abramov, Stefan Chlopicki
Carbon monoxide-releasing molecules (CO-RMs) induce nitric oxide (NO) release (which requires NADPH), and Ca2+ -dependent signalling; however, their contribution in mediating endothelial responses is not clear. Here, we studied the effects of CO liberated from CORM-401 on NO production, calcium signalling and pentose phosphate pathway (PPP) activity in human endothelial cell line (EA.hy926). CORM-401 induced NO production and two types of calcium signalling: a peak-like calcium signal and a gradual increase in cytosolic calcium...
February 21, 2018: FEBS Journal
Nuria Beneit, José Luis Martín-Ventura, Carlota Rubio-Longás, Óscar Escribano, Gema García-Gómez, Silvia Fernández, Giorgio Sesti, Marta Letizia Hribal, Jesús Egido, Almudena Gómez-Hernández, Manuel Benito
BACKGROUND: Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear...
February 20, 2018: Cardiovascular Diabetology
Wei Zhang, Terunao Takahara, Takuya Achiha, Hideki Shibata, Masatoshi Maki
NFAT is a cytoplasm-localized hyper-phosphorylated transcription factor that is activated through dephosphorylation by calcineurin, a Ca2+ /calmodulin-dependent phosphatase. A non-palindromic NFAT-response element (RE) found in the IL2 promoter region has been commonly used for a Ca2+ -response reporter gene system, but requirement of concomitant activation of AP-1 (Fos/Jun) often complicates the interpretation of obtained results. A new nanoluciferase (NanoLuc) reporter gene containing nine-tandem repeats of a pseudo-palindromic NFAT-RE located upstream of the IL8 promoter was designed to monitor Ca2+ -induced transactivation activity of NFAT in human embryonic kidney (HEK) 293 cells by measuring luciferase activities of NanoLuc and co-expressed firefly luciferase for normalization...
February 18, 2018: International Journal of Molecular Sciences
Shi-Hong Gu, Gen Li, Hsiao-Yen Hsieh, Pei-Ling Lin, Sheng Li
In this study, phosphorylation of c-Jun N-terminal kinase (JNK) by the prothoracicotropic hormone (PTTH) was investigated in prothoracic glands (PGs) of the silkworm, Bombyx mori . Results showed that JNK phosphorylation was stimulated by the PTTH in time- and dose-dependent manners. In vitro activation of JNK phosphorylation in PGs by the PTTH was also confirmed in an in vivo experiment, in which a PTTH injection greatly increased JNK phosphorylation in PGs of day-6 last instar larvae. JNK phosphorylation caused by PTTH stimulation was greatly inhibited by U73122, a potent and specific inhibitor of phospholipase C (PLC) and an increase in JNK phosphorylation was also detected when PGs were treated with agents (either A23187 or thapsigargin) that directly elevated the intracellular Ca2+ concentration, thereby indicating involvement of PLC and Ca2+ ...
2018: Frontiers in Physiology
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