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Hartmut T Bocker, Theresa Heinrich, Lutz Liebmann, J Christopher Hennings, Eric Seemann, Melanie Gerth, Igor Jakovcevski, Julia Preobraschenski, Michael M Kessels, Martin Westermann, Dirk Isbrandt, Reinhard Jahn, Britta Qualmann, Christian A Hübner
Brain functions are extremely sensitive to pH changes because of the pH-dependence of proteins involved in neuronal excitability and synaptic transmission. Here, we show that the Na+/H+ exchanger Nhe1, which uses the Na+ gradient to extrude H+, is expressed at both inhibitory and excitatory presynapses. We disrupted Nhe1 specifically in mice either in Emx1-positive glutamatergic neurons or in parvalbumin-positive cells, mainly GABAergic interneurons. While Nhe1 disruption in excitatory neurons had no effect on overall network excitability, mice with disruption of Nhe1 in parvalbumin-positive neurons displayed epileptic activity...
December 12, 2018: Cerebral Cortex
Xiao Li, Jiaywei Tsauo, Chong Geng, He Zhao, Xuelian Lei, Xiao Li
Na <mml:math xmlns:mml=""> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> /H <mml:math xmlns:mml=""> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> exchanger 1 (NHE1) plays a vital role in the oncogenesis and development of hepatocellular carcinoma (HCC) and has been regarded as a promising target for the treatment of HCC...
December 10, 2018: American Journal of Chinese Medicine
Helene H Jensen, Gitte A Pedersen, Jeanette J Morgen, Maddy Parsons, Stine F Pedersen, Lene N Nejsum
Exogenous NHE1 expression stimulated collective migration of epithelial cell sheets Stimulation with epidermal growth factor (EGF), a key morphogen, primarily increased migration of the front row of cells, whereas NHE1 increased that of submarginal cell rows, and the two stimuli were additive Accordingly, NHE1 localized not only to the leading edges of leader cells, but also in cryptic lamellipodia in submarginal cell rows NHE1 expression disrupted the morphology of epithelial cell sheets and 3D cysts ABSTRACT: Collective cell migration plays essential roles in embryonic development, in normal epithelial repair processes, and in many diseases including cancer...
November 24, 2018: Journal of Physiology
Haixia Wang, Xingtao Long, Dong Wang, Meng Lou, Dongling Zou, Rui Chen, Weiqi Nian, Qi Zhou
Na+ /H+ exchanger isoform 1 (NHE1), which is a regulator of intracellular and extracellular pH via ion exchange, has been demonstrated to serve an important role in cell differentiation, migration and invasion in solid tumors and hematological malignancies. However, the potential role of NHE1 in epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression pattern and the prognostic value of NHE1 were investigated in EOC. EOC tissues, non-cancerous tumors and normal ovarian tissues were collected, and the expression levels of NHE1 were determined using the reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry...
November 2018: Oncology Letters
Nicolai M Doliba, Andriy M Babsky, Mary D Osbakken
Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na+ ) in diabetic cardiomyopathy and provides unique data on the linkage between Na+ flux and energy metabolism, studied with non-invasive 23 Na, and 31 P-NMR spectroscopy, polarography, and mass spectroscopy...
2018: Frontiers in Physiology
Xiudong Guan, Lanxin Luo, Gulnaz Begum, Gary Kohanbash, Qingkun Song, Aparna Rao, Nduka Amankulor, Baoshan Sun, Dandan Sun, Wang Jia
BACKGROUND: Sodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans, is the main H+ efflux mechanism in maintaining alkaline intracellular pH (pHi ) and Warburg effects in glioma. However, to date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment. In this study, we investigated NHE1 expression in gliomas and its relationship with glioma clinical outcome. METHODS: The Chinese Glioma Genome Atlas (CGGA) dataset containing transcriptome sequencing data of 325 glioma samples and the Cancer Genome Atlas (TCGA) with 698 glioma mRNAseq data were analyzed in this study...
October 17, 2018: Journal of Experimental & Clinical Cancer Research: CR
Maria Raffaella Greco, Emeline Bon, Rosa Rubino, Lorenzo Guerra, Manuel Bernabe-Garcia, Stefania Cannone, Maria-Luisa Cayuela, Loredana Ciaccia, Séverine Marionneau-Lambot, Thibauld Oullier, Gaëlle Fromont, Roseline Guibon, Sébastien Roger, Stephan Joel Reshkin, Rosa Angela Cardone
Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns...
October 13, 2018: Biochimica et biophysica acta. Molecular basis of disease
Hong-Ming Zhang, Mo-Yan Liu, Jun-Xiu Lu, Mo-Li Zhu, Qun Jin, Song Ping, Peng Li, Xu Jian, Ya-Ling Han, Shuang-Xi Wang, Xiao-Yan Li
AIMS: The impaired angiogenesis is the major cause of diabetic delayed wound healing. The molecular insight remains unknown. Previous study has shown that high glucose (HG) activates Na+ /H+ exchanger 1 (NHE1) and induces intracellular alkalinization, resulting in endothelial dysfunction. The aim of this study is to investigate whether activation of NHE1 in endothelial cells by HG damages the angiogenesis in vitro and in vivo. METHODS AND RESULTS: We used western blot to detect the phosphorylations of both Akt and Girdin, and pH-sensitive BCECF fluorescence to assay NHE1 activity and pHi value, respectively...
August 10, 2018: International Journal of Cardiology
Simon Fuchs, Sierra C Hansen, Marie Markones, Evgeny V Mymrikov, Heiko Heerklotz, Carola Hunte
The Na+ /H+ exchanger NHE1 is critical for cell vitality as it controls intracellular pH and cell volume. Its functionality is influenced by calcineurin B homologous proteins (CHPs). The human isoform CHP3 is important for transport of NHE1 to the plasma membrane and for its activity. Here, we characterized the binding interaction of human CHP3 with the regulatory domain of NHE1. The exact binding site of CHP3 was previously debated. CHP3 as well as both regions of NHE1 in question were produced and purified...
October 4, 2018: Scientific Reports
Xiudong Guan, Md Nabiul Hasan, Gulnaz Begum, Gary Kohanbash, Karen E Carney, Victoria M Pigott, Anders I Persson, Maria G Castro, Wang Jia, Dandan Sun
The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pHi ) of glioma cells and acidic microenvironment. In addition, NHE1 is expressed in tumor-associated microglia and tumor-associated macrophages (TAMs) and involved in protumoral communications between glioma and TAMs. Therefore, we hypothesize that NHE1 plays a role in developing tumor resistance and immunosuppressive tumor microenvironment. In this study, we investigated the efficacy of pharmacological inhibition of NHE1 on combinatorial therapies...
September 27, 2018: Cell Death & Disease
Gül Şimşek, Richard D Vaughan-Jones, Pawel Swietach, H Burak Kandilci
The heart is highly active metabolically but relatively underperfused and, therefore, vulnerable to ischemia. In addition to acidosis, a key component of ischemia is hypoxia that can modulate gene expression and protein function as part of an adaptive or even maladaptive response. Here, using cardiac-derived HL-1 cells, we investigate the effect of various hypoxic stimuli on the expression and activity of Na+ /H + exchanger 1 (NHE1), a principal regulator of intracellular pH. Acute (10 min) anoxia produced a reversible decrease in the sarcolemmal NHE1 activity attributable to NHE1 internalization...
September 7, 2018: Journal of Cellular Physiology
Marta Peretti, Federica Maddalena Raciti, Valentina Carlini, Ivan Verduci, Sarah Sertic, Sara Barozzi, Massimiliano Garré, Alessandra Pattarozzi, Antonio Daga, Federica Barbieri, Alex Costa, Tullio Florio, Michele Mazzanti
Glioblastoma (GB) is the most lethal, aggressive, and diffuse brain tumor. The main challenge for successful treatment is targeting the cancer stem cell (CSC) subpopulation responsible for tumor origin, progression, and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro , CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo Here, we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs...
November 2018: Molecular Cancer Therapeutics
Alexandra Charruyer, Ruby Ghadially
Intracellular pH influences proliferation and differentiation in a range of stem-like and progenitor cells, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, and cancer stem cells. Sodium hydrogen exchanger (NHE1), a glycoprotein that plays a major role in regulating intracellular pH, has a major role in the proliferation and cell differentiation in multiple cell types. We review observations collected on the influence of pH on multiple stem-like cell populations. Altering pH, either intracellular or extracellular, can influence stem cell maintenance, self-renewal, differentiation, and pluripotency...
2018: Current Problems in Dermatology
Muna Suleiman, Nabeel Abdulrahman, Huseyin Yalcin, Fatima Mraiche
Cardiac remodeling, characterized by excessive extracellular matrix (ECM) remodeling, predisposes the heart to failure if left unresolved. Understanding the signaling mechanisms involved in excessive extracellular matrix (ECM) remodeling is necessary to identify the means to regress the development of cardiac remodeling and heart failure. Recently, hyaluronan (HA), a ubiquitously expressed glycosaminoglycan in the ECM, was shown to participate in tissue fibrosis and myofibroblast proliferation through interacting with its ubiquitously expressed cell-surface receptor, CD44...
September 15, 2018: Life Sciences
Rittwika Bhattacharya, Chinmay Kumar Panda, Sourav Nandi, Ashis Mukhopadhyay
Mechanical or fostered molecular events define metastatic cascade. Three distinct sets of molecular events characterize metastasis, viz invasion of extracellular matrix; angiogenesis, vascular dissemination and anoikis resistance; tumor homing and relocation of tumor cells to selective organ. Invasion of extracellular matrix requires epithelial to mesenchymal transition through disrupted lamellopodia formation and contraction of actin cytoskeleton; aberration of Focal adhesion complex formation involving integrins and the extracellular matrix; degradation of extracellular matrix by matrix metalloproteases; faulty immune surveillance in tumor microenvironment and an upregulated proton efflux pump NHE1 in tumors...
August 2018: Pathology, Research and Practice
Debajyoti Dutta, Larry Fliegel
Na+ /H+ exchanger isoform one (NHE1) is a mammalian plasma membrane protein that removes intracellular protons, thereby elevating intracellular pH (pHi ). NHE1 uses the energy of allowing an extracellular sodium down its gradient into cells to remove one intracellular proton. The ubiquitous protein has several important physiological and pathological influences on mammalian cells as a result of its activity. The three-dimensional structure of human NHE1 (hNHE1) is not known. Here, we modeled NHE1 based on the structure of MjNhaP1 of Methanocaldoccocus jannaschii in combination with biochemical surface accessibility data...
July 30, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Harry C Blair, Quitterie C Larrouture, Irina L Tourkova, Li Liu, Jing Hao Bian, Donna Beer Stolz, Deborah J Nelson, Paul H Schlesinger
Osteoblasts secrete collagen and isolate bone matrix from extracellular space. In the matrix, alkaline phosphatase generates phosphate that combines with calcium to form mineral, liberating 8 H+ per 10 Ca+2 deposited. However, pH-dependent hydroxyapatite deposition on bone collagen had not been shown. We studied the dependency of hydroxyapatite deposition on type I collagen on pH and phosphate by surface plasmon resonance in 0-5 mM phosphate at pH 6.8-7.4. Mineral deposition saturated at <1 mM Ca2+ but was sensitive to phosphate...
October 1, 2018: American Journal of Physiology. Cell Physiology
Shanshan Song, Shaoxia Wang, Victoria M Pigott, Tong Jiang, Lesley M Foley, Abhishek Mishra, Rachana Nayak, Wen Zhu, Gulnaz Begum, Yejie Shi, Karen E Carney, T Kevin Hitchens, Gary E Shull, Dandan Sun
Na+ /H+ exchanger (NHE1) activation is required for multiple microglial functions. We investigated effects of selective deletion of microglial Nhe1 in Cx3cr1-CreER ;Nhe1f/f mice on neuroinflammation and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)-treated mice at 48 hr and 14 days post-stroke. However, the Tam-treated mice showed significantly higher survival rate and faster neurological function recovery during day 1-14 post-stroke. Deletion of microglial Nhe1 prevented the elevation of CD11b+ /CD45low-med microglia in the ischemic hemisphere at day 3 post-stroke, but stimulated expression of Ym1, CD68, TGF-β, IL-10, decreased expression of CD86 and IL-1β, and reduced GFAP+ reactive astrocytes...
July 25, 2018: Glia
Peng Wang, Xin Wang, Ling Li, Quancheng Kan, Zujiang Yu, Rongfang Feng, ZiXiao Chen, Yan Shi, Jinling Gao
BACKGROUND: The "secondary injury" theory of liver failure indicated that hyperammonaemia due to liver failure causes further deterioration of hepatocytes. Our previous studies have demonstrated that high blood ammonia levels may lead to hepatocyte apoptosis, as NH4 Cl loading caused metabolic acidosis and an increase in sodium-hydrogen exchanger isoform 1 (NHE1). In this study, we established a hyperammonia hepatocyte model to determine the role of NHE1 in the regulation of hepatocyte apoptosis induced by NH4 Cl...
October 2018: Gastroenterología y Hepatología
Jin Xue, Dan Zhou, Orit Poulsen, Iain Hartley, Toshihiro Imamura, Edward X Xie, Gabriel G Haddad
Numerous studies have demonstrated that Na+ /H+ exchanger isoform 1 (NHE1) is elevated in myocardial diseases and its effect is detrimental. To better understand the involvement of NHE1, we have previously studied cardiac-specific NHE1 transgenic mice and shown that these mice develop cardiac hypertrophy, interstitial fibrosis, and cardiac dysfunction. The purpose of current study was to identify microRNAs and their mRNA targets involved in NHE1-mediated cardiac injury. An unbiased high-throughput sequencing study was performed on both microRNAs and mRNAs...
October 1, 2018: Physiological Genomics
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