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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 Garrè, 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) sub-population 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...
August 22, 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 1 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 dependency of hydroxyapatite deposition on type I collagen on pH and phosphate by surface plasmon resonance in 0-5 mM phosphate at pH 6.9-7.6. Mineral deposition saturated at <1 mM Ca2+ , but was sensitive to phosphate...
July 25, 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
Kazuhiro Iwama, Hitoshi Osaka, Takahiro Ikeda, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto
The mammalian Na+ /H+ exchanger isoform one (NHE1), encoded by Solute Carrier Family 9, member 1 (SLC9A1), consists of 12 membrane domains and a cytosolic C-terminal domain. NHE1 plays an important role in maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion. Mice with a homozygous null mutation in Slc9a1 (Nhe1) exhibited ataxia, recurrent seizures, and selective neuronal cell death. In humans, three unrelated patients have been reported: a patient with a homozygous missense mutation in SLC9A1, c...
October 2018: Journal of Human Genetics
Vanessa Gerolde Cardoso, Guilherme Lopes Gonçalves, Juliana Martins Costa-Pessoa, Karina Thieme, Bruna Bezerra Lins, Fernando Augusto Malavazzi Casare, Mariana Charleaux de Ponte, Niels Olsen Saraiva Camara, Maria Oliveira-Souza
BACKGROUND: Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis. METHODS: Wistar rats were treated with Ang II (200 ng·kg-1 ·min-1 , 42 days) and or losartan (10 mg·kg-1 ·day-1 , 14 days)...
July 13, 2018: BMC Nephrology
Shiao-Pieng Lee, Shih-Chi Chao, Shu-Fu Huang, Yen-Lin Chen, Yi-Ting Tsai, Shih-Hurng Loh
BACKGROUND/AIMS: To functionally characterize intracellular pH (pHi) regulating mechanisms, such as Na+-H+ exchanger (NHE) and Na+-HCO3- co-transporter (NBC), and further examine effects of ethanol on the pHi regulating mechanism in human oral epidermoid carcinoma (OEC-M1) cells. METHODS: OEC-M1 cells were a gift from Tri-Service General Hospital. Changes of pHi were detected by microspectrofluroimetry with a pH-sensitive fluorescent dye, BCECF. Isoforms of transporters were examined by Western blot technique...
2018: Cellular Physiology and Biochemistry
Xiaohui Zhao, Tian Xie, Ting Dai, Wenhui Zhao, Jing Li, Rui Xu, Chao Jiang, Peiqiong Li, Junyao Deng, Xiaobo Su, Ningfang Ma
Calcineurin B homologous protein isoform 2 (CHP2), an essential cofactor for Na+ /H+ exchanger isoform 1 (NHE1), is identified to be expressed in various malignant cell lines. However, the clinical significance and biological role of CHP2 in breast cancer remain to be established. Here, CHP2 was markedly overexpressed in breast cancer cells and clinical tumor specimens. Immunohistochemical analysis revealed that the expression of CHP2 was significantly correlated with patients' clinicopathologic characteristics like clinical stage, and breast cancer patients with high CHP2 expression had shorter overall survival compared with patients with low CHP2 expression...
October 2018: Molecular Cancer Research: MCR
Yen-Cheng Chen, Chung-Yi Cheng, Chung-Te Liu, Yuh-Mou Sue, Tso-Hsiao Chen, Yung-Ho Hsu, Pai-An Hwang, Cheng-Hsien Chen
ETHNOPHARMACOLOGICAL RELEVANCE: Brown seaweed is a common food for Asians, and the bioactive ingredient fucoxanthin exerts anti-apoptotic activities in several cell types. Renal tubular cell apoptosis is one of the common cellular events leading to renal fibrosis and chronic kidney disease (CKD). However, the influence of fucoxanthin-containing brown seaweed extract on CKD is still unknown. We intended to evaluate the inhibitory effect of fucoxanthin-containing extract from brown seaweed on renal apoptosis under CKD condition and its molecular mechanism...
October 5, 2018: Journal of Ethnopharmacology
Mette Flinck, Signe Hoejland Kramer, Julie Schnipper, Anne Poder Andersen, Stine Falsig Pedersen
Precise acid-base homeostasis is essential for maintaining normal cell proliferation and growth. Conversely, dysregulated acid-base homeostasis, with increased acid extrusion and marked extracellular acidification, is an enabling feature of solid tumors, yet the mechanisms through which intra- and extracellular pH (pHi , pHe ) impact proliferation and growth are incompletely understood. The aim of this study was to determine the impact of pH, and specifically of the Na+ /H+ exchanger NHE1 and Na+ , HCO3 - transporter NBCn1, on cell cycle progression and its regulators in human breast cancer cells...
2018: Cell Cycle
Huilong Luo, Matthieu Gauthier, Xi Tan, Christophe Landry, Joël Poupon, Marie-Pierre Dehouck, Fabien Gosselet, Nicolas Perrière, Frank Bellivier, Salvatore Cisternino, Xavier Declèves
Variability in drug response to lithium (Li+ ) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li+ . Li+ can be transported by sodium (Na+ ) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na+ transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li+ transport in human brain endothelial cells...
July 2, 2018: Molecular Pharmaceutics
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