scholarly journals Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

2019 ◽  
Vol 20 (17) ◽  
pp. 4278 ◽  
Author(s):  
Salvador Harguindey ◽  
Julian Polo Orozco ◽  
Khalid O. Alfarouk ◽  
Jesús Devesa
Keyword(s):  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Hydrogen Ion ◽  
Ion Dynamics ◽  
Short Survival ◽  
Novel Treatments ◽  
The Past ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Ph Dependent

The treatment of cancer has been slowly but steadily progressing during the last fifty years. Some tumors with a high mortality in the past are curable nowadays. However, there is one striking exception: glioblastoma multiforme. No real breakthrough has been hitherto achieved with this tumor with ominous prognosis and very short survival. Glioblastomas, being highly glycolytic malignancies are strongly pH-dependent and driven by the sodium hydrogen exchanger 1 (NHE1) and other proton (H+) transporters. Therefore, this is one of those pathologies where the lessons recently learnt from the new pH-centered anticancer paradigm may soon bring a promising change to treatment. This contribution will discuss how the pH-centric molecular, biochemical and metabolic perspective may introduce some urgently needed and integral novel treatments. Such a prospective therapeutic approach for malignant brain tumors is developed here, either to be used alone or in combination with more standard therapies.

scholarly journals An update of nanoparticle-based approaches for glioblastoma multiforme immunotherapy

Nanomedicine ◽  
2020 ◽  
Vol 15 (19) ◽  
pp. 1861-1871
Author(s):  
Lorenzo Taiarol ◽  
Beatrice Formicola ◽  
Roberta Dal Magro ◽  
Silvia Sesana ◽  
Francesca Re
Keyword(s):  
Drug Delivery ◽  
Glioblastoma Multiforme ◽  
Adverse Effects ◽  
Brain Tumors ◽  
Nucleic Acids ◽  
Targeted Drug Delivery ◽  
The Past ◽  
Targeted Drug ◽  
The Brain ◽  
Made In

Glioblastoma multiforme is a serious medical issue in the brain oncology field due to its aggressiveness and recurrence. Immunotherapy has emerged as a valid approach to counteract the growth and metastasization of glioblastoma multiforme. Among the different innovative approaches investigated, nanoparticles gain attention because of their versatility which is key in allowing precise targeting of brain tumors and increasing targeted drug delivery to the brain, thus minimizing adverse effects. This article reviews the progress made in this field over the past 2 years, focusing on nonspherical and biomimetic particles and on vectors for the delivery of nucleic acids. However, challenges still need to be addressed, considering the improvement of the particles passage across the blood–meningeal barrier and/or the blood–brain barrier, promoting the clinical translatability of these approaches.

scholarly journals Novel Treatments from Inhibition of the Intestinal Sodium–Hydrogen Exchanger 3

2021 ◽  
Vol Volume 14 ◽  
pp. 411-420
Author(s):  
Csaba P Kovesdy ◽  
Adebowale Adebiyi ◽  
David Rosenbaum ◽  
Jeffrey W Jacobs ◽  
L Darryl Quarles
Keyword(s):  
Novel Treatments ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger

scholarly journals Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway

2011 ◽  
Vol 195 (5) ◽  
pp. 903-920 ◽  
Author(s):  
Marco A. O. Magalhaes ◽  
Daniel R. Larson ◽  
Christopher C. Mader ◽  
Jose Javier Bravo-Cordero ◽  
Hava Gil-Henn ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tyrosine Phosphorylation ◽  
Cell Invasion ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Ph Dependent ◽  
Ph Increase ◽  
Dependent Pathway ◽  
Cortactin Tyrosine Phosphorylation ◽  
Local Ph

Invadopodia are invasive protrusions with proteolytic activity uniquely found in tumor cells. Cortactin phosphorylation is a key step during invadopodia maturation, regulating Nck1 binding and cofilin activity. The precise mechanism of cortactin-dependent cofilin regulation and the roles of this pathway in invadopodia maturation and cell invasion are not fully understood. We provide evidence that cortactin–cofilin binding is regulated by local pH changes at invadopodia that are mediated by the sodium–hydrogen exchanger NHE1. Furthermore, cortactin tyrosine phosphorylation mediates the recruitment of NHE1 to the invadopodium compartment, where it locally increases the pH to cause the release of cofilin from cortactin. We show that this mechanism involving cortactin phosphorylation, local pH increase, and cofilin activation regulates the dynamic cycles of invadopodium protrusion and retraction and is essential for cell invasion in 3D. Together, these findings identify a novel pH-dependent regulation of cell invasion.

scholarly journals Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2999
Author(s):  
Benjamin J. Buckley ◽  
Ashna Kumar ◽  
Ashraf Aboelela ◽  
Richard S. Bujaroski ◽  
Xiuju Li ◽  
...  
Keyword(s):  
Selectivity Ratio ◽  
Dual Targeting ◽  
Sodium Hydrogen ◽  
Type Plasminogen Activator ◽  
Single Target ◽  
Urokinase Type Plasminogen Activator ◽  
Anti Cancer ◽  
Sodium Hydrogen Exchanger ◽  
A Cell ◽  
Cell Invasiveness

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

scholarly journals HGG-43. CONGENITAL GLIOBLASTOMA MULTIFORME: A CASE REPORT OF A RARE PEDIATRIC BRAIN TUMOR, MOLECULAR ANALYSIS, AND REVIEW OF THE LITERATURE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii351-iii351
Author(s):  
Christina Amend ◽  
James Stadler ◽  
Shahriar Salamat ◽  
Erik Dedekam ◽  
Angela Waanders ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Pediatric Brain Tumor ◽  
Review Of The Literature ◽  
Who Grade ◽  
Molecular Features ◽  
Pediatric Brain ◽  
Congenital Brain Tumors

Abstract Congenital brain tumors are rare, accounting for less than 4% of all pediatric brain tumors. Congenital glioblastoma multiforme (GBM) is rarer still, accounting for 3–15% of congenital brain tumors. There is literature to suggest that these tumors differ from pediatric and adult GBM clinically and molecularly, and as such should be treated as their own distinct entity. Our case is a 4 week old male who initially presented to his pediatrician for enlarging head circumference and upward gaze palsy. An MRI was obtained revealing a right parietal mass. He underwent gross total resection the following day with pathology revealing glioblastoma, WHO grade IV. Further analysis revealed ATRX retained, p53 immunoreactivity in 15–20% of nuclei, IDH1 and IDH2 wildtype, MGMT promoter not methylated, H3K27M wildtype, no 1p and/or 19q deletion/codeletion. Interestingly, RNA analysis of his tumor detected the PPP1CB-ALK fusion transcript as well as amplification of the ALK gene. Co-occurrence of these mutations has been reported in a small number of pediatric glioblastoma patients and PPP1CB-ALK fusions are one of the most common receptor tyrosine kinase fusions in infantile gliomas. ALK rearrangements and amplifications suggest a potential therapeutic target with tyrosine kinase inhibitors in glioblastoma. This patient serves as an example of a rare congenital glioblastoma with unique molecular features that may suggest novel treatment opportunities. We present his clinical course along with a pertinent review of the literature.

scholarly journals Phosphoproteomic Analysis of Two Contrasting Maize Inbred Lines Provides Insights into the Mechanism of Salt-Stress Tolerance

2019 ◽  
Vol 20 (8) ◽  
pp. 1886 ◽  
Author(s):  
Xiaoyun Zhao ◽  
Xue Bai ◽  
Caifu Jiang ◽  
Zhen Li
Keyword(s):  
Salt Stress ◽  
Inbred Line ◽  
Carbon Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glutathione Metabolism ◽  
Label Free ◽  
Plasma Membrane Intrinsic Protein ◽  
Sodium Hydrogen ◽  
Salt Response ◽  
Sodium Hydrogen Exchanger

Salinity is a major abiotic stress that limits maize yield and quality throughout the world. We investigated phosphoproteomics differences between a salt-tolerant inbred line (Zheng58) and a salt-sensitive inbred line (Chang7-2) in response to short-term salt stress using label-free quantitation. A total of 9448 unique phosphorylation sites from 4116 phosphoproteins in roots and shoots of Zheng58 and Chang7-2 were identified. A total of 209 and 243 differentially regulated phosphoproteins (DRPPs) in response to NaCl treatment were detected in roots and shoots, respectively. Functional analysis of these DRPPs showed that they were involved in carbon metabolism, glutathione metabolism, transport, and signal transduction. Among these phosphoproteins, the expression of 6-phosphogluconate dehydrogenase 2, pyruvate dehydrogenase, phosphoenolpyruvate carboxykinase, glutamate decarboxylase, glutamate synthase, l-gulonolactone oxidase-like, potassium channel AKT1, high-affinity potassium transporter, sodium/hydrogen exchanger, and calcium/proton exchanger CAX1-like protein were significantly regulated in roots, while phosphoenolpyruvate carboxylase 1, phosphoenolpyruvate carboxykinase, sodium/hydrogen exchanger, plasma membrane intrinsic protein 2, glutathione transferases, and abscisic acid-insensitive 5-like protein were significantly regulated in shoots. Zheng58 may activate carbon metabolism, glutathione and ascorbic acid metabolism, potassium and sodium transportation, and the accumulation of glutamate to enhance its salt tolerance. Our results help to elucidate the mechanisms of salt response in maize seedlings. They also provide a basis for further study of the mechanism underlying salt response and tolerance in maize and other crops.

scholarly journals Platelet sodium/hydrogen ion exchange in normal pregnancy and non-proteinuric pre-eclampsia

1997 ◽  
Vol 11 (7) ◽  
pp. 453-458 ◽  
Author(s):  
D Graham ◽  
JCP Kingdom ◽  
J McDonald ◽  
DL Davies ◽  
CJ Kenyon
Keyword(s):  
Ion Exchange ◽  
Normal Pregnancy ◽  
Hydrogen Ion ◽  
Sodium Hydrogen

scholarly journals Mineralocorticoid Action and Sodium-Hydrogen Exchange: Studies in Experimental Cardiac Fibrosis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3848-3851 ◽  
Author(s):  
Morag Young ◽  
John Funder
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Hydrogen Exchange ◽  
Cardiac Fibrosis ◽  
Inflammatory Cell ◽  
Mineralocorticoid Receptor Antagonist ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Coronary Vasculitis ◽  
Potassium Canrenoate

Abstract There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.

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