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Intracellular acidosis

Md Fazlur Rahman, Radhika Raj, Rajgopal Govindarajan
Combination antiretroviral drug treatments depend on 3'-deoxy-nucleoside analogs such as AZT (3'-azido-3'-deoxythymidine) and DDI (2'3'-dideoxyinosine). Despite being effective in inhibiting HIV viral replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. While the cell surface localized nucleoside transporters (e.g., human equilibrative nucleoside transporter 2 (hENT2), human concentrative nucleoside transporter 1 (hCNT1)) are known to increase the carrier mediated uptake of 3'-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter, namely, hENT3, has been implicated in the mitochondrial transport of 3'-deoxy-nucleoside analogs...
March 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Gunng-Shinng Chen, Shiao-Pieng Lee, Shu-Fu Huang, Shih-Chi Chao, Chung-Yi Chang, Gwo-Jang Wu, Chung-Hsing Li, Shih-Hurng Loh
OBJECTIVE: Homeostasis of intracellular pH (pHi ) plays vital roles in many cell functions, such as proliferation, apoptosis, differentiation and metastasis. Thus far, Na+ -H+ exchanger (NHE), Na+ -HCO3 - co-transporter (NBC), Cl- /HCO3 - exchanger (AE) and Cl- /OH- exchanger (CHE) have been identified to co-regulate pHi homeostasis. However, functional and biological pHi -regulators in human dental pulp stem cells (hDPSCs) have yet to be identified. DESIGN: Microspectrofluorimetry technique with pH-sensitive fluorescent dye, BCECF, was used to detect pHi changes...
March 6, 2018: Archives of Oral Biology
Paul C McDonald, Mridula Swayampakula, Shoukat Dedhar
Hypoxia is a prominent feature of the tumor microenvironment (TME) and cancer cells must dynamically adapt their metabolism to survive in these conditions. A major consequence of metabolic rewiring by cancer cells in hypoxia is the accumulation of acidic metabolites, leading to the perturbation of intracellular pH (pHi) homeostasis and increased acidosis in the TME. To mitigate the potentially detrimental consequences of an increasingly hypoxic and acidic TME, cancer cells employ a network of enzymes and transporters to regulate pH, particularly the extracellular facing carbonic anhydrase IX (CAIX) and CAXII...
March 8, 2018: Metabolites
Manoj Kamal, Geeta Singariya, Om Prakash Suthar, Ashwini S
Acute hypokalemic paralysis is a reversible but potentially lethal clinical condition. We report a case, who developed rapidonset quadriparesis in immediate postoperative period after undergoing right percutaneous nephrolithotomy for bilateral renal stones. On evaluation, she was found to have hypernatremic, hyperchloremic, hypokalemic acidosis. This severe hypokalemia-induced quadriparesis was precipitated by repeated furosemide injections, use of potassium-free fluid as maintenance, intracellular shift due to free water administration in this patient, who had pre-existing distal renal tubular acidosis...
March 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Erik R Swenson
Maintenance of intracellular pH is critical for clinical homeostasis. The metabolism of glucose, fatty acids, and amino acids yielding the generation of adenosine triphosphate in the mitochondria is accompanied by the production of acid in the Krebs cycle. Both the nature of this acidosis and the mechanism of its disposal have been argued by two investigators with a long-abiding interest in acid-base physiology. They offer different interpretations and views of the molecular mechanism of this intracellular pH regulation during normal metabolism...
February 15, 2018: Anesthesiology
Evan J Myers, Aniko Marshall, Mark D Parker
Mutations in the sodium bicarbonate cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA). We recently described a novel pRTA mutation p.Gln913Arg (Q913R), inherited in compound heterozygous form with p.Arg510His (R510H). Q913R causes intracellular retention of NBCe1 and a 'gain of function' Cl - leak. To learn more about the importance of glutamine at position 913, we substituted a variety of alternative amino-acid residues (Cys, Glu, Lys, Leu, Ser) at position 913. Studying cRNA-injected Xenopus oocytes by voltage clamp, we find that most de novo mutants exhibit close-to-normal NBCe1 activity; only Q913K expresses a Cl - leak...
February 15, 2018: Scientific Reports
Rebecca Grammer, Jingping Wang, Edward Lahey
Rhabdomyolysis is a condition in which damaged muscle tissue breaks down and intracellular contents, including myoglobin, are released into the circulation. This produces a nonspecific clinical syndrome including electrolyte disturbances, hypovolemia, metabolic acidosis, coagulopathies, and risk of acute kidney injury. Rhabdomyolysis has been reported as a complication of prolonged surgical procedures but has rarely been reported in the oral and maxillofacial surgery literature. Early diagnosis and treatment of rhabdomyolysis are important to avoid long-term complications such as renal failure...
February 2, 2018: Journal of Oral and Maxillofacial Surgery
Tugba Ugurlu, Candan Ozogul, Gulistan Sanem Saribas, Seren Gulsen Gurgen, Seda Nur Akyol, Bahar Kartal
The aim of this study was to investigate the effect of antioxidants on angiogenesis in uterine transplantation. We used 24 female rats equally divided into four groups: Group 1 had the uterus stored in HTK (Histidine-Tryptophan-Ketoglutarate) solution at 4 °C cold storage for 4 h. Group 2 had the uterine tissue stored in HTK solution combined with acetyl L-carnitine (10-8  M) for 4 h at +4 °C. The same procedures with Group 1 and 2 were repeated for 24 h for Groups 3 and 4, respectively. Histological investigation and immunohistochemical analysis were performed...
January 31, 2018: Journal of Obstetrics and Gynaecology: the Journal of the Institute of Obstetrics and Gynaecology
Michael Brannen, Kathleen M Gilmour
Rainbow trout (Oncorhynchus mykiss) exposed to acid-base challenges activate branchial mechanisms for the excretion of acid-base equivalents. Current models of branchial acid-base excretion in freshwater rainbow trout propose two main ionocyte types; the peanut lectin agglutinin-positive (PNA+) mitochondrion-rich cell or ionocyte is believed to secrete HCO3- in exchange for Cl-, whereas H+ secretion is thought to occur across PNA- ionocytes in exchange for Na+ Both HCO3- and H+ are supplied by intracellular hydration of CO2 catalyzed by cytosolic carbonic anhydrase (CAc)...
January 29, 2018: Journal of Experimental Biology
Aniket V Mali, Sunita S Bhise, Surendra S Katyare, Mahabaleshwar V Hegde
Recent studies have been noted that the erythrocytes from Type II diabetic patients show significantly altered structural and functional characteristics along with the changed intracellular concentrations of glycolytic intermediates. More recent studies from our laboratory have shown that the activities of enzymes of glycolytic pathway changed significantly in RBCs from Type II diabetic patients. In particular the levels of lactate dehydrogenase (LDH) increased significantly. Lactic acidosis is an established feature of diabetes and LDH plays a crucial role in conversion of pyruvate to lactate and reportedly, the levels of lactate are significantly high which is consistent with our observation on increased levels of LDH...
January 2018: Indian Journal of Clinical Biochemistry: IJCB
Alejandro Ciocci Pardo, Romina G Díaz, Luisa F González Arbeláez, Nestor G Perez, Erik Richard Swenson, Susana M Mosca, Bernardo V Alvarez
During ischemia, increased anaerobic glycolysis results in intracellular acidosis. Activation of alkalinizing transport mechanisms associated with carbonic anhydrases (CA) leads to myocardial intracellular Ca2+ increase. We characterize the effects of inhibition of CA with benzolamide (BZ) during cardiac ischemia-reperfusion (I/R). Langendorff perfused isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion. Other hearts were treated with BZ (5 μM) during the initial 10 min of reperfusion or perfused with acid solution (AR, pH 6...
December 21, 2017: Journal of Applied Physiology
José Teixeira, Farhan Basit, Herman G Swarts, Marleen Forkink, Paulo J Oliveira, Peter H G M Willems, Werner J H Koopman
The extracellular pH (pHe) is a key determinant of the cellular (micro)environment and needs to be maintained within strict boundaries to allow normal cell function. Here we used HEK293 cells to study the effects of pHe acidification (24h), induced by mitochondrial inhibitors (rotenone, antimycin A) and/or extracellular HCl addition. Lowering pHe from 7.2 to 5.8 reduced cell viability by 70% and was paralleled by a decrease in cytosolic pH (pHc), hyperpolarization of the mitochondrial membrane potential (Δψ), increased levels of hydroethidine-oxidizing ROS and stimulation of protein carbonylation...
December 30, 2017: Redox Biology
Sally Esmail, Norbert Kartner, Yeqi Yao, Joo Wan Kim, Reinhart A F Reithmeier, Morris F Manolson
The a subunit is the largest of 15 different subunits that make up the vacuolar H+-ATPase (V-ATPase) complex, where it functions in proton translocation. In mammals, this subunit has four paralogous isoforms, a1-a4, which may encode signals for targeting assembled V-ATPases to specific intracellular locations. Despite the functional importance of the a subunit, its structure remains controversial. By studying molecular mechanisms of human disease-causing missense mutations within a subunit isoforms, we may identify domains critical for V-ATPase targeting, activity and/or regulation...
January 8, 2018: Journal of Biological Chemistry
Romain Helleringer, Oana Chever, Hervé Daniel, Micaela Galante
During brain ischemia, intense energy deficiency induces a complex succession of events including pump failure, acidosis and exacerbated glutamate release. In the cerebellum, glutamate is the principal mediator of Purkinje neuron anoxic depolarization during episodes of oxygen and glucose deprivation (OGD). Here, the impact of OGD is studied in Bergmann glia, specialized astrocytes closely associated to Purkinje neurons. Patch clamp experiments reveal that during OGD Bergmann glial cells develop a large depolarizing current that is not mediated by glutamate and purinergic receptors but is mainly due to the accumulation of K+ in the extracellular space...
2017: Frontiers in Cellular Neuroscience
Valery V Khramtsov
<i><b>Significance:</b></i> A key role of the tumor microenvironment (TME) in cancer progression, treatment resistance and as a target for therapeutic intervention is increasingly appreciated. Among physiological components of the TME are tissue hypoxia, acidosis, high reducing capacity, elevated concentrations of intracellular glutathione (GSH) and interstitial inorganic phosphate (Pi). Noninvasive <i>in vivo</i> assessment of these parameters provide unique insights into biological processes in TME, and may serve as a tool for pre-clinical screening of anticancer drugs and optimizing TME-targeted therapeutic strategies...
November 13, 2017: Antioxidants & Redox Signaling
Vennetia R Danes, Josephine Anthony, Kaveh Rayani, Kenneth W Spitzer, Glen F Tibbits
The ability of cardiomyocytes to recover from a proton load was examined in the hearts of exercise-trained (T) and sedentary control (C) rats in CO2/HCO3--free media. Acidosis was created by the NH4Cl pre-pulse technique and pHi was determined using fluorescence microscopy on carboxy-SNARF-1 AM loaded isolated cardiomyocytes. CO2-independent intracellular pH buffering capacity (βi) was measured by incrementally reducing the [NH4Cl]o in steps of 50% from 20 to 1.25 mM. βi increased as pHi decreased in both T and C groups...
November 3, 2017: American Journal of Physiology. Heart and Circulatory Physiology
Katie L Barott, Megan E Barron, Martin Tresguerres
Maintaining stable intracellular pH (pHi) is essential for homeostasis, and requires the ability to both sense pH changes that may result from internal and external sources, and to regulate downstream compensatory pH pathways. Here we identified the cAMP-producing enzyme soluble adenylyl cyclase (sAC) as the first molecular pH sensor in corals. sAC protein was detected throughout coral tissues, including those involved in symbiosis and calcification. Application of a sAC-specific inhibitor caused significant and reversible pHi acidosis in isolated coral cells under both dark and light conditions, indicating sAC is essential for sensing and regulating pHi perturbations caused by respiration and photosynthesis...
November 15, 2017: Proceedings. Biological Sciences
José-Carlos Fernández-Morales, Martin Morad
Ischemic heart disease is an arrhythmogenic condition, accompanied by hypoxia, acidosis, and impaired Ca2+ signaling. Here we report on effects of acute hypoxia and acidification in rat neonatal cardiomyocytes cultures. RESULTS: Two populations of neonatal cardiomyocyte were identified based on inactivation kinetics of L-type ICa : rapidly-inactivating ICa (τ~20ms) myocytes (prevalent in 3-4-day cultures), and slow-inactivating ICa (τ≥40ms) myocytes (dominant in 7-day cultures). Acute hypoxia (pO2 <5mmHg for 50-100s) suppressed ICa reversibly in both cell-types to different extent and with different kinetics...
January 2018: Journal of Molecular and Cellular Cardiology
Ren-Peng Zhou, Bei-Bei Dai, Ya-Ya Xie, Xiao-Shan Wu, Zhi-Sen Wang, Yue Li, Zhi-Qiang Wang, Sheng-Qin Zu, Jin-Fang Ge, Fei-Hu Chen
The acute-phase proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) demonstrate high-level expression and pleiotropic biological effects, and contribute to the progression and persistence of rheumatoid arthritis (RA). Acid hydrarthrosis is also an important pathological characteristic of RA, and the acid-sensing ion channel 1a (ASIC1a) plays a critical role in acidosis-induced chondrocyte cytotoxicity. However, the roles of IL-1β and TNF-α in acid-induced apoptosis of chondrocytes remain unclear...
January 2018: Biochimica et Biophysica Acta
Ebbe Boedtkjer
Metabolic regulation of cerebrovascular tone directs blood flow to areas of increased neuronal activity and during disease states partially compensates for insufficient perfusion by enhancing blood flow in collateral blood vessels. Acid-base disturbances frequently occur as result of enhanced metabolism or insufficient blood supply, but despite definitive evidence that acid-base disturbances alter arterial tone, effects of individual acid-base equivalents and the underlying signaling mechanisms are still being debated...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
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