Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Baccharis illinita DC (Compositae) is used in folk medicine to treat gastric disturbances. Preliminary studies with other extracts of B. Illinita showed gastric protection against ethanol-, indometacin- and stress-induced ulcers and the inhibition of gastric secretion. Based on these data, the aim of this study was to verify the pathways involved in the inhibition of gastric secretion. The chloroform extract (CE) of flowers from B. illinita (3, 10, 30 and 100 mg kg(-1) i.p.) tested on rats with pylorus ligature reduced the volume and the total acidity of gastric content by approximately 50% (ED50 = 69 mg kg(-1)). Treatment with CE (100 mg kg(-1) i.p.) reduced the gastric total acidity stimulated by histamine, bethanechol and pentagastrin to 42%, 27% and 57% of that in the stimulated control group, respectively. The CE (10, 30 and 100 microM) inhibited H+/K+ ATPase activity in-vitro, with an IC50 of 37 microM. The isolated flavonoid luteolin (1, 3, 10 and 30 microM) also inhibited H+/K+ ATPase activity by 50%, at a dose of 30 microM. Our results suggest that the reduction in gastric secretion occurs through inhibition of H+/K+ ATPase, which is the final step in acid secretion and therefore one of the most important steps.
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PMID:Inhibition of H+/K+ ATPase in the gastroprotective effect of Baccharis illinita DC. 1864 3

The lumen of endosomal organelles becomes increasingly acidic when going from the cell surface to lysosomes. Luminal pH thereby regulates important processes such as the release of internalized ligands from their receptor or the activation of lysosomal enzymes. The main player in endosomal acidification is the vacuolar ATPase (V-ATPase), a multi-subunit transmembrane complex that pumps protons from the cytoplasm to the lumen of organelles, or to the outside of the cell. The active V-ATPase is composed of two multi-subunit domains, the transmembrane V(0) and the cytoplasmic V(1). Here we found that the ratio of membrane associated V(1)/Vo varies along the endocytic pathway, the relative abundance of V(1) being higher on late endosomes than on early endosomes, providing an explanation for the higher acidity of late endosomes. We also found that all membrane-bound V-ATPase subunits were associated with detergent resistant membranes (DRM) isolated from late endosomes, raising the possibility that association with lipid-raft like domains also plays a role in regulating the activity of the proton pump. In support of this, we found that treatment of cells with U18666A, a drug that leads to the accumulation of cholesterol in late endosomes, affected acidification of late endosome. Altogether our findings indicate that the activity of the vATPase in the endocytic pathway is regulated both by reversible association/dissociation and the interaction with specific lipid environments.
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PMID:Regulation of the V-ATPase along the endocytic pathway occurs through reversible subunit association and membrane localization. 1864 2

Exposure of trout hepatocytes to hypertonicity induced a decrease in acridine orange (AO) fluorescence, indicating a corresponding decrease in pH inside the lumen of acidic compartments (pH(L)). Pre-exposure of cells to the specific V-ATPase inhibitor bafilomycin A1 (0.3 micromol l(-1)) increased AO fluorescence - unmasking H(+) leaks under steady-state conditions - and partially removed the hypertonicity-induced pH(L) decrease. The sustainability of the luminal acidification, but not the acidification itself, appeared to depend on a low K(+) and a high Cl(-) conductance under hypertonic conditions. Increasing K(+) conductance using the specific ionophore valinomycin (10 micromol l(-1)) or removal of extracellular Cl(-) after an instant drop in AO fluorescence resulted in a reversal of luminal acidity. The alkalinization measured under hypertonic conditions in the absence of Cl(-) was largely attenuated when cells were bathed in HCO(3)(-)-free medium, signifying the possible presence of Cl(-)/HCO(3)(-) exchange. Under steady-state conditions, while a slight and brief pH(L) increase was measured upon exposure of cells to valinomycin, Cl(-) removal, unexpectedly, induced a decrease in pH(L), indicating a role for extracellular Cl(-) in limiting luminal acidification. This was confirmed by the substantial pH(L) decrease measured upon exposure of cells to the anion exchanger inhibitor SITS (0.5 mmol l(-1)). Furthermore, hypertonicity-induced acidification was still noticeable in the presence of SITS. On the other hand, the hypertonicity-induced acidification was significantly reduced in the absence of extracellular Na(+) or Ca(2+). However, BAPTA-AM induced an increase in steady-state pH(L) that was independent of V-ATPase inhibition. Moreover, the BAPTA-induced alkalinization was still apparent after depletion of intracellular Ca(2+) using the Ca(2+) ionophore A23187 in Ca(2+)-free medium. We conclude that pH(L) of trout hepatocytes is sensitive to hypertonicity and ionic determinants of hypertonicity. Thus, changes in pH(L) should be considered when studying pH adaptations to hypertonic stress.
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PMID:Ionic determinants of pH of acidic compartments under hypertonic conditions in trout hepatocytes. 1884 Jun 65

Vacuolar ATPases (V-ATPases) are ATP-dependent proton pumps that maintain the acidity of cellular compartments. They are composed of a membrane-integrated proton-translocating V(0) and an extrinsic cytoplasmic catalytic domain V(1), joined by several connecting subunits. To clarify the arrangement of these peripheral connections and their interrelation with other subunits of the holocomplex, we have determined the solution structures of isolated EG and EGC connecting subcomplexes by small angle X-ray scattering and the 3D map of the yeast V-ATPase by electron microscopy. In solution, EG forms a slightly kinked rod, which assembles with subunit C into an L-shaped structure. This model is supported by the microscopy data, which show three copies of EG with two of these linked by subunit C. However, the relative arrangement of the EG and C subunits in solution is more open than that in the holoenzyme, suggesting a conformational change of EGC during regulatory assembly and disassembly.
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PMID:A different conformation for EGC stator subcomplex in solution and in the assembled yeast V-ATPase: possible implications for regulatory disassembly. 1908 Oct 55

PtdIns(3,5)P(2) is one of the seven regulatory PPIn (polyphosphoinositides) that are ubiquitous in eukaryotes. It controls membrane trafficking at multiple points in the endosomal/lysosomal system and consequently regulates the size, shape and acidity of at least one endo-lysosomal compartment. PtdIns(3,5)P(2) appears to exert this control via multiple effector proteins, with each effector specific for a subset of the various PtdIns(3,5)P(2)-dependent processes. Some putative PtdIns(3,5)P(2) effectors have been identified, including Atg18p-related PROPPIN [beta-propeller(s) that bind PPIn] proteins and the epsin-like proteins Ent3p and Ent5p, whereas others remain to be defined. One of the principal functions of PtdIns(3,5)P(2) is to regulate the fission/fragmentation of endo-lysosomal sub-compartments. PtdIns(3,5)P(2) is required for vesicle formation during protein trafficking between endo-lysosomes and also for fragmentation of endo-lysosomes into smaller compartments. In yeast, hyperosmotic stress accelerates the latter process. In the present review we highlight and discuss recent studies that reveal the role of the HOPS-CORVET complex and the vacuolar H(+)-ATPase in the process of endo-lysosome fission, and speculate on connections between these machineries and the Fab1p pathway. We also discuss new evidence linking PtdIns(3,5)P(2) and PtdIns5P to the regulation of exocytosis.
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PMID:Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. 1927 20

Fast reaction kinetics of ATP hydrolysis by Na,K-ATPase has been investigated by following absorption pattern of pH sensitive dye in stopped flow spectrophotometer. Distinct pre-steady state phase signal could be recorded with an initial decrease in acidity followed by increase in acidity. Average half time for H(+) absorption and peak alkalinity was, respectively, 30 ms and 60 ms. Under optimal Na(+) (120 mM) and K(+) (30 mM) concentrations, magnitude of both H(+) absorption and H(+) release are found to be about 1.0 H(+)/ATPase molecule. H(+) absorption and release decreased with decrease in Na(+) concentration, H(+) release was more affected. Both H(+) absorption and H(+) release are found to be independent of K(+) concentration in the pre-steady state phase. No H(+) absorption or release was observed following mixing of either ADP, Na(+) or K(+) alone with ATPase. Effect of delayed mixing of Na(+) or K(+) on two phases of pre-steady state cycle indicates that ATP hydrolytic cycle starts without K(+) ions if optimal Na(+) is present. ATP hydrolytic cycle does not start in the absence of Na(+) ions. Results obtained have been interpreted in terms of an extended kinetic scheme for Na,K-ATPase.
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PMID:Pre-steady state kinetics of ATP hydrolysis by Na,K-ATPase. 1927 93

One of the mechanisms of multiple drug resistance (MDR) is inappropriate sequestration of basic chemotherapeutic agents in acidic endo-lysosomes of cells. The protonation, sequestration, and secretion (PSS) model indicates that drug distribution can be affected by intracellular pH such as lysosomal pH. The vacuolar-H(+)-ATPase (V-ATPase) plays an important role in regulation of intracellular pH by pumping protons into acidic endosomes via an ATP-driven process. In this study, ATP6L, the 16kDa subunit of V-ATPase, was knocked-down by anti-ATP6L small interfering RNA (siRNA) to study the effect on chemosensitivity in the human drug-resistant breast cancer cells MCF-7/ADR. Introduction of anti-ATP6L small interfering RNA duplex into drug-resistant cancer cells significantly inhibited the expression of ATP6L mRNA and protein, as detected by qRT-PCR and Western blot. Inhibition of ATP6L expression by siRNA in MCF-7/ADR sensitized the cells to the cytotoxicity of basic chemotherapeutic agents like doxorobicin, 5-fluorourocil and vincristine. This effect was mediated by a significant increase in lysosomal pH and retention of anticancer drugs into nuclei of cells. These results support the role of tumor acidity in resistance to chemotherapy and provide a rationale for the use of tumor pH modifier agents as coadjuvants in novel anticancer therapies.
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PMID:Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. 1929 75

Acidity is one of the main characteristics of OSCC (oral squamous cell carcinoma) as a solid tumor. The V-ATPase is the primary regulator of the tumor microenvironment, by means of proton extrusion to the extracellular medium. The decrease in extracellular pH confers the cells a resistant, highly invasive and metastatic phenotype. However, the acid medium confers an optimum pH to the degradative enzymes (such as proteases and MMPs) for their proper functioning. The C subunit (ATP6V1C) of V1 intra-membrane domain of the V-ATPase, is primarily responsible for its enzymatic function, through the control of a reversible dissociation of V0 and V1 domains. In this review, we describe the importance of V-ATPases in the control of tumor microenvironment, the potential strategies as protein targeting to improve the effectiveness of drug treatment and the role of the C subunit as the primarily responsible of the enzymatic control. The inhibition of the V-ATPase activity through PPIs (proton inhibitors) seems to reduce the destructive and metastatic capacity in tumors, such as hepatocellular carcinoma. Nevertheless, none of these inhibitors was proven to be useful in OSCC; therefore, it is highly important to carry out further studies in order to develop specific inhibitors of the C subunit, to control the devastating effects of OSCC.
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PMID:Role of V-ATPases in solid tumors: importance of the subunit C (Review). 1942 68

In the epididymis, spermatozoa acquire their ability to become motile and to fertilize an egg. A luminal acidic pH and a low bicarbonate concentration help keep spermatozoa in a quiescent state during their maturation and storage in this organ. Net proton secretion is crucial to maintain the acidity of the luminal fluid in the epididymis. A sub-population of epithelial cells, the clear cells, express high levels of the proton-pumping V-ATPase in their apical membrane and are important contributors to luminal acidification. This review describes selected aspects of V-ATPase regulation in clear cells. The assembly of a particular set of V-ATPase subunit isoforms governs the targeting of the pump to the apical plasma membrane. Regulation of V-ATPase-dependent proton secretion occurs via recycling mechanisms. The bicarbonate-activated adenylyl cyclase is involved in the non-hormonal regulation of V-ATPase recycling, following activation of bicarbonate secretion by principal cells. The V-ATPase is also regulated in a paracrine manner by luminal angiotensin II by activation of the angiotensin II type 2 receptor (AGTR2), which is located in basal cells. Basal cells have the remarkable property of extending long and slender cytoplasmic projections that cross the tight junction barrier to monitor the luminal environment. Clear cells are activated by a nitric oxide signal that originates from basal cells. Thus, a complex interplay between the different cell types present in the epithelium leads to activation of the luminal acidifying capacity of the epididymis, a process that is crucial for sperm maturation and storage.
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PMID:Regulation of luminal acidification in the male reproductive tract via cell-cell crosstalk. 1944 84

The gastrointestinal activity of hydroalcoholic extract (HE) of Salvia officinalis was evaluated in a model of ethanol-induced gastric lesion. HE showed excellent activity, with ID(50) 84.0 (54.8-128.9) mg/kg. The acetic acid-induced ulcer and the total acidity of the gastric secretion were also reduced by HE, and, in vitro experiments, the H(+),K(+)-ATPase activity was inhibited. Carnosol was identified as a possible active constituent for the gastroprotective effect of HE.
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PMID:Gastroprotective constituents of Salvia officinalis L. 1948 90


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