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)

The virulence of pathogenic bacteria is dependent on their adaptation to and survival in the stressful conditions encountered in their hosts. Helicobacter pylori exclusively colonizes the acid stomach of primates, making it an ideal study model. Little is known about how H. pylori responds to the moderately acidic conditions encountered at its colonization site, the gastric mucus layer. Thus, we compared gene expression profiles of H. pylori 26695 grown at neutral and acidic pH, and validated the data for a selection of genes by real-time polymerase chain reaction, dot-blots or enzymatic assays. During growth in acidic conditions, 56 genes were upregulated and 45 genes downregulated. We found that acidity is a signal modulating the expression of several virulence factors. Regulation of genes related to metal ion homeostasis suggests protective mechanisms involving diminished transport and enhanced storage. Genes encoding subunits of the F0F1 ATPase and of a newly identified Na+/H+ antiporter (NhaC-HP0946) were downregulated, revealing that this bacterium uses original mechanisms to control proton entry. Five of the upregulated genes encoded proteins controlling intracellular ammonia synthesis, including urease, amidase and formamidase, underlining the major role of this buffering compound in the protection against acidity in H. pylori. Regulatory networks and transcriptome analysis as well as enzymatic assays implicated two metal-responsive transcriptional regulators (NikR and Fur) and an essential two-component response regulator (HP0166, OmpR-like) as effectors of the H. pylori acid response. Finally, a nikR-fur mutant is attenuated in the mouse model, emphasizing the link between response to acidity, metal metabolism and virulence in this gastric pathogen.
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PMID:Responsiveness to acidity via metal ion regulators mediates virulence in the gastric pathogen Helicobacter pylori. 1522 39

Inorganic polyphosphate (polyP) has been identified and measured in human platelets. Millimolar levels (in terms of Pi residues) of short chain polyP were found. The presence of polyP of approximately 70-75 phosphate units was identified by 31P NMR and by urea-polyacrylamide gel electrophoresis of platelet extracts. An analysis of human platelet dense granules, purified using metrizamide gradient centrifugation, indicated that polyP was preferentially located in these organelles. This was confirmed by visualization of polyP in the dense granules using 4',6-diamidino-2-phenylindole and by its release together with pyrophosphate and serotonin upon thrombin stimulation of intact platelets. Dense granules were also shown to contain large amounts of calcium and potassium and both bafilomycin A1-sensitive ATPase and pyrophosphatase activities. In agreement with these results, when human platelets were loaded with the fluorescent calcium indicator Fura-2 acetoxymethyl ester to measure their intracellular Ca2+ concentration ([Ca2+]i), they were shown to possess a significant amount of Ca2+ stored in an acidic compartment. This was indicated by the following: 1) the increase in [Ca2+]i induced by nigericin, monensin, or the weak base, NH4Cl, in the nominal absence of extracellular Ca2 and 2) the effect of ionomycin, which could not take Ca2+ out of acidic organelles and was more effective after alkalinization of this compartment by the previous addition of nigericin, monensin, or NH4Cl. All of these characteristics of the platelet dense granules, together with their known acidity and high density (both by weight and by electron microscopy), are similar to those of acidocalcisomes (volutin granules, polyP bodies) of bacteria and unicellular eukaryotes. The results suggest that acidocalcisomes have been conserved during evolution from bacteria to humans.
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PMID:Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. 1530 50

Effect of various doses (125, 250, 500 and 1000 mg/kg, po) of Normacid was studied on gastric secretion and gastric ulcers in pylorus-ligation and on ethanol-induced gastric mucosal injury in rats. The reduction in ulcer index in both the models along with the reduction in total acidity and an increase in the pH of gastric fluid in pylorus-ligated rats proved the anti-ulcer activity of Normacid. The increase in the levels of superoxide dismutase, catalase, reduced glutathione and membrane bound enzymes like Ca2+ ATPase, Mg2+ ATPase and Na+K+ ATPase and decrease in lipid peroxidation in both the models showed the antioxidant activity of the formulation. Thus it can be concluded that the anti-ulcer activity shown by Normacid may be due to the modulation of defensive factors by improvenent in gastric cytoprotection and partly due to antioxidant property.
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PMID:Anti-ulcer and antioxidant activity of Normacid, a herbomineral formulation. 1533 31

Pepticare, a herbomineral formulation of the Ayurveda medicine consisting of the herbal drugs: Glycyrrhiza glabra, Emblica officinalis and Tinospora cordifolia, was tested for its anti-ulcer and anti-oxidant activity in rats. Effects of various doses (125, 250, 500 and 1000mg/kg, p.o.) of Pepticare were studied on gastric secretion and gastric ulcers in pylorus-ligation and on ethanol-induced gastric mucosal injury in rats. The reduction in ulcer index in both the models along with the reduction in volume and total acidity, and an increase in the pH of gastric fluid in pylorus-ligated rats proved the anti-ulcer activity of Pepticare. It was also found that Pepticare was more potent than G. glabra alone in protecting against pylorus-ligation and ethanol-induced ulcers. The increase in the levels of superoxide dismutase, catalase, reduced glutathione and membrane bound enzymes like Ca2+ ATPase, Mg2+ ATPase and Na+ K+ ATPase and decrease in lipid peroxidation in both the models proved the anti-oxidant activity of the formulation. Thus it can be concluded that Pepticare possesses anti-ulcer activity, which can be attributed to its anti-oxidant mechanism of action.
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PMID:Anti-ulcer and anti-oxidant activity of pepticare, a herbomineral formulation. 1589 3

Solanum nigrum, an herbal plant which is recommended in ayurveda for the management of gastric ulcers. Therefore, the purpose of the study was to investigate the antiulcer effect of Solanum nigrum fruits extract (SNE) on cold restraint stress (CRU), indomethacin (IND), pyloric ligation (PL) and ethanol (EtOH) induced gastric ulcer models and ulcer healing activity on acetic acid induced ulcer model in rats. The treatment with SNE at higher dose significantly inhibited the gastric lesions induced by CRU (76.6%), IND (73.8%), PL (80.1%) and EtOH (70.6%), respectively, with equal or higher potency than omeprazole. SNE showed concomitant attenuation of gastric secretory volume, acidity and pepsin secretion in ulcerated rats. In addition, SNE (200 and 400mg/kgb.w.) accelerated the healing of acetic acid induced ulcers after the treatment for 7 days. Further, to ascertain the antisecretory action, the effects of SNE on H(+)K(+)ATPase activity and plasma concentration of gastrin hormone in ulcerated rats were determined. SNE significantly inhibits H(+)K(+)ATPase activity and decreases the gastrin secretion in EtOH-induced ulcer model. The severity of the reaction of ulcerogen and the reduction of ulcer size by SNE was evident by histological findings. Toxicity studies of SNE have also been carried out for its safety evaluation. SNE, thus, offers antiulcer activity by blocking acid secretion through inhibition of H(+)K(+)ATPase and decrease of gastrin secretion. These results further suggest that SNE was found to possess antiulcerogenic as well as ulcer healing properties, which might also be due to its antisecretory activity.
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PMID:Antiulcerogenic and ulcer healing effects of Solanum nigrum (L.) on experimental ulcer models: possible mechanism for the inhibition of acid formation. 1620 48

Tumor microenvironment may play a key role in tumor malignancy. It is hypothesized that hypoxia and acidity may contribute to the progression from benign to malignant growth. In particular, the unfavorable environment may induce the selection of tumor cells able to survive in acidic and hypoxic conditions. In fact, the common components of the cancer phenotype result from active selection, and characteristics of tumor microenvironment may create the best condition for this selection. Acidity, in particular, has been shown to have a role in resistance to chemotherapy, proliferation and metastatic behavior. In fact, a mechanism of resistance to cytotoxic drugs may be the alteration of the tumor microenvironment through changes of the pH gradient between the extracellular environment and cell cytoplasm. The extracellular pH of solid tumors is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumors. An important determinant of tumor acidity is the anaerobic metabolism that allows selection of cells able to survive in an hypoxic-anoxic environment with the generation of lactate. However, this is not the major mechanism responsible for the development of an acidic environment within solid tumors. It appears clear that a complex framework of protein-protein, protein-lipid and lipid-lipid interactions underlay the pH homeostasis in mammalian cells. Malignant tumor cells seem to hijack some of these mechanism to protect themselves from the acidic environment and to maintain acidity in an environment unsuitable for normal or more differentiated cells. Recent data suggest that vacuolar-type (V-type) H(+)-ATPases, that pump protons across the plasma membrane, may have a key role in the acidification of the tumor microenvironment. Some human tumor cells are characterized by an increased V-type H(+)-ATPase expression and activity, and pretreatment with proton pump inhibitors -- a class of H(+)-ATPase inhibitors -- sensitized tumor cell lines to the effect of a variety of anticancer drugs. Proton pump inhibitor pretreatment has been associated with inhibition of V-type H(+)-ATPase activity and increase in both extracellular pH and pH of lysosomal organelles. In vivo experiments in human/mouse xenografts have shown that oral pretreatment with proton pump inhibitors is able to sensitize human solid tumors to anticancer drugs. These data suggest that tumor alkalinization may represent a key target of future antitumor strategies.
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PMID:Tumor acidity, chemoresistance and proton pump inhibitors. 1655 57

One of the main functions of the airway epithelium is to inactivate and remove infectious particles from inhaled air and thereby prevent infection of the distal lung. This function is achieved by mucociliary and cough clearance and by antimicrobial factors present in the airway surface liquid (ASL). There are indications that airway defenses are affected by the pH of the ASL and historically, acidification of the airway surfaces has been suggested as a measure of airway disease. However, even in health, the ASL is slightly acidic, and this acidity might be part of normal airway defense. Only recently research has focused on the mechanisms responsible for acid and base secretion into the ASL. Advances resulted from research into the airway disease associated with cystic fibrosis (CF) after it was found that the CFTR Cl(-) channel conducts HCO (3) (-) and, therefore, may contribute to ASL pH. However, the acidity of the ASL indicated parallel mechanisms for H(+) secretion. Recent investigations identified several H(+) transporters in the apical membrane of the airway epithelium. These include H(+) channels and ATP-driven H(+) pumps, including a non-gastric isoform of the H(+)-K(+) ATPase and a vacuolar-type H(+) ATPase. Current knowledge of acid and base transporters and their potential roles in airway mucosal pH regulation is reviewed here.
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PMID:Mechanisms of acid and base secretion by the airway epithelium. 1709 Dec 14

This work assessed the mechanism underlying the antisecretory gastric acid effect of Plectranthus barbatus Andrews (Lamiaceae) and active constituents. Popularly known as "false-boldo", this plant is used in Brazilian folk medicine to treat gastrointestinal and hepatic ailments. The plant aqueous extract (AE) and isolated compounds were assayed in vivo in pylorus-ligated mice, and in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands and gastric H(+),K(+)-ATPase preparations. Injected into the duodenal lumen, the AE of the plant leaves (0.5 and 1.0 g/kg) decreased the volume (62 and 76%) and total acidity (23 and 50%) of gastric acid secretion in pylorus-ligated mice. Bioguided purification of the AE yielded an active fraction (IC(50)=24 microg/ml) that inhibited acid secretion in rabbit gastric glands with a potency 10 to 18 times greater than that of the originating extract, on both the basal and stimulated acid secretion by histamine (His) (1 microM) or bethanechol (100 microM). At the same concentrations the gastric H(+),K(+)-ATPase activity was also inhibited. The active constituent was chemically identified as the abietanoid dienedione plectrinone A which reduced the H(+),K(+)-ATPase activity with IC(50)=171 microM. The results indicate that inhibition of the gastric proton pump by this diterpenoid may account for the antisecretory acid effect and reputed anti ulcer activity of Plectranthus barbatus.
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PMID:Inhibition of the gastric H+,K+ -ATPase by plectrinone A, a diterpenoid isolated from Plectranthus barbatus Andrews. 1716 78

Resistance to anticancer drugs and consequent failure of chemotherapy is a complex problem severely limiting therapeutic options in metastatic cancer. Many studies have shown a role for drug efflux pumps of the ATP-binding cassette transporters family in the development of drug resistance. ClC-3, a member of the CLC family of chloride channels and transporters, is expressed in intracellular compartments of neuronal cells and involved in vesicular acidification. It has previously been suggested that acidification of intracellular organelles can promote drug resistance by increasing drug sequestration. Therefore, we hypothesized a role for ClC-3 in drug resistance. Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles co-labeled with the late endosomal/lysosomal marker LAMP-1. ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC(50) in either BON or HEK293 cell lines. Prevention of organellar acidification, by inhibition of the vacuolar H(+)-ATPase, reduced etoposide resistance. No expression of common multidrug resistance transporters, such as P-glycoprotein or multidrug-related protein-1, was detected in either the BON parental cell line or the derivative clone overexpressing ClC-3. The probable mechanism of enhanced etoposide resistance can be attributed to the increase of vesicular acidification as consequence of ClC-3 overexpression. This study therefore provides first evidence for a role of intracellular CLC proteins in the modulation of cancer drug resistance.
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PMID:ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. 1736 91

To be able to function as a probiotic, bacteria have to survive the passage through the gastrointestinal tract. We have examined survival and gene expression of Lactobacillus reuteri ATCC 55730 after a sudden shift in environmental acidity to a pH close to the conditions in the human stomach. More than 80% of the L. reuteri cells survived at pH 2.7 for 1 h. A genomewide expression analysis experiment using microarrays displayed 72 differentially expressed genes at this pH. The early response to severe acid shock in L. reuteri differed from long-term acid adaptation to milder acid stress studied in other lactic acid bacteria. The genes induced included the following: clpL, genes putatively involved in alterations of the cell membrane and the cell wall; genes encoding transcriptional regulators; phage genes; and genes of unknown function. Two genes, clpL, encoding an ATPase with chaperone activity, and lr1516, encoding a putative esterase, were selected for mutation analyses. The mutants were significantly more sensitive to acid than the wild type was. Thus, these genes could contribute to the survival of L. reuteri in the gastrointestinal tract.
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PMID:The early response to acid shock in Lactobacillus reuteri involves the ClpL chaperone and a putative cell wall-altering esterase. 1744 83


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