Ion pumps as targets for therapeutic intervention: Old and new paradigms

Perlin, David S.

doi:10.2225/vol1-issue2-fulltext-2

Cited by 9 publications

(8 citation statements)

References 37 publications

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“…29 In the recent years, the drugs that reduce the acid secretion and H + K + ATPase inhibition have become preferred therapeutic choice due to their clinical efficacy. 30 The inhibition of H + K + ATPase results in the reduction of gastric acid secretion, 31 which is concordant with the present study. While the Pylorus ligationinduced gastric ulcerations are caused by enhanced acidpepsin secretion leading to auto digestion of the gastric mucosa and breakdown of mucosal barrier.…”

Section: Discussionsupporting

confidence: 90%

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Arumugasamy

Kannan

Vora³

et al. 2015

Int J Res Med Sci

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Peptic ulcer diseases comprise of heterogeneous disorders, which manifest as a lesion in the lining of the gastrointestinal mucosa bathed by acid and pepsin. It is the most predominant of the gastrointestinal diseases 1,2 with a worldwide prevalence of about 33% in the developed countries and 50% affliction in humans in the developing countries due to H. pylori infection. It is generally recognized that peptic ulcer is caused by a lack of equilibrium between the gastric aggressive factors and the mucosal defensive factors. 3 However, the peptic ulcer, characterized by mucosal damage, is predominantly caused by Helicobacter pylori or antiplatelet agents such as acetylsalicylic acid, 4 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and oral bisphosphonates, potassium chloride, immunosuppressive medications, 5 serotonin reuptake inhibitors, 6 alcohol consumption, as well as cigarette smoking. 7 Symptoms of peptic ulcer disease include abdominal pain, vomiting, and reflux symptoms. Other general symptoms of peptic ulcer disease include loss of appetite and weight. 8 The disease may lead to upper gastrointestinal haemorrhage and perforation, 9 which may have high morbidity and mortality rates. In the majority of cases, H. pylori increases the production of reactive oxygen species ABSTRACT Background: Ulcers of the lower part of the oesophagus, the stomach and the first part of the duodenum are also known as peptic ulcers. Peptic ulcers can affect people of any age, but they are more common as you get older. There is a focus on research for better tolerated and efficacious anti-ulcer agents. Methods: Effect of anti-ulcer activity of fish oil and Arasco oil was evaluated in different animal models of ulcers i.e. ethanol induced, water immersion and pyloric ligation techniques. The Superoxide dismutase activity in gastric tissue was also ascertained in two groups of animals. The animals received either fish oil (40 µl, PO), Arasco oil (40 µl, PO), omeprazole (20 mg/kg PO) or ranitidine (30 mg/kg PO). The gastro-protection was calculated based on ulcer index, pH and gastric juice volume. Results: The results of this study suggest that poly unsaturated fatty acid (PUFA) contained in fish oil and Arasco oil have moderate anti-ulcer activity although probably lesser in potency than the available anti-ulcer drugs like omeprazole and ranitidine. Conclusion: These results have shown that PUFA containing oils provided moderate gastrointestinal protection in all the induced ulcer models employed. Thus it can be concluded that PUFA containing oils like the Fish oil and Arasco oil have anti-ulcer properties and the mechanisms involved in these actions need to be investigated.

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Section: Discussionsupporting

confidence: 90%

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Arumugasamy

Kannan

Vora³

et al. 2015

Int J Res Med Sci

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“…The H ϩ -ATPase has recently been proposed as a target for antifungal drug development, largely because of its well-characterized biochemical and genetic properties (20) and the availability of several high-throughput screens that target unique functional properties of the enzyme (24). In addition, the H ϩ -ATPase is a typical member of the P-type family of ion translocating enzymes (16), which serve as selective targets for cardiac glycosides and antiulcer therapeutics (22).…”

mentioning

confidence: 99%

Molecular Characterization of the Plasma Membrane H⁺-ATPase, an Antifungal Target inCryptococcus neoformans

Soteropoulos

Vaz

Santangelo

et al. 2000

Antimicrob Agents Chemother

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The Cryptococcus neoformans PMA1 gene, encoding a plasma membrane H ؉ -ATPase, was isolated from a genomic DNA library of serotype A strain ATCC 6352. An open reading frame of 3,380 nucleotides contains six introns and encodes a predicted protein consisting of 998 amino acids with a molecular mass of approximately 108 kDa. Plasma membranes were isolated, and the H ؉ -ATPase was shown by sodium dodecyl sulfatepolyacrylamide gel electrophoresis to be slightly larger than the S. cerevisiae H ؉ -ATPase, consistent with its predicted molecular mass. The plasma membrane-bound enzyme exhibited a pH 6.5 optimum for ATP hydrolysis, K m and V max values of 0.5 mM and 3.1 mol mg ؊1 min ؊1, respectively, and an apparent K i for vanadate inhibition of 1.6 M. ATP hydrolysis in plasma membranes and medium acidification by whole cells were inhibited by ebselen, a nonspecific H ؉ -ATPase antagonist which was also fungicidal. The predicted C. neoformans protein is 35% identical to proton pumps of both pathogenic and nonpathogenic fungi but exhibits more than 50% identity to PMA1 genes from plants. Collectively, this study provides the basis for establishing the Cryptococcus H ؉ -ATPase as a viable target for antifungal drug discovery.The opportunistic pathogen Cryptococcus neoformans causes pulmonary and central nervous system disease in immunocompromised individuals and is known to produce life-threatening meningoencephalitis in 5 to 10% of AIDS patients (1). Treatment of cryptococossis typically involves combined and sequential therapy with the polyene antibiotic amphotericin and azole-based drugs such as fluconazole. However, such therapy presents clinical problems, since amphotericin treatment results in a high degree of nephrotoxicity and azole resistance has emerged as a complicating factor, especially in AIDS patients with repeated or chronic exposure to fluconazole (4). As is the case with other fungal pathogens, the development of newer antifungal drugs with alternative sites of action that can reduce toxicity and be used in combination to minimize resistance is an important goal.The plasma membrane H ϩ -ATPase is a high-capacity proton pump that plays a critical role in fungal cell physiology by helping to regulate intracellular pH and maintain transmembrane electrochemical proton gradients necessary for nutrient uptake (26). The H ϩ -ATPase has been characterized biochemically from various fungi in which it is known to be a predominant membrane protein comprised of a single 100-kDa subunit that contains both a membrane-spanning transport domain and a cytoplasmically located catalytic ATP hydrolysis domain. The gene encoding this enzyme, PMA1, has been cloned from diverse fungi and has been shown to be highly conserved (31). Gene-disruption experiments in Saccharomyces cerevisiae have confirmed the essential nature of this gene product (27). The H ϩ -ATPase has recently been proposed as a target for antifungal drug development, largely because of its well-characterized biochemical and genetic properties (20) and the ava...

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“…In all cases, the catalytic ATP hydrolysis domain and closely linked transmembrane segments display the highest level of conservation. Regions at the N and C termini of the P-type ATPases are most divergent, while the extracellular loop domains linking transmembrane segments are more (25,28,29). It is this well-documented diversity that has facilitated the development of drug specificity between P-type enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…The P-type cardiac and gastric ATPases are well-known targets for therapeutics, and there is a high degree of target specificity for these ATPases (29). The highly conserved functional properties of the fungal H ϩ -ATPases suggest that a specific antagonist could present broad reactivity to fungal species.…”

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confidence: 99%

Molecular Evaluation of the Plasma Membrane Proton Pump fromAspergillus fumigatus

Burghoorn¹,

Soteropoulos²,

Paderu³

et al. 2002

Antimicrob Agents Chemother

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The gene encoding the plasma membrane proton pump (H ؉ -ATPase) of Aspergillus fumigatus, PMA1, was characterized from A. fumigatus strain NIH 5233 and clinical isolate H11-20. An open reading frame of 3,109 nucleotides with two introns near the N terminus predicts a protein consisting of 989 amino acids with a molecular mass of approximately 108 kDa. The predicted A. fumigatus enzyme is 89 and 51% identical to H ؉ -ATPases of Aspergillus nidulans and Saccharomyces cerevisiae, respectively. The A. fumigatus PMA1 is a typical member of the P-type ATPase family that contains 10 predicted transmembrane segments and conserved sequence motifs TGES, CSDKTGT, MLTGD, and GDGVN within the catalytic region. The enzyme represents 2% of the total plasma membrane protein, and it is characteristically inhibited by orthovanadate, with a 50% inhibitory concentration of ϳ1.8 M. H ؉ -ATPases from Aspergillus spp. contain a highly acidic insertion region of 60 amino acids between transmembrane segments 2 and 3, which was confirmed for the membraneassembled enzyme with a peptide-derived antibody. An increasing A. fumigatus PMA1 copy number confers enhanced growth in low-pH medium, consistent with its role as a proton pump. These results provide support for the development of the A. fumigatus H ؉ -ATPase as a potential drug discovery target.

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Ion pumps as targets for therapeutic intervention: Old and new paradigms

Cited by 9 publications

References 37 publications

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Molecular Characterization of the Plasma Membrane H⁺-ATPase, an Antifungal Target inCryptococcus neoformans

Molecular Evaluation of the Plasma Membrane Proton Pump fromAspergillus fumigatus

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Ion pumps as targets for therapeutic intervention: Old and new paradigms

Cited by 9 publications

References 37 publications

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Anti-ulcer activity of arachidonic acid (PUFA) oils in different induced ulcer animal models

Molecular Characterization of the Plasma Membrane H+-ATPase, an Antifungal Target inCryptococcus neoformans

Molecular Evaluation of the Plasma Membrane Proton Pump fromAspergillus fumigatus

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Molecular Characterization of the Plasma Membrane H⁺-ATPase, an Antifungal Target inCryptococcus neoformans