Advertisement

Topics

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na/K-ATPase-dependent PI3K_PDK1 axis signaling.

08:00 EDT 24th July 2018 | BioPortfolio

Summary of "The cardenolide ouabain suppresses coronaviral replication via augmenting a Na/K-ATPase-dependent PI3K_PDK1 axis signaling."

Cardenolides are plant-derived toxic substances. Their cytotoxicity and the underlying mechanistic signaling axes have been extensively documented, but only a few anti-viral activities of cardenolides and the associated signaling pathways have been reported. Previously, we reported that a variety of cardenolides impart anti-transmissible gastroenteritis coronavirus (TGEV) activity in swine testicular (ST) cells, through targeting of the cell membrane sodium/potassium pump, Na/K-ATPase. Herein, we further explore the potential signaling cascades associated with this anti-TGEV activity in ST cells. Ouabain, a representative cardenolide, was found to potently diminish TGEV titers and inhibit the TGEV-induced production of IL-6 in a dose dependent manner, with 50% inhibitory concentrations of 37 nM and 23 nM respectively. By pharmacological inhibition and gene silencing, we demonstrated that PI3K_PDK1_RSK2 signaling was induced in TGEV-infected ST cells, and ouabain imparted a degree of anti-TGEV activity via further augmentation of this existing PI3K_PDK1 axis signaling, in a manner dependent upon its association with the Na/K-ATPase. Finally, inhibition of PI3K by LY294002 or PDK1 by BX795 antagonized the anti-viral activity of ouabain and restored the TGEV virus titer and yields. This finding is the first report of a PI3K_PDK1 signaling axis further induced by ouabain and implicated in the suppression of TGEV activity and replication; greatly illuminates the underlying mechanism of cardenolide toxicity; and is expected to result in one or more anti-viral applications for the cardenolides in the future.

Affiliation

Journal Details

This article was published in the following journal.

Name: Toxicology and applied pharmacology
ISSN: 1096-0333
Pages:

Links

DeepDyve research library

PubMed Articles [6941 Associated PubMed Articles listed on BioPortfolio]

Interaction of ouabain and progesterone on induction of bull sperm capacitation.

The endogenous steroid hormone ouabain induces capacitation of bull sperm acting through its receptor Na/K-ATPase on the sperm plasma membrane. Progesterone (P4) is believed to act through the sperm m...

Revisiting the binding kinetics and inhibitory potency of cardiac glycosides on Na,K-ATPase (α1β1): Methodological considerations.

Ouabain and digoxin are classical inhibitors of the Na,K-ATPase. In addition to their conventional uses as therapeutic agents or experimental tools there is renewed interest due to evidence suggesting...

DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways.

Reduced Na-K-ATPase function is reported in various renal diseases. This implies that increase of Na-K-ATPase function may be a new target in treatment of renal injury. We previously reported that Na-...

Na, K-ATPase inhibition causes hyperactivity and impulsivity in mice via dopamine D2 receptor-mediated mechanism.

Hyperactivity and impulsivity are common symptoms in several psychiatric disorders. Although dysfunction of Na, K-ATPase has been reported to be associated with the psychiatric disorders, it is not cl...

Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements.

DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. One mechanism that triggers these errors is mitotic entry before th...

Clinical Trials [1641 Associated Clinical Trials listed on BioPortfolio]

Influence of Pantoprazole on Human Myocardial Contractility at Patients With Congestive Heart Failure

Recently literature revealed facts, that show H+/K+ ATPase expression is not limited tot he stomach. H+/K+ ATPase was also found in smooth muscle cells and in other tissues (McCabe, R.D. e...

Preop Digifab in CABG to Reduce Ouabain Levels and Prevent AKI

Acute kidney injury (AKI) occurs in up to 30% of patients undergoing coronary artery bypass graft (CABG) surgery, and often requires patients to go on dialysis. In patients needing dialysi...

Dolutegravir Impact on Residual Replication

Several studies have suggested that despite suppressive combination antiretroviral therapy (ART) in people who are HIV-positive, in some individuals there may be on-going viral replication...

The Effect of Ixazomib on the Latent HIV Reservoir

The goal of this study is to determine the safety and tolerability of Ixazomib in HIV infected patients who are on a stable regimen of ART that suppresses HIV replication. A secondary goal...

Effects of Spironolactone in Dialysis

Several studies indicate that chronic kidney disease patients give a high cardiovascular risk and have an intrinsic relationship with hypertension and cardiomyopathy: characterized by left...

Medical and Biotech [MESH] Definitions

A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like DIGITALIS. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-EXCHANGING ATPASE.

Endoproteases that contain proteolytic core domains and ATPase-containing regulatory domains.

ATP-dependent cellular enzyme which catalyzes DNA replication, repair and recombination through formation of internucleotide ester bonds between phosphate and deoxyribose moieties. Vertebrate cells encode three well-characterized DNA ligases, DNA ligase I, III and IV, all of which are related in structure and sequence. DNA ligases either require ATP or NAD. However, archaebacterial, viral, and some eubacterial DNA ligases are ATP-dependent.

A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)

An enzyme that catalyzes the hydrolysis of ATP and is activated by millimolar concentrations of either Ca(2+) or Mg(2+). Unlike CA(2+)-TRANSPORTING ATPASE it does not require the second divalent cation for its activity, and is not sensitive to orthovanadate. (Prog Biophys Mol Biol 1988;52(1):1). A subgroup of EC 3.6.1.3.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topic

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...


Searches Linking to this Article