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Cardiotonic Steroids: From Toxins to Hormones 3.0
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Cardiotonic Steroids: From Toxins to Hormones 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 2462

Special Issue Editors

Dr. Alexei Y. Bagrov

E-Mail Website
Guest Editor
Padakonn Pharma, 20309 Narva, Estonia
Interests: salt-sensitive hypertension; preeclampsia; chronic renal failure; Na/K-ATPase inhibitors; endogenous cardiotonic steroids; marinobufagenin; antibody to marinobufagenin; immunotherapy: gene expression; fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Olga V. Fedorova

E-Mail Website
Guest Editor
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, 251 Bayview Blvd, Baltimore, MD 21224, USA
Interests: cardiotonic steroids; Na/K-ATPase inhibitors; marinobufagenin; gene expression; growth factors; arterial wall diseases; fibrosis; vascular dementia; Alzheimer’s disease; amyloidosis; salt-sensitive hypertension; chronic kidney disease; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiotonic steroids (CS), obtained from plants such as Digitalis purpurea and Strophanthus, and animals such as toad Bufo Marinus, were once widely used components of traditional medicine. The use of CS ouabain by Skou in the discovery of Na/K-ATPase consolidated the function of CS as inhibitors and regulators of Na/K-ATPase, opening a new era in the studies of these steroidal agents. Several decades later, the endogenous forms of CS were discovered in mammals, specifically in humans and rodents. Numerous important findings and discoveries have been made since then. While our understanding of CT function is still incomplete, the importance of this class of hormones is considerable. Endogenous CS were found to be mostly presented by cardenolides, such as ouabain, and bufadienolides, such as marinobufagenin and telocinobufagin. CS functions include not only the inhibition of Na/K-ATPase, and regulation of the monovalent ions balance and cell homeostasis, but also the initiation of multisignal cascade transduction pathways. CS can affect cell growth and differentiation, apoptosis and proliferation, glucose metabolism, and control of central nervous functions via binding to the Na pump. Dysregulation of CS plays an important role in multiple diseases, including chronic kidney disease, cancer, preeclampsia, hypertension, and other cardiovascular disorders. The understanding of the mechanisms of action of this class of hormones will lead to the discovery of novel therapeutic strategies in the regulation of physiological functions and in curing diseases, in which the participation of CS was reported. The present issue of “Cardiotonic Steroids” is dedicated to recent findings related to the multifaceted role of these incredible molecules in health and disease.  

Dr. Alexei Y. Bagrov
Dr. Olga V. Fedorova
Guest Editors

Manuscript Submission Information

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Keywords

  • cardiotonic steroids
  • biosynthesis
  • physiological and pathological function
  • immunoregulation

Published Papers (3 papers)

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Research

14 pages, 2153 KiB  
Article
Evaluation of Ouabain’s Tissue Distribution in C57/Black Mice Following Intraperitoneal Injection, Using Chromatography and Mass Spectrometry
by Denis A. Abaimov, Rogneda B. Kazanskaya, Ruslan A. Ageldinov, Maxim S. Nesterov, Yulia A. Timoshina, Angelina I. Platova, Irina J. Aristova, Irina S. Vinogradskaia, Tatiana N. Fedorova, Anna B. Volnova, Raul R. Gainetdinov and Alexander V. Lopachev
Int. J. Mol. Sci. 2024, 25(8), 4318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25084318 - 13 Apr 2024
Viewed by 398
Abstract
Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain–blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs’ applicability in the clinic and [...] Read more.
Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain–blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs’ applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC–MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: Cmax = 882.88 ± 21.82 ng/g; Tmax = 0.08 ± 0.01 h; T1/2 = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: Cmax = 145.24 ± 44.03 ng/g (undetectable at 60 min); Tmax = 0.08 ± 0.02 h; T1/2 = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: Cmax = 1072.3 ± 260.8 ng/g; Tmax = 0.35 ± 0.19 h; T1/2 = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: Cmax = 2558.0 ± 382.4 ng/g; Tmax = 0.35 ± 0.13 h; T1/2 = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS. Full article
(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones 3.0)
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13 pages, 1641 KiB  
Article
Involvement of the Na+, K+-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors
by Noa Horesh, Ilana Pelov, Ilana Pogodin, Hiba Zannadeh, Haim Rosen, Anastasiia Leonidovna Mikhrina, Moran Dvela-Levitt, Vishnu Priya Sampath and David Lichtstein
Int. J. Mol. Sci. 2024, 25(3), 1644; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031644 - 29 Jan 2024
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Abstract
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na+, K+-ATPase is a major [...] Read more.
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na+, K+-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na+, K+-ATPase are present in the brain. Previous studies have supported the involvement of the Na+, K+-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1+/− mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1+/− but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na+, K+-ATPase activity in wt and α1+/− mice. The serum ECS was lower in α1+/− than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na+, K+-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na+, K+-ATPase/ECS system participates in the etiology of BD. Full article
(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones 3.0)
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19 pages, 4166 KiB  
Article
Ouabain’s Influence on TRPV4 Channels of Epithelial Cells: An Exploration of TRPV4 Activity, Expression, and Signaling Pathways
by Arturo Ponce, Isabel Larre, Lidia Jimenez, Maria Luisa Roldán, Liora Shoshani and Marcelino Cereijido
Int. J. Mol. Sci. 2023, 24(23), 16687; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242316687 - 24 Nov 2023
Cited by 1 | Viewed by 837
Abstract
Ouabain, a substance originally obtained from plants, is now classified as a hormone because it is produced endogenously in certain animals, including humans. However, its precise effects on the body remain largely unknown. Previous studies have shown that ouabain can influence the phenotype [...] Read more.
Ouabain, a substance originally obtained from plants, is now classified as a hormone because it is produced endogenously in certain animals, including humans. However, its precise effects on the body remain largely unknown. Previous studies have shown that ouabain can influence the phenotype of epithelial cells by affecting the expression of cell–cell molecular components and voltage-gated potassium channels. In this study, we conducted whole-cell clamp assays to determine whether ouabain affects the activity and/or expression of TRPV4 channels. Our findings indicate that ouabain has a statistically significant effect on the density of TRPV4 currents (dITRPV4), with an EC50 of 1.89 nM. Regarding treatment duration, dITRPV4 reaches its peak at around 1 h, followed by a subsequent decline and then a resurgence after 6 h, suggesting a short-term modulatory effect related to on TRPV4 channel activity and a long-term effect related to the promotion of synthesis of new TRPV4 channel units. The enhancement of dITRPV4 induced by ouabain was significantly lower in cells seeded at low density than in cells in a confluent monolayer, indicating that the action of ouabain depends on intercellular contacts. Furthermore, the fact that U73122 and neomycin suppress the effect caused by ouabain in the short term suggests that the short-term induced enhancement of dITRPV4 is due to the depletion of PIP2 stores. In contrast, the fact that the long-term effect is inhibited by PP2, wortmannin, PD, FR18, and IKK16 suggests that cSrc, PI3K, Erk1/2, and NF-kB are among the components included in the signaling pathways. Full article
(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones 3.0)
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