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Nature Metabolism Nov 2019Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but...
Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the pro-apoptotic Bcl2-family protein NOXA. We show that cardiac glycosides synergize with anti-cancer drugs to kill tumor cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent preneoplastic cells. Our findings suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanism. Given the broad range of senescent cells targeted by cardiac glycosides their use against age-related diseases warrants further exploration.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cardiac Glycosides; Cellular Senescence; Humans; Mice; Ouabain; Quercetin; Rats
PubMed: 31799499
DOI: 10.1038/s42255-019-0122-z -
Annals of the Rheumatic Diseases Apr 2022Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage...
OBJECTIVES
Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA.
METHODS
Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes.
RESULTS
Serial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin's regulations of chondrocytes.
CONCLUSIONS
These findings not only provide new insights into the understanding of digoxin's chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.
Topics: Cartilage, Articular; Chondrocytes; Cohort Studies; Digoxin; Drug Repositioning; Humans; LDL-Receptor Related Proteins; Osteoarthritis; Ouabain
PubMed: 34853001
DOI: 10.1136/annrheumdis-2021-221380 -
International Journal of Physiology,... 2017Hypoxia and reoxygenation, ischemia and reperfusion, catecholamine infusion, ouabain, sodium pentobarbital and caffeine, can all be used experimentally to induce...
Hypoxia and reoxygenation, ischemia and reperfusion, catecholamine infusion, ouabain, sodium pentobarbital and caffeine, can all be used experimentally to induce ventricular arrhythmias. According to the Lambeth Convention guidelines our experimentally-induced ventricular arrhythmias include but are not limited to: ventricular premature beats (VPB), ventricular salvos (VS), ventricular bigeminy (VB), nonsustained ventricular tachycardia (VTn), sustained ventricular tachycardia (VTs) and ventricular fibrillation (VF, or if the heart is not defibrillated, sudden cardiac death). We have studied these arrhythmias in the absence and presence of adenosine deaminase, methyl xanthines, and more recently, acetaminophen. Our laboratory was the first to discover the anti-arrhythmic properties of acetaminophen an analgesic used in Western medicine for more than 100 years before our publication. We have also identified other cardioprotective properties of acetaminophen, and have begun to work out some of the cellular/molecular mechanisms. For example, we know that acetaminophen protects hypoxic/ischemic cardiac mitochondria, in part, by sustaining function of the mitochondrial permeability transition pore (MPTP, a protein involved in regulating mitochondrial pH). Acetaminophen also attenuates the actions of matrix metalloproteinases that can be harmful to myocardial contractile proteins. Of course, like all science, more work is needed to expand on these and related topics.
PubMed: 29348797
DOI: No ID Found -
Hypertension (Dallas, Tex. : 1979) Sep 2016In this brief article, we summarize recent reports about endogenous ouabain (EO), a cardiotonic steroid (CTS). This includes analysis of mammalian EO, the discovery of... (Review)
Review
In this brief article, we summarize recent reports about endogenous ouabain (EO), a cardiotonic steroid (CTS). This includes analysis of mammalian EO, the discovery of EO isomers, regulation of intracellular signaling by EO, and the roles of EO in hypertension, pregnancy, and heart and kidney diseases. Novel ouabain-resistant mice that elucidate the key roles of α2 Na pumps and their CTS binding site are also discussed.
Topics: Adrenal Cortex; Animals; Blood Pressure Determination; Cardiovascular Diseases; Female; Humans; Hypertension; Kidney Diseases; Male; Mice; Needs Assessment; Ouabain; Sodium-Potassium-Exchanging ATPase
PubMed: 27456525
DOI: 10.1161/HYPERTENSIONAHA.116.06599 -
Frontiers in Pharmacology 2022Cardiotonic steroids are natural compounds that present many physiological and pharmacological functions. They bind Na/K-ATPase (NKA) modifying cellular ion... (Review)
Review
Cardiotonic steroids are natural compounds that present many physiological and pharmacological functions. They bind Na/K-ATPase (NKA) modifying cellular ion concentration and trigger cell signaling mechanisms without altering ion balance. These steroids are known to modulate some immune responses, including cytokine production, neutrophil migration, and inflammation (peripherally and in the nervous system). Inflammation can occur in response to homeostasis perturbations and is related to the development of many diseases, including immune-mediated diseases and neurodegenerative disorders. Considering the neutrophils role in the general neuroinflammatory response and that these cells can be modulated by cardiac steroids, this work aims to review the possible regulation of neutrophilic neuroinflammation by the cardiac steroid ouabain.
PubMed: 35173621
DOI: 10.3389/fphar.2022.824907 -
Toxins May 2021Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and... (Review)
Review
Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na/K-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.
Topics: Animals; Antineoplastic Agents; Cardiac Glycosides; Cattle; Digitoxin; Digoxin; Humans; Molecular Targeted Therapy; Neoplasms; Ouabain; Sodium-Potassium-Exchanging ATPase
PubMed: 34064873
DOI: 10.3390/toxins13050344 -
Comprehensive Physiology Sep 2018The colon has large capacities for K absorption and K secretion, but its role in maintaining K homeostasis is often overlooked. For many years, passive diffusion and/or... (Review)
Review
The colon has large capacities for K absorption and K secretion, but its role in maintaining K homeostasis is often overlooked. For many years, passive diffusion and/or solvent drag were thought to be the primary mechanisms for K absorption in human and animal colon. However, it is now clear that apical H ,K -ATPase, in coordination with basolateral K -Cl cotransport and/or K and Cl channels operating in parallel, mediate electroneutral K absorption in animal colon. We now know that K absorption in rat colon reflects ouabain-sensitive and ouabain-insensitive apical H ,K -ATPase activities. Ouabain-insensitive and ouabain-sensitive H ,K -ATPases are localized in surface and crypt cells, respectively. Colonic H ,K -ATPase consists of α- (HKC ) and β- (HKC ) subunits which, when coexpressed, exhibit ouabain-insensitive H ,K -ATPase activity in HEK293 cells, while HKC coexpressed with the gastric β-subunit exhibits ouabain-sensitive H ,K -ATPase activity in Xenopus oocytes. Aldosterone enhances apical H ,K -ATPase activity, HKC specific mRNA and protein expression, and K absorption. Active K secretion, on the other hand, is mediated by apical K channels operating in a coordinated way with the basolateral Na -K -2Cl cotransporter. Both Ca -activated intermediate conductance K (IK) and large conductance K (BK) channels are located in the apical membrane of colonic epithelia. IK channel-mediated K efflux provides the driving force for Cl secretion, while BK channels mediate active (e.g., cAMP-activated) K secretion. BK channel expression and activity are increased in patients with end-stage renal disease and ulcerative colitis. This review summarizes the role of apical H ,K -ATPase in K absorption, and apical BK channel function in K secretion in health and disease. © 2018 American Physiological Society. Compr Physiol 8:1513-1536, 2018.
Topics: Animals; Colon; Humans; Intestinal Absorption; Potassium; Potassium Channels
PubMed: 30215859
DOI: 10.1002/cphy.c170030 -
Genes & Diseases May 2021With an exception of few reports, the plasma concentration of ouabain and marinobufagenin, mostly studied cardiotonic steroids (CTS) assessed by immunoassay techniques,... (Review)
Review
With an exception of few reports, the plasma concentration of ouabain and marinobufagenin, mostly studied cardiotonic steroids (CTS) assessed by immunoassay techniques, is less than 1 nM. During the last 3 decades, the implication of these endogenous CTS in the pathogenesis of hypertension and other volume-expanded disorders is widely disputed. The threshold for inhibition by CTS of human and rodent α1-Na,K-ATPase is ∼1 and 1000 nM, respectively, that rules out the functioning of endogenous CTS (ECTS) as natriuretic hormones and regulators of cell adhesion, cell-to-cell communication, gene transcription and translation, which are mediated by dissipation of the transmembrane gradients of monovalent cations. In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase, decrease the [Na]/[K]-ratio and increase cell proliferation. Possible physiological significance and mechanism of non-canonical Na /K -dependent and Na /K -independent cell responses to CTS are discussed.
PubMed: 33997173
DOI: 10.1016/j.gendis.2020.01.008 -
Evidence-based Complementary and... 2019Nerol (CHO) is a monoterpene found in many essential oils, such as lemon balm and hop. In this study, we explored the contractile and electrophysiological properties of...
Nerol (CHO) is a monoterpene found in many essential oils, such as lemon balm and hop. In this study, we explored the contractile and electrophysiological properties of nerol and demonstrated its antiarrhythmic effects in guinea pig heart preparation. Nerol effects were evaluated on atrial and ventricular tissue contractility, electrocardiogram (ECG), voltage-dependent L-type Ca current (I), and ouabain-triggered arrhythmias. Overall our results revealed that by increasing concentrations of nerol (from 0.001 to 30 mM) there was a significant decrease in left atrium contractile force. This effect was completely and rapidly reversible after washing out (~ 2 min). Nerol (at 3 mM concentration) decreased the left atrium positive inotropic response evoked by adding up CaCl in the extracellular medium. Interestingly, when using a lower concentration of nerol (30 M), it was not possible to clearly observe any significant ECG signal alterations but a small reduction of ventricular contractility was observed. In addition, 300 M nerol promoted a significant decrease on the cardiac rate and contractility. Important to note is the fact that in isolated cardiomyocytes, peak I was reduced by 58.9 ± 6.31% after perfusing 300 M nerol (n=7, p<0.05). Nerol, at 30 and 300 M, delayed the time of onset of ouabain-triggered arrhythmias and provoked a decrease in the diastolic tension induced by the presence of ouabain (50 M). Furthermore, nerol preincubation significantly attenuated arrhythmia severity index without changes in the positive inotropism elicited by ouabain exposure. Taken all together, we may be able to conclude that nerol primarily by reducing Ca influx through L-type Ca channel blockade lessened the severity of ouabain-triggered arrhythmias in mammalian heart.
PubMed: 30984275
DOI: 10.1155/2019/5935921