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The Journal of Membrane Biology Jun 2023The nature of odoroside A, a cardiac glycoside (CG) extracted from Nerium oleander, as well as its chemical structure is quite similar to a well-known CG, ouabain...
The nature of odoroside A, a cardiac glycoside (CG) extracted from Nerium oleander, as well as its chemical structure is quite similar to a well-known CG, ouabain possessing a steroid skeleton, a five-membered unsaturated lactone ring, and a sugar moiety as a common structure. Like ouabain, odoroside A inhibits the activity of Na/K-ATPase (NKA) and shows significant anticancer activity, however its inhibitory mechanism remains unknown. CGs show various physiological activities, including cardiotonic and anticancer activities, through the inhibition of NKA by direct interaction. Additionally, X-ray crystallographic analysis revealed the inhibitory mechanism of ouabain and digoxin in relation to NKA. By using different molecular modeling techniques, docking simulation of odoroside A and NKA was conducted based on the results of these X-ray crystallographic analyses. Furthermore, a comparison of the results with the binding characteristics of three known CGs (ouabain, digoxin, and digitoxin) was also conducted. Odoroside A fitted into the CG binding pocket on the α-subunit of NKA revealed by X-ray crystallography. It had key interactions with Thr797 and Phe783. Also, three known CGs showed similar interactions with Thr797 and Phe783. Interaction modes of odoroside A were quite similar to those of ouabain, digoxin, and digitoxin. Docking simulations indicated that the sugar moiety enhanced the interaction between NKA and CGs, but did not show enhanced NKA inhibitory activity because the sugar moiety was placed outside the entrance of active site. Thus, these results suggest that the inhibitory mechanism of odoroside A to NKA is the same as the known CGs.
Topics: Cardiac Glycosides; Ouabain; Sodium-Potassium-Exchanging ATPase; Digoxin; Digitoxin; Sugars
PubMed: 36840763
DOI: 10.1007/s00232-023-00281-1 -
Molecules (Basel, Switzerland) Mar 2021Maintenance of Na and K gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process,... (Review)
Review
Maintenance of Na and K gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication-cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Digitoxin; Digoxin; Drug Repositioning; Enzyme Inhibitors; Glioblastoma; Humans; Isoenzymes; Lung Neoplasms; Models, Molecular; Ouabain; Protein Binding; Protein Conformation; Sodium-Potassium-Exchanging ATPase
PubMed: 33800655
DOI: 10.3390/molecules26071905 -
Journal of Chromatography. B,... Jan 2023Therapeutic drug monitoring (TDM) of cardiovascular drugs is essential to improve treatment efficacy and minimize toxicity because of the usage of multiple drugs with a...
Development and validation of an analytical method using liquid chromatography-tandem mass spectrometry for the therapeutic drug monitoring of seven cardiovascular drugs in clinical usage.
Therapeutic drug monitoring (TDM) of cardiovascular drugs is essential to improve treatment efficacy and minimize toxicity because of the usage of multiple drugs with a very limited therapeutic range and the high pharmacokinetic variation in patients. We developed and validated a reliable and economical liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of seven cardiovascular drugs-procainamide, lidocaine, quinidine, deslanoside, digoxin, atorvastatin, and digitoxin-for clinical usage. Serum samples were prepared by simple protein precipitation with an organic solvent consisting of acetonitrile and methanol (2:1 v/v) and analyzed under optimized LC-MS/MS conditions. The chromatographic separations were accomplished within 15 min on a reversed-phase C18 column with a gradient elution of aqueous solvent and acetonitrile while maintaining 0.1 (v/v) % formic acid and 2 mM ammonium formate. The optimized MS/MS conditions in ESI-positive mode offered sufficient sensitivity for the seven cardiovascular drugs (LOQs between 0.5 and 1 ng/mL). This method was fully validated including linearity, selectivity, accuracy, precision, carry-over, and matrix effects. Additionally, stability under several conditions was tested to determine how to handle the standard solutions and serum samples. The seven cardiovascular drugs, simultaneously, were precisely and accurately analyzed in intra- and inter-day assays (RSD < 6 % and recovery between 96.3 and 102.8 %) using only two isotope-labeled internal standards (lidocaine-(diethyl-d10) and digoxin-21, 21, 22-d3). The presented method also showed good accuracy in analyzing the seven drugs in hyperlipidemia, hyperalbuminemia, and hyperglycemia serum, allowing it to be recommended as a common and routine analysis method for cardiovascular drugs in clinical practice.
Topics: Humans; Chromatography, Liquid; Cardiovascular Agents; Tandem Mass Spectrometry; Drug Monitoring; Solvents; Digoxin; Lidocaine; Chromatography, High Pressure Liquid; Reproducibility of Results
PubMed: 36469961
DOI: 10.1016/j.jchromb.2022.123552 -
Toxins Apr 2020Cardiac glycosides (CGs) are naturally occurring plant secondary metabolites that can be toxic to humans and animals. The aim of this work was to develop a targeted...
Development and Validation of a UHPLC-ESI-MS/MS Method for Quantification of Oleandrin and Other Cardiac Glycosides and Evaluation of Their Levels in Herbs and Spices from the Belgian Market.
Cardiac glycosides (CGs) are naturally occurring plant secondary metabolites that can be toxic to humans and animals. The aim of this work was to develop a targeted analytical method utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS) for quantification of these plant toxins in a herbal-based food and human urine. The method included oleandrin, digoxin, digitoxin, convallatoxin, and ouabain. Samples of culinary herbs were extracted with acetonitrile and cleaned using Oasis MAX solid-phase extraction (SPE), while samples of urine were diluted with acidified water and purified on Oasis HLB SPE cartridges. Limits of quantification were in the range of 1.5-15 ng/g for herbs and 0.025-1 ng/mL for urine. The mean recovery of the method complied with the acceptable range of 70-120% for most CGs, and relative standard deviations were at maximum 14% and 19% for repeatability and reproducibility, respectively. Method linearity was good with calculated R² values above 0.997. The expanded measurement uncertainty was estimated to be in the range of 7-37%. The LC-MS/MS method was used to examine 65 samples of culinary herbs and herb and spice mixtures collected in Belgium, from supermarkets and local stores. The samples were found to be free from the analyzed CGs.
Topics: Belgium; Cardenolides; Cardiac Glycosides; Chromatography, High Pressure Liquid; Humans; Limit of Detection; Plant Preparations; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Spices; Supermarkets; Tandem Mass Spectrometry; Urinalysis
PubMed: 32283845
DOI: 10.3390/toxins12040243 -
Journal of Cellular Biochemistry Dec 2021Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na /K -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides...
Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na /K -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na /K -ATPase, sarco/endoplasmic reticulum Ca -ATPase (SERCA), and plasma membrane Ca -ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na /K -ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.
Topics: Cell Membrane; Digitoxigenin; HeLa Cells; Humans; Plasma Membrane Calcium-Transporting ATPases; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Potassium-Exchanging ATPase
PubMed: 34553411
DOI: 10.1002/jcb.30150 -
Foods (Basel, Switzerland) Jan 2021Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na/K-ATPase, and some are routinely utilized in the...
Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na/K-ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na/K-ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na/K-ATPase inhibition, but also as novel cancer therapeutics.
PubMed: 33440629
DOI: 10.3390/foods10010136 -
Blood Purification 2021While several intoxications can be successfully treated with specific antidotes, intoxications with the steroid glycoside digitoxin still represent a major challenge....
While several intoxications can be successfully treated with specific antidotes, intoxications with the steroid glycoside digitoxin still represent a major challenge. Besides conventional approaches, CytoSorb® hemoadsorption might be another treatment option. We report on an 81-year-old female patient treated in our intensive care unit (ICU) with severe digitoxin intoxication, acute renal failure, and urinary tract infection (UTI). As physiological digitoxin elimination kinetics are known to appear slow, and also in regard to the renal failure, the decision was made to initiate continuous renal replacement therapy combined with CytoSorb hemoadsorption. The patient was hemodynamically stabilized within the first 4 h of treatment and initially required catecholamines to be stopped within 24 h of treatment. Pre- and post-adsorber drug level measurements showed a rapid elimination of digitoxin. Antibiotic treatment with piperacillin/tazobactam was initiated, and despite CytoSorb hemoadsorption therapy and its known potential to reduce plasma concentrations of several drugs, the UTI was successfully treated. After 3 days of CytoSorb treatment, digitoxin plasma levels were stable and almost normalized, and no clinical signs of intoxication were present. Five days after presentation, the patient was transferred from the ICU in a stable condition. CytoSorb hemoadsorption may be an easily available, efficient, and less cost-intensive therapy option than treatment with the Fab fragment, which is the currently recommended therapy for digitalis intoxications. Therefore, the use of CytoSorb might represent an alternative treatment for life-threatening complications of digitoxin intoxications.
Topics: Acute Kidney Injury; Aged, 80 and over; Continuous Renal Replacement Therapy; Digitoxin; Female; Hemoperfusion; Humans; Piperacillin, Tazobactam Drug Combination; Urinary Tract Infections
PubMed: 32937619
DOI: 10.1159/000510292 -
Scientific Reports Jul 2022COVID-19 is a global pandemic impacting the daily living of millions. As variants of the virus evolve, a complete comprehension of the disease and drug targets becomes a...
COVID-19 is a global pandemic impacting the daily living of millions. As variants of the virus evolve, a complete comprehension of the disease and drug targets becomes a decisive duty. The Omicron variant, for example, has a notably high transmission rate verified in 155 countries. We performed integrative transcriptomic and network analyses to identify drug targets and diagnostic biomarkers and repurpose FDA-approved drugs for SARS-CoV-2. Upon the enrichment of 464 differentially expressed genes, pathways regulating the host cell cycle were significant. Regulatory and interaction networks featured hsa-mir-93-5p and hsa-mir-17-5p as blood biomarkers while hsa-mir-15b-5p as an antiviral agent. MYB, RRM2, ERG, CENPF, CIT, and TOP2A are potential drug targets for treatment. HMOX1 is suggested as a prognostic biomarker. Enhancing HMOX1 expression by neem plant extract might be a therapeutic alternative. We constructed a drug-gene network for FDA-approved drugs to be repurposed against the infection. The key drugs retrieved were members of anthracyclines, mitotic inhibitors, anti-tumor antibiotics, and CDK1 inhibitors. Additionally, hydroxyquinone and digitoxin are potent TOP2A inhibitors. Hydroxyurea, cytarabine, gemcitabine, sotalol, and amiodarone can also be redirected against COVID-19. The analysis enforced the repositioning of fluorouracil and doxorubicin, especially that they have multiple drug targets, hence less probability of resistance.
Topics: Biomarkers; Drug Repositioning; Host Microbial Interactions; Humans; MicroRNAs; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35831333
DOI: 10.1038/s41598-022-15898-w -
Journal of Natural Medicines Jan 2022The outbreak of COVID-19 disease has led to a search for effective vaccines or drugs. However, insufficient vaccine supplies to meet global demand and no effective... (Review)
Review
The outbreak of COVID-19 disease has led to a search for effective vaccines or drugs. However, insufficient vaccine supplies to meet global demand and no effective approved prescribed drugs for COVID-19 have led some people to consider the use of alternative or complementary medicines, such as traditional herbal medicine. Medicinal plants have various therapeutic properties that depend on the active compounds they contain. Obviously, herbal medicine has had an essential role in treatment and prevention during COVID-19 outbreak, especially in Asian cultures. Hence, we reviewed the uses of herbal medicine in Asian cultures and described the prominent families and species that are sources of antiviral agents against COVID-19 on the basis of case reports, community surveys, and guidelines available in the literature databases. Antiviral efficacy as determined in laboratory testing was assessed, and several promising active compounds with their molecular targets in cell models against SARS-CoV-2 viral infection will be discussed. Our review findings revealed the highly frequent use of Lamiaceae family members, Zingiber officinale, and Glycyrrhiza spp. as medicinal sources for treatment of COVID-19. In addition, several plant bioactive compounds derived from traditional herbal medicine, including andrographolide, panduratin A, baicalein, digoxin, and digitoxin, have shown potent SARS-CoV-2 antiviral activity as compared with some repurposed FDA-approved drugs. These commonly used plants and promising compounds are recommended for further exploration of their safety and efficacy against COVID-19.
Topics: Antiviral Agents; Herbal Medicine; Humans; Plant Extracts; Plants, Medicinal; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34623617
DOI: 10.1007/s11418-021-01575-1 -
Journal of Basic and Clinical... Jul 2020Background Numerous food wastes have been identified to possess potent bioactive compounds used for the treatment of several diseases. Therefore this study evaluated the... (Comparative Study)
Comparative Study Review
Background Numerous food wastes have been identified to possess potent bioactive compounds used for the treatment of several diseases. Therefore this study evaluated the potentials of cardiac and quercetin glycosides extracted from Dacryodes edulis seeds to reverse vascular and endothelial damage (VAED). Methods The glycoside composition of the seeds was extracted using standard methods and characterized by gas chromatography. We then recruited rats with L-NAME-induced VAED based on confirmatory biomarkers cardiac troponin (CnT), cellular adhesion molecule (VCAM-1), lipoprotein associated phospholipase A2 (Lp-PLA2), RAAS, VWF, endothelin, eNOx, and homocysteine. Only rats that showed total alterations of all biomarkers were recruited into the respective experimental groups and treated with either metaprolol succinate (met.su) + losartan or glycoside extracts of D. edulis seeds (NPSG). Results Chromatographic isolation of glycosides in the seed showed predominance of artemetin (1.59 mg/100 g), amygdalin (3.68 mg/100 g), digitoxin (19.21 mg/100 g), digoxin (27.23 mg/100 g), avicularin (133.59 mg/100 g), and hyperoside (481.76 mg/100 g). We observed decreased water intake and higher heart beats under vascular damage as the experiment progressed up to the fourth week. The met.su + losartan and H.D NPSG proved effective in restoring troponin, but both doses of NPSG normalized the VCAM-1 and RAAS activities excluding aldosterone and Lp-PLA2. Among the endothelial dysfunction biomarkers, H.D NPSG produced equivalent effects to met.su + losartan towards restoring the eNOx and VWF activities, but showed higher potency in normalizing the endothelin and Hcy levels. Conclusions We thus propose that the synergistic effect of the isolated glycosides from D. edulis shown in our study proved potent enough at high doses in treatment of vascular and endothelial dysfunction.
Topics: Animals; Biomarkers; Burseraceae; Cardiac Glycosides; Dose-Response Relationship, Drug; Drug Synergism; Endothelium, Vascular; Losartan; Male; Metoprolol; Mice; NG-Nitroarginine Methyl Ester; Plant Extracts; Quercetin; Rats; Seeds
PubMed: 32653874
DOI: 10.1515/jbcpp-2019-0116