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European Journal of Pharmaceutical... Apr 2024In this communication, the solubility of digitoxin drug in supercritical CO was studied at different operating conditions (311 < T (K) < 343, 120 < P (bar) < 300). The...
In this communication, the solubility of digitoxin drug in supercritical CO was studied at different operating conditions (311 < T (K) < 343, 120 < P (bar) < 300). The results revealed digitoxin drug solubility (in mole fraction) was between 0.095 × 10 to 1.12 × 10. In the case of thermodynamic solubility modeling, cubic and non-cubic equation of states i.e. SAFT (statistical associating fluid theory), SRK (Soave-Redlich-Kwong) and sPC-SAFT (simplified perturbed chain SAFT) EoSs and six density-based correlations (Chrastil, Kumar-Johnston (KJ), Mendez-Santiago-Teja (MST), Garlapati and Madras (GM), Bartle et al. and Sung-Shim models) were considered. All used equations indicated reasonable behavior with appropriate accuracy for the solubility of the digitoxin drug. Meanwhile, sPC-SAFT EoS and Kumar-Johnston correlation with AARD% set to 8.96 % and 6.25 %, respectively exhibited greater accuracy in fitting the solubility data. Moreover, total, solvation and vaporization enthalpies of the digitoxin/supercritical carbon dioxide binary mixture were calculated based on KJ, Chrastil and Bartle et al. models.
Topics: Carbon Dioxide; Solubility; India; Thermodynamics
PubMed: 38387711
DOI: 10.1016/j.ejps.2024.106731 -
Molecules (Basel, Switzerland) Sep 2022The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as...
In Silico Study towards Repositioning of FDA-Approved Drug Candidates for Anticoronaviral Therapy: Molecular Docking, Molecular Dynamics and Binding Free Energy Calculations.
The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins-papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)-in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs.
Topics: Antiviral Agents; COVID-19; Cysteine Endopeptidases; Digitoxin; Digoxin; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Niclosamide; Ouabain; Papain; Proscillaridin; RNA-Dependent RNA Polymerase; SARS-CoV-2
PubMed: 36144718
DOI: 10.3390/molecules27185988 -
Cardiovascular & Hematological... 2020The relationship between vascular damage and diabetes mellitus was exploited using avocado seed extracts. The purpose of the study was to understand the therapeutic...
BACKGROUND AND OBJECTIVES
The relationship between vascular damage and diabetes mellitus was exploited using avocado seed extracts. The purpose of the study was to understand the therapeutic relevance of glycosides compared to standard vascular and anti-diabetic drugs. Constituent Avocado Seed Glycosides (ASG) were analysed and administered to rats with Diabetes-Induced Vascular Damage (DIVD).
METHODS
The rats were first administered with streptozotocin and screened after seven days for alterations in blood glucose, insulin, vascular cell adhesion molecule (VCAM-1), Von Willebrand factor (VWF), Renin-Angiotensin-Aldosterone System (RAS), eNOx, and endothelin-1 (ET-1). Only rats that satisfied these criteria were recruited and treated with either glibenclamide, met.su + losart, or 200 mg/kg body weight ASG for 28 days.
RESULTS
There was an abundance of digitoxin (13.41 mg/100g), digoxin (17.98 mg/100g), avicularin (165.85 mg/100g), and hyperoside (282.51 mg/100g). ASG or met.su + losart exhibited slight modulatory properties on glucose homeostasis. Rats with DIVD showed elevated renin, angiotensin, VCAM-1 and Lp-PLA2 levels but slightly decreased with glibenclamide treatment and normalized with ASG or met.su + losart administration. All treatments normalized Hcy levels. DIVD caused the overproduction of CnT, LDH, Crt-K, LDL-c, TG, and TC and suppressed HDL-c but was completely normalized by the ASG. Water intake remained altered in treated rats.
CONCLUSION
The ASG had no relevant effect on glucose homeostasis during DIVD but showed significant vasoprotective properties.
Topics: Animals; Diabetes Mellitus, Experimental; Endothelium, Vascular; Glycosides; Hypoglycemic Agents; Persea; Plant Extracts; Protective Agents; Rats; Seeds
PubMed: 32386502
DOI: 10.2174/1871529X20666200510012012 -
Advanced Science (Weinheim,... Mar 2022Eliminating primary tumor ("roots") and inhibiting associated-circulating tumor cells (associated-CTCs, "seeds") are vital issues that need to be urgently addressed in...
Eliminating primary tumor ("roots") and inhibiting associated-circulating tumor cells (associated-CTCs, "seeds") are vital issues that need to be urgently addressed in cancer therapy. Associated-CTCs, which include single CTCs, CTC clusters, and CTC-neutrophil clusters, are essential executors in metastasis and the cause of metastasis-related death in cancer patients. Herein, a "roots and seeds" multipoint costriking nanodevice (GV-Lipo/sorafenib (SF)/digitoxin (DT)) is developed to eliminate primary tumors and inhibit the spread of associated-CTCs for enhancing metastasis inhibition and the therapeutic effect on hepatocellular carcinoma (HCC). GV-Lipo/SF/DT eliminates primary tumor cells by the action of SF, thus reducing CTC production at the roots and improving the therapeutic effect on HCC. GV-Lipo/SF/DT inhibits associated-CTCs effectively via the enhanced identification and capture effects of glypican-3 and/or vascular cell adhesion molecule 1 (VCAM1) targeting, dissociating CTC clusters using DT, blocking the formation of CTC-neutrophil clusters using anti-VCAM1 monoclonal antibody, and killing CTCs with SF. It is successfully verified that GV-Lipo/SF/DT increases the CTC elimination efficiency in vivo, thus effectively preventing metastasis, and shows enhanced antitumor efficacy in both an H22-bearing tumor model and orthotopic HCC models. Overall, the "roots and seeds" multipoint costriking strategy may open a new cancer treatment model for the clinic.
Topics: Carcinoma, Hepatocellular; Cell Count; Cell Line, Tumor; Humans; Liver Neoplasms; Neoplastic Cells, Circulating
PubMed: 35356152
DOI: 10.1002/advs.202101472 -
IScience Nov 2020Selecting appropriate cell lines to represent a disease is crucial for the success of biomedical research, because the usage of less relevant cell lines could deliver...
Selecting appropriate cell lines to represent a disease is crucial for the success of biomedical research, because the usage of less relevant cell lines could deliver misleading results. However, systematic guidance on cell line selection is unavailable. Here we developed a clinical Genomics-guided Prioritizing Strategy for Cancer Cell Lines (CCL-cGPS) and help to guide this process. Statistical analyses revealed CCL-cGPS selected cell lines were among the most appropriate models. Moreover, we observed a linear correlation between the drug response and CCL-cGPS score of cell lines for breast and thyroid cancers. Using RT4 cells selected by CCL-GPS, we identified mebendazole and digitoxin as candidate drugs against bladder cancer and validate their promising anticancer effect through and experiments. Additionally, a web tool was developed. In conclusion, CCL-cGPS bridges the gap between tumors and cell lines, presenting a helpful guide to select the most suitable cell line models.
PubMed: 33225250
DOI: 10.1016/j.isci.2020.101748 -
Biochimica Et Biophysica Acta. General... Apr 2020Imatinib mesylate (imatinib) is the first-line treatment for newly diagnosed chronic myeloid leukemia (CML) due to its remarkable hematologic and cytogenetic responses....
BACKGROUND
Imatinib mesylate (imatinib) is the first-line treatment for newly diagnosed chronic myeloid leukemia (CML) due to its remarkable hematologic and cytogenetic responses. We previously demonstrated that the imatinib-resistant CML cells (Myl-R) contained elevated Lyn activity and intracellular creatine pools compared to imatinib-sensitive Myl cells.
METHODS
Stable isotope metabolic labeling, media creatine depletion, and Na/K-ATPase inhibitor experiments were performed to investigate the origin of creatine pools in Myl-R cells. Inhibition and shRNA knockdown were performed to investigate the specific role of Lyn in regulating the Na/K-ATPase and creatine uptake.
RESULTS
Inhibition of the Na/K-ATPase pump (ouabain, digitoxin), depletion of extracellular creatine or inhibition of Lyn kinase (ponatinib, dasatinib), demonstrated that enhanced creatine accumulation in Myl-R cells was dependent on uptake from the growth media. Creatine uptake was independent of the Na/creatine symporter (SLC6A8) expression or de novo synthesis. Western blot analyses showed that phosphorylation of the Na/K-ATPase on Tyr 10 (Y10), a known regulatory phosphorylation site, correlated with Lyn activity. Overexpression of Lyn in HEK293 cells increased Y10 phosphorylation (pY10) of the Na/K-ATPase, whereas Lyn inhibition or shRNA knockdown reduced Na/K-ATPase pY10 and decreased creatine accumulation in Myl-R cells. Consistent with enhanced uptake in Myl-R cells, cyclocreatine (Ccr), a cytotoxic creatine analog, caused significant loss of viability in Myl-R compared to Myl cells.
CONCLUSIONS
These data suggest that Lyn can affect creatine uptake through Lyn-dependent phosphorylation and regulation of the Na/K-ATPase pump activity.
GENERAL SIGNIFICANCE
These studies identify kinase regulation of the Na/K-ATPase as pivotal in regulating creatine uptake and energy metabolism in cells.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Creatine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tumor Cells, Cultured; src-Family Kinases
PubMed: 31881245
DOI: 10.1016/j.bbagen.2019.129507 -
Organic Letters Feb 2023This letter describes the development of an α-selective glycosylation using l-oleandrose, a 2-deoxysugar that is frequently found in natural products, and its...
This letter describes the development of an α-selective glycosylation using l-oleandrose, a 2-deoxysugar that is frequently found in natural products, and its application to the total synthesis of the natural cardiotonic steroids oleandrin and beaumontoside. To improve the reaction diastereoselectivity and to minimize side-product formation, an extensive evaluation and optimization of the conditions leading to α-selective glycosylation of digitoxigenin with l-oleandrose-based donors was conducted. These studies led to the exploration of 8 different phosphine·acid complexes or salts and yielded HBr·PPh as the optimal catalyst, which provided in the cleanest α-glycosylation and produced protected beaumontoside in 67% yield. Subsequent application of these conditions to synthetic oleandrigenin afforded the desired α-product in 69% isolated yield─enabling the completion of the first synthesis of oleandrin in 17 steps (1.2% yield) from testosterone.
Topics: Glycosylation; Cardiac Glycosides; Digitoxigenin
PubMed: 36739571
DOI: 10.1021/acs.orglett.2c04358 -
Basic Research in Cardiology Jun 2020Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive...
Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive adhesiotropy", was demonstrated to be a function of sympathetic signaling and to be relevant for a sufficient inotropic response. We used the inotropic agent digitoxin to investigate the link between inotropy and adhesiotropy. In contrast to wild-type hearts, digitoxin failed to enhance pulse pressure in perfused mice hearts lacking the desmosomal protein plakoglobin which was paralleled with abrogation of plaque thickening indicating that positive inotropic response requires intact desmosomal adhesion. Atomic force microscopy revealed that digitoxin increased the binding force of the adhesion molecule desmoglein-2 at cell-cell contact areas. This was paralleled by enhanced cardiac myocyte cohesion in both HL-1 cardiac myocytes and murine cardiac slices as determined by dissociation assays as well as by accumulation of desmosomal proteins at cell-cell contact areas. However, total protein levels or cytoskeletal anchorage were not affected. siRNA-mediated depletion of desmosomal proteins abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, digitoxin caused activation of ERK1/2. In line with this, inhibition of ERK1/2 signaling abrogated the effects of digitoxin on cell-cell adhesion and desmosomal reorganization. These results show that the positive inotropic agent digitoxin enhances cardiac myocyte cohesion with reorganization of desmosomal proteins in an ERK1/2-dependent manner. Desmosomal adhesion seems to be important for a sufficient positive inotropic response of digitoxin treatment, which can be of medical relevance for the treatment of heart failure.
Topics: Animals; Cardiotonic Agents; Cell Adhesion; Cell Line; Desmosomes; Digitoxin; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Myocytes, Cardiac
PubMed: 32556797
DOI: 10.1007/s00395-020-0805-3 -
Pharmacological Research Jan 2023Increasing studies have suggested that some cardiac glycosides, such as conventional digoxin (DIG) and digitoxin, can induce immunogenic cell death (ICD) in various...
Increasing studies have suggested that some cardiac glycosides, such as conventional digoxin (DIG) and digitoxin, can induce immunogenic cell death (ICD) in various tumors. We previously found that 3'-epi-12β-hydroxyfroside (HyFS), a novel cardenolide compound isolated by our group, could induce cytoprotective autophagy through inactivation of the Akt/mTOR pathway. However, whether HyFS can induce ICD remains unknown. In this study, we extend our work to further investigate whether HyFS could induce both autophagy and ICD, and we investigated the relationship between autophagy and ICD in three TNBC cell lines. Unexpectedly, compared to DIG, we found that HyFS could induce complete autophagy flux but not ICD in three human triple-negative breast cancer (TNBC) cell lines and one murine TNBC model. Inhibition of HyFS-induced autophagy resulted in the production of ICD in TNBC MDA-MB-231, MDA-MB-436, and HCC38 cells. A further mechanism study showed that formation of RIPK1/RIPK3 necrosomes was necessary for ICD induction in DIG-treated TNBC cells, while HyFS treatment led to receptor-interacting serine-threonine kinase (RIPK)1/3 necrosome degradation via an autophagy process. Additionally, inhibition of HyFS-induced autophagy by the autophagy inhibitor chloroquine resulted in the reoccurrence of ICD and reversion of the tumor microenvironment, leading to more significant antitumor effects in immunocompetent mice than in immunodeficient mice. These findings indicate that HyFS-mediated autophagic degradation of RIPK1/RIPK3 necrosomes leads to inactivation of ICD in TNBC cells. Moreover, combined treatment with HyFS and an autophagy inhibitor may enhance the antitumor activities, suggesting an alternative therapeutic for TNBC treatment.
Topics: Animals; Humans; Mice; Apoptosis; Autophagy; Cell Line, Tumor; Immunogenic Cell Death; Receptor-Interacting Protein Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 36535569
DOI: 10.1016/j.phrs.2022.106613 -
ESC Heart Failure Oct 2020Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post-transplant survival, but their...
AIMS
Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post-transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post-transplant outcomes.
METHODS AND RESULTS
This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post-transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post-transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post-transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02-2.77; P = 0.04).
CONCLUSIONS
Combined pre-transplant amiodarone and digitalis therapy is associated with increased post-transplant mortality.
Topics: Amiodarone; Digitalis; Heart Transplantation; Humans; Retrospective Studies; Stroke Volume; Ventricular Function, Left
PubMed: 32608191
DOI: 10.1002/ehf2.12807