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In Vivo (Athens, Greece) 2020Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by...
BACKGROUND/AIM
Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment.
RESULTS
The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus.
CONCLUSION
Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.
Topics: Animals; Betacoronavirus; COVID-19; Coronavirus Infections; Cytokines; Digitoxin; Disease Models, Animal; Humans; Influenza, Human; Lung; Male; NF-kappa B; Pandemics; Pneumonia, Viral; Prostatic Neoplasms; Rats; SARS-CoV-2; Tumor Necrosis Factor-alpha
PubMed: 33144490
DOI: 10.21873/invivo.12221 -
Journal of Biomolecular Structure &... Feb 2022Most recently, the new coronavirus (SARS-CoV-2) has been recognized as a pandemic by the World Health Organization (WHO) while this virus shares substantial similarity...
Most recently, the new coronavirus (SARS-CoV-2) has been recognized as a pandemic by the World Health Organization (WHO) while this virus shares substantial similarity with SARS-CoV. So far, no definitive vaccine or drug has been developed to cure Covid-19 disease, since many important aspects about Covid-19 such as pathogenesis and proliferation pathways are still unclear. It was proven that human ACE2 is the main receptor for the entry of Covid-19 into lower respiratory tract epithelial cells through interaction with SARS-CoV-2 S protein. Based on this observation, it is expected that the virus infection can be inhibited if protein-protein interaction is prevented. In this study, using structure-based virtual screening of FDA databases, several lead drugs were discovered based on the ACE2-binding pocket of SARS-CoV-2 S protein. Then, binding affinity, binding modes, critical interactions, and pharmaceutical properties of the lead drugs were evaluated. Among the previously approved drugs, Diammonium Glycyrrhizinate, Digitoxin, Ivermectin, Rapamycin, Rifaximin, and Amphotericin B represented the most desirable features, and can be possible candidates for Covid-19 therapies. Furthermore, molecular dynamics (MD) simulation was accomplished for three S protein/drug complexes with the highest binding affinity and best conformation and binding free energies were also computed with the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Results demonstrated the stable binding of these compounds to the S protein; however, in order to confirm the curative effect of these drugs, clinical trials must be done.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Drug Repositioning; Humans; Molecular Docking Simulation; Pharmaceutical Preparations; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 32969333
DOI: 10.1080/07391102.2020.1824816 -
Contemporary Clinical Trials Nov 2020The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to...
The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to supervise trials in the usual way and precautionary measures had to be implemented to care for medication supply and general safety of study participants it is now important to consider, how the impact of the pandemic on trial outcome can be assessed, which measures are needed to decide, how to proceed with the trial and what is needed to compensate to irregularity introduced by the pandemic situation. Obviously not all trials will suffer to the same degree: some trials may be close to finalizing recruitment, others may not yet have started. Similarly not all clinical trials investigate vulnerable patient populations, but some will and may in addition have recruited to an extent that beneficial effects achieved in the initial phase of the trial may be outweighed by an increase e.g. in mortality that impacts both treatment groups. The situation is further complicated by the fact that the pandemic reached different countries in the world and even cities in one country at different points in time with different severity. Our example is a randomized and double-blind clinical trial comparing digitoxin and placebo in patients with advanced chronic heart failure. This trial has recruited roughly 1/3 of the overall 2200 patients when the disease outbreak reached Germany. We discuss how simulations and theoretical considerations can be used to address questions about the need to increase the overall sample-size to be recruited to compensate for a potential shrinkage of the treatment effect caused by the COVID-19 pandemic and what role the degree of consistency could play when comparing pre-, during- and post- COVID-19 periods of trial conduct regarding the question, whether the treatment effect can be considered consistent and with this generalizable. This is dependent on the size of the treatment effect and the impact of the pandemic. We argue, that in case of doubt, it may be wise to proceed with the original study plan.
Topics: COVID-19; Clinical Trials as Topic; Early Termination of Clinical Trials; Germany; Global Health; Humans; Infection Control; Organizational Innovation; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Research Design; SARS-CoV-2; Sample Size; Vulnerable Populations
PubMed: 32961360
DOI: 10.1016/j.cct.2020.106155 -
Oncology Letters Oct 2020Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed...
Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell-based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin-resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G/M cell cycle arrest via the serine/threonine-protein kinase ATR (ATR)-serine/threonine-protein kinase Chk2 (CHK2)-M-phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double-stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl-2 and Bax, the release of cytochrome , as well as the activation of the caspase-3 and -9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti-HCC effect on HepG2/ADM cells through G/M cell cycle arrest, which was mediated by the ATR-CHK2-CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.
PubMed: 32863904
DOI: 10.3892/ol.2020.11932 -
Inorganic Chemistry Sep 2020The cationic enantiopure () and luminescent Eu(III) complex [Eu(bQcd)(HO)] OTf (with bQcd = -bis(2-quinolinmethyl)--1,2-diaminocyclohexane -diacetate and OTf = triflate)...
The cationic enantiopure () and luminescent Eu(III) complex [Eu(bQcd)(HO)] OTf (with bQcd = -bis(2-quinolinmethyl)--1,2-diaminocyclohexane -diacetate and OTf = triflate) was synthesized and characterized. At physiological pH, the 1:1 [Eu(bQcd)(HO)] species, possessing two water molecules in the inner coordination sphere, is largely dominant. The interaction with bovine serum albumin (BSA) was studied by means of several experimental techniques, such as luminescence spectroscopy, isothermal titration calorimetry (ITC), molecular docking (MD), and molecular dynamics simulations (MDS). In this direction, a ligand competition study was also performed by using three clinically established drugs (i.e., ibuprofen, warfarin, and digitoxin). The nature of this interaction is strongly affected by the type of the involved heteroaromatic antenna in the Eu(III) complexes. In fact, the presence of quinoline rings drives the corresponding complex toward the protein superficial area containing the tryptophan residue 134 (Trp134). As the main consequence, the metal center undergoes the loss of one water molecule upon interaction with the side chain of a glutamic acid residue. On the other hand, the similar complex containing pyridine rings ([Eu(bpcd)(HO)]Cl with bpcd = -bis(2-pyridylmethyl)-trans-1,2-diaminocyclohexane -diacetate) interacts more weakly with the protein in a different superficial cavity, without losing the coordinated water molecules.
Topics: Animals; Cattle; Coordination Complexes; Europium; Hydrocarbons, Aromatic; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Serum Albumin, Bovine; Stereoisomerism; Water
PubMed: 32806003
DOI: 10.1021/acs.inorgchem.0c01663 -
Chinese Journal of Integrative Medicine Sep 2020To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2...
OBJECTIVE
To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.
METHODS
The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.
RESULTS
It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.
CONCLUSIONS
A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.
Topics: COVID-19; China; Computer Simulation; Coronavirus Infections; Drug Repositioning; Drugs, Chinese Herbal; Glycoproteins; Humans; Imaging, Three-Dimensional; Mass Screening; Molecular Docking Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; United States; United States Food and Drug Administration
PubMed: 32740825
DOI: 10.1007/s11655-020-3427-6 -
Biochimica Et Biophysica Acta. General... Nov 2020Cardiac glycosides (CGs), such as digitoxin, are traditionally used for treatment of congestive heart failure; recently they also gained attention for their anticancer...
BACKGROUND
Cardiac glycosides (CGs), such as digitoxin, are traditionally used for treatment of congestive heart failure; recently they also gained attention for their anticancer properties. Previous studies showed that digitoxin and a synthetic L-sugar monosaccharide analog treatment decreases cancer cell proliferation, increases apoptosis, and pro-adhesion abilities; however, no reports are available on their potential to alter lung cancer cell cytoskeleton structure and reduce migratory ability. Herein, we investigated the anticancer effects of digitoxin and its analog, digitoxigenin-α-L-rhamnoside (D6MA), to establish whether cytoskeleton reorganization and reduced motility are drug-induced cellular outcomes.
METHODS
We treated non-small cell lung carcinoma cells (NSCLCs) with sub-therapeutic, therapeutic, and toxic concentrations of digitoxin and D6MA respectively, followed by both single point and real-time assays to evaluate changes in cellular gene and protein expression, adhesion, elasticity, and migration.
RESULTS
Digitoxin and D6MA induced a decrease in matrix metalloproteinases expression via altered focal adhesion signaling and a suppression of the phosphoinositide 3-kinases / protein kinase B pathway which lead to enhanced adhesion, altered elasticity, and reduced motility of NSCLCs. Global gene expression analysis identified dose-dependent changes to nuclear factor kappa-light-chain-enhancer, epithelial tumor, and microtubule dynamics signaling.
CONCLUSIONS
Our study demonstrates that digitoxin and D6MA can target antitumor signaling pathways to alter NSCLC cytoskeleton and migratory ability to thus potentially reduce their tumorigenicity.
SIGNIFICANCE
Discovering signaling pathways that control cancer's cell phenotype and how such pathways are affected by CG treatment will potentially allow for active usage of synthetic CG analogs as therapeutic agents in advanced lung conditions.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cytoskeleton; Digitoxin; Humans; Lung Neoplasms
PubMed: 32679249
DOI: 10.1016/j.bbagen.2020.129683 -
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 -
Biomedicine & Pharmacotherapy =... Sep 2020Nerium oleander L., commonly known as oleander, is a toxic shrub and also a medicinal plant. All parts of oleander are rich in cardiac glycosides that inhibits... (Review)
Review
Nerium oleander L., commonly known as oleander, is a toxic shrub and also a medicinal plant. All parts of oleander are rich in cardiac glycosides that inhibits Na/K-ATPase and induce inotropic effect on the cardiomyocytes. Several pre-clinical and clinical reports indicate acute toxicity due to intentional, accidental and suicidal oleander consumption. Contrarily, oleander is used for the treatment of diverse ailments in traditional medicinal practices around the globe and several evidence-based pre-clinical studies indicated metabolic and immunological health benefits of polyphenol-rich oleander extracts. Thus, the current review aims to address this pharmaco-toxicological conundrum of oleander by addressing the possible role of gut microflora in the differential oleander toxicity. Additionally, a comprehensive account of ethnopharmacological usage, metabolic and immunological health benefits has been documented that supplement the conflicting arguments of pharmaco-toxicological properties of oleander. Finally, by addressing the gap of knowledge of ethnomedicinal, pharmacological and toxicological reports of oleander, the current review is expected to pave the way to address the differential pharmaco-toxicological effects of oleander.
Topics: Animals; Bacteria; Biotransformation; Ethnopharmacology; Gastrointestinal Microbiome; Humans; Intestines; Nerium; Plant Extracts; Plants, Medicinal; Risk Assessment
PubMed: 32563990
DOI: 10.1016/j.biopha.2020.110422 -
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