-
International Immunopharmacology Feb 2024Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active...
Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active ingredient in the anti-rheumatic and anti-inflammatory herb, cortex periplocae. We conducted a study using a CIA model and an in vitro model of fibroblast-like synoviocytes (FLS) induced by Tumor Necrosis Factor-alpha (TNF-α) stimulation. We evaluated cell activity, proliferation, and migration using the CCK8 test, EDU kit, and transwell assays, as well as network pharmacokinetic analysis of periplogenin targets and RA-related effects. Furthermore, we measured inflammatory factors and matrix metalloproteinases (MMPs) expression using ELISA and qRT-PCR assays. We also evaluated joint destruction using HE and Safranin O-Fast Green Staining and examined the changes in the JAK2/3-STAT3 pathway using western blot. The results indicated that periplogenin can effectively inhibit the secretion of inflammatory factors, suppress the JAK2/3-STAT3 pathway, and impede the proliferation and migration of RA FLS. Thus, periplogenin alleviated the Synovial inflammatory infiltration of RA.
Topics: Humans; Animals; Arthritis, Rheumatoid; Synoviocytes; Inflammation; Cell Proliferation; Fibroblasts; Synovial Membrane; Cells, Cultured; Arthritis, Experimental; Janus Kinase 2; STAT3 Transcription Factor; Digitoxigenin
PubMed: 38183911
DOI: 10.1016/j.intimp.2024.111487 -
Chemistry & Biodiversity Jan 2024Streptocaulon juventas (Lour.) Merr. (SJ) is a herbal medicine can promote wound healing. Cardiac glycosides, especially periplogenin, digitoxigenin, and their...
Streptocaulon juventas (Lour.) Merr. (SJ) is a herbal medicine can promote wound healing. Cardiac glycosides, especially periplogenin, digitoxigenin, and their glycosides were the main constituents of SJ. We aim to establish a method for the simultaneous determination of periplogenin and digitoxigenin in SJ and evaluate the wound healing activities of these two components. UPLC-QqQ-MS/MS was used for the determination of periplogenin and digitoxigenin. Meanwhile, rats were subjected to full-thickness skin resection on the back to investigate the wound healing effects of periplogenin and digitoxigenin. The content of periplogenin and digitoxigenin in 13 batches of SJ extracts ranged from 43.26 to 97.15 μg/g and 18.04 to 55.55 μg/g, respectively. Periplogenin and digitoxigenin significantly increased the rate of wound healing in rats, increased the content of hydroxyproline in wound tissue, and improved the pathological state of wound skin tissue.
Topics: Rats; Animals; Digitoxigenin; Tandem Mass Spectrometry; Apocynaceae; Wound Healing
PubMed: 38061998
DOI: 10.1002/cbdv.202301585 -
Virology Jan 2024A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and...
A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with ECs in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulation. Furthermore, the compounds acted post virus entry. While the antiviral activity of digitoxin was dependent upon activation of the MEK and JNK signaling pathways but not signaling through GPCRs, the antiviral effect of monensin was reversed upon inhibition of several signaling pathways. Together, the data demonstrates the potent anti-coronavirus properties of two classes of FDA approved drugs that function by altering the properties of the infected cell, rendering it unable to support virus replication.
Topics: Humans; Cardiac Glycosides; Monensin; Ouabain; Coronavirus 229E, Human; Digitoxin; Antiviral Agents
PubMed: 37931588
DOI: 10.1016/j.virol.2023.109915 -
The Journal of Organic Chemistry Aug 2023The Mislow-Evans rearrangement was used as a key reaction to construct digitoxose-derived glycals. The same rearrangement was iteratively performed on di- and...
The Mislow-Evans rearrangement was used as a key reaction to construct digitoxose-derived glycals. The same rearrangement was iteratively performed on di- and trisaccharides to form the digoxose glycal donor component present in the cardenolides digitoxin, digoxin, and gitoxin. The scalability of the trisaccharide synthesis was shown by performing the reactions on a multigram scale. Glycosylation reactions were also performed between the synthesized digoxin glycal donor and aglycons digoxigenin and gitoxigenin to synthesize novel cardenolide derivatives.
PubMed: 37555372
DOI: 10.1021/acs.joc.3c01067 -
Journal of Cardiology Cases Aug 2023We present the case series of two women aged 35 and 60 years who presented to our emergency department with severe vomiting, nausea, and malaise. Their symptoms...
UNLABELLED
We present the case series of two women aged 35 and 60 years who presented to our emergency department with severe vomiting, nausea, and malaise. Their symptoms started approximately 2 h after the ingestion of home-made mixed vegetables with freshly picked vegetables and leaves from the patients' garden, of which one was supposed to be borage. An electrocardiogram revealed diffuse ST-segment depression with down-up sloping in both patients. We supposed an accidental confusion of wild borage () with foxglove (). Both patients were subsequently admitted to the intermediate-care-unit for close monitoring and continuous activated charcoal administration. Digitoxin serum concentrations were elevated in both patients (40.9 and >50 ng/ml, respectively - reference therapeutic range 8-18 ng/ml). The younger woman, despite the relatively lower serum digitoxin concentrations, presented a single episode of advanced atrioventricular block and long-lasting sinus bradycardia. Both showed a complete recovery. Although not uncommon, our case series reiterates the fact that such plant misclassifications are potentially life-threating and warrant the treating physicians' full attention.
LEARNING OBJECTIVE
Plant poisoning is a frequent reason for consultation of poison information centers and may result in life-threatening cardiac arrhythmias. Confusion of foxglove leaves () with borage leaves (), which is a popular food ingredient for mixed salads, is not uncommon. Without a dedicated medical history, such cases are difficult to diagnose and warrant the treating physicians' full attention and the involvement of a local poison information center.
PubMed: 37521578
DOI: 10.1016/j.jccase.2023.04.007 -
Cell Biology and Toxicology Dec 2023Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and...
Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.
Topics: Humans; Apoptosis; Phosphorylation; Cell Line, Tumor; Cardiac Glycosides; Down-Regulation; Molecular Docking Simulation; ATP Binding Cassette Transporter, Subfamily G, Member 2; Parthanatos; G2 Phase Cell Cycle Checkpoints; Neoplasm Proteins; Leukemia; Cardenolides; Mitogen-Activated Protein Kinase Kinases; Drug Resistance, Neoplasm
PubMed: 37322258
DOI: 10.1007/s10565-023-09813-w -
Clinical Research in Cardiology :... Aug 2023The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial.
METHODS AND RESULTS
In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m, and BMI < 27 kg/m each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively.
CONCLUSION
In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m, BMI < 27 kg/m, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.
Topics: Humans; Female; Aged; Heart Failure; Digitoxin; Stroke Volume; ROC Curve; Sensitivity and Specificity
PubMed: 37087503
DOI: 10.1007/s00392-023-02199-z -
Journal of Fluorescence Sep 2023The interaction of orphenadrine hydrochloride (ORD) with the model protein, bovine serum albumin (BSA), was investigated using a variety of spectroscopic techniques such...
The interaction of orphenadrine hydrochloride (ORD) with the model protein, bovine serum albumin (BSA), was investigated using a variety of spectroscopic techniques such as steady-state fluorescence, ultraviolet-visible, Fourier transform infrared, 3-D spectroscopy, and electrochemical methods under physiological conditions. Stern-Volmer plots were used to calculate fluorescence quenching at various temperatures. The findings point to a static quenching mechanism between ORD and BSA. At various reaction times, the binding sites (n) and binding constants (K) of ORD to BSA were recorded. Thermodynamic parameters ∆H, ∆S and ∆G between ORD and BSA were calculated and reported. The average binding distance (r) between the donor (BSA) and acceptor (ORD) molecules was predicted using Förster's theory. Three-dimensional fluorescence spectra, Fourier transform infrared spectra, and synchronous fluorescence studies all supported the alternations in protein structure following the interaction with ORD. A displacement study using site probes such as warfarin, ibuprofen, and digitoxin confirmed ORD binding at Sudlow's site I of BSA. The effect of common metal ions such as Cu, Ni, Ca, Co, and Zn on binding constant values was investigated and reported.
Topics: Serum Albumin, Bovine; Orphenadrine; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Binding Sites; Thermodynamics; Protein Binding; Circular Dichroism
PubMed: 36976401
DOI: 10.1007/s10895-023-03199-y