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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 -
Parasitology Research Jan 2021Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process,...
Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC and CC, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 μg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 μg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum-infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Deoxycholic Acid; Digitoxigenin; Drug Combinations; Drug Repositioning; Female; Leishmania infantum; Leishmaniasis, Visceral; Liver; Macrophages; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Micelles; Parasite Load; Poloxamer; Reactive Oxygen Species; Spleen
PubMed: 33191446
DOI: 10.1007/s00436-020-06971-2 -
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 -
Pharmaceutics Jun 2023Decoration of nanoparticles with specific molecules such as antibodies, peptides, and proteins that preserve their biological properties is essential for the recognition...
Decoration of nanoparticles with specific molecules such as antibodies, peptides, and proteins that preserve their biological properties is essential for the recognition and internalization of their specific target cells. Inefficient preparation of such decorated nanoparticles leads to nonspecific interactions diverting them from their desired target. We report a simple two-step procedure for the preparation of biohybrid nanoparticles containing a core of hydrophobic quantum dots coated with a multilayer of human serum albumin. These nanoparticles were prepared by ultra-sonication, crosslinked using glutaraldehyde, and decorated with proteins such as human serum albumin or human transferrin in their native conformations. These nanoparticles were homogeneous in size (20-30 nm), retained the fluorescent properties of quantum dots, and did not show a "corona effect" in the presence of serum. The uptake of transferrin-decorated quantum dot nanoparticles was observed in A549 lung cancer and SH-SY5Y neuroblastoma cells but not in non-cancerous 16HB14o- or retinoic acid dopaminergic neurons differentiated SH-SY5Y cells. Furthermore, digitoxin-loaded transferrin-decorated nanoparticles decreased the number of A549 cells without effect on 16HB14o-. Finally, we analyzed the in vivo uptake of these biohybrids by murine retinal cells, demonstrating their capacity to selectively target and deliver into specific cell types with excellent traceability.
PubMed: 37376099
DOI: 10.3390/pharmaceutics15061651 -
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 -
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 -
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 -
Frontiers in Pharmacology 2021Drugs commonly prescribed for heart rate control may induce adverse drug reactions in Alzheimer patients treated with acetylcholinesterase inhibitors (AChEIs). We have...
Use of Drugs With Risk of Heart Rate-Related Problems is Common in Norwegian Dementia Patients Treated With Acetylcholinesterase Inhibitors: A Prevalence Study Based on the Norwegian Prescription Database.
Drugs commonly prescribed for heart rate control may induce adverse drug reactions in Alzheimer patients treated with acetylcholinesterase inhibitors (AChEIs). We have studied use of drugs with a known risk of Torsades de pointes (TdP) and drugs used to treat behavioral and psychological symptoms of dementia, as well as a combination of drugs with a known risk of TdP and drugs with a known heart rate-lowering effect, before and after initiating treatment with AChEIs. The study applied data from the Norwegian Prescription Database for the period 2004-2016. Prescriptions of concomitant use of drugs in persistent users of AChEIs was studied in a follow-up period from 4 years before to 2 years after AChEI initiation in men and women of two age groups: 37-80 and 81-88 years. A small number of patients were prescribed haloperidol (∼1.5% The second year after AChEI initiation), digoxin/digitoxin (∼3%), and verapamil (∼1.3%), while a substantial proportion of the patients were prescribed betablockers (∼28%) and citalopram/escitalopram (∼17%). During follow-up, up to 6% of the study population were prescribed both betablockers and citalopram/citalopram in addition to AChEIs, a combination that increased over the follow-up period and was observed most frequently in women in the oldest age group. A large proportion (∼44%) of patients treated with AChEIs were prescribed drugs that could cause bradycardic and prolonged time from the start of the Q wave to the end of the T wave (QT interval). Thus, action should be taken to reduce the combination of drugs with risk of bradycardia and prolonged QT interval. Medication review on a regular basis could be an option as an important risk-reducing intervention.
PubMed: 35273492
DOI: 10.3389/fphar.2021.791578 -
Drug and Chemical Toxicology Nov 2020Digoxin is a cardiac glycoside derived from the common foxglove and has been available for several centuries as a medicinal agent. Despite extensive patient experience...
Digoxin is a cardiac glycoside derived from the common foxglove and has been available for several centuries as a medicinal agent. Despite extensive patient experience over many years, there remains some controversy regarding the possibility that digoxin might have a deleterious effect on survival. This study was constructed to assess trends in digoxin toxicity research using well-established qualitative and quantitative bibliometric indicators. The current study is based on publications that have been indexed in Scopus. Articles referring to the subject of digoxin toxicity between 1849 and 2015 were assessed according to the document type, publication language, countries/territories, institutions, journal, impact factors, total number of citations, -index, average number of citations per publication, and international collaborations. There were 2900 publications that included 2542 (87.7%) original research articles, while 5.3% were reviews and 4.6% letters. The country of origin was the USA in 849 publications, Germany in 241, the UK in 150, and France in 143. The USA and the UK had the highest number of international collaborations. The average number of citations per publications related to digoxin toxicity was 8.1, and the -index was 59. The USA and Canada had the highest -indices by country at 46 and 22, respectively. This study presents the first bibliometric analysis on digoxin toxicity publications. The USA was the most important contributors to digoxin toxicity literature with the greatest international collaboration, largest number of articles and highest -index, followed by Germany and the UK. There has been a trend towards reduced publication numbers related to digoxin toxicity at global level, although it is still an important issue and we present the current research themes related to digoxin toxicity that were identified.
Topics: Animals; Bibliometrics; Biomedical Research; Cardiovascular Agents; Digitoxin; Humans; Internationality; Risk Assessment; Toxicity Tests; Toxicology
PubMed: 30239237
DOI: 10.1080/01480545.2018.1518453