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Frontiers in Immunology 2022Osteoarthritis (OA) is a common orthopedic degenerative disease, leading to high disability in activities of daily living. There remains an urgent need to identify the...
Osteoarthritis (OA) is a common orthopedic degenerative disease, leading to high disability in activities of daily living. There remains an urgent need to identify the underlying mechanisms and identify new therapeutic targets in OA diagnosis and treatment. Circular RNAs (circRNAs) play a role in the development of multiple diseases. Many studies have reported that circRNAs regulate microRNAs (miRNAs) through an endogenous competitive mechanism. However, it remains unclear if an interplay between circRNAs, miRNAs, and target genes plays a deeper regulatory role in OA. Four datasets were downloaded from the GEO database, and differentially expressed circRNAs (DECs), differentially expressed miRNAs (DEMs), and differentially expressed genes (DEGs) were identified. Functional annotation and pathway enrichment analysis of DEGs and DECs were carried out to determine the main associated mechanism in OA. A protein-protein network (PPI) was constructed to analyze the function of, and to screen out, hub DEGs in OA. Based on the artificial intelligence prediction of protein crystal structures of two hub DEGs, TOP2A and PLK1, digitoxin and oxytetracycline were found to have the strongest affinity, respectively, with molecular docking. Subsequently, overlapping DEMs and miRNAs targeted by DECs obtained target DEMs (DETMs). Intersection of DEGs and genes targeted by DEMs obtained target DEGs (DETGs). Thus, a circRNA-miRNA-mRNA regulatory network was constructed from 16 circRNAs, 32 miRNAs, and 97 mRNAs. Three hub DECs have the largest number of regulated miRNAs and were verified through experiments. In addition, the expression level of 16 DECs was validated by RT-PCR. In conclusion, we constructed a circRNA-miRNA-mRNA regulatory network in OA and three new hub DECs, hsa_circ_0027914, hsa_circ_0101125, and hsa_circ_0102564, were identified as novel biomarkers for OA.
Topics: Humans; RNA, Messenger; MicroRNAs; RNA, Circular; Molecular Docking Simulation; Artificial Intelligence; Activities of Daily Living; Gene Regulatory Networks; Gene Expression Profiling; Osteoarthritis
PubMed: 36700234
DOI: 10.3389/fimmu.2022.1050743 -
PloS One 2017Cardiac glycosides (CGs) including digitalis, digoxin and digitoxin are used in the treatment of congestive heart failure and atrial fibrillation. Pre-clinical studies... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiac glycosides (CGs) including digitalis, digoxin and digitoxin are used in the treatment of congestive heart failure and atrial fibrillation. Pre-clinical studies have investigated the anti-neoplastic properties of CGs since 1960s. Epidemiological studies concerning the association between CGs use and cancer risk yielded inconsistent results. We have performed a systematic review and meta-analysis to summarize the effects of CGs on cancer risk and mortality.
METHODS
PubMed, Scopus, Cochrane library, Medline and Web of Knowledge were searched for identifying relevant studies. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects model.
RESULTS
We included 14 case-control studies and 15 cohort studies published between 1976 and 2016 including 13 cancer types. Twenty-four studies reported the association between CGs and cancer risk and six reported the association between CGs and mortality of cancer patients. Using CGs was associated with a higher risk of breast cancer (RR = 1.330, 95% CI: 1.247-1.419). Subgroup analysis showed that using CGs increased the risk of ER+ve breast cancer but not ER-ve. Using CGs wasn't associated with prostate cancer risk (RR = 1.015, 95% CI: 0.868-1.87). However, CGs decreased the risk in long term users and showed a protective role in decreasing the risk of advanced stages. CGs use was associated with increased all-cause mortality (HR = 1.35, 95% CI: 1.248-1.46) but not cancer-specific mortality (HR = 1.075, 95% CI: 0.968-1.194).
CONCLUSION
The anti-tumor activity of CGs observed in pre-clinical studies requires high concentrations which can't be normally tolerated in humans. However, the estrogen-like activity of CGs could be responsible for increasing the risk of certain types of tumors.
Topics: Cardiac Glycosides; Female; Humans; Male; Neoplasms; Observational Studies as Topic; Risk Factors
PubMed: 28591151
DOI: 10.1371/journal.pone.0178611 -
International Journal of Molecular... Jul 2022Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the...
Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Digitoxin; Humans; Pancreatic Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species
PubMed: 35897809
DOI: 10.3390/ijms23158237 -
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 -
Oncoimmunology Apr 2015The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an... (Review)
Review
The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.
PubMed: 26137404
DOI: 10.1080/2162402X.2015.1008866 -
Biomaterials Mar 2021Cancer immunotherapy, particularly the inhibition of immune checkpoints with neutralizing antibodies, has revolutionized the treatment of some cancer patients. However,...
Cancer immunotherapy, particularly the inhibition of immune checkpoints with neutralizing antibodies, has revolutionized the treatment of some cancer patients. However, immune checkpoint blockade has not provided survival benefits to most patients with colorectal and ovarian cancers. This work reports the design of acid-sensitive core-shell nanoscale coordination polymer particles (NCP) comprising a carboplatin prodrug and an siRNA against PD-L1 (siPD-L1) in the core and digitoxin on the shell for tri-modality cancer therapy. Upon cellular uptake, NCP particles rapidly burst in acidic organelles to release carboplatin for apoptosis, digitoxin for inducing immunogenicity, and siPD-L1 for PD-L1 knockdown. With long blood circulation and high tumor accumulation, NCP particles efficiently suppress the growth and metastasis of syngeneic cancers through reactivating innate and adaptive immune responses. NCP particles thus provide a promising platform to synergistically combine chemotherapy and immunotherapy for the treatment of advanced and aggressive cancers.
Topics: Carboplatin; Humans; Immunotherapy; Nanoparticles; Neoplasms; Polymers
PubMed: 33561626
DOI: 10.1016/j.biomaterials.2021.120690 -
Frontiers in Pharmacology 2023Calotropin is a pharmacologically active compound isolated from milkweed plants like and that belong to the Asclepiadaceae family. All of these plants are recognised... (Review)
Review
Calotropin is a pharmacologically active compound isolated from milkweed plants like and that belong to the Asclepiadaceae family. All of these plants are recognised as medical traditional plants used in Asian countries. Calotropin is identified as a highly potent cardenolide that has a similar chemical structure to cardiac glycosides (such as digoxin and digitoxin). During the last few years, cytotoxic and antitumor effects of cardenolides glycosides have been reported more frequently. Among cardenolides, calotropin is identified as the most promising agent. In this updated and comprehensive review, we aimed to analyze and discuss the specific mechanisms and molecular targets of calotropin in cancer treatment to open new perspectives for the adjuvant treatment of different types of cancer. The effects of calotropin on cancer have been extensively studied in preclinical pharmacological studies using cancer cell lines and in experimental animal models that have targeted antitumor mechanisms and anticancer signaling pathways. The analyzed information from the specialized literature was obtained from scientific databases until December 2022, mainly from PubMed/MedLine, Google Scholar, Scopus, Web of Science, and Science Direct databases using specific MeSH search terms. The results of our analysis demonstrate that calotropin can be a potential chemotherapeutic/chemopreventive adjunctive agent in cancer pharmacotherapeutic management.
PubMed: 37138852
DOI: 10.3389/fphar.2023.1160616 -
Toxicology and Applied Pharmacology Jan 2012Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or...
Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potency than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin.
Topics: Antineoplastic Agents; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Survival; Checkpoint Kinase 1; Cyclin B1; Cytochromes c; Digitoxin; Humans; Lung Neoplasms; Protein Kinases; Rhamnose; Sodium-Potassium-Exchanging ATPase
PubMed: 22037315
DOI: 10.1016/j.taap.2011.10.007 -
Tidsskrift For Den Norske Laegeforening... May 2012
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Diabetes Mellitus, Type 2; Digitoxin; Humans; Male
PubMed: 22614312
DOI: 10.4045/tidsskr.12.0266 -
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