Cardiac glycosides (CGs), which are traditionally used for heart disease, show promise for cancer therapy. However, there is a lack of a comprehensive review of clinical studies in this area, and so far, CGs have not been widely integrated into clinical cancer treatment. This review covers clinical studies from the past five years, highlighting the potential of CGs to reduce cancer risk, enhance chemotherapy effectiveness, mitigate chemotherapy-induced side effects and improve quality of life. Future clinical trials should personalize the dosage of CGs, integrate molecular testing and investigate immunogenic cell death induction and the potential of CGs for treating bone cancer and metastasis. Optimizing the repurposing of CGs for anticancer treatment requires consideration of specific CGs, cancer types and concurrent medications.

(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large, observational study in recipients of cardiac resynchronization therapy (CRT). (2) Methods: Consecutive patients receiving a CRT-defibrillator in three European tertiary referral centers were enrolled and followed-up for a mean 37 months ± 28 months. Digitalis use was assessed at the time of CRT implantation. A multivariate Cox-regression model and propensity score matching were used to determine all-cause mortality as the primary endpoint. CRT-response (defined as improvement of ≥1 NYHA class), echocardiographic improvement (defined as improvement of LVEF of ≥ 5%) and incidence of ICD shocks and rehospitalization were assessed as secondary endpoints in a subgroup of patients. (3) Results: The study comprised 552 CRT-recipients with standard indications, including 219 patients (40%) treated with digitalis. Compared to patients without digitalis, they had more often atrial fibrillation, poorer LVEF and a higher NYHA class (all p ≤ 0.002). Crude analysis of all-cause mortality demonstrated a similar relative risk of death for patients with and without digitalis (HR = 1.14; 95% CI 0.88-1.5; p = 0.40). After adjustment for independent predictors of mortality, digitalis therapy did not alter the risk for death (adjusted HR = 1.04; 95% CI 0.75-1.45; p = 0.82). Furthermore, in comparison to 286 propensity-score-matched patients, mortality was not affected by digitalis intake (propensity-adjusted HR = 1.11; 95% CI 0.72-1.70; p = 0.64). A CRT-response was predominant in digitalis non-users, concerning both improvement of HF symptoms and LVEF (NYHA p < 0.01; LVEF p < 0.01), while patients on digitalis had more often ventricular tachyarrhythmias requiring ICD shock (p = 0.01); although, rehospitalization for cardiac reasons was significantly lower among digitalis users compared to digitalis non-users (HR = 0.58; 95% C. I. 0.40-0.85; p = 0.01). (4) Conclusions: Digitalis therapy had no effect on mortality, but was associated with a reduced response to CRT and increased susceptibility to ventricular arrhythmias requiring ICD shock treatment. Although, digitalis administration positively altered the likelihood for cardiac rehospitalization during follow-up.

Cardenolides are specialized, steroidal metabolites produced in a wide array of plant families1,2. Cardenolides play protective roles in plants, but these molecules, including digoxin from foxglove (Digitalis spp.), are better known for treatment of congenital heart failure, atrial arrhythmia, various cancers and other chronic diseases3-9. However, it is still unknown how plants synthesize \'high-value\', complex cardenolide structures from, presumably, a sterol precursor. Here we identify two cytochrome P450, family 87, subfamily A (CYP87A) enzymes that act on both cholesterol and phytosterols (campesterol and β-sitosterol) to form pregnenolone, the first committed step in cardenolide biosynthesis in the two phylogenetically distant plants Digitalis purpurea and Calotropis procera. Arabidopsis plants overexpressing these CYP87A enzymes ectopically accumulated pregnenolone, whereas silencing of CYP87A in D. purpurea leaves by RNA interference resulted in substantial reduction of pregnenolone and cardenolides. Our work uncovers the key entry point to the cardenolide pathway, and expands the toolbox for sustainable production of high-value plant steroids via synthetic biology.

Digoxin is used to treat atrial fibrillation and heart failure. Previous studies have reported an association between digoxin and higher mortality, but the results have been conflicting. This study assessed the association between digoxin use and all-cause mortality using comprehensive health data of patients treated for acute coronary syndrome (ACS). This was a retrospective analysis of 8,388 consecutive ACS patients treated in Tays Heart Hospital between 2007 and 2017, with a follow-up until the end of 2018. The adjusted Cox regression model was used to analyze the association between digoxin treatment and all-cause mortality with and without the inverse probability of treatment weighting (IPTW) method. IPTW was applied to estimate the residual confounding by the treatment selection. Clinical phenotype data were collected from various sources, including a prospectively updated online database maintained by physicians. The median follow-up time was 6.0 years (interquartile range 3.5 to 9.0 years). During the follow-up, 30.8% (n = 2,580) of the patients died. Altogether, 4.0% (n = 333) of the patients were treated with digoxin during hospitalization. In the Cox regression model, digoxin associated with increased mortality (age- and sex-adjusted hazard ratio [HR] 1.76 [1.51 to 2.05], p <0.001 and in the full risk factor-adjusted HR 1.23 [1.04 to 1.45], p = 0.016). The IPTW Cox analysis average treatment effect HR was 1.71 (1.12 to 2.62, p = 0.013), standardized average treatment effect HR was 1.35 (0.96 to 1.90, p = 0.082), and treatment effect among the treated HR was 1.32 (1.09 to 1.59, p = 0.004). In conclusion, digoxin treatment during ACS associates with increased mortality, despite adjusting for other risk factors and after accounting for factors explaining the residual confounding by selection bias.

BACKGROUND: Digitalis purpurea (L) is an important medicinal plant growing at Alpine region of Himalayas and withstands low temperatures and harsh climatic conditions existing at high altitude. It serves as an ideal plant system to decipher the tolerance to cold stress (CS) in plants from high altitudes.
RESULTS: To understand the complexity of plant response to CS, we performed a comparative physiological and biochemical study complemented with proteomics in one-month-old D. purpurea grown at 25 °C (control) and 4 °C (CS). We observed an enhanced accumulation of different osmo-protectants (glycine betaine, soluble sugar and proline) and higher transcription (mRNA levels) of various antioxidant enzymes with an increased antioxidant enzyme activity in D. purpurea when exposed to CS. Furthermore, higher concentrations of non-enzymatic antioxidants (flavonoids, phenolics) was also associated with the response to CS. Differential proteomic analysis revealed the role of various proteins primarily involved in redox reactions, protein stabilization, quinone and sterol metabolism involved in CS response in D. purpurea..
CONCLUSIONS: Our results provide a framework for better understanding the physiological and molecular mechanism of CS response in D. purpurea at high altitudes.

3β-hydroxy-Δ5-steroid dehydrogenases (3βHSDs) are supposed to be involved in 5β-cardenolide biosynthesis. Here, a novel 3βHSD (Dl3βHSD2) was isolated from Digitalis lanata shoot cultures and expressed in E. coli. Recombinant Dl3βHSD1 and Dl3βHSD2 shared 70% amino acid identity, reduced various 3-oxopregnanes and oxidised 3-hydroxypregnanes, but only rDl3βHSD2 converted small ketones and secondary alcohols efficiently. To explain these differences in substrate specificity, we established homology models using borneol dehydrogenase of Salvia rosmarinus (6zyz) as the template. Hydrophobicity and amino acid residues in the binding pocket may explain the difference in enzyme activities and substrate preferences. Compared to Dl3βHSD1, Dl3βHSD2 is weakly expressed in D. lanata shoots. High constitutive expression of Dl3βHSDs was realised by Agrobacterium-mediated transfer of Dl3βHSD genes fused to the CaMV-35S promotor into the genome of D. lanata wild type shoot cultures. Transformed shoots (35S:Dl3βHSD1 and 35S:Dl3βHSD2) accumulated less cardenolides than controls. The levels of reduced glutathione (GSH), which is known to inhibit cardenolide formation, were higher in the 35S:Dl3βHSD1 lines than in the controls. In the 35S:Dl3βHSD1 lines cardenolide levels were restored after adding of the substrate pregnane-3,20-dione in combination with buthionine-sulfoximine (BSO), an inhibitor of GSH formation. RNAi-mediated knockdown of the Dl3βHSD1 yielded several shoot culture lines with strongly reduced cardenolide levels. In these lines, cardenolide biosynthesis was fully restored after addition of the downstream precursor pregnan-3β-ol-20-one, whereas upstream precursors such as progesterone had no effect, indicating that no shunt pathway could overcome the Dl3βHSD1 knockdown. These results can be taken as the first direct proof that Dl3βHSD1 is indeed involved in 5β-cardenolide biosynthesis.

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The medicinal plant Digitalis purpurea produces cardiac glycosides that are useful in the pharmaceutical industry. These bioactive compounds are in high demand due to ethnobotany\'s application to therapeutic procedures. Recent studies have investigated the role of integrative analysis of multi-omics data in understanding cellular metabolic status through systems metabolic engineering approach, as well as its application to genetically engineering metabolic pathways. In spite of numerous omics experiments, most molecular mechanisms involved in metabolic pathways biosynthesis in D. purpurea remain unclear. Using R Package Weighted Gene Co-expression Network Analysis, co-expression analysis was performed on the transcriptome and metabolome data. As a result of our study, we identified transcription factors, transcriptional regulators, protein kinases, transporters, non-coding RNAs, and hub genes that are involved in the production of secondary metabolites. Since jasmonates are involved in the biosynthesis of cardiac glycosides, the candidate genes for Scarecrow-Like Protein 14 (SCL14), Delta24-sterol reductase (DWF1), HYDRA1 (HYD1), and Jasmonate-ZIM domain3 (JAZ3) were validated under methyl jasmonate treatment (MeJA, 100 μM). Despite early induction of JAZ3, which affected downstream genes, it was dramatically suppressed after 48 hours. SCL14, which targets DWF1, and HYD1, which induces cholesterol and cardiac glycoside biosynthesis, were both promoted. The correlation between key genes and main metabolites and validation of expression patterns provide a unique insight into the biosynthesis mechanisms of cardiac glycosides in D. purpurea.

BACKGROUND: Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients.
METHODS: We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used.
RESULTS: Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46-1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17-2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34-2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92-2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80-1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results.
CONCLUSIONS: ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

BACKGROUND: Digoxin poisoning commonly occurs in people treated with digoxin. It has been suggested that treatment with dantrolene may be a suitable strategy for digoxin-induced cardiotoxicity.
OBJECTIVE: The aim of this study was to evaluate the protective effect of dantrolene on digoxin-induced cardiotoxicity in male rats.
METHODS: This study was approved by the ethics committee of Birjand University of Medical Sciences (Ethical number: IR.BUMS.REC.1400.067). Forty-two Wistar rats weighing between 300- 350 gr were randomly allocated to 7 groups (n=6) as follows:Normal Saline (NS) group, Normal Saline + Ethanol (NS + ETOH) group), Normal Saline + dantrolene 10 mg/kg (NS + Dan 10) group, Digoxin (Dig) group), Digoxin + dantrolene 5 mg/kg (Dig + Dan 5) group),Digoxin + dantrolene 10 mg/kg (Dig + Dan 10) group), Digoxin + dantrolene 20 mg/kg (Dig + Dan 20) group), Dig was injected intravenously at 12 mL / h (0.25 mg / mL). Dan (5, 10 and 20 mg/kg) was injected intravenously at 5-8 min/mL. After 1 hour, blood samples were obtained from the animals&#039; cavernous sinus and each animal&#039;s heartremoved. The blood sample was rapidly centrifuged at 2,500 rpm for 10 minutes and the serum was separated for measurement of creatine phosphokinase (CPK), potassium (K), sodium (Na), calcium (Ca), and magnesium (Mg). The samples were stored at -20 oC. The heart samples were fixed in formalin 10% for histopathological evaluation.
RESULTS: K levels slightly increased in the dig group versus the NS group. A significant increase in the K levels was observed in the Dig + Dan 20 group versus the NS group (p < 0.001). dig slightly decreased Ca levels in the treated group versus the NS group. The levels of Ca significantly increased in the Dig + Dan 10 group versus the Dig group (p < 0.05). Histological examination of the heart tissue in the dig group showed cardiomyocyte degeneration, increased edematous intramuscular space associated with hemorrhage, and congestion. Focal inflammatory cell accumulation in the heart tissue was also seen. Cardiomyocytes were clear and arranged in good order in the Dig + Dan 10 group.
CONCLUSIONS: dantrolene (10 mg/kg) was cardioprotective in a model of digoxin-induced cardiotoxicity, secondary to cardiac remodeling and hyperkalemia. However, further research is necessary to determine dantrolene&#039;s cardioprotective and cardiotoxic doses in animal models.