Apigenin's Modulation of Doxorubicin Efficacy in Breast Cancer.

Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.

Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity.

Anthracyclines currently play a key role in the treatment of many cancers, but the limiting factor of their use is the widespread phenomenon of drug resistance and untargeted toxicity. Flavonoids have pleiotropic, beneficial effects on human health that, apart from antioxidant activity, are currently considered small molecules-starting structures for drug development and enhancers of conventional therapeutics. This paper is a review of the current and most important data on the participation of a selected series of flavonoids: chrysin, apigenin, kaempferol, quercetin and myricetin, which differ in the presence of an additional hydroxyl group, in the formation of a synergistic effect with anthracycline antibiotics. The review includes a characterization of the mechanism of action of flavonoids, as well as insight into the physicochemical parameters determining their bioavailability in vitro. The crosstalk between flavonoids and the molecular activity of anthracyclines discussed in the article covers the most important common areas of action, such as (1) disruption of DNA integrity (genotoxic effect), (2) modulation of antioxidant response pathways, and (3) inhibition of the activity of membrane proteins responsible for the active transport of drugs and xenobiotics. The increase in knowledge about the relationship between the molecular structure of flavonoids and their biological effect makes it possible to more effectively search for derivatives with a synergistic effect with anthracyclines and to develop better therapeutic strategies in the treatment of cancer.

Interplay between Thyroid Hormones and Stearoyl-CoA Desaturase 1 in the Regulation of Lipid Metabolism in the Heart.

Stearoyl-CoA desaturase 1 (SCD1), an enzyme that is involved in the biosynthesis of monounsaturated fatty acids, induces the reprogramming of cardiomyocyte metabolism. Thyroid hormones (THs) activate both lipolysis and lipogenesis. Many genes that are involved in lipid metabolism, including Scd1, are regulated by THs. The present study used SCD1 knockout (SCD1-/-) mice to test the hypothesis that THs are important factors that mediate the anti-steatotic effect of SCD1 downregulation in the heart. SCD1 deficiency decreased plasma levels of thyroid-stimulating hormone and thyroxine and the expression of genes that regulate intracellular TH levels (i.e., Slc16a2 and Dio1-3) in cardiomyocytes. Both hypothyroidism and SCD1 deficiency affected genomic and non-genomic TH pathways in the heart. SCD1 deficiency is known to protect mice from genetic- or diet-induced obesity and decrease lipid content in the heart. Interestingly, hypothyroidism increased body adiposity and triglyceride and diacylglycerol levels in the heart in SCD1-/- mice. The accumulation of triglycerides in cardiomyocytes in SCD1-/- hypothyroid mice was caused by the activation of lipogenesis, which likely exceeded the upregulation of lipolysis and fatty acid oxidation. Lipid accumulation was also observed in the heart in wildtype hypothyroid mice compared with wildtype control mice, but this process was related to a reduction of triglyceride lipolysis and fatty acid oxidation. We also found that simultaneous SCD1 and deiodinase inhibition increased triglyceride content in HL-1 cardiomyocytes, and this process was related to the downregulation of lipolysis. Altogether, the present results suggest that THs are an important part of the mechanism of SCD1 in cardiac lipid utilization and may be involved in the upregulation of energetic metabolism that is associated with SCD1 deficiency.

Correction to: Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

The original version of this article unfortunately contained a mistake. The published paper presented an incorrect version of Table 1. The corrected Table is given here.

Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

αE-catenin is a component of adherens junctions that link the cadherin-catenin complex to the actin cytoskeleton. The signaling function of this protein was recently revealed. In the present study, we investigated the role of αE-catenin in the pathogenesis of heart failure. We mated αE-catenin conditional knockout mice with αMHC-Cre mice and evaluated their mutant offspring. We found that αE-catenin knockout caused enlargement of the heart and atria, fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via the transcriptional activity of Yap and ß-catenin. The activation of canonical Wnt and Yap decreased the activity of main regulators of energy metabolism (i.e., adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor α) and dysregulated hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase/Akt, cyclic adenosine monophosphate/protein kinase A, and MEK1/extracellular signal regulated kinase 1/2). The loss of αE-catenin also negatively affected cardio-hemodynamic function via the protein kinase A pathway. Overall, we found that the embryonic heart-specific ablation of αE-catenin leads to the development of heart failure with age and premature death in mice. Thus, αE-catenin appears to have a crucial signaling function in the postnatal heart, and the dysfunction of this gene causes heart failure through canonical Wnt and Yap activation.

The role of stearoyl-CoA desaturase in the regulation of cardiac metabolism.

The uptake and utilization of energetic substrates in the myocardium are under strict control, any disturbances of which may lead to myocardial dysfunction, such as in the case of ischemia and heart failure. Stearoyl-CoA desaturase (SCD) is an enzyme that converts saturated fatty acids to monounsaturated fatty acids. It is an important player in the regulation of heart metabolism. Our previous studies showed that SCD1 affects substrate utilization by the heart, with a preference for glucose. Large cohort studies established a positive correlation between the plasma fatty acid desaturation index and cardiovascular disease mortality. Therefore, SCD1 might serve as a potential target for future therapies. We review recent findings on the role of SCD1 in the heart, with a focus on cardiac metabolism reprogramming and its involvement in heart dysfunction.

Stearoyl-CoA desaturase 1 deficiency reduces lipid accumulation in the heart by activating lipolysis independently of peroxisome proliferator-activated receptor α.

Stearoyl-CoA desaturase 1 (SCD1) has recently been shown to be a critical control point in the regulation of cardiac metabolism and function. Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of myocardial fatty acid uptake and utilization. The present study used SCD1 and PPARα double knockout (SCD1-/-/PPARα-/-) mice to test the hypothesis that PPARα is involved in metabolic changes in the heart that are caused by SCD1 downregulation/inhibition. SCD1 deficiency decreased the intracellular content of free fatty acids, triglycerides, and ceramide in the heart of SCD1-/- and SCD1-/-/PPARα-/- mice. SCD1 ablation in PPARα-/- mice decreased diacylglycerol content in cardiomyocytes. These results indicate that the reduction of fat accumulation in the heart associated with SCD1 deficiency occurs independently of the PPARα pathway. To elucidate the mechanism of the observed changes, we treated HL-1 cardiomyocytes with the SCD1 inhibitor A939572 and/or PPARα inhibitor GW6471. SCD1 inhibition decreased the level of lipogenic proteins and increased lipolysis, reflected by a decrease in the content of adipose triglyceride lipase inhibitor G0S2 and a decrease in the ratio of phosphorylated hormone-sensitive lipase (HSL) at Ser565 to HSL (pHSL[Ser565]/HSL). PPARα inhibition alone did not affect the aforementioned protein levels. Finally, PPARα inhibition decreased the phosphorylation level of 5'-adenosine monophosphate-activated protein kinase, indicating lower mitochondrial fatty acid oxidation. In summary, SCD1 ablation/inhibition decreased cardiac lipid content independently of the action of PPARα by reducing lipogenesis and activating lipolysis. The present data suggest that SCD1 is an important component in maintaining proper cardiac lipid metabolism.

Biomaterials in Cancer Therapy: Investigating the Interaction between Kaempferol and Zinc Ions through Computational, Spectroscopic and Biological Analyses.

A complex of the natural flavonoid kaempferol with zinc (Kam-Zn) was synthesized, and its physicochemical properties were investigated using spectroscopic methods such as Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible (UV-Vis) spectroscopy and theoretical chemistry. Biological studies were conducted to evaluate the cytotoxic and antiproliferative effects of these complexes on MCF-7 breast cancer cells. Treatment with Kam 100 µM (84.86 ± 7.79%; 64.37 ± 8.24%) and Kam-Zn 100 µM (91.87 ± 3.80%; 87.04 ± 13.0%) showed no significant difference in proliferation between 16 h and 32 h, with the gap width remaining stable. Both Kam-Zn 100 µM and 200 µM demonstrated effective antiproliferative and cytotoxic activity, significantly decreasing cell viability and causing cell death and morphology changes. Antioxidant assays revealed that Kam (IC50 = 5.63 ± 0.06) exhibited higher antioxidant potential compared to Kam-Zn (IC50 = 6.80 ± 0.075), suggesting that zinc coordination impacts the flavonoid's radical scavenging activity by the coordination of metal ion to hydroxyl groups. Computational studies revealed significant modifications in the electronic structure and properties of Kam upon forming 1:1 complexes with Zn2+ ions. Spectroscopy analyses confirmed structural changes, highlighting shifts in absorption peaks and alterations in functional group vibrations indicative of metal-ligand interactions. FT-IR and UV-Vis spectra analysis suggested that Zn coordinates with the 3-OH and 4C=O groups of ligand. These findings suggest that the Kam-Zn complex exhibits interesting antiproliferative, cytotoxic and modified antioxidant effects on MCF-7 cells, providing valuable insights into their structural and anticancer properties.

SCD1-related epigenetic modifications affect hormone-sensitive lipase (Lipe) gene expression in cardiomyocytes.

Stearoyl-CoA desaturase 1 (SCD1) is an enzyme that is involved in the regulation of lipolysis in the heart. SCD1 also affects epigenetic mechanisms, such as DNA and histone modifications, in various tissues. Both epigenetic modifications and changes in lipid metabolism are involved in the heart's response to hypoxia. The present study tested the hypothesis that SCD1 and epigenetic modifications interact to control lipolysis in cardiomyocytes under normoxic and hypoxic conditions. We found that the inhibition of SCD1 activity and loss of SCD1 expression reduced global DNA methylation levels, DNA methyltransferase (DNMT) activity, and DNMT1 expression in HL-1 cardiomyocytes and the mouse heart. We also found that the inhibition of adipose triglyceride lipase is involved in the control of global DNA methylation levels in cardiomyocytes in an SCD1-independent manner. Additionally, SCD1 inhibition reduced expression of the hormone-sensitive lipase (Lipe) gene through an increase in methylation of the Lipe gene promoter. Under hypoxic conditions, SCD1 inhibition abolished hypoxia-inducible transcription factor 1α, likely through decreases in histone deacetylase, protein kinase A, and abhydrolase domain containing 5 protein levels, leading to the attenuation of DNA hypomethylation by DNMT1. Hypoxia led to demethylation of the Lipe promoter in cardiomyocytes with SCD1 inhibition, which increased Lipe expression. These results indicate that SCD1 is involved in the control of epigenetic mechanisms in the heart and may affect Lipe expression through changes in methylation in its promoter region. Therefore, SCD1 may be considered a key player in the epigenetic response to normoxia and hypoxia in cardiomyocytes.

Literature Review-Transthoracic Echocardiography, Computed Tomography Angiography, and Their Value in Clinical Decision Making and Outcome Predictions in Patients with COVID-19 Associated Cardiovascular Complications.

The sudden outbreak of the COVID-19 pandemic posed a great threat to the world's healthcare systems. It resulted in the development of new methods and algorithms for the diagnosis and treatment of both COVID-19 and its complications. Diagnostic imaging played a crucial role in both cases. Among the most widely used examinations are transthoracic echocardiography (TTE) and computed tomography angiography (CTA). Cardiovascular complications in COVID-19 are frequently associated with a severe inflammatory response, which results in acute respiratory failure, further leading to severe complications of the cardiovascular system. Our review aims to discuss the value of TTE and CTA in clinical decision making and outcome prediction in patients with COVID-19-associated cardiovascular complications. Our review revealed the high clinical value of various TTE findings and their association with mortality and the prediction of patients' clinical outcomes, especially when used with other laboratory parameters. The strongest association between increased mortality and findings in TTE was observed for tachycardia and decreased left ventricular ejection fraction (odds ratio (OR) 24.06) and tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio (TAPSE/PASP ratio) < 0.31 mm/mmHg (OR 17.80). CTA is a valuable tool in diagnosing COVID-19-associated pulmonary embolism, but its association with mortality and its predictive role should always be combined with laboratory findings and patients' medical history. D-dimers > 3000 ng/mL were found as the strongest predictors of pulmonary embolism (PE) (OR 7.494). Our review indicates the necessity for an active search for cardiovascular complications in patients with severe COVID-19, as they are linked with an increased probability of fatal outcomes.

Assessment of the Immune Response in Patients with Insulin Resistance, Obesity, and Diabetes to COVID-19 Vaccination.

The SARS-CoV-19 pandemic overwhelmed multiple healthcare systems across the world. Patients with underlying medical conditions such as obesity or diabetes were particularly vulnerable, had more severe symptoms, and were more frequently hospitalized. To date, there have been many studies on the severity of SARS-CoV-2 in patients with metabolic disorders, but data on the efficiency of vaccines against COVID-19 are still limited. This paper aims to provide a comprehensive overview of the effectiveness of COVID-19 vaccines in individuals with diabetes, insulin resistance, and obesity. A comparison is made between the immune response after vaccination in patients with and without metabolic comorbidities. Additionally, an attempt is made to highlight the mechanisms of immune stimulation affected by SARS-CoV-2 vaccines and how metabolic comorbidities modulate these mechanisms. The focus is on the most common COVID-19 vaccines, which include mRNA vaccines such as Pfizer-BioNTech and Moderna, as well as viral vector vaccines such as AstraZeneca and Johnson & Johnson. Furthermore, an effort is made to clarify how the functional differences between these vaccines may impact the response in individuals with metabolic disorders, drawing from available experimental data. This review summarizes the current knowledge regarding the post-vaccination response to COVID-19 in the context of metabolic comorbidities such as diabetes, insulin resistance, and obesity.

Untargeted Metabolomics Analysis of the Serum Metabolic Signature of Childhood Obesity.

Obesity rates among children are growing rapidly worldwide, placing massive pressure on healthcare systems. Untargeted metabolomics can expand our understanding of the pathogenesis of obesity and elucidate mechanisms related to its symptoms. However, the metabolic signatures of obesity in children have not been thoroughly investigated. Herein, we explored metabolites associated with obesity development in childhood. Untargeted metabolomic profiling was performed on fasting serum samples from 27 obese Caucasian children and adolescents and 15 sex- and age-matched normal-weight children. Three metabolomic assays were combined and yielded 726 unique identified metabolites: gas chromatography-mass spectrometry (GC-MS), hydrophilic interaction liquid chromatography coupled to mass spectrometry (HILIC LC-MS/MS), and lipidomics. Univariate and multivariate analyses showed clear discrimination between the untargeted metabolomes of obese and normal-weight children, with 162 significantly differentially expressed metabolites between groups. Children with obesity had higher concentrations of branch-chained amino acids and various lipid metabolites, including phosphatidylcholines, cholesteryl esters, triglycerides. Thus, an early manifestation of obesity pathogenesis and its metabolic consequences in the serum metabolome are correlated with altered lipid metabolism. Obesity metabolite patterns in the adult population were very similar to the metabolic signature of childhood obesity. Identified metabolites could be potential biomarkers and used to study obesity pathomechanisms.

ß-Catenin Regulates Cardiac Energy Metabolism in Sedentary and Trained Mice.

The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of ß-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific ß-catenin knockout that were subjected to a swimming training model. ß-Catenin haploinsufficient mice subjected to endurance training displayed a decreased ß-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase-Akt (Pi3K-Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and ß-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained ß-catenin haploinsufficient mice. Taken together, Wnt/ß-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.