The occurrence of atherosclerosis and diabetes is expanding rapidly worldwide. These two metabolic disorders often co-occur, and are part of what is often referred to as the metabolic syndrome. In order to determine future therapies, we propose that molecular mechanisms should be investigated. Once the aetiology of the metabolic syndrome is clear, a nutritional intervention should be assessed. Here we focus on the protective effects of some dietary flavonoids, and their metabolites. Further studies may also pave the way for development of novel drug candidates.

The petals of the saffron crocus (Crocus sativus L.) are considered a waste material in saffron production, but may be a sustainable source of natural biologically active substances of nutraceutical interest. The aim of this work was to study the cardiovascular effects of kaempferol and crocin extracted from saffron petals. The antiarrhythmic, inotropic, and chronotropic effects of saffron petal extract (SPE), kaempferol, and crocin were evaluated through in vitro biological assays. The antioxidant activity of kaempferol and crocin was investigated through the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay using rat cardiomyoblast cell line H9c2. The MTT assay was applied to assess the effects of kaempferol and crocin on cell viability. SPE showed weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on the ileum greater than on the aorta: EC₅₀ = 0.66 mg/mL versus EC₅₀ = 1.45 mg/mL. Kaempferol and crocin showed a selective negative inotropic activity. In addition, kaempferol decreased the contraction induced by KCl (80 mM) in guinea pig aortic and ileal strips, while crocin had no effect. Furthermore, following oxidative stress, both crocin and kaempferol decreased intracellular ROS formation and increased cell viability in a concentration-dependent manner. The results indicate that SPE, a by-product of saffron cultivation, may represent a good source of phytochemicals with a potential application in the prevention of cardiovascular diseases.

Naturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3′,4′,5′-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes.

Acute Myeloid Leukaemia (AML) is a heterogeneous disease of dismal prognosis, with vulnerabilities in epigenetic and metabolic regulation. DNA demethylating agents, e.g. azacytidine (AZA), are used as first-line therapy in AML patients unable to tolerate intensive chemotherapy regimens, often in combination with BCL-2 inhibitor venetoclax. However, the impact on survival is limited, indicating the need for alternative therapeutic strategies. Methyl-group usage for epigenetic modifications depends on methionine availability and MAT2A-driven conversion to S-adenosyl-methionine. Methyl-group production is a vulnerability in multiple tumours, including AML, and has been variably linked to impairment of different histone methyl-modifications. In contrast, we herein align MAT2A effects in AML with DNA methylation and proteostasis. We show that MAT2A inhibition can be mimicked by combining AZA with unfolded protein response (UPR) activation through targeting of valosin-containing protein (VCP)/P97. Combined AZA and P97 inhibition exceeded AZA-driven restriction of human AML cell expansion, and specifically impaired colony-formation and maintenance of CD34+ patient blasts, suggesting targeting of AML stem/progenitor-like cells. Overall, our data support combined targeting of DNA methylation and the UPR as a promising therapeutic strategy in AML.