This study demonstrates that flavonoids inhibit TMEM16A currents and suggests that flavonoids could have anticancer effects via this mechanism.

Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-à-go-go-related gene (hERG) channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells), and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 μM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Δ23.2 mV). Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea) or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Δ30.8 mV and Δ26.0 mV, respectively). Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities.

Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Volume-regulated anion channels (VRACs), which are essential for cell volume regulation, have been proposed to play a key role in cell proliferation and migration, apoptosis, transepithelial transport, and cancer development. In this study, we screened a group of 53 structurally related natural flavonoids and three synthetic flavonoids for their inhibitory activities on VRAC currents. A whole-cell patch technique was used to record VRAC currents in the human embryonic kidney (HEK) 293 and human umbilical vein endothelial (HUVEC) cells. The 5'-bromo-2-deoxyuridine (BrdU) assay technique was used to investigate cell proliferation. At 100 μM, 34 of 53 compounds significantly inhibited hypotonic extrasolution-induced VRAC currents by > 50% in HEK293 cells. Among these compounds, luteolin, baicalein, eupatorin, galangin, quercetin, fisetin, karanjin, Dh-morin, genistein, irisolidone, and prunetin exhibited the highest efficacy for VRAC blockade (the mean inhibition > 80%) with ICs of 5-13 μM and Es of about 87-99%. We also studied the effects of three synthetic flavonoids on VRAC currents in HEK293 cells. Flavoxate showed high inhibition efficacy toward VRAC currents (IC = 2.3 ± 0.3 μM; E = 91.8% ± 2.7%). Finally, these flavonoids inhibited endogenous VRAC currents and cell proliferation in endothelial cells. This study demonstrates that natural and synthetic flavonoids are potent VRAC current inhibitors, and VRAC inhibition by flavonoids might be responsible for their anti-angiogenic effects.

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Naringenin (Nar) is a natural flavonoid extracted from citrus fruits with abundant pharmacological properties against cardiac diseases, but existing studies are unsystematic and scattered. The present research systematically investigates the mechanism of action of Nar in the treatment of myocardial ischemia (MI). Network pharmacology was used to analyze the relevant targets of Nar against MI as well as the biological mechanisms. The protective effect of Nar was initially assessed in H9c2 cells induced by CoCl2. In acutely isolated rat cardiomyocytes, Nar was further explored for effects on L-type Ca2+ currents, cell contractility and Ca2+ transients by using patch-clamp technique and Ion Optix system. Network pharmacology analysis indicated that Nar improved apoptosis, mitochondrial energy metabolism, inflammation and oxidative stress. Experimental validation demonstrated that Nar decreased ROS and MDA levels and increased antioxidant activity (e.g., GSH-PX, SOD, and CAT), mitochondrial membrane potential, ATP and Ca2+-ATPase contents. Nar also markedly reduced inflammatory factor levels, apoptosis, and intracellular Ca2+ concentrations in H9c2 cells. Based on the experimental results, it is speculated that Ca2+ signals play an essential role in the process of Nar against MI. Thus, we further confirmed that Nar significantly inhibited the L-type Ca2+ currents, contractility and Ca2+ transients in acutely isolated cardiomyocytes. The inhibition of Ca2+ overload by Nar may be a novel cardioprotective mechanism. The present study may serve as a basis for future clinical research, and Nar as a Ca2+ channel inhibitor may provide new perspectives for the treatment of myocardial ischemic diseases.