Morus alba L.

2.1. Morus alba L Morus alba L., commonly known as mulberry, is a plant widely used for the prevention and treatment of several cardiovascular ailments, primarily in Chinese, Japanese and Korean Traditional Medicines. Phytochemical analysis revealed the presence, in MA leaves, of flavonoids, chalcones, phenolic acids, polyphenols, and benzofurans (moracins) (Doi et al., 2001; Katsube et al., 2006; Memon et al., 2010; Yang et al., 2010). The most soundly documented modes of action of M. alba leaves and leaf extracts resulting in hypotensive effect are: calcium channel blockade, α 1 -antagonism, increased endothelium NO production. The ethyl acetate extract from M. alba leaves caused a concentration-dependent relaxation of the intact and endothelium-denuded aortas pre-contracted by KCl, suggesting a calcium antagonistic effect towards voltage operated calcium channels. In addition, this extract inhibited aorta smooth muscle contraction elicited by phenylephrine, suggesting its ability to suppress inositol trisphosphate and/or ryanodine receptordependent release of intracellular calcium (Xia et al., 2008). Carrizzo (Carrizzo et al., 2016) demonstrated that, in mice vessels, the extract from M. alba leaves evokes vasodilation, which was reverted by L-NAME, thus proposing the involvement of endothelium in its activity. Furthermore, this effect seemed to be also mediated by the activation of the stress sensors and chaperones Protein Kinase RNA-like Endoplasmic Reticulum Kinase and heat shock protein 90, which, in turn, induced the phosphorylation of endothelial isoform of NO synthase (eNOS). These data were confirmed also in vivo, as the oral administration of the extract was ineffective in eNOS-deficient mice, while it caused a decrease in BP in the wild type strain. In addition, the oral administration of a M. alba leaf extract to diabetic rats was shown to lower the increased systolic BP, diastolic BP and mean arterial pressure and to restore the vascular responses to the vasodilators as acetylcholine and sodium nitroprusside (Naowaboot et al., 2009). These results are consistent with those obtained by Lee (Lee et al., 2011), who observed that the oral administration of a water extract from M. alba leaves decreases BP and partially restores the relaxation to acetylcholine of aortic rings from rats fed with an atherogenic diet. Further effects that may contribute to inhibit hypertension may be due, at least in part, to the antioxidant and antiatherosclerotic activities of M. alba leaf extract (Enkhmaa et al., 2005) and to mulberry leaves antidiabetic, antibacterial, anticancer, hypolipidemic, and anti-inflammatory properties, likely due to moracins (Naik et al., 2015). In particular, there are sound documented evidences for the effectiveness of M. alba leaf extract in control of hyperlipidemic conditions and in management of obesity (Trimarco et al., 2017; Lupo et al., 2019; Mahboubi, 2019). Fig. 1 reports the structures of the compounds that individually exert an antihypertensive effect and whose mode of action has been investigated. They can be structurally grouped into flavonoids, phenol acids and polyphenol acids. Stevioside stands alone. Enhancement of endothelial NO production is the most frequently invoked mode of action for flavonoids, namely quercetin, its more bioavailable glycosides, isquercitrin and rutin, and for kaempferol (Emura et al., 2007; Wani, 2017). In addition, for kaempferol, prevention of the angiotensin II effects has been recently documented (Chen et al., 2016), while ACE inhibition and direct and endothelium independent vascular smooth muscle relaxation through calcium channels blockade has been not excluded for quercetin (Larson et al., 2010). Reduction of oxidative stress due to antioxidant properties and consequent increased bioavailability of nitric oxide is widely documented for phenol and polyphenol acids which are present in M. alba leaves, namely vanillic acid (Kumar et al., 2014; Kumar et al., 2012b), syringic acid (Kumar et al., 2012a, 2012b), ferulic acid (Jain et al., 2018), protocatechuic acid (Juurlink et al., 2014; Safaeian et al., 2018), and 5-O-caffeoylquinic acid (Suzuki et al., 2006). For gallic acid, recent studies have demonstrated its antihypertensive effect via regulation of histone deacetilase 1 or 2 (Jin et al., 2017a,b), while, among the hydroxybenzoic acid isomers exerting activity on cardiovascular system, 3-hydroxybenzoic acid has been proposed for reduction in adipocyte lipolysis by activation of the hydroxycarboxylic acid receptors with potential improvements of blood lipid profiles (Juurlink et al., 2014). Lastly, the antihypertensive effect of stevioside has been imputed to its inhibitory action on calcium influx into smooth muscle cells of blood vessels (Lee et al., 2001).Published as part of Micucci, M., Bolchi, C., Budriesi, R., Cevenini, M., Maroni, L., Capozza, S., Chiarini, A., Pallavicini, M. & Angeletti, A., 2020, Antihypertensive phytocomplexes of proven efficacy and well-established use: Mode of action and individual characterization of the active constituents, pp. 1-19 in Phytochemistry (112222) (112222) 170 on pages 2-3, DOI: 10.1016/j.phytochem.2019.112222, http://zenodo.org/record/829299