Chemical profile and nutraceutical features of Salsola soda (agretti): Anti-inflammatory and antidiabetic potential of its flavonoids

Highlights

• Four flavonoids and three saponins are identified in Salsola soda aerial parts.

• Aldose reductase, aldose reductase-like and carbonyl reductase1 are targeted.

• Quercetin 3-O-glucuronopyranoside is active on the three target enzymes.

• Quercetin-3-O-glucuronopyranoside confers nutraceutical features to Salsola.

Abstract

The chemical profile and the nutraceutical features of cultivated Salsola soda buds, in comparison with the wild plant, were investigated. Four flavonoids, rutin (1), quercetin 3-O-glucuronopyranoside (2), isorhamnetin 3-O-rutinoside (3), and isorhamnetin 3-O-glucuronopyranoside (4), were isolated from the wild S. soda and tested to target three human recombinant enzymes, i.e., aldose reductase (hAKR1B1), aldose-reductase-like protein (hAKR1B10), and carbonyl reductase 1 (hCBR1). Furthermore, three saponins, namely momordin IId (5), momordin IIc (6), and dihexosyl-pentosyl-glucuronosyl oleanolic acid (7) were identified in the plant and tested together for inhibitory activity of hAKR1B1. While no inhibitory activity was measured for the saponin mixture, flavonoids were shown to be able to inhibit the three target enzymes. Compound 2, the only flavonoid significantly represented in the cultivated edible S. soda, was shown to be the most effective inhibitor of the target enzymes. Indeed, it resulted in an appreciable inhibition of both hAKR1B1 and hCBR1, acting as an uncompetitive $(K_i^{\text{'}},0.97\pm 0.24\mu \text{M})$ and as a mixed noncompetitive inhibitor (Ki, 0.84 ± 0.04; Ki’, 0.51 ± 0.05 μM), respectively. These results suggested the potential of S. soda components to favorably intervene in pathological conditions linked to diabetic complications, inflammatory processes, and in cancer therapy.

Introduction

The genus Salsola (Amaranthaceae) includes about 120 species of herbaceous or shrubby plants, widespread especially in the brackish grounds of the moderate and subtropical regions of Europe, Asia, Africa, and North America (Hammer, 1986, pp. 145–170). Among the species, wild Salsola soda L. is an erect glabrous annual halophyte shrub widespread in south Europe, particularly in marginal areas near the coast (Pignatti, 2017). The plant buds, called in Italy “agretti” or “barba di frate” are edible and commonly consumed from cultivated plants during the spring in Italy. In the past, the plant was also used as a source of sodium carbonate, from which the name “soda”. Previous phytochemical investigations of members of this genus reported the isolation of alkaloids, flavonoids, saponins, coumarins, and sterols (Hamed et al., 2011; Rasheed et al., 2013; Tundis et al., 2009). Salsola species are known in folk medicine as anti-hypertensive, diuretic, anti-cancer, antioxidant, emollient, purgative, anti-ulcer, and anti-inflammatory, and some studies reported the activity of some Salsola species extracts as hypoglycaemic, antioxidant, anti-cholinesterase, and antimicrobial (Tundis et al., 2007, 2009). However, only preliminary phytochemical and biological studies on wild and non-edible S. soda have been reported (Tundis et al., 2007, 2009), while the cultivated one has not been investigated.

Aldose reductase (AKR1B1) catalyzes the first step of the so-called polyol pathway, a route of glucose metabolism which becomes relevant with hyperglycemic conditions. The activity of the enzyme is considered co-causative of secondary diabetic complications; thus AKR1B1 has been identified as a target to be inhibited to counteract the onset of diabetic complications (Maccari & Ottanà, 2015). Several molecules both from chemical synthesis (Mucke et al., 2014) and natural origin (Veeresham et al., 2014) have been shown to be AKR1B1 inhibitors. Indeed, on the basis of the presence of components showing AKR1B1 inhibitory activity, edible vegetables have been defined as functional foods (Balestri et al., 2016; Devi et al., 2018). Another feature of AKR1B1 is its ability to reduce cytotoxic hydrophobic aldehydes coming from lipid peroxidation processes, such as 4-hydroxy-2-nonenal (HNE), and their glutathionyl adducts (Srivastava et al., 1999). The ability of AKR1B1 to reduce the 3-glutathionyl-4-hydroxynonane (GS-HNE), the most relevant derivative of the HNE degradation pathway, makes the enzyme responsible for a pro-inflammatory response (Ramana et al., 2006). 3-Glutathionyl-1,4-dihydroxynonane (GS-DHN), the reaction product of GS-HNE reduction, acts as a signal able to elicit the nuclear factor κ-light-chain-enhancer of activated B cells (NF-ĸB) activation cascade (Frohnert et al., 2014). This is the basis of the anti-inflammation potential reported for a number of AKR1B1 inhibitors. Like AKR1B1, carbonyl reductase 1 (CBR1) is able to reduce the aldehydic group of GS-HNE (and of other glutathionylated alkanals) to the corresponding alcohol (Rotondo et al., 2016). CBR1 is also able to direct GS-HNE towards a secretion trail, through the hemiacetal oxidation to glutathionyl-4-hydroxynonanoic acid δ-lactone (GS-HNA-lactone) (Moschini et al., 2015). CBR1 was induced in tumor cells (Lopez de Cerain et al., 1999) and the advantages coming from its inhibition are debated. While a reduced CBR1 activity has been reported as an enhancing factor for cancer development (Osawa et al., 2015), on the other hand CBR1 activity is positively responsible for the anti-tumor anthracycline therapy resistance (Jo et al., 2017; Plebuch et al., 2007). The aldose-reductase-like protein (AKR1B10), another member of the aldo keto reductase superfamily, while acting on the reduction of aldoses, alkanals and alkenals, does not recognize GS-HNE as a substrate (Shen et al., 2011). This enzyme was significantly induced with cancer and its inhibition has been shown to be beneficial against tumor progression (Zhang et al., 2014).

Thus, the present study was carried out to investigate the chemical profile of S. soda cultivated buds and to quantify their major compounds to evaluate their nutraceutical potential. In addition, with regard to secondary metabolites production, a comparison with wild S. soda, collected before the flowering stage, was done. Isolated compounds were evaluated for their inhibitory activity on three target enzymes, whose action is differently involved in the inflammatory processes connected to oxidative stress. In particular two isoforms of the aldo keto reductase superfamily, namely AKR1B1 (EC 1.1.1.21) and AKR1B10, as well as the secondary-alcohol:NADP⁺ oxidoreductase (EC 1.1.1.184), CBR1, were studied.