Melitidin

Defining the Cholesterol Lowering Mechanism of Bergamot (Citrus bergamia) Extract in HepG2 and Caco-2 Cells.[Pubmed:34579033]

Nutrients. 2021 Sep 10;13(9). pii: nu13093156.

Bergamot, a Mediterranean citrus fruit native to southern Italy, has been reported to have cholesterol-lowering properties; however, the mechanism of action is not well understood. Due to structural similarities with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, it has been proposed that the phenolic compounds in bergamot may also inhibit HMGCR. Statins are widely used for their cholesterol-lowering properties; however, they are not universally well tolerated, suggesting there is a need to identify novel cholesterol-lowering strategies. In the present study, we investigated bergamot fruit extract (BFE) and its principal components (neoeriocitrin, naringin, neohesperidin, Melitidin, and brutieridin) for their ability to regulate cholesterol levels in HepG2 and Caco-2 cells. BFE at increasing concentrations decreased the levels of total and free cholesterol in HepG2 cells. BFE and its constituents did not directly inhibit HMGCR activity. However, BFE and neohesperidin decreased HMGCR levels in HepG2 cells, suggesting that neohesperidin and BFE may downregulate HMGCR expression. An increase in AMP-kinase phosphorylation was observed in BFE and neohesperidin-treated cells. In Caco-2 cells, brutieridin exhibited a significant reduction in cholesterol uptake and decreased the level of Niemann-Pick C1 Like 1, an important cholesterol transporter. Taken together, our data suggest that the cholesterol-lowering activity of bergamot is distinct from statins. We hypothesize that BFE and its principal constituents lower cholesterol by inhibiting cholesterol synthesis and absorption.

Structural elucidation of flavonoids from Shatianyu (Citrus grandis L. Osbeck) pulp and screening of key antioxidant components.[Pubmed:34311239]

Food Chem. 2022 Jan 1;366:130605.

The Citrus genus is a good source of dietary flavonoids, which have many health benefits. As a representative citrus fruit, the flavonoids composition in Shatianyu (Citrus grandis L. Osbeck) pulp remains to be investigated. In the present study, 11 flavonoids were isolated and identified from Shatianyu pulp flavonoid extracts (SPFEs). Among them, 4 flavonoids were previously undescribed and 2 flavonoids were firstly isolated from pummelo. The cellular antioxidant activity (CAA) and oxygen radical absorbance capacity (ORAC) of isolated compounds were evaluated. Naringin and rhoifolin showed the highest ORAC activity, and the presence of a 3-hydroxy-3-methylglutaryl or a 4'-glucose decreased the ORAC activity of flavonoids. The contribution of isolated flavonoids to the holistic antioxidant activity of SPFEs was determined by an online knockout method. Melitidin, bergamjuicin and naringin contributed most to ORAC activity, while bergamjuicin, Melitidin and apigenin-4'-O-beta-d-glucopyranosyl-7-O-alpha-l-rhamnopyranosyl-(1 --> 2)-[6''-O-(3- hydroxy-3-methylgltaryl)]-beta-d-glucopyranoside contributed most to CAA activity.

Bergamot (Citrus bergamia, Risso): The Effects of Cultivar and Harvest Date on Functional Properties of Juice and Cloudy Juice.[Pubmed:31336933]

Antioxidants (Basel). 2019 Jul 12;8(7). pii: antiox8070221.

Reggio Calabria province (South Italy) is known for being almost the only area of cultivation of the bergamot fruit, grown principally for its essential oil, but today much studied for the health benefits of its juice. The biometrics and physico-chemical properties of the three (Citrus bergamia Risso) existing genotypes namely Castagnaro, Fantastico and Femminello were studied during fruit ripening from October to March. Castagnaro cultivar had the biggest and heaviest fruit during this harvest period. degrees Brix (7.9-10.0), pH (2.2-2.8) and formol number (1.47-2.37 mL NaOH 0.1 N/100 mL) were shown to be influenced by both the genotype and harvest date. Titratable acidity (34.98-59.50 g/L) and vitamin C (ascorbic acid) (341-867 g/L) decreased during fruit ripening. The evolution of flavonoids such as neoeriocitrin, naringin, neohesperidin, brutieridin and Melitidin was studied both in bergamot juice and in the bergamot cloudy juice which is the aqueous extract of bergamot during fruit processing. Bergamot cloudy juice contained a higher quantity of flavonoids compared to the juice. This study gives important information regarding the cultivar and the harvest date for producers who want to obtain the highest juice quantity or the highest juice quality from the bergamot fruit.

Clinical application of bergamot (Citrus bergamia) for reducing high cholesterol and cardiovascular disease markers.[Pubmed:31057945]

Integr Food Nutr Metab. 2019 Mar;6(2).

The bergamot is a citrus fruit native to southern Italy with traditional uses that include improving immune response and cardiovascular function. There are a variety of phytochemicals that have been found in the bergamot including brutieridin and Melitidin as well as other flavonoids, flavones O-glucosides and C-glucosides. Multiple clinical trials have provided evidence that different forms of orally administered bergamot can reduce total cholesterol and low-density lipoprotein cholesterol. In vitro mechanistic studies have provided evidence that polyphenols from the bergamot can alter the function of AMPK and pancreatic cholesterol ester hydrolase (pCEH). The use of bergamot in multiple clinical trials has consistently shown that it is well tolerated in studies ranging from 30 days to 12 weeks. This mini-review reports on the clinical studies performed with different forms of bergamot along with their effectiveness in reducing total cholesterol and LDL cholesterol in patients with hypercholesterolemia.

New C-2 diastereomers of flavanone glycosides conjugated with 3-hydroxy-3-methylglutaric acid from the pericarp of Citrus grandis (L.) Osbeck.[Pubmed:30005202]

Bioorg Chem. 2018 Oct;80:519-524.

Two new 3-hydroxy-3-methylglutaryl (HMG) flavanone 7-O-diglycosides, cigranosides A and B (1 and 2), the known naringenin 7-(2''-alpha-rhamnosyl-6''-(3''''-hydroxy-3''''-methylglutaryl)-glucoside (Melitidin, 3), their common biosynthetic precursor flavanone 7-O-diglycoside (naringin, 4), and one known flavone 7-O-diglycoside (rhoifolin, 5) were isolated from the pericarp of Citrus grandis (L.) Osbeck. The structures of these compounds were elucidated by spectroscopic and chemical techniques. The relative ratios and absolute configurations of the C-2 diastereomers of compounds 1, 2 and 4 were determined by online normal-phase HPLC-CD using a Chiralcel column. The absolute configuration of the HMG fragment in compounds 1-3 was assigned to be S through spectroscopic analysis of the mevalonamide obtained by amidation and reduction of the HMG moiety. The NO inhibitory activities of compounds 1-5 were evaluated using lipopolysaccharide-induced RAW264.7 cells. Compounds 1-5 were not cytotoxic to RAW264.7 cells at 10muM.

Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism.[Pubmed:29626418]

Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):984-996.

Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed "BMF", has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy.

Melitidin: a flavanone glycoside from Citrus grandis 'Tomentosa'.[Pubmed:23738451]

Nat Prod Commun. 2013 Apr;8(4):457-8.

Citrus grandis 'Tomentosa' is a traditional Chinese medicine, used as an antitussive. In this research, Melitidin, a flavanone glycoside, was isolated from this species for the first time by using chromatographic methods. The structure was confirmed through comprehensive analyses of its ultraviolet, infrared, 1H and 13C NMR, HMBC and HMQC spectroscopic and high-resolution mass spectrometric data. Meliditin showed a good antitussive effect on cough induced by citric acid in Guinea pig, suggesting that it was a contributor to the antitussive effect of C. grandis 'Tomentosa'.

HPLC-PDA-MS and NMR characterization of a hydroalcoholic extract of Citrus aurantium L. var. amara peel with antiedematogenic activity.[Pubmed:22957519]

J Agric Food Chem. 2013 Feb 27;61(8):1686-93.

The phytochemical profile of a hydroalcoholic extract of Citrus aurantium var. amara L. peel, used as herbal medicine, was characterized by HPLC-PDA-MS. Two di-C-glycosyl flavones (vincenin II and diosmetin 6,8-di-C-glucoside), a series of flavones (luteolin 7-O-neohesperidoside, rhoifolin, and neodiosmin), and flavanone (neoeriocitrin, naringin, and neohesperidin) 7-O-neohesperidosides and two methoxyflavones (nobiletin and tangeretin), commonly present in Citrus, were identified. Furthermore, brutieridin and Melitidin, two 3-hydroxy-3-methylglutaryl flavanone glycosides, were also characterized along with rhoifolin 4'-glucoside and three coumarins (8,3'-beta-D-glucopyranosyloxy-2'-hydroxy-3'-methylbutyl-7-methoxycoumarin, merazin hydrate, and isomerazin). A preparative isolation procedure followed by NMR spectroscopy confirmed the proposed structures of the major flavonoids and identified the coumarins. The phenolic content was found to be 14.8 mg mL(-1), and naringin and neohesperidin were the compounds present in the highest concentration (3.6 and 2.6 mg mL(-1)). The extract of C. aurantium peel inhibited significantly (p < 0.05) both histamine- and dextran-induced edema in rats in a concentration-dependent manner (IC(50) = 119.6 and 118.3 mg kg(-1), respectively), providing evidence for the therapeutic use of C. aurantium var. amara peel.

On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme.[Pubmed:20843083]

J Agric Food Chem. 2010 Oct 13;58(19):10768-73.

Density functional theory was applied to study the binding mode of new flavonoids as possible inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), an enzyme that catalyzes the four-electron reduction of HMGCoA to mevalonate, the committed step in the biosynthesis of sterols. The investigated flavonoid conjugates brutieridin and Melitidin were recently quantified in the bergamot fruit extracts and identified to be structural analogues of statins, lipids concentration lowering drugs that inhibit HMGR. Computations allowed us to perform a detailed analysis of the geometrical and electronic features affecting the binding of these compounds, as well as that of the excellent simvastatin drug, to the active site of the enzyme and to give better insight into the inhibition process.

Statin-like principles of bergamot fruit (Citrus bergamia): isolation of 3-hydroxymethylglutaryl flavonoid glycosides.[Pubmed:19572741]

J Nat Prod. 2009 Jul;72(7):1352-4.

The 3-hydroxy-3-methylglutaryl neohesperidosides of hesperetin (brutieridin, 1) and naringenin (Melitidin, 2) were isolated and detected from the fruits of bergamot (Citrus bergamia). The structures of these compounds were determined by spectroscopic and chemical methods.