Acute inhibitory effect of alpha‐mangostin on sarcoplasmic reticulum calcium‐ATPase and myocardial relaxation

The benefits of α‐mangostin for various tissues have been reported, but its effect on the heart has not been clarified. This study aimed to evaluate the effects of α‐mangostin on cardiac function. Using a cardiac sarcoplasmic reticulum (SR) membrane preparation, α‐mangostin inhibited SR Ca²⁺‐ATPase activity in a dose‐dependent manner (IC₅₀ of 6.47 ± 0.7 μM). Its suppressive effect was specific to SR Ca²⁺‐ATPase but not to myofibrillar Ca²⁺‐ATPase. Using isolated cardiomyocytes, 50 μM of α‐mangostin significantly increased the duration of cell relengthening and increased the duration of Ca²⁺ transient decay, suggesting altered myocyte relaxation. The relaxation effect of α‐mangostin was also supported in vivo after intravenous infusion. A significant suppression of both peak pressure and rate of ventricular relaxation (–dP/dt) relative to DMSO infusion was observed. The results from the present study demonstrated that α‐mangostin exerts specific inhibitory action on SR Ca²⁺‐ATPase activity, leading to myocardial relaxation dysfunction.     

Xanthones from Hypericum chinense and their cytotoxicity evaluation

A xanthonolignoid, 2-O-demethylkielcorin, and a phenylxanthone, chinexanthone A, were isolated from stems of Hypericum chinense together with four known xanthonolignoids and seven known xanthones. Their structures were established by spectroscopic analysis, as their optical properties and absolute stereochemistry determined. The cytotoxicities of the isolated xanthone derivatives as well as additional 32 xanthones against a panel of human cancer cell lines were also evaluated.     

<i>In Vitro</i> and <i>in Silico</i> Insights on the Biological Activities,Phenolic Compounds Composition of <i>Hypericum perforatum</i> L. Hairy Root Cultures

Three Hypericum perforatum hairy root lines (HR B, HR F and HR H) along with non-transformed roots were analyzed for phenolic compounds composition and in vitro enzyme inhibitory properties. In silico molecular modeling was performed to predict the interactions of the most representative phenolic compounds in HR clones with enzymes related to depression, neurodegeneration and diabetes. Chromatographic analyses revealed that HR clones represent an efficient source of quinic acid and hydroxybenzoic acids, epicatechin and procyanidin derivatives, quercetin and kaempferol glycosides, as well numerous xanthones. In vitro antidepressant activity of HR extracts through monoamine oxidase A (MAO-A) inhibition was attributed to the production of oxygenated and prenylated xanthones. The neuroprotective potential of HR extracts was related to the accumulation of quercetin 6-C-glucoside, epicatechin, procyanidins and γ-mangostin isomers as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Vanillic acid and prenylated xanthones in HR clones as promising inhibitors of tyrosinase additionally contributed to the neuroprotective activity. Five preeminent xanthones in HR (γ-mangostin, mangiferin, garcinone C, garcinone E and 1,3,7-trihydroxy-6-metoxy-8-prenyl xanthone) along with the flavonol quercetin 6-C-glucoside effectively inhibited α-amylase and α-glucosidase indicating the antidiabetic properties of HR extracts. Transgenic roots of H. perforatum can be exploited for the preparation of novel phytoproducts with multi-biological activities.     

Inhibition of wheat embryo calcium-dependent protein kinase and other kinases by mangostin and gamma-mangostin.

The hull of the fruit of the mangosteen tree (Garcinia mangostana) contains four inhibitors of plant Ca(2+)-dependent protein kinase. Two of these inhibitors have been purified and identified as the xanthones 1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H- xanthen-9-one (mangostin) and 1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-butenyl)- 9H-xanthen-9-one (gamma-mangostin). Both xanthones also inhibit avian myosin light chain kinase and rat liver cyclic AMP-dependent protein kinase. This is the first report of inhibition of plant and animal second messenger-regulated protein kinases by plant-derived xanthones.     

A bitter plant with a sweet future? A comprehensive review of an oriental medicinal plant: Andrographis paniculata

Andrographis paniculata (Burm.f) Nees is one of the most popular and important medicinal plant of the Orient, and South East Asia. It finds mention in various forms in Indian, Chinese, Malay, Thai, Unani, and Japanese systems of medicine. The plant exhibits anti-cancer, anti-inflammatory, anti-diabetic, anti-hypertensive, anti-venom, cholestatic, hepatoprotective, anti-thrombotic, anti-retroviral, anti-microbial, anti-pyretic, anti-malarial, anti-oxidant, immunomodulatory, and cardioprotective effects. The major active principles contributing to biological activity are diterpene lactones, but flavonoids, xanthones and caffeic acid derivatives also contribute to anti-oxidant, anti-proliferative, anti-atherosclerotic, and anti-malarial effects. As a result of its wide spectrum of pharmacological activity, almost impeccable safety profile, being a widely cultivated medicinal plant, we have collected and compiled various facets of this plant. Extensive datamining of the phytochemistry and pharmacology of Andrographis paniculata revealed more than 50 diterpene lactones, 30 flavonoids, 8 quinic acid derivatives, and 4 xanthones. This review contains information on around 80 isolated compounds, out of which more than half of the compounds have no reported pharmacological activity. Though there are some good reviews available on Andrographis paniculata, the authors of the earlier reviews focused on one or two aspects of the plant and none have attempted to integrate the available information on this plant. This provided us the much needed impetus, warranting a full-fledged and complete review on Andrographis paniculata, one of the most popular and important Oriental medicinal plant.     

Biological Factors Influencing Production of Xanthones in Aphloia theiformis

Xanthones, and more specifically mangiferin, are molecules used in cosmetics for their photoprotective and anti‐aging properties. The richness in xanthones of Aphloia theiformis leaves, a common shrub in Madagascar, can reach almost 12% (in relation to dry biomass). Amongst the A. theiformis studied, two major groups of individuals have been determined: those presenting a high proportion of mangiferin (up to 80% of the xanthones) and those presenting a high proportion of polar xanthones (not yet identified). Our study shows that: i) for each subject, the xanthone content remains stable over time (no seasonal variation); ii) the majority of the trees developing in the light belong to the first group (rich in mangiferin), whereas the individuals growing in the undergrowth are richer in polar xanthones; iii) the distribution of the two groups seems not to have any correlation with taxonomy and, moreover, with the known varieties of A. theiformis, although the micrantha variety is richer in mangiferin. Overall, this information indicates that A. theiformis is a reservoir of xanthones and makes it possible to define a framework for its reasoned management.     

Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin

Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases. This has led to considerable interest in the antioxidant activity of dietary compounds. Flavonoids have received the most attention and much is known about the structural requirements for antioxidant activity. However, little is known about the antioxidant activity of other plant derived phenolic compounds such as the xanthones. We have previously shown that the prenylated xanthone, mangostin, can inhibit the oxidation of low density lipoprotein. In order to examine the effects of structure modification on antioxidant activity of this class of compound we have prepared a number of derivatives of mangostin and tested antioxidant activity in an isolated LDL and plasma assay. The results of this study show that structural modification of mangostin can have a profound effect on antioxidant activity. Derivatisation of the C-3 and C-6 hydroxyl groups with either methyl, acetate, propane diol or nitrile substantially reduces antioxidant activity. In contrast, derivatisation of C-3 and C-6 with aminoethyl derivatives enhanced antioxidant activity, which may be related to changes in solubility. Cyclisation of the prenyl chains had little influence on antioxidant activity.     

Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin

Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases. This has led to considerable interest in the antioxidant activity of dietary compounds. Flavonoids have received the most attention and much is known about the structural requirements for antioxidant activity. However, little is known about the antioxidant activity of other plant derived phenolic compounds such as the xanthones. We have previously shown that the prenylated xanthone, mangostin, can inhibit the oxidation of low density lipoprotein. In order to examine the effects of structure modification on antioxidant activity of this class of compound we have prepared a number of derivatives of mangostin and tested antioxidant activity in an isolated LDL and plasma assay. The results of this study show that structural modification of mangostin can have a profound effect on antioxidant activity. Derivatisation of the C-3 and C-6 hydroxyl groups with either methyl, acetate, propane diol or nitrile substantially reduces antioxidant activity. In contrast, derivatisation of C-3 and C-6 with aminoethyl derivatives enhanced antioxidant activity, which may be related to changes in solubility. Cyclisation of the prenyl chains had little influence on antioxidant activity.     

Flavonoids and xanthones from the leaves of Amorphophallus titanum (Araceae)

The flavonoids and xanthones in the leaves of Amorphophallus titanum, which has the largest inflorescence among all Araceous species, were surveyed. Eight C-glycosylflavones, five flavonols, one flavone O-glycoside and two xanthones were isolated and characterized as vitexin, isovitexin, orientin, isoorientin, schaftoside, isoschaftoside, vicenin-2 and lucenin-2 (C-glycosylflavones), kaempferol 3-O-robinobioside, 3-O-rutinoside and 3-O-rhamnosylarabinoside, and quercetin 3-O-robinobioside and 3-O-rutinoside (flavonols), luteolin 7-O-glucoside (flavone), and mangiferin and isomangiferin (xanthones). Although the inflorescence of this species has been surveyed for flavonoids, those of the leaves were reported for the first time.     

Identification and characterization of xanthone biosynthetic genes contributing to the vivid red coloration of red-flowered gentian

Cultivated Japanese gentians traditionally produce vivid blue flowers because of the accumulation of delphinidin-based polyacylated anthocyanins. However, recent breeding programs developed several red-flowered cultivars, but the underlying mechanism for this red coloration was unknown. Thus, we characterized the pigments responsible for the red coloration in these cultivars. A high-performance liquid chromatography with photodiode array analysis revealed the presence of phenolic compounds, including flavones and xanthones, as well as the accumulation of colored cyanidin-based anthocyanins. The chemical structures of two xanthone compounds contributing to the coloration of red-flowered gentian petals were determined by mass spectrometry and nuclear magnetic resonance spectroscopy. The compounds were identified as norathyriol 6-O-glucoside (i.e., tripteroside designated as Xt1) and a previously unreported norathyriol-6-O-(6′-O-malonyl)-glucoside (designated Xt2). The copigmentation effects of these compounds on cyanidin 3-O-glucoside were detected in vitro. Additionally, an RNA sequencing analysis was performed to identify the cDNAs encoding the enzymes involved in the biosynthesis of these xanthones. Recombinant proteins encoded by the candidate genes were produced in a wheat germ cell-free protein expression system and assayed. We determined that a UDP-glucose-dependent glucosyltransferase (StrGT9) catalyzes the transfer of a glucose moiety to norathyriol, a xanthone aglycone, to produce Xt1, which is converted to Xt2 by a malonyltransferase (StrAT2). An analysis of the progeny lines suggested that the accumulation of Xt2 contributes to the vivid red coloration of gentian flowers. Our data indicate that StrGT9 and StrAT2 help mediate xanthone biosynthesis and contribute to the coloration of red-flowered gentians via copigmentation effects.     

Synthesis,oxygen radical absorbance capacity,and tyrosinase inhibitory activity of glycosides of resveratrol,pterostilbene, and pinostilbene

The stilbene compound resveratrol was glycosylated to give its 4′-O-β-D-glucoside as the major product in addition to its 3-O-β-D-glucoside by a plant glucosyltransferase from Phytolacca americana expressed in recombinant Escherichia coli. This enzyme transformed pterostilbene to its 4′-O-β-D-glucoside, and converted pinostilbene to its 4′-O-β-D-glucoside as a major product and its 3-O-β-D-glucoside as a minor product. An analysis of antioxidant capacity showed that the above stilbene glycosides had lower oxygen radical absorbance capacity (ORAC) values than those of the corresponding stilbene aglycones. The 3-O-β-D-glucoside of resveratrol showed the highest ORAC value among the stilbene glycosides tested, and pinostilbene had the highest value among the stilbene compounds. The tyrosinase inhibitory activities of the stilbene aglycones were improved by glycosylation; the stilbene glycosides had higher activities than the stilbene aglycones. Resveratrol 3-O-β-D-glucoside had the highest tyrosinase inhibitory activity among the stilbene compounds tested.     

Xanthones and flavonoids from <Emphasis Type="Italic">Gentiana algida</Emphasis> Pall

This article is devoted to phytochemical investigation of xanthones and flavonoids from the Gentiana algida Pall. (cold gentian, the Gentianaceae family). The following xanthones and flavones have been isolated from the top of the gentian: bellidifolin, isobellidifolin, swerchirin, 1,5,8-tirhydroxy-3,4-dimethoxyxanthone, swertisin, and swertianolin (flavone-C-glycoside). The isolated compounds have been identified on the basis of their chemical conversions and by their UV, mass, ¹H, and ¹³C NMR spectra. Derivatives of 1,3,5,8-tetrahydroxyxanthone were mainly found in the top of the cold gentian.     

1,2,3-Trioxygenated glucosyloxyxanthones from Polygala triphylla

Four B-ring oxygen-free trioxygenated xanthones, viz. 1-OH-2,3-(OMe)₂-, 1,2,3-(OMe)₃-, 1-OH-2,3- (OCH₂O)-, 1-OMe-2,3-(OCH₂O)-xanthone, two B-ring oxygen-free glucosyloxyxanthones, viz. 1-O-gl.-2-OH-3-OMe- and 1-O-gl.-2,3-(OCH₂0)-xanthone, and a pentaoxygenated xanthone, 1-OMe-2,3,6,7-(OCH₂O)₂-xanthone, have been isolated from the flowering top of Polygala triphylla. The xanthones have been characterized on the basis of chemical transformation, comprehensive spectral evidence, and by direct comparison where possible. This is the first report of occurrence of the glucosyloxyxanthones in nature. The biochemical significance of these chemical characters in higher plants is appraised.     

Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created the need for better therapeutic options. In this study, five natural xanthones were extracted and purified from the fruit hull of Garcinia mangostana and their antimicrobial properties were investigated. α-Mangostin was identified as the most potent among them against Gram-positive pathogens (MIC = 0.78–1.56 μg/mL) which included two MRSA isolates. α‐Mangostin also exhibited rapid in vitro bactericidal activity (3-log reduction within 5 min). In a multistep (20 passage) resistance selection study using a MRSA isolated from the eye, no resistance against α-mangostin in the strains tested was observed. Biophysical studies using fluorescence probes for membrane potential and permeability, calcein encapsulated large unilamellar vesicles and scanning electron microscopy showed that α‐mangostin rapidly disrupted the integrity of the cytoplasmic membrane leading to loss of intracellular components in a concentration-dependent manner. Molecular dynamic simulations revealed that isoprenyl groups were important to reduce the free energy for the burial of the hydrophobic phenyl ring of α-mangostin into the lipid bilayer of the membrane resulting in membrane breakdown and increased permeability. Thus, we suggest that direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action.     

Cinnamic acid is a precursor of benzoic acids in cell cultures of Hypericum androsaemum L. but not in cell cultures of Centaurium erythraea RAFN

Benzoic acids are precursors of xanthone biosynthesis which has been studied in cell cultures of Hypericum androsaemum (Hypericaceae) and Centaurium erythraea (Gentianaceae). In both cell cultures, methyl jasmonate induces the intracellular accumulation of a new xanthone. Under these inductive conditions, feeding experiments were performed with [U-¹⁴C]L-phenylalanine, [7-¹⁴C]benzoic acid and [7-¹⁴C]3-hydroxybenzoic acid. All three precursors were efficiently incorporated into the elicited xanthone in H. androsaemum, whereas 3-hydroxybenzoic acid was the only precursor to be incorporated into xanthones in C. erythraea. In addition, an appreciable increase in phenylalanine ammonia-lyase activity occurred only in methyl-jasmonate-treated cell cultures of H. androsaemum. Benzoic acids thus appear to be formed by different pathways in the two cell cultures studied. In H. androsaemum, benzoic acid is derived from cinnamic acid by side-chain degradation. In C. erythraea 3-hydroxybenzoic acid appears to originate directly from the shikimate pathway. Received: 21 January 2000 / Accepted: 12 July 2000     

Anthelminthic properties of mangostin and mangostin diacetate

Few anthelminthic drugs are available for human use despite the significant burden caused by helminth infections. We studied the activities of mangostin, a major bioactive xanthone isolated from the pericarp and fruit of Garcinia mangostana and of the synthetic derivative mangostin diacetate. Mangostin and mangostin diacetate lacked activity against the nematodes Heligmosomoides polygyrus (third-stage larvae (L3)), Ancylostoma ceylanicum L3, and Trichuris muris adults and showed only low activity against A. ceylanicum adults (IC₅₀s of 91 μg/ml) in vitro. Mangostin showed promising activities (IC₅₀ of 2.9–15.6 μg/ml) against the trematodes Schistosoma mansoni, Echinostoma caproni, and Fasciola hepatica in vitro. Single oral doses (400 mg/kg and 800 mg/kg) of the drugs achieved worm burden reductions ranging from 0 to 38% and 11–54% against S. mansoni and E. caproni in vivo, respectively. Pharmacokinetic studies would be helpful to understand the differences observed between in vitro and in vivo activities and lacking dose–response relationships.     

Hairy roots of Hypericum perforatum L.: a promising system for xanthone production

Hypericum perforatum L. is a common perennial plant with a reputed medicinal value. Investigations have been made to develop an efficient protocol for the identification and quantification of secondary metabolites in hairy roots (HR) of Hypericum perforatum L. HR were induced from root segments of in vitro grown seedlings from H. perforatum, after co-cultivation with Agrobacterium rhizogenes A4. Transgenic status of HR was confirmed by PCR analysis using rolB specific primers. HR had an altered phenolic profile with respect to phenolic acids, flavonol glycosides, flavan-3-ols, flavonoid aglycones and xanthones comparing to control roots. Phenolics in control and HR cultures were observed to be qualitatively and quantitatively distinct. Quinic acid was the only detectable phenolic acid in HR. Transgenic roots are capable of producing flavonol glycosides such as quercetin 6-C-glucoside, quercetin 3-O-rutinoside (rutin) and isorhamnetin O-hexoside. The HPLC analysis of flavonoid aglycones in HR resulted in the identification of kaempferol. Transformed roots yielded higher levels of catechin and epicatechin than untransformed roots. Among the twenty-eight detected xanthones, four of them were identified as 1,3,5,6-tetrahydroxyxanthone, 1,3,6,7-tetrahydroxyxanthone, γ-mangostin and garcinone C were de novo synthesized in HR. Altogether, these results indicated that H. perforatum HR represent a promising experimental system for enhanced production of xanthones.     

Root cultures of <Emphasis Type="Italic">Hypericum perforatum</Emphasis> subsp. <Emphasis Type="Italic">angustifolium</Emphasis> elicited with chitosan and production of xanthone-rich extracts with antifungal activity

Hypericum perforatum is a well-known medicinal plant which contains a wide variety of metabolites, including xanthones, which have a wide range of biological properties, including antifungal activity. In the present study, we evaluated the capability of roots regenerated from calli of H. perforatum subsp. angustifolium to produce xanthones. Root biomass was positively correlated with the indole-3-butyric acid concentration, whereas a concentration of 1 mg l⁻¹ was the most suitable for the development of roots. High auxin concentrations also inhibited xanthone accumulation. Xanthones were produced in large amounts, with a very stable trend throughout the culture period. When the roots were treated with chitosan, the xanthone content dramatically increased, peaking after 7 days. Chitosan also induced a release of these metabolites into the culture. The maximum accumulation (14.26 ± 0.62 mg g⁻¹ dry weight [DW]) and release (2.64 ± 0.13 mg g⁻¹ DW) of xanthones were recorded 7 days after treatment. The most represented xanthones were isolated, purified, and spectroscopically characterized. Antifungal activity of the total root extracts was tested against a broad panel of human fungal pathogen strains (30 Candida species, 12 Cryptococcus neoformans, and 16 dermatophytes); this activity significantly increased when using chitosan. Extracts obtained after 7 days of chitosan treatment showed high antifungal activity (mean minimum inhibitory concentration of 83.4, 39.1, and 114 μg ml⁻¹ against Candida spp., C. neoformans, and dermatophytes, respectively). Our results suggest that root cultures can be considered as a potential tool for large-scale production of extracts with stable quantities of xanthones.     

QTL analysis of agronomic traits in recombinant inbred lines of sunflower under partial irrigation

The objective of the present research was to map QTLs associated with agronomic traits such as days from sowing to flowering, plant height, yield and leaf-related traits in a population of recombinant inbred lines (RILs) of sunflower (Helianthus annuus). Two field experiments were conducted with well-irrigated and partially irrigated conditions in randomized complete block design with three replications. A map with 304 AFLP and 191 SSR markers with a mean density of 1 marker per 3.7 cM was used to identify QTLs related to the studied traits. The difference among RILs was significant for all studied traits in both conditions. Three to seven QTLs were found for each studied trait in both conditions. The percentage of phenotypic variance (R ²) explained by QTLs ranged from 4 to 49%. Three to six QTLs were found for each yield-related trait in both conditions. The most important QTL for grain yield per plant on linkage group 13 (GYP-P-13-1) under partial-irrigated condition controls 49% of phenotypic variance (R ²). The most important QTL for 1,000-grain weight (TGW-P-11-1) was identified on linkage group 11. Favorable alleles for this QTL come from RHA266. The major QTL for days from sowing to flowering (DSF-P-14-1) were observed on linkage group 14 and explained 38% of the phenotypic variance. The positive alleles for this QTL come from RHA266. The major QTL for HD (HD-P-13-1) was also identified on linkage group 13 and explained 37% of the phenotypic variance. Both parents (PAC2 and RHA266) contributed to QTLs controlling leaf-related traits in both conditions. Common QTL for leaf area at flowering (LAF-P-12-1, LAF-W-12-1) was detected in linkage group 12. The results emphasise the importance of the role of linkage groups 2, 10 and 13 for studied traits. Genomic regions on the linkage groups 9 and 12 are specific for QTLs of leaf-related traits in sunflower.