RESUMO
Four new stilbenes (1-4) and one new flavonoid (5), named cajanines D-H, together with three known stilbenes (6-8) were isolated from the leaves of Cajanus cajan (L.) Millsp. (pigeon pea). The structures of these compounds were elucidated unambiguously on the basis of IR, 1D, and 2D NMR, as well as HRESIMS data. Structurally, stilbenes 1-4 bore an isopentyl side chain, and further hydroxylation of compounds 1-3 generated a greater variety of structural forms. Compound 5 was a flavonoid owning an isopentyl side chain. Besides, antibacterial activity of the isolated compounds against Staphylococcus aureus, Bacillus cereus, and Escherichia coli was studied in vitro. Compounds 1-8 were endowed with profound antibacterial activity. Among them, the MIC values of compounds 4, 6, and 7 against S. aureus were 1.56, 0.78, and 0.78 µg/mL, respectively, among which 6 and 7 had better antibacterial activity than the positive control Vancomycin with the MIC values of 1.56 µg/mL. Additionally, the anti-SARS-CoV-2 main protease activity of all the isolated compounds was evaluated, and it was worth mentioning that the IC50 values of compounds 5-7 were 8.27, 4.65, and 8.30 µM, respectively, being comparable to the positive control Ebselen. Our findings may provide valuable guidance for the application of stilbenes as lead compounds in the future for the development of drugs with antibacterial or anti-COVID-19 activity.
Assuntos
COVID-19 , Cajanus , Estilbenos , Flavonoides/farmacologia , Cajanus/química , Staphylococcus aureus , Estilbenos/química , SARS-CoV-2 , Antibacterianos/farmacologiaRESUMO
Two new stilbenoids, cajanstilbenoid C (1) and cajanstilbenoid D (2), together with eight other known stilbenoids (3-10) and seventeen known flavonoids (11-27), were isolated from the petroleum ether and ethyl acetate portions of the 95% ethanol extract of leaves of Cajanus cajan (L.) Millsp. The planar structures of the new compounds were elucidated by NMR and high-resolution mass spectrometry, and their absolute configurations were determined by comparison of their experimental and calculated electronic circular dichroism (ECD) values. All the compounds were assayed for their inhibitory activities against yeast α-glucosidase. The results demonstrated that compounds 3, 8-9, 11, 13, 19-21, and 24-26 had strong inhibitory activities against α-glucosidase, with compound 11 (IC50 = 0.87 ± 0.05 µM) exhibiting the strongest activity. The structure-activity relationships were preliminarily summarized. Moreover, enzyme kinetics showed that compound 8 was a noncompetitive inhibitor, compounds 11, 24-26 were anticompetitive, and compounds 9 and 13 were mixed-competitive.
Assuntos
Cajanus , Estilbenos , Flavonoides/farmacologia , Flavonoides/química , Cajanus/química , alfa-Glucosidases , Estilbenos/farmacologia , Estilbenos/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases/farmacologiaRESUMO
Rheum lhasaense A. J. Li et P. K. Hsiao, a stout herb plant from the Polygonaceae, is a typical Tibetan folk herb with heat-clearing and detoxifying effects, but does not have the typical laxative effect compared with other rhubarb plants. Nevertheless, its chemical composition and pharmacological activities still lack in-depth research. The present study endeavored to analyze the possible phytochemical constituents in R. lhasaense and explore the main compound piceatannol-3'-O-ß-D-glucopyranoside (PG) effect on cognitive impairment and its underlying mechanism. The chemical profile of R. lhasaense discovered 46 compounds, including 27 stilbenoids and 13 gallotannins using UPLC-Q-TOF-MS/MS. The UPLC determined the contents of 6 main stilbenoids, among which the content of PG was the highest, up to 61.06 mg/g. Moreover, behavioral tests showed that PG (40 mg/kg and 160 mg/kg) administration markedly ameliorated memory impairments of scopolamine-induced mice. Biochemical parameters showed that PG treatment alleviated the levels of Ach, AchE, and inflammatory factors while elevating the levels of antioxidants in mice. In addition, network pharmacology was performed to reveal PG exert an mild cognitive impairment effect by participating in neurodegenerative disease pathways, proliferation and apoptosis-, and inflammation-related pathways. Eventually, the results of molecular docking and the qRT-PCR revealed that PG down-regulated the mRNA expressions of MMP3, MMP9 and BACE1 in cognitive impairment mice brain tissue. In conclusion, our results demonstrated that PG mitigated scopolamine-induced cognitive dysfunction in mice by targeting the BACE1-MMP3/9 pathway, and PG might be a promising mild AD drug candidate.
Assuntos
Doenças Neurodegenerativas , Rheum , Estilbenos , Camundongos , Animais , Rheum/química , Espectrometria de Massas em Tandem , Secretases da Proteína Precursora do Amiloide , Metaloproteinase 3 da Matriz , Simulação de Acoplamento Molecular , Ácido Aspártico Endopeptidases , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Estilbenos/química , Derivados da EscopolaminaRESUMO
One unusual stilbene trimer-flavonoid hybrid, paeonilactiflobenoid (1), together with six known stilbenes (2-7) were isolated from the seeds of Paeonia lactiflora. The structure of 1 was elucidated with the aid of HRESIMS, 1D and 2D NMR, [α]D spectroscopic data and ECD calculation. Compounds 2-7 showed stimulative effects on GLP-1 secretion with promoting rates of 79.8%-880.4% (25 µM) and 217.6%-1089.4% (50 µM), more potent than the positive control, oleoylethanolamide (250.2% at 50 µM). Moreover, compounds 4 and 6 exhibited agonistic activity on the G protein-coupled receptor (GPCR) TGR5 with stimulative ratios of 40.2% and 40.5% at 50 µM, and 54.2% and 49.1% at 100 µM, respectively. Docking study manifested that 6 well located in the catalytic pocket of TGR5 by hydrogen-bond and hydrophobic interactions. The GLP-1 promotion of 6 could be attenuated by IP3, Ca2+/CaMKII and MEK/ERK pathway inhibitors, suggesting that these pathways played important roles in GLP-1 secretion. Thus, stilbenes in peony seeds maybe regarded as potential GLP-1 secretagogues through TGR5-IP3-Ca2+/CaMKII-MEK/ERK pathways.
Assuntos
Paeonia , Estilbenos , Paeonia/química , Peptídeo 1 Semelhante ao Glucagon , Secretagogos/análise , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/análise , Estrutura Molecular , Sementes/química , Estilbenos/farmacologia , Estilbenos/química , Quinases de Proteína Quinase Ativadas por Mitógeno/análiseRESUMO
Resveratrol is a plant-derived phytoalexin found in grapes, red wine and many other plants used in Asian folk medicine. It is extensively studied for pleiotropic biological activity. The most crucial are anticancer and chemopreventive properties. Resveratrol has also been reported to be an antioxidant and phytoestrogen. The phytoestrogenic activity of resveratrol was assayed in different in vitro and in vivo models. Although these works brought some, on the first look, conflicting results, it is commonly accepted that resveratrol interacts with estrogen receptors and functions as a mixed agonist/antagonist. It is widely accepted that the hydroxyl groups are crucial for resveratrol's cytotoxic and antioxidative activity and are responsible for binding estrogen receptors. In this work, we assayed 11 resveratrol analogues, seven barring methoxy groups and six hydroxylated analogues in different combinations at positions 3, 4, 5 and 3',4',5'. For this purpose, recombined estrogen receptors and estrogen-dependent MCF-7 and Ishikawa cells were used. Our study was supported by in silico docking studies. We have shown that, resveratrol and 3,4,4'5'-tetrahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene and 3,3',4,4',5,5'-hexahydroxystilbene may act as selective estrogen receptor modulators.
Assuntos
Receptores de Estrogênio , Estilbenos , Resveratrol/farmacologia , Receptores de Estrogênio/metabolismo , Fitoestrógenos , Moduladores Seletivos de Receptor Estrogênico , Antioxidantes , Estilbenos/química , Estrogênios/farmacologia , Relação Estrutura-Atividade , Transdução de SinaisRESUMO
Six undescribed stilbene derivatives Reflexanbene DH (1-4, 6) and Reflexanbene J (5), as well as one known stilbene 3,5-dimethoxystilbene (7), were isolated from the dried roots of Lindera reflexa Hemsl. Their structures and absolute configurations were elucidated using spectroscopy and electronic circular dichroism (ECD) analysis. In cytotoxic assays, moderately inhibitory activities of Reflexanbene F (3) against MGC80-3 and A549 cell lines were observed, with IC50 values of 15.42 and 5.09 µM, respectively. The IC50 value of Reflexanbene E (2) on A549 cell lines was 19.78 µM. The isolated compounds were also tested for their inhibitory effect against LPS-induced NO and IL-6 production in RAW 264.7 cells. In particular, Reflexanbene J (5) and Reflexanbene H (6) showed significant inhibition of NO production in LPS-stimulated macrophage RAW 264.7 cells at the concentration of 20 µM. Furthermore, the expression of IL-6 protein in the LPS-induced RAW 264.7 cells can also be significantly inhibited by different concentrations (5, 10 and 20 µM, p < 0.05 or p < 0.01) of compounds 1-7.
Assuntos
Anti-Inflamatórios , Antineoplásicos , Lindera , Estilbenos , Humanos , Anti-Inflamatórios/farmacologia , Interleucina-6 , Lindera/química , Lipopolissacarídeos , Estrutura Molecular , Estilbenos/farmacologia , Estilbenos/química , Células A549 , Células RAW 264.7 , Animais , Camundongos , Antineoplásicos/farmacologiaRESUMO
Eighteen stilbenes (1-18), including six previously undescribed ones (1-6), with diverse modification patterns were isolated from the leaves of edible and medicinal plant Cajanus cajan. Among the new isolates, compounds 1-3 were initially obtained as three racemic mixtures, which were further resolved into three pairs of optically pure enantiomers, respectively, by chiral HPLC. Besides, compounds 8, 10, 11, and 18 were obtained from C. cajan for the first time. The chemical structures and absolute configurations of the new stilbenes were elucidated unambiguously on the basis of extensive spectroscopic analyses, single crystal X-ray crystallographic study, and quantum chemical electronic circular dichroism (ECD) calculations. In addition, the in vitro anti-inflammatory activities of all isolated stilbenes were evaluated. Compounds 2, 9, 10, 11, and 14 exerted moderate suppression of nitric oxide (NO) secretion in lipopolysaccharide (LPS)-induced RAW264.7 cells without exhibiting substantial cytotoxicity.
Assuntos
Cajanus , Estilbenos , Anti-Inflamatórios/farmacologia , Cajanus/química , Estrutura Molecular , Folhas de Planta/química , Estilbenos/química , Estilbenos/farmacologiaRESUMO
Widely used in global households, fenugreek is well known for its culinary and medicinal uses. The various reported medicinal properties of fenugreek are by virtue of the different natural phytochemicals present in it. Regarded as a promising target, interleukin 2 receptor subunit alpha (IL2Rα) has been shown to influence immune responses. In the present research, using in silico techniques, we have demonstrated the potential IL2Rα binding properties of three polyphenol stilbenes (desoxyrhaponticin, rhaponticin, rhapontigenin) from fenugreek. As the first step, molecular docking was performed to assess the binding potential of the fenugreek phytochemicals with IL2Rα. All three phytochemicals demonstrated interactions with active site residues. To confirm the reliability of our molecular docking results, 100 ns molecular dynamics simulations studies were undertaken. As discerned by the RMSD and RMSF analyses, IL2Rα in complex with the desoxyrhaponticin, rhaponticin, and rhapontigenin indicated stability. The RMSD analysis of the phytochemicals alone also demonstrated no significant structural changes. Based on the stable molecular interactions and comparatively slightly better MM/PBSA binding free energy, rhaponticin seems promising. Additionally, ADMET analysis performed for the stilbenes indicated that all of them obey the ADMET rules. Our computational study thus supports further in vitro IL2Rα binding studies on these stilbenes, especially rhaponticin.
Assuntos
Subunidade alfa de Receptor de Interleucina-2/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/química , Polifenóis/química , Estilbenos/química , Trigonella/química , Sítios de Ligação , Fenômenos Químicos , Ligação de Hidrogênio , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estrutura Molecular , Compostos Fitoquímicos/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Ligação Proteica , Estilbenos/farmacologiaRESUMO
A new type of film packaging made from natural polysaccharide materials, with its environmental safety and friendliness, is considered as a potential substitute for plastics. Novel polysaccharide composite films based upon citrus pectin (CP) and sodium alginate (SA) were successfully prepared and characterized, containing pterostilbene (PTE) at various concentrations (0.2, 0.4, 0.8, 1.6, 3.2 mM). The rheological analysis displayed that all film-forming liquids performed no gelation behavior with G" > G' at low frequency and weak gelation with G" < G' at high frequency. The SA-CP films had good tensile strength (TS) and elongation at break (EB), while adding PTE as an antioxidant to the film reduced both the values. Of note, the SA-CP films with PTE had better moisture resistance than that of the pure SA-CP films, which was related to the changes of its microstructure. The increased roughness of the films containing PTE was observed by microscope. After calcium chloride cross-linking, the water solubility of the films was reduced, while its thermal stability was improved. Notably, the accretion of PTE expressively enhanced the antioxidant properties of the SA-CP films. Thus, the SA-CP composite films containing PTE could be utilized as an excellent antioxidant packaging material.
Assuntos
Alginatos/química , Antioxidantes/química , Embalagem de Alimentos/métodos , Pectinas/química , Estilbenos/química , Cloreto de Cálcio/química , Solubilidade , Resistência à Tração/efeitos dos fármacos , Água/químicaRESUMO
Peanut produces prenylated stilbenoids upon biotic stress. However, the role of these compounds against oxidative stress have not been thoroughly elucidated. To this end, the antioxidant capacity of extracts enriched in prenylated stilbenoids and derivatives was studied. To produce these extracts, hairy root cultures of peanut cultivars Hull, Tifrunner, and Georgia Green were co-treated with methyl jasmonate, cyclodextrin, hydrogen peroxide, and magnesium chloride and then the stilbenoids were extracted from the culture medium. Among the three cultivars, higher levels of the stilbenoid derivatives arachidin-1 and arachidin-6 were detected in cultivar Tifrunner. Upon reaction with 2,2-diphenyl-1picrylhydrazyl, extracts from cultivar Tifrunner showed the highest antioxidant capacity with an IC50 of 6.004 µg/mL. Furthermore, these extracts had significantly higher antioxidant capacity at 6.25 µg/mL and 3.125 µg/mL when compared to extracts from cultivars Hull and Georgia Green. The stilbenoid-rich extracts from peanut hairy roots show high antioxidant capacity and merit further study as potential nutraceuticals to promote human health.
Assuntos
Arachis/metabolismo , Estresse Oxidativo/fisiologia , Estilbenos/metabolismo , Antioxidantes/análise , Antioxidantes/farmacologia , Meios de Cultura , Ácidos Eicosanoicos , Fabaceae/metabolismo , Humanos , Extratos Vegetais/farmacologia , Raízes de Plantas/metabolismo , Prenilação de Proteína/fisiologia , Estilbenos/química , Estilbenos/isolamento & purificação , Estresse Fisiológico/fisiologiaRESUMO
Cocrystal engineering can alter the physicochemical properties of a drug and generate a superior drug candidate for formulation design. Oxyresveratrol (ORV) exhibits a poor solubility in aqueous environments, thereby resulting in a poor bioavailability. Extensive cocrystal screening of ORV with 67 cocrystal formers (coformers) bearing various functional groups was therefore conducted using grinding, liquid-assisted grinding, solvent evaporation, and slurry methods. Six cocrystals (ORV with betaine (BTN), L-proline (PRL), isonicotinamide, nicotinamide, urea, and ethyl maltol) were found, including four novel cocrystals. Powder X-ray diffraction, low frequency Raman spectroscopy, and thermal analysis revealed unique crystal forms in all obtained samples. Conventional Raman and infrared data differentiated the cocrystals by the presence or absence of a hydrogen bond interacting with the aromatic ring of ORV. The crystal structures were then elucidated by single-crystal X-ray diffraction. Two new cocrystals consisting of ORV : BTN (2 : 3) and ORV : PRL : H2O (1 : 2 : 1) were identified, and their crystal structures were solved. We report novel cocrystalline solids of ORV with improved aqueous solubilities and the unique cage-like crystal structures.
Assuntos
Betaína/química , Extratos Vegetais/química , Estilbenos/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura MolecularRESUMO
Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 26g was a potent hypoglycemic agent. In addition, the possible binding modes for compound 26g in the PPARγ protein have been investigated in this study.
Assuntos
PPAR gama/antagonistas & inibidores , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Cajanus/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , PPAR gama/metabolismo , Extratos Vegetais/síntese química , Extratos Vegetais/química , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
Stilbenoids are interesting natural compounds with pleiotropic in vitro and in vivo activity. Their well-documented biological properties include anti-inflammatory effects, anticancer effects, effects on longevity, and many others. Therefore, they are nowadays commonly found in foods and dietary supplements, and used as a part of treatment strategy in various types of diseases. Bioactivity of stilbenoids strongly depends on different types of factors such as dosage, food composition, and synergistic effects with other plant secondary metabolites such as polyphenols or vitamins. In this review, we summarize the existing in vitro, in vivo, and clinical data from published studies addressing the optimization of bioavailability of stilbenoids. Stilbenoids face low bioavailability due to their chemical structure. This can be improved by the use of novel drug delivery systems or enhancers, which are discussed in this review. Current in vitro and in vivo evidence suggests that both approaches are very promising and increase the absorption of the original substance by several times. However, data from more clinical trials are required.
Assuntos
Resveratrol/farmacocinética , Estilbenos/farmacocinética , Animais , Disponibilidade Biológica , Suplementos Nutricionais , Sistemas de Liberação de Medicamentos , Humanos , Resveratrol/química , Resveratrol/uso terapêutico , Estilbenos/química , Estilbenos/uso terapêuticoRESUMO
RATIONALE: Rhapontigenin, a stilbene compound isolated from the medicinal plant of rhubarb rhizomes, has shown a variety of biological activities. The purpose of this study was to identify and characterize the metabolites of rhapontigenin in rat liver microsomes, hepatocytes, urine, and human liver microsomes and hepatocytes. METHODS: The samples were analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q/Orbitrap-HRMS). The structures of the metabolites were interpreted by MS, MS/MS data, and elemental compositions. RESULTS: A total of 11 metabolites were detected and tentatively identified. M1, identified as piceatannol, was unambiguously identified using reference standard. Our results suggested that rhapontigenin was metabolized through the following pathways: (a) demethylation to produce piceatannol (M1), which further underwent oxidation to form ortho-quinone intermediate. This intermediate was reactive and conjugated with GSH (M10 and M11), which were further converted into N-acetyl-cysteine and excreted in urine. M1 also underwent sulfation (M8) and glucuronidation (M5); (b) direct sulfation, forming M6 and M7; and (c) direct glucuronidation to form M2, M3, and M4. Glucuronidation was a major metabolic pathway in hepatocytes and urine. CONCLUSIONS: The current study provides an overview of the metabolism of rhapontigenin, which is of great importance for us to understand the disposition of this compound.
Assuntos
Estilbenos/química , Estilbenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos , Estilbenos/urinaRESUMO
One of the main current strategies for cancer treatment is represented by combination chemotherapy. More recently, this strategy shifted to the "hybrid strategy", namely the designing of a new molecular entity containing two or more biologically active molecules and having superior features compared with the individual components. Moreover, the term "hybrid" has further extended to innovative drug delivery systems based on biocompatible nanomaterials and able to deliver one or more drugs to specific tissues or cells. At the same time, there is an increased interest in plant-derived polyphenols used as antitumoral drugs. The present review reports the most recent and intriguing research advances in the development of hybrids based on the polyphenols curcumin and resveratrol, which are known to act as multifunctional agents. We focused on two issues that are particularly interesting for the innovative chemical strategy involved in their development. On one hand, the pharmacophoric groups of these compounds have been used for the synthesis of new hybrid molecules. On the other hand, these polyphenols have been introduced into hybrid nanomaterials based on gold nanoparticles, which have many potential applications for both drug delivery and theranostics in chemotherapy.
Assuntos
Produtos Biológicos/uso terapêutico , Curcumina/uso terapêutico , Neoplasias/tratamento farmacológico , Resveratrol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Produtos Biológicos/química , Curcumina/química , Sistemas de Liberação de Medicamentos , Ouro/química , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Resveratrol/química , Estilbenos/químicaRESUMO
Pterostilbene, a natural metabolite of resveratrol, has been indicated as a potent anticancer molecule. Recently, several pterostilbene derivatives have been reported to exhibit better anticancer activities than that of the parent pterostilbene molecule. In the present study, a series of pterostilbene derivatives were designed and synthesized by the hybridization of pterostilbene, chalcone, and cinnamic acid. The cytotoxic effect of these hybrid molecules was determined using two oral cancer cell lines, HSC-3 and OECM-1. (E)-3-(2-((E)-4-Hydroxystyryl)-4,6-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (4d), with IC50 of 16.38 and 18.06 µM against OECM-1 and HSC-3, respectively, was selected for further anticancer mechanism studies. Results indicated that compound 4d effectively inhibited cell proliferation and induced G2/M cell cycle arrest via modulating p21, cyclin B1, and cyclin A2. Compound 4d ultimately induced cell apoptosis by reducing the expression of Bcl-2 and surviving. In addition, cleavage of PARP and caspase-3 were enhanced following the treatment of compound 4d with increased dose. To conclude, a number of pterostilbene derivatives were discovered to possess potent anticancer potentials. Among them, compound 4d was the most active, more active than the parent pterostilbene.
Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Estilbenos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Poli(ADP-Ribose) Polimerases/metabolismo , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. (PM) has attracted great interest, and tetrahydroxy stilbene glucoside (TSG) was the main idiosyncratic hepatotoxicity constituent, but biological detoxification on idiosyncratic hepatotoxicity of PM was not well investigated. AIM OF THE STUDY: This study aimed to illustrate biological detoxification mechanism on PM-induced idiosyncratic hepatotoxicity by Ganoderma lucidum (G. lucidum). MATERIALS AND METHODS: G. lucidum was used for biological detoxification of tetrahydroxy stilbene glucoside (TSG)-induced idiosyncratic hepatotoxicity of PM. The TSG consumption and products formation were dynamically determined during transformation using high-performance liquid chromatography coupled with diode-array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-MSn). The transformation invertases (ß-D-glucosidase and lignin peroxidase) were evaluated by using intracellular and extracellular distribution and activity assay. The key functions of lignin peroxidase (LiP) were studied by experiments of adding inhibitors and agonists. The entire TSG transformation process was confirmed in vitro simulated test. The cellular toxicity of TSG and the transformation products was detected by MTT. RESULTS: A suitable biotransformation system of TSG was established with G. lucidum, then p-hydroxybenzaldehyde and 2,3,5-trihydroxybenzaldehyde can be found as transformation products of TSG. The transformation mechanism involves two extracellular enzymes, ß-D-glucosidase and LiP. ß-D-glucosidase can remove glycosylation of TSG firstly and then LiP can break the double bond of remaining glycosides. The toxicity of TSG after biotransformation by G. lucidum was attenuated. CONCLUSIONS: This study would reveal a novel biological detoxification method for PM and explain degradation processes of TSG by enzymic methods.
Assuntos
Fallopia multiflora/química , Glucosídeos/metabolismo , Glucosídeos/toxicidade , Hepatócitos/efeitos dos fármacos , Reishi/enzimologia , Estilbenos/metabolismo , Estilbenos/toxicidade , Biotransformação , Linhagem Celular , Fermentação , Glucosídeos/química , Humanos , Peroxidases/metabolismo , Reishi/metabolismo , Estilbenos/químicaRESUMO
Oxyresveratrol, a polyphenol extracted from the plant Artocarpus lakoocha Roxb, has been reported to be an antioxidant and an oxygen-free radical scavenger. We investigated whether oxyresveratrol affects the generation of superoxide anion (O2-) by human monocytes, which are powerful reactive oxygen species (ROS) producers. We found that oxyresveratrol inhibited the O2- production induced upon stimulation of monocytes with ß-glucan, a well known fungal immune cell activator. We then investigated whether the inclusion of oxyresveratrol into nanoparticles could modulate its effects on O2- release. We synthesized poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and we assessed their effects on monocytes. We found that empty PLGA nanoparticles induced O2- production by resting monocytes and enhanced the formation of this radical in ß-glucan-stimulated monocytes. Interestingly, the insertion of oxyresveratrol into PLGA nanoparticles significantly inhibited the O2- production elicited by unloaded nanoparticles in resting monocytes as well as the synergistic effect of nanoparticles and ß-glucan. Our results indicate that oxyresveratrol is able to inhibit ROS production by activated monocytes, and its inclusion into PLGA nanoparticles mitigates the oxidative effects due to the interaction between these nanoparticles and resting monocytes. Moreover, oxyresveratrol can contrast the synergistic effects of nanoparticles with fungal agents that could be present in the patient tissues. Therefore, oxyresveratrol is a natural compound able to make PLGA nanoparticles more biocompatible.
Assuntos
Materiais Biocompatíveis/química , Radicais Livres/metabolismo , Monócitos/efeitos dos fármacos , Nanopartículas/química , Oxigênio/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estilbenos/química , Estilbenos/farmacologia , Antioxidantes/farmacologia , Artocarpus/química , Células Cultivadas , Humanos , Monócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The biological activities of shancigusin C (1) and bletistrin G (2), natural products isolated from orchids, are reported along with their first total syntheses. The total synthesis of shancigusin C (1) was conducted by employing the Perkin reaction to forge the central stilbene core, whereas the synthesis of bletistrin G (2) was achieved by the Wittig olefination followed by several regioselective aromatic substitution reactions. Both syntheses were completed by applying only renewable starting materials according to the principles of xylochemistry. The cytotoxic properties of shancigusin C (1) and bletistrin G (2) against tumor cells suggest suitability as a starting point for further structural variation.
Assuntos
Produtos Biológicos/farmacologia , Resistência a Múltiplos Medicamentos , Orchidaceae , Extratos Vegetais/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Química Farmacêutica/métodos , Di-Hidroestilbenoides/química , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , Estilbenos/químicaRESUMO
BACKGROUND: Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system. RESULTS: Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice. CONCLUSIONS: p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases.