Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.683
Filtrar
1.
Food Chem ; 366: 130582, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34303205

RESUMO

Leaf removal applied in the upper canopy of modified vertical shooting positioning trellis system has been proposed as an effective strategy to mitigate the adverse effects of global warming on grape and wine quality. In this study, we removed the upper leaves of Cabernet Sauvignon canopy in a semi-arid climate for three consecutive years (2018-2020). About one-third of the whole canopy leaves were removed at the beginning of véraison (LR1) and post-véraison (LR2). All leaf removal treatments included two schemes: (i) leaf removal in the same vines in all vintages to investigate the carry-over effects (1-LR1 and 1-LR2); (ii) leaf removal in different vines in each vintage as repeated experiments among vintages (2-LR1 and 2-LR2). Results showed that leaf removal treatments significantly decreased total soluble solids accumulation in grapes without affecting titratable acidity and pH. LR1 treatments could delay ripening to 6.6 days on average, which was 2.6 days longer than LR2 treatments. LR treatments did not affect the yield but decreased soluble sugar content in canes. Leaves net assimilation rate showed no compensation for the loss of leaves. For phenolic composition, LR treatments increased flavonol concentration in both wines and grapes while had inconsistent effects on anthocyanins and flavanols over three seasons. Principal component analysis (PCA) showed that different LR treatment stages (LR1s vs LR2s) and whether LR in the same vines over consecutive years (1-LRs vs 2-LRs) had limited effects on phenolic profiles. In conclusion, LR in consecutive years at the upper canopy of grapevines was a practical strategy to face global warming in Xinjiang.


Assuntos
Vitis , Vinho , Antocianinas/análise , Flavonóis , Frutas/química , Folhas de Planta/química , Vinho/análise
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120311, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34481255

RESUMO

The inhibitory effects of engeletin on the activities of human cytochrome P450 3A4 and 2D6 (CYP3A4 and CYP2D6) were investigated by enzyme kinetics, multi-spectroscopy and molecular docking. Engeletin was found to strongly inhibit CYP3A4 and CYP2D6, with the IC50 of 1.32 µM and 2.87 µM, respectively. The inhibition modes of engeletin against CYP3A4 and CYP2D6 were a competitive type and a mixed type, respectively. The fluorescence of the two CYPs was quenched statically by engeletin, which was bound to CYP3A4 stronger than to CYP2D6 at the same temperature. Circular dichroism spectroscopy, three-dimensional fluorescence, ultraviolet-visible spectroscopy and synchronous fluorescence confirmed that the conformation and micro-environment of the two CYPs protein were changed after binding with engeletin. Molecular docking, ultraviolet-visible spectroscopy and the fluorescence data revealed that engeletin had strong binding affinity to the two CYPs through hydrogen and van der Waals forces. The findings here suggested that engeletin may cause the herb-drug interactions for its inhibition of CYP3A4 and CYP2D6 activities.


Assuntos
Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450 , Flavonóis , Glicosídeos , Humanos , Simulação de Acoplamento Molecular , Análise Espectral
3.
Nanomedicine (Lond) ; 16(27): 2431-2448, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632809

RESUMO

Aim: To evaluate the feasibility of using dipotassium glycyrrhizinate (DG) as a nanocarrier-loading fisetin (FIT) with strengthened treatment efficacies against liver injury induced by acetaminophen overdose. Methods: DG-FIT was prepared, and its efficacy against liver injury induced by acetaminophen overdose was evaluated. Results: DG-FIT was successfully fabricated with excellent physicochemical properties. DG-FIT could be easily dissolved in water to form a clear micelle solution with high FIT encapsulation efficiency. FIT in DG-FIT exhibited a dramatically improved aqueous solubility. DG-FIT improved intestinal permeation. Regarding in vivo efficacies, DG-FIT exhibited significant effect against acetaminophen overdose by suppressing oxidative stress and proinflammatory cytokines involved. Conclusion: DG-FIT formulation possibly represents a promising method for strengthening the efficacy of FIT against acetaminophen-induced liver injury.


Assuntos
Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Flavonoides/metabolismo , Flavonóis , Humanos , Fígado/metabolismo , Estresse Oxidativo
4.
Clin Nutr ESPEN ; 45: 134-140, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34620309

RESUMO

BACKGROUND AND AIMS: Diabetes Mellitus (D.M.) is a chronic metabolic disease characterized by hyperglycemia due to insufficient or inefficient insulin secretory response that has become a widespread epidemic primarily due to the increasing prevalence and incidence of type 2 diabetes. Phytochemicals such as flavonoids and regular physical activity have recently attracted attention to developing new anti-diabetic drugs or alternative therapy to control diabetes. The aim of this study was to compare effects of dietary Flavonol consumption in white tea, with or without aerobic training, among patients with type 2 diabetes mellitus as a randomized trial. METHODS: 49 women with T2D were randomly assigned into groups including control, white tea, aerobic training, and aerobic training + white tea. The interventions were carried out for six months. Weight, Body Mass Index (BMI), body Fat, peak oxygen consumption (VO2Max), and Blood Pressure were evaluated at both the first and last days of the research period. Blood samples were withdrawn on the same days via venipuncture to test blood glucose, insulin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglycerides (T.G.). RESULTS: Characteristics analysis showed significant improvements in treated groups. In addition, glucose, insulin, LDL, Cholesterol, and T.G. were significantly reduced while HDL was remarkably increased in treated groups compared to pre-experiment values or the diabetic control group. CONCLUSION: Collectively, white tea combined with aerobic training favorably affects glycemic parameters, lipid profile, blood pressure, and VO2Max in six months in women with T2D. Registered under Clinical Trials.gov Identifier no. NCT00123456.


Assuntos
Diabetes Mellitus Tipo 2 , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Flavonóis , Humanos , Chá , Triglicerídeos
5.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638751

RESUMO

Obesity is a risk factor for metabolic diseases including type 2 diabetes, nonalcoholic steatohepatitis (NASH), heart diseases, and cancer. This study aimed to investigate the anti-obesity effect of Polygalin C (PC) isolated from Polygala japonica Houtt. in 3T3-L1 adipocytes. Based on Oil Red O assay results, PC significantly decreased lipid accumulation compared to the control. We found that PC suppressed adipogenesis transcription factors including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAAT/enhancer-binding protein (C/EBP) α, and lipogenic factors such as sterol regulatory element-binding protein 1c (SREBP 1c) and fatty acid synthase (FAS), in 3T3-L1 adipocytes using Western blotting and real-time polymerase chain reaction (PCR). Moreover, PC inhibited the differentiation of 3T3-L1 cells by regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinase/protein kinase B (MAPK/Akt) signaling pathways. Additionally, we confirmed that PC inhibited early adipogenesis factors C/EBP ß and C/EBP δ. Therefore, PC inhibited adipogenesis and lipogenesis in vitro. Thus, PC appears to exert potential therapeutic effects on obesity by suppressing lipid metabolism.


Assuntos
Adipogenia/efeitos dos fármacos , Flavonóis/farmacologia , Lipogênese/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Obesidade , Polygala/química , Células 3T3-L1 , Animais , Ácido Graxo Sintase Tipo I/biossíntese , Flavonóis/química , Flavonóis/isolamento & purificação , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
6.
Phytochemistry ; 192: 112931, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34478991

RESUMO

The cylindrical conflorescences of the Banksia spinulosa Sm complex have several different colour types, i.e., black, red, maroon, lemon, and yellow. It is unknown if colour variation is due to extrinsic factors, importantly soil pH. Recent morphological observations have indicated that style colour are not contiguous, so follow-up chemical and soil analysis was conducted to further characterize the colour difference with respect to putative taxa and abiotic factors. Conflorescences of all known colours were sampled from across the eastern Australian distribution of B. spinulosa, and the respective soils were sampled and analysed for pH and total nitrogen. Regression analyses of this data demonstrated that pH and nitrogen gave nil and limited predictability for style colour respectively, i.e., only the taxa with black styles demonstrated a correlation, which was to a soil with slightly higher nitrogen content (p < 0.05). Furthermore, differences of pH were more often between taxa with conflorescences of the same colour. For chemical characterisation, the coloured styles were removed from conflorescences, extracted, and analysed by liquid chromatography-mass spectrometry (HPLC-MS/MS-DAD). Ten anthocyanin and twelve flavonol monoglycosides were identified by mass spectral fragmentation patterns (MS1 and MS2) and retention times. The data demonstrates that style colour differences are caused by the concentration of anthocyanins and their specific chemistry. It remains to be determined if the differences of anthocyanin expression are caused by other abiotic factors, or if it is intrinsic to the respective taxon.


Assuntos
Antocianinas , Proteaceae , Austrália , Cor , Flavonóis , Concentração de Íons de Hidrogênio , Solo , Espectrometria de Massas em Tandem
7.
J Agric Food Chem ; 69(37): 10932-10942, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34505780

RESUMO

The intestinal flora serves a critical role in the development of hyperuricemia-induced chronic kidney disease (CKD). We previously found that natural flavonol fisetin exhibited nephroprotective effects in hyperuricemic mice. However, the mechanism remains largely unknown. To investigate the underlying mechanism of fisetin, mice were fed with potassium oxonate and adenine to introduce hyperuricemia-induced CKD. Fisetin improved kidney function, ameliorated renal fibrosis, and restored enteric dysbacteriosis in hyperuricemia-induced CKD mice. Meanwhile, gut microbiota-derived tryptophan metabolites, especially l-kynurenine, showed correlations with nephroprotective profiles of fisetin. Additionally, the kidney expression of the aryl hydrocarbon receptor (AHR), an endogenous receptor of l-kynurenine, was enhanced in hyperuricemic mice and further reduced in fisetin-treated mice. Finally, in vitro results showed that inhibition of AHR activation attenuated l-kynurenine-induced fibrosis. These results highlighted that fisetin protected against hyperuricemia-induced CKD via modulating gut microbiota-mediated tryptophan metabolism and AHR activation.


Assuntos
Microbioma Gastrointestinal , Hiperuricemia , Insuficiência Renal Crônica , Animais , Flavonóis , Hiperuricemia/tratamento farmacológico , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Insuficiência Renal Crônica/tratamento farmacológico , Triptofano
8.
Plant Cell Rep ; 40(10): 1923-1946, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34333679

RESUMO

KEY MESSAGE: Combined transcriptomic and metabolic analyses reveal that fruit of Rubus chingii Hu launches biosynthesis of phenolic acids and flavonols at beginning of fruit set and then coordinately accumulated or converted to their derivatives. Rubus chingii Hu (Chinese raspberry) is an important dual functional food with nutraceutical and pharmaceutical values. Comprehensively understanding the mechanisms of fruit development and bioactive components synthesis and regulation could accelerate genetic analysis and molecular breeding for the unique species. Combined transcriptomic and metabolic analyses of R. chingii fruits from different developmental stages, including big green, green-to-yellow, yellow-to-orange, and red stages, were conducted. A total of 89,188 unigenes were generated and 57,545 unigenes (64.52%) were annotated. Differential expression genes (DEGs) and differentially accumulated metabolites (DAMs) were mainly involved in the biosynthesis of secondary metabolites. The fruit launched the biosynthesis of phenolic acids and flavonols at the very beginning of fruit set and then coordinately accumulated or converted to their derivatives. This was tightly regulated by expressions of the related genes and MYB and bHLH transcription factors. The core genes products participated in the biosynthesis of ellagic acid (EA) and kaempferol-3-O-rutinoside (K-3-R), such as DAHPS, DQD/SDH, PAL, 4CL, CHS, CHI, F3H, F3'H, FLS, and UGT78D2, and their corresponding metabolites were elaborately characterized. Our research reveals the molecular and chemical mechanisms of the fruit development of R. chingii. The results provide a solid foundation for the genetic analysis, functional genes isolation, fruit quality improvement and modifiable breeding of R. chingii.


Assuntos
Ácido Elágico , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Rubus/crescimento & desenvolvimento , Ácido Elágico/metabolismo , Flavonóis/biossíntese , Flavonóis/genética , Frutas/genética , Perfilação da Expressão Gênica , Hidroxibenzoatos/metabolismo , Quempferóis/genética , Quempferóis/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Controle de Qualidade , Rubus/genética , Rubus/metabolismo , Terpenos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
J Am Geriatr Soc ; 69(11): 3023-3033, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34375437

RESUMO

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.


Assuntos
COVID-19/tratamento farmacológico , Senescência Celular/efeitos dos fármacos , Flavonóis/uso terapêutico , Instituições de Cuidados Especializados de Enfermagem , Idoso , COVID-19/prevenção & controle , Ensaios Clínicos como Assunto , Monitoramento de Medicamentos , Humanos
10.
J Photochem Photobiol B ; 222: 112263, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34339994

RESUMO

The biosynthesis of polyphenolic compounds in cabbage waste, outer green leaves of white head cabbage (Brassica oleracea L. var. capitata subvar. alba), was stimulated by postharvest irradiation with UVB lamps or sunlight. Both treatments boosted the content of kaempferol and quercetin glycosides, especially in the basal leaf zone, as determined by the HPLC analysis of leaf extracts and by a non-destructive optical sensor. The destructive analysis of samples irradiated by the sun for 6 days at the end of October 2015 in Skierniewice (Poland) showed an increase of leaf flavonols by 82% with respect to controls. The treatment by a broadband UVB fluorescent lamp, with irradiance of 0.38 W m-2 in the 290-315 nm range (and 0.59 W m-2 in the UVA region) for 12 h per day at 17 °C along with a white light of about 20 µmol m-2 s-1, produced a flavonols increase of 58% with respect to controls. The kinetics of flavonols accumulation in response to the photochemical treatments was monitored with the FLAV non-destructive index. The initial FLAV rate under the sun was proportional to the daily radiation doses with a better correlation for the sun global irradiance (R2 = 0.973), followed by the UVA (R2 = 0.965) and UVB (R2 = 0.899) irradiance. The sunlight turned out to be more efficient than the UVB lamp in increasing the flavonols level of waste leaves, because of a significant role played by UVA and visible solar radiation in the regulation of the flavonoid accumulation in cabbage. The FLAV index increase induced on the adaxial leaf side was accompanied by a lower but still significant FLAV increase on the unirradiated abaxial side, likely due to a systemic signaling by mean of the long-distance movement of macromolecules. Our present investigation provides useful data for the optimization of postharvest photochemical protocols of cabbage waste valorization. It can represent a novel and alternative tool of vegetable waste management for the recovery of beneficial phytochemicals.


Assuntos
Brassica/efeitos da radiação , Luz , Brassica/química , Brassica/metabolismo , Clorofila/química , Cromatografia Líquida de Alta Pressão , Flavonóis/análise , Flavonóis/metabolismo , Armazenamento de Alimentos , Folhas de Planta/química , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Espectrometria de Fluorescência , Raios Ultravioleta
11.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361014

RESUMO

A link between the scent and color of Narcissus tazetta flowers can be anticipated due to their biochemical origin, as well as their similar biological role. Despite the obvious aesthetic and ecological significance of these colorful and fragrant components of the flowers and the molecular profiles of their pigments, fragrant formation has addressed in some cases. However, the regulatory mechanism of the correlation of fragrant components and color patterns is less clear. We simultaneously used one way to address how floral color and fragrant formation in different tissues are generated during the development of an individual plant by transcriptome-based weighted gene co-expression network analysis (WGCNA). A spatiotemporal pattern variation of flavonols/carotenoids/chlorophyll pigmentation and benzenoid/phenylpropanoid/ monoterpene fragrant components between the tepal and corona in the flower tissues of Narcissus tazetta, was exhibited. Several candidate transcription factors: MYB12, MYB1, AP2-ERF, bZIP, NAC, MYB, C2C2, C2H2 and GRAS are shown to be associated with metabolite flux, the phenylpropanoid pathway to the production of flavonols/anthocyanin, as well as related to one branch of the phenylpropanoid pathway to the benzenoid/phenylpropanoid component in the tepal and the metabolite flux between the monoterpene and carotenoids biosynthesis pathway in coronas. It indicates that potential competition exists between floral pigment and floral fragrance during Narcissus tazetta individual plant development and evolutionary development.


Assuntos
Flavonóis/metabolismo , Flores/metabolismo , Redes Reguladoras de Genes , Narcissus/genética , Pigmentação , Transcriptoma , Antocianinas/genética , Antocianinas/metabolismo , Flavonóis/genética , Flores/genética , Narcissus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Molecules ; 26(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34443358

RESUMO

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13, described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7-O-rhamnosyl-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside, 8-10, inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC50 value of 24 nM.


Assuntos
Flavonóis/química , Flavonóis/farmacologia , HIV-1/efeitos dos fármacos , Iridoides/química , Iridoides/farmacologia , Scrophularia/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Concentração Inibidora 50 , Folhas de Planta/química
13.
Biomolecules ; 11(8)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439780

RESUMO

The aim of the study was to investigate changes in the content of biologically active compounds during the fermentation and aging of natural meads with the addition of three Cornelian cherry juices from three cultivars: 'Koralovyi', 'Podolski' and 'Yantarnyi', in the amount of 10% v/v. After the fermentation process the content of gallic and ellagic acids significantly increased, in relation to wort. Whereas the greatest losses were observed among unstable anthocyanins. The three-month aging process also reduced the content of the analyzed compounds except for ellagic acid, the content of which increased by up to 90%. The content of biologically active compounds, including iridoids and antioxidant phenolics, are constantly changing in the process of fermentation and aging of fruit meads. The studies proved that the addition of Cornelian cherry juice allows significantly enriched classic meads with new biologically active compounds, such as: exceptional iridoids (loganic acid, cornuside, loganine, sweroside), flavonols, phenolic acids and anthocyanins.


Assuntos
Bebidas Alcoólicas/análise , Tecnologia de Alimentos/métodos , Mel/análise , Iridoides/química , Fenóis/química , Saccharomyces/metabolismo , Antocianinas/biossíntese , Antocianinas/química , Antocianinas/classificação , Antocianinas/isolamento & purificação , Antioxidantes/química , Antioxidantes/classificação , Antioxidantes/isolamento & purificação , Antioxidantes/metabolismo , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Ácido Elágico/química , Ácido Elágico/isolamento & purificação , Ácido Elágico/metabolismo , Fermentação , Flavonóis/química , Flavonóis/classificação , Flavonóis/isolamento & purificação , Flavonóis/metabolismo , Frutas/química , Sucos de Frutas e Vegetais/análise , Ácido Gálico/química , Ácido Gálico/isolamento & purificação , Ácido Gálico/metabolismo , Humanos , Iridoides/classificação , Iridoides/isolamento & purificação , Iridoides/metabolismo , Fenóis/classificação , Fenóis/isolamento & purificação , Fenóis/metabolismo , Picratos/antagonistas & inibidores , Prunus avium/química , Ácido Quínico/análogos & derivados , Ácido Quínico/química , Ácido Quínico/isolamento & purificação , Ácido Quínico/metabolismo , Ácidos Sulfônicos/antagonistas & inibidores
14.
Phytomedicine ; 91: 153704, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34419736

RESUMO

BACKGROUND: COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 Mpro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 Mpro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained. PURPOSE: The coronavirus main protease (Mpro) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of Mpro. Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients. METHODS: FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 Mpro. Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 Mpro. The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells. RESULTS: In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 Mpro with a half-maximum inhibitory concentration (IC50) of 1.716 ± 0.419 µM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3'- and 4'-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by inhibiting the infiltration of inflammation cells and the secretion of inflammation factors in the early process and also ameliorate pulmonary fibrosis by improving pulmonary function and down-regulate the expression of α-SMA and fibronectin in vivo. Our results also showed that dihydromyricetin inhibits the migration and activation of myofibroblasts and extracellular matrix production via transforming growth factor (TGF)-ß1/Smad signaling pathways. CONCLUSION: Dihydromyricetin is an effective inhibitor for SARS-CoV-2 Mpro and it prevents BLM-induced pulmonary inflammation and fibrosis in mice. Dihydromyricetin will be a potential medicine for the treatment of COVID-19 and its sequelae.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Flavonóis/farmacologia , Inibidores de Proteases , SARS-CoV-2 , Replicação Viral , Animais , Antivirais/farmacologia , COVID-19 , Fibrose , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
15.
Sci Rep ; 11(1): 15596, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341423

RESUMO

Dihydroquercetin (DHQ), an extremely low content compound (less than 3%) in plants, is an important component of dietary supplements and used as functional food for its antioxidant activity. Moreover, as downstream metabolites of DHQ, an extremely high content of dihydromyricetin (DHM) is up to 38.5% in Ampelopsis grossedentata. However, the mechanisms involved in the biosynthesis and regulation from DHQ to DHM in A. grossedentata remain unclear. In this study, a comparative transcriptome analysis of A. grossedentata containing extreme amounts of DHM was performed on the Illumina HiSeq 2000 sequencing platform. A total of 167,415,597 high-quality clean reads were obtained and assembled into 100,584 unigenes having an N50 value of 1489. Among these contigs, 57,016 (56.68%) were successfully annotated in seven public protein databases. From the differentially expressed gene (DEG) analysis, 926 DEGs were identified between the B group (low DHM: 210.31 mg/g) and D group (high DHM: 359.12 mg/g) libraries, including 446 up-regulated genes and 480 down-regulated genes (B vs. D). Flavonoids (DHQ, DHM)-related DEGs of ten structural enzyme genes, three myeloblastosis transcription factors (MYB TFs), one basic helix-loop-helix (bHLH) TF, and one WD40 domain-containing protein were obtained. The enzyme genes comprised three PALs, two CLs, two CHSs, one F3'H, one F3'5'H (directly converts DHQ to DHM), and one ANS. The expression profiles of randomly selected genes were consistent with the RNA-seq results. Our findings thus provide comprehensive gene expression resources for revealing the molecular mechanism from DHQ to DHM in A. grossedentata. Importantly, this work will spur further genetic studies about A. grossedentata and may eventually lead to genetic improvements of the DHQ content in this plant.


Assuntos
Ampelopsis/genética , Vias Biossintéticas/genética , Flavonóis/biossíntese , Genes de Plantas , Quercetina/análogos & derivados , Análise por Conglomerados , Flavonoides/biossíntese , Flavonoides/química , Flavonoides/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Anotação de Sequência Molecular , Quercetina/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética
16.
Int J Biol Macromol ; 187: 976-987, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34333006

RESUMO

Coronavirus 3C-like protease (3CLpro) is a crucial target for treating coronavirus diseases including COVID-19. Our preliminary screening showed that Ampelopsis grossedentata extract (AGE) displayed potent SARS-CoV-2-3CLpro inhibitory activity, but the key constituents with SARS-CoV-2-3CLpro inhibitory effect and their mechanisms were unrevealed. Herein, a practical strategy via integrating bioactivity-guided fractionation and purification, mass spectrometry-based peptide profiling and time-dependent biochemical assay, was applied to identify the crucial constituents in AGE and to uncover their inhibitory mechanisms. The results demonstrated that the flavonoid-rich fractions (10-17.5 min) displayed strong SARS-CoV-2-3CLpro inhibitory activities, while the constituents in these fractions were isolated and their SARS-CoV-2-3CLpro inhibitory activities were investigated. Among all isolated flavonoids, dihydromyricetin, isodihydromyricetin and myricetin strongly inhibited SARS-CoV-2 3CLpro in a time-dependent manner. Further investigations demonstrated that myricetin could covalently bind on SARS-CoV-2 3CLpro at Cys300 and Cys44, while dihydromyricetin and isodihydromyricetin covalently bound at Cys300. Covalent docking coupling with molecular dynamics simulations showed the detailed interactions between the orthoquinone form of myricetin and two covalent binding sites (surrounding Cys300 and Cys44) of SARS-CoV-2 3CLpro. Collectively, the flavonoids in AGE strongly and time-dependently inhibit SARS-CoV-2 3CLpro, while the newly identified SARS-CoV-2 3CLpro inhibitors in AGE offer promising lead compounds for developing novel antiviral agents.


Assuntos
Proteases Virais 3C/química , Proteases Virais 3C/metabolismo , Ampelopsis/química , Antivirais/farmacologia , Flavonoides/farmacologia , SARS-CoV-2/enzimologia , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Cisteína/metabolismo , Flavonoides/química , Flavonóis/química , Flavonóis/farmacologia , Espectrometria de Massas , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica/efeitos dos fármacos , Conformação Proteica/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos
17.
Biochem Pharmacol ; 192: 114676, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256044

RESUMO

Fisetin is a bioactive flavonol that inhibits osteoclastogenesis and promotes osteoblastogenesis. However, the osteogenic activity of fisetin needs to be comprehensively elucidated. In the present study, we observed that fisetin significantly increased alkaline phosphatase (ALP) activity and bone mineralization in MC3T3-E1 preosteoblasts, accompanied by a significant increase in runt-related transcription factor 2 (RUNX2), ALP, collagen type Ⅰ alpha 1 (Col1α1), osterix (OSX), osteocalcin (OCN), and bone morphogenetic protein 4 (BMP4) expression. Furthermore, fisetin promoted vertebral formation in zebrafish larvae, with the highest fisetin concentration comparable with that observed in ß-glycerophosphate treatment. Fisetin also inhibited prednisolone (PDS)-induced anti-osteoblastic genes, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase-6 (ACP6), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK). Fisetin potently mitigated the PDS-induced inhibition of ALP activity and bone mineralization, as well as vertebral resorption in zebrafish larvae. Moreover, we confirmed that fisetin-induced osteogenic effect was activated through phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9, consequently releasing ß-catenin from the destructive complex to promote its nuclear translocation. ß-Catenin inhibition by FH535 and the stabilization of GSK-3ß by DOI hydrochloride remarkably inhibited fisetin-induced osteogenic activities, indicating that the GSK-3ß/ß-catenin signaling pathway plays a vital role in fisetin-induced osteogenesis. Collectively, our findings suggest that fisetin stimulates osteogenic activity and could be used as an effective strategy to prevent bone resorption.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Flavonóis/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , beta Catenina/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Linhagem Celular , Relação Dose-Resposta a Droga , Flavonóis/uso terapêutico , Camundongos , Osteogênese/fisiologia , Osteoporose/prevenção & controle , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Serina/metabolismo , Peixe-Zebra
18.
J Steroid Biochem Mol Biol ; 213: 105954, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298098

RESUMO

BACKGROUND: The present study was conducted to investigate the therapeutic effects of a potent polyphenol, fisetin, on the letrozole-induced rat model of polycystic ovary syndrome (PCOS). METHODOLOGY: Twenty-four female Wistar rats (42 days old) were divided into four groups: control group (received carboxy methylcellulose (CMC 0.5 %)), PCOS group treated with letrozole (1 mg/kg), fisetin group received same dose of letrozole + fisetin (10 mg/kg), and metformin group received same dose of letrozole + metformin (300 mg/kg). At the end of the experiment, biochemical (glucose, lipid profile) and hormonal (insulin, testosterone, estradiol, and progesterone) parameters were analyzed. Histological examinations of ovaries were also conducted by hematoxylin and eosin (H&E) staining. Real-time polymerase chain reaction (PCR) and western blotting were carried out for cytochrome P450 17A1 (CYP17A1), sirtuin-1 (SIRT1), and 5' AMP-activated protein kinase (AMPK) gene expression in the ovaries. Furthermore, enzymatic activities of antioxidants including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the ovaries were analyzed by colorimetric method. RESULTS: Letrozole administration resulted in a remarkable abnormality in biochemical and hormonal parameters. Fisetin normalized levels of glucose, lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR), testosterone, estradiol, and progesterone. Moreover, fisetin increased expression levels of SIRT1 and AMPK, and decreased expression level of CYP17A1 in the ovaries. Additionally, fisetin showed protective effect by enhancing antioxidant activities of CAT, SOD, and GPx depleted secondary to induction of PCOS. Fisetin effects were comparable to metformin, as the standard drug used for treatment of PCOS. CONCLUSION: Our results showed that, fisetin treatment caused significant alleviating effects by restoring PCOS-induced alterations in the key genes involved in energy homeostasis and antioxidant enzymes, suggesting that it may have a key role in combating with PCOS.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonóis/farmacologia , Letrozol/antagonistas & inibidores , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/sangue , Proteínas Quinases Ativadas por AMP/genética , Animais , Glicemia/metabolismo , Carboximetilcelulose Sódica/administração & dosagem , Catalase/sangue , Catalase/genética , Modelos Animais de Doenças , Estradiol/sangue , Feminino , Expressão Gênica , Glutationa Peroxidase/sangue , Glutationa Peroxidase/genética , Humanos , Insulina/sangue , Letrozol/toxicidade , Metformina/farmacologia , Ovário/metabolismo , Ovário/patologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Progesterona/sangue , Ratos , Ratos Wistar , Sirtuína 1/sangue , Sirtuína 1/genética , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/sangue , Esteroide 17-alfa-Hidroxilase/genética , Superóxido Dismutase/sangue , Superóxido Dismutase/genética , Testosterona/sangue
19.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299083

RESUMO

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5ß3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.


Assuntos
Intoxicação Alcoólica/prevenção & controle , Encéfalo/metabolismo , Etanol/toxicidade , Flavonóis/farmacologia , Intoxicação Alcoólica/etiologia , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Depressores do Sistema Nervoso Central/toxicidade , Feminino , Flavonóis/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Braz J Med Biol Res ; 54(10): e11028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34287581

RESUMO

Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs) oxygen-glucose deprivation and reoxygenation (OGD/R) model system and a middle cerebral artery occlusion (MCAO) rat model of cerebral ischemia and reperfusion injury. These analyses revealed that engeletin (10, 20, or 40 mg/kg) was able to reduce the infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of vascular endothelial growth factor (VEGF), vasohibin-2 (Vash-2), angiopoietin-1 (Ang-1), phosphorylated human angiopoietin receptor tyrosine kinase 2 (p-Tie2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly, engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and VEGF expression of HUVECs in an OGD/R model system, while the VEGF receptor (R) inhibitor axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2, VEGF, and CD31 expression. These data suggested that engeletin exhibited significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Angiopoietina-1 , Animais , Isquemia Encefálica/prevenção & controle , Células Endoteliais , Flavonóis , Glicosídeos , Infarto da Artéria Cerebral Média , Ratos , Traumatismo por Reperfusão/prevenção & controle , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...