RESUMO
Flavonoids are an abundant class of naturally occurring compounds with broad biological activities, but their limited abundance in nature restricts their use in medicines and food additives. Here we present the synthesis and determination of the antibacterial and antioxidant activities of twenty-two structurally related flavonoids (five of which are new) by scientifically validated methods. Flavanones (FV1-FV11) had low inhibitory activity against the bacterial growth of MRSA 97-7. However, FV2 (C5,7,3',4' = OH) and FV6 (C5,7 = OH; C4' = SCH3) had excellent bacterial growth inhibitory activity against Gram-negative E. coli (MIC = 25 µg/mL for both), while Chloramphenicol (MIC = 25 µg/mL) and FV1 (C5,7,3' = OCH3; 4' = OH) showed inhibitory activity against Gram-positive L. monocytogenes (MIC = 25 µg/mL). From the flavone series (FO1-FO11), FO2 (C5,7,3',4' = OH), FO3 (C5,7,4' = OH; 3' = OCH3), and FO5 (C5,7,4' = OH) showed good inhibitory activity against Gram-positive MRSA 97-7 (MIC = 50, 12, and 50 µg/mL, respectively), with FO3 being more active than the positive control Vancomycin (MIC = 25 µg/mL). FO10 (C5,7= OH; 4' = OCH3) showed high inhibitory activity against E. coli and L. monocytogenes (MIC = 25 and 15 µg/mL, respectively). These data add significantly to our knowledge of the structural requirements to combat these human pathogens. The positions and number of hydroxyl groups were key to the antibacterial and antioxidant activities.
Assuntos
Antibacterianos , Antioxidantes , Flavonoides , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Flavonoides/farmacologia , Flavonoides/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/crescimento & desenvolvimento , Flavanonas/farmacologia , Flavanonas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacosRESUMO
The metabolism and absorption of citrus flavanones are intrinsically linked to the gut microbiota, creating a bidirectional relationship where these compounds influence the microbiome, and in turn, the microbiota affects their metabolism. This study evaluates the effect of acute and chronic consumption of orange juice (OJ) on the urinary excretion of gut-derived flavanone metabolites and the gut microbiota. Health volunteers ingested 500 mL of OJ for 60 days in a single-arm human intervention study. Blood and feces were collected at baseline and after 60 days, with an additional 24-hour urine collection after a single dose on day 1 and day 63. LC-MS/MS analyzed urinary flavanone metabolites, while 16S rRNA sequencing characterized gut microbiota. Total urinary hesperetin conjugates excretion significantly decreased over 60 days, while gut-derived total phenolic acids, particularly three hydroxybenzoic acids, increased. Moreover, the heterogeneity of the total amount of flavanone conjugates, initially categorizing individuals into high-, medium- and low- urinary excretor profiles, shifted towards medium-excretor, except for five individuals who remained as low-excretors. This alteration was accompanied by a decrease in intestinal ß-glucosidase activity and a shift in the relative abundance of specific genera, such as decreases in Blautia, Eubacterium hallii, Anaerostipes, and Fusicatenibacter, among which, Blautia was associated with higher urinary flavanone conjugates excretion. Conversely, an increase in Prevotella was observed. In summary, chronic OJ consumption induced transient changes in gut microbiota and altered the metabolism of citrus flavanones, leading to distinct urinary excretion profiles of flavanone metabolites.
Assuntos
Citrus sinensis , Fezes , Flavanonas , Sucos de Frutas e Vegetais , Microbioma Gastrointestinal , Humanos , Flavanonas/urina , Masculino , Adulto , Feminino , Fezes/microbiologia , Fezes/química , Hesperidina/urina , Espectrometria de Massas em Tandem , Pessoa de Meia-Idade , Adulto Jovem , Bactérias/classificação , Bactérias/metabolismo , Bactérias/genética , Hidroxibenzoatos/urinaRESUMO
Alzheimer's disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped. Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5'-dimethylallyl and 4'-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3ß-mediated tau phosphorylation previously reported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3ß. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD.
Assuntos
Doença de Alzheimer , Flavanonas , Fármacos Neuroprotetores , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos Transgênicos , Proteínas tau/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Fosforilação , Peptídeos beta-Amiloides/metabolismoRESUMO
BACKGROUND: Endotoxemia is a severe and dangerous clinical syndrome that results in elevated morbidity, especially in intensive care units. Neonates are particularly susceptible to endotoxemia due to their immature immune systems. There are few effective treatments for neonatal endotoxemia. One group of compounds with potential in the treatment of neonatal inflammatory diseases such as endotoxemia is the flavonoids, mainly due to their antioxidant and anti-inflammatory properties. Among these, naringenin (NGN) is a citrus flavonoid which has already been reported to have anti-inflammatory, antioxidant, anti-nociceptive and anti-cancer effects. Unfortunately, its clinical application is limited by its low solubility and bioavailability. However, cyclodextrins (CDs) have been widely used to improve the solubility of nonpolar drugs and enhance the bioavailability of these natural products. OBJECTIVE: We, therefore, aimed to investigate the effects of NGN non-complexed and complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on neonatal endotoxemia injuries in a rodent model and describe the probable molecular mechanisms involved in NGN activities. METHOD: We used exposure to a bacterial lipopolysaccharide (LPS) to induce neonatal endotoxemia in the mice. RESULTS: It was found that NGN (100 mg/kg i.p.) exposure during the neonatal period reduced leukocyte migration and decreased pro-inflammatory cytokine (TNF-α, IL-1ß and IL-6) levels in the lungs, heart, kidneys or cerebral cortex. In addition, NGN upregulated IL-10 production in the lungs and kidneys of neonate mice. The administration of NGN also enhanced antioxidant enzyme catalase and SOD activity, reduced lipid peroxidation and protein carbonylation and increased the reduced sulfhydryl groups in an organ-dependent manner, attenuating the oxidative damage caused by LPS exposure. NGN decreased ERK1/2, p38MAPK and COX-2 activation in the lungs of neonate mice. Moreover, NGN complexed with HPßCD was able to increase the animal survival rate. CONCLUSION: NGN attenuated inflammatory and oxidative damage in the lungs, heart and kidneys caused by neonatal endotoxemia through the MAPK signaling pathways regulation. Our results show that NGN has beneficial effects against neonatal endotoxemia and could be useful in the treatment of neonatal inflammatory injuries.
Assuntos
Citrus , Endotoxemia , Flavanonas , Camundongos , Animais , Flavonoides/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Anti-Inflamatórios/farmacologiaRESUMO
Dietary polyphenol consumption is associated with a wide range of neuroprotective effects by improving mitochondrial function and signaling. Consequently, the use of polyphenol supplementation has been investigated as an approach to prevent neurodevelopmental diseases during gestation; however, the data obtained are still very inconclusive, mostly because of the difficulty of choosing the correct doses and period of administration to properly prevent neurodegenerative diseases without undermining normal brain development. Thus, we aimed to evaluate the effect of naringin supplementation during the third week of gestation on mitochondrial health and signaling in the cerebellum of 21-day-old offspring. The offspring born to naringin-supplemented dams displayed higher mitochondrial mass, membrane potential, and superoxide content in the cerebellum without protein oxidative damage. Such alterations were associated with dynamin-related protein 1 (DRP1) and phosphorylated AKT (p-AKT) downregulation, whereas the sirtuin 3 (SIRT3) levels were strongly upregulated. Our findings suggest that high dietary polyphenol supplementation during gestation may reduce mitochondrial fission and affect mitochondrial dynamics even 3 weeks after delivery via SIRT3 and p-AKT. Although the offspring born to naringin dams did not present neurobehavioral defects, the mitochondrial alterations elicited by naringin may potentially interfere during neurodevelopment and need to be further investigated.
Assuntos
Flavanonas , Sirtuína 3 , Ratos , Animais , Feminino , Gravidez , Ratos Wistar , Sirtuína 3/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cerebelo/metabolismo , Suplementos Nutricionais , Mitocôndrias/metabolismo , Polifenóis/metabolismoRESUMO
Orange juice is an important food source of bioactive compounds, mainly the flavanones hesperidin and narirutin. This study aimed to investigate the underlying molecular mechanisms of action of orange juice's health properties by analyzing changes in the plasma proteome of healthy Brazilian volunteers after consuming juices made from 'Bahia' (BOJ-source of flavanones) and 'Cara Cara' (CCOJ-source of flavanones and carotenoids) oranges cultivated in Brazil. We used an untargeted proteomic approach, with a particular emphasis on the juices' effects on blood coagulant activity. We identified 247 differentially expressed proteins, of which 170 significantly increased or decreased after BOJ consumption and 145 after CCOJ. These proteins are involved in 105 processes that can significantly regulate cell adhesion, cell signaling, cell metabolism, inflammation, or others. Bioinformatic analysis evidenced proteins with major cellular regulatory capacity (e.g., FN1 and GAPDH) and predicted transcription factors (TFs) (e.g., SP1 and CEBPA) and miRNAs (e.g., miR-1-3p and miR-615-3p) that could be involved in the regulation of differentially expressed proteins. In-silico docking analyses between flavanone metabolites and TFs evidenced the higher binding capacity of narirutin phase II metabolites with akt1 and p38, interactions that suggest how the expression of genes of differentially expressed proteins were activated or inhibited. Moreover, the study shed light on proteins of coagulation cascade that presented expression modulated by both juices, proposing the modulation of blood coagulant activity as a potential benefit of OJ (mainly CCOJ) consumption. Taken together, this study revealed that BOJ and CCOJ consumption affected plasma proteome in healthy individuals, suggesting potential molecular targets and mechanisms of OJ bioactive compounds in humans.
Assuntos
Citrus sinensis , Coagulantes , Flavanonas , MicroRNAs , Humanos , Citrus sinensis/química , Brasil , Proteoma/análise , Proteômica , Flavanonas/metabolismo , Sucos de Frutas e Vegetais , Frutas/química , MicroRNAs/metabolismo , Coagulantes/análise , Coagulantes/metabolismoRESUMO
A supercritical CO2 method was optimized to recover naringenin-rich extract from Mexican oregano (Lippia graveolens), a flavanone with high antioxidant and anti-inflammatory activity. The effect of the extraction parameters like pressure, temperature, and co-solvent on naringenin concentration was evaluated. We used response surface methodology to optimize the naringenin extraction from oregano; the chemical composition by UPLC-MS of the optimized extract and the effect of simulated gastrointestinal digestion on its antioxidant capacity and total phenolic content were also evaluated. The optimum conditions were 58.4 °C and 12.46% co-solvent (ethanol), with a pressure of 166 bar, obtaining a naringenin content of 46.59 mg/g extract. Also, supercritical optimized extracts yielded high quantities of cirsimaritin, quercetin, phloridzin, apigenin, and luteolin. The results indicated that the naringenin-rich extract obtained at optimized conditions had higher total phenolic content, antioxidant capacity by TEAC and ORAC, and flavonoid content, compared with the methanolic extract, and the simulated gastrointestinal digestion reduced all these values.
Assuntos
Flavanonas , Lippia , Origanum , Antioxidantes/química , Lippia/química , Origanum/química , Dióxido de Carbono , Cromatografia Líquida , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Espectrometria de Massas em Tandem , Fenóis , Solventes/química , DigestãoRESUMO
We have studied the effects of individual and combined treatment of insulin (I) and naringin (NAR) on the bone structure and biomechanical properties of femurs from streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups: (1) controls, (2) STZ-induced diabetic rats, (3) STZ-induced diabetic rats treated with I, (4) STZ-induced diabetic rats treated with NAR, and (5) STZ-induced diabetic rats treated with I + NAR. Bone mineral density (BMD), bone histomorphometry, biomechanical testing, and bone biomarker expressions were accomplished in femur of all animals, as well as serum biochemical analyses. The combined treatment of I + NAR increased the body weight and the femur BMD from STZ-induced diabetic rats. The bone biomechanical properties and the bone morphology of the femurs from STZ-induced diabetic rats were also improved by the combined treatment. The increased number of osteoclasts in STZ-induced diabetic rats was partially prevented by I, NAR, or I + NAR. NAR or I + NAR completely blocked the decrease in the number of osteocalcin (+) cells in the femur from STZ-induced diabetic rats. RUNX family transcription factor 2 immunostaining was much lower in STZ-induced diabetic rats than in control animals; the combination of I + NAR totally blocked this effect. The combined treatment not only ameliorated bone quality and function, but also normalized the variables related to glucose metabolism. Therefore, the combination of I + NAR might be a better therapeutic strategy than the individual I or NAR administration to reduce bone complications in diabetic patients.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Flavanonas , Humanos , Ratos , Masculino , Animais , Diabetes Mellitus Tipo 1/complicações , Insulina , Ratos Wistar , Diabetes Mellitus Experimental/complicações , Densidade ÓsseaRESUMO
IMPORTANCE: Flavonoids are a group of compounds generally produced by plants with proven biological activity, which have recently beeen recommended for the treatment and prevention of diseases and ailments with diverse causes. In this study, naringenin was produced in adequate amounts in yeast after in silico design. The four genes of the involved enzymes from several organisms (bacteria and plants) were multi-expressed in two vectors carrying each two genes linked by a short viral peptide sequence. The batch kinetic behavior of the product, substrate, and biomass was described at lab scale. The engineered strain might be used in a more affordable and viable bioprocess for industrial naringenin procurement.
Assuntos
Flavanonas , Flavonoides , Flavonoides/metabolismo , Saccharomyces cerevisiae/metabolismo , Flavanonas/metabolismoRESUMO
Understanding the role of 3CLpro protease for SARS-CoV-2 replication and knowing the potential of flavonoid molecules like rutin, myricetin, and baicalein against 3CLpro justify an investigation into their inhibition. This study investigates possible bonds and reactivity descriptors of rutin, myricetin, and baicalein through conformational and electronic properties. Density functional theory was used to determine possible interactions. Analyses were carried out through the molecular electrostatic potential, electron localization function, Fukui function descriptors based on frontier orbitals, and non-covalent interactions. A docking study was performed using a resolution of 1.55 Å for 3CLpro to analyze the interactions of rutin, myricetin, and baicalein. Scores of structures showed that rutin is the best ligand, followed by myricetin and baicalein. Docking studies showed that baicalein and rutin can establish effective interactions with residues of the catalytic dyad (Cys145 and His41), but just rutin forms a hydrogen bond. Myricetin, in turn, could not establish an effective interaction with Cys145. Baicalein interaction arose with active residues such as Arg188, Val186, Gln189, and Gln192. Interactions of rutin and myricetin with Arg188 and Gln189 were also found. A critical interaction was observed only for rutin with the hydroxyls of ring A with His41, and also for Cys145 with rings B and C, which is probably related to the highest score of rutin.