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1.
BMC Complement Med Ther ; 22(1): 10, 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000605

RESUMO

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a pivotal cellular phenomenon involved in tumour metastasis and progression. In gastric cancer (GC), EMT is the main reason for recurrence and metastasis in postoperative patients. Acacetin exhibits various biological activities. However, the inhibitory effect of acacetin on EMT in GC is still unknown. Herein, we explored the possible mechanism of acacetin on EMT in GC in vitro and in vivo. METHODS: In vitro, MKN45 and MGC803 cells were treated with acacetin, after which cell viability was detected by CCK-8 assays, cell migration and invasion were detected by using Transwell and wound healing assays, and protein expression was analysed by western blots and immunofluorescence staining. In vivo, a peritoneal metastasis model of MKN45 GC cells was used to investigate the effects of acacetin. RESULTS: Acacetin inhibited the proliferation, invasion and migration of MKN45 and MGC803 human GC cells by regulating the expression of EMT-related proteins. In TGF-ß1-induced EMT models, acacetin reversed the morphological changes from epithelial to mesenchymal cells, and invasion and migration were limited by regulating EMT. In addition, acacetin suppressed the activation of PI3K/Akt signalling and decreased the phosphorylation levels of TGF-ß1-treated GC cells. The in vivo experiments demonstrated that acacetin delayed the development of peritoneal metastasis of GC in nude mice. Liver metastasis was restricted by altering the expression of EMT-related proteins. CONCLUSION: Our study showed that the invasion, metastasis and TGF-ß1-induced EMT of GC are inhibited by acacetin, and the mechanism may involve the suppression of the PI3K/Akt/Snail signalling pathway. Therefore, acacetin is a potential therapeutic reagent for the treatment of GC patients with recurrence and metastasis.


Assuntos
Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavonas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Flavonas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador beta1
2.
Food Chem ; 369: 130896, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34482239

RESUMO

As a typical representative of polymethoxylated flavones, nobiletin (NOB) is beneficial to health but hard to be processed, stored, and absorbed, due to its hydrophobicity and crystallinity. Herein, we developed a stabilization system based on an efficient manufacturing procedure of NOB nanocrystal by anti-solvent method combined with ultrasonic treatment. Metal-phenolic networks composed of tannic acid and metal ions were introduced to conformally coat on formed nanocrystal for further stabilization. From the results, the size and morphology of the prepared particles could be altered by the amount, ratio, and kind of the coating materials. The optimized samples could be redispersed after centrifugation, and keep stable at 4 ℃ for at least 120 days. Moreover, they possessed higher acid stability and more effective release than the control sample during the in vitro digestion experiment. Therefore, this work provided a promising idea for overcoming storage and delivery obstacle of hydrophobic crystalline bioactive components.


Assuntos
Flavonas , Nanopartículas
3.
Microb Pathog ; 162: 105354, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34896203

RESUMO

Streptococcus suis (S. suis), an important zoonotic pathogenic bacterium, can cause multiple diseases and fatal infections in both humans and animals. The emergence of highly virulent and extensively drug-resistant strains of S. suis has raised questions about the efficacy of available therapeutic agents, thereby necessitating novel therapeutic strategies. Suilysin (SLY) is one of the most essential determinants of virulence for the pathogenicity of S. suis capsular type 2 (SS2). In addition, inhibiting the excessive inflammatory response is a strategy to reduce the damage caused by SS2 infection. In this study, we identified acacetin as an effective inhibitor of SLY, which inhibited the oligomerisation of SLY without affecting bacterial growth. Furthermore, the addition of 4-16 µg/ml acacetin to the co-infection system of the cells reduced S. suis-induced inflammation by downregulating the activation of the MAPK signalling pathway, thereby alleviating the S. suis-mediated cell injury. Thus, in addition to the conventional antibiotic therapy, acacetin represent a potential drug candidate and strategy for the treatment of S. suis infections as it simultaneously inhibited the haemolytic activity of SLY and downregulated the inflammatory response.


Assuntos
Infecções Estreptocócicas , Streptococcus suis , Animais , Flavonas , Proteínas Hemolisinas , Humanos , Inflamação/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Virulência
4.
BMC Plant Biol ; 21(1): 591, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903180

RESUMO

BACKGROUND: Agarwood is a highly sought-after resinous wood for uses in medicine, incense, and perfume production. To overcome challenges associated with agarwood production in Aquilaria sinensis, several artificial agarwood-induction treatments have been developed. However, the effects of these techniques on the metabolome of the treated wood samples are unknown. Therefore, the present study was conducted to evaluate the effects of four treatments: fire drill treatment (F), fire drill + brine treatment (FS), cold drill treatment (D) and cold drill + brine treatment (DS)) on ethanol-extracted oil content and metabolome profiles of treated wood samples from A. sinensis. RESULTS: The ethanol-extracted oil content obtained from the four treatments differed significantly (F < D < DS < FS). A total of 712 metabolites composed mostly of alkaloids, amino acids and derivatives, flavonoids, lipids, phenolic acids, organic acids, nucleotides and derivatives, and terpenoids were detected. In pairwise comparisons, 302, 155, 271 and 363 differentially accumulated metabolites (DAM) were detected in F_vs_FS, D_vs_DS, F_vs_D and FS_vs_DS, respectively. The DAMs were enriched in flavonoid/flavone and flavonol biosynthesis, sesquiterpenoid and triterpenoid biosynthesis. Generally, addition of brine to either fire or cold drill treatments reduced the abundance of most of the metabolites. CONCLUSION: The results from this study offer valuable insights into synthetically-induced agarwood production in A. sinensis.


Assuntos
Metaboloma , Óleos Vegetais/química , Thymelaeaceae/metabolismo , Madeira/metabolismo , Alcaloides/metabolismo , Aminoácidos/metabolismo , Ácidos Carboxílicos/metabolismo , Temperatura Baixa , Etanol , Incêndios , Flavonas/metabolismo , Flavonoides/metabolismo , Hidroxibenzoatos/metabolismo , Metabolismo dos Lipídeos , Nucleotídeos/metabolismo , Sais/farmacologia , Terpenos/metabolismo , Thymelaeaceae/química , Thymelaeaceae/efeitos dos fármacos , Madeira/química , Madeira/efeitos dos fármacos
5.
J Agric Food Chem ; 69(51): 15670-15680, 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34923817

RESUMO

Shellac can be used as an ideal delivery vehicle to deliver and protect the hydrophobic quercetagetin; the barriers such as low acid stability and encapsulation efficiency, however, heavily impede the application of shellac. The purpose of this work is to prepare quercetagetin-loaded shellac-quaternized chitosan nanoparticles (Que-Sh-QCS NPs) to overcome these challenges. Herein, quaternized chitosan, with 14% degree of substitution, was successfully synthesized via a quaternization modification. The concentration of quaternized chitosan over 0.05% can prevent the aggregation of shellac nanoparticles at the acid. The encapsulation efficiency of quercetagetin obviously increased from 37.92 to 65.48% with the concentration of QCS varying from 0 to 0.05%. Meanwhile, Que-Sh-QCS0.05 NPs possessed good storage stability, antioxidant property, biocompatibility, and controlled release. Therefore, quaternized chitosan can improve the encapsulation efficiency and acid and storage stabilities of nutraceutical-loaded shellac nanoparticles, providing a new insight into the application of shellac in cosmetics, pharmaceuticals, and food.


Assuntos
Quitosana , Nanopartículas , Portadores de Fármacos , Flavonas , Tamanho da Partícula , Resinas Vegetais
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(6): 678-682, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34821105

RESUMO

Objective: To evaluate the regulation efficacy of oral tangeretin on testosterone and cortisol in sprinters at winter training season. Methods: Twenty-four sprinters were paired and randomly divided into experimental group (EG) and control group (CG). During winter training season, EG were treated with 200 mg tangeretin by oral, and CG were treated with placebo for 4 weeks. Blood samples were collected on the first day of each week (T1, T2, T3, T4) and after the intervention (T5) to detect serum levels of testosterone, cortisol, superoxide dismutase (SOD), and adrenocorticotropic hormone (ACTH). The body composition was tested at T1 and T5. Results: After 4 weeks, ①the serum cortisol level of CG was increased, and the serum levels of testosterone and SOD were decreased significantly (P<0.05). ②In EG, the serum levels of cortisoland ACTH were decreased significantly (P<0.05, P< 0.01), while the serum testosterone level was remained stable, and the level of SOD was increased slightly. ③The muscle mass of EG and CG were increases, but that of EG was increased higher than that of CG. Conclusion: Tangeretin reduces the oxidative stress response that caused by high-intensity exercise during winter training, which maintain the serum testosterone level and inhibit cortisol excessive secretion and promote muscle synthesis.


Assuntos
Hidrocortisona , Testosterona , Flavonas , Estações do Ano , Proteínas do Soro do Leite
7.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 523-528, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816666

RESUMO

Objective: To investigate the effects of 4-week tangeretin supplementation on cortisol stress response induced by high-intensity resistance exercise. Methods: Twenty-four sprinters were paired and randomly divided into experimental group (EG) and control group (CG). EG orally took supplement with tangeretin (200 mg/day) and CG took placebo for 4 weeks. Before and after the 4-week intervention, all sprinters performed a set of high-intensity resistance exercise (shoulder press, squat, bench press and deadlift, 10 RM, 4 sets per movement) to stimulate their cortisol stress responses. Serum levels of cortisol, adreno-corticotropic hormone (ACTH), superoxide dismutase (SOD), white blood cell count (WBC) and blood glucose were obtained by collecting blood sample before the exercise (PRE), immediately after the exercise (P0), and at 10 (P10), 20 (P20), and 30 minutes (P30) after the exercise. Results: Compared with the same period before the intervention, after the 4-week tangeretin intervention, EXP showed significantly reduced serum cortisol level at PRE (P=0.017), P10 (P=0.010), P20 and P30 (P<0.05 or P<0.01), and significantly reduced WBC at PRE, ACTH at P10 (P=0.037) and WBC and ACTH at P30 (P<0.05). Compared with CTROL, EXP showed significantly lower levels of the serum cortisol at PRE and P10 (P<0.05), and significantly lower levels of the ACTH (P<0.05) and WBC (P<0.01) at P30, and significantly increased level of the SOD activity at P30 (P<0.05). Conclusion: Tangeretin supplementation can significantly alleviate the cortisol stress response induced by high-intensity resistance exercise, inhibit the excessive secretion of cortisol, enhance antioxidant capacity, accelerate the elimination of inflammation in the body, and promote the recovery of body functions.


Assuntos
Flavonas , Treinamento de Força , Exercício Físico , Humanos , Hidrocortisona
8.
Molecules ; 26(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34770969

RESUMO

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.


Assuntos
Proteases 3C de Coronavírus/efeitos dos fármacos , Flavonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/farmacologia , Brassicaceae/metabolismo , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Cromonas/farmacologia , Proteases 3C de Coronavírus/metabolismo , Descoberta de Drogas/métodos , Flavonas/metabolismo , Flavonoides/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/farmacologia , Inibidores de Proteases/química , Quercetina/análogos & derivados , Quercetina/farmacologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Células Vero
9.
PLoS One ; 16(10): e0257478, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34618820

RESUMO

BACKGROUND: Montbretins are rare specialized metabolites found in montbretia (Crocosmia x crocosmiiflora) corms. Montbretin A (MbA) is of particular interest as a novel therapeutic for type-2 diabetes and obesity. There is no scalable production system for this complex acylated flavonol glycoside. MbA biosynthesis has been reconstructed in Nicotiana benthamiana using montbretia genes for the assembly of MbA from its various different building blocks. However, in addition to smaller amounts of MbA, the therapeutically inactive montbretin B (MbB) was the major product of this metabolic engineering effort. MbA and MbB differ in a single hydroxyl group of their acyl side chains, which are derived from caffeoyl-CoA and coumaroyl-CoA, respectively. Biosynthesis of both MbA and MbB also require coumaroyl-CoA for the formation of the myricetin core. Caffeoyl-CoA and coumaroyl-CoA are formed in the central phenylpropanoid pathway by acyl activating enzymes (AAEs) known as 4-coumaroyl-CoA ligases (4CLs). Here we investigated a small family of montbretia AAEs and 4CLs, and their possible contribution to montbretin biosynthesis. RESULTS: Transcriptome analysis for gene expression patterns related to montbretin biosynthesis identified eight different montbretia AAEs belonging to four different clades. Enzyme characterization identified 4CL activity for two clade IV members, Cc4CL1 and Cc4CL2, converting different hydroxycinnamic acids into the corresponding CoA thioesters. Both enzymes preferred coumaric acid over caffeic acid as a substrate in vitro. While expression of montbretia AAEs did not enhance MbA biosynthesis in N. benthamiana, we demonstrated that both Cc4CLs can be used to activate coumaric and caffeic acid towards flavanone biosynthesis in yeast (Saccharomyces cerevisiae). CONCLUSIONS: Montbretia expresses two functional 4CLs, but neither of them is specific for the formation of caffeoyl-CoA. Based on differential expression analysis and phylogeny Cc4CL1 is most likely involved in MbA biosynthesis, while Cc4CL2 may contribute to lignin biosynthesis. Both Cc4CLs can be used for flavanone production to support metabolic engineering of MbA in yeast.


Assuntos
Acil Coenzima A/metabolismo , Flavonas/metabolismo , Hipoglicemiantes/metabolismo , Iridaceae/metabolismo , Ligases/metabolismo , Proteínas de Plantas/metabolismo , Trissacarídeos/metabolismo , Acil Coenzima A/genética , Vias Biossintéticas , Flavonas/genética , Regulação da Expressão Gênica de Plantas , Engenharia Genética , Iridaceae/genética , Ligases/genética , Engenharia Metabólica , Proteínas de Plantas/genética , Tabaco/genética , Tabaco/metabolismo , Trissacarídeos/genética
10.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639236

RESUMO

We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). METHODS: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and were divided in two groups. One group received daily intraperitoneal DHF (5 mg/kg) and another vehicle (1%DMSO in 0.9%NaCl) from one day before IONT until processing. Additional intact rats were employed as control (n = 4). At 1, 3 or 7 days (d) after IONT, phosphorylated (p)AKT, p-MAPK, and non-phosphorylated AKT and MAPK expression levels were analyzed in the retina by Western blotting (n = 4/group). Radial sections were also immunodetected for the above-mentioned proteins, and for Brn3a and vimentin to identify RGCs and Müller cells (MCs), respectively (n = 3/group). RESULTS: IONT induced increased levels of p-MAPK and MAPK at 3d in DHF- or vehicle-treated retinas and at 7d in DHF-treated retinas. IONT induced a fast decrease in AKT in retinas treated with DHF or vehicle, with higher levels of phosphorylation in DHF-treated retinas at 7d. In intact retinas and vehicle-treated groups, no p-MAPK or MAPK expression in RGCs was observed. In DHF- treated retinas p-MAPK and MAPK were expressed in the ganglion cell layer and in the RGC nuclei 3 and 7d after IONT. AKT was observed in intact and axotomized RGCs, but the signal intensity of p-AKT was stronger in DHF-treated retinas. Finally, MCs expressed higher quantities of both MAPK and AKT at 3d in both DHF- and vehicle-treated retinas, and at 7d the phosphorylation of p-MAPK was higher in DHF-treated groups. CONCLUSIONS: Phosphorylation and increased levels of AKT and MAPK through MCs and RGCs in retinas after DHF-treatment may be responsible for the increased and long-lasting RGC protection afforded by DHF after IONT.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Axotomia , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Regulação da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/genética , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/metabolismo
11.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638940

RESUMO

Several phytochemical-containing herbal extracts are increasingly marketed as health-promoting products. In particular, chamomile (Matricaria recutita L.) is well known for its anti-inflammatory, analgesic, and antitumor properties. Here, we evaluated differences in chemical composition among six commercially available products and their potential impact on biological activity in human immortalized colonocytes. Our investigation encompassed: (i) preparation of dry extracts and yield evaluation; (ii) qualitative and quantitative analysis of phenol content; (iii) modulation of redox state; and (iv) bioavailability of main bioactive compounds. We demonstrated that apparently identical products showed huge heterogeneity, in terms of yield extraction, chemical composition, and antioxidant effects. All samples contained high amounts of flavonoids and cinnamic acid derivatives, but differentially concentrated in the six extracts. Depending on polyphenol content, chamomile samples possessed variable antioxidant potential, in terms of decreased radical generation and increased reduced glutathione levels. The observed effects might be ascribed to flavones (apigenin, luteolin, and their glycones) highly represented in the six extracts. Nonetheless, chamomile extracts exerted cytotoxic effects at high concentrations, suggesting that a herbal medicine is not always safe. In conclusion, due to the complexity and variability of plant matrices, studies evaluating effectiveness of chamomile should always be accompanied by preliminary characterization of phytochemical composition.


Assuntos
Antioxidantes/química , Camomila/química , Matricaria/química , Compostos Fitoquímicos/química , Extratos Vegetais/química , Plantas Medicinais/química , Polifenóis/análise , Antioxidantes/farmacologia , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/análise , Flavonas/análise , Flavonoides/análise , Humanos , Oxirredução/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Nutrients ; 13(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34684383

RESUMO

Rapid postprandial blood glucose elevation can cause lifestyle-related diseases, such as type II diabetes. The absorption of food-derived glucose is primarily mediated by sodium/glucose cotransporter 1 (SGLT1). Moderate SGLT1 inhibition can help attenuate postprandial blood glucose elevation and prevent lifestyle-related diseases. In this study, we established a CHO cell line stably expressing human SGLT1 and examined the effects of phytochemicals on SGLT1 activity. Among the 50 phytochemicals assessed, tangeretin and cardamonin inhibited SGLT1 activity. Tangeretin and cardamonin did not affect the uptake of L-leucine, L-glutamate, and glycyl-sarcosine. Tangeretin, but not cardamonin, inhibited fructose uptake, suggesting that the inhibitory effect of tangeretin was specific to the monosaccharide transporter, whereas that of cardamonin was specific to SGLT1. Kinetic analysis suggested that the suppression of SGLT1 activity by tangeretin was associated with a reduction in Vmax and an increase in Km, whereas suppression by cardamonin was associated with a reduction in Vmax and no change in Km. Oral glucose tolerance tests in mice showed that tangeretin and cardamonin significantly suppressed the rapid increase in blood glucose levels. In conclusion, tangeretin and cardamonin were shown to inhibit SGLT1 activity in vitro and lower blood glucose level in vivo.


Assuntos
Glicemia/metabolismo , Chalconas/farmacologia , Flavonas/farmacologia , Intestinos/fisiologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Administração Oral , Aminoácidos/metabolismo , Animais , Células CHO , Células CACO-2 , Chalconas/química , Cricetulus , Flavonas/química , Frutose/metabolismo , Humanos , Cinética , Camundongos Endogâmicos ICR , Compostos Fitoquímicos/farmacologia , Sarcosina/metabolismo , Sódio/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo
13.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684783

RESUMO

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the formation and growth of human cancer. Therefore, STAT3 is a therapeutic target for cancer drug discovery. Acacetin, a flavone present in various plants, inhibits constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. Acacetin inhibits STAT3 activity by directly binding to STAT3, which we confirmed by a pull-down assay with a biotinylated compound and two level-free methods, namely, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). Acacetin inhibits STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation in DU145 cells, which leads to the downregulation of STAT3 target genes. Acacetin then induces apoptosis in a time-dependent manner. Interestingly, acacetin induces the production of reactive oxygen species (ROS) that are not involved in the acacetin-induced inhibition of STAT3 activation because the suppressed p-STAT3 level is not rescued by treatment with GSH or NAC, which are general ROS inhibitors. We also found that acacetin inhibits tumor growth in xenografted nude mice. These results suggest that acacetin, as a STAT3 inhibitor, could be a possible drug candidate for targeting STAT3 for the treatment of cancer in humans.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/patologia , Ligação Proteica , Proteínas Tirosina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Molecules ; 26(20)2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34684855

RESUMO

Vitexin is a C-glucoside flavone that exhibits a wide range of pharmaceutical activities. However, the poor solubility of vitexin limits its applications. To resolve this limitation, two glycoside hydrolases (GHs) and four glycosyltransferases (GTs) were assayed for glycosylation activity toward vitexin. The results showed that BtGT_16345 from the Bacillus thuringiensis GA A07 strain possessed the highest glycosylation activity, catalyzing the conversion of vitexin into new compounds, vitexin-4'-O-ß-glucoside (1) and vitexin-5-O-ß-glucoside (2), which showed greater aqueous solubility than vitexin. To our knowledge, this is the first report of vitexin glycosylation. Based on the multiple bioactivities of vitexin, the two highly soluble vitexin derivatives might have high potential for pharmacological usage in the future.


Assuntos
Apigenina/metabolismo , Glucosídeos/metabolismo , Bacillus thuringiensis/metabolismo , Catálise , Flavonas/metabolismo , Glicosilação , Glicosiltransferases/metabolismo , Isoflavonas/metabolismo , Solubilidade
15.
J Agric Food Chem ; 69(43): 12705-12716, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34699208

RESUMO

Polymethoxyflavones (PMFs) are a subgroup of flavonoids possessing various health benefits. 3,5,7,4'-Tetramethoxyflavone (1), 5,6,7,4'-tetramethylflavone (2), 3,7,3',4'-tetramethoxyflavone (3), 5,7,3',4'-tetramethoxyflavone (4), 5-hydroxy-3,7,2',4'-tetramethoxyflavone (5), 3,5,7,2',4'-pentamethoxyflavone (6), 5-hydroxy-3,7,3',4'-tetramethoxyflavone (7), 3-hydroxy-5,7,3',4'-tetramethylflavone (8), 3,5,7,3',4'-pentamethoxyflavone (9), 5-hydroxy-3,7,3',4',5'-pentamethoxyflavone (10), 3-hydroxy-5,7,3',4',5'-pentamethoxyflavone (11), and 3,5,7,3',4',5'-hexamethoxylflavone (12) were 12 bioactive and available PMFs. The aim of this study was to investigate the pharmacokinetic, metabolite, and antitumor activities as well as the structure-pharmacokinetic-antitumor activity relationships of these 12 PMFs to facilitate further studies of their medicinal potentials. The cytotoxicity of PMFs with a hydroxy group toward HeLa, A549, HepG2, and HCT116 cancer cell lines was generally significantly more potent than that of PMFs without a hydroxy group. Compounds 5, 7, 8, 10, and 11 were all undetectable in rat plasma, while compounds 1-4, 6, 9, and 12 were detectable. Both the number and position of hydroxy and methoxy groups played an important role in modulating PMF pharmacokinetics and metabolites.


Assuntos
Flavonas , Células A549 , Animais , Flavonas/farmacocinética , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Ratos , Relação Estrutura-Atividade
16.
Phytother Res ; 35(11): 6063-6079, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34679214

RESUMO

Polyphenols are a group of diverse chemical compounds present in a wide range of plants. Various biological properties such as antiallergic, antiviral, antibacterial, anticarcinogenic, antiinflammatory, antithrombotic, vasodilatory, and hepatoprotective effect of different polyphenols have been reported in the scientific literature. The major classes of polyphenols are flavonoids, stilbenoids, lignans, and polyphenolic acids. Flavonoids are a large class of food constituents comprising flavones, isoflavanones, flavanones, flavonols, catechins, and anthocyanins sub-classes. Even with seemingly broad biological activities, their use is minimal clinically. Among the other concurrent problems such as limited bioavailability, rapid metabolism, untargeted delivery, the toxicity associated with these polyphenols has been a topic of concern lately. These polyphenols have been reported to result in different forms of toxicity that include organ toxicity, genotoxicity, mutagenicity, cytotoxicity, etc. In the present article, we have tried to unravel the toxicological aspect of these polyphenols to healthy cells. Further high-quality studies are needed to establish the clinical efficacy and toxicology concern leading to further exploration of these polyphenols.


Assuntos
Antineoplásicos , Flavonas , Antocianinas , Flavonoides/toxicidade , Polifenóis/toxicidade
17.
Int J Mol Sci ; 22(17)2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34502526

RESUMO

Methylated flavonoids are promising pharmaceutical agents due to their improved metabolic stability and increased activity compared to unmethylated forms. The biotransformation in cultures of entomopathogenic filamentous fungi is a valuable method to obtain glycosylated flavones and flavanones with increased aqueous solubility and bioavailability. In the present study, we combined chemical synthesis and biotransformation to obtain methylated and glycosylated flavonoid derivatives. In the first step, we synthesized 2'-methylflavanone and 2'-methylflavone. Afterwards, both compounds were biotransformed in the cultures of two strains of entomopathogenic filamentous fungi Beauveria bassiana KCH J1.5 and Isaria fumosorosea KCH J2. We determined the structures of biotransformation products based on NMR spectroscopy. Biotransformations of 2'-methyflavanone in the culture of B. bassiana KCH J1.5 resulted in three glycosylated flavanones: 2'-methylflavanone 6-O-ß-d-(4″-O-methyl)-glucopyranoside, 3'-hydroxy-2'-methylflavanone 6-O-ß-d-(4″-O-methyl)-glucopyranoside, and 2-(2'-methylphenyl)-chromane 4-O-ß-d-(4″-O-methyl)-glucopyranoside, whereas in the culture of I. fumosorosea KCH J2, two other products were obtained: 2'-methylflavanone 3'-O-ß-d-(4″-O-methyl)-glucopyranoside and 2-methylbenzoic acid 4-O-ß-d-(4'-O-methyl)-glucopyranoside. 2'-Methylflavone was effectively biotransformed only by I. fumosorosea KCH J2 into three derivatives: 2'-methylflavone 3'-O-ß-d-(4″-O-methyl)-glucopyranoside, 2'-methylflavone 4'-O-ß-d-(4″-O-methyl)-glucopyranoside, and 2'-methylflavone 5'-O-ß-d-(4″-O-methyl)-glucopyranoside. All obtained glycosylated flavonoids have not been described in the literature until now and need further research on their biological activity and pharmacological efficacy as potential drugs.


Assuntos
Beauveria/metabolismo , Cordyceps/metabolismo , Flavanonas/metabolismo , Flavonas/metabolismo , Biotransformação
18.
J Environ Pathol Toxicol Oncol ; 40(3): 63-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587405

RESUMO

Allergic rhinitis (AR) is a common type of inflammatory disease with symptoms including rhinorrhea, fatigue, sneezing, and disturbed sleep. AR affects nearly 40% of peoples worldwide with the increased numbers of new cases. In this work, the study was conducted to disclose the anti-inflammatory and antiallergic properties of cirsilineol against the ovalbumin (OVA)-sensitized AR in mice. AR was provoked in BALB/c mice through the OVA challenge 30 days along with 10 and 20 mg/kg of cirsilineol treatment. The nasal symptoms, i.e., rubbing and sneezing was monitored after the final OVA challenge. The status of OVA-specific IgE, PGD2, and LTC4 was investigated using assay kits. The status of pro-inflammatory markers also examined using assay kits. The levels of oxidative markers, SOD activity, and pro-inflammatory markers in the spleen mononuclear cells (SMEs) were studied by using respective assay kits. The mRNA expression of TXNIP was assessed using RT-PCR study. The 10 and 20 mg/kg of cirsilineol treatment effectively decreased the sneezing and nasal rubbings in OVA-provoked mice. Cirsilineol also decreased the IgE, PGD2, and LTC4 status in the AR animals. The status of pro-inflammatory markers, i.e., IL-4, IL-5, IL-6, IL-33 and TNF-α was found to be decreased in the cirsilineol administered AR mice. Cirsilineol effectively reduced the ROS and MDA and improved SOD in the OVA-challenged SMCs. The mRNA expression of TXNIP was appreciably suppressed by the cirsilineol treatment. Altogether, these findings proved the beneficial actions of cirsilineol against the OVA-triggered AR in mice. The additional studies on the cirsilineol could lead to the development of new drug for AR management.


Assuntos
Antialérgicos/farmacologia , Flavonas/farmacologia , Rinite Alérgica/prevenção & controle , Animais , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Histamina/sangue , Imunoglobulina E/sangue , Imunoglobulina E/metabolismo , Leucotrieno C4/metabolismo , Camundongos Endogâmicos BALB C , Líquido da Lavagem Nasal , Ovalbumina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Prostaglandina D2/metabolismo , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Baço/citologia , Tiorredoxinas/genética
19.
Int J Mol Sci ; 22(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576006

RESUMO

Tumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinase-2 (JAK2) and signal transduction, thus activating transcription 3 (STAT3) to results in the regulation of PD-L1 expression. Chemotherapy with commercially available drugs against NSCLC has struggled in the prospect of adverse effects. Nobiletin is a natural flavonoid isolated from the citrus peel that exhibits anti-cancer activity. Here, we demonstrated the role of nobiletin in evasion of immunosuppression in NSCLC cells by Western blotting and real-time polymerase chain reaction methods for molecular signaling analysis supported by gene silencing and specific inhibitors. From the results, we found that nobiletin inhibited PD-L1 expression through EGFR/JAK2/STAT3 signaling. We also demonstrated that nobiletin exhibited p53-independent PD-L1 suppression, and that miR-197 regulates the expression of STAT3 and PD-L1, thereby enhancing anti-tumor immunity. Further, we evaluated the combination ability of nobiletin with an anti-PD-1 monoclonal antibody in NSCLC co-culture with peripheral blood mononuclear cells. Similarly, we found that nobiletin assisted the induction of PD-1/PD-L1 blockade, which is a key factor for the immune escape mechanism. Altogether, we propose nobiletin as a modulator of tumor microenvironment for cancer immunotherapy.


Assuntos
Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Flavonas/farmacologia , Neoplasias Pulmonares/imunologia , MicroRNAs/imunologia , Proteínas de Neoplasias/imunologia , RNA Neoplásico/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Transdução de Sinais/imunologia
20.
Int J Mol Sci ; 22(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34576019

RESUMO

The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bioinformatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the -250 and -121 positions that responded to tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Flavonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Proteínas Semelhantes a Angiopoietina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/tratamento farmacológico , Flavonas/uso terapêutico , Células Hep G2 , Humanos , Lipase/metabolismo
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