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1.
Chem Biol Drug Des ; 103(6): e14564, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845574

RESUMO

The leaves of Araucaria cunninghamii are known to be nonedible and toxic. Previous studies have identified biflavones in various Araucaria species. This study aimed to investigate the in vitro cytotoxicity of the isolated compounds from Araucaria cunninghamii after metabolomics and network pharmacological analysis. Methanol extract of Araucaria cunninghamii leaves was subjected to bioassay-guided fractionation. The active fraction was analyzed using LC-HRMS, through strategic database mining, by comparing the data to the Dictionary of Natural Products to identify 12 biflavones, along with abietic acid, beta-sitosterol, and phthalate. Eight compounds were screened for network pharmacology study, where in silico ADME analysis, prediction of gene targets, compound-gene-pathway network and hierarchical network analysis, protein-protein interaction, KEGG pathway, and Gene Ontology analyses were done, that showed PI3KR1, EGFR, GSK3B, and ABCB1 as the common targets for all the compounds that may act in the gastric cancer pathway. Simultaneously, four biflavones were isolated via chromatography and identified through NMR as dimeric apigenin with varying methoxy substitutions. Cytotoxicity study against the AGS cell line for gastric cancer showed that AC1 biflavone (IC50 90.58 µM) exhibits the highest cytotoxicity and monomeric apigenin (IC50 174.5 µM) the lowest. Besides, the biflavones were docked to the previously identified targets to analyze their binding affinities, and all the ligands were found to bind with energy ≤-7 Kcal/mol.


Assuntos
Mineração de Dados , Metabolômica , Simulação de Acoplamento Molecular , Humanos , Linhagem Celular Tumoral , Folhas de Planta/química , Folhas de Planta/metabolismo , Farmacologia em Rede , Biflavonoides/química , Biflavonoides/farmacologia , Biflavonoides/metabolismo , Biflavonoides/isolamento & purificação , Traqueófitas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Cromatografia Líquida , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Espectrometria de Massas
2.
Food Res Int ; 188: 114508, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823847

RESUMO

Procyanidins, which are oligomerized flavan-3-ols with a polyphenolic structure, are bioactive substances that exhibit various biological effects. However, the relationship between the degree of polymerization (DP) of procyanidins and their bioactivities remains largely unknown. In this study, the preventive effects of procyanidins with different DP (EC, PB2 and PC1) on glucose improvement and liver lipid deposition were investigated using a high-fat diet/streptozotocin-induced diabetes mouse model. The results demonstrated that all the procyanidins with different DP effectively reduced fasting blood glucose and glucose/insulin tolerance, decreased the lipid profile (total cholesterol, triglyceride, and low-density lipoprotein cholesterol content) in serum and liver tissue as well as the liver oil red staining, indicating the improvement of glucose metabolism, insulin sensitivity and hepatic lipid deposition in diabetic mice. Furthermore, the procyanidins down-regulated expression of glucose regulated 78-kDa protein (GRP78) and C/EBP homologous protein (CHOP), indicating a regulation role of endoplasmic reticulum (ER) stress. The inhibition of ER stress by tauroursodeoxycholic acid (TUDCA) treatment abolished the effects of procyanidins with different DP in PA-induced HepG2 cells, confirming that procyanidins alleviate liver hyperlipidemia through the modulation of ER stress. Molecular docking results showed that EC and PB2 could better bind GRP78 and CHOP. Collectively, our study reveals that the structure of procyanidins, particularly DP, is not directly correlated with the improvement of blood glucose and lipid deposition, while highlighting the important role of ER stress in the bioactivities of procyanidins.


Assuntos
Glicemia , Diabetes Mellitus Experimental , Dieta Hiperlipídica , Chaperona BiP do Retículo Endoplasmático , Metabolismo dos Lipídeos , Fígado , Proantocianidinas , Animais , Proantocianidinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Células Hep G2 , Humanos , Polimerização , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Simulação de Acoplamento Molecular , Biflavonoides/farmacologia , Camundongos Endogâmicos C57BL , Estreptozocina , Resistência à Insulina , Catequina/farmacologia
3.
J Cell Mol Med ; 28(11): e18442, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38842135

RESUMO

Epithelial-mesenchymal transition (EMT) and its reversal process are important potential mechanisms in the development of HCC. Selaginella doederleinii Hieron is widely used in Traditional Chinese Medicine for the treatment of various tumours and Amentoflavone is its main active ingredient. This study investigates the mechanism of action of Amentoflavone on EMT in hepatocellular carcinoma from the perspective of bioinformatics and network pharmacology. Bioinformatics was used to screen Amentoflavone-regulated EMT genes that are closely related to the prognosis of HCC, and a molecular prediction model was established to assess the prognosis of HCC. The network pharmacology was used to predict the pathway axis regulated by Amentoflavone. Molecular docking of Amentoflavone with corresponding targets was performed. Detection and evaluation of the effects of Amentoflavone on cell proliferation, migration, invasion and apoptosis by CCK-8 kit, wound healing assay, Transwell assay and annexin V-FITC/propidium iodide staining. Eventually three core genes were screened, inculding NR1I2, CDK1 and CHEK1. A total of 590 GO enrichment entries were obtained, and five enrichment results were obtained by KEGG pathway analysis. Genes were mainly enriched in the p53 signalling pathway. The outcomes derived from both the wound healing assay and Transwell assay demonstrated significant inhibition of migration and invasion in HCC cells upon exposure to different concentrations of Amentoflavone. The results of Annexin V-FITC/PI staining assay showed that different concentrations of Amentoflavone induces apoptosis in HCC cells. This study revealed that the mechanism of Amentoflavone reverses EMT in hepatocellular carcinoma, possibly by inhibiting the expression of core genes and blocking the p53 signalling pathway axis to inhibit the migration and invasion of HCC cells.


Assuntos
Apoptose , Biflavonoides , Carcinoma Hepatocelular , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Transdução de Sinais , Proteína Supressora de Tumor p53 , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Biflavonoides/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Transdução de Sinais/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Biologia Computacional/métodos
4.
J Ethnopharmacol ; 331: 118284, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38735420

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaf and seed have been traditionally used in ancient China for the treatment of cough and asthma. However, there is limited literature available on the anti-COPD effects and mechanisms of Ginkgo biloba. AIMS OF THE STUDY: The aim of this study was to comprehensively investigate the therapeutic potential of ginkgo extracts in COPD through a combination of in vivo and in vitro functional experiments. Transcriptomic analyses were also employed to uncover novel molecular mechanisms underlying the therapeutic effects of ginkgetin in COPD. MATERIALS AND METHODS: The therapeutic efficacy of ginkgo extracts was assessed in a COPD model. The anti-inflammatory effects of ginkgetin and its underlying molecular mechanisms were examined in A549 cells treated with cigarette smoke extract (CSE). Additionally, transcriptomic analyses were conducted to identify novel molecular pathways influenced by ginkgetin. These findings were further validated using quantitative real-time polymerase chain reaction (qPCR) and Western blot techniques. RESULTS: The ethyl acetate extract of Ginkgo biloba L. seeds and ginkgetin treatment significantly reduced cytokine production in COPD mice. Following drug administration, lung function improved in different groups. The transcriptome data strongly supports the inhibitory effect of ginkgetin on CSE-induced inflammation through the downregulation of the c/EBPß signaling pathway and subsequent inhibition of CCL2 expression. CONCLUSION: Our results demonstrate that ginkgetin, one of the biflavones found in Ginkgo biloba, exhibits inhibitory effects on smoke-induced airway inflammation. This effect is achieved through the downregulation of the c/EBPß signaling pathway and the reduction of CCL2 expression.


Assuntos
Biflavonoides , Quimiocina CCL2 , Regulação para Baixo , Ginkgo biloba , Doença Pulmonar Obstrutiva Crônica , Transdução de Sinais , Animais , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Humanos , Transdução de Sinais/efeitos dos fármacos , Ginkgo biloba/química , Regulação para Baixo/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Camundongos , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fumaça/efeitos adversos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células A549 , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Extrato de Ginkgo
5.
Appl Microbiol Biotechnol ; 108(1): 322, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713216

RESUMO

Schisandra henryi is an endemic species of medicinal potential known from traditional Chinese medicine. As part of this study, a complex biotechnological and phytochemical assessment was conducted on S. henryi with a focus on phenolic compounds and antioxidant profiling. The following in vitro cultures were tested: microshoot agar and callus, microshoot agitated, and suspension, along with the microshoot culture in PlantForm bioreactors. Qualitative profiling was performed by ultra-high-performance liquid chromatography with a photodiode array detector coupled with ion-trap mass spectrophotometry with electrospray ionization and then quantitative analysis by high-performance liquid chromatography with a diode array detector using standards. In the extracts, mainly the compounds from procyanidins were identified as well as phenolic acids (neochlorogenic acid, caffeic acid, protocatechuic acid) and catechin. The highest content of phenolic compounds was found for in vitro agar microshoot culture (max. total content 229.87 mg/100 g DW) and agitated culture (max. total content 22.82 mg/100 g DW). The max. TPC measured using the Folin-Ciocalteu assay was equal to 1240.51 mg GAE/100 g DW (agar microshoot culture). The extracts were evaluated for their antioxidant potential by the DPPH, FRAP, and chelate iron ion assays. The highest potential was indicated for agar microshoot culture (90% of inhibition and 59.31 nM/L TEAC, respectively). The research conducted on the polyphenol profiling and antioxidant potential of S. henryi in vitro culture extracts indicates the high therapeutic potential of this species. KEY POINTS: • Different types of S. henryi in vitro cultures were compared for the first time. • The S. henryi in vitro culture strong antioxidant potential was determined for the first time. • The polyphenol profiling of different types of S. henryi in vitro cultures was shown.


Assuntos
Antioxidantes , Biflavonoides , Fenóis , Extratos Vegetais , Schisandra , Antioxidantes/farmacologia , Antioxidantes/química , Fenóis/análise , Fenóis/química , Cromatografia Líquida de Alta Pressão , Schisandra/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Proantocianidinas/análise , Hidroxibenzoatos/análise , Hidroxibenzoatos/química , Catequina/química , Catequina/análise , Catequina/metabolismo , Catequina/farmacologia , Reatores Biológicos
6.
J Food Sci ; 89(6): 3554-3568, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38660920

RESUMO

Lotus rhizome is an important aquatic vegetable, but the blackening of lotus rhizome epidermis (LRE) seriously affects its appearance and quality, which makes lotus rhizome products unmarketable. In this study, the effects of polyphenols and iron on the LRE color were studied to explore the possible mechanism of LRE blackening. Results indicated that the measurable total phenols contents in the mud treatment (MT) group were significantly reduced, and the total iron contents were significantly increased compared with the bruised treatment group (p < 0.05). The high-performance liquid chromatography results showed that the main polyphenols in LRE were dopa, gallocatechin, and catechin, as well as a small amount of catechol, epicatechin, proanthocyanidin B2, and proanthocyanidin C1. Moreover, the results of color difference and ultraviolet adsorption spectroscopy showed that there were obviously black or brown-gray of dopa (525 nm), gallocatechin (504.5 nm), and catechin (550 and 504.5 nm) with FeCl2. The simulated system treatment of LRE further confirmed that the chromaticity effect of dopa and iron in bruised LRE was similar to that of the MT group, whereas 1% (w/w) ascorbic acid, 2% (w/w) EDTA-2Na, or 3% (w/w) citric acid could solely prohibit the blackening. This suggested that the dopa in LRE and FeCl2 in mud may mainly combine into [2(DOPA-2H+)+Fe3+]- through non-covalent interaction, which leads to the blackening of bruised LRE under neutral conditions. These results can guide the storage of lotus rhizomes and improve the development of the lotus rhizome industry.


Assuntos
Catequina , Cor , Ferro , Lotus , Polifenóis , Rizoma , Rizoma/química , Polifenóis/farmacologia , Polifenóis/análise , Ferro/análise , Catequina/farmacologia , Catequina/análise , Lotus/química , Cromatografia Líquida de Alta Pressão , Epiderme Vegetal/química , Proantocianidinas/farmacologia , Proantocianidinas/análise , Catecóis/farmacologia , Di-Hidroxifenilalanina/química , Biflavonoides
7.
J Nutr Sci Vitaminol (Tokyo) ; 70(2): 164-173, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38684387

RESUMO

Bitterness and astringency are the aversive tastes in mammals. In humans, aversion to bitterness and astringency may be reduced depending on the eating experience. However, the cellular and molecular mechanisms underlying plasticity in preference to bitter and astringent tastants remain unknown. This study aimed to investigate the preference plasticity to bitter and astringent tea polyphenols, including catechins and tannic acids, in the model animal Caenorhabditis elegans. C. elegans showed avoidance behavior against epigallocatechin gallate (EGCG), tannic acid, and theaflavin. However, they displayed diminishing avoidance against EGCG depending on their EGCG-feeding regime at larval stages. Additionally, the behavioral plasticity in avoiding EGCG required the transcription factor DAF-16/FOXO. Isoform-specific deletion mutant analysis and cell-specific rescue analysis revealed that the function of daf-16 isoform b in AIY interneurons is necessary for experience-dependent behavioral plasticity to EGCG.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Catequina , Fatores de Transcrição Forkhead , Interneurônios , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/metabolismo , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Aprendizagem da Esquiva/efeitos dos fármacos , Biflavonoides/farmacologia , Paladar/efeitos dos fármacos , Chá/química , Comportamento Animal/efeitos dos fármacos , Larva/efeitos dos fármacos
8.
Int J Biol Macromol ; 268(Pt 1): 131739, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38657920

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disease with high prevalence, long duration and poor prognosis. The blood-brain barrier (BBB) is a physiologic barrier in the central nervous system, which hinders the entry of most drugs into the brain from the blood, thus affecting the efficacy of drugs for AD. Natural products are recognized as one of the promising and unique therapeutic approaches to treat AD. To improve the efficiency and therapeutic effect of the drug across the BBB, a natural polyphenolic compound, procyanidin C-1 (C1) was encapsulated in glucose-functionalized bovine serum albumin (BSA) nanoparticles to construct Glu-BSA/C1 NPs in our study. Glu-BSA/C1 NPs exhibited good stability, slow release, biocompatibility and antioxidant properties. In addition, Glu-BSA/C1 NPs penetrated the BBB, accumulated in the brain by targeting Glut1, and maintained the BBB integrity both in vitro and in vivo. Moreover, Glu-BSA/C1 NPs alleviated memory impairment of 5 × FAD mice by reducing Aß deposition and Tau phosphorylation and promoting neurogenesis. Mechanistically, Glu-BSA/C1 NPs significantly activated the PI3K/AKT pathway and inhibited the NLRP3/Caspase-1/IL-1ß pathway thereby suppressing neuroinflammation. Taken together, Glu-BSA/C1 NPs could penetrate the BBB and mitigate neuroinflammation in AD, which provides a new therapeutic approach targeting AD.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Modelos Animais de Doenças , Glucose , Nanopartículas , Soroalbumina Bovina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Animais , Soroalbumina Bovina/química , Camundongos , Glucose/metabolismo , Nanopartículas/química , Proantocianidinas/farmacologia , Proantocianidinas/química , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Biflavonoides/farmacologia , Biflavonoides/química , Catequina/farmacologia , Catequina/química , Catequina/análogos & derivados , Humanos , Masculino
9.
Food Chem ; 450: 139285, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38631203

RESUMO

Theaflavins are beneficial to human health due to various bioactivities. Biosynthesis of theaflavins using polyphenol oxidase (PPO) is advantageous due to cost effectiveness and environmental friendliness. In this review, studies on the mechanism of theaflavins formation, the procedures to screen and prepare PPOs, optimization of reaction systems and immobilization of PPOs were described. The challenges associated with the mass biosynthesis of theaflavins, such as poor enzyme activity, undesirable subproducts and inclusion bodies of recombinant PPOs were presented. Further strategies to solve these challenges and improve theaflavins production, including enzyme engineering, immobilization enzyme technology, water-immiscible solvent-water biphasic systems and recombinant enzyme technology, were proposed.


Assuntos
Biflavonoides , Catequina , Catecol Oxidase , Biflavonoides/química , Biflavonoides/metabolismo , Biocatálise , Catequina/química , Catequina/metabolismo , Catecol Oxidase/metabolismo , Catecol Oxidase/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo
10.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473794

RESUMO

MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the ß-amyloid peptide (Aß, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that ß-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-ß, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aß, as well as inflammatory cytokines IL1-ß, IL-6, and NOS2. In cells stimulated with Aß, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD.


Assuntos
Doença de Alzheimer , Biflavonoides , MicroRNAs , Humanos , Biflavonoides/farmacologia , Microglia/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Citocinas/metabolismo , MicroRNAs/genética , Fator de Transcrição STAT3/metabolismo
11.
J Cell Mol Med ; 28(7): e18177, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38494843

RESUMO

Atherosclerosis, a chronic inflammatory disease of aorta, remains the major cause of morbidity and mortality among cardiovascular disease patients. Macrophage foam cell formation and inflammation are critically involved in early stages of atherosclerosis, hence chemopreventive targeting of foam cell formation by nutraceuticals may be a promising approach to curbing the progression of atherosclerosis. However, many nutraceuticals including berberine and ginkgetin have low stability, tissue/cell penetration and bioavailability resulting in inadequate chemotherapeutic effects of these nutraceuticals. We have used avocado-derived extracellular vesicles (EV) isolated from avocado (EVAvo ) as a novel carrier of nutraceuticals, in a strategy to alleviate the build-up of macrophage foam cells and expression of inflammatory genes. Our key findings are: (i) Avocado is a natural source of plant-derived EVs as shown by the results from transmission electron microscopy, dynamic light scattering and NanoBrook Omni analysis and atomic force microscopy; (ii) EVAvo are taken up by macrophages, a critical cell type in atherosclerosis; (iii) EVAvo can be loaded with high amounts of ginkgetin and berberine; (iv) ginkgetin plus berberine-loaded EVAvo (EVAvo(B+G) ) suppress activation of NFκB and NLRP3, and inhibit expression of pro-inflammatory and atherogenic genes, specifically Cd36, Tnfα, Il1ß and Il6; (v) EVAvo(B+G) attenuate oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation and (vi) EVAvo(B+G) inhibit oxLDL uptake but not its cell surface binding during foam cell formation. Overall, our results suggest that using EVAvo as a natural carrier of nutraceuticals may improve strategies to curb the progression of atherosclerosis by limiting inflammation and pro-atherogenic responses.


Assuntos
Aterosclerose , Berberina , Biflavonoides , Persea , Humanos , Células Espumosas , Berberina/farmacologia , Macrófagos , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Lipoproteínas LDL
12.
Food Funct ; 15(6): 3130-3140, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38436057

RESUMO

Nitrite widely exists in meat products, and has the functions of bacteriostasis, antisepsis, and color development. However, in an acidic environment, nitrite will react with amines, and further generate nitrosamines with carcinogenic and teratogenic effects. Polyphenols have good antioxidant and nitrite-scavenging effects. This study aimed to evaluate the inhibitory effects of gallic acid, catechin, and procyanidin B2 on the nitrosation reaction under stomach simulating conditions and discuss the potential inhibitory mechanism. The nitrite scavenging rate and nitrosamine synthesis blocking rate of gallic acid, catechin, and procyanidin B2 under different reaction times and contents was determined by UV-vis spectrophotometry. The possible products of the reaction of the three polyphenols with nitrite were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) to reveal the mechanism of inhibiting nitrification. The results showed that the scavenging rate of the three polyphenols on nitrite and the blocking rate of nitrosamine synthesis increased with the increase of the content and reaction time. The ability of the three polyphenols to inhibit nitrosation was catechin > procyanidin B2 > gallic acid. HPLC-MS analysis showed that under simulated gastric juice conditions, the three phenolics were oxidized by nitrous acid to form their semiquinone radicals as the intermediates and nitrosated derivatives, while nitrite might be converted to ˙NO. These results suggested that gallic acid, catechin, and procyanidin B2 could inhibit nitrosation reactions in an acidic environment and may be used as food additives to reduce nitrite residues and nitrosamines in food.


Assuntos
Biflavonoides , Catequina , Nitrosaminas , Proantocianidinas , Ácido Gálico/farmacologia , Nitritos , Nitrosação , Polifenóis , Estômago
13.
J Ethnopharmacol ; 327: 117997, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442805

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yataprasen is a topical Thai herbal remedy for the treatment of musculoskeletal pain and is included in Kumpe Thart Phra Narai, the first Thai textbook of traditional medicine. The herbal preparation is made from a hydroethanolic extract of a mixture of 13 medicinal plants, of which Putranjiva roxburghii Wall. leaves are the major ingredient. AIM OF THE STUDY: In this study, we investigated the underlying mechanism of action for the anti-inflammatory effects of the Yataprasen remedy, its main ingredients, and the phytochemicals isolated from P. roxburghii leaves. MATERIALS AND METHODS: The anti-inflammatory effects of the Yataprasen remedy, along with its main ingredients, including the leaves of Baliospermum solanifolium (Burm.) Suresh, Melia azedarach L., P. roxburghii, Senna siamea (Lam.) Irwin & Barneby, and Tamarindus indica L. were determined by measuring prostaglandin E2 (PGE2) secretion, nitric oxide (NO) production, and the synthesis of inflammatory biomarkers in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. The active ingredients of the P. roxburghii leaves were separated by chromatography and spectroscopic measurements were used to identify their chemical structures. RESULTS: Ethanol extracts of the Yataprasen remedy and some of its ingredients significantly suppressed LPS-induced PGE2 secretion and NO production in a dose-dependent manner. Treatment of RAW264.7 cells with ethanolic extracts of the Yataprasen remedy (50 µg/mL) significantly inhibited LPS-induced mRNA expression of TNF-α, COX-2, iNOS, and NF-κB. Among the plant ingredient extracts, P. roxburghii leaf extract exhibited the highest inhibitory effects on LPS-induced TNF-α and iNOS expression. Moreover, T. indica leaf extract showed the highest activity on the inhibition of LPS-induced COX-2 and NF-κB expression. Putraflavone, podocarpusflavone A, and amentoflavone were isolated biflavonoids from P. roxburghii leaf extract and showed the inhibitory effects on LPS-induced PGE2 secretion and NO synthesis in RAW264.7 cells. Of the isolated biflavonoids, amentoflavone exhibited the strongest anti-inflammatory activity by inhibiting the expression of TNF-α, COX-2, and iNOS. CONCLUSION: The results support reported the anti-inflammatory effects of the Yataprasen remedy, which are associated with the downregulation of proinflammatory mediators. P. roxburghii, along with its biflavonoids, are the impact components that contribute to the anti-inflammatory effects of the herbal remedy.


Assuntos
Biflavonoides , NF-kappa B , NF-kappa B/metabolismo , Biflavonoides/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Tailândia , Linhagem Celular , Macrófagos , Extratos Vegetais/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Etanol/farmacologia , Óxido Nítrico/metabolismo
14.
J Cell Mol Med ; 28(4): e18139, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38334198

RESUMO

Platelets assume a pivotal role in the cardiovascular diseases (CVDs). Thus, targeting platelet activation is imperative for mitigating CVDs. Ginkgetin (GK), from Ginkgo biloba L, renowned for its anticancer and neuroprotective properties, remains unexplored concerning its impact on platelet activation, particularly in humans. In this investigation, we delved into the intricate mechanisms through which GK influences human platelets. At low concentrations (0.5-1 µM), GK exhibited robust inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Intriguingly, thrombin and U46619 remained impervious to GK's influence. GK's modulatory effect extended to ATP release, P-selectin expression, intracellular calcium ([Ca2+ ]i) levels and thromboxane A2 formation. It significantly curtailed the activation of various signaling cascades, encompassing phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß and mitogen-activated protein kinases. GK's antiplatelet effect was not reversed by SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor), and GK had no effect on the phosphorylation of vasodilator-stimulated phosphoproteinSer157 or Ser239 . Moreover, neither cyclic AMP nor cyclic GMP levels were significantly increased after GK treatment. In mouse studies, GK notably extended occlusion time in mesenteric vessels, while sparing bleeding time. In conclusion, GK's profound impact on platelet activation, achieved through inhibiting PLCγ2-PKC cascade, culminates in the suppression of downstream signaling and, ultimately, the inhibition of platelet aggregation. These findings underscore the promising therapeutic potential of GK in the CVDs.


Assuntos
Biflavonoides , Nucleotídeos Cíclicos , Fosfolipases , Humanos , Animais , Camundongos , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/farmacologia , Fosfolipase C gama/metabolismo , Ácido Araquidônico/farmacologia , Ácido Araquidônico/metabolismo , Fosfolipases/metabolismo , Fosfolipases/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Ativação Plaquetária , Plaquetas/metabolismo , Agregação Plaquetária , Proteína Quinase C/metabolismo , Fosforilação , Colágeno/metabolismo
15.
J Agric Food Chem ; 72(8): 4023-4034, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38357881

RESUMO

In this study, an effective method for preparation of bioactive galloylated procyanidin B2-3'-O-gallate (B2-3'-G) was first developed by incomplete depolymerization of grape seed polymeric procyanidins (PPCs) using l-cysteine (Cys) in the presence of citric acid. The structure-activity relationship of B2-3'-G was further evaluated in vitro through establishing lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. The results suggested that the better protective effects of B2-3'-G against inflammation were attributed to its polymerization degree and the introduction of the galloyl group, compared to its four corresponding structural units. In vivo experiments demonstrated that the B2-3'-G prototype was distributed in plasma, small intestine, liver, lung, and brain. Remarkably, B2-3'-G was able to penetrate the blood-brain barrier and appeared to play an important role in improving brain health. Furthermore, a total of 18 metabolites were identified in tissues. Potential metabolic pathways, including reduction, methylation, hydration, desaturation, glucuronide conjugation, and sulfation, were suggested.


Assuntos
Biflavonoides , Catequina , Proantocianidinas , Humanos , Proantocianidinas/farmacologia , Proantocianidinas/química , Cisteína , Distribuição Tecidual , Biflavonoides/farmacologia , Biflavonoides/química , Catequina/química , Inflamação , Anti-Inflamatórios/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-38366688

RESUMO

Procyanidins are gaining attention due to their potential health benefits. We found that cacao liquor procyanidin (CLPr) from Theobroma cacao seeds increased the lifespan of Caenorhabditis elegans, a representative model organism for aging studies. The genetic dependence of the lifespan-extending effect of CLPr was consistent with that of blueberry procyanidin, which is dependent on unc-43, osr-1, sek-1, and mev-1, but not on daf-16, sir-2.1, or skn-1. The lifespan-extending effect of CLPr was inhibited by neuron-specific RNA interference (RNAi) targeting unc-43 and pmk-1, and in worms with loss-of-function mutations in the odr-3, odr-1, or tax-4 genes, which are essential in sensory neurons, including AWC neurons. It was also inhibited in worms in which AWC neurons or AIB interneurons had been eliminated, and in worms with loss-of-function mutations in eat-4 or glr-1, which are responsible for glutamatergic synaptic transmission. These results suggest that the lifespan-extending effect of CLPr is dependent on the nervous system. In addition, it also requires unc-43 and pmk-1 expression in nonneuronal cells, as demonstrated by the experiments with RNAi in wild-type worms, the neuronal cells of which are not affected by systemic RNAi. The osr-1 gene is expressed in hypodermal and intestinal cells and regulates the response to osmotic stress along with unc-43/calcium/calmodulin-dependent protein kinase II and the p38 mitogen-activated protein kinase pathway. Consistent with this, CLPr improved osmotic stress tolerance in an unc-43- and pmk-1-dependent manner, and it was also dependent on AWC neurons. The lifespan-extending and osmotic-tolerance-improving activities were attributed to procyanidins with a tetrameric or higher-order oligomeric structure.


Assuntos
Biflavonoides , Cacau , Proteínas de Caenorhabditis elegans , Catequina , Proantocianidinas , Animais , Caenorhabditis elegans/fisiologia , Longevidade/fisiologia , Proantocianidinas/farmacologia , Proantocianidinas/metabolismo , Cacau/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/farmacologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sistema Nervoso/metabolismo
17.
Pestic Biochem Physiol ; 198: 105715, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38225072

RESUMO

Paraquat (PQ) is a ubiquitous and water-soluble herbicide which has potential to cause systematic poisoning. PQ intoxication is known to be associated with various clinical complications including hepatotoxicity. Amentoflavone (AMF) is an active phenolic compound that exhibits a broad range of biological as well as pharmacological activities. This study was designed to determine the hepato-protective potential of AMF against PQ instigated hepatotoxicity in rats. Forty-eight rats were distributed into four groups such as control group, PQ-treated group (5 mg/kg), PQ (5 mg/kg) + AMF (40 mg/kg) exposed group and AMF (40 mg/kg) only supplemented group. It was revealed that PQ exposure reduced nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidative genes expression whereas increase the expression of Kelch-like ECH-associated protein 1(Keap1). Besides, PQ intoxication reduced the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR), glutathione peroxidase (GPx), Heme- oxygenase-1 (HO-1) & glutathione (GSH) content. Furthermore, the levels of reactive oxygen species (ROS) & malondialdehyde (MDA) were increased. In addition, PQ significantly increased the hepatic serum enzymes including alkaline phosphatase (ALP), aspartate transaminase (AST), & alanine transaminase (ALT) along with inflammatory biomarkers levels such as tumor necrosis- α (TNF- α), nuclear factor- κB (NF-κB), interleukin-6 (IL-6), interleukin 1beta (IL-1ß), & cyclo­oxygenase-2 (COX-2) activity. PQ intoxication increased the expressions of pro-apoptotic markers i.e., Bcl-2-associated X protein (Bax) & Cysteine-aspartic protease-3 (Caspase-3) while reducing the expression of anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). Furthermore, PQ intoxication prompted various histopathological impairments. However, the co-administration of AMF significantly improved the abovementioned hepatic damages induced by PQ. The present study indicated that AMF may be an effective therapeutic candidate to mitigate PQ provoked hepatic impairments due to its anti-apoptotic, antioxidant & anti-inflammatory properties.


Assuntos
Biflavonoides , Doença Hepática Induzida por Substâncias e Drogas , Paraquat , Ratos , Animais , Paraquat/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo , Glutationa/metabolismo , NF-kappa B/metabolismo , Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
18.
Biomed Pharmacother ; 171: 116114, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38171247

RESUMO

Oxidative stress-induced apoptosis is an important pathological process in renal ischemia/reperfusion injury (RIRI). Theaflavin (TF) is the main active pigment and polyphenol in black tea. It has been widely reported because of its biological activity that can reduce oxidative stress and protect against many diseases. Here, we explored the role of theaflavin in the pathological process of RIRI. In the present study, the RIRI model of 45 min ischemia and 24 h reperfusion was established in C57BL/6 J male mice, and theaflavin was used as an intervention. Compared with the RIRI group, the renal filtration function, renal tissue damage and antioxidant capacity of the theaflavin intervention group were significantly improved, while the level of apoptosis was reduced. TCMK-1 cells were incubated under hypoxia for 48 h and then reoxygenated for 6 h to simulate RIRI in vitro. The application of theaflavin significantly promoted the translocation of p53 from cytoplasm to nucleus, upregulated the expression of glutathione peroxidase 1 (GPx-1) in cells, and inhibited oxidative stress damage and apoptosis. Transfection with p53 siRNA can partially inhibit the effect of theaflavin. Thus, theaflavin exerted a protective effect against RIRI by inhibiting apoptosis and oxidative stress via regulating the p53/GPx-1 pathway. We conclude that theaflavin has the potential to become a candidate drug for the prevention and treatment of RIRI.


Assuntos
Antioxidantes , Biflavonoides , Catequina , Traumatismo por Reperfusão , Masculino , Camundongos , Animais , Antioxidantes/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Isquemia/tratamento farmacológico , Apoptose
19.
Int J Biol Macromol ; 259(Pt 1): 129189, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38181909

RESUMO

Tea polyphenols have been reported as potential α-amylase inhibitors. However, the quantitative structure-activity relationship (QSAR) between tea polyphenols and human pancreas α-amylase (HPA) is not well understood. Herein, the inhibitory effect of twelve tea polyphenol monomers on HPA was investigated in terms of inhibitory activity, as well as QSAR analysis and interaction mechanism. The results revealed that the HPA inhibitory activity of theaflavins (TFs), especially theaflavin-3'-gallate (TF-3'-G, IC50: 0.313 mg/mL), was much stronger than that of catechins (IC50: 18.387-458.932 mg/mL). The QSAR analysis demonstrated that the determinant for the inhibitory activity of HPA was not the number of hydroxyl and galloyl groups in tea polyphenol monomers, while the substitution sites of these groups potentially might play a more important role in modulating the inhibitory activity. The inhibition kinetics and molecular docking revealed that TF-3'-G as a mixed-type inhibitor had the lowest inhibition constant and bound to the active sites of HPA with the lowest binding energy (-7.74 kcal/mol). These findings could provide valuable insights into the structures-activity relationships between tea polyphenols and the HPA inhibitors.


Assuntos
Biflavonoides , Catequina , Ácido Gálico/análogos & derivados , Polifenóis , Humanos , Polifenóis/farmacologia , Polifenóis/química , alfa-Amilases Pancreáticas , Simulação de Acoplamento Molecular , Chá/química , Catequina/farmacologia , Catequina/química
20.
Phytother Res ; 38(3): 1367-1380, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38217097

RESUMO

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.


Assuntos
Biflavonoides , Células Estreladas do Fígado , Tioacetamida , Camundongos , Animais , Humanos , Tioacetamida/metabolismo , Tioacetamida/farmacologia , Tioacetamida/uso terapêutico , Interleucina-6/metabolismo , Cirrose Hepática/tratamento farmacológico , Modelos Animais de Doenças , Apoptose , Fígado/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/farmacologia
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