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1.
J Sci Food Agric ; 104(7): 3982-3991, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38252712

RESUMO

BACKGROUND: Many diseases may be caused by pathogens and oxidative stress resulting from carcinogens. Earlier studies have highlighted the antimicrobial and antioxidant effects of plant essential oils (EO). It is crucial to effectively utilize agricultural waste to achieve a sustainable agricultural economy and protect the environment. The present study aimed to evaluate the potential benefits of EO extracted from the discarded peels of Citrus depressa Hayata (CD) and Citrus microcarpa Bunge (CM), synonyms of Citrus deliciosa Ten and Citrus japonica Thunb, respectively. RESULTS: Gas chromatography-mass spectrometry analysis revealed that the main compounds in CD-EO were (R)-(+)-limonene (38.97%), γ-terpinene (24.39%) and linalool (6.22%), whereas, in CM-EO, the main compounds were (R)-(+)-limonene (48.00%), ß-pinene (13.60%) and γ-terpinene (12.07%). CD-EO exhibited inhibitory effects on the growth of common microorganisms, including Candida albicans, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. However, CM-EO showed only inhibitory effects on E. coli. Furthermore, CD-EO exhibited superior antioxidant potential, as demonstrated by its ability to eliminate 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-3-ethylbenzthiazoline-6-sulfonate free radicals. Furthermore, CD-EO at a concentration of 100 µg mL-1 significantly inhibited 12-O-tetradecanoylphorbol-13-acetate-induced cancer transformation in mouse epidermal JB6 P+ cells (P < 0.05), possibly by up-regulating protein expression of nuclear factor erythroid 2-related factor 2 and its downstream antioxidant enzymes, such as NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1 and UGT1A. CONCLUSION: These findings suggest that CD-EO exhibits inhibitory effects on pathogenic microorganisms, possesses antioxidant properties and has cancer chemopreventive potential. © 2024 Society of Chemical Industry.


Assuntos
Anti-Infecciosos , Citrus , Monoterpenos Cicloexânicos , Neoplasias , Óleos Voláteis , Animais , Camundongos , Óleos Voláteis/química , Antioxidantes/farmacologia , Antioxidantes/química , Limoneno/farmacologia , Citrus/química , Escherichia coli , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Óleos de Plantas/química
2.
Carcinogenesis ; 39(5): 669-680, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29547900

RESUMO

Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms could play an important role in the initiation and progression of colon cancer. Curcumin, a dietary phytochemical, shows promising effects in suppressing colitis-associated colon cancer in azoxymethane-dextran sulfate sodium (AOM-DSS) mice. However, the potential epigenetic mechanisms of curcumin in colon cancer remain unknown. In this study, the anticancer effect of curcumin in suppressing colon cancer in an 18-week AOM-DSS colon cancer mouse model was confirmed. We identified lists of differentially expressed and differentially methylated genes in pairwise comparisons and several pathways involved in the potential anticancer effect of curcumin. These pathways include LPS/IL-1-mediated inhibition of RXR function, Nrf2-mediated oxidative stress response, production of NO and ROS in macrophages and IL-6 signaling. Among these genes, Tnf stood out with decreased DNA CpG methylation of Tnf in the AOM-DSS group and reversal of the AOM-DSS induced Tnf demethylation by curcumin. These observations in Tnf methylation correlated with increased and decreased Tnf expression in RNA-seq. The functional role of DNA methylation of Tnf was further confirmed by in vitro luciferase transcriptional activity assay. In addition, the DNA methylation level in a group of inflammatory genes was decreased in the AOM+DSS group but restored by curcumin and was validated by pyrosequencing. This study shows for the first time epigenomic changes in DNA CpG methylation in the inflammatory response from colitis-associated colon cancer and the reversal of their CpG methylation changes by curcumin. Future clinical epigenetic studies with curcumin in inflammation-associated colon cancer would be warranted.


Assuntos
Colite/complicações , Neoplasias do Colo/etiologia , Neoplasias do Colo/prevenção & controle , Curcumina/farmacologia , Metilação de DNA/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Azoximetano/farmacologia , Colo/efeitos dos fármacos , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
3.
Chem Res Toxicol ; 31(2): 88-96, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29228771

RESUMO

The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-bis-(3,4,5-trimethoxybenzylidene)-tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy-benzylidene)-tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin, and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed real-time quantitative PCR and Western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter was doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 is more potent in activating Nrf2-ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation.


Assuntos
Antioxidantes/metabolismo , Curcumina/análogos & derivados , Curcumina/farmacologia , Epigênese Genética/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Neoplasias da Próstata/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Carcinogenesis ; 37(6): 616-624, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27207670

RESUMO

Colorectal cancer (CRC) is the third most common cancer worldwide. Chronic inflammation appears to enhance the risk of CRC. Emerging evidence has suggested that epigenetic mechanisms play an important role in CRC. Aspirin [acetylsalicylic acid (ASA)] has been shown to prevent CRC; however, the epigenetic mechanisms of its action remain unknown. This study investigated the protective role of ASA in azoxymethane (AOM)-initiated and dextran sulfate sodium (DSS)-promoted colitis-associated colon cancer (CAC) and examined the epigenetic effects, particularly on histone 3 lysine 27 acetylation (H3K27ac), underlying the preventive effect of ASA. CF-1 mice were fed with AIN-93M diet with or without 0.02% ASA from 1 week prior to AOM initiation until the mice were killed 20 weeks after AOM injection. Our results showed that AOM/DSS + ASA significantly suppressed inflammatory colitis symptoms and tumor multiplicity. AOM/DSS + ASA reduced AOM/DSS-induced protein expression and the activity of histone deacetylases (HDACs) and globally restored H3K27ac. Furthermore, AOM/DSS + ASA inhibited AOM/DSS-induced enrichment of H3K27ac in the promoters of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) that corresponded to the dramatic suppression of the messenger RNA (mRNA) and protein levels. Surprisingly, no significant changes in the H3K27ac abundance in the prostaglandin-endoperoxide synthase 2 (Cox-2) promoters or in the Cox-2 mRNA and protein expression were observed. Collectively, our results suggest that a potential novel epigenetic mechanism underlies the chemopreventive effects of ASA, and this mechanism attenuates CAC in AOM/DSS-induced CF-1 mice via the inhibition of HDACs and the modification of H3K27ac marks that suppress iNOS, TNF-α and IL-6.


Assuntos
Aspirina/farmacologia , Neoplasias do Colo/prevenção & controle , Epigênese Genética/efeitos dos fármacos , Animais , Anticarcinógenos/farmacologia , Aspirina/administração & dosagem , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colite/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Ciclo-Oxigenase 2/genética , Sulfato de Dextrana/toxicidade , Histona Desacetilases/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Masculino , Camundongos Endogâmicos , Neoplasias Experimentais , Óxido Nítrico Sintase Tipo II/genética
5.
Chem Res Toxicol ; 29(4): 694-703, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-26991801

RESUMO

It has previously been shown that curcumin can effectively inhibit prostate cancer proliferation and progression in TRAMP mice, potentially acting through the hypomethylation of the Nrf2 gene promoter and hence activation of the Nrf2 pathway to enhance cell antioxidative defense. FN1 is a synthetic curcumin analogue that shows stronger anticancer activity than curcumin in other reports. We aimed to explore the epigenetic modification of FN1 that restores Nrf2 expression in TRAMP-C1 cells. Stably transfected HepG2-C8 cells were used to investigate the effect of FN1 on the Nrf2- antioxidant response element (ARE) pathway. Real-time quantitative PCR and Western blotting were applied to study the influence of FN1 on endogenous Nrf2 and its downstream genes. Bisulfite genomic sequencing (BGS) and methylated DNA immunoprecipitation (MeDIP) were then performed to examine the methylation profile of the Nrf2 promoter. An anchorage-independent colony-formation analysis was conducted to examine the tumor inhibition activity of FN1. Epigenetic modification enzymes, including DNMTs and HDACs, were investigated by Western blotting. The luciferase reporter assay indicated that FN1 was more potent than curcumin in activating the Nrf2-ARE pathway. FN1 increased the expression of Nrf2 and its downstream detoxifying enzymes. FN1 significantly inhibited the colony formation of TRAMP-C1 cells. BGS and MeDIP assays revealed that FN1 treatment (250 nM for 3 days) reduced the percentage of CpG methylation of the Nrf2 promoter. FN1 also downregulated epigenetic modification enzymes. In conclusion, our results suggest that FN1 is a novel anticancer agent for prostate cancer. In the TRAMP-C1 cell line, FN1 can increase the level of Nrf2 and downstream genes via activating the Nrf2-ARE pathway and inhibit the colony formation potentially through the decreased expression of keap1 coupled with CpG demethylation of the Nrf2 promoter. This CpG demethylation effect may come from decreased epigenetic modification enzymes, such as DNMT1, DNMT3a, DNMT3b, and HDAC4.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Epigênese Genética/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Ilhas de CpG/efeitos dos fármacos , Curcumina/análogos & derivados , Metilação de DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Camundongos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
6.
J Pharmacokinet Pharmacodyn ; 42(4): 401-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26138223

RESUMO

3,3'-Diindolylmethane (DIM) has been investigated as a potential anti-cancer chemopreventive agent in many preclinical and clinical studies. In this study, we sought to characterize the pharmacokinetics of DIM and to build a pharmacokinetic (PK) and pharmacodynamic (PD) model of the DIM-induced gene expression of phase II drug metabolizing enzymes (DME), which potentially links DIM's molecular effects to its in vivo chemopreventive efficacy. DIM (10 mg/kg) was administered intravenously (i.v.) to male Sprague-Dawley rats and blood samples were collected at selected time points for 48 h. The plasma concentration of DIM was determined using a validated HPLC method. The mRNA expression of NQO1, GSTP1 and UGT1A1 in blood lymphocytes was measured using quantitative PCR. An indirect response model was employed to relate the concentration of DIM to the expression of the genes NQO1, GSTP1 and UGT1A1, which were chosen as PD markers for DIM. After i.v. administration, the plasma concentration of DIM declined quickly, and the expression of target genes increased significantly, peaking at 1-2 h and then returning to basal levels after 24 h. The parameters in the PK-PD model were estimated. The PK-PD model aptly described the time delay and magnitude of gene expression induced by DIM. Our results indicate that DIM is effective at inducing various phase II DME, which are capable of detoxify carcinogens. This PK-PD modeling approach provides a framework for evaluating the acute effects of DIM or other similar drugs in clinical trials.


Assuntos
Anticarcinógenos/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Glutationa S-Transferase pi/genética , Indóis/farmacocinética , Modelos Biológicos , NAD(P)H Desidrogenase (Quinona)/genética , Animais , Anticarcinógenos/sangue , Anticarcinógenos/farmacologia , Indóis/sangue , Indóis/farmacologia , Injeções Intravenosas , Masculino , Desintoxicação Metabólica Fase II , Ratos Sprague-Dawley
7.
Biopharm Drug Dispos ; 36(7): 440-51, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25904312

RESUMO

Apigenin (API) and luteolin (LUT) have been used as therapeutic agents in folk medicine for thousands of years. These compounds exert a variety of biological activities, including anticancer, antioxidant and antiinflammatory activities. This study investigated whether API and LUT could activate Nrf2-antioxidant response element (ARE)-mediated gene expression and induce antiinflammatory activities in human hepatoma HepG2 cells. The compounds did not exhibit any substantial toxicity at low doses (1.56-6.25 µm). The induction of ARE activity was assessed in HepG2-C8 cells after treatment with low doses of API and LUT for 6 and 12 h. It was found that the induction of ARE activity by these compounds at the higher doses was comparable to the effects of the positive control, SFN at a dose of 6.25 µm. Exposure to the PI3K inhibitor LY294002 abolished ARE activation by both API and LUT, whereas the ERK-1/2 inhibitor PD98059 only decreased ARE activity induced by API. Both compounds significantly increased the endogenous mRNA and protein levels of Nrf2 and Nrf2 target genes with important effects on heme oxygenase-1 (HO-1) expression. API and LUT significantly and dose-dependently decreased the production of nitric oxide (NO), nitric oxide synthase (iNOS) and cytosolic phospholipase A2 (cPLA2), which were induced by the treatment of HepG2 cells with 1 µg/ml of lipopolysaccharide (LPS) for 24 h. The results indicate that API and LUT significantly activate the PI3K/Nrf2/ARE system, and this activation may be responsible for their antiinflammatory effects, as demonstrated by the suppression of LPS-induced NO, iNOS and cPLA2.


Assuntos
Apigenina/farmacologia , Flavonas/farmacologia , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/biossíntese , Compostos Fitoquímicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/genética
8.
Chem Res Toxicol ; 27(1): 34-41, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24304388

RESUMO

Inflammation plays a critical defensive role in the human body. However, uncontrolled or aberrant inflammatory responses contribute to various acute and chronic diseases. The Nrf2-ARE pathway plays a pivotal role in the regulation of inflammatory markers, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). On the basis of this concept, we synthesized a novel anti-inflammatory 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione (HPT), and in vitro experiments using HepG2-C8 ARE-luciferase-transfected cells demonstrated the induction of Nrf2-ARE activity. In lipopolysaccharide (LPS)-induced RAW 264.7 cells, HPT treatment reduced the production of nitric oxide (NO) as well as the protein and mRNA expression levels of COX-2 and iNOS, in a dose-dependent manner. In addition, HPT suppressed the mRNA expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. In LPS-induced macrophages, HPT inhibited COX-2 and iNOS by blocking the activation of p38 and c-Jun NH2-terminal kinase (JNK) but not extracellular signal-regulated kinase (ERK1/2). Furthermore, an in vivo anti-inflammatory study was performed using a TPA-induced skin inflammation mouse model, and the results showed that HPT reduced TPA-induced inflammation and attenuated the expression of COX-2 and iNOS in TPA-induced mouse skin tissue. Thus, HPT demonstrated anti-inflammatory activity both in LPS-induced RAW 264.7 cells and TPA-stimulated mouse skin and may therefore serve as a potential anti-inflammatory agent.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Pirimidinas/farmacologia , Tionas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células Hep G2 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Tionas/química , Células Tumorais Cultivadas
9.
J Food Drug Anal ; 32(2): 213-226, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38934690

RESUMO

Citrus peels contain abundant polyphenols, particularly flavonoids, and have been shown to exert lipid accumulation decreasing ability. In this study, Citrus depressa peel applied to oven drying and extracted with ethanol extract as CDEE to analyze its flavonoids compositions and investigated its effects on a high-fat diet (HFD)-induced obese mice model. CDEE contained several flavonoids such as hesperidin, sinesentin, nobiletin, tangeretin, 5-demethylnobiletin, and 5-demethyltangeretin. The mice fed an HFD, and administration of 2% CDEE to could decrease weight gain, abdominal fat weight, inguinal fat weight, and the adipocyte size, and CDEE also reduced serum total cholesterol (TCHO), triacylglycerol (TG) compared with mice fed only on HFD. CDEE hindered lipid accumulation through a decreased fatty acid synthase (FAS) protein expression via upregulation of the protein expression of AMP-activated protein kinase α (AMPKα). Moreover, CDEE modulated gut microbiota that altered by HFD through an increased abundance of Lactobacillus reuteri compared with the HFD group. The results demonstrated that CDEE helps decrease lipid accumulation through the AMPK pathway, which also indicates a prebiotic-like effect on gut microbiota.


Assuntos
Citrus , Dieta Hiperlipídica , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade , Extratos Vegetais , Prebióticos , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Citrus/química , Masculino , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Prebióticos/administração & dosagem , Prebióticos/análise , Dieta Hiperlipídica/efeitos adversos , Humanos , Triglicerídeos/metabolismo , Triglicerídeos/sangue , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/metabolismo , Bactérias/efeitos dos fármacos
10.
Top Curr Chem ; 329: 133-62, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22836898

RESUMO

Oxidative stress is caused by an imbalance of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidative stress defense systems in cells. ROS/RNS or carcinogen metabolites can attack intracellular proteins, lipids, and nucleic acids, which can result in genetic mutations, carcinogenesis, and other diseases. Nrf2 plays a critical role in the regulation of many antioxidative stress/antioxidant and detoxification enzyme genes, such as glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1), UDP-glucuronyl transferases (UGTs), and heme oxygenase-1 (HO-1), directly via the antioxidant response element (ARE). Recently, many studies have shown that dietary phytochemicals possess cancer chemopreventive potential through the induction of Nrf2-mediated antioxidant/detoxification enzymes and anti-inflammatory signaling pathways to protect organisms against cellular damage caused by oxidative stress. In addition, carcinogenesis can be caused by epigenetic alterations such as DNA methylation and histone modifications in tumor-suppressor genes and oncogenes. Interestingly, recent studies have shown that several naturally occurring dietary phytochemicals can epigenetically modify the chromatin, including reactivating Nrf2 via demethylation of CpG islands and the inhibition of histone deacetylases (HDACs) and/or histone acetyltransferases (HATs). The advancement and development of dietary phytochemicals in cancer chemoprevention research requires the integration of the known, and as-yet-unknown, compounds with the Nrf2-mediated antioxidant, detoxification, and anti-inflammatory systems and their in vitro and in vivo epigenetic mechanisms; human clinical efficacy studies must also be performed.


Assuntos
Dieta , Epigênese Genética , Fator 2 Relacionado a NF-E2/fisiologia , Neoplasias/prevenção & controle , Estresse Oxidativo , Fitoterapia , Humanos , Fator 2 Relacionado a NF-E2/genética , Neoplasias/metabolismo , Transdução de Sinais
11.
Chem Res Toxicol ; 26(3): 477-85, 2013 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-23441843

RESUMO

Cancer development has been linked to epigenetic modifications of cancer oncogenes and tumor suppressor genes; in advanced metastatic cancers, severe epigenetic modifications are present. We previously demonstrated that the progression of prostate tumors in TRAMP mice is associated with methylation silencing of the Nrf2 promoter and a reduced level of transcription of Nrf2 and Nrf2 target genes. Radix Angelicae Sinensis (RAS; Danggui) is a medicinal herb and health food supplement that has been widely used in Asia for centuries. Z-Ligustilide (Lig) is one of the bioactive components of RAS. We investigated the potential of Lig and RAS to restore Nrf2 gene expression through epigenetic modification in TRAMP C1 cells. Lig and RAS induced the mRNA and protein expression of endogenous Nrf2 and Nrf2 downstream target genes, such as HO-1, NQO1, and UGT1A1. Bisulfite genomic sequencing revealed that Lig and RAS treatment decreased the level of methylation of the first five CpGs of the Nrf2 promoter. A methylation DNA immunoprecipitation assay demonstrated that Lig and RAS significantly decreased the relative amount of methylated DNA in the Nrf2 gene promoter region. Lig and RAS also inhibited DNA methyltransferase activity in vitro. Collectively, these results suggest that Lig and RAS are able to demethylate the Nrf2 promoter CpGs, resulting in the re-expression of Nrf2 and Nrf2 target genes. Epigenetic modifications of genes, including Nrf2, may therefore contribute to the overall health benefits of RAS, including the anticancer effect of RAS and its bioactive component, Lig.


Assuntos
4-Butirolactona/análogos & derivados , Angelica sinensis/química , Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neoplasias da Próstata/tratamento farmacológico , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ilhas de CpG/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Epigênese Genética/efeitos dos fármacos , Masculino , Camundongos , Regiões Promotoras Genéticas/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
12.
Biopharm Drug Dispos ; 34(6): 303-11, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23640758

RESUMO

The root of Angelica sinensis (Oliv.) Diels (abbreviated as AS) (Danggui) has a long history in Asian herbal medicine. Recently, it was demonstrated that AS possesses anti-cancer and anti-oxidant activities. Because the transcription factor Nrf2 mediates the expression of many cellular anti-oxidative stress genes, including genes that are involved in phase II drug metabolism and anti-oxidative stress, this study sought to investigate whether pure compounds from AS or an AS extract could activate antioxidant response element (ARE)-mediated gene expression and induce anti-inflammatory activities. Z-Ligustilide (Ligu), 3-butylidenephthalide (Buty) and CO2 supercritical fluid-extracted lipophilic AS extract (SFE) were tested in HepG2-C8 cells stabilized with ARE luciferase reporter gene. Ligu and Buty caused significant toxicity only at 100 µm. All three samples induced ARE-luciferase activity; however, SFE at 8.5 µg/ml induced ARE-luciferase activity 2-3 fold more potently than did either of the pure compounds. SFE also significantly increased the endogenous mRNA of Nrf2 and the Nrf2 target anti-oxidative gene NAD(P)H dehydrogenase, quinone 1 (NQO1). The protein expression of NQO1 was also significantly induced by SFE. In RAW 264.7 cells, SFE suppressed lipopolysaccharide (LPS)-induced IL-1ß and TNF-α expression about 2 fold stronger than sulforaphane, whereas both pure compounds and SFE suppressed inflammatory nitric oxide (NO) production. In summary, this study demonstrates that AS has anti-inflammatory effects and activates the Nrf2 pathway, which protects against oxidative stress.


Assuntos
4-Butirolactona/análogos & derivados , Angelica sinensis , Anti-Inflamatórios/farmacologia , Fator 2 Relacionado a NF-E2/genética , Anidridos Ftálicos/farmacologia , Extratos Vegetais/farmacologia , 4-Butirolactona/farmacologia , Animais , Linhagem Celular Tumoral , Expressão Gênica , Células Hep G2 , Humanos , Interleucina-1beta/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/farmacologia , RNA Mensageiro/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Fator de Necrose Tumoral alfa/genética
13.
Chem Biol Interact ; 382: 110650, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37517432

RESUMO

Polymethoxyflavones (PMFs) in citrus fruits have a variety of biological activities, including antioxidant, anti-inflammatory, anticancer, and anti-atherosclerotic effects. The liver is the major detoxifying organ of the human body; however, factors such as acetaminophen (APAP) overdose may increase oxidative stress in liver cells and lead to severe liver failure. In this study we examined the effects of tangeretin (TAN), a common citrus PMF, and its metabolite 4'-demethyltangeretin (4'-OH-TAN) on activation of the Nrf2 antioxidant system in mouse AML-12 hepatocytes through regulation by epigenetic mechanisms. The ability of TAN and 4'-OH-TAN to inhibit APAP-induced hepatotoxicity was also evaluated. The results showed that TAN and 4'-OH-TAN significantly increased the mRNA and protein levels of Nrf2 and Nrf2-mediated antioxidant and detoxifying enzymes (UGT1A, HO-1, and NQO1) in AML-12 cells. TAN and 4'-OH-TAN also suppressed protein expression of histone deacetylases (HDACs) and DNA methyltransferases (DMNTs) and reduced DNA methylation of the nrf2 promoter. Furthermore, TAN and 4'-OH-TAN prevented APAP-induced injury and inhibited APAP-induced ROS generation in AML-12 cells. Based on these results, we conclude that TAN and 4'-OH-TAN may increase the antioxidant capacity of liver cells by regulating epigenetic alteration to activate the Nrf2-related antioxidant system, thereby preventing liver cells from being damaged by APAP-induced oxidative stress.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Leucemia Mieloide Aguda , Animais , Camundongos , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Acetaminofen/metabolismo , Estresse Oxidativo , Fígado/metabolismo , Hepatócitos , Epigênese Genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Camundongos Endogâmicos C57BL
14.
J Tradit Complement Med ; 13(4): 337-344, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37396151

RESUMO

Background and aim: Skin is one barrier protecting from environmental risk factors that can make skin cells cancerous through DNA damage and oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is an anti-stress defense system that can be regulated by DNA methylation and histone modification. Dietary phytochemicals have chemopreventive properties that can inhibit or delay carcinogenesis. The lotus leaf is a traditional medicinal plant containing many polyphenols whose extracts show many biological activities, including antioxidant, anti-obesity, and anti-cancer. This study aim to investigate the effect of lotus leaves on neoplastic transformation in murine skin JB6 P+ cells. Experimental procedure: Lotus leaves were extracted with water (LL-WE) and ethanol (LL-EE), and the LL-WE residues were further extracted with ethanol (LL-WREE). JB6 P+ cells were treated with different extracts. The chemoprotective effect would be evaluated by heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase (NQO1), and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression. Results and conclusion: LL-EE contained higher total phenolics and quercetin among extracts. In mouse skin JB6 P+ cells with 12-O-tetradecanoylphorbol-13-acetate treatment, LL-EE showed the greatest potential to suppress skin carcinogenesis. LL-EE activated the NRF2 pathway by upregulating antioxidant and detoxification enzymes upregulates antioxidant and detoxification enzymes, including HO-1, NQO1, and UGT1A1, and downregulates DNA methylation, which might be caused by lower DNA methyltransferase and histone deacetylase levels. Therefore, our results show that LL-EE reduces the neoplastic transformation of skin JB6 P+ cells, potentially by activating the NRF2 pathway and regulating epigenetic DNA methylation and histone acetylation.

15.
Chem Res Toxicol ; 25(8): 1574-80, 2012 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-22780686

RESUMO

Ginseng has long been used in Asian countries for more than 2000 years. Currently, in the "Western World or Western Medicines", many reports have indicated that they have used herbal medicines, and ginseng is one of the most popular herbs. Several recent reports have indicated that the antioxidant/antioxidative stress activities of ginseng play a role in the benefits of ginseng; however, the precise mechanism is lacking. The antioxidant response element (ARE) is a critical regulatory element for the expression of many antioxidant enzymes and phase II/III drug metabolizing/transporter genes, mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The aim of this study was to examine the potential activation and synergism of Nrf2-ARE-mediated transcriptional activity between three common ginsenosides present in ginseng, ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1), and ginsenoside 20(S)-protopanaxatriol (20S). We tested whether these ginsenosides and their combinations could induce Nrf2-ARE activities in HepG2-C8 cells with stably transfected ARE luciferase reporter gene. Cell proliferation, antioxidant and ARE activities, Western blotting of Nrf2 protein, and qPCR of mRNA of Nrf2 were conducted for Rb1, Rg1, and 20S as well as the combinations of 20S with Rb1 or Rg1. To determine the combination effects, the combination index (CI) was calculated. Rb1 and Rg1 are relatively nontoxic to the cells, while 20S at 50 µM or above significantly inhibited the cell proliferation. Rb1, Rg1, or 20S induced total antioxidant activity and ARE activity in a concentration-dependent manner. Furthermore, combinations of 20S with either Rb1 or Rg1 induced total antioxidant and ARE activity synergistically. The induction of Nrf2 protein and mRNA was also found to be synergistic with the combination treatments. In summary, in this study, we show that ginsenosides Rb1, Rg1, and 20S possess antioxidant activity, transcriptionally activating ARE as well as the potential of synergistic activities. The Nrf2-ARE-mediated antioxidant pathway could play a role for the overall antioxidative stress activities, which could be important for ginseng's health beneficial effects such as cancer chemopreventive activities.


Assuntos
Antioxidantes/química , Ginsenosídeos/química , Fator 2 Relacionado a NF-E2/metabolismo , Sapogeninas/química , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Ginsenosídeos/farmacologia , Células Hep G2 , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Panax/química , Sapogeninas/farmacologia
16.
ACS Appl Bio Mater ; 4(3): 2821-2828, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35014321

RESUMO

In this study, a catalytic polydopamine-remodeling gold nanoparticle sensitized with an antinucleolin AS1411 probe (pAu nanoprobe) is synthesized, where the surface of the gold nanoparticles (AuNPs) is modified with a spontaneous self-polymerization of a polydopamine coating that imparts the probe functionalization ability and antispecific protein binding while the intrinsic catalytic property of the AuNPs is preserved. The functionalized AS1411 probe exerts specific recognition with nucleolin protein that is found to be overexpressed on the surface of breast cancer cells (MDA-MB-231). Scanning electron microscopy (SEM) confirms that the specific binding of the pAu nanoprobe occurs at the cancer cell surface. Taking advantage of the catalytic ability of the pAu nanoprobe in reducing blue-colored methylene blue (MB) to colorless leuco-MB, a colorimetric biosensing platform is established based on the accessible catalytic active sites on the pAu nanoprobe toward MB. The specific binding inhibits the pAu nanoprobe from efficiently catalyzing the reduction of MB, resulting in a "turn-off" catalytic biosensing platform. The catalytic conversion of MB is inversely proportional to the concentration of the nucleolin protein and the cancer cells, yielding a detection limit of 15 pM of the nucleolin protein and two cancer cells. The presence of five orders of magnitude higher concentration of bovine serum albumin hardly affects the catalytic ability of the pAu nanoprobe, that is, 88% catalytic ability is still preserved, which validates the specificity of the proposed pAu nanoprobe. In particular, a distinct color contrast creates a significant signal-to-noise ratio so as to enable single-cell level detection of two cancer cells by naked-eye judgment. Moreover, the undiluted, real human serum samples spiked with the cancer cells were examined with an impressive recovery of 94 ± 0.3%, which holds great promise in cancer cell screening.


Assuntos
Aptâmeros de Nucleotídeos/química , Materiais Biocompatíveis/química , Neoplasias da Mama/diagnóstico , Ouro/química , Indóis/química , Nanopartículas Metálicas/química , Oligodesoxirribonucleotídeos/química , Polímeros/química , Análise de Célula Única , Animais , Técnicas Biossensoriais , Catálise , Bovinos , Células Cultivadas , Humanos , Teste de Materiais , Estrutura Molecular , Tamanho da Partícula , Fosfoproteínas/análise , Proteínas de Ligação a RNA/análise , Soroalbumina Bovina/análise , Nucleolina
17.
Biomed Pharmacother ; 136: 111260, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33465676

RESUMO

OBJECTIVE: Cryptotanshinone (CPT) and dihydrotanshinone (DHT) are diterpenoid anthraquinone compounds extracted from traditional Chinese herbal medicine (TCM). Recent studies have shown that CPT regulates the signal transduction pathways via microRNA (miRNA) alterations. However, few studies have investigated the role of DHT in miRNA alterations affecting cell-signaling pathways. This study aimed to investigate the miRNA alterations and post-transcriptional regulation activities of DHT in comparison to CPT. METHODS: HepG2 and HT-29 cells were treated with DHT or CPT for 72 h. MiRNA, transcription factor encoding mRNA, and downstream gene expression were determined using real-time quantitative PCR. Protein expression was analyzed using western blotting. RESULTS: The results revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via miR-15a-5p, miR-27a-5p, miR-100-5p, and miR-200a-5p alterations.In silico target predictions showed that downregulation of epidermal growth factor receptor (EGFR) mRNA expression by DHT might also suppress the expression of STAT family proteins and lead to anti-proliferation effects. We also found that, compared to CPT, DHT might possess higher potency in cell growth regulation via multi-miRNA and transcription factor alterations. CONCLUSION: This study revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via alterations in miRNAs and transcription factors. In addition, the findings of this study suggest that DHT is more potent than CPT in cancer chemopreventive activities. Therefore, DHT at a low dose is a TCM compound with less toxic side effects and may contribute to the development of natural medicine as a potential cancer chemopreventive agent.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Furanos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , Fenantrenos/farmacologia , Quinonas/farmacologia , Transcriptoma/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HT29 , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
AAPS J ; 21(5): 86, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292765

RESUMO

Prostate cancer ranks the second in incidence and the fifth in mortality cancer in male globally. Citrus polymethoxyflavonoids (PMFs), such as tangeretin (PMF1), have been found to exhibit various biological activities. Here, we evaluated the inhibitory effects and mechanism of synthetic 5,4'-didemethyltangeretin (PMF2) on human prostate cancer LNCaP cells. We found that PMF2 inhibited the growth of LNCaP cells (GI50 14.6 µM) more strongly than PMF1, and it was less cytotoxic against the normal human prostate RWPE-1 cells. PMF2 upregulated Bad and Bax, downregulated Bcl-2, and activated caspase-3 and PARP in the LNCaP cells, thereby inducing apoptosis. PMF2 also suppressed the anchorage-independent growth of the LNCaP cells. It triggered p21 gene expression by demethylation of the p21 promoter region, and inhibited the protein expressions of DNMT 3B and HDACs 1, 2, and 4/5/9 by epigenetic regulations. We further found that PMF2 showed interactions with DNMTs 1, 2, and 3A ex vivo, which might inhibit DNMT activity. Additionally, PMF2 decreased the anchorage-independent growth of isolated LNCaP cancer stem-like cells (CSLCs) with high CD166 mRNA expression. These results indicated that PMF2 might inhibit the growth of human prostate cancer cells through different mechanisms, suggesting that PMF2 could be an innovative agent for prostate cancer therapy and prevention.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Flavonas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Epigênese Genética , Flavonas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
19.
Am J Chin Med ; 47(8): 1833-1851, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31795743

RESUMO

Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blocked in vitro DNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Citrus/química , Medicamentos de Ervas Chinesas/farmacologia , Fator 2 Relacionado a NF-E2/genética , Acetaminofen/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Medicamentos de Ervas Chinesas/análise , Flavonoides/análise , Flavonoides/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
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