RESUMO
BACKGROUND: Esophageal cancer (EC) is highly prevalent in Eastern Asia (including China) with high rates of mortality. The metastatic tendency in EC is associated with a poor prognosis. Our previous studies have demonstrated the suppressive effects of Andrographis paniculata water extract (APW) on metastatic esophageal cancer in vitro and in tumor-bearing mice models, as well as illustrated the potential underlying mechanism by transcriptome analysis. HYPOTHESIS: High expressions of several membrane protein tetraspanins were reported to lead to a high risk of metastasis in esophageal cancer in patients. We hypothesized that APW could downregulate the expression of tetraspanin CD81 in esophageal cancer cells and xenografts. METHODS: Human esophageal cancer cells EC109 and KYSE520 were incubated with APW for 24 hours in cell culture, while mice bearing EC109 xenograft tumors were treated with APW for 21 days. The expressions of CD81 in cancer cells and in tumors from mice were evaluated. Molecular docking and microscale thermophoresis analyses were applied to identify the components in APW interacting with CD81. The influence of the identified components on CD81 expression was further evaluated in EC109 cells. RESULTS: APW could significantly suppress the expressions of CD81 in both EC109 and KYSE520 cells in a concentration-dependent manner. Treatment of APW in xenograft-bearing mice reduces the metastasis in lungs, livers, and lymph nodes. The expression of CD81 in xenograft tumors of APW-treated mice was significantly lower than those of untreated control mice. The binding of andrographolide, bisandrographolide A, and bisandrographolide C with CD81 were elucidated by microscale thermophoresis. The suppressive effects of these compounds on the motility of EC109 cells, as well as CD81 protein and mRNA expressions, were further confirmed. CONCLUSION: This is the first time to demonstrate that andrographolide, bisandrographolide A, and bisandrographolide C, which are present in APW, bind to CD81 and suppress its function. These compounds are likely to be responsible for the anti-metastatic activities of APW in esophageal cancer.
Assuntos
Andrographis paniculata , Diterpenos , Neoplasias Esofágicas , Extratos Vegetais/química , Tetraspanina 28 , Andrographis paniculata/química , Animais , Linhagem Celular Tumoral , Diterpenos/química , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Extratos Vegetais/farmacologiaRESUMO
Antitumor and antimetastatic effects of the medicinal herb Andrographis paniculata (AP) in esophageal cancer (EC) have been previously reported. In this study, we aimed to uncover the potential functional components and the underlying molecular mechanisms of AP in EC treatment using network pharmacology and experimental validation. Twenty-two potential active AP compounds against EC were revealed, including the antitumor/antiinflammatory compounds panicolin, moslosooflavone, and deoxyandrographiside. Epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), chemokine (C-X-C motif) ligand 8 (CXCL8), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha (PIK3CA), and toll-like receptor 4 (TLR4) were most highly ranked among the predicted targets of AP in EC treatment and may play important roles in the anti-EC effects of AP. KEGG pathway analysis revealed the enrichment of multiple cancer-related pathways and signaling pathways. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting validation showed that overnight treatment with 850.3 µg/ml of AP water extract significantly reduced the mRNA expressions of EGFR and AKT in human EC-109 cells. The presence of panicolin and moslosooflavone in the AP water extract samples were confirmed using LC-MS against reference standards. This study has comprehensively revealed for the first time the potential functional components of AP in EC and explored the underlying molecular mechanisms. Future studies should characterize the potential pharmacological properties of the other highly ranked yet understudied compounds in AP detected.
Assuntos
Andrographis , Neoplasias Esofágicas , Andrographis paniculata , Receptores ErbB , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Farmacologia em Rede , ÁguaRESUMO
Quality inconsistency of herbal medicine is an obstacle that limits the extensive use and study of traditional Chinese medicine. Differences in environmental conditions and processing methods of herbal medicine often result in varying clinical outcomes in patients. Standard chemical markers used for the quality control (QC) of herbal medicine are usually the most abundant and characteristic components, which may not be therapeutically relevant or cannot comprehensively reflect the biological quality of the herbs. In view of this, a novel QC method for better assessment of herbal medicine has been developed via bioactivities analysis. Immunological activities of Dictamni Cortex, a typical herbal medicine for the treatment of various inflammatory diseases, from different geographical locations in China, were evaluated. Upon in vitro treatment of their water and ethanol extracts, distinct patterns of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-6, IL-12p70, IL-1ß, and chemokine CXCL8 were released from the lipopolysaccharides- and/or phytohaemagglutinin-stimulated human peripheral blood mononuclear cells (PBMC). Thus, in addition to the commonly used morphological, chemical, or DNA markers, the novel high-throughput profiling of inflammatory cytokines and chemokines of PBMC upon treatment with herbal extracts could be an important reference to help for the quality control of herbal medicine in the future.
Assuntos
Medicamentos de Ervas Chinesas/análise , Medicina Herbária/classificação , Medicina Herbária/normas , Ensaios de Triagem em Larga Escala , Imunoensaio , Plantas Medicinais/classificação , Biomarcadores , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/classificação , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Imunoensaio/métodos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/anatomia & histologia , Plantas Medicinais/química , Controle de QualidadeRESUMO
BACKGROUND: Esophageal cancer (EC) is a malignant gastrointestinal cancer with high morbidity worldwide and is the fourth leading cause of cancer-related deaths in China. Even though surgery and/or chemotherapy/chemoradiation might achieve good therapeutic response, recurrence rate is high due to cancer metastasis. Hence, the use of alternative adjuvant treatments, such as herbal medicines, for metastatic EC remains a great desire of the patients. Our previous studies have demonstrated the anti-metastatic efficacy of hot water extract of Andrographis paniculata (APW) in human esophageal cancer cells and tumor-bearing nude mice. PURPOSE: In the present study, the immunomodulatory activities of APW were further evaluated in human peripheral blood mononuclear cells (PBMCs) and in a carcinogen-induced esophageal tumorigenesis model using immune-competent C57BL/6 mice. Besides, the inhibitory effects of APW on esophageal cancer cell line-based xenografts and patient-derived xenografts (PDX) were examined so as to illustrate the potential multi-targeted efficacies of APW in esophageal cancer in pre-clinical models. RESULTS: In vitro results showed that APW could stimulate proliferation of PBMCs, as well as TNF-α and IFN-γproductions. In mice with 4-nitroquinoline 1-oxide-induced tumorigenesis, 21-day oral treatment with APW (1600â¯mg/kg) decreased the level of dysplasia in esophagus and significantly modulated the population of regulatory T cells. The cytokines productions by spleen lymphocytes of APW-treated mice were shifted towards normal resting state (i.e. unchallenged with carcinogen). Furthermore, APW treatment suppressed the growth of cell line-based xenografts by significantly increasing apoptosis in tumors, without causing severe body weight loss as chemotherapeutics did. Most importantly, the inhibitory effects of APW treatment on esophageal patient-derived xenografts growth were demonstrated for the first time. Besides, several diterpenes were detected in the plasma after oral administration of APW in mice, suggesting that multi-components of APW were bioavailable and might have contributed towards the varied pharmacological activities demonstrated in our studies. CONCLUSION: APW was shown to possess anti-tumor, anti-metastatic and immunomodulatory activities in esophageal cancer cell-based and animal models, including immunocompromised mice model and clinically relevant PDX model. Our findings illustrated the potential multi-targeted efficacies of APW in esophageal cancer management.
Assuntos
Andrographis/química , Neoplasias Esofágicas/tratamento farmacológico , Fatores Imunológicos/farmacologia , Extratos Vegetais/farmacologia , 4-Nitroquinolina-1-Óxido/efeitos adversos , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Modelos Animais de Doenças , Diterpenos/sangue , Xenoenxertos , Humanos , Fatores Imunológicos/química , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Extratos Vegetais/química , Plantas MedicinaisRESUMO
Esophageal cancer (EC) is a seriously invasive malignancy with high mortality and poor prognosis. Metastasis of EC is the major cause of mortality. Our studies previously demonstrated that a herbal medicine Andrographis paniculata (AP) significantly suppressed EC growth and metastasis in vitro and in vivo. However, the underlying mechanisms responsible for these effects have not yet been systematically elucidated. In this context, gene expression profiling of AP-treated squamous EC cells (EC-109) was performed to reveal the regulatory mechanisms of AP in antitumor and antimetastasis signaling pathways using gene expression microarray analysis. Differentially expressed genes were identified by Affymetrix Gene Chip, followed by the real-time polymerase chain reaction validation. The results showed that the canonical pathways were significantly regulated by AP treatment, including multiple genes related to proliferation, apoptosis, intercellular adhesion, metastatic processes, and drug resistance, such as WNT, TGF-ß, MAPK and ErbB signaling pathways, and ATP-binding cassette transporter subfamily members. This genomic study emerges candidate molecular targets and pathways to reveal the mechanisms involved in AP's effects, which provides scientific evidence to support the clinical application of AP in EC treatment.
Assuntos
Andrographis/química , Neoplasias Esofágicas/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Fitoterapia/métodos , Plantas Medicinais/metabolismo , Neoplasias Esofágicas/patologia , HumanosRESUMO
Esophageal cancer (EC) is the fourth and sixth leading cause of cancer-related deaths in China and United States, respectively. The dismal prognosis of EC is mainly attributed to distant metastases, which may not be overcome by chemotherapy alone. Hence, the use of alternative adjuvant treatments, such as herbal medicines, for metastatic EC remains a great desire of patients. Our previous study demonstrated the in vivo anti-tumor and in vitro anti-invasion activities of Andrographis paniculata (AP) in esophageal cancer. In the present study, the chemical constituents of absorbed AP components through human intestinal Caco-2 cell monolayer were verified for the first time. The anti-migratory activities and suppressive effects on metastasis-related factors such as HER2, MMP2, MMP9, TM4SF3, CXCR4 of the absorbed AP components were revealed in esophageal cancer cells EC-109. The anti-tumor and anti-metastatic effects of AP water extract (1600 mg/kg) were further confirmed in metastatic esophageal xenograft-bearing mice. Besides, AP water extract acted synergistically with cisplatin plus 5-fluorouracil on inhibiting tumor nodule growth (with combination index <0.7). Meanwhile, chemotherapeutics-induced side-effects could also be reduced by AP water extract. The present findings provide evidence on safety and advantages of the combined use of AP with chemotherapeutics in pre-clinical setting.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Andrographis/química , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Neoplasias Esofágicas/patologia , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMO
According to Chinese Pharmacopoeia 2015 edition, Ganoderma (Lingzhi) is a species complex that comprise of Ganoderma lucidum and Ganoderma sinense. The bioactivity and chemical composition of G. lucidium had been studied extensively, and it was shown to possess antitumor activities in pharmacological studies. In contrast, G. sinense has not been studied in great detail. Our previous studies found that the stipe of G. sinense exhibited more potent antitumor activity than the pileus. To identify the antitumor compounds in the stipe of G. sinense, we studied its chemical components by merging the bioactivity results with liquid chromatography-mass spectrometry-based chemometrics. The stipe of G. sinense was extracted with water, followed by ethanol precipitation and liquid-liquid partition. The resulting residue was fractionated using column chromatography. The antitumor activity of these fractions were analysed using MTT assay in murine breast tumor 4T1 cells, and their chemical components were studied using the LC-QTOF-MS with multivariate statistical tools. The chemometric and MS/MS analysis correlated bioactivity with five known cytotoxic compounds, 4-hyroxyphenylacetate, 9-oxo-(10E,12E)-octadecadienoic acid, 3-phenyl-2-propenoic acid, 13-oxo-(9E,11E)-octadecadienoic acid and lingzhine C, from the stipe of G. sinense. To the best of our knowledge, 4-hyroxyphenylacetate, 3-phenyl-2-propenoic acid and lingzhine C are firstly reported to be found in G. sinense. These five compounds will be investigated for their antitumor activities in the future.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Cromatografia Líquida de Alta Pressão , Ganoderma/genética , Espectrometria de Massas em Tandem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ganoderma/química , Camundongos , Análise MultivariadaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Herba Cistanches (HC, Cistanche deserticola or Cistanche tubulosa) is a Chinese herb traditionally used for muscle problems. Previous studies demonstrated that HC extract could reduce muscle damage and improve ATP storage in post-exercised rats. However, its effect on statin-induced muscle toxicity has never been investigated. AIM: The objective of this study was to determine if the aqueous extract of HC (HCE) could prevent simvastatin-induced toxicity in L6 rat skeletal muscle cells; and whether verbascoside is the major bioactive constituent which contributes to the effects. MATERIALS AND METHODS: MTT was performed to determine the effects of HCE (0-2000µg/ml) or verbascoside (0-160µM) on simvastatin (10µM)-treated L6 cells. Annexin V-FITC/PI apoptosis assay and Caspase 3 assay were performed to determine the protective role of HCE on simvastatin-induced cell death, and to evaluate if HCE exerted its protective effect through the caspase pathway. ATP production was measured to investigate if HCE could prevent simvastatin-induced reduction in ATP production in vitro. RESULTS: Simvastatin significantly increased apoptotic cell death in L6 cells. HCE significantly exerted a dose-dependent reduction on simvastatin-induced apoptotic cells, possibly via caspase-3 pathway. Simvastatin reduced the ATP production in L6 cells, which was dose-dependently prevented by HCE. There was only a trend but not significant effect (except at high dose) of verbascoside on the protection of simvastatin-induced muscle toxicity. CONCLUSIONS: In conclusion, we demonstrated for the first time that HCE could exert dose-dependent protective effect on simvastatin-induced toxicity in vitro, which was unlikely due to the presence of verbascoside. Our study suggested the potential use of HC under the situation of simvastatin-induced muscle toxicity.
Assuntos
Apoptose/efeitos dos fármacos , Cistanche/química , Glucosídeos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Sinvastatina/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Caspase 3/metabolismo , Linhagem Celular , Cromatografia Líquida , Citoproteção , Relação Dose-Resposta a Droga , Glucosídeos/isolamento & purificação , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Fenóis/isolamento & purificação , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Substâncias Protetoras/isolamento & purificação , RatosRESUMO
Turmeric is commonly used as a medicinal herb and dietary supplement. Its active ingredient, curcumin, has been shown to possess antitumor effects in colorectal cancer patients. However, poor absorption of curcumin in intestine impedes its wide clinical application. Our previous findings showed that the presence of turmerones increased the accumulation of curcumin inside colonic cells. Hence, we hypothesized that curcumin with turmerones or present in turmeric ethanolic extract would augment its anti-tumor activities in tumor-bearing mice. The pharmacokinetics of curcumin in different preparations (containing same amount of curcumin) were studied in mice. The anti-tumor efficacies of curcumin or turmeric extract (with absorbable curcumin) in combination with bevacizumab were further investigated in HT29 colon tumor-bearing mice. Pharmacokinetic results showed that the plasma curcumin level of turmeric extract-fed mice was the highest, suggesting turmeric extract had the best bioavailability of curcumin. Besides, combined turmeric extract plus bevacizumab treatment significantly inhibited the tumor growth. Such inhibitory effects were stronger than those of curcumin plus bevacizumab or bevacizumab alone and were comparable with those of 5-fluorouracil+leucovorin+oxaliplatin (FOLFOX) plus bevacizumab. Notably, there was no observable side effect induced by turmeric extract treatment while significant side effects were found in FOLFOX-treated mice. In conclusion, combination of turmeric extract with bevacizumab possessed potent anti-tumor effects without observable side effects, strongly suggesting the adjuvant use of turmeric extract in colorectal cancer therapy. Our current findings warrant the confirmation regarding the benefits arising from the combined use of bevacizumab and turmeric in colorectal cancer patients in the near future.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Neoplasias do Colo/tratamento farmacológico , Curcumina/farmacologia , Etanol/química , Absorção Gastrointestinal , Extratos Vegetais/farmacologia , Solventes/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Curcuma/química , Curcumina/química , Curcumina/farmacocinética , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Schisandrae is traditionally used as a liver-toning Chinese herb. Recent studies suggested Fructus Schisandrae could prevent high-fat diet-induced hepatic steatosis as well as improving anti-oxidative status within the liver, which is a proposed mechanism against statin-induced liver toxicity. AIM: The aim of the present study was to determine if the combination use of Atorvastatin (AS) and Fructus Schisandrae aqueous extract (FSE) could (a) exert potent therapeutic effects not only on high-fat diet-induced hyperlipidemia, but also on hepatomegaly (enlarge of liver size) and hepatic steatosis (fatty liver); and (b) reduce side effects caused by intake of statin alone including increased incidence of elevated liver enzymes and liver toxicity in Sprague Dawley rats. MATERIALS AND METHODS: We studied 5 groups of Sprague Dawley rats that were given the following treatment for 8 weeks: (i) Normal-chow diet; (ii) High-fat diet (contains 21% fat and 0.15% cholesterol); (iii) High-fat diet (contains 21% fat and 0.15% cholesterol)+0.3% Atorvastatin; (iv) High-fat diet (contains 21% fat and 0.15% cholesterol)+0.45% FSE; (v) High-fat diet (contains 21% fat and 0.15% cholesterol)+0.3% Atorvastatin+0.45% FSE. After 8 weeks of treatment, body weight, adipose tissue and liver mass were measured, and liver and plasma lipid levels were determined to evaluate to effect of FSE with or without AS treatment on diet-induced obesity, hyperlipidemia and hepatic steatosis. Liver enzyme activities, anti-oxidative status and membrane permeability transition were also assessed to determine if FSE could reduce the side effects induced by AS. RESULTS: From the results, FSE treatment alone resulted in significant inhibitory effect on diet-induced increase in: (a) body weight; (b) fat pad mass (epididymal, perirenal and inguinal fat); (c) liver weight; (d) total liver lipid; (e) liver triglyceride and cholesterol levels; and (f) plasma lipid levels, suggesting FSE has a potential preventive beneficial effect on weight control and lipid metabolism in Sprague Dawley rats with diet-induced obesity. However, FSE supplementation exerted no further beneficial effect on diet-induced metabolic syndrome when it is combined with AS treatment, compared with rats given AS-treatment alone. At the dose of 0.45%, dietary FSE supplementation resulted in: (a) reduced liver enzymes (ALT and AST) levels; (b) reduced macrophage infiltration (CD68); (c) improved liver glutathione levels (anti-oxidative status); (d) reduced liver reactive oxidative species; (e) a trend to reduce calcium-induced membrane permeability transition within the liver. Most importantly, these improvements induced by FSE treatment were not only observed in the livers of rats given high-fat-diet, but also in high-fat-fed rats with atorvastatin-induced hepatotoxicity. CONCLUSIONS: Taken together, these data suggested FSE has a potential beneficial effect on weight control and lipid metabolism in Sprague Dawley rats with diet-induced obesity, and the combination use of FSE with AS could significantly prevent liver toxicity and anti-oxidative status induced by AS alone.
Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipidemias/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Schisandra/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada/métodos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-DawleyRESUMO
Atopic dermatitis (AD) is a widely prevalent and chronically relapsing inflammatory skin disease. Penta Herbs Formula (PHF) is efficacious in improving the quality of life and reducing topical corticosteroid used in children with AD and one of the active herbs it contains is Cortex Moutan. Recent studies showed that altered functions of dendritic cells (DC) were observed in atopic individuals, suggesting that DC might play a major role in the generation and maintenance of inflammation by their production of pro-inflammatory cytokines. Hence, the aims of the present study were to identify the major active component(s) of Cortex Moutan, which might inhibit DC functions and to investigate their possible interactions with conventional corticosteroid on inhibiting the development of DC from monocytes. Monocyte-derived dendritic cells (moDC) culture model coupled with the high-speed counter-current chromatography (HSCCC), high pressure liquid chromatography (HPLC) and Liquid Chromatography-Mass Spectrometry (LCMS) analyses were used. Gallic acid was the major active component from Cortex Moutan which could dose dependently inhibit interleukin (IL)-12 p40 and the functional cluster of differentiation (CD) surface markers CD40, CD80, CD83 and CD86 expression from cytokine cocktail-activated moDC. Gallic acid could also lower the concentration of hydrocortisone required to inhibit the activation of DC.
Assuntos
Células Dendríticas/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Ácido Gálico/química , Ácido Gálico/farmacologia , Monócitos/citologia , Paeonia/química , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , HumanosRESUMO
The pneumo- and hepato-toxicity of 4-vinylphenol (4VP), a styrene metabolite, has been previously reported. Nevertheless, the present study reported the novel anti-angiogenic activities of 4VP which was firstly isolated from the aqueous extract of a Chinese medicinal herb Hedyotis diffusa. Our results showed that 4VP at non-toxic dose effectively suppressed migration, tube formation, adhesion to extracellular matrix proteins, as well as protein and mRNA expressions of metalloproteinase-2 of human endothelial cells (HUVEC and HMEC-1). Investigation of the signal transduction revealed that 4VP down-regulated PI3K/AKT and p38 MAPK. Besides, 4VP interfered with the phosphorylation of ERK1/2, the translocation and expression of NFkappaB. In zebrafish embryo model, the new blood vessel growth was significantly blocked by 4VP (6.25-12.5 µg/mL medium). The VEGF-induced blood vessel formation in Matrigel plugs in C57BL/6 mice was suppressed by 4VP (20-100 µg/mL matrigel). In addition, the blood vessel number and tumor size were reduced by intraperitoneal 4VP (0.2-2 mg/kg) in 4T1 breast tumor-bearing BALB/c mice, with doxorubicin as positive control. Together, the in vitro and in vivo anti-angiogenic activities of 4VP were demonstrated for the first time. These findings suggest that 4VP has great potential to be further developed as an anti-angiogenic agent.