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1.
Phytomedicine ; 128: 155524, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38552435

RESUMEN

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disease. Current research suggests that the long-term persistence and recurrence of psoriasis are closely related to the feedback loop formed between keratinocytes and immune cells, especially in Th 17 or DC cells expressing CCR6. CCL20 is the ligand of CCR6. Therefore, drugs that block the expression of CCL20 or CCR6 may have a certain therapeutic effect on psoriasis. Glycyrrhetinic acid (GA) is the main active ingredient of the plant drug licorice and is often used to treat autoimmune diseases, including psoriasis. However, its mechanism of action is still unclear. METHODS: Psoriasis like skin lesion model was established by continuously applying imiquimod on the back skin of normal mice and CCR6-/- mice for 7 days. The therapeutic and preventive effects of glycyrrhetinic acid (GA) on the model were observed and compared. The severity of skin injury is estimated through clinical PASI scores and histopathological examination. qRT-PCR and multiple cytoline assay were explored to detect the expression levels of cytokines in animal dorsal skin lesions and keratinocyte line HaCaT cells, respectively. The dermis and epidermis of the mouse back were separated for the detection of CCL20 expression. Transcription factor assay was applied to screen, and luciferase activity assay to validate transcription factors regulated by GA. Technology of surface plasmon laser resonance with LC-MS (SPR-MS), molecular docking, and enzyme activity assay were used to identified the target proteins for GA. Finally, we synthesized different derivatives of 18beta-GA and compared their effects, as well as glycyrrhetinic acid (GL), on the skin lesion of imiquimod-induced mice to evaluate the active groups of 18beta-GA. RESULTS: 18ß-glycyrrhetinic acid (GA) improved IMQ-induced psoriatic lesions, and could specifically reduce the chemokine CCL20 level of the epidermis in lesion area, especially in therapeutic administration manner. The process was mainly regulated by transcription factor ATF2 in the keratinocytes. In addition, GUSB was identified as the primary target of 18ßGA. Our findings indicated that the subject on molecular target research of glycyrrhizin should be glycyrrhetinic acid (GA) instead of glycyrrhizic acid (GL), because GL showed little activity in vitro or in vivo. Apart from that, α, ß, -unsaturated carbonyl in C11/12 positions was crucial or unchangeable to its activity of 18ßGA, while proper modification of C3 or C30 position of 18ßGA may vastly increase its activity. CONCLUSION: Our research indicates that 18ßGA exerted its anti-psoriasis effect mainly by suppressing ATF2 and downstream molecule CCL20 predominately through α, ß, -unsaturated carbonyl at C11/12 position binding to GUSB in the keratinocytes, and then broke the feedback loop between keratinocytes and CCR6-expressing immune cells. GA has more advantages than GL in the external treatment of psoriasis. A highlight of this study is to investigate the influence of special active groups on the pharmacological action of a natural product, inspired by the molecular docking result.


Asunto(s)
Quimiocina CCL20 , Ácido Glicirretínico , Ácido Glicirretínico/análogos & derivados , Psoriasis , Receptores CCR6 , Transducción de Señal , Animales , Ácido Glicirretínico/farmacología , Quimiocina CCL20/metabolismo , Psoriasis/tratamiento farmacológico , Humanos , Ratones , Transducción de Señal/efectos de los fármacos , Receptores CCR6/metabolismo , Factor de Transcripción Activador 2/metabolismo , Modelos Animales de Enfermedad , Queratinocitos/efectos de los fármacos , Células HaCaT , Imiquimod , Piel/efectos de los fármacos , Piel/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Glycyrrhiza/química
2.
FASEB J ; 35(9): e21870, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34436790

RESUMEN

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Flavanonas/farmacología , Glucósidos/farmacología , Inflamación/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Ubiquitina Tiolesterasa/deficiencia , Animales , Línea Celular , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Proteínas Cullin/metabolismo , Citocinas/metabolismo , Sulfato de Dextran/farmacología , Sulfato de Dextran/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Flavanonas/uso terapéutico , Glucósidos/uso terapéutico , Inflamación/inducido químicamente , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Pirroles/farmacología , Pirrolidinas/farmacología , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitinación
3.
Molecules ; 25(10)2020 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-32429384

RESUMEN

Epigallocatechin gallate (EGCG), the main green tea polyphenol, exerts a wide variety of biological actions. Epigenetically, the catechin has been classified as a DNMTs inhibitor, however, its impact on histone modifications and chromatin structure is still poorly understood. The purpose of this study was to find the impact of EGCG on the histone posttranslational modifications machinery and chromatin remodeling in human endothelial cells of both microvascular (HMEC-1) and vein (HUVECs) origin. We analyzed the methylation and acetylation status of histones (Western blotting), as well as assessed the activity (fluorometric assay kit) and gene expression (qPCR) of the enzymes playing a prominent role in shaping the human epigenome. The performed analyses showed that EGCG increases histone acetylation (H3K9/14ac, H3ac), and methylation of both active (H3K4me3) and repressive (H3K9me3) chromatin marks. We also found that the catechin acts as an HDAC inhibitor in cellular and cell-free models. Additionally, we observed that EGCG affects chromatin architecture by reducing the expression of heterochromatin binding proteins: HP1α, HP1γ. Our results indicate that EGCG promotes chromatin relaxation in human endothelial cells and presents a broad epigenetic potential affecting expression and activity of epigenome modulators including HDAC5 and 7, p300, CREBP, LSD1 or KMT2A.


Asunto(s)
Catequina/análogos & derivados , Cromatina/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histonas/genética , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Acetilación/efectos de los fármacos , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Catequina/aislamiento & purificación , Catequina/farmacología , Línea Celular , Cromatina/química , Cromatina/metabolismo , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Epigénesis Genética , Inhibidores de Histona Desacetilasas/aislamiento & purificación , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Metilación/efectos de los fármacos , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Té/química , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismo
4.
Int J Oncol ; 53(4): 1691-1702, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30066913

RESUMEN

MicroRNAs (miRNAs or miRs) play important roles in numerous cellular processes, including development, proliferation, tumorigenesis and apoptosis. It has been reported that miRNA expression is induced by ionizing radiation (IR) in cancer cells. However, the underlying molecular mechanisms are not yet fully understood. In this study, endogenous miR­320a and its primary precursor (pri­miR­320a) were assayed by reverse transcription­quantitative PCR (RT­qPCR). Luciferase activities were measured using a dual­luciferase reporter assay system. Western blot analysis was used to determine the protein expressions of upstream and downstream genes of miR­320a. Cell apoptosis was evaluated by Annexin V apoptosis assay and cell proliferation was measured using the trypan blue exclusion method. The results revealed that miR­320a expression increased linearly with the IR dose and treatment duration. Three transcription factors, activating transcription factor 2 (ATF2), ETS transcription factor (ELK1) and YY1 transcription factor (YY1), were activated by p38 mitogen­activated protein kinase (MAPK) and mitogen­activated protein kinase 8 (JNK) and by upregulated miR­320a expression under IR conditions. In addition, it was identified that X­linked inhibitor of apoptosis (XIAP) was an miR­320a target gene during the IR response. By targeting XIAP, miR­320a induced apoptosis and inhibited the proliferation of the cancer cells. On the whole, the results of this study demonstrated that miRNA­320a, regulated by the p38 MAPK/JNK pathway, enhanced the radiosensitivity of cancer cells by inhibiting XIAP and this may thus prove to be a potential therapeutic approach with which to overcome radioresistance in cancer treatment.


Asunto(s)
Apoptosis/efectos de la radiación , Sistema de Señalización de MAP Quinasas/efectos de la radiación , MicroARNs/genética , Neoplasias/radioterapia , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Sistema de Señalización de MAP Quinasas/genética , MicroARNs/metabolismo , Neoplasias/genética , Regiones Promotoras Genéticas , ARN Interferente Pequeño/metabolismo , Tolerancia a Radiación/genética , Radiación Ionizante , Resultado del Tratamiento , Regulación hacia Arriba/efectos de la radiación , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismo , Proteína Elk-1 con Dominio ets/genética , Proteína Elk-1 con Dominio ets/metabolismo
5.
J Proteome Res ; 17(7): 2470-2479, 2018 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-29812950

RESUMEN

Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment. DHE affected cancer-associated signaling pathways, including NF-κB, ß-catenin, and endoplasmic reticulum stress. Through quantitative pathway and key node analysis of the proteomics data, activating transcription factor 2 (ATF-2) and c-Jun kinase (JNK) were found to be the key components in DHE's modulated biological pathways. Based on the pathway analysis as well as chemical similarity to estradiol, DHE is proposed to be a phytoestrogen. The proteomic, bioinformatic, and chemoinformatic analyses were further verified with individual cell-based experiments. Our study demonstrates a workflow for identifying the mechanisms of action of DHE through shotgun proteomic analysis.


Asunto(s)
Antineoplásicos/farmacología , Fenantrenos/farmacología , Fitoquímicos/farmacología , Factor de Transcripción Activador 2/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neoplasias/patología , Fitoestrógenos , Poaceae/química , Proteómica/métodos , Transducción de Señal/efectos de los fármacos
6.
Sci Rep ; 6: 34314, 2016 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-27708346

RESUMEN

Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-ß driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-ß activation and its effects contributing to OSF. However, the mechanism for activation of TGF-ß signaling in OSF is still unknown. In this study we demonstrate activation of TGF-ß signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-ß transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-ß promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-ß signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Areca/química , MAP Quinasa Quinasa 4/metabolismo , Mucosa Bucal , Neoplasias de la Boca , Nueces/química , Proteína Oncogénica p65(gag-jun)/metabolismo , Extractos Vegetales/farmacología , Lesiones Precancerosas , Factor de Crecimiento Transformador beta/metabolismo , Línea Celular Transformada , Femenino , Fibrosis , Humanos , Masculino , Mucosa Bucal/metabolismo , Mucosa Bucal/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Extractos Vegetales/química , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología
7.
Genet Mol Res ; 15(3)2016 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-27706758

RESUMEN

Ginsenoside Rh2 has been shown to have an anti-tumor effect on a wide range of cancers. A previous study has shown that ginsenoside Rh2 can inhibit the proliferation of the human lung adenocarcinoma A549 cell line in a dose-dependent manner by activating caspase-8/3 activity to promote apoptosis. However, the association of the JNK signaling pathways and transcription factors with ginsenoside Rh2 in the suppression of non-small cell lung cancer has not yet been reported. In this study, we found that ginsenoside Rh2 can activate the JNK/MAPKs signaling pathway and increase the phosphorylation and transcriptional activity of the transcription factors AP-1 and ATF2. Ginsenoside Rh2 also reduced the expression of transcription factors E2F1 and c-Myc. Furthermore, ginsenoside Rh2 affected the expression levels of cyclin D1 and the CDK4 protein, which are key regulatory factors of the G1/S cyclin-dependent kinase. The anti-proliferative and induced apoptotic effects of ginsenoside Rh2 on A549 cell provide evidence to support the application of traditional Chinese medicine to lung cancer treatment.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Ginsenósidos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células A549 , Factor de Transcripción Activador 2/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Apoptosis/efectos de los fármacos , Caspasa 8/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Factor de Transcripción AP-1/metabolismo
8.
J Nutr Biochem ; 34: 17-29, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27162022

RESUMEN

Benzo(a)pyrene [B(a)P] is an environmental toxicant that alters the steroidogenic profile of testis and induces testicular dysfunction. In the present study, we have investigated the molecular signaling of B(a)P and the ameliorative potential of the natural aryl hydrocarbon receptor (AhR) antagonist and antioxidant, resveratrol, on B(a)P-induced male reproductive toxicity. Studies showed that B(a)P treatment resulted in p38 MAPK activation and increased inducible nitric oxide synthase (iNOS) production along with testicular apoptosis and steroidogenic dysfunction. Resveratrol cotreatment maintained testicular redox potential, increased serum testosterone level and enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3ßHSD, 17ßHSD) and prevented subsequent onset of apoptosis. Resveratrol cotreatment resulted inhibition of testicular cytochrome P4501A1 (CYP1A1) expression, which is the major B(a)P metabolizing agent for BPDE-DNA adduct formation. Resveratrol also significantly decreased the B(a)P-induced AhR protein level, its nuclear translocation and subsequent promoter activation, thereby decreased the expression of CYP1A1. Resveratrol also down-regulated B(a)P-induced testicular iNOS production through suppressing the activation of p38 MAPK and ATF2, thus improved the oxidative status of the testis and prevented apoptosis. Our findings cumulatively suggest that resveratrol inhibits conversion of B(a)P into BPDE by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis.


Asunto(s)
Antioxidantes/uso terapéutico , Benzo(a)pireno/antagonistas & inhibidores , Suplementos Dietéticos , Contaminantes Ambientales/antagonistas & inhibidores , Infertilidad Masculina/prevención & control , Estilbenos/uso terapéutico , Testículo/efectos de los fármacos , Factor de Transcripción Activador 2/agonistas , Factor de Transcripción Activador 2/antagonistas & inhibidores , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Antioxidantes/efectos adversos , Apoptosis/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Benzo(a)pireno/administración & dosificación , Benzo(a)pireno/toxicidad , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Suplementos Dietéticos/efectos adversos , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Ratas Wistar , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Resveratrol , Estilbenos/efectos adversos , Testículo/metabolismo , Testículo/patología , Testosterona/agonistas , Testosterona/antagonistas & inhibidores , Testosterona/sangre
9.
Nutr Diabetes ; 6: e210, 2016 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-27136448

RESUMEN

The mechanisms whereby prolonged plasma free fatty acids elevation, as found in obesity, causes hepatic insulin resistance are not fully clarified. We herein investigated whether inhibition of p38 mitogen-activated protein kinase (MAPK) prevented hepatic insulin resistance following prolonged lipid infusion. Chronically cannulated rats were subdivided into one of four intravenous (i.v.) treatments that lasted 48 h: Saline (5.5 µl min(-1)), Intralipid plus heparin (IH, 20% Intralipid+20 U ml(-1) heparin; 5.5 µl min(-1)), IH+p38 MAPK inhibitor (SB239063) and SB239063 alone. During the last 2 h of treatment, a hyperinsulinemic (5 mU kg(-1) min(-1)) euglycemic clamp together with [3-(3)H] glucose methodology was carried out to distinguish hepatic from peripheral insulin sensitivity. We found that SB239063 prevented IH-induced hepatic insulin resistance, but not peripheral insulin resistance. SB239063 also prevented IH-induced phosphorylation of activating transcription factor 2 (ATF2), a marker of p38 MAPK activity, in the liver. Moreover, in another lipid infusion model in mice, SB239063 prevented hepatic but not peripheral insulin resistance caused by 48 h combined ethyloleate plus ethylpalmitate infusion. Our results suggest that inhibition of p38 MAPK may be a useful strategy in alleviating hepatic insulin resistance in obesity-associated disorders.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácidos Grasos no Esterificados/sangre , Imidazoles/farmacología , Resistencia a la Insulina , Hígado/efectos de los fármacos , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Animales , Glucemia/metabolismo , Emulsiones/administración & dosificación , Emulsiones/efectos adversos , Técnica de Clampeo de la Glucosa , Heparina/administración & dosificación , Heparina/efectos adversos , Insulina/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/sangre , Fosfolípidos/administración & dosificación , Fosfolípidos/efectos adversos , Fosforilación , Ratas , Ratas Wistar , Aceite de Soja/administración & dosificación , Aceite de Soja/efectos adversos
10.
Zhongguo Zhong Yao Za Zhi ; 41(3): 514-520, 2016 Feb.
Artículo en Chino | MEDLINE | ID: mdl-28868873

RESUMEN

To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin-resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRⅡ, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPß, PGC1α, PPARγ and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat-induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine.


Asunto(s)
Tejido Adiposo Blanco/efectos de los fármacos , Berberina/administración & dosificación , Proteína Morfogenética Ósea 4/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Grasa Intraabdominal/efectos de los fármacos , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Proteína Morfogenética Ósea 4/metabolismo , Cricetinae , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Masculino
11.
Biol Pharm Bull ; 38(6): 862-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26027825

RESUMEN

Berberine is a natural product that shows benefits for metabolic syndrome (MS). However, the effects of berberine on the improvement of vascular inflammation and remodeling in MS remain unclear. This study aimed to investigate whether berberine could prevent vascular remodeling and inflammation in the MS condition. A rat model of MS was established, and MS rats were divided into two groups: MS group without berberine treatment, and MSB group with berberine treatment (each group n-10). Ten normal Wistar rats were used as controls (NC group). Vascular damage was examined by transmission electron microscopy and pathological staining. Compared to the NC group, the secretion of inflammatory factors was increased and the aortic wall thicker in the MS group. The MSB group exhibited decreased secretion of inflammatory factors and improved vascular remodeling, compared to the MS group. In addition, the levels of p38 mitogen-activated protein kinase (p38 MAPK), activating transcription factor 2 (ATF-2) and matrix metalloproteinase 2 (MMP-2) were significantly decreased in the MSB group compared to the MS group. In conclusion, our data show that berberine improves vascular inflammation and remodeling in the MS condition, and this is correlated with the ability of berberine to inhibit p38 MAPK activation, ATF-2 phosphorylation, and MMP-2 expression.


Asunto(s)
Berberina/uso terapéutico , Inflamación/prevención & control , Síndrome Metabólico/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Remodelación Vascular/efectos de los fármacos , Factor de Transcripción Activador 2/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/patología , Berberina/farmacología , Modelos Animales de Enfermedad , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Síndrome Metabólico/complicaciones , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Fosforilación , Extractos Vegetales/farmacología , Ratas Wistar , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
12.
J Biol Chem ; 289(33): 22942-22957, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-24982422

RESUMEN

Current views on the control of IL-23 production focus on the regulation of il23a, the gene encoding IL-23 p19, by NF-κB in combination with other transcription factors. C/EBP homologous protein (CHOP), X2-Box-binding protein 1 (XBP1), activator protein 1 (AP1), SMAD, CCAAT/enhancer-binding protein (C/EBPß), and cAMP-response element-binding protein (CREB) have been involved in response to LPS, but no data are available regarding the mechanism triggered by the fungal mimic and ß-glucan-containing stimulus zymosan, which produces IL-23 and to a low extent the related cytokine IL-12 p70. Zymosan induced the mobilization of CHOP from the nuclear fractions to phagocytic vesicles. Hypha-forming Candida also induced the nuclear disappearance of CHOP. Assay of transcription factor binding to the il23a promoter showed an increase of Thr(P)-71-Thr(P)-69-activating transcription factor 2 (ATF2) binding in response to zymosan. PKC and PKA/mitogen- and stress-activated kinase inhibitors down-regulated Thr(P)-71-ATF2 binding to the il23a promoter and il23a mRNA expression. Consistent with the current concept of complementary phosphorylations on N-terminal Thr-71 and Thr-69 of ATF2 by ERK and p38 MAPK, MEK, and p38 MAPK inhibitors blunted Thr(P)-69-ATF2 binding. Knockdown of atf2 mRNA with siRNA correlated with inhibition of il23a mRNA, but it did not affect the expression of il12/23b and il10 mRNA. These data indicate the following: (i) zymosan decreases nuclear proapoptotic CHOP, most likely by promoting its accumulation in phagocytic vesicles; (ii) zymosan-induced il23a mRNA expression is best explained through coordinated κB- and ATF2-dependent transcription; and (iii) il23a expression relies on complementary phosphorylation of ATF2 on Thr-69 and Thr-71 dependent on PKC and MAPK activities.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Subunidad p19 de la Interleucina-23/biosíntesis , Regiones Promotoras Genéticas/fisiología , Activación Transcripcional/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Zimosan/farmacología , Factor de Transcripción Activador 2/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Subunidad p19 de la Interleucina-23/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Activación Transcripcional/fisiología , Respuesta de Proteína Desplegada/fisiología
13.
Biochem Pharmacol ; 90(1): 34-49, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24780446

RESUMEN

The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H2O2)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H2O2 induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H2O2 induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.


Asunto(s)
Benzofuranos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Western Blotting , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Proteínas de Ciclo Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Humanos , Peróxido de Hidrógeno/farmacología , Microscopía Fluorescente , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Oxidantes/farmacología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
14.
J Ethnopharmacol ; 154(1): 218-28, 2014 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-24735861

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Korean Red Ginseng (KRG) is one of the representative traditional herbal medicines prepared from Panax ginseng Meyer (Araliaceae) in Korea. It has been reported that KRG exhibits a lot of different biological actions such as anti-aging, anti-fatigue, anti-stress, anti-atherosclerosis, anti-diabetic, anti-cancer, and anti-inflammatory activities. Although systematic studies have investigated how KRG is able to ameliorate various inflammatory diseases, its molecular inhibitory mechanisms had not been carried out prior to this study. MATERIALS AND METHODS: In order to investigate these mechanisms, we evaluated the effects of a water extract of Korean Red Ginseng (KRG-WE) on the in vitro inflammatory responses of activated RAW264.7 cells, and on in vivo gastritis and peritonitis models by analyzing the activation events of inflammation-inducing transcription factors and their upstream kinases. RESULTS: KRG-WE reduced the production of nitric oxide (NO), protected cells against NO-induced apoptosis, suppressed mRNA levels of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and interferon (IFN)-ß, ameliorated EtOH/HCl-induced gastritis, and downregulated peritoneal exudate-derived NO production from lipopolysaccharide (LPS)-injected mice. The inhibition of these inflammatory responses by KRG-WE was regulated through the suppression of p38, c-Jun N-terminal kinase (JNK), and TANK-binding kinase 1 (TBK1) and by subsequent inhibition of activating transcription factor (ATF)-2, cAMP response element-binding protein (CREB), and IRF-3 activation. Of ginsensides included in this extract, interestingly, G-Rc showed the highest inhibitory potency on IRF-3-mediated luciferase activity. CONCLUSION: These results strongly suggest that the anti-inflammatory activities of KRG-WE could be due to its inhibition of the p38/JNK/TBK1 activation pathway.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Antiinflamatorios/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Panax , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Citocinas/genética , Etanol , Gastritis/inducido químicamente , Gastritis/tratamiento farmacológico , Gastritis/metabolismo , Células HEK293 , Humanos , Ácido Clorhídrico , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Extractos Vegetales/uso terapéutico , ARN Mensajero/metabolismo , Solventes/química , Factor de Transcripción AP-1/metabolismo , Agua/química
15.
Free Radic Biol Med ; 67: 159-70, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24140706

RESUMEN

This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L., in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondrial caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratio, resulting in AIF and EndoG nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/NADPH oxidase 1 interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 with a specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, and then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation.


Asunto(s)
Epigénesis Genética , Furanos/farmacología , Regulación Neoplásica de la Expresión Génica , Lignanos/farmacología , Fitoestrógenos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Etilenodiaminas/farmacología , Femenino , Histonas/genética , Histonas/metabolismo , Humanos , Glándulas Mamarias Humanas/efectos de los fármacos , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/patología , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Estrógenos/deficiencia , Receptores de Estrógenos/genética , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
16.
Mol Biol Rep ; 40(12): 7017-25, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24178343

RESUMEN

Adiponectin is an adipokine hormone that influences glucose utilization, insulin sensitivity and energy homeostasis. To investigate the effect of adiponectin on lipids deposition in broilers, rosiglitazone and dexamethasone were used to treat broilers. A total of 120 twenty-three-day-old male Cobb broilers were randomly divided into 3 groups for 3 weeks of drug treatment. Serum adiponectin level and fatty acid composition in muscles were measured. Adiponectin, adiponectin receptors (adipoR1, adipoR2) and lipid metabolism-related genes expression levels in muscles were measured using real-time PCR. Western blot was used to measure the expression levels of lipid metabolism-related proteins and the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK)/activating transcription factor 2 (ATF2) pathway marker proteins. Rosiglitazone increased serum adiponectin concentration and the expression levels of adiponectin and adipoR1 (P < 0.05), while dexamethasone had the opposite effect. Intramuscular fat content, total fatty acid, saturated fatty acid and monounsaturated fatty acid reduced in the rosiglitazone treatment group (P < 0.05). In the rosiglitazone treatment group, the expression levels of lipogenic genes and proteins decreased in the muscles, whereas the expression levels of lipolysis genes increased. Meanwhile, the phosphorylation levels of p38MAPK and ATF2 increased with supplementation of rosiglitazone and decreased in the dexamethasone treatment group (P < 0.01). These results indicated that rosiglitazone and dexamethasone could regulate adiponectin expression in muscle of broilers and adiponectin had an anti-lipogenic effect by p38 MAPK/ATF2 signaling pathway.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Adiponectina/metabolismo , Pollos/metabolismo , Metabolismo de los Lípidos , Músculos/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adiponectina/sangre , Adiponectina/genética , Animales , Pollos/sangre , Pollos/genética , Pollos/crecimiento & desarrollo , Extremidades , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/genética , Masculino , Músculos/efectos de los fármacos , Músculos/enzimología , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Adiponectina/metabolismo , Rosiglitazona , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tiazolidinedionas/farmacología
17.
Mol Pain ; 9: 13, 2013 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-23517865

RESUMEN

BACKGROUND: Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. RESULTS: EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat's paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. CONCLUSIONS: The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.


Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Electroacupuntura , Inflamación/enzimología , Dolor/enzimología , Columna Vertebral/enzimología , Canales Catiónicos TRPV/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Analgesia , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Conducta Animal/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Activación Enzimática/efectos de los fármacos , Adyuvante de Freund , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/patología , Inflamación/terapia , Masculino , Dolor/tratamiento farmacológico , Dolor/patología , Fosforilación/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/enzimología , Células del Asta Posterior/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Columna Vertebral/patología , Canales Catiónicos TRPV/genética , Factores de Tiempo
18.
Oxid Med Cell Longev ; 2012: 390385, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22919439

RESUMEN

BACKGROUND: Epidemiological studies suggest that coffee consumption reduces the risk of cancer, but the molecular mechanisms of its chemopreventive effects remain unknown. OBJECTIVE: To identify differentially expressed genes upon incubation of HT29 colon cancer cells with instant caffeinated coffee (ICC) or caffeic acid (CA) using whole-genome microarrays. RESULTS: ICC incubation of HT29 cells caused the overexpression of 57 genes and the underexpression of 161, while CA incubation induced the overexpression of 12 genes and the underexpression of 32. Using Venn-Diagrams, we built a list of five overexpressed genes and twelve underexpressed genes in common between the two experimental conditions. This list was used to generate a biological association network in which STAT5B and ATF-2 appeared as highly interconnected nodes. STAT5B overexpression was confirmed at the mRNA and protein levels. For ATF-2, the changes in mRNA levels were confirmed for both ICC and CA, whereas the decrease in protein levels was only observed in CA-treated cells. The levels of cyclin D1, a target gene for both STAT5B and ATF-2, were downregulated by CA in colon cancer cells and by ICC and CA in breast cancer cells. CONCLUSIONS: Coffee polyphenols are able to affect cyclin D1 expression in cancer cells through the modulation of STAT5B and ATF-2.


Asunto(s)
Factor de Transcripción Activador 2/genética , Café/química , Ciclina D1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias/genética , Polifenoles/farmacología , Factor de Transcripción STAT5/genética , Factor de Transcripción Activador 2/metabolismo , Ácidos Cafeicos/farmacología , Cafeína/farmacología , Línea Celular Tumoral , Ciclina D1/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Humanos , Neoplasias/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factor de Transcripción STAT5/metabolismo
19.
Mol Nutr Food Res ; 56(2): 325-35, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22147653

RESUMEN

SCOPE: Chlorogenic acid (CA), caffeine (CAFF), pyrogallol (PYR), catechol (CAT), (ß)N-alkanoyl-hydroxytryptamides (C5HT) and N-methylpyridinium (N-MP) were evaluated for their influence on mechanisms of gastric acid secretion as single compounds and in biomimetic mixtures. METHODS AND RESULTS: Compounds were tested in coffee representative concentrations. Human gastric cancer cells (HGT-1) were used to study the proton secretory activity by Ussing chamber experiments and FACS analysis. For activation of EGFr, Akt1, ERK1/2, ATF-2 and cAMP levels, we performed pathway screening assays. Time-dependent expression of related genes were determined by real-time PCR. Part of the data was used for neural network modeling to identify the most relevant compounds. N-MP increased the expression of the anti-secretory somatostatin receptor by 114%, whereas C5HT decreased its expression by 52%. N-MP down-regulated the pro-secretory CHRM3 receptor by 36% and the H⁺,K⁺-ATPase by 36%. CAFF stimulated the secretory activity in the functional assays, whereas N-MP and CA decreased proton secretion. After applying a pathway analysis, we were able to discriminate between CAFF, CA, CAT, C5HT, PYR and histamine-activating EGFr signaling and N-MP-associated ERK1/2 signaling. CONCLUSION: By applying a multi-parametric approach, N-MP was shown to effectively down-regulate mechanisms of gastric acid secretion in human parietal gastric cells.


Asunto(s)
Café/efectos adversos , Café/química , Ácido Gástrico/metabolismo , Células Parietales Gástricas/efectos de los fármacos , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Alcaloides/farmacología , Cafeína/farmacología , Catecoles/farmacología , Línea Celular Tumoral , Ácido Clorogénico/farmacología , AMP Cíclico/metabolismo , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Células Parietales Gástricas/metabolismo , Protones , Compuestos de Piridinio/farmacología , Pirogalol/farmacología , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo
20.
Integr Cancer Ther ; 11(1): 48-60, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21665879

RESUMEN

Nomilin is a triterpenoid present in common edible citrus fruits with putative anticancer properties. In this study, the authors investigated the antimetastatic potential of nomilin and its possible mechanism of action. Metastasis was induced in C57BL/6 mice through the lateral tail vein using highly metastatic B16F-10 melanoma cells. Administration of nomilin inhibited tumor nodule formation in the lungs (68%) and markedly increased the survival rate of the metastatic tumor-bearing animals. These results correlated with the biochemical parameters and histopathological analysis. Nomilin showed an inhibition of tumor cell invasion and activation of matrix metalloproteinases. Treatment with nomilin induced apoptotic response, characterized by an increase in the sub-G1 fraction of cells with chromatin condensation and membrane blebbing, a typical ladder of DNA fragmentation, and detection of apoptotic cells by TUNEL assay. Nomilin treatment also exhibited a downregulated Bcl-2 and cyclin-D1 expression and upregulated p53, Bax, caspase-9, caspase-3, p21, and p27 gene expression in B16F-10 cells. Proinflammatory cytokine production and gene expression were found to be downregulated in nomilin-treated cells. The study also reveals that nomilin could inhibit the activation and nuclear translocation of antiapoptotic transcription factors such as nuclear factor (NF)-κB, CREB, and ATF-2 in B16F-10 cells.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Benzoxepinas/farmacología , Limoninas/farmacología , Melanoma Experimental/tratamiento farmacológico , Factores de Transcripción/genética , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Animales , Apoptosis/genética , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 9/genética , Caspasa 9/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Fragmentación del ADN/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tasa de Supervivencia , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Proteína X Asociada a bcl-2/genética
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