RESUMEN
Microbiota-derived catabolism of nutrients is closely related to ulcerative colitis (UC). The level of indole-3-acetic acid (IAA), a microbiota-dependent metabolite of tryptophan, was decreased significantly in the feces of UC patients. Thus supplementation with IAA could be a potential therapeutic method for ameliorating colitis. In this work, the protective effect of supplementation with IAA on dextran sulfate sodium (DSS)-induced colitis was evaluated, and the underlying mechanism was elucidated. The results indicated that the administration of IAA significantly relieved DSS-induced weight loss, reduced the disease activity index (DAI), restored colon length, alleviated intestinal injury, and improved the intestinal tight junction barrier. Furthermore, IAA inhibited intestinal inflammation by reducing the expression of proinflammatory cytokines and promoting the production of IL-10 and TGF-ß1. In addition, the ERK signaling pathway is an important mediator of various physiological processes including inflammatory responses and is closely associated with the expression of IL-10. Notably, IAA treatment induced the activation of extracellular signal-regulated kinase (ERK), which is involved in the progression of colitis, while the ERK inhibitor U0126 attenuated the beneficial effects of IAA. In summary, IAA could attenuate the clinical symptoms of colitis, and the ERK signaling pathway was involved in the underlying mechanism. Supplementation with IAA could be a potential option for preventing or ameliorating UC.
Asunto(s)
Colitis Ulcerosa , Colitis , Ácidos Indolacéticos , Humanos , Animales , Ratones , Interleucina-10/metabolismo , Sulfato de Dextran/toxicidad , Sulfato de Dextran/metabolismo , Colon/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/efectos adversos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. OBJECTIVE: This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. MATERIALS & METHODS: Animals were randomly divided into 6 groups, control, vehicle, donepezil (10 mg/kg, p.o.), and isofraxidin (3, 10, and 30 mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1 mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. RESULTS: Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). DISCUSSION & CONCLUSIONS: These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Escopolamina , Animales , Ratones , Escopolamina/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/efectos adversos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Acetilcolinesterasa/metabolismo , Donepezilo/farmacología , Donepezilo/uso terapéutico , Memoria , Hipocampo/metabolismo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Cumarinas/farmacología , Cumarinas/uso terapéutico , Aprendizaje por Laberinto , Transducción de Señal , CogniciónRESUMEN
The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (-)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-ß-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-ß-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-ß-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-ß-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-ß-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-ß-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself.
Asunto(s)
Catequina/análogos & derivados , Quinasas MAP Reguladas por Señal Extracelular/efectos adversos , Luteolina/farmacología , Miofibroblastos/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/efectos adversos , Catequina/farmacología , Línea Celular , Sinergismo Farmacológico , Humanos , Miofibroblastos/citología , Miofibroblastos/metabolismo , FenotipoRESUMEN
The cytokine and potent angiogenic factor vascular endothelial growth factor (VEGF) plays an important role in airway remodelling in various airway diseases such as idiopathic pulmonary fibrosis, pulmonary hypertension, lung cancer, asthma and chronic obstructive pulmonary disease (COPD). The effect of cigarette-smoking on VEGF expression, the modulatory role of extracellular signal-regulated kinase (ERK)-1,-2, p38mitogen-activated protein kinase (MAPK), histone acetylation and the anti-inflammatory effect of dexamethasone on TNFalpha-induced VEGF expression were examined in human airway smooth muscle cells (HASMC) of five non-smokers, 17 smokers without airflow limitation and 15 smokers with COPD. TNFalpha increased VEGF expression 5.4-fold and 4.0-fold in HASMC from non-smokers and smokers without airflow limitation, respectively, but only 2.5-fold in HASMC from smokers with COPD compared with non-stimulated HASMC. VEGF production was dependent on phosphorylation of ERK-1,-2 and p38MAPK, as was shown by examining the effects of PD 098059 (10 microM), an inhibitor of the upstream activator of MAPKkinase (MKK)-1, and SB 203580 (10 microM), an inhibitor of p38MAPK; there were no differences between non-smokers, smokers without airflow limitation and smokers with COPD in this respect. Dexamethasone (DEX; 10(-12)-10(-4) M) reduced TNFalpha-induced phosphorylation of ERK-1/-2 and prevented TNFalpha-induced VEGF generation without differences between non-smokers, smokers with and without COPD. There was an additional inhibitory effect of DEX (10(-12) M) on VEGF-release when PD 098059 was added. The basal and TNFalpha-induced acetylation status of the VEGF-promoter (chromatin immunoprecipitation [ChIP] assay) was increased in HASMC from smokers with COPD compared with smokers without airflow limitation and non-smokers. In comparison to non-stimulated HASMC, TNFalpha decreased the acetylation status of the VEGF-promoter by approximately 46% and approximately 43% in HASMC from non-smokers and smokers without COPD compared with approximately 68% in HASMC from smokers with COPD. The data suggest that HASMC express VEGF in response to TNFalpha and that this may be reduced in HASMC of smokers with COPD in a smoking-independent manner. VEGF expression is directly modulated by phosphorylation of ERK-1,-2 and p38MAPK and by histone acetylation and the acetylation status of the VEGF gene is increased in HASMC of smokers with COPD in a smoking-independent manner. TNFalpha reduced the acetylation status of the VEGF promoter in HASMC.