ABSTRACT
Indole-3 carbinol (I3C) has shown dual effects on the promotion and progression stages of colon carcinogenesis while synbiotics (Syn) have exerted anti-carcinogenic activities in most rodent studies. This study aimed to investigate the effects of I3C given alone or together with a Syn intervention on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. All animals were given four subcutaneous DMH injections (4×40 mg/kg bodyweight, twice a week for two weeks) and then received either basal diet (G1), basal diet containing I3C (1g/kg chow) (G2) or basal diet containing I3C+Syn (I3C + inulin 50g/kg chow + Bifidobacterium lactis BB-12®), 2.5×1010 cfu/g of basal diet), (G3) for 21 weeks. Dietary I3C (G2) significantly increased tumour volume and cell proliferation when compared to the DMH control group (G1). Syn intervention (G3) significantly reduced tumour volume and cell proliferation when compared to I3C (G2). The colon tumours found were classified into well-differentiated tubular adenomas or adenocarcinomas. Dietary I3C or I3C+Syn did not significantly affect the incidence and the multiplicity of tumours in comparison with the DMH control group. Furthermore, Syn intervention (G3) increased Gstm1 and reduced Mapk9 gene expression in colonic tumours. The findings of the present study show that the dietary I3C shows a weak promoting activity, while the combination with Syn ameliorates I3C effects.
Subject(s)
Carcinogenesis , Colonic Neoplasms , Indoles , Synbiotics , Animals , Carcinogenesis/drug effects , Colonic Neoplasms/prevention & control , Indoles/adverse effectsABSTRACT
The mechanisms that are responsible for the restricted pattern of expression of the VE-cadherin gene in endothelial cells are not clearly understood. Regulation of expression is under the control of an approximately 140 bp proximal promoter that provides basal, non-endothelial specific expression. A larger region contained within the 2.5 kb genomic DNA sequence located ahead of the transcription start is involved in the specific expression of the gene in endothelial cells. We show here that the VE-cadherin promoter contains several putative hypoxia response elements (HRE) which are able to bind endothelial nuclear factors under normoxia. The VE-cadherin gene is not responsive to hypoxia but hypoxia-inducible factor (HIF)-2alpha specifically activates the promoter while HIF-1alpha does not. The HRE, that are involved in this activity have been identified. Further, we show that HIF-2alpha cooperates with the Ets-1 transcription factor for activation of the VE-cadherin promoter and that this synergy is dependent on the binding of Ets-1 to DNA. This cooperative action of HIF-2alpha with Ets-1 most probably participates to the transcriptional regulation of expression of the gene in endothelial cells. This mechanism may also be involved in the expression of the VE-cadherin gene by tumor cells in the process of vascular mimicry.
Subject(s)
Antigens, CD/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Cadherins/genetics , Gene Expression Regulation/physiology , Proto-Oncogene Protein c-ets-1/physiology , 3T3 Cells , Animals , Antigens, CD/biosynthesis , Cadherins/biosynthesis , Cell Hypoxia/genetics , Endothelial Cells/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Myocardium/cytology , Promoter Regions, Genetic , Proto-Oncogene Protein c-ets-1/genetics , Response Elements , Transcriptional Activation , TransfectionABSTRACT
A técnica de análise térmica apresenta aplicações em diversos ramos da ciência, entre eles a indústria farmacêutica, a qual pode utilizá-la para caracterização e estudo das matérias primas e produtos finais. Os compostos farmacêuticos apresentam diferentes formas morfológicas ou estruturais,que afetam diretamente na sua estabilidade, ação e liberação. O desenvolvimento e fabricação de medicamentos requerem intenso cuidado devido a pureza, qualidade e estabilidade dos componentes. Um dos itens para se obter uma formulação estável e efetiva depende dos cuidados na escolha dos excipientes utilizados, onde uma de suas propriedades é a de interferir na biodisponibilidade e proteção do fármaco frente a degradação. Neste trabalho foram utilizadas técnicas de análise térmica (TG/DTG/DSC/DTA) e a espectroscopia Raman para estudar possíveis interações entre o fármaco e seus excipientes. Foram selecionados para o estudo os medicamentos Aspirina® e AAS®, comparados com o seu princípio ativo ácido acetil salicílico. As amostras não sofreram pré tratamento e foram analisadas como adquiridas no mercado. Os resultados obtidos através das técnicas de análise térmica evidenciaram uma possível interação entre os diferentes excipientes utilizados e o princípio ativo. Os espectros Raman corroboram com os resultados obtidos das análises térmicas dos medicamentos. Através dos resultados obtidos concluímos que as diferentes composições existentes na formulação dos medicamentos podem promover mudanças em suas propriedades físicas e consequentemente na sua atividade biológica.
