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Can J Gastroenterol Hepatol ; 2018: 4379673, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186819


Background: The wnt/APC/ß-catenin pathway is a critical initiator in colorectal carcinogenesis in both hereditary and sporadic colorectal cancer (CRC). The progression of this process remains incompletely understood, although inflammation is pivotal. Drivers of inflammation are elevated in malignant tissue and have been shown to regulate ß-catenin expression. Interleukin-17A (IL-17A) is protumorigenic at elevated levels via COX-2 stimulation. Elevated peroxisome proliferator-activated receptor γ (PPARγ) expression has reduced risk of carcinogenesis and good overall prognosis in established CRC. Activation of PPARγ has inhibitory effect on ß-catenin. Methods: Using qPCR and IHC, we compared ß-catenin, PPARγ, COX-2, and IL-17A in the colonic mucosa of patients with sporadic CRC, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS), against a normal control population. Results: ß-catenin mRNA and protein expression progressively increased from the Normal group, through IBS and IBD reaching statistical significance in CRC. COX-2 mRNA levels increased similarly with statistical significance in IBD and CRC. However, COX-2 protein expression was inverted with significant expression in the Normal and IBS groups and reduced levels in IBD and CRC. PPARγ mRNA expression was unchanged in IBD and CRC but was significantly elevated in the IBS. IL-17A mRNA was significantly reduced in IBS and CRC but unchanged in IBD. There were no differences in all parameters tested in the Normal and IBS groups. Conclusion: ß-catenin is confirmed as a major driver of colorectal carcinogenesis but is controlled by many more players other than APC. Elevated levels of PPARγ may have an anticarcinogenic effect. The role of COX-2 expression, especially its posttranscriptional regulation in colorectal cancer, needs further elucidation.

Biol Reprod ; 89(4): 94, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24006284


Human placental syncytiotrophoblasts lack expression of most types of human leukocyte antigen (HLA) class I and class II molecules; this is thought to contribute to a successful pregnancy. However, the HLA class Ib antigens HLA-G, -E, and -F and the HLA class Ia antigen HLA-C are selectively expressed on extravillous trophoblast cells, and they are thought to play a major role in controlling feto-maternal tolerance. We have hypothesized that selective expression, coupled with the preferential physical association of pairs of HLA molecules, contribute to the function of HLA at the feto-maternal interface and the maternal recognition of the fetus. We have developed a unique analytical model that allows detection and quantification of the heterotypic physical associations of HLA class I molecules expressed on the membrane of human trophoblast choriocarcinoma cells, ACH-3P and JEG-3. Automated image analysis was used to estimate the degree of overlap of HLA molecules labeled with different fluorochromes. This approach yields an accurate measurement of the degree of colocalization. In both JEG-3 and ACH-3P cells, HLA-C, -E, and -G were detected on the cell membrane, while the expression of HLA-F was restricted to the cytoplasm. Progesterone treatment alone induced a significant increase in the expression level of the HLA-G/HLA-E association, suggesting that this heterotypic association is modulated by this hormone. Our data shows that the cell-surface HLA class I molecules HLA-G, -E, and -C colocalize with each other and have the potential to form preferential heterotypic associations.

Membrana Celular/metabolismo , Antígenos HLA-C/metabolismo , Antígenos HLA-G/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Histocompatibilidade Materno-Fetal , Trofoblastos/metabolismo , Linhagem Celular , Membrana Celular/imunologia , Citoplasma/metabolismo , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Antígenos HLA-G/química , Antígenos de Histocompatibilidade Classe I/química , Humanos , Células Híbridas , Processamento de Imagem Assistida por Computador , Microscopia Confocal , Gravidez , Progesterona/metabolismo , Transporte Proteico , Propriedades de Superfície , Trofoblastos/citologia , Trofoblastos/imunologia , Regulação para Cima
Am J Reprod Immunol ; 68(2): 95-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22531035


Implantation is a major landmark in life. It involves the correct apposition of the embryo in the maternal endometrium. The cellular environment influences placenta development, and direct contact of the fetus with maternal tissues is achieved through decidual cells. At the decidua, and at systemic level, the correct balance of cells potentially acting as antigen-presenting cells and histocompatibility products play a pivotal role in achieving feto-maternal tolerance. Here, we review some of the current issues associated with the interplay between cells and molecules needed for pregnancy development.

Implantação do Embrião/imunologia , Histocompatibilidade , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Desenvolvimento Fetal/imunologia , Feto/imunologia , Antígenos HLA/imunologia , Humanos , Tolerância Imunológica , Gravidez/imunologia
Phytother Res ; 26(12): 1830-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22422585


High fat diet induced insulin resistance correlates with dyslipidaemia and ectopic fat deposits in skeletal muscle and liver. The effects of Sutherlandia frutescens, an antidiabetic medicinal plant, on lipid metabolism were evaluated in an insulin resistant (IR) rat model and in 3 T3-preadipocytes. Wistar rats received normal diet (ND) or high fat diet (HFD). After the onset of IR in the HFD group, the rats were subdivided into two subgroups, which either continued with HFD or were treated with 50 mg S. frutescens/kg BW/day and HFD (HFD + SF). After 4 weeks, the HFD + SF rats had a significantly lower body weight than the HFD rats (p < 0.05). Blood plasma analysis showed a decrease in insulin, free fatty acids and triglycerides. Related changes in lipid parameters were observed in the liver, skeletal muscle and adipose tissue. To investigate the effects of S. frutescens on adipose tissue, 3 T3-L1 cells were used as a model. Treatment with S. frutescens led to a decrease in triglyceride accumulation, whilst glucose consumption and lactate production were increased (p < 0.05). These results indicate that S. frutescens directly affects mitochondrial activity and lipid biosynthesis in adipose tissue and provide a mechanism by which S. frutescens can restore insulin sensitivity by modulating fatty acid biosynthesis.

Adipócitos/metabolismo , Fabaceae/química , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar
Phytother Res ; 23(11): 1609-14, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19370539


Intake of high caloric food induces raised plasma free fatty acids, culminating in insulin resistance (IR) and Diabetes mellitus type 2 (DMT2). The present study has shown for the first time that Sutherlandia frutescens reduces plasma free fatty acid levels in rats fed a high fat diet, thereby preventing the development of insulin resistance. A commercially available S. frutescens extract was administered to rats to examine its effects on the progression of high fat diet induced IR. In comparison to rats fed high fat diet only (positive control for IR), levels of plasma free fatty acids (FFA) were significantly reduced after one week (p < 0.025). Twelve weeks of treatment with S. frutescens reduced the level of plasma free fatty acids below that of rats fed a normal diet (negative control) (p < 0.025). QUICKI and HOMA-IR index confirmed that S. frutescens treated rats did not develop IR when fed a high fat diet for twelve weeks. In addition to preventing IR and reducing plasma FFA, chronic medication over twelve weeks decreased total cholesterol levels and the LDL/HDL ratio. We propose that S. frutescens is an effective medicinal remedy to prevent elevated plasma free fatty acids and IR, and therefore DMT2.

Ácidos Graxos não Esterificados/sangue , Resistência à Insulina , Fitoterapia , Extratos Vegetais/farmacologia , Animais , Glicemia , Colesterol/sangue , Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Gorduras na Dieta/efeitos adversos , Fabaceae , Hipoglicemiantes/farmacologia , Insulina/sangue , Masculino , Ratos , Ratos Wistar
Anticancer Res ; 25(6B): 4197-202, 2005 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16309216


BACKGROUND: Cyclo(Phe-Pro) has been shown to inhibit cancer cell growth and induce apoptosis in HT-29 colon cancer cells. MATERIALS AND METHODS: The molecular mechanisms mediating cyclo(Phe-Pro)-induced apoptosis in HT-29 cells were investigated. Cells were treated with 5 mM or 10 mM cyclo(Phe-Pro) for varying times. Immunoblot analysis was used to detect poly(ADP-ribose)polymerase (PARP) cleavage. A fluorescence-based enzymatic assay was used to measure caspase-3 activity. RESULTS: Cyclo(Phe-Pro) (10 mM) induced time-dependent cleavage of PARP, detected as early as 8 hours post treatment. PARP cleavage was blocked by co-administration with the broad-range caspase inhibitor Z-VAD-FMK Cyclo(Phe-Pro) also induced a time-dependent increase (p < 0.01) in caspase-3 activity. This increase in activity was blocked in the presence of the caspase-3 inhibitor Ac-DEVD-CHO. CONCLUSION: These results provide evidence that cyclo(Phe-Pro)-induced apoptosis in HT-29 cells is mediated by a caspase cascade. These findings warrant further investigation into the potential antitumour activity of cyclo(Phe-Pro) and its related cyclic dipeptide derivatives.

Caspases/metabolismo , Dipeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Células CACO-2 , Caspase 3 , Inibidores de Caspase , Caspases/biossíntese , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/toxicidade , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Células HT29 , Humanos , Peptídeos Cíclicos/toxicidade