MARIA ANGELA HENRIQUES ZANELLA FORTES
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina
8 resultados
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- MTP-493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients(2012) SIQUEIRA, E. R. F.; OLIVEIRA, C. P. M. S.; CORREA-GIANNELLA, M. L.; STEFANO, J. T.; CAVALEIRO, A. M.; FORTES, M. A. H. Z.; MUNIZ, M. T. C.; SILVA, F. S.; PEREIRA, L. M. M. B.; CARRILHO, F. J.The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8% of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3% of the patients with fibrosis grade 1+2 (OR = 1.8; 95%CI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95%CI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.
- Differential expression of genes encoding proteins of the HGF/MET system in insulinomas(2015) MURAT, Cahue de Bernardis; ROSA, Paula Waki Lopes da; FORTES, Maria Angela Henriques Zanella; CORREA, Luciana; MACHADO, Marcel Cerqueira Cesar; NOVAK, Estela Maria; SIQUEIRA, Sheila Aparecida Coelho; PEREIRA, Maria Adelaide Albergaria; CORREA-GIANNELLA, Maria Lucia; GIANNELLA-NETO, Daniel; GIORGI, Ricardo RodriguesBackground: Insulinomas are the most common functional pancreatic neuroendocrine tumors, whereas histopathological features do not predict their biological behaviour. In an attempt to better understand the molecular processes involved in the tumorigenesis of islet beta cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two inhibitors of HGF activator and of matriptase). Methods: Quantitative real-time reverse transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes in 24 sporadic insulinomas: 15 grade 1 (G1), six grade 2 (G2) and three hepatic metastases. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. Results: Overexpression of MET was observed in the three hepatic metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. A positive correlation was observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. Conclusion: The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoral progression and metastatization in insulinomas.
- Hyperinsulinism/hyperammonemia (HI/HA) syndrome due to a mutation in the glutamate dehydrogenase gene(2012) CORREA-GIANNELLA, Maria Lucia; FREIRE, Daniel Soares; CAVALEIRO, Ana Mercedes; FORTES, Maria Angela Zanella; GIORGI, Ricardo Rodrigues; PEREIRA, Maria Adelaide AlbergariaThe hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high-protein meals, and by elevated serum ammonia. HI/HA is the second most common cause of hyperinsulinemic hypoglycemia of infancy, and it is caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Biochemical evaluation, as well as direct sequencing of exons and exon-intron boundary regions of the GLUD1 gene, were performed in a 6-year old female patient presenting fasting hypoglycemia and hyperammonemia. The patient was found to be heterozygous for one de novo missense mutation (c.1491A>G; p.Il497Met) previously reported in a Japanese patient. Treatment with diazoxide 100 mg/day promoted complete resolution of the hypoglycemic episodes.
- Antitumoural activity of Brazilian red propolis fraction enriched with xanthochymol and formononetin: An in vitro and in vivo study(2014) NOVAK, Estela Maria; SILVA, Martha Silveira e Costa; MARCUCCI, Maria Cristina; SAWAYA, Alexandra Christine Helena Frankland; LOPEZ, Begona Gimenez-Cassina; FORTES, Maria Angela Henriques Zanella; GIORGI, Ricardo Rodrigues; MARUMO, Kamila Tamie; RODRIGUES, Rosangela Felipe; MARIA, Durvanei AugustoIn this study, ultra-high performance liquid chromatography-mass spectrometry and tandem mass spectrometry of selected ions were used to characterise the ethanolic extract of a sample of Brazilian red propolis (EEBRP) and an active fraction (BRP-IV) containing xanthochymol and formononetin. The antiproliferative effect of BRP-IV was assayed using melanoma tumour xenografts in mice and HL-60, K562, RPMI8226, B16F10 cell lines. This fraction inhibited growth of tumour cell lines with IC50 values of 20.5 +/- 2.4 to 32.6 +/- 2.6 mu g/mL while EEBRP induced cytotoxic effect with IC50 values of 29.7 +/- 1.5 to 42.1 +/- 8.7 mu g/mL. BRP-IV also inhibited the proliferation of B16F10 cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Administration of 10 mg/kg/day BRP-IV suppressed the growth of B16F0 tumour xenografts in C57BL/6 mice with less general toxicity than control groups. Taken together, these results indicate that BRP-IV can be considered a promising anticancer drug for the treatment of human cancers.
- HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis(2013) CHILE, Thais; FORTES, Maria Angela Henriques Zanella; CORREA-GIANNELLA, Maria Lucia Cardillo; BRENTANI, Helena Paula; MARIA, Durvanei Augusto; PUGA, Renato David; PAULA, Vanessa de Jesus R. de; KUBRUSLY, Marcia Saldanha; NOVAK, Estela Maria; BACCHELLA, Telesforo; GIORGI, Ricardo RodriguesBackground: Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression of HOXB7 homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated. Methods: Real time quantitative PCR (qRT-PCR) (Taqman) was employed to assess HOXB7 mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdown HOXB7 mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively. Results: Overexpression of HOXB7 mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1. HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquit-independent catabolic process and cell cycle. Conclusion: The present study confirms the overexpression of HOXB7 mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes. HOXB7 might be a promising target for future therapies.
- Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas(2012) MURAT, C. B.; BRAGA, P. B. S.; FORTES, M. A. H. Z.; BRONSTEIN, M. D.; CORREA-GIANNELLA, M. L. C.; GIORGI, R. R.The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-alpha catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number >= 4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland.
- Expression of CRABP1, GRP, and RERG mRNA in clinically non-functioning and functioning pituitary adenomas(2011) CHILE, T.; CORREA-GIANNELLA, M. L.; FORTES, M. A. H. Z.; BRONSTEIN, M. D.; CUNHA-NETO, M. B.; GIANNELLA-NETO, D.; GIORGI, R. R.Background: Pituitary tumors account for approximately 10-15% of intracranial neoplasms. Aim: Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1 (cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen-regulated, growth inhibitor). Material and methods: The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR. Results: A significantly higher content of CRABP1 mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary. Conclusions: The findings of differential expression of CRABP1 in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis. (J. Endocrinol. Invest. 34: e214-e218, 2011) (C) 2011, Editrice Kurtis
- Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus(2011) VIEIRA, Suzana M.; MONTEIRO, Maria B.; MARQUES, Tatiana; LUNA, Ana M.; FORTES, Maria A.; NERY, Marcia; QUEIROZ, Marcia; DIB, Sergio A.; VENDRAMINI, Marcio F.; AZEVEDO, Mirela J.; CANANI, Luis H.; PARISI, Maria C.; PAVIN, Elizabeth J.; GIANNELLA-NETO, Daniel; CORREA-GIANNELLA, Maria L.Background: Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O(2)(center dot-) (-675 T -> A in CYBA, unregistered) and in glutathione metabolism (-129 C -> T in GCLC [rs17883901] and -65 T -> C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients. Methods: 401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: >= 60 mL (n = 265) or < 60 mL/min/1.73 m(2) (n = 136) and were genotyped. Results: No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068). Conclusions: The functional SNPs CYBA -675 T -> A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.