Genistein Affects HER2 Protein Concentration, Activation and Promoter Regulation via Estrogen Receptor-and non-Estrogen Receptor-Mediated Mechanisms

The HER2 proto-oncogene, a member of the epidermal growth factor receptor family, is overexpressed in 20–30% of breast cancers. Genistein, the main soy isoflavone, interacts with estrogen receptors (ER) and it is also a potent tyrosine kinase inhibitor. Previously, our laboratory found that genistein delayed mammary tumor onset in transgenic mice that overexpress HER2 gene. Our goal was to define the mechanism through which genistein affects mammary tumorigenesis inHER2 overexpressing mice. We hypothesized that genistein inhibits HER2 activation and expression through ER-dependent and ER-independent mechanisms. Genistein inhibited total HER2 protein expression and tyrosine phosphorylation in BT-474, an ERα (−) and ERβ (+) human breast cancer cell line, however, E2 had no effect. Taken together, these data suggest that genistein has an ER-independent inhibitory effect, presumably, through tyrosine kinase inhibition activity. Genistein at 1.0 μM mimicked E2 and down-regulated HER2 protein phosphorylation when BT-474 was co-transfected with ERα, but not ERβ. Although E2 and overexpression of HER2 can promote mammary tumorigenesis, an inverse relationship between ER expression and HER2 overexpression has been found in human breast cancer. We cloned a 500-bp promoter region upstream of theHER2 transcription initiation site. Co-transfection with ERα, but not with ERβ, down-regulated HER2promoter reporter in BT-474. At concentrations ≥1 μM, genistein inhibited HER2 promoter reporter in the absence of ERα. In conclusion, genistein at ≥1 μM inhibited HER2 protein expression, phosphorylation, and promoter activity through an ER-independent mechanism. In the presence of ERα, genistein mimicked E2 and inhibited HER2 protein phosphorylation. These data support genistein’s chemo-prevention and potential chemo-therapeutic roles in breast cancer

Quantitative near-infrared spectroscopy of cervical dysplasia in vivo

The aims of this study were: (i) to quantify near-infrared optical properties of normal cervical tissues and high-grade squamous intra-epithelial lesions (H-SIL); (ii) to assess the feasibility of differentiating normal cervical tissues from H-SIL on the basis of these properties; and (iii) to determine how cervical tissue optical properties change following photodynamic therapy (PDT) of H-SIL in vivo. Using the frequency domain photon migration technique, non-invasive measurements of normal and dysplastic ecto-cervical tissue optical properties, i.e. absorption (μa) and effective scattering coefficients, and physiological parameters, i.e. tissue water and haemoglobin concentration, percentage oxygen saturation (%SO2), were performed on 10 patients scheduled for PDT of histologically-proven H-SIL. Cervix absorption and effective scattering parameters were up to 15% lower in H-SIL sites compared with normal cervical tissue for all wavelengths studied (674, 811, 849, 956 nm). Following PDT, all μa values increased significantly, due to elevated tissue blood and water content associated with PDT-induced hyperaemia and oedema. Tissue total haemoglobin concentration ([TotHb]) and arterio-venous oxygen saturation measured in H-SIL sites were lower than normal sites ([TotHb]: 88.6 ± 35.8 μmol/l versus 124.7 ± 22.6 μmol/l; %SO2: 76.5 ± 14.7% versus 84.9 ± 3.4%

Oral exposure to methylmercury modifies the prostatic microenvironment in adult rats

Methylmercury (MeHg) is an environmental pollutant that is highly toxic to the central nervous system. As its effects on male reproductive system are poorly understood, this study was carried out to analyse the effects of MeHg on the rat prostate. To evaluate the MeHg toxicity on ventral prostate, three groups of adult male Wistar rats received oral doses of 0.5, 1.0 and 3.0mg/kg MeHg, respectively, on a daily basis for 14days. A fourth group was used as a control. The prostate weight was decreased in rats treated orally with 0.5mg/kg MeHg compared to controls. Also, Hg concentration increased significantly in the prostate after treatments. There were reductions in serum testosterone levels and androgen receptor immunoreactivity in animals receiving 3.0mgMeHg/kg. The stereological data showed changes in the prostatic epithelial, stromal and luminal compartments which varied according to the different doses. Histopathological alterations, such as chronic inflammation, stratified epithelial hyperplasia and epithelial inflammatory reactive atypia, were observed in the 0.5mg/kg MeHg-treated group. Epithelial atrophy was observed in the 3.0mg/kg MeHg-treated group. In conclusion, the MeHg affects prostatic homoeostasis resulting in histopathological changes that may be relevant in the pathogenesis of prostatic disease.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2007/56458-4

Elderly and drugs: risks and necessity of rational use

In recent decades, the world has undergone a demographic transformation with a rapid growth of the elderly population, resulting in an increased demand for funds to maintain their health and drug consumption. Pharmacokinetic and pharmacodynamic changes occurring in the elderly can interfere directly in the adverse effects of drugs and increase the risk of intoxication. In addition, there are external factors interfering with the pharmacotherapy of the elderly, such as inappropriate use and the lack of access to information. Many therapeutic classes of drugs should be used with caution or avoided in the elderly population, such as anti-inflammatory and some anti-hypertensive drugs, diuretics and digitalis. If not managed carefully, these medicines can affect the safety and quality of life in the elderly. Thus, the aim of this review was to identify drugs that should be used with caution in elderly patients in order to avoid intoxication and/or adverse drug events.Durante as últimas décadas, o mundo passou por uma transformação demográfica, com um rápido crescimento da população idosa e, portanto, tanto a demanda para a manutenção da saúde deste grupo populacional, quanto o consumo de medicamentos estão aumentando. Ainda, as mudanças farmacocinéticas e farmacodinâmicas que ocorrem em idosos podem interferir diretamente nos efeitos adversos dos medicamentos e aumentar o risco de intoxicação. Além disso, há fatores externos que interferem na farmacoterapia dos idosos, tais como o uso inadequado e a falta de acesso à informação. Existem várias classes terapêuticas de medicamentos que devem ser utilizados com cautela ou evitados na população idosa, tais como antiinflamatórios, alguns anti-hipertensivos, diuréticos, digitálicos entre outros. Estes medicamentos, se não forem utilizados com cuidado, podem afetar a qualidade de vida e a segurança desta população. Assim, este trabalho visa identificar medicamentos que devem ser utilizados com cuidado em pacientes idosos para evitar intoxicações e/ou eventos adversos aos medicamentos.FAPESPCNPqCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Quantitative near-infrared spectroscopy of cervical dysplasia in vivo

The aims of this study were: (i) to quantify near-infrared optical properties of normal cervical tissues and high-grade squamous intra-epithelial lesions (H-SIL); (ii) to assess the feasibility of differentiating normal cervical tissues from H-SIL on the basis of these properties; and (iii) to determine how cervical tissue optical properties change following photodynamic therapy (PDT) of H-SIL in vivo. Using the frequency domain photon migration technique, non-invasive measurements of normal and dysplastic ecto-cervical tissue optical properties, i.e. absorption (μa) and effective scattering coefficients, and physiological parameters, i.e. tissue water and haemoglobin concentration, percentage oxygen saturation (%SO2), were performed on 10 patients scheduled for PDT of histologically-proven H-SIL. Cervix absorption and effective scattering parameters were up to 15% lower in H-SIL sites compared with normal cervical tissue for all wavelengths studied (674, 811, 849, 956 nm). Following PDT, all μa values increased significantly, due to elevated tissue blood and water content associated with PDT-induced hyperaemia and oedema. Tissue total haemoglobin concentration ([TotHb]) and arterio-venous oxygen saturation measured in H-SIL sites were lower than normal sites ([TotHb]: 88.6 ± 35.8 μmol/l versus 124.7 ± 22.6 μmol/l; %SO2: 76.5 ± 14.7% versus 84.9 ± 3.4%

Targets of Hsa-miR-488* in Human Prostate Carcinoma Cells

Prostate cancer (PCa) is one of the most prevalent forms of cancer among men in America and is second only to lung cancer as a cause of cancer-related deaths in men. Recent epidemiological study shows that one in every six men over the age of forty five is at risk of PCa. Androgen receptor (AR) plays a causative role in the development of PCa. Hormonal blockade therapy which inhibits the expression of AR eventually fails and disease progresses to fatal androgen-refractory stage from androgen-dependent stage. Therefore, novel molecular approaches which can target and block the expression of AR are required. We propose that microRNAs (miRNA) that function as negative gene regulators have potential as PCa therapeutics. Using bioinformatics methods, we have identified that human miRNA hsa-miR-488* has potential to modulate AR expression. In the present study, we have validated the target site in AR 3\u27UTR and established that AR is a target of Hsa-miR-488*. Our data show that the ectopically expressed hsa-miR-488* as well as the synthetic miRNA mimic can suppress the expression of luciferase activity in chimeric plasmid harboring AR3\u27UTR with dose dependent effects. In addition, miR-488* negatively regulated the expression of endogenous androgen receptor in PCa cells LNCaP. Thus hsa-miR-488* that function as negative gene regulators has potential as PCa therapeutic

Targets of Hsa-miR-488* in Human Prostate Carcinoma Cells

Prostate cancer (PCa) is one of the most prevalent forms of cancer among men in America and is second only to lung cancer as a cause of cancer-related deaths in men. Recent epidemiological study shows that one in every six men over the age of forty five is at risk of PCa. Androgen receptor (AR) plays a causative role in the development of PCa. Hormonal blockade therapy which inhibits the expression of AR eventually fails and disease progresses to fatal androgen-refractory stage from androgen-dependent stage. Therefore, novel molecular approaches which can target and block the expression of AR are required. We propose that microRNAs (miRNA) that function as negative gene regulators have potential as PCa therapeutics. Using bioinformatics methods, we have identified that human miRNA hsa-miR-488* has potential to modulate AR expression. In the present study, we have validated the target site in AR 3\u27UTR and established that AR is a target of Hsa-miR-488*. Our data show that the ectopically expressed hsa-miR-488* as well as the synthetic miRNA mimic can suppress the expression of luciferase activity in chimeric plasmid harboring AR3\u27UTR with dose dependent effects. In addition, miR-488* negatively regulated the expression of endogenous androgen receptor in PCa cells LNCaP. Thus hsa-miR-488* that function as negative gene regulators has potential as PCa therapeutic

Targets of Hsa-miR-488* in Human Prostate Carcinoma Cells

Prostate cancer (PCa) is one of the most prevalent forms of cancer among men in America and is second only to lung cancer as a cause of cancer-related deaths in men. Recent epidemiological study shows that one in every six men over the age of forty five is at risk of PCa. Androgen receptor (AR) plays a causative role in the development of PCa. Hormonal blockade therapy which inhibits the expression of AR eventually fails and disease progresses to fatal androgen-refractory stage from androgen-dependent stage. Therefore, novel molecular approaches which can target and block the expression of AR are required. We propose that microRNAs (miRNA) that function as negative gene regulators have potential as PCa therapeutics. Using bioinformatics methods, we have identified that human miRNA hsa-miR-488* has potential to modulate AR expression. In the present study, we have validated the target site in AR 3\u27UTR and established that AR is a target of Hsa-miR-488*. Our data show that the ectopically expressed hsa-miR-488* as well as the synthetic miRNA mimic can suppress the expression of luciferase activity in chimeric plasmid harboring AR3\u27UTR with dose dependent effects. In addition, miR-488* negatively regulated the expression of endogenous androgen receptor in PCa cells LNCaP. Thus hsa-miR-488* that function as negative gene regulators has potential as PCa therapeutic

Lesões citologicas em um rastreamento populacional para cancer do colo uterino e tempo de atividade sexual das mulheres

Orientador: Luiz Carlos Zeferino, Jose Guilherme CecattiTese(mestrado) - Universidade Estadual de Campinas. Faculdade de Ciencias MedicasMestrad