Dietary polyphenols and their relationship to the modulation of non-communicable chronic diseases and epigenetic mechanisms: A mini-review.

Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

Downregulation of MGMT promotes proliferation of intrahepatic cholangiocarcinoma by regulating p21.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is one of the most devastating cancers of the gastrointestinal tract. It is crucial to determine the accurate prognostic factors and find new therapeutic strategies. Meanwhile, O6-methylguanine-DNA methyltransferase (MGMT) is associated with malignant tumor progression. Thus, further studies are needed to investigate whether MGMT plays a similar role in ICC. MATERIALS AND METHODS: Quantitative real-time PCR, western blot, and immunohistochemistry staining were used to detect the expression of MGMT in ICC tissues. The correlations between MGMT expression and clinicopathologic features were analyzed. The cell-proliferation assay and colony-formation assay were applied to evaluate proliferation ability, while methylation-specific PCR were used to detect the methylation status of the MGMT promoter CpG island in ICC tissues and cells. RESULTS: Our study found that the expression of MGMT was decreased in ICC tissues when compared with paired normal tissues. In addition, we demonstrated that MGMT expression was positively correlated with overall survival rates and tumor histological grade. Silencing of MGMT significantly promoted cell proliferation in ICC. Further research showed that silencing of MGMT induced cells to enter S phase by inhibiting p21, p27, and Cyclin E expression, ultimately promoting ICC proliferation. We also demonstrated that the MGMT promoter was highly methylated in ICC, and the levels of MGMT and p21 mRNA increased after DNA demethylation. In addition, the levels of MGMT and p21 protein were positively correlated in ICC tissues. CONCLUSION: MGMT may play a critical role in carcinogenesis and the development of ICC, and provides a new marker of clinical prognosis and target for ICC treatment.

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions.

Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

Expresión de O6-metilguanina-ADN-metiltransferasa (MGMT) en pacientes chilenos con glioblastoma multiforme / O6-methylguanine-DNA-methyltransferase (MGMT) expression in patients with glioblastoma multiforme

Background: Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. Aim: To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. Material and Methods: Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. Results: The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. Conclusions: Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.

The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes.

Tobacco smoke and air pollutants contain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and tobacco specific nitrosamines (TSNA), that are substrates of metabolizing enzymes generating reactive metabolites that can bind to DNA. Variation in the activity of these enzymes may modify the extent to which these metabolites can interact with DNA. We compared the levels of bulky DNA adducts in blood leukocytes from 93 volunteers living in Mexico City with the presence of 13 single nucleotide polymorphisms (SNPs) in genes related to PAH and TSNA metabolism (AhR rs2044853, CYP1A1 rs1048943, CYP1A1 rs1048943, CYP1A1 rs1799814, EPHX1 rs1051740, EPHX1 rs2234922, GSTM1 null, GSTT1 null and GSTP1 rs947894), DNA repair (XRCC1 rs25487, ERCC2 rs13181 and MGMT rs12917) and cell cycle (TP53 rs1042522). (32)P-postlabeling analysis was used to quantify bulky DNA adduct formation. Genotyping was performed using PCR-RFLP. The mean levels of bulky DNA adducts were 8.51±3.66 adducts/10(8) nucleotides (nt) in smokers and 8.38±3.59 adducts/10(8) nt in non-smokers, being the difference not statistically significant. Without taking into account the smoking status, GSTM1 null individuals had a marginally significant lower adduct levels compared with GSTM1 volunteers (p=0.0433) and individuals heterozygous for MGMT Leu/Phe had a higher level of bulky adducts than those who were homozygous wild type (p=0.0170). A multiple regression analysis model showed a significant association between the GSTM1 (deletion) and MGMT rs12917 (Phe/Phe) haplotype and the formation of DNA adducts in smokers (R(2)=0.2401, p=0.0215). The presence of these variants conferred a greater risk for higher adduct levels in this Mexican population.

Gliomas: marcadores tumorais e prognóstico / Gliomas: tumors biomarkers and prognosis

Os gliomas representam 30%-40% de todas as neoplasias intracranianas e aproximadamente 50% são glioblastomas. São classificados em graus pela OMS, de acordo com sua patologia. Apresentam altas taxas de mortalidade. Existem marcadores tumorais que podem auxiliar na detecção precoce e avaliar prognóstico. Realizada revisão sobre o tema marcadores tumorais por meio do site PubMed. MGMT é uma proteína que restaura o DNA, impedindo a sua alquilação. A metilação do MGMT por meio de fenômeno epigenético impede sua transcrição inibindo sua ação, tornando o tumor suscetível a fármacos. IDH e codeleção cromossômica 1p19q são marcadores tumorais e estão associados a melhor prognóstico. As neoplasias intracranianas apresentam altas taxas de mortalidade e sua detecção precoce por meio de marcadores e o conhecimento de alterações que conferem bom prognóstico podem auxiliar no tratamento dessa doença. A análise molecular auxilia na detecção e no tratamento de tumores.

Gliomas represent 30%-40% of all intracranial tumors and approximately 50% are glioblastomas. They are classified by the WHO in degrees, according to their pathology. Have high mortality rates. There are tumor markers may help in early detection and assess prognosis. Was performed a review about the topic tumor markers through PubMed. MGMT is a protein that restores the DNA, preventing its alkylation. Methylation of MGMT through epigenetic phenomenon prevents their transcription and inhibits its action, making the tumor susceptible to drugs. IDH and chromosomal deletion 1p19q are tumor markers and are associated with better prognosis. The intracranial tumors have high rates of mortality and early detection through biomarkers and knowledge of changes that confer a good prognosis can help in treating this disease. Molecular analysis allows the detection and treatment of tumors.

Avaliação da expressão do gene MGMT nos tecidos normal e neoplásico de doentes com câncer colorretal / Evaluation of the expression of the MGMT gene in normal and neoplastic tissue of patients with colorectal cancer

OBJETIVO: Avaliar a expressão tecidual do gene de reparo MGMT comparando a mucosa cólica normal e neoplásica em doentes com câncer colorretal. MÉTODOS: Foram estudados 44 portadores de adenocarcinoma colorretal confirmado por estudo histopatológico. Foram excluídos doentes suspeitos de pertencerem a famílias com câncer colorretal hereditário (HNPCC e PAF) e os portadores de câncer do reto médio e inferior submetidos a tratamento quimioradioterápico neoadjuvante. A expressão do gene MGMT foi avaliada pela técnica da reação de polimerase em cadeia em tempo real (RT-PCR). A comparação dos resultados encontrados para expressão do gene MGMT entre tecidos normais e neoplásicos foi feita pelo teste t de Student pareado, adotando-se nível de significância de 5% (p <0,05). RESULTADOS: A expressão tecidual do gene MGMT em todos os doentes foi menor no tecido neoplásico quando comparada a do tecido normal (p=0,002). CONCLUSÃO: O gene de reparo MGMT encontra-se menos expresso no tecido neoplásico quando comparados aos tecidos normais em portadores de CCR esporádico.

OBJECTIVE: To evaluate the expression of tissue repair gene MGMT by comparing normal and neoplastic colonic mucosa in patients with colorectal cancer (CRC). METHODS: We studied 44 patients with colorectal cancer confirmed by histopathology. We excluded patients suspected of belonging to families with hereditary colorectal cancer (HNPCC and FAP) and patients with cancer of the lower or medium rectum treated with neoadjuvant chemoradiotherapy. The MGMT gene expression was assessed by the technique of polymerase chain reaction in real time (RT-PCR). The comparison of results for MGMT gene expression between normal and neoplastic tissues was made by paired Student's t test, adopting a significance level of 5% (p <0.05). RESULTS: Tissue expression of the MGMT gene in all patients was lower in tumor tissue when compared to normal tissue (p = 0.002). CONCLUSION: The repair gene MGMT is less expressed in tumor tissue compared to normal tissues in patients with sporadic CRC.