RESUMO

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

RESUMO

Benign prostatic hyperplasia (BPH) is characterised by increases in prostate volume and contraction. Downregulation of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway contributes to prostate dysfunctions. Previous studies in cancer cells or vessels have shown that the epigenetic mechanisms control the gene and protein expression of the enzymes involved in the production of NO and cGMP. This study is aimed to evaluate the effect of a 2-week treatment of 5-azacytidine (5-AZA), a DNA-methyltransferase inhibitor, in the prostate function of mice fed with a high-fat diet. Functional, histological, biochemical and molecular assays were carried out. Obese mice presented greater prostate weight, α-actin expression and contractile response induced by the α-1adrenoceptors agonist. The relaxation induced by the NO-donor and the protein expression of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) were significantly decreased in the prostate of obese mice. The treatment with 5-AZA reverted the higher expression of α-actin, reduced the hypercontractility state of the prostate and increased the expression of eNOS and sGC and intraprostatic levels of cGMP. When prostates from obese mice treated with 5-AZA were incubated in vitro with inhibitors of the NOS or sGC, the inhibitory effect of 5-AZA was reverted, therefore, showing the involvement of NO and cGMP. In conclusion, our study paves the way to develop or repurpose therapies that recover the expression of eNOS and sGC and, hence, to improve prostate function in BPH.

Assuntos

Óxido Nítrico , Hiperplasia Prostática , Masculino , Humanos , Camundongos , Animais , Óxido Nítrico/metabolismo , Guanilato Ciclase/metabolismo , Próstata/metabolismo , Camundongos Obesos , Guanosina Monofosfato/metabolismo , Azacitidina/metabolismo , Hiperplasia Prostática/metabolismo , Actinas/metabolismo , GMP Cíclico/metabolismo

RESUMO

OBJECTIVE: The aim was to investigate the intergenerational inheritance induced by a high-fat diet on sensitivity to insulin and leptin in the hypothalamic control of satiety in second-generation offspring, which were fed a control diet. METHODS: Progenitor rats were fed a high-fat or a control diet for 59 d until weaning. The first-generation and second-generation offspring were fed the control diet until 90 d of age. Body mass and adiposity index of the progenitors fed the high-fat diet and the second-generation offspring from progenitors fed the high-fat diet were evaluated as were the gene expression of DNA methyltransferase 3a, angiotensin-converting enzyme type 2, angiotensin II type 2 receptor, insulin and leptin signaling pathway (insulin receptor, leptin receptor, insulin receptor substrate 2, protein kinase B, signal transducer and transcriptional activator 3, pro-opiomelanocortin, and neuropeptide Agouti-related protein), superoxide dismutase activity, and the concentration of carbonyl protein and satiety-regulating neuropeptides, pro-opiomelanocortin and neuropeptide Agouti-related protein, in the hypothalamus. RESULTS: The progenitor group fed a high-fat diet showed increased insulin resistance and reduced insulin-secreting beta-cell function and reduced food intake, without changes in caloric intake. The second-generation offspring from progenitors fed a high-fat diet, compared with second-generation offspring from progenitors fed a control diet group, had decreased insulin-secreting beta-cell function and increased food and caloric intake, insulin resistance, body mass, and adiposity index. Furthermore, second-generation offspring from progenitors fed a high-fat diet had increased DNA methyltransferase 3a, neuropeptide Agouti-related protein, angiotensin II type 1 receptor, and nicotinamide adenine dinucleotide phosphate oxidase p47phox gene expression, superoxide dismutase activity, and neuropeptide Agouti-related protein concentration in the hypothalamus. In addition, there were reduced in gene expression of the insulin receptor, leptin receptor, insulin receptor substrate 2, pro-opiomelanocortin, angiotensin II type 2 receptor, angiotensin-converting enzyme type 2, and angiotensin-(1-7) receptor and pro-opiomelanocortin concentration in the second-generation offspring from progenitors fed the high-fat diet. CONCLUSIONS: Overall, progenitors fed a high-fat diet induced changes in the hypothalamic control of satiety of the second-generation offspring from progenitors fed the high-fat diet through intergenerational inheritance. These changes led to hyperphagia, alterations in the hypothalamic pathways of insulin, and leptin and adiposity index increase, favoring the occurrence of different cardiometabolic disorders in the second-generation offspring from progenitors fed the high-fat diet fed only with the control diet.

Assuntos

Resistência à Insulina , Neuropeptídeos , Ratos , Animais , Leptina/metabolismo , Insulina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Proteína Relacionada com Agouti/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptores para Leptina/genética , DNA Metiltransferase 3A , Ratos Sprague-Dawley , Obesidade/genética , Obesidade/metabolismo , Hiperfagia/complicações , Hipotálamo/metabolismo , Neuropeptídeos/metabolismo , Superóxido Dismutase/metabolismo , Angiotensinas/metabolismo

RESUMO

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Assuntos

Antidepressivos , Encéfalo , Ácido Butírico , Epigênese Genética , Privação Materna , Ratos Wistar , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/tratamento farmacológico , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ratos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Depressão/tratamento farmacológico , Histona Acetiltransferases/metabolismo , Natação/psicologia

RESUMO

Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor suppressor genes to promote cancer development. Several factors are associated with changes in the DNA methylation pattern, and recently, the gastrointestinal microbiota could be associated with this epigenetic change. The predominant phyla in gut microbiota are Firmicutes and Bacteroidetes; however, an enrichment of Bacteroides fragilis, Fusobacterium nucleatum, and Streptococcus bovis, among others, has been reported in colorectal cancer, although the composition could be influenced by several factors, including diet, age, sex, and cancer stage. Fusobacterium nucleatum, a gram-negative anaerobic bacillus, is mainly associated with colorectal cancer patients positive for the CpG island methylator phenotype, although hypermethylation in genes such as MLH1, CDKN2A, MTSS1, RBM38, PKD1, PTPRT, and EYA4 has also been described. Moreover, Hungatella hathewayi, a gram-positive, rod-shaped bacterium, is related to hypermethylation in SOX11, THBD, SFRP2, GATA5, ESR1, EYA4, CDX2, and APC genes. The underlying epigenetic mechanism is unclear, although it could be implicated in the regulation of DNA methyltransferases, enzymes that catalyze the transfer of a methyl group on cytosine of CpG sites. Since DNA methylation is a reversible event, changes in gut microbiota could modulate the gene expression through DNA methylation and improve the colorectal cancer prognosis.

RESUMO

Although the pathogenesis of Parkinson's Disease (PD) is not completely understood, there is a consensus that it can be caused by multifactorial mechanisms involving genetic susceptibility, epigenetic modifications induced by toxins and mitochondrial dysfunction. In the past 20 years, great efforts have been made in order to clarify molecular mechanisms that are risk factors for this disease, as well as to identify bioactive agents for prevention and slowing down of its progression. Nutraceutical products have received substantial interest due to their nutritional, safe and therapeutic effects on several chronic diseases. The aim of this review was to gather the main evidence of the epigenetic mechanisms involved in the neuroprotective effects of phenolic compounds currently under investigation for the treatment of toxin-induced PD. These studies confirm that the neuroprotective actions of polyphenols involve complex epigenetic modulations, demonstrating that the intake of these natural compounds can be a promising, low-cost, pharmacogenomic strategy against the development of PD.

Assuntos

Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/prevenção & controle , Polifenóis/farmacologia , Nutrigenômica , Epigênese Genética , Predisposição Genética para Doença

RESUMO

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.

RESUMO

BACKGROUND: Graves' disease is an autoimmune disorder characterised by excessive production of thyroid hormones, which induces increased cellular metabolism in most tissues and increased production of reactive oxygen species (ROS). The aim of this work was to analyse the effect of ROS on cell viability and the expression of catalase (CAT), glutathione peroxidase-1 (GPx-1), superoxide dismutase (SOD-1) and DNA methyltransferase-1 (DNMT-1) in peripheral blood mononuclear cells (PBMC) from patients with newly diagnosed Graves' disease or treated with methimazole. PATIENTS AND METHODS: For this study, women patients with newly diagnosed Graves' disease (n=18), treated with methimazole (n=6) and healthy subjects (n=15) were recruited. ROS were evaluated by flow cytometry, and the viability/apoptosis of PBMC was analysed by flow cytometry and fluorescence microscopy. Genomic expression of CAT, GPx-1, SOD-1 and DNMT-1 was quantified by real-time PCR. RESULTS: We found high levels of ROS and increased expression of CAT, GPx-1, SOD-1 and DNMT-1 in PBMC from patients with newly diagnosed Graves' disease. Methimazole treatment reversed these parameters. Cell viability was similar in all study groups. CONCLUSIONS: ROS induces the expression of CAT, GPx-1, and SOD-1. The activity of these enzymes may contribute to the protection of PBMC from the harmful effect of free radicals on cell viability. Increased expression of DNMT-1 may be associated with aberrant methylation patterns in immunoregulatory genes contributing to autoimmunity in Graves' disease.

Assuntos

Doença de Graves , Metimazol , DNA/metabolismo , Feminino , Doença de Graves/tratamento farmacológico , Humanos , Leucócitos Mononucleares/metabolismo , Metimazol/farmacologia , Metimazol/uso terapêutico , Metiltransferases/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo

RESUMO

Epigenetic mechanisms such as DNA methylation (DNAm) have been associated with stress responses and increased vulnerability to depression. Abnormal DNAm is observed in stressed animals and depressed individuals. Antidepressant treatment modulates DNAm levels and regulates gene expression in diverse tissues, including the brain and the blood. Therefore, DNAm could be a potential therapeutic target in depression. Here, we reviewed the current knowledge about the involvement of DNAm in the behavioural and molecular changes associated with stress exposure and depression. We also evaluated the possible use of DNAm changes as biomarkers of depression. Finally, we discussed current knowledge limitations and future perspectives.

Assuntos

Biomarcadores/sangue , Depressão/tratamento farmacológico , Depressão/genética , Metiltransferases/antagonistas & inibidores , Animais , Antidepressivos/farmacologia , Encéfalo/metabolismo , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Depressão/sangue , Epigenômica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Modelos Animais , Ratos , Ratos Wistar , Estresse Psicológico

RESUMO

The presence of DNA methylation marks within genic intervals, also called gene body methylation, is an evolutionarily-conserved epigenetic hallmark of animal and plant methylomes. In social insects, gene body methylation is thought to contribute to behavioural plasticity, for example between foragers and nurse workers, by modulating gene expression. However, recent studies have suggested that the majority of DNA methylation is sequence-specific, and therefore cannot act as a flexible mediator between environmental cues and gene expression. To address this paradox, we examined whole-genome methylation patterns in the brains and ovaries of young honey bee workers that had been subjected to divergent social contexts: the presence or absence of the queen. Although these social contexts are known to bring about extreme changes in behavioral and reproductive traits through differential gene expression, we found no significant differences between the methylomes of workers from queenright and queenless colonies. In contrast, thousands of regions were differentially methylated between colonies, and these differences were not associated with differential gene expression in the subset of genes examined. Methylation patterns were highly similar between brain and ovary tissues and only differed in nine regions. These results strongly indicate that DNA methylation is not a driver of differential gene expression between tissues or behavioral morphs. Finally, despite the lack of difference in methylation patterns, queen presence affected the expression of all four DNA methyltransferase genes, suggesting that these enzymes have roles beyond DNA methylation. Therefore, the functional role of DNA methylation in social insect genomes remains an open question.

Assuntos

Metilação de DNA , Genoma de Inseto , Animais , Abelhas/genética , Encéfalo , Feminino , Expressão Gênica , Ovário

RESUMO

Social insects are notable for having two female castes that exhibit extreme differences in their reproductive capacity. The molecular basis of these differences is largely unknown. Vitellogenin (Vg) is a powerful antioxidant and insulin-signalling regulator used in oocyte development. Here we investigate how Royal Jelly (the major food of honeybee queens) and queen mandibular pheromone (a major regulator of worker fertility), affect the longevity and reproductive status of honey bee workers, the expression of Vg, its receptor VgR and associated regulatory proteins. We find that Vg is expressed in the ovaries of workers and that workers fed a queen diet of Royal Jelly have increased Vg expression in the ovaries. Surprisingly, we find that expression of Vg is not associated with ovary activation in workers, suggesting that this gene has potentially acquired non-reproductive functions. Therefore, Vg expression in the ovaries of honeybee workers provides further support for the Ovarian Ground Plan Hypothesis, which argues that genes implicated in the regulation of reproduction have been co-opted to regulate behavioural differences between queens and workers.

Assuntos

Abelhas/fisiologia , Evolução Biológica , Expressão Gênica , Proteínas de Insetos/genética , Características de História de Vida , Vitelogeninas/genética , Animais , Abelhas/genética , Feminino , Proteínas de Insetos/metabolismo , Ovário/metabolismo , Reprodução/genética , Comportamento Social , Vitelogeninas/metabolismo

RESUMO

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.

Assuntos

Aminoácidos de Cadeia Ramificada/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Doença da Urina de Xarope de Bordo/metabolismo , Animais , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar

RESUMO

The search for novel therapeutic compounds remains an overwhelming task owing to the time-consuming and expensive nature of the drug development process and low success rates. Traditional methodologies that rely on the one drug-one target paradigm have proven insufficient for the treatment of multifactorial diseases, leading to a shift to multitarget approaches. In this emerging paradigm, molecules with off-target and promiscuous interactions may result in preferred therapies. In this study, we developed a general pipeline combining machine learning algorithms and a deep generator network to train a dual inhibitor classifier capable of identifying putative pharmacophoric traits. As a case study, we focused on dual inhibitors targeting DNA methyltransferase 1 (DNMT) and histone deacetylase 2 (HDAC2), two enzymes that play a central role in epigenetic regulation. We used this approach to identify dual inhibitors from a novel large natural product database in the public domain. We used docking and atomistic simulations as complementary approaches to establish the ligand-interaction profiles between the best hits and DNMT1/HDAC2. By using the combined ligand- and structure-based approaches, we discovered two promising novel scaffolds that can be used to simultaneously target both DNMT1 and HDAC2. We conclude that the flexibility and adaptability of the proposed pipeline has predictive capabilities of similar or derivative methods and is readily applicable to the discovery of small molecules targeting many other therapeutically relevant proteins.

RESUMO

Triple-negative breast cancer is an aggressive disease frequently associated with resistance to chemotherapy. Evidence supports that small molecules showing DNA methyltransferase inhibitory activity (DNMTi) are important to sensitize cancer cells to cytotoxic agents, in part, by reverting the acquired epigenetic changes associated with the resistance to therapy. The present study aimed to evaluate if chemical compounds derived from propolis could act as epigenetic drugs (epi-drugs). We selected three phenolic acids (caffeic, dihydrocinnamic, and p-coumaric) commonly detected in propolis and the (-)-epigallocatechin-3-gallate (EGCG) from green tea, which is a well-known DNA demethylating agent, for further analysis. The treatment with p-coumaric acid and EGCG significantly reduced the cell viability of four triple-negative breast cancer cell lines (BT-20, BT-549, MDA-MB-231, and MDA-MB-436). Computational predictions by molecular docking indicated that both chemicals could interact with the MTAse domain of the human DNMT1 and directly compete with its intrinsic inhibitor S-Adenosyl-l-homocysteine (SAH). Although the ethanolic extract of propolis (EEP) did not change the global DNA methylation content, by using MS-PCR (Methylation-Specific Polymerase Chain Reaction) we demonstrated that EEP and EGCG were able to partly demethylate the promoter region of RASSF1A in BT-549 cells. Also, in vitro treatment with EEP altered the RASSF1 protein expression levels. Our data indicated that some chemical compound present in the EEP has DNMTi activity and can revert the epigenetic silencing of the tumor suppressor RASSF1A. These findings suggest that propolis are a promising source for epi-drugs discovery.

Assuntos

Epigênese Genética , Hidroxibenzoatos/farmacologia , Própole/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidroxibenzoatos/química , Simulação de Acoplamento Molecular , Própole/química , Neoplasias de Mama Triplo Negativas/patologia

RESUMO

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.

Assuntos

Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/genética , Colangiocarcinoma/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Ilhas de CpG , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética

RESUMO

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.

RESUMO

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.

Assuntos

Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias Encefálicas/enzimologia , Biomarcadores Tumorais/metabolismo , Glioblastoma/enzimologia , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Prognóstico , Neoplasias Encefálicas/genética , Imuno-Histoquímica , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Chile , Taxa de Sobrevida , Estudos Retrospectivos , Glioblastoma/genética , O(6)-Metilguanina-DNA Metiltransferase/genética

RESUMO

A cultural trend in developed countries is favoring a delay in maternal age at first childbirth. In mammals fertility and chronological age show an inverse correlation. Oocyte quality is a contributing factor to this multifactorial phenomenon that may be influenced by age-related changes in the oocyte epigenome. Based on previous reports, we hypothesized that advanced maternal age would lead to alterations in the oocyte's epigenome. We tested our hypothesis by determining protein levels of various epigenetic modifications and modifiers in fully-grown (≥70 µm), germinal vesicle (GV) stage oocytes of young (10-13 weeks) and aged (69-70 weeks) mice. Our results demonstrate a significant increase in protein amounts of the maintenance DNA methyltransferase DNMT1 (P = 0.003) and a trend toward increased global DNA methylation (P = 0.09) with advanced age. MeCP2, a methyl DNA binding domain protein, recognizes methylated DNA and induces chromatin compaction and silencing. We hypothesized that chromatin associated MeCP2 would be increased similarly to DNA methylation in oocytes of aged female mice. However, we detected a significant decrease (P = 0.0013) in protein abundance of MeCP2 between GV stage oocytes from young and aged females. Histone posttranslational modifications can also alter chromatin conformation. Di-methylation of H3K9 (H3K9me2) is associated with permissive heterochromatin while acetylation of H4K5 (H4K5ac) is associated with euchromatin. Our results indicate a trend toward decreasing H3K9me2 (P = 0.077) with advanced female age and no significant differences in levels of H4K5ac. These data demonstrate that physiologic aging affects the mouse oocyte epigenome and provide a better understanding of the mechanisms underlying the decrease in oocyte quality and reproductive potential of aged females.

RESUMO

A cultural trend in developed countries is favoring a delay in maternal age at first childbirth. In mammals fertility and chronological age show an inverse correlation. Oocyte quality is a contributing factor to this multifactorial phenomenon that may be influenced by age-related changes in the oocyte epigenome. Based on previous reports, we hypothesized that advanced maternal age would lead to alterations in the oocyte’s epigenome. We tested our hypothesis by determining protein levels of various epigenetic modifications and modifiers in fully-grown (≥70 µm), germinal vesicle (GV) stage oocytes of young (10-13 weeks) and aged (69-70 weeks) mice. Our results demonstrate a significant increase in protein amounts of the maintenance DNA methyltransferase DNMT1 (P = 0.003) and a trend toward increased global DNA methylation (P = 0.09) with advanced age. MeCP2, a methyl DNA binding domain protein, recognizes methylated DNA and induces chromatin compaction and silencing. We hypothesized that chromatin associated MeCP2 would be increased similarly to DNA methylation in oocytes of aged female mice. However, we detected a significant decrease (P = 0.0013) in protein abundance of MeCP2 between GV stage oocytes from young and aged females. Histone posttranslational modifications can also alter chromatin conformation. Di-methylation of H3K9 (H3K9me2) is associated with permissive heterochromatin while acetylation of H4K5 (H4K5ac) is associated with euchromatin. Our results indicate a trend toward decreasing H3K9me2 (P = 0.077) with advanced female age and no significant differences in levels of H4K5ac. These data demonstrate that physiologic aging affects the mouse oocyte epigenome and provide a better understanding of the mechanisms underlying the decrease in oocyte quality and reproductive potential of aged females.

Assuntos

Animais , Camundongos/anatomia & histologia , Camundongos/genética , Metilação de DNA , Senescência Celular , Oócitos

RESUMO

A cultural trend in developed countries is favoring a delay in maternal age at first childbirth. In mammals fertility and chronological age show an inverse correlation. Oocyte quality is a contributing factor to this multifactorial phenomenon that may be influenced by age-related changes in the oocyte epigenome. Based on previous reports, we hypothesized that advanced maternal age would lead to alterations in the oocytes epigenome. We tested our hypothesis by determining protein levels of various epigenetic modifications and modifiers in fully-grown (≥70 µm), germinal vesicle (GV) stage oocytes of young (10-13 weeks) and aged (69-70 weeks) mice. Our results demonstrate a significant increase in protein amounts of the maintenance DNA methyltransferase DNMT1 (P = 0.003) and a trend toward increased global DNA methylation (P = 0.09) with advanced age. MeCP2, a methyl DNA binding domain protein, recognizes methylated DNA and induces chromatin compaction and silencing. We hypothesized that chromatin associated MeCP2 would be increased similarly to DNA methylation in oocytes of aged female mice. However, we detected a significant decrease (P = 0.0013) in protein abundance of MeCP2 between GV stage oocytes from young and aged females. Histone posttranslational modifications can also alter chromatin conformation. Di-methylation of H3K9 (H3K9me2) is associated with permissive heterochromatin while acetylation of H4K5 (H4K5ac) is associated with euchromatin. Our results indicate a trend toward decreasing H3K9me2 (P = 0.077) with advanced female age and no significant differences in levels of H4K5ac. These data demonstrate that physiologic aging affects the mouse oocyte epigenome and provide a better understanding of the mechanisms underlying the decrease in oocyte quality and reproductive potential of aged females.(AU)

Assuntos

Animais , Camundongos/anatomia & histologia , Camundongos/genética , Senescência Celular , Metilação de DNA , Oócitos