BDNF promoter methylation and suicidal behavior in depressive patients

Introduction

Suicide is a major health problem, and depression is a major psychiatric cause of suicide. Suicide is influenced by the multifactorial interaction of many risk factors. Therefore, epigenetic research may lead to understandings that are applicable to suicide. This study investigated whether epigenetic changes are associated with suicidal behavior and evaluated the treatment outcome of suicidal ideation in depressive patients.

Methods

In 108 patients with major depression, the promoter methylation of the gene encoding brain-derived neurotrophic factor (BDNF) was measured. Sociodemographic and clinical characteristics including a history of previous depressive episodes, age at onset, duration of illnesses, family history of depression, and number of stressful life events as well as subjective perception of stress and assessment scales for depression (HAMD), anxiety (HAMA), function (SOFAS), disability (WHODAS-12), and quality of life (WHOQOL-BREF) were evaluated at baseline. Suicidal behavior was ascertained using a semistructured clinical interview with questions about severity and intent. Beck Scale for Suicide Ideation (BSS) was administered during 12 weeks of treatment with antidepressants.

Results

A higher BDNF promoter methylation status was significantly associated with a previous suicidal attempt history, suicidal ideation during treatment, and suicidal ideation at last evaluation as well as with higher BSS scores and poor treatment outcomes for suicidal ideation.

Limitations

Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small.

Conclusions

BDNF methylation status could be a proxy marker for previous suicidal attempts and a clinical biomarker for poor treatment outcomes of suicidal ideation in depression.     

Epigenetic regulation in antiviral innate immunity

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators — chromatin remodeling and histone modification — in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.     

Induction and stability of the anergic phenotype in T cells

One of the mechanisms that are in place to control the activation of mature T cells that bear self-reactive antigen receptors is anergy, a long-term state of hyporesponsiveness that is established in T cells in response to suboptimal stimulation. T cells receive signals that result not only from antigen recognition and costimulation but also from other sources, including cytokine receptors, inhibitory receptors or metabolic sensors. Integration of those signals will determine T cell fate. Under conditions that induce anergy, T cells activate a program of gene expression that leads to the production of proteins that block T cell receptor signaling and inhibit cytokine gene expression. In this review we will examine those signals that determine functional outcome following antigen encounter, review current knowledge of the factors that ensure signaling inhibition and epigenetic gene silencing in anergic cells and explore the mechanisms that lead to the reversal of anergy and the reacquisition of effector functions.     

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

An improvement in pancreatic cancer treatment represents an urgent medical goal.Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades.Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations,such as mutations of K-ras,and especially epigenetic dysregulation of tumor-associated genes,such as silencing of the tumor suppressor p16ink4a,are hallmarks of pancreatic cancer.Here,we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation,histone acetylation or miRNA(microRNA)expression,and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition,morphological pattern formation,or cancer stem cell regulation during carcinogenesis from PanIN(pancreatic intraepithelial lesions)to invasive cancer and resistance development.Epigenetic drugs,such as DNA methyltransferases or histone deactylase inhibitors,have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development.Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.     

Oxidative stress in alcohol-related liver disease

Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P4502E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.     

Długotrwała odpowiedź na leczenie azacytydyną pacjentki z ostrą białaczką szpikową z niekorzystnym profilem cytogenetycznym – prezentacja przypadku

Acute myeloid leukemia (AML) is the most common type of leukaemia found in adults and the number of disease cases increases with age. Despite the advances in the AML treatment, the results in patients over the age of 60 remain unsatisfactory.In this study we present the case of a 73-year-old female patient with an unfavourable cytogenetic profile, in whom we observe long-term response to azacitidine, after previous failures of classic polychemotherapy.In February 2010, a 70-year-old patient was admitted to the Department of Haematology USK in Bialystok on suspicion of AML. The patient was qualified for intensive chemotherapy regimen of daunorubicin (DNR) and cytarabine (Ara-C).Cytogenetic examination revealed the presence of double minutes – acentric fragments of extrachromosomal DNA, which is associated with resistance to standard chemotherapy. Induction chemotherapy was complicated by febrile neutropenia, pneumonia and episodes of atrial fibrillation. Due to the lack of remission and severe after-induction period, a brief reinduction chemotherapy with DNR and Ara-C was applied to obtain complete remission with incomplete regeneration (CRi).Due to the recurrence in October 2010, reinduction chemotherapy was given followed by two cycles of maintenance chemotherapy. After another relapse in February 2011 (23,6% blasts in the bone marrow), a chemotherapy regimen designed for refractory and relapsed leukaemia was given, without any effect. In April 2011, the patient began azacitidine treatment. By the end of March 2013, the patient received twenty-one treatment cycles. The twelfth cycle of chemotherapy was complicated by pulmonary embolism which was treated successfully. The complete blood count remains at normal values.Recent reports indicate a clear relationship processes such as epigenetic regulation of DNA methylation with leukaemogenesis. The use of hypomethylating drugs in AML is yielding promising results.     

Epigenetic mechanisms in Alzheimer's disease: Implications for pathogenesis and therapy

The vast majority of Alzheimer's disease (AD) are late-onset forms (LOAD) likely due to the interplay of environmental influences and individual genetic susceptibility. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNAs, constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that epigenetic mechanisms play a pivotal role in aging the pathogenesis of AD. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and AD. Moreover, we also consider how aberrant epigenetic modifications may lead to AD pathogenesis, and we review the therapeutic potential of epigenetic treatments for AD.     

表观遗传学对乙型肝炎病毒复制的调节

全球有4亿多人感染了乙型肝炎病毒(HBV),慢性HBV感染仍是造成终末期肝病(肝硬化和肝细胞肝癌)最主要的原因[1-2].一旦形成慢性感染,人体便很难有效清除HBV.HBV在肝细胞内不断利用自身和宿主蛋白酶合成稳定的共价闭合环状DNA(covalently closed circular DNA,cccDNA)寄生于肝细胞核内,使得现有抗病毒药物难以根治HBV感染[3].近年来,研究者们发现HBV复制与许多非免疫调控机制有关,如HBV利用自噬系统促进自身复制[4-5].表观遗传学作为重要的转录后调节机制也受到关注,其中的cccDNA甲基化、miRNA、组蛋白修饰均参与了HBV基因表达的调控[6-13].通过进一步研究表观遗传学对HBV调控的机制,可能为揭示HBV感染慢性化原因、研发新的抗病毒药物治疗靶点提供思路.以下,我们分别就miRNA、cccDNA甲基化、组蛋白乙酰化对HBV调节机制的研究进展进行综述.