水痘-带状疱疹病毒的潜伏与再激活机制研究进展

水痘-带状疱疹病毒(varicella-zoster virus,VZV)原发性感染通常会引起儿童期水痘,之后病毒可潜伏于人类外周神经节中,在数十年后重新激活造成带状疱疹,也与危及生命的脑炎、血管病变和脑膜炎等疾病有关。VZV潜伏和再激活的机制尚未得到很好的解释,原因之一是VZV只感染人类,无法使用大多数动物及动物来源的神经元模型。越来越多的证据表明,VZV潜伏是表观遗传学调控的,可用于信号通路分析和表观遗传调节鉴定的体外模型为探索VZV潜伏与再激活机制提供了帮助。此文综述了VZV的分子生物学和VZV潜伏与再激活机制方面的研究进展,并提出了未来的研究方向。     

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.     

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.