Medical Radiation Exposure and Human Carcinogenesis-Genetic and Epigenetic Mechanisms

Ionizing radiation （IR） is a potential carcinogen. Evidence for the carcinogenic effect of IR radiation has been shown after long-term animal investigations and observations on survivors of the atom bombs in Hiroshima and Nagasaki. However, IR has been widely used in a controlled manner in the medical imaging for diagnosis and monitoring of various diseases and also in cancer therapy. The collective radiation dose from medical imagings has increased six times in the last two decades, and grow continuously day to day. A large number of evidence has revealed the increased cancer risk in the people who had frequently exposed to x-rays, especially in childhood. It has also been shown that secondary malignancy may develop within the five years in cancer survivors who have received radiotherapv, because of IR-mediated damage to healthy cells. In this article, we review the current knowledge about the role of medical x-ray exposure in cancer development in humans, and recently recognized epigenetic mechanisms in IR-induced carcinogenesis.

Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases

The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.

Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

AIM： TO examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.METHODS： Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 （Bortezomib, Velcade^TM） by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei.RESULTS： Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation.CONCLUSION： The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption.

MicroRNAs:A novel signature in the metastasis of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC)is a malignant epithelial tumor,characterized by squamous cell differentiation,it is the sixth leading cause of cancer-related deaths globally.The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered,coupled with higher risk of metastasis,which is an exceedingly malignant charac-teristic of cancer,frequently leading to a high mortality rate.Unfortunately,there is currently no specific and effective marker to predict and treat metastasis in ESCC.MicroRNAs(miRNAs)are a class of small non-coding RNA molecules,approximately 22 nucleotides in length.miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence,progression,and prognosis of cancer.Here,we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis,and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors.This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis,with the ultimate aim of reducing the mortality rate among patients with ESCC.

Nuclear effects of ethanol-induced proteasome inhibition in liver cells

Alcohol ingestion causes alteration in several cellular mechanisms, and leads to inflammation, apoptosis, immunological response defects, and fibrosis. These phenomena are associated with significant changes in the epigenetic mechanisms, and subsequently, to liver cell memory. The ubiquitin-proteasome pathway is one of the vital pathways in the cell that becomes dysfunctionial as a result of chronic ethanol consumption. Inhibition of the proteasome activity in the nucleus causes changes in the turnover of transcriptional factors, histone modifying enzymes, and therefore, affects epigenetic mechanisms. Alcohol consumption has been associated with an increase in histone acetylation and a decrease in histone methylation, which leads to gene expression changes. DNA and histone modifications that result from ethanol-induced proteasome inhibition are key players in regulating gene expression, especially genes involved in the cell cycle, immunological responses, and metabolism of ethanol. The present review highlights the consequences of ethanol-induced proteasome inhibition in the nucleus of liver cells that are chronically exposed to ethanol.

Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets

Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia,causes long term health consequences.Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability.Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology.Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase,decrease in fibroblast and keratinocyte functioning,neuropathy,altered leukocyte functioning,infection,etc.,plays a significant role in impaired wound healing in diabetic people.Apart from the current pharmacotherapy,different other approaches like the use of conventional drugs,antidiabetic medication,antibiotics,debridement,offloading,platelet-rich plasma,growth factor,oxygen therapy,negative pressure wound therapy,low-level laser,extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds.Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis,inhibition of MMPs,reduction of oxidative stress,controlling hyperglycemia,increase growth factors,regulate inflammatory cytokines,cause NO induction,induce fibroblast and keratinocyte proliferation,control microbial infections are considered important in controlling diabetic wound.Further,medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound.The focus of the present review is to highlight the molecular and cellular mechanisms,and discuss the drug targets and treatment strategies involved in the diabetic wound.

Mechanism for winter cold-mediated epigenetic silencing of a potent floral repressor in plants

Subject Code:C02With the support by the Chinese Academy of Sciences(CAS),the research team of Plant Environmental Epigenetics led by Prof.He Yuehui(何跃辉)at the Shanghai Center for Plant Stress Biology,CAS and CAS Center for Excellence of Molecular Plant Sciences,discovered a molecular epigenetic mechanism underlying how winter cold enables plants to flower in spring,which was published in Nature Genetics(2016,48:1527—1534).

How might epigenetics contribute to ecological speciation？

Speciation research has seen a renewed interest in ecological speciation, which emphasises divergent ecological se- lection leading to the evolution of reproductive isolation. Selection from divergent ecologies means that phenotypic plasticity can play an important role in ecological speciation. Phenotypic plasticity involves the induction of phenotypes over the lifetime of an organism and emerging evidence suggests that epigenetic marks such as cytosine and protein （histone） modifications might regu- late such environmental induction. Epigenetic marks play a wide role in a variety of processes including development, sex dif- ferentiation and allocation, sexual conflict, regulation of transposable elements and phenotypic plasticity. Here we describe recent studies that investigate epigenetic mechanisms in a variety of contexts. There is mounting evidence for environmentally induced epigenetic variation and for the stable inheritance of epigenetic marks between generations. Thus, epigenetically-based pheno- typic plasticity may play a role in adaptation and ecological speciation. However, there is less evidence for the inheritance of in- duced epigenetic variation across multiple generations in animals. Currently few studies of ecological speciation incorporate the potential for the involvement of epigenetically-based induction of phenotypes, and we argue that this is an important omission [Current Zoology 59 （5）： 686-696, 2013 ].

The role of epigenetics in childhood autoimmune diseases with hematological manifestations

Autoimmune diseases with hematological manifestations are often characterized by chronicity and relapses despite treatment,and the underlying pathogenetic mechanisms remain unknown.Epigenetic alterations play a vital role in the deregulation of immune tolerance and the development of autoimmune diseases.In recent years,study of epigenetic mechanisms in both adult and childhood autoimmune disorders has been seeking to explain the pathophysiology of these heterogeneous diseases and to elucidate the interaction between genetic and environmental factors.Various mechanisms,including DNA methylation,histone modifications(chromatin remodeling),and noncoding RNAs(ncRNAs),have been studied extensively in the context of autoimmune diseases.This paper summarizes the epigenetic patterns in some of the most common childhood autoimmune disorders with hematological manifestations,based on epigenetic studies in children with primary immune thrombocytopenia(ITP),systemic lupus erythematosus(SLE),and juvenile idiopathic arthritis(JIA).Research findings indicate that methylation changes in genes expressed on T cells,modifications at a variety of histone sites,and alterations in the expression of several ncRNAs are involved in the pathogenesis of these diseases.These mechanisms not only determine the development of these diseases but also affect the severity of the clinical presentation and biochemical markers.Further studies will provide new tools for the prevention and diagnosis of childhood autoimmune disorders,and possible novel treatment options.

Pathological conditions re-shape physiological Tregs into pathological Tregs

CD4^(+)FOXP3^(+)regulatory T cells(Tregs)are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance,controlling acute and chronic inflammation,allergy,autoimmune diseases,and anti-cancer immune responses.Over the past 20 years,a significant progress has been made since Tregs were first characterized in 1995.Many concepts and principles regarding Tregs generation,phenotypic features,subsets(tTregs,pTregs,iTregs,and iTreg35),tissue specificity(central Tregs,effector Tregs,and tissue resident Tregs),homeostasis(highly dynamic and apoptotic),regulation of Tregs by receptors for PAMPs and DAMPs,Treg plasticity(re-differentiation to other CD4 T helper cell subsets,Th1,Th2,Tfh,and Th17),and epigenetic regulation of Tregs phenotypes and functions have been innovated.In this concise review,we want to briefly analyze these eight new progresses in the study of Tregs.We have also proposed for the first time a novel concept that“physiological Tregs”have been re-shaped into“pathological Tregs”in various pathological environments.Continuing of the improvement in our understanding on this important cellular component about the immune tolerance and immune suppression would lead to the future development of novel therapeutics approaches for acute and chronic inflammatory diseases,allergy,allogeneic transplantation-related immunity,sepsis,autoimmune diseases,and cancers.