Epigenetic changes are changes in gene expression by regulating gene transcription and translation without changing the nucleotide sequence of the genome. Although the genome itself changes during the occurrence and d...Epigenetic changes are changes in gene expression by regulating gene transcription and translation without changing the nucleotide sequence of the genome. Although the genome itself changes during the occurrence and development of most malignant tumors, recent studies have found that epigenetic changes also play an important role in the occurrence and development of tumors. Epigenetic modification mainly includes DNA methylation, histone modification and miRNA regulation. This review focuses on the role and mechanism of epigenetic modification in the occurrence, metastasis and invasion of hepatocellular carcinoma (HCC), and summarizes the latest methods for the treatment of HCC by restoring dysregulated epigenetic modification. It provides a theoretical basis for revealing the pathogenesis of liver cancer and developing new methods of diagnosis and treatment.展开更多
BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/aut...BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.展开更多
Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with...Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with genetics,advanced glycosylation end-product deposition,polyol pathway and protein C activation,lipid metabolism abnormalities,microcirculatory dysfunction,oxidative stress,inflammatory factors,and the kallikrein-kinin system.Epigenetics is the science studying gene expression regulation without changes in the DNA sequence.In recent years,increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD.For instance,epigenetic modifications such as DNA methylation,histone modifications,and non-coding RNAs can influence the expression of DKD-related genes,thereby regulating the development and progression of DKD.On the other hand,metabolic memory is an important concept in DKD research.Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors.This state can influence cell function and fate.In DKD,metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells,affecting their function and fate,ultimately leading to the development and progression of DKD.Therefore,to further explore the pathogenesis of DKD,research on epigenetics should be strengthened,aiming to provide new ideas and methods for the prevention and treatment of DKD.展开更多
Hepatocellular carcinoma(HCC),the predominant form of adult liver malignancies,is a global health concern.Its dismal prognosis has prompted recent significant advances in the understanding of its etiology and pathogen...Hepatocellular carcinoma(HCC),the predominant form of adult liver malignancies,is a global health concern.Its dismal prognosis has prompted recent significant advances in the understanding of its etiology and pathogenesis.The deregulation of epigenetic mechanisms,which maintain heritable gene expression changes and chromatin organization,is implicated in the development of multiple cancers,including HCC.This review summarizes the current knowledge of epigenetic mechanisms in the pathogenesis of HCC,with an emphasis on HCC mediated by chronic hepatitis B virus infection.This review also discusses the encouraging outcomes and lessons learnt from epigenetic therapies for hematological and other solid cancers,and highlights the future potential of similar therapies in the treatment of HCC.展开更多
Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromat...Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer(CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.展开更多
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 unchang...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.展开更多
Cancers,like other diseases,arise from gene mutations and/or altered gene expression,which eventually cause dysregulation of numerous proteins and noncoding RNAs.Changes in gene expression,i.e.,upregulation of oncogen...Cancers,like other diseases,arise from gene mutations and/or altered gene expression,which eventually cause dysregulation of numerous proteins and noncoding RNAs.Changes in gene expression,i.e.,upregulation of oncogenes and/or downregulation of tumor suppressor genes,can be generated not only by genetic and environmental factors but also by epigenetic factors,which are inheritable but nongenetic modifications of cellular chromosome components.Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies.The search for genetic and environmental factors has a long history in cancer research,but epigenetic factors only recently began to be associated with cancer formation,progression,and metastasis.Epigenetic alterations of chromatin include DNA methylation and histone modifications,which can affect gene-expression profiles.Recent studies have revealed diverse mechanisms by which chromatin modifiers,including writers,erasers and readers of the aforementioned modifications,contribute to the formation and progression of cancer.Furthermore,functional RNAs,such as microRNAs and long noncoding RNAs,have also been identified as key players in these processes.This review highlights recent findings concerning the epigenetic alterations associated with cancers,especially gastric cancer.展开更多
Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inher...Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEPNET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microR NA and long non-coding RNA(lncR NA) differential expression profiles that are distinctive of GEPNETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.展开更多
The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for...The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for selfrenewal and their pluripotency. Pluripotent stem cells are able to differentiate into the cells of all three germ layers, and because of this property they represent a promising therapeutic tool in the treatment of diseases such as Parkinson's disease and diabetes, or in the healing of lesions after heart attack. As the basic nuclear unit, chromatin is responsible for the regulation of the functional status of cells, including pluripotency and differentiation. Therefore, in this review we discuss the functional changes in chromatin during differentiation and the correlation between epigenetics events and the differentiation potential of embryonic stem cells. In particular we focus on post-translational histone modification, DNA methylation and the heterochromatin protein HP1 and its unique function in mouse and human embryonic stem cells.展开更多
Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease.Recent studies have found the aberrant epigenetics in TAO,including DNA methylation,noncoding RNAs,and histone modification.Many genes have an aberrant le...Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease.Recent studies have found the aberrant epigenetics in TAO,including DNA methylation,noncoding RNAs,and histone modification.Many genes have an aberrant level of methylation in TAO.For example,higher levels are found in CD14,MBP,ANGLE1,LYAR and lower levels in DRD4 and BOLL.Non-coding RNAs are involved in the immune response(miR-146a,miR-155,miR-96,miR-183),fibrosis regulation(miR-146a,miR-21,miR-29),adipogenesis(miR-27)and are thought to play roles in TAO.MicroRNA is also related to the clinical activity score(miR-Let7d-5p)and may be a predictor of glucocorticoid therapy(miR-224-5p).The quantities of H4 in TAO are increased compared with euthyroid control subjects,and the role of histone modifications in Graves*disease may lead to better understanding of its role in TAO.More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.展开更多
Epigenetic is the study of those alterations regulating gene expression without altering DNA sequence and inherited by transmission through cell division. Mutational and epimutational events that alterate cellular gro...Epigenetic is the study of those alterations regulating gene expression without altering DNA sequence and inherited by transmission through cell division. Mutational and epimutational events that alterate cellular growth and division are combined in carcinogenesis. Advances in genome and epigenome-wide analysis identify DNA hypomethylation,hypermethylation of tumor suppressor genes,aberrant histone modifications and/or specific mi RNA expression profiles to contribute to tumor initiation and progression. The major challenge for cancer researchers is to enlighten the complex relationship between the epigenetic and genetic machinery in order tooptimize combined therapies,reducing chemoresistance and minimizing adverse effects in cancer patients. In this review we will cover many distinct aspects of epigenetic phenomenon. Firstly,we will globally explain the most common epigenetic events and their effects on gene expression regulation. Secondly,we will review the evidence of the correlation between epigenetics and cancer progression,focusing in particular on the effect of aberrant hypo- and hyper-methylation. We will also consider the main methods currently used for methylation analysis,covering both locus-specific technologies and genome-wide analysis. Finally,we will discuss the introduction of novel epigenetic drugs in combination with conventional treatments in order to develop more effective cancer therapies. Such information could help in understanding the important role of epigenetics in cancer.展开更多
Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Ep...Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence.Epigenetic alterations are involved in virtually all key cancerassociated pathways and are fundamental to the genesis of cancer.In recent years,the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis,prognosis,and therapeutic intervention have been clarified.In this review,we summarize the current knowledge of the best-studied epigenetic modifications in CTCL,including DNA methylation,histone modifications,micro RNAs,and chromatin remodelers.These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.展开更多
Academic biology-medicine refers to a couple of philosophies, Organicism and Mechanism, which translates into an association of Cybernetic diagrams and molecular Reductionism. This association presents logical difficu...Academic biology-medicine refers to a couple of philosophies, Organicism and Mechanism, which translates into an association of Cybernetic diagrams and molecular Reductionism. This association presents logical difficulties which make it unsuitable to describe correctly biological effects of electromagnetic fields, EMF. But these logical difficulties may be overcome when renewing the organic cell idea by means of a Philosophy of Nature which juxtaposes causality order and sense order in the cell. The signalsome, the set of descriptive components resulting from the genome, is constantly reorganized. This remodeling may become epigenetic when the phenotype becomes transformed by experience of perceptions in a given medium, because the perception of overall information coming from the extracellular medium becomes functional within the system. In that cellular perception, it is stated that the significance base which contributes to the sense order results from the qualitative topological structure of the extracellular medium. Therefore the EMF interactions target is not only the membrane and its molecules;it is also the structure of the extracellular medium which bathes the membrane. Knowing that the sense order modulation constitutes the global soil of the (localized) causality order, it is possible to obtain a same EMF bioeffect on a membrane molecule by treating a culture of cells in its bath or by treating only the extracellular aqueous medium. Consequently, the double bioeffect resulting from EMF exposure is described simply, because the sense order, such as it results from the qualitative structuring of the medium, forms the significance base which directs the causal mechanics of the cellular answer.展开更多
Epigenetic regulations are heritable changes in gene expression that occur in the absence of alterations in DNA sequences. Various epigenetic mechanisms include histone modifications and DNA methylations. In this revi...Epigenetic regulations are heritable changes in gene expression that occur in the absence of alterations in DNA sequences. Various epigenetic mechanisms include histone modifications and DNA methylations. In this review, we examine methods to study DNA methylations and their contribution to degenerative diseases by mediating the complex gene-by-environment interactions. Such epigenetic modifications despite being heritable and stably maintained are also potentially reversible and there is scope for the development of epigenetic therapies for this disease.展开更多
Recent debate among the experts of cancer research regarding the main causes of carcinogenesis encouraged us to review the etiology of cancer pathogenesis. The somatic mutation theory attributes carcinogenesis to rand...Recent debate among the experts of cancer research regarding the main causes of carcinogenesis encouraged us to review the etiology of cancer pathogenesis. The somatic mutation theory attributes carcinogenesis to random errors in DNA multiplication while the tissue organization field theory ascribes causation to environmental factors. We recognize complexity in cancer pathogenesis and accept the premise of both DNA multiplication errors and environmental factors in cancer development. Furthermore, it should also be noted that the combination of these factors and the relative importance of the each differ in various types of cancers. For example, in some cancers, genetics plays a prominent role while in others environment such as obesity plays a much stronger role. Additionally, the cancer mitigating factors should also be considered. The balance of cancer-enhancing and cancer-suppressing forces determines the cancer incidence. Ultimately, identifying the lifestyle factors that revise somatic mutations or epigenetic alterations will lead to a clear understanding of pathogenic mechanisms of cancer and to the optimal preventive strategies. This narrative review evaluates the published evidence on carcinogenesis pertaining to the whole organism(thus, holistic) incorporating genetics, epigenetics, immunology, inflammation and infections with emphasis on oral infections.展开更多
Celiac disease(CeD)is a multifactorial autoimmune disorder spread worldwide.The exposure to gluten,a protein found in cereals like wheat,barley and rye,is the main environmental factor involved in its pathogenesis.Eve...Celiac disease(CeD)is a multifactorial autoimmune disorder spread worldwide.The exposure to gluten,a protein found in cereals like wheat,barley and rye,is the main environmental factor involved in its pathogenesis.Even if the genetic predisposition represented by HLA-DQ2 or HLA-DQ8 haplotypes is widely recognised as mandatory for CeD development,it is not enough to explain the total predisposition for the disease.Furthermore,the onset of CeD comprehend a wide spectrum of symptoms,that often leads to a delay in CeD diagnosis.To overcome this deficiency and help detecting people with increased risk for CeD,also clarifying CeD traits linked to disease familiarity,different studies have tried to make light on other predisposing elements.These were in many cases genetic variants shared with other autoimmune diseases.Since inherited traits can be regulated by epigenetic modifications,also induced by environmental factors,the most recent studies focused on the potential involvement of epigenetics in CeD.Epigenetic factors can in fact modulate gene expression with many mechanisms,generating more or less stable changes in gene expression without affecting the DNA sequence.Here we analyze the different epigenetic modifications in CeD,in particular DNA methylation,histone modifications,non-coding RNAs and RNA methylation.Special attention is dedicated to the additional predispositions to CeD,the involvement of epigenetics in developing CeD complications,the pathogenic pathways modulated by epigenetic factors such as microRNAs and the potential use of epigenetic profiling as biomarker to discriminate different classes of patients.展开更多
Comparative analysis of epigenetic alterations between acute and chronic leukemia, with an emphasis on histone modifications, was conducted. We focused on the promoter regions of the whole genomes as well as oncogenes...Comparative analysis of epigenetic alterations between acute and chronic leukemia, with an emphasis on histone modifications, was conducted. We focused on the promoter regions of the whole genomes as well as oncogenes. Our results revealed that obvious differential histone modifications pattern existed between the two subtypes. H3K27ac had a high tag density in the promoter region in both Dnd41 cell lines and K562 cell lines. H3K27ac and H3K4me1 had high correlation between the two cell lines of oncogenes. Similar results were also achieved in the promoter region of high expression genes in the Jurkat and K562 cell lines based on RNA-seq data. This suggested that H2K27ac and H3K4me1 were active regulators in leukemia cell lines.展开更多
Air pollution is a global problem with far-reaching environmental impacts. Exposure has been linked to a number of different adverse health effects. Understanding the impact of ambient air pollution is complicated giv...Air pollution is a global problem with far-reaching environmental impacts. Exposure has been linked to a number of different adverse health effects. Understanding the impact of ambient air pollution is complicated given the diversity of both the pollutants involved as well as the complexity of associated diseases. While we see a positive correlation between levels of exposure and health issues, the mechanisms of pathogenesis are still under investigation. The study of epigenetic regulation as it relates to disease is emerging as an exciting new way to interpret the possible effects of ambient air pollution on DNA. In this review we provide an overview of epigenetic modifications as well as an analysis of how epigenetic mechanisms are involved in the adverse effects associated with the most common components of ambient air pollution.展开更多
“After this, there is no turning back. You take the blue pill—the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill—you stay in Wonderland, and I show you how deep ...“After this, there is no turning back. You take the blue pill—the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill—you stay in Wonderland, and I show you how deep the rabbit hole goes. Remember: all I’m offering is the truth.” Epigenetics is a bit like the red pill—the more it is researched the further down the rabbit hole we are going—the realisation that my choices today as my parents’ and grandparents’ choices yesterday influence who I am now and who I am going to be tomorrow. Through the study of gene influencers, scientists are discovering that it is not only the DNA that makes us but which portion of is selected for use that tells us who we are. In the field of depression, epigenetics is still in its infancy, nonetheless significant connections have been uncovered. This paper gives a brief overview on epigenetics and the different mechanisms correlated with it. It also discusses factors affecting an individual’s epigenetic patterns and the effect of epigenetics itself. It specifically delves into the epigenetic effects on psychiatry, mainly depression, depressive symptoms and antidepressant treatments and the mediation of mechanism of action of the epigenetic modifications involved.展开更多
文摘Epigenetic changes are changes in gene expression by regulating gene transcription and translation without changing the nucleotide sequence of the genome. Although the genome itself changes during the occurrence and development of most malignant tumors, recent studies have found that epigenetic changes also play an important role in the occurrence and development of tumors. Epigenetic modification mainly includes DNA methylation, histone modification and miRNA regulation. This review focuses on the role and mechanism of epigenetic modification in the occurrence, metastasis and invasion of hepatocellular carcinoma (HCC), and summarizes the latest methods for the treatment of HCC by restoring dysregulated epigenetic modification. It provides a theoretical basis for revealing the pathogenesis of liver cancer and developing new methods of diagnosis and treatment.
基金Supported by the following Brazilian funding agencies:Financiamento e IncentivoàPesquisa from Hospital de Clínicas de Porto Alegre(FIPE/HCPA),No.2021-0105(toÁlvares-da-Silva MR)Coordination for the Improvement of Higher Education Personnel,CAPES/PNPDand this study was financed in part by the Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)(toÁlvares-da-Silva MR).
文摘BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.
文摘Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with genetics,advanced glycosylation end-product deposition,polyol pathway and protein C activation,lipid metabolism abnormalities,microcirculatory dysfunction,oxidative stress,inflammatory factors,and the kallikrein-kinin system.Epigenetics is the science studying gene expression regulation without changes in the DNA sequence.In recent years,increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD.For instance,epigenetic modifications such as DNA methylation,histone modifications,and non-coding RNAs can influence the expression of DKD-related genes,thereby regulating the development and progression of DKD.On the other hand,metabolic memory is an important concept in DKD research.Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors.This state can influence cell function and fate.In DKD,metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells,affecting their function and fate,ultimately leading to the development and progression of DKD.Therefore,to further explore the pathogenesis of DKD,research on epigenetics should be strengthened,aiming to provide new ideas and methods for the prevention and treatment of DKD.
文摘Hepatocellular carcinoma(HCC),the predominant form of adult liver malignancies,is a global health concern.Its dismal prognosis has prompted recent significant advances in the understanding of its etiology and pathogenesis.The deregulation of epigenetic mechanisms,which maintain heritable gene expression changes and chromatin organization,is implicated in the development of multiple cancers,including HCC.This review summarizes the current knowledge of epigenetic mechanisms in the pathogenesis of HCC,with an emphasis on HCC mediated by chronic hepatitis B virus infection.This review also discusses the encouraging outcomes and lessons learnt from epigenetic therapies for hematological and other solid cancers,and highlights the future potential of similar therapies in the treatment of HCC.
文摘Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer(CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.
文摘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.
基金Supported by National Research Foundation of Korea,No.2013056334
文摘Cancers,like other diseases,arise from gene mutations and/or altered gene expression,which eventually cause dysregulation of numerous proteins and noncoding RNAs.Changes in gene expression,i.e.,upregulation of oncogenes and/or downregulation of tumor suppressor genes,can be generated not only by genetic and environmental factors but also by epigenetic factors,which are inheritable but nongenetic modifications of cellular chromosome components.Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies.The search for genetic and environmental factors has a long history in cancer research,but epigenetic factors only recently began to be associated with cancer formation,progression,and metastasis.Epigenetic alterations of chromatin include DNA methylation and histone modifications,which can affect gene-expression profiles.Recent studies have revealed diverse mechanisms by which chromatin modifiers,including writers,erasers and readers of the aforementioned modifications,contribute to the formation and progression of cancer.Furthermore,functional RNAs,such as microRNAs and long noncoding RNAs,have also been identified as key players in these processes.This review highlights recent findings concerning the epigenetic alterations associated with cancers,especially gastric cancer.
文摘Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEPNET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microR NA and long non-coding RNA(lncR NA) differential expression profiles that are distinctive of GEPNETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.
基金Supported by Grants P302/12/G157 and 13-07822S from the Grant Agency of the Czech Republicby COST-CZ project LD11020 of the Ministry of Education Youth and Sport of the Czech RepublicBártová E is a coordinator of the EU Marie Curie Project PIRSES-GA-2010-269156-LCS
文摘The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for selfrenewal and their pluripotency. Pluripotent stem cells are able to differentiate into the cells of all three germ layers, and because of this property they represent a promising therapeutic tool in the treatment of diseases such as Parkinson's disease and diabetes, or in the healing of lesions after heart attack. As the basic nuclear unit, chromatin is responsible for the regulation of the functional status of cells, including pluripotency and differentiation. Therefore, in this review we discuss the functional changes in chromatin during differentiation and the correlation between epigenetics events and the differentiation potential of embryonic stem cells. In particular we focus on post-translational histone modification, DNA methylation and the heterochromatin protein HP1 and its unique function in mouse and human embryonic stem cells.
基金the National Natural Science Foundation of China(No.82071006)Natural Science Foundation of Hunan Province(No.2020JJ4129)Independent Exploration and Innovation Project of Graduate Students in Central South University(No.2021zzts1086)。
文摘Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease.Recent studies have found the aberrant epigenetics in TAO,including DNA methylation,noncoding RNAs,and histone modification.Many genes have an aberrant level of methylation in TAO.For example,higher levels are found in CD14,MBP,ANGLE1,LYAR and lower levels in DRD4 and BOLL.Non-coding RNAs are involved in the immune response(miR-146a,miR-155,miR-96,miR-183),fibrosis regulation(miR-146a,miR-21,miR-29),adipogenesis(miR-27)and are thought to play roles in TAO.MicroRNA is also related to the clinical activity score(miR-Let7d-5p)and may be a predictor of glucocorticoid therapy(miR-224-5p).The quantities of H4 in TAO are increased compared with euthyroid control subjects,and the role of histone modifications in Graves*disease may lead to better understanding of its role in TAO.More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.
文摘Epigenetic is the study of those alterations regulating gene expression without altering DNA sequence and inherited by transmission through cell division. Mutational and epimutational events that alterate cellular growth and division are combined in carcinogenesis. Advances in genome and epigenome-wide analysis identify DNA hypomethylation,hypermethylation of tumor suppressor genes,aberrant histone modifications and/or specific mi RNA expression profiles to contribute to tumor initiation and progression. The major challenge for cancer researchers is to enlighten the complex relationship between the epigenetic and genetic machinery in order tooptimize combined therapies,reducing chemoresistance and minimizing adverse effects in cancer patients. In this review we will cover many distinct aspects of epigenetic phenomenon. Firstly,we will globally explain the most common epigenetic events and their effects on gene expression regulation. Secondly,we will review the evidence of the correlation between epigenetics and cancer progression,focusing in particular on the effect of aberrant hypo- and hyper-methylation. We will also consider the main methods currently used for methylation analysis,covering both locus-specific technologies and genome-wide analysis. Finally,we will discuss the introduction of novel epigenetic drugs in combination with conventional treatments in order to develop more effective cancer therapies. Such information could help in understanding the important role of epigenetics in cancer.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81872214 and 81922058)。
文摘Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence.Epigenetic alterations are involved in virtually all key cancerassociated pathways and are fundamental to the genesis of cancer.In recent years,the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis,prognosis,and therapeutic intervention have been clarified.In this review,we summarize the current knowledge of the best-studied epigenetic modifications in CTCL,including DNA methylation,histone modifications,micro RNAs,and chromatin remodelers.These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.
文摘Academic biology-medicine refers to a couple of philosophies, Organicism and Mechanism, which translates into an association of Cybernetic diagrams and molecular Reductionism. This association presents logical difficulties which make it unsuitable to describe correctly biological effects of electromagnetic fields, EMF. But these logical difficulties may be overcome when renewing the organic cell idea by means of a Philosophy of Nature which juxtaposes causality order and sense order in the cell. The signalsome, the set of descriptive components resulting from the genome, is constantly reorganized. This remodeling may become epigenetic when the phenotype becomes transformed by experience of perceptions in a given medium, because the perception of overall information coming from the extracellular medium becomes functional within the system. In that cellular perception, it is stated that the significance base which contributes to the sense order results from the qualitative topological structure of the extracellular medium. Therefore the EMF interactions target is not only the membrane and its molecules;it is also the structure of the extracellular medium which bathes the membrane. Knowing that the sense order modulation constitutes the global soil of the (localized) causality order, it is possible to obtain a same EMF bioeffect on a membrane molecule by treating a culture of cells in its bath or by treating only the extracellular aqueous medium. Consequently, the double bioeffect resulting from EMF exposure is described simply, because the sense order, such as it results from the qualitative structuring of the medium, forms the significance base which directs the causal mechanics of the cellular answer.
文摘Epigenetic regulations are heritable changes in gene expression that occur in the absence of alterations in DNA sequences. Various epigenetic mechanisms include histone modifications and DNA methylations. In this review, we examine methods to study DNA methylations and their contribution to degenerative diseases by mediating the complex gene-by-environment interactions. Such epigenetic modifications despite being heritable and stably maintained are also potentially reversible and there is scope for the development of epigenetic therapies for this disease.
基金Supported by Helsinki University Hospital funds,NoTYH2015323(to Meurman JH)
文摘Recent debate among the experts of cancer research regarding the main causes of carcinogenesis encouraged us to review the etiology of cancer pathogenesis. The somatic mutation theory attributes carcinogenesis to random errors in DNA multiplication while the tissue organization field theory ascribes causation to environmental factors. We recognize complexity in cancer pathogenesis and accept the premise of both DNA multiplication errors and environmental factors in cancer development. Furthermore, it should also be noted that the combination of these factors and the relative importance of the each differ in various types of cancers. For example, in some cancers, genetics plays a prominent role while in others environment such as obesity plays a much stronger role. Additionally, the cancer mitigating factors should also be considered. The balance of cancer-enhancing and cancer-suppressing forces determines the cancer incidence. Ultimately, identifying the lifestyle factors that revise somatic mutations or epigenetic alterations will lead to a clear understanding of pathogenic mechanisms of cancer and to the optimal preventive strategies. This narrative review evaluates the published evidence on carcinogenesis pertaining to the whole organism(thus, holistic) incorporating genetics, epigenetics, immunology, inflammation and infections with emphasis on oral infections.
文摘Celiac disease(CeD)is a multifactorial autoimmune disorder spread worldwide.The exposure to gluten,a protein found in cereals like wheat,barley and rye,is the main environmental factor involved in its pathogenesis.Even if the genetic predisposition represented by HLA-DQ2 or HLA-DQ8 haplotypes is widely recognised as mandatory for CeD development,it is not enough to explain the total predisposition for the disease.Furthermore,the onset of CeD comprehend a wide spectrum of symptoms,that often leads to a delay in CeD diagnosis.To overcome this deficiency and help detecting people with increased risk for CeD,also clarifying CeD traits linked to disease familiarity,different studies have tried to make light on other predisposing elements.These were in many cases genetic variants shared with other autoimmune diseases.Since inherited traits can be regulated by epigenetic modifications,also induced by environmental factors,the most recent studies focused on the potential involvement of epigenetics in CeD.Epigenetic factors can in fact modulate gene expression with many mechanisms,generating more or less stable changes in gene expression without affecting the DNA sequence.Here we analyze the different epigenetic modifications in CeD,in particular DNA methylation,histone modifications,non-coding RNAs and RNA methylation.Special attention is dedicated to the additional predispositions to CeD,the involvement of epigenetics in developing CeD complications,the pathogenic pathways modulated by epigenetic factors such as microRNAs and the potential use of epigenetic profiling as biomarker to discriminate different classes of patients.
文摘Comparative analysis of epigenetic alterations between acute and chronic leukemia, with an emphasis on histone modifications, was conducted. We focused on the promoter regions of the whole genomes as well as oncogenes. Our results revealed that obvious differential histone modifications pattern existed between the two subtypes. H3K27ac had a high tag density in the promoter region in both Dnd41 cell lines and K562 cell lines. H3K27ac and H3K4me1 had high correlation between the two cell lines of oncogenes. Similar results were also achieved in the promoter region of high expression genes in the Jurkat and K562 cell lines based on RNA-seq data. This suggested that H2K27ac and H3K4me1 were active regulators in leukemia cell lines.
文摘Air pollution is a global problem with far-reaching environmental impacts. Exposure has been linked to a number of different adverse health effects. Understanding the impact of ambient air pollution is complicated given the diversity of both the pollutants involved as well as the complexity of associated diseases. While we see a positive correlation between levels of exposure and health issues, the mechanisms of pathogenesis are still under investigation. The study of epigenetic regulation as it relates to disease is emerging as an exciting new way to interpret the possible effects of ambient air pollution on DNA. In this review we provide an overview of epigenetic modifications as well as an analysis of how epigenetic mechanisms are involved in the adverse effects associated with the most common components of ambient air pollution.
文摘“After this, there is no turning back. You take the blue pill—the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill—you stay in Wonderland, and I show you how deep the rabbit hole goes. Remember: all I’m offering is the truth.” Epigenetics is a bit like the red pill—the more it is researched the further down the rabbit hole we are going—the realisation that my choices today as my parents’ and grandparents’ choices yesterday influence who I am now and who I am going to be tomorrow. Through the study of gene influencers, scientists are discovering that it is not only the DNA that makes us but which portion of is selected for use that tells us who we are. In the field of depression, epigenetics is still in its infancy, nonetheless significant connections have been uncovered. This paper gives a brief overview on epigenetics and the different mechanisms correlated with it. It also discusses factors affecting an individual’s epigenetic patterns and the effect of epigenetics itself. It specifically delves into the epigenetic effects on psychiatry, mainly depression, depressive symptoms and antidepressant treatments and the mediation of mechanism of action of the epigenetic modifications involved.
