AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analy...AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DI C-1, SFRP-1, DKK and E-cad.26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DIC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tis- sue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP＋ （≥3 methylated genes） was detected in 68 （60.2%） tumor tissue samples and 62 （57.4%） plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node- metastasis stage （P 〈 0.05）. Similar results were obtained with plasma samples （P 〈 0.05）. There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP＋ group were significantly higher than in the CIMP- group as assessed with plasma samples （P 〈 0.05）. CONCLUSION： Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.展开更多
AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We...AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We analyzed the serum ClMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infec- tion in serum was assayed with an anti-H, pylori immu- noglobulin G antibody test and a rapid urease test. RESULTS： The frequencies of high-level methylation in GC tissues for the seven genes were： 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad.The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP＋ （defined as ≥ 3 methylated genes） was associated with 47 （62.67%） GC tissue samples and 44 （58.67%） GC serum samples. CIMP＋ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 （68%） were H. pylori＋, and 24 （32%） were H. pylori-. Of the 51 H. pylori＋ cases, 36 were CIMP＋ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP＋, and 13 were CIMP-. The difference was signifi- cant between the H. pylori＋ and H. pylori- groups χ2 = 4.27, P 〈 0.05）. Of the 51 H. pylori＋ GC patients, 34 were CIMP＋ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP＋ and 14 were CIMP-. The difference was significant between the H. pylori＋ and H. pylori- groups （χ2 = 4.21, P 〈 0.05）. A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori＋/CIMP＋ cases and the H. pylori＋/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum （P 〈 0.05）. However, there were no significant differences in sur- vival rates between the two groups. CONCLUSION： H. pylori＋/CIMP＋ cases are associ- ated with higher rates of metastasis and recurrence thanH, pylori＋/CIMP- cases. Serum may be useful for examining CIMP status.展开更多
Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational res...Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.展开更多
To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for ...To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSIONWe report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.展开更多
Methylmercury(MeHg)is a potent neurotoxin and bioaccumulates in food webs.Microbial transformation of inorganic mercury(Hg)produces most of the MeHg in the marine environment.The gene pair hgcAB encodes for Hg methyla...Methylmercury(MeHg)is a potent neurotoxin and bioaccumulates in food webs.Microbial transformation of inorganic mercury(Hg)produces most of the MeHg in the marine environment.The gene pair hgcAB encodes for Hg methylation,a process predominantly attributed to anaerobic bacteria.However,recent studies indicate the formation of methylmercury in low-oxygen zones within marine water columns,although the mechanisms remain poorly understood.“Blue holes”are marine sinkholes containing redox gradients stratified with depth and high microbial diversity across a range of biogeochemical cycles.Here,we present the first metagenomic analysis focused on the potential for Hg methylation in a blue hole ecosystem.Yongle Blue Hole(YBH),currently the world’s deepest known blue hole,was selected as a representative site to investigate the genetic potential for Hg methylation and to explore the functional capabilities of putative Hg-methylators within this unique environment.Metagenomic analysis showed that the anoxic sulfidic deep water was likely to be a hotspot for Hg methylation,driven by abundant and diverse Deltaproteobacteria.In the suboxic intermediate layer,Nitrospina and Myxococcota dominated the Hg-methylating community.Furthermore,Hg methylators were found to have different lifestyles(free-living or particle-associated)and to occupy distinct ecological niches within the YBH.In addition,the contribution of sinking particles to Hg methylation,especially in the deep anoxic water column,was highlighted.Our study unveils the biodiversity and survival strategies of Hg methylators across distinct environments.The findings suggest that blue holes could serve as model stratified ecosystems for studying Hg methylation processes across different habitats.展开更多
The escalating pace of industrialization has significantly intensified water pollution challenges,for instance,the persistent organic pollutants like methyl orange(MO).Conventional remediation techniques,such as adsor...The escalating pace of industrialization has significantly intensified water pollution challenges,for instance,the persistent organic pollutants like methyl orange(MO).Conventional remediation techniques,such as adsorption and biological degradation,are often hampered by low efficiency and the risk of secondary pollution.Photocatalysis emerges as a promising sustainable alternative;however,the benchmark material titanium dioxide(TiO_(2))suffers from its intrinsic limitations,notably its wide bandgap energy(≥3.4 eV)restricting its activity to the region of the ultraviolet light and its rapid recombination of photogenerated charge carriers.To overcome these constraints,this research focused on synthesizing novel TiO_(2)/Sn_(3)O_(4) heterojunction composite photocatalysts via a solvothermal approach.Comprehensive characterization techniques confirmed the successful formation of the composite,which revealed that ultrathin Sn3O4 nanosheets uniformly coated TiO_(2) nanospheres.This unique architecture effectively reduced the overall crystallinity and introduced the beneficial oxygen vacancies.Under visible-light irradiation(λ≥420 nm),the optimized TiO_(2)/Sn3O4 composite exhibited the exceptional photocatalytic performance,which achieved 96%degradation of MO within just 60 minutes.The calculated apparent kinetic rate constant(0.103 min^(-1))was remarkably(5.15 times)higher than that of pristine TiO_(2).ESR experiments identified that hydroxyl radicals(·OH)was the predominant active species driving the degradation.Furthermore,cyclic degradation tests demonstrated its excellent material stability,with the composite retaining 85%of its initial efficiency after four consecutive reuse cycles.This work underscored the synergistic effects within the TiO_(2)/Sn_(3)O_(4) heterojunction,which significantly enhanced the visible-light absorption,charge separation,and photocatalytic activity,which provided the valuable insights for designing efficient,stable catalysts for the advanced environmental remediation applications.展开更多
DNA methylation is an important promising biomarker for cancer diagnosis and monitoring.Therefore,the assessment of DNA methylation levels is helpful for the prognosis and diagnosis of cancer.However,it is still a hug...DNA methylation is an important promising biomarker for cancer diagnosis and monitoring.Therefore,the assessment of DNA methylation levels is helpful for the prognosis and diagnosis of cancer.However,it is still a huge challenge to sensitively and accurately quantify the levels of DNA methylation in clinical sample.In this work,we proposed a protospacer adjacent motif(PAM)-free mediated CRISPR-Cas12a ultra-sensitive and quantitative DNA methylation detection method.Through recognizing the ds DNA with toehold region,CRISPR-Cas12a not only got rid of the limitation of PAM,but also improved its distinction ability for single Cp G site methylation,nearly 5-fold that of conventional PAM-containing ds DNA.We further introduced assist-strand and design an artificial mismatch to greatly improve the ability to distinguish single Cp G methylation site.Our results showed that the discrimination factor was >200.Then,we constructed toe-ds DNA by using “heating and freezing”,which made our method universally applicable and feasible.In addition,we greatly simplified the difficulty of primer design.Our method detected four highly methylated genes acyl carrier protein(ACP),CLV3/ESR-related(CLE),Disabled(DAB) and Homeobox(HOX) with a detection limit of 0.01 % and excellent linearity in DNA methylation standards.Then,we verified the clinical utility of this method in 29 hepatocellular carcinomas,11 ovarian cancers and4 health people.In conclusion,we have successfully constructed a PAM-free CRISPR-Cas12a DNA methylation quantification method,which achieves high congruence in sensitivity,specificity and universality,fully demonstrating its significant clinical application value.展开更多
Fig(Ficus carica L.)with purple-red peel cultivars are popular among consumers and exhibit better storability.While DNA methylation influences fruit ripening and color development,its specific role in fig fruit remain...Fig(Ficus carica L.)with purple-red peel cultivars are popular among consumers and exhibit better storability.While DNA methylation influences fruit ripening and color development,its specific role in fig fruit remains unclear.This study explores the impact of DNA methylation on the fig peel coloration.Enzymatic colorimetric detection revealed that the level of‘Purple Peel’fig DNA methylation decreases with fig fruit ripening and coloring.Treatment of young fruit with the DNA-methylation inhibitor azacytidine induced peel coloration,suggesting that a decrease in DNA-methylation level promotes fig peel coloration.Seven members of DNA methyltransferases and three members of DNA demethylases were identified from a high-level fig genome,highlighting FcMET1 and FcDRM2 as stable proteins,ensuring functional expression.Reference to the Arabidopsis protein interaction network map predicted that FcMET1 is in a central position,suggesting a crucial regulatory role in multiple biological processes.Correlation analysis revealed a positive correlation between FcMET1 expression during peel development and the level of total DNA methylation.Weighted gene co-expression network analysis identified co-expression of FcMET1 with the color-related transcription factors MYB,bHLH and WD40,as well as with eight structural genes in the flavonoid-biosynthesis pathway.The expression of FcUFGT3 was negatively correlated with that of FcMET1.McrBC-PCR and Bisulfite Sequencing detection showed that a low methylation level of the FcUFGT3 promoter corresponds with its high expression in colored fig.This investigation of the mechanism of DNA methylation provides a theoretical basis for understanding the role of DNA-methylation modifications in fig ripening and coloring.展开更多
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.展开更多
Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytoki...Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma me...BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.展开更多
Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylat...Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.展开更多
Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells...Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.展开更多
Peri-implant diseases are characterized by the resorption of hard tissue and the inflammation of soft tissue.Epigenetics refers to alterations in the expression of genes that are not encoded in the DNA sequence,influe...Peri-implant diseases are characterized by the resorption of hard tissue and the inflammation of soft tissue.Epigenetics refers to alterations in the expression of genes that are not encoded in the DNA sequence,influencing diverse physiological activities,including immune response,inflammation,and bone metabolism.Epigenetic modifications can lead to tissue-specific gene expression variations among individuals and may initiate or exacerbate inflammation and disease predisposition.However,the impact of these factors on peri-implantitis remains inconclusive.To address this gap,we conducted a comprehensive review to investigate the associations between epigenetic mechanisms and peri-implantitis,specifically focusing on DNA methylation and microRNAs(miRNAs or miRs).We searched for relevant literature on PubMed,Web of Science,Scopus,and Google Scholar with keywords including“epigenetics,”“peri-implantitis,”“DNA methylation,”and“microRNA.”DNA methylation and miRNAs present a dynamic epigenetic mechanism operating around implants.Epigenetic modifications of genes related to inflammation and osteogenesis provide a new perspective for understanding how local and environmental factors influence the pathogenesis of peri-implantitis.In addition,we assessed the potential application of DNA methylation and miRNAs in the prevention,diagnosis,and treatment of peri-implantitis,aiming to provide a foundation for future studies to explore potential therapeutic targets and develop more effective management strategies for this condition.These findings also have broader implications for understanding the pathogenesis of other inflammation-related oral diseases like periodontitis.展开更多
DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Ca...DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Camellia sinensis).In this study,we combined the methylome,transcriptome,and metabolome to investigate the dynamic changes in DNA methylation and its potential regulatory roles in secondary metabolite biosynthesis.In this study,the level of genomic DNA methylation increased as leaf development progressed from tender to old leaf.It additionally exhibited a similar distribution across the genomic background at the two distinct developmental stages studied.Notably,integrated analysis of transcriptomic and methylomic data showed that DNA hypermethylation primarily occurred in genes of the phenylpropanoid,flavonoid,and terpenoid biosynthesis pathways.The effect of methylation on transcription of these secondary metabolite biosynthesis genes was dependent on the location of methylation(i.e.,in the promoter,gene or intergenic regions)and the sequence context(i.e.,CpG,CHG,or CHH).Changes in the content of catechins and terpenoids were consistent with the changes in gene transcription and the methylation state of structural genes,such as serine carboxypeptidase-like acyltransferases 1A(SCPL1A),leucoanthocyanidin reductase(LAR),and nerolidol synthase(NES).Our study provides valuable information for dissecting the effects of DNA methylation on regulation of genes involved in secondary metabolism during tea leaf development.展开更多
Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the m...Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.展开更多
BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge...BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.展开更多
During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipit...During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.展开更多
Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This s...Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.展开更多
基金Supported by The Department of Health of Jiangsu Province,China,No.H200957
文摘AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DI C-1, SFRP-1, DKK and E-cad.26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DIC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tis- sue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP＋ （≥3 methylated genes） was detected in 68 （60.2%） tumor tissue samples and 62 （57.4%） plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node- metastasis stage （P 〈 0.05）. Similar results were obtained with plasma samples （P 〈 0.05）. There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP＋ group were significantly higher than in the CIMP- group as assessed with plasma samples （P 〈 0.05）. CONCLUSION： Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.
基金Supported by Department of Health of Jiangsu Province o China,No.H200957
文摘AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We analyzed the serum ClMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infec- tion in serum was assayed with an anti-H, pylori immu- noglobulin G antibody test and a rapid urease test. RESULTS： The frequencies of high-level methylation in GC tissues for the seven genes were： 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad.The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP＋ （defined as ≥ 3 methylated genes） was associated with 47 （62.67%） GC tissue samples and 44 （58.67%） GC serum samples. CIMP＋ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 （68%） were H. pylori＋, and 24 （32%） were H. pylori-. Of the 51 H. pylori＋ cases, 36 were CIMP＋ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP＋, and 13 were CIMP-. The difference was signifi- cant between the H. pylori＋ and H. pylori- groups χ2 = 4.27, P 〈 0.05）. Of the 51 H. pylori＋ GC patients, 34 were CIMP＋ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP＋ and 14 were CIMP-. The difference was significant between the H. pylori＋ and H. pylori- groups （χ2 = 4.21, P 〈 0.05）. A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori＋/CIMP＋ cases and the H. pylori＋/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum （P 〈 0.05）. However, there were no significant differences in sur- vival rates between the two groups. CONCLUSION： H. pylori＋/CIMP＋ cases are associ- ated with higher rates of metastasis and recurrence thanH, pylori＋/CIMP- cases. Serum may be useful for examining CIMP status.
基金funded by the Intramural program of the National Human Genome Research Institute,the National Institutes of Health
文摘Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.
文摘To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSIONWe report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.
基金supported by The University of Melbourne’s Research Computing Services and the Petascale Campus Initiative.
文摘Methylmercury(MeHg)is a potent neurotoxin and bioaccumulates in food webs.Microbial transformation of inorganic mercury(Hg)produces most of the MeHg in the marine environment.The gene pair hgcAB encodes for Hg methylation,a process predominantly attributed to anaerobic bacteria.However,recent studies indicate the formation of methylmercury in low-oxygen zones within marine water columns,although the mechanisms remain poorly understood.“Blue holes”are marine sinkholes containing redox gradients stratified with depth and high microbial diversity across a range of biogeochemical cycles.Here,we present the first metagenomic analysis focused on the potential for Hg methylation in a blue hole ecosystem.Yongle Blue Hole(YBH),currently the world’s deepest known blue hole,was selected as a representative site to investigate the genetic potential for Hg methylation and to explore the functional capabilities of putative Hg-methylators within this unique environment.Metagenomic analysis showed that the anoxic sulfidic deep water was likely to be a hotspot for Hg methylation,driven by abundant and diverse Deltaproteobacteria.In the suboxic intermediate layer,Nitrospina and Myxococcota dominated the Hg-methylating community.Furthermore,Hg methylators were found to have different lifestyles(free-living or particle-associated)and to occupy distinct ecological niches within the YBH.In addition,the contribution of sinking particles to Hg methylation,especially in the deep anoxic water column,was highlighted.Our study unveils the biodiversity and survival strategies of Hg methylators across distinct environments.The findings suggest that blue holes could serve as model stratified ecosystems for studying Hg methylation processes across different habitats.
文摘The escalating pace of industrialization has significantly intensified water pollution challenges,for instance,the persistent organic pollutants like methyl orange(MO).Conventional remediation techniques,such as adsorption and biological degradation,are often hampered by low efficiency and the risk of secondary pollution.Photocatalysis emerges as a promising sustainable alternative;however,the benchmark material titanium dioxide(TiO_(2))suffers from its intrinsic limitations,notably its wide bandgap energy(≥3.4 eV)restricting its activity to the region of the ultraviolet light and its rapid recombination of photogenerated charge carriers.To overcome these constraints,this research focused on synthesizing novel TiO_(2)/Sn_(3)O_(4) heterojunction composite photocatalysts via a solvothermal approach.Comprehensive characterization techniques confirmed the successful formation of the composite,which revealed that ultrathin Sn3O4 nanosheets uniformly coated TiO_(2) nanospheres.This unique architecture effectively reduced the overall crystallinity and introduced the beneficial oxygen vacancies.Under visible-light irradiation(λ≥420 nm),the optimized TiO_(2)/Sn3O4 composite exhibited the exceptional photocatalytic performance,which achieved 96%degradation of MO within just 60 minutes.The calculated apparent kinetic rate constant(0.103 min^(-1))was remarkably(5.15 times)higher than that of pristine TiO_(2).ESR experiments identified that hydroxyl radicals(·OH)was the predominant active species driving the degradation.Furthermore,cyclic degradation tests demonstrated its excellent material stability,with the composite retaining 85%of its initial efficiency after four consecutive reuse cycles.This work underscored the synergistic effects within the TiO_(2)/Sn_(3)O_(4) heterojunction,which significantly enhanced the visible-light absorption,charge separation,and photocatalytic activity,which provided the valuable insights for designing efficient,stable catalysts for the advanced environmental remediation applications.
基金financially supported by the Natural Science Foundation of Wuhan City (Chenguang Project) (No.2024040801020331)the Natural Science Foundation of Hubei Province of China (No.2023AFB402)+1 种基金the National Key Research and Development Program of China (No.2023YFE0210200)Interdisciplinary Research Program of HUST。
文摘DNA methylation is an important promising biomarker for cancer diagnosis and monitoring.Therefore,the assessment of DNA methylation levels is helpful for the prognosis and diagnosis of cancer.However,it is still a huge challenge to sensitively and accurately quantify the levels of DNA methylation in clinical sample.In this work,we proposed a protospacer adjacent motif(PAM)-free mediated CRISPR-Cas12a ultra-sensitive and quantitative DNA methylation detection method.Through recognizing the ds DNA with toehold region,CRISPR-Cas12a not only got rid of the limitation of PAM,but also improved its distinction ability for single Cp G site methylation,nearly 5-fold that of conventional PAM-containing ds DNA.We further introduced assist-strand and design an artificial mismatch to greatly improve the ability to distinguish single Cp G methylation site.Our results showed that the discrimination factor was >200.Then,we constructed toe-ds DNA by using “heating and freezing”,which made our method universally applicable and feasible.In addition,we greatly simplified the difficulty of primer design.Our method detected four highly methylated genes acyl carrier protein(ACP),CLV3/ESR-related(CLE),Disabled(DAB) and Homeobox(HOX) with a detection limit of 0.01 % and excellent linearity in DNA methylation standards.Then,we verified the clinical utility of this method in 29 hepatocellular carcinomas,11 ovarian cancers and4 health people.In conclusion,we have successfully constructed a PAM-free CRISPR-Cas12a DNA methylation quantification method,which achieves high congruence in sensitivity,specificity and universality,fully demonstrating its significant clinical application value.
基金supported by 111 Project(Grant No.B17043)China Postdoctoral Science Foundation(Grant No.2022M723425).
文摘Fig(Ficus carica L.)with purple-red peel cultivars are popular among consumers and exhibit better storability.While DNA methylation influences fruit ripening and color development,its specific role in fig fruit remains unclear.This study explores the impact of DNA methylation on the fig peel coloration.Enzymatic colorimetric detection revealed that the level of‘Purple Peel’fig DNA methylation decreases with fig fruit ripening and coloring.Treatment of young fruit with the DNA-methylation inhibitor azacytidine induced peel coloration,suggesting that a decrease in DNA-methylation level promotes fig peel coloration.Seven members of DNA methyltransferases and three members of DNA demethylases were identified from a high-level fig genome,highlighting FcMET1 and FcDRM2 as stable proteins,ensuring functional expression.Reference to the Arabidopsis protein interaction network map predicted that FcMET1 is in a central position,suggesting a crucial regulatory role in multiple biological processes.Correlation analysis revealed a positive correlation between FcMET1 expression during peel development and the level of total DNA methylation.Weighted gene co-expression network analysis identified co-expression of FcMET1 with the color-related transcription factors MYB,bHLH and WD40,as well as with eight structural genes in the flavonoid-biosynthesis pathway.The expression of FcUFGT3 was negatively correlated with that of FcMET1.McrBC-PCR and Bisulfite Sequencing detection showed that a low methylation level of the FcUFGT3 promoter corresponds with its high expression in colored fig.This investigation of the mechanism of DNA methylation provides a theoretical basis for understanding the role of DNA-methylation modifications in fig ripening and coloring.
基金supported by the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
基金supported by the National Natural Science Foundation of China,Nos.32070735(to QL),82371321(to QL),82171270(to ZL)Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1(to ZL)+2 种基金the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)。
文摘Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金Supported by the Medical Talents of Wuhan Health and Family Planning Commission,No.2017[51](to Yu J)the Medical Talents of Wuhan Hospital of Traditional Chinese and Western Medicine(to Yu J)+1 种基金the Hubei Natural Science Foundation,No.2023AFB1091Wuhan Medical Research Project,No.WX23A36(to Yu J).
文摘BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.
文摘Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.
基金supported by grants from the National Key R&D Program of China(2022YFC2403000 and 2021YFC2400500)the National Natural Science Foundation of China(32200728 and 32170925)+3 种基金the Clinical Research Project of Shenzhen Medical Academy of Research and Translation(C2301008)Shenzhen Science and Technology Program(JCYJ20220531100406014,JCYJ2022081800807016,RCBS20221008093336088,KQTD20210811090115019)Guangdong Basic and Applied Basic Research Foundation(2021A1515110375)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210601).
文摘Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.
基金supported by the Basic Public Welfare Research Project of Zhejiang Province(No.LGF22H140007)the Research and Development Project of Stomatology Hospital Affiliated to Zhejiang University School of Medicine(No.RD2022JCXK01)+1 种基金the National Natural Science Foundation of China(No.82301072)the Postdoctoral Science Foundation of China(Nos.2021TQ0277 and 2022M722741)。
文摘Peri-implant diseases are characterized by the resorption of hard tissue and the inflammation of soft tissue.Epigenetics refers to alterations in the expression of genes that are not encoded in the DNA sequence,influencing diverse physiological activities,including immune response,inflammation,and bone metabolism.Epigenetic modifications can lead to tissue-specific gene expression variations among individuals and may initiate or exacerbate inflammation and disease predisposition.However,the impact of these factors on peri-implantitis remains inconclusive.To address this gap,we conducted a comprehensive review to investigate the associations between epigenetic mechanisms and peri-implantitis,specifically focusing on DNA methylation and microRNAs(miRNAs or miRs).We searched for relevant literature on PubMed,Web of Science,Scopus,and Google Scholar with keywords including“epigenetics,”“peri-implantitis,”“DNA methylation,”and“microRNA.”DNA methylation and miRNAs present a dynamic epigenetic mechanism operating around implants.Epigenetic modifications of genes related to inflammation and osteogenesis provide a new perspective for understanding how local and environmental factors influence the pathogenesis of peri-implantitis.In addition,we assessed the potential application of DNA methylation and miRNAs in the prevention,diagnosis,and treatment of peri-implantitis,aiming to provide a foundation for future studies to explore potential therapeutic targets and develop more effective management strategies for this condition.These findings also have broader implications for understanding the pathogenesis of other inflammation-related oral diseases like periodontitis.
基金supported by the Natural Science Foundation of Guangdong Province(Grant Nos.2022A1515111141 and 2023A1515010786)。
文摘DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Camellia sinensis).In this study,we combined the methylome,transcriptome,and metabolome to investigate the dynamic changes in DNA methylation and its potential regulatory roles in secondary metabolite biosynthesis.In this study,the level of genomic DNA methylation increased as leaf development progressed from tender to old leaf.It additionally exhibited a similar distribution across the genomic background at the two distinct developmental stages studied.Notably,integrated analysis of transcriptomic and methylomic data showed that DNA hypermethylation primarily occurred in genes of the phenylpropanoid,flavonoid,and terpenoid biosynthesis pathways.The effect of methylation on transcription of these secondary metabolite biosynthesis genes was dependent on the location of methylation(i.e.,in the promoter,gene or intergenic regions)and the sequence context(i.e.,CpG,CHG,or CHH).Changes in the content of catechins and terpenoids were consistent with the changes in gene transcription and the methylation state of structural genes,such as serine carboxypeptidase-like acyltransferases 1A(SCPL1A),leucoanthocyanidin reductase(LAR),and nerolidol synthase(NES).Our study provides valuable information for dissecting the effects of DNA methylation on regulation of genes involved in secondary metabolism during tea leaf development.
基金supported by the Shandong Province Natural Science Foundation of Major Basic Research Program (No.ZR2020ZD34)the Key Projects of the National Natural Science Foundation of China (No.42230706)+3 种基金the National Natural Science Foundation of China (No.42307164)the China Postdoctoral Science Foundation (Nos.2023TQ0191 and 2023M732060)the Shandong Postdoctoral Science Foundation (No.SDBX2023041)and the Qingdao Postdoctoral Science Foundation (No.QDBSH20230202052).
文摘Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.
基金Supported by National Natural Science Foundation of China,No.82360231Yunnan Basic Research Program General Project,No.202401AT070075+1 种基金Dali Basic Research Program Key Project,No.202301A020021Youth Special Project for Basic Research of Local Universities in Yunnan Province,No.202301BA070001-127.
文摘BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.
基金supported by the National Key R&D Program of China(2022YFE0131000)the National Natural Science Foundation of China(82220108012,82271306,and 82071307)+1 种基金The Science and Education for Health Foundation of Suzhou for Youth(KJXW2023001)the Boxi Youth Natural Science Foundation(BXQN2023028).
文摘During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
基金supported by the National Natural Science Foundation of China(Nos.82274211 and 82474190)the Natural Science Foundation of Tianjin(Nos.24JCZDJC00120 and 24PTLYHZ00280)Liaoning Provincial Department of Education Basic Research Projects for Higher Education Institutions(No.LJ212510163021)。
文摘Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
