TOXICOLOGY
·
2024
·
IF 4.8
Jingyu Wang,Xiaoli Guo,Yujiao Chen,Wei Zhang,Jing Ren,Ai Gao
Benzene exposure leads to hematotoxicity, and epigenetic modification is considered to be a potential mechanism of benzene pathogenesis. As a newly discovered post-transcriptional modification, the roles of N6-methyladenosine (m6A) in benzene hematotoxicity are still unclear. m6A can only exert its gene regulatory function after being recognized by m6A reading proteins. In this study, we found that the expression of m6A reader IGF2BP1 decreased in benzene poisoning workers and in 20 μM benzene metabolite 1,4-BQ-treated AHH-1 cells. Further overexpression of IGF2BP1 in mice alleviated 50 ppm benzene-induced hematopoietic damage, suggesting that IGF2BP1 plays a critical role in benzene hematotoxicity. Next, we examined transcriptome-wide m6A methylation in vitro to search for target genes of IGF2BP1. We found that benzene metabolite 1,4-BQ treatment altered the m6A methylation levels of various genes. The comprehensive analysis of mRNA expression and m6A methylation uncovered that the hypomethylated Ribosomal Protein L36 (RPL36) and its consequent reduced expression impaired cell proliferation. Mechanically, m6A modification reduced RNA stability to down-regulate RPL36 expression. Moreover, overexpression of IGF2BP1 relieved RPL36 reduction and cell proliferation inhibition caused by benzene in vitro and in vivo by directly binding with RPL36 mRNA. In conclusion, the m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification. IGF2BP1 and RPL36 may be key molecules and potential therapeutic targets for benzene hematotoxicity.
研究领域:
毒理学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2023
·
IF 5.4
Xiuyuan Wang,Shusheng Yu,Yuqiu He,Fuan Wang,Xiaoqing Liu
Comprehensive Summary A label-free deoxyribozyme (DNAzyme) biosensor for m 6 A demethylase activity detection is developed. When demethylase FTO (Fat mass and obesity-associated protein), an important m 6 A demethylase of ALKBH demethylase family is present, the m 6 A group is specifically demethylated, and the cleavage activity of DNAzyme is restored. This allows the cleavage product that contains G-quadruplex sequence to bind to thioflavin T (ThT) and generate fluorescence signals. The biosensor shows high specificity and sensitivity, and fast reaction speed. Our study demonstrates a new design of allosteric DNAzyme for sensing. This method represents the first label-free nucleic acid biosensor for FTO assay, providing a feasible route towards inhibitors screening.
研究领域:
生物化学
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分子生物学
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产品关联
DOI
高影响因子
EMBO REPORTS
·
2021
·Vol. 22
·期 5
·e52146
·
IF 8.807
Yushi Chen,Ruifan Wu,Wei Chen,Youhua Liu,Xing Liao,Botao Zeng,Guanqun Guo,Fangfang Lou,Yun Xiang,Yizhen Wang,Xinxia Wang
Obesity has become a major health problem that has rapidly prevailed over the past several decades worldwide. Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. However, its underlying mechanism remains largely unknown. Here, we show that the administration of curcumin significantly prevents HFD-induced obesity and decreases the fat mass of the subcutaneous inguinal WAT (iWAT) and visceral epididymal WAT (eWAT) in mice. Mechanistically, curcumin inhibits adipogenesis by reducing the expression of AlkB homolog 5 (ALKHB5), an m6A demethylase, which leads to higher m6A-modified TNF receptor-associated factor 4 (TRAF4) mRNA. TRAF4 mRNA with higher m6A level is recognized and bound by YTHDF1, leading to enhanced translation of TRAF4. TRAF4, acting as an E3 RING ubiquitin ligase, promotes degradation of adipocyte differentiation regulator PPARγ by a ubiquitin–proteasome pathway thereby inhibiting adipogenesis. Thus, m6A-dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin-induced obesity prevention. Our findings provide mechanistic insights into how m6A is involved in the anti-obesity effect of curcumin.
研究领域:
分子生物学
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代谢学
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营养学
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药理学
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产品关联
DOI
PubMed
高影响因子
Turkish Journal of Gastroenterology
·
2025
·Vol. 36
·期 7
·431
·
IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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药理学
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转化医学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Xinyao Zheng,Shaohui Deng,Yuan Li,Zhipeng Luo,Ziqi Gan,Zhaoping Zheng,Rui Xu,Shan Xiao,Yuxiong Cai,Jianfu Meng,Li Li,Changxing Li,Xiaowen Xue,Wei Dai,Si Qin,Mengying Wang,Kang Zeng,Zecong Xiao,Laixin Xia
Chronic diabetic wounds are a prevalent and severe complication of diabetes, contributing to higher rates of limb amputations and mortality. N6-methyladenosine (m 6 A) is a common RNA modification that has been shown to regulate tissue repair and regeneration. However, whether targeting m 6 A could effectively improve chronic diabetic wound healing remains largely unknown. Here, we found a significant reduction in mRNA m 6 A methylation levels within human diabetic foot ulcers, and the expression level of fat mass and obesity-associated protein (FTO) was significantly increased. We identified that m 6 A modifies the RNA of matrix Metalloproteinase 9 (MMP9), a key factor in diabetic wound healing, to regulate its expression. Importantly, we developed a ROS-scavenging nanocolloidal hydrogel loaded with an FTO inhibitor to increase the m 6 A level of MMP9 RNA in wounds. The hydrogel can effectively accelerate wound healing and skin appendage regeneration in streptozotocin-induced type I diabetic rats at day 14 (approximately 98% compared to 76.98% in the control group) and type II diabetic db/db mice at day 20 (approximately 93% compared to 60% in the control group). Overall, our findings indicate that targeting m 6 A with ROS-scavenging hydrogel loaded with FTO inhibitor may be an effective therapeutic strategy for diabetic wound healing.
研究领域:
分子生物学
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再生医学
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药剂学
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产品关联
DOI
PubMed
高影响因子
Journal of Hematology & Oncology
·
2020
·Vol. 13
·期 1
·1-20
·
IF 11.059
Zuo Xueliang,Chen Zhiqiang,Gao Wen,Zhang Yao,Wang Jinguo,Wang Junfeng,Cao Ming,Cai Juan,Wu Jindao,Wang Xuehao
Background Long non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear.Methods Differentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pull-down, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration.Results We identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N6-methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy.Conclusion sOur results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.
研究领域:
肿瘤学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2024
·Vol. 19
·期 8
·e0306043
·
IF 2.9
Yuping Liao,Feng Zhang,Fang Yang,Shijin Huang,Sha Su,Xuemei Tan,Linlin Zhong,Lingjie Deng,Lihong Pang
Background
Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M 6 A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease.
Method
The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction.
Results
METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody.
Conclusion
METTL16 may affect the expression of SLC5A3 by changing its m 6 A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.
研究领域:
分子生物学
·
血液学
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表观遗传学
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细胞生物学
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DOI
PubMed
高影响因子
GENOMICS PROTEOMICS & BIOINFORMATICS
·
2020
·
IF 7.051
Yuhuan Li,Qingyang Zhang,Guanshen Cui,Fang Zhao,Xin Tian,Bao-Fa Sun,Ying Yang,Wei Li
N 6 -methyladenosine (m 6 A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m 6 A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 ( Mettl3 ). However, the functions of Mettl3 and m 6 A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m 6 A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance . In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m 6 A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m 6 A in HFD-induced metabolic disorders and hepatogenous diabetes.
研究领域:
分子生物学
·
代谢学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
APOPTOSIS
·
2025
·
IF 8.1
Miao Jintian,Jiang Xinyan,Wang Siyun
Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2025
·
IF 6
Mimi Li,Lina Wang,Yue Hu,Yi Liu,Shuang Xu,Kexing Peng,Chenghong Li,Hui Huang,Lichao Fang,Lulu Li,Huamin Liu,Xiaolong Wang,Junsong Zheng
Sensitive and efficient detection of RNA methylation sites is considered an integral part of epigenetic assessment. Contrary to previous studies on the detection of RNA m5C or m6A methylation alone, this study innovatively designed a biosensor capable of detecting RNA m5C or m6A methylation at the same time. Substances with specific electrochemical reactions such as ferrocene (FC) or methylene blue (MB) were modified onto the hairpin probe. When the hairpin probe was activated under specific conditions, it triggered a dendritic nonlinear hybridization chain reaction (HCR), which resulted in signal amplification. Gold (Au) and iron tetraoxide (Fe 3 O 4 ) composite nanomaterials were employed as the linking materials: the carboxylated ends of Fe 3 O 4 were connected to an antibody that specifically recognizes the m5C and m6A methylation sites, while Au nanoparticle ends adhering to the carboxylated Fe 3 O 4 surface are connected to the HCR enhanced signal amplifier. The m5C antibody was linked to Fc-containing HCR amplification products by this material, and similarly, the m6A antibody was linked to MB-containing amplifiers. Thus, the dandelion complex, a multifunctional body with methyl recognition and signal amplification, was formed. The capture probe immobilized on the surface of the gold electrode by Au–S recognized the target RNA sequence by base complementary pairing. Upon addition of the dandelion complex, due to its multi-functionality, the amplified signals were carried to the electrode by the antigen-antibody recognition mechanism, generating a current signal. The positions and heights of the current signal peaks enabled rapid determination of target RNA methyl modification sites and their abundance. The detection limits of this biosensor for RNA m5C and m6A were 4.68 × 10 −16 M and 1.10 × 10 −15 M, respectively, and the linear range was from 10 −15 mol/L to 10 −8 mol/L. The sensor developed in this study has the advantages of cost-effectiveness, ease of fabrication, and fast response time, and has the potential to be promoted for RNA methylation detection.
研究领域:
分子生物学
·
生物传感技术
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表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2025
·
IF 3.5
Yongna Zhu,Xiang Ge,Zhi Chen,Tingting Chen,Yue Wu,Hebao Wen,Zeyu He,Caiyun Ma
Stem cells from the apical papilla (SCAPs) show strong odontogenic ability and can form root dentin. However, the underlying mechanisms that control the odontogenic differentiation of SCAPs in an inflammatory environment need further exploration. In the present study, we explored the regulatory role of METTL3 in the differentiation of SCAPs originating from tooth with apical periodontitis. Stem cells from the apical papilla derived from healthy teeth (SCAPs) and teeth with apical periodontitis (AP-SCAPs) were successfully isolated and cultured. The expressions of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) were higher in AP-SCAPs. A decrease in METTL3 expression accompanied the decreased osteo-/odontogenic differentiation ability of AP-SCAPs. Exploring the role of METTL3 on the osteo-/odontogenic differentiation of AP-SCAPs revealed that overexpression of METTL3 upregulated the odontogenic ability of AP-SCAPs. However, silencing METTL3 exerted the opposite effect. Overexpression of METTL3 suppressed the expression of TNF-α and IL-6 in AP-SCAPs, whereas knockdown of METTL3 in these cells enhanced TNF-α and IL-6 expression. METTL3 regulates the osteo-/odontogenic differentiation of SCAPs and modulates their inflammatory response. Furthermore, overexpression of METTL3 upregulated the methylation level, mRNA, and protein expression of nuclear factor-IC (NFIC) during mineralization induction. NFIC silencing attenuated osteo-/odontogenic differentiation of METTL3-overexpressed AP-SCAPs. In conclusion, METTL3-mediated-m6A upregulated the odontogenic differentiation of AP-SCAPs via NFIC. This paper elucidates a novel mechanism regulating the odontogenic differentiation of AP-SCAPs, and METTL3 may be a new target for regenerative endodontic treatment.
研究领域:
口腔医学
·
干细胞研究
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2024
·
IF 6.9
Du Kaixuan,Luo Yongbo,Zhang Lei,Zeng Youmiao,Dai Yiheng,Ren Mengda,Pan Wenbang,Liu Yuanhao,Tian Fengyan,Zhou Lijie,Gu Chaohui
Cuproptosis, a cell death process caused by copper ions, is mediated by protein lipidation related to lipoic acid metabolism. There is a close connection between cuproptosis and the progression and prognosis of various tumors. Here, we identified lipoyltransferase 1 (LIPT1), a key gene related to cuproptosis, was downregulated in bladder cancer (BLCA) and was associated with unfavorable patient prognosis. Restoring the LIPT1 expression in BLCA cells suppressed the proliferation and promoted cuproptosis. Moreover, the consequences of RNA sequencing and Bodipy staining showed that the metabolic pathway mediated by LIPT1 inhibited the accumulation of lipid droplets in cells, disrupted endoplasmic reticulum (ER) homeostasis, and promoted cell apoptosis. Additionally, overexpression of LIPT1 not only repressed the proliferation rate of BLCA cells in vitro but also in vivo. Mechanistically, YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) promoted the degradation of LIPT1 mRNA in a m 6 A-dependent manner. In summary, these conclusions reveal that LIPT1 promotes cuprotosis and ER stress to inhibit the progression of BLCA, indicating that LIPT1 will provide a powerful treatment direction and drug target for treating BLCA.
研究领域:
癌症生物学
·
分子生物学
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细胞生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）