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
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
·
2025
·
IF 4.7
Long Li,Quanyou Chai,Chunling Guo,Junyi Wei,Yuqiao Qin,Huimin Liu,Zhaoyang Lu
Aim Vascular calcification (VC) is a major adverse cardiovascular event in chronic kidney disease (CKD) patients. N6-methyladenosine (m6A) modification is vital for many biological processes, but its function and possible molecular mechanisms in VC are poorly understood. This study aimed to clarify the function and molecular mechanisms of N6-adenosine-methyltransferase-like 3 (METTL3) in VC. Methods and results The results of the bioinformatic analysis showed that METTL3 expression was significantly upregulated in calcified VSMCs. This finding was corroborated by phosphate-induced VSMCs calcification models and 5/6 nephrectomy-induced CKD mouse VC models. Afterward, Alizarin Red S staining and m6A dot blot analysis demonstrated METTL3 overexpression elevated m6A levels and encouraged calcification in VSMCs and mouse aortic rings, while METTL3 knockdown decreased m6A levels and inhibited calcium deposition in these experimental models. Furthermore, METTL3 promoted VC via the PTEN/AKT pathway, and MeRIP verified that METTL3 induced PTEN mRNA degradation by modifying it with m6A. In addition, molecular docking simulations and DARTS assays revealed that quercetin is a natural small-molecule inhibitor of METTL3. The current investigation demonstrated that quercetin mitigated VC by reducing METTL3-dependent m6A levels in vivo and in vitro. Conclusion In conclusion, this study unraveled the pathogenic mechanism of METTL3-mediated m6A modification in VC and provided new insights to establish METTL3 as a therapeutic target for VC.
研究领域:
分子生物学
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心血管疾病
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表观遗传学
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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
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
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
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表观转录组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
AGING CELL
·
2025
·
IF 7.1
Yu Zhang,Xiaojie Liu,Hairong Lian,Yanchao Chai,Yang Zhou,Dongqi Kan,Jilong Ren,Cui Han,Jiaxin Yang
Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6–methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well–established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5–methyltetrahydrofolate–homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S–adenosylmethionine (SAM), a critical metabolite in the one–carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.
研究领域:
遗传学
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表观遗传学
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分子生物学
·
衰老研究
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产品关联
DOI
PubMed
高影响因子
Biology Direct
·
2024
·Vol. 19
·期 1
·1-17
·
IF 5.7
Yu Zhengtao,Xia Ying,Li Jiameng,Jiang Junwen,Li You,Li Youjun,Wang Liu
Background Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets. Methods We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3 . The reverse effects of YTHDC1 overexpression were also examined. Results MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects. Conclusion The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.
研究领域:
神经科学
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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
Biomolecules
·
2025
·Vol. 15
·期 10
·1353
·
IF 4.8
Hao Zhang,Yajin Guan,Meng Li,Yilin Wu,Xiaoou Sun
Cerebral ischemia/reperfusion (I/R) injury is a devastating neurological disorder with limited treatment options. Emerging evidence suggests that the N6-methyladenosine (m6A) modification and its regulatory factors play pivotal roles in the pathophysiology of I/R. This study aimed to elucidate the function of METTL3-mediated m6A modification of the long non-coding RNA (lncRNA) AU020206 in ferroptosis during cerebral I/R injury and to identify potential molecular targets for neuroprotection. A murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) were established to assess m6A levels and ferroptosis-related changes. Effects of METTL3 overexpression and lncRNA-AU020206 silencing on neuronal apoptosis, inflammation, and ferroptosis were investigated in vitro and in vivo. The interaction between lncRNA-AU020206 and YTHDC2 and the resulting regulation of SLC7A11 mRNA stability and GPX4 expression were evaluated using molecular and biochemical assays. Both MCAO/R mice and OGD/R-treated N2a cells exhibited decreased m6A levels and upregulation of lncRNA-AU020206 accompanied by enhanced ferroptosis. METTL3 overexpression increased the m6A modification of AU020206, promoting its degradation and attenuating neuronal injury, whereas silencing AU020206 or overexpressing YTHDC2 decreased SLC7A11 mRNA stability and enhanced ferroptosis. Restoring the expression of SLC7A11/GPX4 can enhance cell viability, alleviate neuronal apoptosis, and reduce Fe2+overload. Disruption of the METTL3–AU020206–YTHDC2 axis abolished these neuroprotective effects. METTL3-mediated m6A modification of lncRNA-AU020206 restrained ferroptosis and neuronal injury in cerebral I/R by maintaining the stability of the SLC7A11/GPX4 axis via interactions with YTHDC2. Targeting this epitranscriptomic signalling pathway may represent a promising therapeutic strategy for the treatment of ischemic stroke and related neurological disorders.
研究领域:
神经生物学
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表观遗传学
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分子生物学
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脑血管病学
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细胞死亡机制
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RNA代谢
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2025
·
IF 11
Ruonan Chen,Xiaoqin Chai,Yunxiao Zhang,Tianxiu Zhou,Yinyin Xia,Xuejun Jiang,Bo Lv,Jun Zhang,Lixiao Zhou,Xin Tian,Ruonan Wang,Lejiao Mao,Feng Zhao,Hongyang Zhang,Jun Hu,Jingfu Qiu,Zhen Zou,Chengzhi Chen
Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut–brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut–brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.
研究领域:
毒理学
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微生物学
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神经科学
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分子生物学
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胃肠病学
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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
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
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分子生物学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
TISSUE & CELL
·
2025
·
IF 2.5
Xiaoxue Zhao,Bingyu Zhang,Sining Duan,Tengfei Wu,Xiaojiao Yang,Yuxiang Liu
Growing evidence demonstrated the involvement of ferroptosis in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). The nature compound Wedelolactone (Wed) exhibits anti-ferroptosis effects. The current study aims to explore the impact of Wed on MIRI and reveal whether Wed could protect cardiomyocytes from ferroptosis. Rats underwent cardiac IR operation, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Rats or cell in Wed-treated group were subdivided into 2 different dose regimens: low and high. Wed intervention alleviated myocardial infarction and left ventricle dysfunction, and diminished the levels of biochemical markers for cardiac injury caused by cardiac IR. The content of Fe 2+ and MDA, 4-HNE expression, and ROS production were increased in infarct zone, as well as GSH content, GSH-Px activity, and the levels of ferroptosis-related proteins were reduced. Treatment with Wed reversed the aforementioned changes. Similar results were observed in vitro experiments. Molecular docking analysis showed good binding affinity between Wed and the target protein METTL3. In OGD/R-induced H9c2 cells, Wed downregulated METTL3 protein expression and further blocked METTL3-mediated m 6 A modification of BRD4 mRNA. Overexpression of METTL3 reversed the antagonistic effect of Wed on cardiomyocyte ferroptosis. Collectively, our findings uncovered that Wed showed anti-ferroptosis effects in cardiomyocytes through downregulating the METTL3/BRD4 axis, thereby ameliorating MIRI.
研究领域:
药理学
·
心脏病学
·
分子生物学
·
生物化学
·
生物医学研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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