INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Jianan Yang,Tonglian Jiang,Xun Lu,Xiang li,Xuling Zhou,Xinxin Guo,Chengxin Ma,Xiaobei Xie,Dongxiao Li,Siqi Yu,Jiayi An,Binghai Zhao,Hongzhi Li
Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.
研究领域:
肾病学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 8
·4538
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IF 4.9
Yue Zhu,Yadong Zhang,Yaoqi Jiang,Hongshi Cai,Jianfeng Liang,Hongyu Li,Cheng Wang,Jinsong Hou
Cleft palate only (CPO) is one of the most common craniofacial birth defects. Environmental factors can induce cleft palate by affecting epigenetic modifications such as DNA methylation, histone acetylation, and non-coding RNA. However, there are few reports focusing on the RNA modifications. In this study, all-trans retinoic acid (atRA) was used to simulate environmental factors to induce a C57BL/6J fetal mouse cleft palate model. Techniques such as dot blotting and immunofluorescence were used to find the changes in m6A modification when cleft palate occurs. RNA-seq and KEGG analysis were used to screen for significantly differentially expressed pathways downstream. Primary mouse embryonic palate mesenchymal (MEPM) cells were successfully isolated and used for in vitro experimental verification. We found that an increased m6A methylation level was correlated with suppressed cell proliferation in the palatine process mesenchyme of cleft palate mice. This change is due to the abnormally high expression of m6A methyltransferase METTL14. When using siRNAs and the m6A methyltransferase complex inhibitor SAH to interfere with the expression or function of METTL14, the teratogenic effect of atRA on primary cells was partially alleviated. In conclusion, METTL14 regulates palatal mesenchymal cell proliferation and cycle-related protein expression relies on m6A methylation modification, affecting the occurrence of cleft palate.
CAS / MDL:
研究领域:
发育生物学
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表观遗传学
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分子生物学
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2024
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IF 6.7
Miao Zhang,Haowei Zhang,Yunlei Zhou,Huanshun Yin,Zhengkun Yu,Xinyue Zhang,Shiyun Ai,Minghui Wang
The OPECT biosensing platform, which connects optoelectronics and biological systems, offers significant amplification and more possibilities for research in biological applications. In this work, a homogeneous organic photoelectrochemical transistor (OPECT) biosensor based on a Bi2S3/Bi2MoO6 heterojunction was constructed to detect METTL3/METTL14 protein activity. The METTL3/METTL14 complex enzyme was used to catalyze adenine (A) on an RNA strand to m6A, protecting m6A-RNA from being cleaved by an E. coli toxin (MazF). Alkaline phosphatase (ALP) catalyzed the conversion of Na3SPO3 to H2S through an enzymatic reaction. Due to the adoption of the strategy of no fixation on the electrode, the generated H2S was easy to diffuse to the surface of the ITO electrode. The Bi2S3/Bi2MoO6 heterojunction was formed in situ through a chemical replacement reaction with Bi2MoO6, improving photoelectric conversion efficiency and realizing signal amplification. Based on this “signal on” mode, METTL3/METTL14 exhibited a wide linear range (0.00001–25 ng/μL) between protein concentration and photocurrent intensity with a limit of detection (LOD) of 7.8 fg/μL under optimal experimental conditions. The applicability of the developed method was evaluated by investigating the effect of four plasticizers on the activity of the METTL3/METTL14 protein, and the molecular modeling technique was employed to investigate the interaction between plasticizers and the protein.
研究领域:
生物化学
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生物传感器
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光电化学
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蛋白质活性检测
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Feng Chen,Mingyi Zhou,Wei Chen,Wenjing Geng,Liang Lu,Guanwang Shen,Ping Lin,Qingyou Xia,Ping Zhao,Zhiqing Li
N6-methyladenosine (m6A) is the most prevalent internal modification on mRNA and plays critical roles in various biological processes including virus infection. It has been shown that m6A methylation is able to regulate virus proliferation and host innate immunity in mammals and plants, however, this antiviral defense in insects is largely unknown. Here we investigated function of m6A and its associated methyltransferases in nucleopolyhedrovirus (BmNPV) infection in silkworm. We reported significant changes of m6A methyltransferases METTL3 and METTL14 upon BmNPV treatment. Knockdown of METTL3 and METTL14 enhanced BmNPV infection and promoted viral proliferation, whereas overexpression of these enzymes could prevent viral replication. Further study revealed that host heat shock cognate 70 ( Hsc70 ) as a target gene of m6A would contribute to BmNPV proliferation. CRISPR-dCas9-targeted methylation of Hsc70 by METTL3/METTL14 decreased its expression and further attenuated BmNPV infection. Consistently, knockout of METTL3 in silkworm individuals by CRISPR-Cas9 reduced overall m6A levels, which led to rapid death of silkworms and increase of BmNPV upon virus infection likely due to upregulated expression of Hsc70 . Collectively, these findings provided a novel insight into antiviral activity of m6A and demonstrated a distinct immune response via attenuating host Hsc70 expression to counteract BmNPV replication in lepidopteran silkworm.
CAS / MDL:
研究领域:
昆虫学
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分子生物学
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病毒学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
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IF 8
Huanhuan Wang,Hanshu Zhao,Jiadi Gao,Sihan Liu,Yuanqi Xu,Xinyue Zhao,Shanshan Yang,Baozhi Gang,Zhongling Zhang
Vascular dementia (VaD) is a major cause of cognitive decline in the elderly, with chronic cerebral hypoperfusion (CCH) as its core pathogeny linked to neuroinflammation. Microglial M1 polarization drives CCH-related neuroinflammation, but its epigenetic regulation remains unclear. N6-methyladenosine (m6A) modification, centered on methyltransferase-like 14 (METTL14), is abundant in the brain, while CCAAT enhancer binding protein delta (CEBPD) is associated with central nervous system inflammation. This study explored METTL14’s role in microglial polarization and CCH pathology. In vitro , HMC3 cells induced by LPS/TNF-α (10 μg/mL, 50 ng/mL) showed upregulated METTL14 and CEBPD. METTL14 knockdown via short hairpin RNA inhibited the expression of M1 phenotypic markers (iNOS, CD86), reduced the release of pro-inflammatory factors (IL-1β, IL-6), and blocked NF-κB nuclear translocation, indicating that METTL14 silencing suppresses LPS/TNF-α-induced microglial M1 polarization and inflammatory response. In bilateral common carotid artery occlusion (BCCAo)-induced CCH rats, hippocampal METTL14/CEBPD was elevated. Adeno-associated virus-mediated METTL14 knockdown not only attenuated neuroinflammation and neuronal apoptosis in hippocampal CA1, but also significantly improved spatial learning memory and object recognition ability. Mechanistically, RIP-PCR and MeRIP-qPCR confirmed METTL14 enhances CEBPD mRNA stability via m6A modification. CEBPD overexpression reversed METTL14 knockdown’s effect, identifying it as a key downstream mediator. In conclusion, METTL14 knockdown impairs CEBPD mRNA stability via m6A, inhibits TLR4/MyD88/NF-κB pathway and microglial M1 polarization, alleviating CCH-related neuroinflammation and cognitive impairment, providing a potential epigenetic target for VaD.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Yan Zhang,Fuqing Yi,Ying He,Yidan Ma,Xinyi Mu,Yanqing Geng,Xin Yin,Rufei Gao,Liping Yan,Xuemei Chen,Junlin He
Dibutyl phthalate (DBP), a common environmental endocrine-disrupting chemical, is known to impair female reproduction, yet its specific effects on ovarian reserve and underlying epigenetic mechanisms are not fully understood. Here, using gestational exposure models ( in vivo ) and fetal ovarian culture models ( in vitro ), we show that gestational DBP exposure disrupts the ovarian reserve through a dual assault: impairing primordial follicle formation ("input") and, more critically, driving primordial follicle premature activation ("output"). Mechanistically, DBP induces METTL14-dependent m⁶A hypermethylation, which activates the PI3K-AKT-FOXO3a signaling axis to promote aberrant follicular activation. Knockdown of Mettl14 rescues this pathway activation and the follicular disruption. Long‑term follow‑up revealed that such precocious activation leads to progressive ovarian reserve depletion, culminating in a premature ovarian insufficiency (POI)-like phenotype with hormonal dysfunction, reduced oocyte quality, and compromised fertility in adult offspring. Collectively, these findings indicate that gestational DBP exposure activates the PI3K-AKT-FOXO3a signaling pathway via METTL14-mediated m⁶A modification, causing impaired follicle formation, follicular over-activation, and ultimately ovarian reserve depletion and a POI-like phenotype in offspring. This study reveals a novel m⁶A‑mediated epigenetic mechanism in plasticizer-induced ovarian toxicity, advancing our understanding of POI etiology and highlighting a significant environmental risk to female fertility.
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DOI
PubMed
高影响因子
Cancer Immunology Research
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2024
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IF 8.1
Meng Meng,Zhong Zhaoyang,Song Liang,Zhang Zhaohui,Yin Xiaofeng,Xie Xiqiang,Tian Lei,Wu Wei,Yang Yao,Deng Yafei,Peng Hongyan,Wu Shuting,Ran Guanghe,Lin Yuqing,Lai Qiangqiang,Bi Qinghua,Yan Fulin,Ji Yan,Wang Yang,Li Xiaohui,Yi Ping,Yu Jianhua,Deng Youcai
Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
研究领域:
免疫学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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