Applied Biological Chemistry
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2025
·Vol. 68
·期 1
·1-11
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IF 2.7
Dou Yufeng,Yang Jiao,Huang Na,Lu Xiaoxiao,Yan Liping
Background Pneumonia is a serious respiratory disease that significantly impacts human health. Quercetin (QUE), a plant extract, has been shown to exert protective effects against lung injury, but its precise mechanisms remain unclear. Methods Lipopolysaccharide (LPS) was used to induce injury in embryonic lung fibroblasts. Cell viability, proliferation, and apoptosis were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 5-ethynyl-2’-deoxyuridine (EdU) staining, and flow cytometry assay, respectively. Reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ levels were evaluated using corresponding assay kits. The levels of inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). Quantitative real-time PCR (qRT-PCR) and western blot were employed to analyze the expression and correlation of related genes. Methylated RNA immunoprecipitation (MeRIP) was employed to verify the regulatory mechanism between genes. Results QUE inhibited embryonic lung fibroblast injury. Both transducin β-like 1 X-linked receptor 1 (TBL1XR1) and methyltransferase 3 (METTL3) were highly expressed in lung injury tissues and cells, which were decreased by QUE treatment. TBL1XR1 deficiency weakened LPS-induced embryonic lung fibroblast injury. Mechanistically, METTL3 mediated the N 6 -methyladenosine (m6A) methylation and stabilized the TBL1XR1 mRNA. TBL1XR1 up-regulation alleviated the retardation of METTL3 absence on embryonic lung fibroblast injury. Furthermore, METTL3 overexpression reversed the inhibition of QUE on embryonic lung fibroblast injury. Conclusion QUE inhibited embryonic lung fibroblast injury by regulating the METTL3-mediated m6A methylation of TBL1XR1 mRNA.
研究领域:
分子生物学
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药理学
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呼吸医学
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表观遗传学
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细胞生物学
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高影响因子
Molecular Biomedicine
·
2025
·Vol. 6
·期 1
·1-18
·
IF 10.1
Zhang Shuqin,Cheng Yajia,Gao Yujia,Xu Feifei,Wang Yuna,Zhang Junling,Shang Yue,Li Deguan,Fan Saijun
With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N 6 -methyladenosine (m 6 A), the most pervasive representative of post-transcriptional modifications, plays critical roles in diverse biological events. Non-coding RNA comprises the vast majority of the human genome. This study aimed to explore the role of long non-coding RNA (lncRNA) m 6 A modification in γ-ray irradiation-induced hematopoietic injury. By using mouse models, it was found that γ-radiation rapidly damaged hematopoietic bone marrow cells (BMCs), triggering apoptosis, oxidative stress and DNA damage, along with up-regulation of m 6 A Reader proteins. We revealed the time-conditioned landscape of lncRNA m 6 A methylome of BMCs in the short term after radiation and found that a dynamic “change-then-recover” trend involved. LncRNA Snhg15 was identified as a key regulator through integration analysis of the methylome and transcriptome data. Its m 6 A modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel m 6 A Reader LRPPRC could interact with the modification site of Snhg15 , stabilize Snhg15 and promote its expression, thereby exacerbating radiation-induced injury to BMCs both in vitro and in vivo. Knockdown of Lrpprc or Snhg15 could alleviate the radiation injury to the hematopoietic system. Additionally, the LRPPRC- Snhg15 axis was involved in the radio-protective efficacy of gut microbiota-derived valeric acid. These findings uncover a novel mechanism by which m 6 A-modified lncRNA Snhg15 is stabilized by LRPPRC modulates γ-irradiation-induced hematopoietic injury, providing potential therapeutic targets for the prevention and treatment of radiation injuries.
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高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Haowei Fu,Xiaofang Zhu,Qiannan Di,Jiahui Sun,Qianqian Jiang,Qian Xu
Di(2-ethyl-hexyl) phthalate (DEHP), an environmental endocrine disruptor, can destroy the sperm genomic integrity and impairs spermatogenesis. N6-methyladenosine (m6A) is involved in the cellular effects of DEHP. However, the genotoxic effect of DEHP on spermatocytes and the possible role of m6A in this process remain unclear. This study demonstrated that m6A alleviates DEHP genotoxicity in GC-2 cells. In DEHP-treated mice, DNA double-strand breaks (DSBs) were induced in the testis and spermatocytes. To further explore the molecular mechanism of DEHP genotoxicity on spermatocytes, GC-2 cells were exposed to DEHP. DEHP produced distinct genotoxicity and caused DSBs, which led to the inhibition of DNA synthesis and cell cycle arrest. The DNA damage response (DDR) was initiated to repair the DSBs induced by environmentally relevant levels of DEHP (100 μM and 200 μM). During this process, METTL3 upregulated m6A, which facilitated the DDR via stabilizing the DNA damage repair factors ( Rad51 and Xrcc5 ) mRNA to maintain the pro-survival state. Moreover, Mettl3 knockdown partially inhibited DDR. Interestingly, high-dose DEHP (400 μM and 600 μM) directly induced apoptosis rather than the pro-survival state. Altogether: METTL3-mediated m6A participates in maintaining the pro-survival state by upregulating DDR, providing guidance for mitigating the genotoxicity of environment-related level DEHP exposure.
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BIOMATERIALS
·
2025
·
IF 12.9
Guisong Shan,Wanrong Wang,Xueqian Li,Zhaoxing Zhai,Mengyu Liu,Rui Peng,Qiuting Sun,Huiru Zhang,Tao Guo,Xiaoyan He
Epithelial–mesenchymal transition (EMT) is a key driver of chemoresistance and poor clinical outcomes in cancer. Strategies to reverse EMT-mediated drug resistance and to dynamically monitor treatment response are critical for improving therapeutic efficacy. Previous studies have implicated METTL3-regulated N 6 -methyladenosine (m 6 A) methylation in promoting EMT and tumor progression,highlighting its potential as a therapeutic target. Here, we develop a glutathione-responsive biomimetic nanomedicine (termed ACVS) that encapsulates METTL3 inhibitors within tumor-targeting cell membrane vesicles for controlled drug release. ACVS effectively reverse EMT phenotypes in vitro in transforming growth factor-β (TGF-β)-induced EMT cell models and restory chemosensitivity to standard therapeutics. In vivo validation in tumor-bearing mice and patient-derived circulating tumor cells (CTCs) further demonstrate that METTL3 inhibition enhance tumor suppression when combine with chemotherapy. To dynamically assess the relationship between EMT and chemoresistance, we implement single-cell resolution in situ mRNA profiling, which revealed spatial heterogeneity in EMT marker expression correlated with drug response. These findings propose a combinatorial strategy to overcome chemoresistance through METTL3-targeted modulation of EMT, while providing a methodological framework for real-time treatment monitoring in personalized oncology.
研究领域:
癌症生物学
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纳米医学
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表观遗传学
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药理学
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分子生物学
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精准医学
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PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Hao Tian,Hongpei Deng,Xinlong Liu,Chang Liu,Chuan Zhang,Kam W. Leong,Jing Ruan,Xianqun Fan
Uveal melanoma (UM) is the most prevalent primary ocular malignancy in adults, with high lethality and limited effective treatment options. Despite identified driver mutations in GNAQ , GNA11 , and BAP1 , therapeutic advancements have been minimal. This study highlights the pivotal role of N6-methyladenosine (m 6 A) modifications in UM pathogenesis and progression, focusing on the demethylase FTO as a therapeutic target. Elevated FTO expression in UM tissues correlates with decreased m 6 A levels, increased aggressiveness, and poor prognosis. The FTO inhibitor meclofenamic acid (MA) restored m 6 A levels, upregulated SLC7A11, and induced disulfidptosis, a unique form of cell death triggered by GSH depletion and NADPH consumption. To address MA's limitations in bioavailability and tumor targeting, we developed an MA-loaded nucleic acid nanodrug (SNAMA). SNAMA demonstrated effective tumor growth inhibition in orthotopic and metastatic UM models through GSH-responsive release and m 6 A-mediated disulfidptosis activation. Incorporating a PD-L1 aptamer into SNAMA further improved tumor targeting and immune modulation, enhancing therapeutic efficacy. This study identifies FTO as a critical target for UM therapy and introduces SNAMA-apt as a promising nanodrug. The findings offer a foundation for m 6 A-targeted approaches in UM and other malignancies, addressing bioavailability, targeting, and immune evasion challenges.
研究领域:
肿瘤学
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分子生物学
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药理学
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免疫学
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PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 12
·1-16
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IF 8.1
Hou Rui,Sun Xinrui,Cao Shiyao,Wang Yadong,Jiang Luo
The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH + CD133 + FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3’UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.
研究领域:
肿瘤学
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分子生物学
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代谢组学
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癌症生物学
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表观遗传学
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高影响因子
Materials Horizons
·
2024
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IF 12.2
Xiaolan Zheng,Tianyou Wang,Jixing Gong,Peng Yang,Yulin Zhang,Yue Zhang,Nan Cao,Kaiyu Zhou,Yiwen Li,Yimin Hua,Donghui Zhang,Zhipeng Gu,Yifei Li
Preservation of mitochondrial functionality is essential for heart hemostasis and cardiovascular diseases treatment. However, the current nanomedicines including liposomes, polymers and inorganic nanomaterials are severely hindered by poor stability, high manufacturing costs and potential biotoxicity. In this research, we present novel polyphenolic nanoparticles (NPs) derived from naturally occurring pomegranate peel (PP, labelled as PPP NPs), which exhibit potent antioxidative and anti-inflammatory properties, serving as a modulator of mitochondrial function. PPP NPs have been identified to improve survival rates in models of mitochondrial depletion through enhancement of cardiomyocyte proliferation and the reduction of DNA damage. Moreover, PPP NPs can effectively inhibit the production of reactive oxygen species and inflammatory mediators in lipopolysaccharide (LPS)-induced mitochondrial damage. Utilizing human engineered heart tissue and mice models, PPP NPs were found to significantly improve contractile function and alleviate inflammation activities after LPS treatment. Mechanically, PPP NPs regulated inflammatory responses via a m6A dependent manner, as determined using RNA-seq and MeRIP-seq analyses. Collectively, these insights underscore the potential of PPP NPs as a novel therapeutic approach for mitochondrial dysfunction.
研究领域:
纳米技术
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心脏病学
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药理学
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分子生物学
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PubMed
高影响因子
JOR Spine
·
2024
·Vol. 7
·期 1
·e1316
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IF 3.4
Libangxi Liu,Hong Sun,Yang Zhang,Chang Liu,Yong Zhuang,Miao Liu,Xuezheng Ai,Dan Long,Bo Huang,Changqing Li,Yue Zhou,Shiwu Dong,Chencheng Feng
Background The N6-methyladenosine (m6A) dynamics in the progression of intervertebral disc (IVD) aging remain largely unknown. This study aimed to explore the distribution and pattern of m 6 A modification in nucleus pulpous (NP) tissues of rats at different ages. Methods Histological staining and MRI were performed to evaluate the degeneration of IVD. The expression of m6A modifiers was analyzed using qRT-PCR and western blot. Subsequently, methylated RNA immunoprecipitation next generation sequencing and RNA-seq were conducted to identify differences in m6A methylome and transcriptome of NP tissues. Results Compared to 2-month-old rats, we found significant changes in the global m6A level and the expression of Mettl3 and FTO in NP tissues from 20-month-old rats. During the progression of NP aging, there were 1126 persistently differentially m6A peaks within 931 genes, and 51 persistently differentially expressed genes. GO and KEGG analyses showed that these m6A peaks and m6A modified genes were mainly engaged in the biological processes and pathways of intervertebral disc degermation (IDD), such as extracellular matrix metabolism, angiogenesis, inflammatory response, mTOR and AMPK signaling pathways. Meanwhile, conjoint analyses and Venn diagram revealed a total of 405 aging related genes contained significant methylation and expression levels in 20-month-old rats in contrast to 2-month-old and 10-month-old rats. Moreover, it was found that four aging related genes with hypermethylated modification including BUB1, CA12, Adamts1, and Adamts4 depicted differentially expressed at protein level, of which BUB1 and CA12 were decreased, while Adamts1 and Adamts4 were increased during the progression of NP aging. Conclusion Collectively, this study elucidated the distribution and pattern of m6A modification during the aging of IVD. Furthermore, the m6A modified genes were involved in the IDD related biological processes and pathways. These findings may provide novel insights into the mechanisms and therapies of IDD from the perspective of aging.
CAS / MDL:
研究领域:
分子生物学
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衰老研究
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骨科
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表观遗传学
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高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2024
·
IF 8
Qianhong Chen,Jinglan Cao,Yi Zhao,Ruo Yuan,Yun Xiang
The fat mass and obesity-associated protein (FTO) is vital for modulating dynamic reversible process of N6-methyladenosine (m 6 A) level in the nucleus and the abnormal expression of FTO correlates with generation and development of Alzheimer's disease, obesity and several cancers. The sensitive detection of FTO is therefore of significance for diagnosis of FTO-related diseases. In this work, on the basis of the demethylation enzyme capability of FTO and the dual Mg 2+ -dependent DNAzyme recycled signal magnification strategy, establishment of a highly sensitive electrochemical FTO biosensor is described. The target FTO molecules catalyze the demethylation of m 6 A-modifed sequences to form effective cleavage substrates for the MboI endonuclease, leading to the release of active DNAzyme sequences to trigger subsequent dual DNAzyme recycling cycles. Many methylene blue-tagged ssDNA sequences can thus be yielded via the DNAzyme amplifications and captured on the sensor electrode to generate highly amplified currents for detecting FTO in range of 0.04 pM to 10 nM with 6.11 fM detection limit. Additionally, the sensor demonstrates high selectivity and is able to be used for detecting cell lysate FTO, showing its potential for the diagnosis and study of FTO-related diseases for various application purposes.
研究领域:
生物化学
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分子生物学
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分析化学
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生物医学工程
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诊断学
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高影响因子
ANALYTICAL CHEMISTRY
·
2024
·
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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高影响因子
CELLULAR SIGNALLING
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2024
·
IF 4.4
Wentao Hu,Menghan Wang,Guifang Sun,Limin Zhang,Hong Lu
Parkinson's disease (PD) is a gradually debilitating neurodegenerative syndrome. Here, we analyzed GSE7621 chip data obtained from the Gene Expression Omnibus (GEO) database to explore the pathogenesis of PD. Early B Cell Factor 3 (EBF3), a member of the highly evolutionarily conserved EBF-transcription factor family, is involved in neuronal development. EBF3 expression is low in the substantia nigra of patients with PD. However, whether EBF3 is implicated in dopaminergic neuron death during PD has not yet been investigated. Therefore, we aimed to reveal the potential anti-apoptotic effect and molecular mechanism of EBF3 in PD. We established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model in vivo and a 1-methyl-4-phenylpyridine (MPP + )-induced SH-SY5Y cell model in vitro . EBF3 was downregulated in the substantia nigra of PD mice and SH-SY5Y cells treated with MPP + , and the m6A methylation modification level was low. Fat mass and obesity-associated protein (FTO) siRNA upregulated m6A methylation modification of EBF3 and extended the EBF3 mRNA half-life. Functionally, as demonstrated by the results of the open-field test, pole test and gait analysis, EBF3 overexpression ameliorated MPTP-induced behavioral disorder. Further, EBF3 overexpression suppressed neuronal apoptosis in vivo , as evidenced by decreased TUNEL + cells, and the increased activation of caspase-3 and caspase-9. Similar results were obtained in vitro , as reflected by increased cell viability, decreased LDH activity and restored mitochondrial function, collectively protecting SH-SY5Y cells from MPP + -induced apoptosis. Mechanistically, the results of luciferase reporter, ch-IP and DNA pull-down assays confirmed that, as a transcription factor, EBF3 bound to the promoter of CNTNAP4 (a protein associated with neuronal differentiation) and directly regulated CNTNAP4 transcription. Strikingly, CNTNAP4 knockdown markedly abolished the effect of EBF3 on cell apoptosis, thus aggravating PD. In conclusion, the low level of m6A methylation modification may contribute to the low expression of EBF3 during PD. Additionally, EBF3 attenuates PD by activating CNTNAP4 transcription, suggesting that EBF3 may be a novel therapeutic target in PD.
研究领域:
神经科学
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分子生物学
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转化医学
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PubMed
高影响因子
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