BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jing Zhang,Xuewei Yang,Xing Zhao,Gang Luo,Hong Jiang
Renal fibrosis is recognized as a critical pathway leading to end-stage renal disease in nearly all cases of chronic kidney disease (CKD). Analysis of the gene expression omnibus (GEO) database revealed that the transcription factor Krüppel-like factor 3 (KLF3) was elevated in kidney tissues of CKD patients, however, its specific role in CKD-associated renal fibrosis is yet to be deciphered. This study aimed to investigate the function of KLF3 on unilateral ureteral obstruction (UUO) mice and transforming growth factor-β1 (TGF-β1)-stimulated HK2 cells. Our data demonstrated that KLF3 was remarkably upregulated in the renal cortex of UUO mice and TGF-β1-treated HK-2 cells. We further confirmed that the upregulation of KLF3 was associated with its N6-methyladenosine (m6A) methylation modification. Knockdown of METTL14 reduced m6A methylation level of KLF3 and inhibited its mRNA stability. In vivo results suggested that KLF3 knockdown alleviated the pathological changes in renal tissues triggered by UUO. Additionally, KLF3 silencing mitigated renal fibrosis both in vivo and in vitro , as accompanied by decreased expression of Collagen I, Vimentin, α-SMA and Fibronectin. Mechanistically, KLF3 transcription activated dimethylarginine dimethylaminohydroxylase 2 (DDAH2) and upregulated its expression. Rescue experiments substantiated that DDAH2 overexpression eliminated the effect of KLF3 knockdown on renal fibrosis. Collectively, our findings suggest that inhibition of KLF3 may serve as a potential strategy to prevent CKD-associated renal fibrosis.
研究领域:
分子生物学
·
肾脏病学
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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
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干细胞研究
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表观遗传学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
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
Gut Microbes
·
2025
·
IF 11
Tong Jin,Si-Yuan Li,Hong-Li Zheng,Xiao-Dan Liu,Yue Huang,Gan Ma,Ya-Xuan Zhao,Xiao-Tian Zhao,Li Yang,Qi-Hui Wang,Hong-Jun Wang,Chengyong Gu,Zhiqiang Pan,Fuqing Lin
The gut microbiota has been linked to a number of neurological disorders. However, it is unclear whether the gut microbiota is involved in the genesis of chronic itch, a refractory condition that afflicts patients both physically and mentally. Here, we report that depletion of gut microbiota enhances tolerance to itch in mice orally administered with antibiotics (ABX) and mice free of germ. Of note, oral gavage with Bacteroides fragilis (B. fragilis), a prominent species of the genus Bacteroides with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or B. fragilis depletion caused a decrease in RNA N6-methyladenosine (m6A) demethylase FTO expression in the dorsal horn and a consequent increase in RNA m6A sites in Mas-related G protein-coupled receptor F (MrgprF) mRNA, leading to decreased MRGPRF protein. The downregulation of FTO was triggered by inactivation of ETS proto-oncogene 1 (ETS1), a transcription factor that binds to the Fto promoter. These findings support a gut microbe – spinal connection in modulation of itch sensation in RNA m6A epigenetic-dependent manner and highlight a critical role of ALC in linking the altered B. fragilis and itch dysfunction.
研究领域:
神经科学
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微生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Yubin Long,Yuan Ma,Houzhi Yang,Xiangbin Wang,Jigeng Fan,Yong Li,Bo Tao,Tianwei Sun
Promoting osteogenic differentiation and inhibiting osteoclast formation remain significant challenges in the treatment of osteoporosis. With the growing understanding of osteoporosis, increasing literature has highlighted the regulatory role of m6A methylation in this condition. However, there is currently no reliable method to stably regulate cellular m6A methylation levels. Here, we report a novel approach utilizing alendronate (aln)-modified mesoporous silica nanoparticles (MSNs) to deliver sodium bicarbonate and piR7472, modulating cellular behavior. Our experimental results demonstrate that Aln modification enables the nanoparticles to stably target hydroxyapatite, thereby accumulating in osteoporotic regions. Sodium bicarbonate suppresses osteoclastogenesis, while piR7472 enhances m6A methylation, promoting osteogenic differentiation of bone marrow stromal cells (BMSCs). Computed tomography (CT) and hematoxylin and eosin (HE) staining showed that after 2 weeks of treatment with MSNs-Na@piR7472, cortical bone thickened, trabecular bone density increased, collagen fiber thickness improved, and both the number and staining area of osteoclasts were significantly reduced. These findings indicate a marked improvement in osteoporosis.
研究领域:
医学
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分子生物学
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纳米医学
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DOI
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
·
IF 7.963
Limei Sun,Ming Gao,Qiuhui Qian,Ziyi Guo,Peng Zhu,Xuedong Wang,Huili Wang
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto . Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m 6 A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ , acsl 5, fasn , ppap 2c and ppar γ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m 6 A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m 6 A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m 6 A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m 6 A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
研究领域:
毒理学
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分子生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
REPRODUCTION
·
2022
·
IF 3.923
Luchun Zhang,Meng Yuan,Xingwei Huang,Qianzi Cao,Shaogang Huang,Ruizhen Sun,Lei Lei
In brief: Several factors affect the reprogramming efficiency of nuclear transfer embryos. This study shows that inhibiting 18S rRNA m6A methyltransferase METTL5 during nuclear transfer can improve the developmental rate of nuclear transfer embryos. Abstract: N6-methyladenosine (m6A) is one of the most important epigenetic modifications in eukaryotic RNAs, which regulates development and diseases. It is identified by several proteins. Methyltransferase-like 5 (METTL5), an enzyme that methylates 18S rRNA m6A, controls the translation of proteins and regulates pluripotency in embryonic stem cells. However, the functions of METTL5 in embryonic development have not been explored. Here, we found that Mettl5 was upregulated in somatic cell nuclear transfer (SCNT) embryos compared with normal fertilized embryos. Therefore, we hypothesized that METTL5 knockdown during the early stage of SCNT would improve the developmental rate of SCNT embryos. Notably, injection of Mettl5 siRNA (si-Mettl5) into enucleated oocytes during nuclear transfer increased the rate of development and the number of cells in blastocysts. Moreover, inhibition of METTL5 reduced the activity of phosphorylated ribosomal protein S6, decreased the levels of the repressive histone modification H3K27me3 and increased the expression of activating histone modifications H3K27ac and H3K4me3 and mRNA levels of some 2-cell-specific genes. These results expand our understanding of the role of METTL5 in early embryonic development and provide a novel idea for improving the efficiency of nuclear transfer cloning.
研究领域:
分子生物学
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生殖生物学
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表观遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 8
·4538
·
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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
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
·
分子生物学
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Zhuo Li,Zhengnan Guo,Zhengmeng Yang,Boguang Yang,Yuan Hu,Xian Xie,Zhixian Zong,Zekun Chen,Kunyu Zhang,Pengchao Zhao,Gang Li,Xuefeng Yang,Liming Bian
Intramembranous ossification, a major bone development process, begins with the condensation of precursor cells through the timely structural adaption of extracellular matrix (ECM) catering to rapid cellular morphological changes. Inspired by this, we design a highly cell-adaptable hydrogel to recapitulate an ECM-dependent mechanotransduction-metabolism-epitranscriptomics axis in mesenchymal stromal cells (MSCs). This hydrogel significantly enhances the E-cadherin-mediated cell-cell interactions of MSCs and promotes glucose uptake and tricarboxylic acid (TCA) cycle activities. We further show that elevated succinate inhibits fat mass and obesity-associated protein (FTO), a N6-methyladenosine (m 6 A) demethylase, thereby enhancing methyltransferase-like 3 (METTL3)-driven m 6 A methylation. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) indicates increased m 6 A methylation of runt-related transcription 2 (Runx2), a key osteogenic signaling factor, promoting osteogenesis of hydrogel-delivered MSCs and bone regeneration in critical-sized bone defects. Our findings reveal the mechanism underlying the critical impact of adaptable ECM structures on tissue development and provide valuable guidance for the design of ECM-mimetic cell carriers to enhance the therapeutic outcomes of regenerative medicine.
研究领域:
细胞生物学
·
分子生物学
·
再生医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF GASTROENTEROLOGY
·
2025
·
IF 5.5
Ren Bingyu,Li Han,Liu Shenglu,Huang Zhiwei,Bai Junjie,Jiang Zhonghao,Xu Tongjie,Gu Boyuan,Yu Wenhao,Sun Lei,Tan Peng,Fu Wenguang
Background and Aims Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD. Methods MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment. Results Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m 6 A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis. Conclusions The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.
研究领域:
肝病学
·
免疫学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Mengya Zhang,Xueguang Zhang,Chen Tan,Ting Jiang,Zheng Cao,Yufei Chen,Feng Qiao,Gelin Huang,Chaoye Ma,Huixia Li,Mei Ye,Lei Wang,Liandong Zuo,Jun Yu,Xiaofeng Li,Yunfang Zhang,Yue-Qiu Tan,Shuibin Lin,Wenming Xu,Hao Chen
Recent studies have highlighted RNA modifications as integral regulators of gene expression during spermatogenesis. Ribosomal RNAs (rRNAs) are the most abundant RNA in cells, while the function and clinical relevance of rRNA modifications in spermatogenesis remain poorly understood. Here, we identified 4 pathogenic heterozygous variants of METTL5 in 1,427 patients with male infertility characterized as oligoasthenoteratozoospermia (OAT). The pathogenic variants of METTL5 led to the significantly decreased expression level of METTL5. Null mutation of 18S rRNA methyltransferase Mettl5 led to male infertility attributed to OAT during spermiogenesis, presenting defects in both the sperm head and tail. Notwithstanding the absence of notable changes in global translation after Mettl5 loss, we observed a compromised translational efficiency of mRNAs encoding proteins crucial for spermiogenesis, including Gk2 , Akap4 , Fsip2 , Odf2 , and Pgk2 . Intriguingly, therapeutic interventions via intracytoplasmic sperm injection in OAT couples with these variants resulted in successful pregnancies. These insights not only identify METTL5-mediated 18S rRNA m 6 A modification as a novel genetic determinant for OAT but also offer a new target to the genetic counseling, clinical diagnosis, and potential treatment strategies for male infertility.
研究领域:
分子生物学
·
遗传学
·
生殖医学
·
RNA修饰
·
发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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