AGING CELL
·
2024
·Vol. 23
·期 3
·e14053
·
IF 8
Ying Huai,Xue Wang,Wenjing Mao,Xuehao Wang,Yipu Zhao,Xiaohua Chu,Qian Huang,Kang Ru,Ling Zhang,Yu Li,Zhihao Chen,Airong Qian
Aging impairs osteoblast function and bone turnover, resulting in age-related bone degeneration. Stress granules (SGs) are membrane-less organelles that assemble in response to stress via the recruitment of RNA-binding proteins (RBPs), and have emerged as a novel mechanism in age-related diseases. Here, we identified HuR as a bone-related RBP that aggregated into SGs and facilitated osteogenesis during aging. HuR-positive SG formation increased during osteoblast differentiation, and HuR overexpression mitigated the reduction in SG formation observed in senescent osteoblasts. Moreover, HuR positively regulated the mRNA stability and expression of its target β-catenin by binding and recruiting β-catenin into SGs. As a potential therapeutic target, HuR activator apigenin (API) enhanced its expression and thus aided osteoblasts differentiation. API treatment increased HuR nuclear export, enhanced the recruitment of β-catenin into HuR-positive SGs, facilitated β-catenin nuclear translocation, and contributed osteogenesis. Our findings highlight the roles of HuR and its SGs in promoting osteogenesis during skeletal aging and lay the groundwork for novel therapeutic strategies against age-related skeletal disorders.
研究领域:
老年学
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分子生物学
·
骨生物学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Qiuyun Wu,Qianyi Zhang,Chunmeng Jin,Xue Liu,Hongmin Yu
Background Silicosis, one of the serious occupational diseases, is mainly manifested by pulmonary fibrosis induced by long-term exposure to silica particles in workplace. Evidence demonstrates that circular RNAs (circRNAs) are interesting regulators of pulmonary fibrosis process. So, further elucidation of the role of circRNAs may provide a new perspective into mechanisms driving pulmonary fibrosis and silicosis. Methods The characteristics of circRNA homer scaffold protein 1 (hsa_circ_0006916, circHOMER1) was assessed using Actinomycin D, RNase R, and nucleoplasmic separation assay. The histopathological examination and Enzyme-linked immunosorbent assay (ELISA) were used to confirm circHOMER1 function in mouse lung tissues under silica particle exposure. The expression of circHOMER1, human antigen R (HuR) and NADPH oxidase 4 (NOX4) was identified by western blot or RT-qPCR assay. The RNA immunoprecipitation (RIP) assay and plasmid co-transfection were used to analyze the interaction between circHOMER1, HuR and NOX4. Results We confirmed an upregulated circHOMER1 in silicosis fibrosis. Functional assays showed that the knockdown of circHOMER1 suppressed the viability of fibroblasts and the production of fibrotic molecules and alleviated the histology fibrotic changes in lung tissues from mouse exposed to silica particles. Mechanistically, we found that circHOMER1 directly bound to HuR and promoted its protein expression in fibroblasts. And, circHOMER1 further regulated HuR/NOX4 signaling axis through HuR to stabilize NOX4 mRNA, which enhanced the production of reactive oxygen species (ROS), thereby promoting the silicosis fibrosis process. Conclusion This study revealed the role of circHOMER1 in silica-induced pulmonary fibrosis, suggesting that the inhibition of circHOMER1 may be a potential therapeutic approach to relieve the pathological process of silicosis.
研究领域:
分子生物学
·
肺病学
·
职业医学
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2022
·Vol. 201
·期 1
·295-305
·
IF 4.081
Li Yanyan,Zhang Jianbin,Sun Linlin,Zhao Hongyu,Jia Xiaohan,Zhang Yingri,Li Yuanbin
It is critical to determine the mechanism underlying fluoride (F)-induced damage of the testes to develop appropriate strategies for monitoring and intervention. In the present study, exposure to 50 mg/L sodium fluoride (NaF) for 90 days damaged the normal structure of the testes and quality of the sperm, particularly the spermatocytes, and triggered overexpression of human antigen R (Elavl1/HuR) according to western blotting and immunofluorescence. Furthermore, 0.5 mM NaF exposure for 24 h exposure increased the proportion of apoptosis and expression of caspase-3 and caspase-9 in mouse spermatocytes (GC-2spd cell line), whereas inhibition of HuR reduced apoptosis and the expression of caspase-3 and caspase-9. Additionally, inhibition of HuR alleviated F-induced autophagy based on observation of the autophagy bodies, detection of autophagy activity, and analysis of the expression of the LC3II/LC3I and p62 proteins. These results reveal that excessive F can lead to overexpression of HuR, resulting in high levels of apoptosis and autophagy in spermatocytes. These findings improve the understanding of the mechanisms underlying F-induced male reproductive toxicity, and HuR may be explored as a treatment target for certain conditions. Graphical abstract Excessive fluoride can induce overexpression of HuR in testis and result in excessive apoptosis and autophagy in spermatocytes as well as male reproductive damage, such as a decreased sperm count, decreased sperm motility, and increased deformity rate.
研究领域:
毒理学
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生殖生物学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2012
·
IF 2.484
Da-Quan Sun,Ying Wang,Ding-Gan Liu
AU-rich elements are functional motifs in the 3′untranslated region of mRNA and are binding sites for the RNA binding protein HuR, an mRNA stabilizer and translation enhancer implicated in carcinogenesis. It is not clear whether, and, if so, how the AU-rich elements function in cells when they are separated from their mRNA and form an independent RNA species. Here, we show that a short RNA with AU-rich elements derived from C/EBPβ 3′UTR suppressed growth in a human liver cancer cell line. It specifically bound HuR, and it competed with C/EBPβ mRNA in order to bind to HuR. Our results provide evidence that the cancer cell growth suppression by this 62nt RNA containing AU-rich elements may be due to competitive binding to HuR. This work may open new options for the development of novel anti-cancer drugs.
研究领域:
分子生物学
·
癌症研究
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RNA生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Shuoning Wu,Ting Wang,Zhijie Mao,Zhentong Yang,Zhuoqun Wang,Zhuyin Jia,Zhouqing Huang,Yonghua Wang
Purpose Doxorubicin (DOX), a widely used chemotherapeutic agent for malignancies, exhibits dose-dependent cardiotoxicity, which restricts its clinical utility. While artesunate (ART) demonstrates potentially cardioprotective effects against acute DOX-induced cardiac damage, its role in chronic cardiotoxicity and its underlying mechanisms remain unclear. This study aimed to elucidate the mechanism underlying artesunate-mediated protection against doxorubicin (DOX)-induced cardiotoxicity. Methods Mice were treated with 5 mg/kg DOX (intraperitoneal injection) once weekly for 4 weeks to induce myocardial damage and with 25 mg/kg ART (intragastric administration) for 28 days. Echocardiography and histological staining were used to evaluate cardiac function and structural changes. We also assessed mRNA and protein levels using real-time polymerase chain reaction and Western blotting, respectively, and evaluated HuR-Sirt1 mRNA interaction via RNA immunoprecipitation (RIP). Results ART treatment significantly ameliorated DOX-induced cardiac dysfunction, fibrosis, hypertrophy, and apoptosis both in vivo and in vitro . Furthermore, ART restored cardiac sirtuin-1 (Sirt1) expression, which was suppressed by DOX. Critically, cardiac-specific Sirt1 knockout exacerbated DOX-induced cardiac damage and abolished the protective effects of ART. Mechanistically, we observed that siRNA-mediated HuR knockdown reduced Sirt1 expression, whereas Sirt1 knockdown did not affect HuR expression, indicating that HuR positively regulates Sirt1 expression. ART promotes the nuclear-to-cytoplasmic translocation of HuR, thereby enhancing its binding to Sirt1 mRNA and stabilizing Sirt1 transcripts. Conclusion Collectively, these findings demonstrate that ART attenuates DOX cardiotoxicity by activating the HuR-Sirt1 axis through the stabilization of Sirt1 mRNA.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE
·
2022
·Vol. 42
·期 2
·202-219
·
IF 6.709
Xiu Han,Xuning Shen,Min Wang,Xin Wang,Youli Jian,Chonglin Yang,Weixiang Guo
Multiciliated ependymal cells line the ventricle wall and generate CSF flow through ciliary beating. Defects in ependymal cells cause hydrocephalus; however, there are still significant gaps in our understanding the molecular, cellular and developmental mechanisms involved in the pathogenesis of hydrocephalus. Here, we demonstrate that specific deletion of RNA-binding protein (RBP) Hu antigen R (HuR) in the mouse brain results in hydrocephalus and causes postnatal death. HuR deficiency leads to impaired ependymal cell development with defective motile ciliogenesis in both female and male mice. Transcriptome-wide analysis reveals that HuR binds to mRNA transcripts related to ciliogenesis, including cilia and flagella associated protein 52 (Cfap52), the effector gene of Foxj-1 and Rfx transcriptional factors. HuR deficiency accelerates the degradation of Cfap52 mRNA, while overexpression of Cfap52 is able to promote the development of HuR-deficient ependymal cells. Taken together, our results unravel the important role of HuR in posttranscriptional regulation of ependymal cell development by stabilizing Cfap52 mRNA.SIGNIFICANCE STATEMENT This study identifies Hu antigen R (HuR) as a genetic factor involved in the pathogenesis of hydrocephalus. Mechanistically, HuR regulates ependymal cell differentiation and ciliogenesis through stabilizing Cfap52 mRNA, the effector gene of Foxj-1 and Rfx transcriptional factors.
研究领域:
神经科学
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分子生物学
·
发育生物学
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DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Xin Zhong,Kangwei Wang,Yonghua Wang,Luya Wang,Sudan Wang,Weijian Huang,Zhuyin Jia,Shan-Shan Dai,Zhouqing Huang
Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the C-type domain form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.
研究领域:
心血管疾病
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分子生物学
·
药理学
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DOI
PubMed
高影响因子
ARCHIVES OF PHARMACAL RESEARCH
·
2024
·
IF 6.9
Hu Wenjie,Wang Yujie,Yang Huiling,Zhang Leiming,Liu Bo,Ji Yunxia,Song Xiaodong,Lv Changjun,Zhang Songzi
Pulmonary fibrosis is a chronic and irreversible progressive lung disease caused by various factors, such as age and environmental pollution. With countries stepping into an aging society and the seriousness of environmental pollution caused by global industrialization, the incidence of pulmonary fibrosis is annually increasing. However, no effective drug is available for pulmonary fibrosis treatment. C-phycocyanin (C-PC), extracted from blue-green algae, has good water solubility and antioxidation. This study elucidated that C-PC reinforces autophagy to block pulmonary fibrogenesis by inhibiting long noncoding RNA (lncRNA) biogenesis in vivo and in vitro. Cleavage under targets and release using nuclease (CUT & RUN)-PCR, co-immunoprecipitation (Co-IP), and nuclear–cytoplasmic separation experiments clarified that C-PC blocked the nuclear translocation of activating transcription factor 3 (ATF3) to prevent the binding between ATF3 and transcription factor Smad3, thereby hindering lncIAPF transcription. Human antigen R (HuR) truncation experiment and RNA binding protein immunoprecipitation (RIP) were then performed to identify the binding domain with lncIAPF in the 244–322 aa of HuR. lncIAPF exerted its profibrogenic function through the binding protein HuR, a negative regulator of autophagy. In summary, C-PC promoted autophagy via down-regulating the lncIAPF–HuR-mediated signal pathway to alleviate pulmonary fibrosis, showing its potential as a drug for treating pulmonary fibrosis. Exploring how C-PC interacts with biological molecules will help us understand the mechanism of this drug and provide valuable target genes to design new drugs.
研究领域:
肺病学
·
分子生物学
·
药理学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2022
·
IF 5.223
Bo Jiang,Xinsheng Fu,Qichuan Zhang,Yunfei Du
Dioscin (DS) is a natural compound with inhibitory effects on multiple cancer types and we explored the mechanism driving the antagonizing effect of DS on osteosarcoma (OS). OS cell lines were treated with DS and microRNAs (miRs) responding to DS treatment were determined. Effects of DS on viability, apoptosis, metastasis, and miR-16-5p/HuR/Pim1 pathway activity were assessed. MiR-16-5p was inhibited before DS treatment to confirm its central role in anti-OS effects of DS. The conclusion derived from in vitro assays was verified with a mouse model. DS suppressed viability, invasion and migration, while induced apoptosis in OS cells. Moreover, the compound also induced the expression of miR-16-5p, contributing to the inhibition of HuR/Pim1 pathway. The inhibited expression of miR-16-5p counteracted the anti-OS function of DS, which was also validated in mice. Anti-OS effects of DS depended on the induction of miR-16-5p, making the compound a promising adjuvant agent for treating OS.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
Autophagy
·
2022
·
IF 13.391
Jinjin Zhang,Haixia Wang,Hongbin Chen,Hongbo Li,Pan Xu,Bo Liu,Qian Zhang,Changjun Lv,Xiaodong Song
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated LINC00941/lncIAPF was found to accelerate pulmonary fibrosis by promoting fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation experiments elucidated that histone 3 lysine 27 acetylation (H3K27ac) activated the chromosome region opening in the LINC00941 promoter. As a consequence, the transcription factor ATF3 (activating transcription factor 3) bound to this region, and LINC00941 transcription was enhanced. RNA affinity isolation, RNA immunoprecipitation (RIP), RNase-RIP, half-life analysis, and ubiquitination experiments unveiled that LINC00941 formed a RNA-protein complex with ELAVL1/HuR (ELAV like RNA binding protein 1) to exert its pro-fibrotic function. Dual-fluorescence mRFP-GFP-MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) adenovirus monitoring technology, human autophagy RT2 profiler PCR array, and autophagic flux revealed that the LINC00941-ELAVL1 axis inhibited autophagosome fusion with a lysosome. ELAVL1 RIP-seq, RIP-PCR, mRNA stability, and rescue experiments showed that the LINC00941-ELAVL1 complex inhibited autophagy by controlling the stability of the target genes EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), STAT1 (signal transducer and activators of transcription 1) and FOXK1 (forkhead box K1). Finally, the therapeutic effect of LINC00941 was confirmed in a mouse model and patients with IPF. This work provides a therapeutic target and a new effective therapeutic strategy related to autophagy for IPF.Abbreviations: ACTA2/a-SMA: actin alpha 2, smooth muscle; ATF3: activating transcription factor 3; ATG: autophagy related; Baf-A1: bafilomycin A1; BLM: bleomycin; CDKN: cyclin dependent kinase inhibitor; CLN3: CLN3 lysosomal/endosomal transmembrane protein, battenin; COL1A: collagen type I alpha; COL3A: collagen type III alpha; CXCR4: C-X-C motif chemokine receptor 4; DRAM2: DNA damage regulated autophagy modulator 2; ELAVL1/HuR: ELAV like RNA binding protein 1; EZH2: enhancer of zeste 2 polycomb repressive complex 2 subunit; FADD: Fas associated via death domain; FAP/FAPα: fibroblast activation protein alpha; FOXK1: forkhead box K1; FVC: forced vital capacity; GABARAP: GABA type A receptor-associated protein; GABARAPL2: GABA type A receptor associated protein like 2; IGF1: insulin like growth factor 1; IPF: idiopathic pulmonary fibrosis; LAMP: lysosomal associated membrane protein; lncRNA: long noncoding RNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPC1: NPC intracellular cholesterol transporter 1; RGS: regulator of G protein signaling; RPLP0: ribosomal protein lateral stalk subunit P0; ROC: receiver operating characteristic; S100A4: S100 calcium binding protein A4; SQSTM1/p62: sequestosome 1; STAT1: signal transducers and activators of transcription 1; TGFB1/TGF-β1: transforming growth factor beta 1; TNF: tumor necrosis factor; UIP: usual interstitial pneumonia; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin.
研究领域:
呼吸病学
·
分子生物学
·
细胞生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
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