Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1271
·
IF 7.5
Zhu Jiru,Xia Yutong,Li Xiang,Wen Yingying,Zhang Xuhong,Jin Le,Zhang Liyue,Wang Ziyu,Li Yanqing,Yu Xin,Chen Zhitong,Ge Jiayun,Shen Ye,Tong Jianping
Background Myopia has reached epidemic proportions globally with limited therapeutic targets. This study elucidated the pivotal role of retinal epitranscriptomic regulation in myopia pathogenesis, aiming to identify novel therapeutic targets for myopia control. Methods The study enrolled 38 myopic patients scheduled for refractive surgery to analyze peripheral blood N6-methyladenosine (m6A) levels. In parallel, we established a murine form-deprivation myopia (FDM) model to examine retinal m6A dynamics and Alkylation repair homolog protein 5 (ALKBH5) expression. Pharmacological interventions using the ALKBH5 inhibitor DDO-2728 and Extracellular signal-related kinases 1 and 2 (ERK1/2) activator Ro67-7476 were administered intravitreally. To genetically validate the role of ALKBH5, ALKBH5-knockout (ALKBH5-KO) mice were subjected to the FDM model. Comprehensive assessments included refractive measurements, retinal structure analysis, and molecular profiling of inflammatory and extracellular matrix (ECM) markers. Statistical analyses employed Pearson’s correlation for clinical data and ANOVA with Tukey’s post hoc tests for experimental comparisons. Results Clinical data revealed significant inverse correlations between blood m6A levels and myopia severity (refraction: r = 0.435, p < 0.01; axial length: r = -0.338, p < 0.05). FDM retinas exhibited progressive m6A reduction and specific upregulation of ALKBH5 in the ganglion cell layer (GCL), with no changes observed in other m6A regulators. Mechanistic studies demonstrated that intravitreal injection of the selective ALKBH5 inhibitor DDO-2728 (2.5 mM) effectively attenuated myopia progression, mitigated retinal thinning, suppressed inflammatory mediators, and modulated early ECM dysregulation through specific suppression of ERK1/2 hyperphosphorylation. Crucially, genetic ablation of ALKBH5 recapitulated the protective phenotype of the inhibitor, conferring significant resistance to myopia development and associated retinal pathology. Importantly, co-administration of the ERK1/2 activator Ro 67-7476 completely abolished DDO-2728’s protective effects. Conclusions Peripheral blood m6A reduction correlates with human myopia severity. Retinal ALKBH5 upregulation drives myopia progression through ERK1/2 hyperactivation. Both pharmacological inhibition and genetic deletion of ALKBH5 effectively protect against myopia, attenuate inflammatory responses, and mitigate ECM dysregulation, mechanistically linked to the suppression of ERK1/2 signaling. These findings collectively identify ALKBH5 as a novel therapeutic target and DDO-2728 as a promising strategy for myopia control. Graphical
研究领域:
眼科学
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分子生物学
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表观遗传学
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信号转导
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药理学
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DOI
PubMed
高影响因子
OPHTHALMIC RESEARCH
·
2022
·Vol. 65
·期 6
·678-684
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IF 3.031
Fan Yuzhuo,Li Jiarui,Huang Lvzhen,Wang Kai,Zhao Mingwei
Introduction: The goal of this study was to investigate the presence of ADORA2A-DRD2 heterodimers in human retinal pigment epithelial (RPE) cells; determine if 7-methylxanthine (7-MX), a nonselective adenosine receptor antagonist which was used to control myopia progression, can influence the behavior of RPE cells through the ADORA2A-DRD2 receptor pathway; and assess the changes in the expression of signaling molecules during cellular signal transduction. Methods: Human RPE cells were cultured in vitro in the presence or absence of 7-MX. Cell proliferation was evaluated with the CCK-8 assay. Apoptosis and necrosis rates were determined by annexin V–FITC/propidium iodide staining and flow cytometry. Immunofluorescence and coimmunoprecipitation were used to examine the protein expression and colocalization of ADORA2A and DRD2 in RPE cells. ADORA2A and DRD2 were knocked down with small interfering RNAs (siRNAs). Changes in the protein expression of ERK1/2 and phospho-ERK1/2 (pERK 1/2), which are signaling molecules downstream of dopamine receptors, were evaluated by Western blot analysis. Results: Immunofluorescence and coimmunoprecipitation showed that ADORA2A and DRD2 were colocalized in RPE cells. The expression of ADORA2A in RPE cells was inhibited by treatment with 50 µmol/L 7-MX for 48 h, and the expression of DRD2, ERK1/2, and pERK1/2 was increased after treatment with 50 µmol/L 7-MX for 48 h. After siRNA-mediated knockdown of DRD2 in RPE cells and further treatment with 50 µmol/L 7-MX for 48 h, the expression of DRD2 was nearly restored to the level observed in the native control. At the experimental concentrations, 7-MX and siRNAs did not affect the proliferation or apoptosis of human RPE cells. Conclusions: ADORA2A and DRD2 heterodimers were present in RPE cells. 7-MX may affect the behaviors of RPE cells through the ADORA2A-DRD2 receptor pathway. 7-MX is an inhibitor of ADORA2A receptors that can prevent inhibition of the DRD2 receptor pathway and increase DRD2 receptor pathway activity. This phenomenon may explain the mechanism of action through which 7-MX can control myopia progression
研究领域:
眼科学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2024
·
IF 4.2
Dong-Jing Yang,Yang Bai,Min Wu,Yin-Ming Liang,Bin-Hui Zhou,Wenzhi Guo,Shui-Jun Zhang,Ji-Hua Shi
Vascular endothelial inflammation is crucial in hepatic ischemia–reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.
研究领域:
分子生物学
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肝病学
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炎症
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转录因子
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DOI
PubMed
高影响因子
MOLECULAR REPRODUCTION AND DEVELOPMENT
·
2015
·Vol. 82
·期 4
·305-314
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IF 2.527
Wei-Rong Yang,Yong Wang,Yi Wang,Jiao-Jiao Zhang,Jia-Hua Zhang,Cheng Lu,Xian-Zhong Wang
SUMMARY Mammalian target of rapamycin (mTOR) is known to be involved in mammalian cell proliferation, while S-phase kinase-associated protein 2 (SKP2) plays a vital role in the cell cycle. Within the testis, estrogen also plays an important role in Sertoli cell proliferation, although it is not clear how. The present study asked if mTOR is involved in 17β-estradiol-dependent Sertoli cell proliferation. We specifically assessed if extracellular signal-regulated kinase 1/2 (ERK1/2) and/or phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) exert convergent effects toward the activation of mTOR signaling, and if this signaling regulates the expression of SKP2 through retinoblastoma (RB) and early mitotic inhibitor 1 (EMI1) protein and on CCNE1 and CCND1 mRNA levels. Treatment with 17β-estradiol for 15–90 min activated mTOR, with mTOR phosphorylation peaking after 30 min. U0126 (5 μM), a specific inhibitor of (MEK1/2), and 10-DEBC (2 μM), a selective inhibitor of AKT, both significantly reduced 17β-estradiol-induced phosphorylation of mTOR. Rapamycin suppressed 17β-estradiol-induced Sertoli cell proliferation, appearing to act by reducing the abundance of SKP2 , CCND1 , and CCNE1 mRNA as well as RB and EMI1 protein. These data indicated that 17β-estradiol enhances Sertoli cell proliferation via mTOR activation, which involves both ERK1/2 and PI3K/AKT signaling. Activated mTOR subsequently increases SKP2 mRNA and protein expression by enhancing the expression of CCND1 and CCNE1 , and inhibits SKP2 protein degradation by increasing EMI1 abundance. Mol. Reprod. Dev. 82: 305–314, 2015. © 2015 Wiley Periodicals, Inc .
研究领域:
生殖生物学
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细胞信号传导
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内分泌学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Guan-feng Xu,Ya-Xuan Wang,Hao-fang Wan,Jia-huan Shen,Yong-qi Li,Jie-hong Yang,Yu He,Hai-tong Wan
ISO induces myocardial injury, collagen accumulation, and cardiac fibrosis. • Luteolin alleviates ISO-induced myocardial fibrosis and Ang II-induced endothelial cell injury. • Luteolin inhibits oxidative stress, apoptosis, EndMT, and extracellular matrix remodeling. • Multi-method analysis identifies the ERK1/2-GATA4 axis as a potential target of luteolin. • Blocking ERK1/2 partly abolishes the protective effects of luteolin against myocardial fibrosis. Introduction Myocardial fibrosis is a common pathological feature of cardiovascular diseases and is closely associated with oxidative stress, apoptosis, extracellular matrix remodeling, and endothelial-to-mesenchymal transition (EndMT). Luteolin (Lut), a naturally occurring flavonoid, exhibits cardioprotective properties; however, its anti-fibrotic effects and underlying mechanisms remain unclear. Methods Myocardial fibrosis was induced in rats by subcutaneous isoproterenol injection for 7 days, followed by Lut treatment. Cardiac function was evaluated by echocardiography, while myocardial injury and fibrosis were assessed by histological and molecular analyses. Potential anti-fibrotic targets of Lut were identified using network pharmacology and validated by molecular docking and molecular dynamics simulation. In vitro , HUVECs were stimulated with angiotensin II (Ang II) and then incubated with Lut. Oxidative stress, mitochondrial membrane potential (MMP), apoptosis, and ERK1/2-GATA4 signaling were examined. The involvement of ERK1/2 was further confirmed using the pharmacological inhibitor PD98059. Results Lut significantly improved cardiac function, alleviated myocardial injury, reduced collagen deposition, and attenuated myocardial fibrosis in ISO-treated rats. In Ang II-induced HUVECs, Lut suppressed ROS generation, preserved MMP, and inhibited apoptosis. Mechanistically, Lut activated ERK1/2 and GATA4 phosphorylation, regulated apoptosis-related proteins, and inhibited EndMT by decreasing α-SMA and FSP-1 while restoring VE-cadherin and CD31 expression. These protective effects were partially abolished by PD98059 both in vivo and in vitro . Conclusion Our findings demonstrate that Lut attenuates myocardial fibrosis by regulating oxidative stress, apoptosis, and EndMT, at least in part, via activation of the ERK1/2-GATA4 phosphorylation axis, suggesting its therapeutic potential for myocardial fibrosis.
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DOI
PubMed
高影响因子
Genes & Diseases
·
2026
·
IF 14.6
Longfei Dai,Qiuxing Chen,Chao Yu,Haosheng Tan,Zhen Zhang
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colorectum and a major risk factor for colitis-associated colorectal cancer (CAC). However, the role of deubiquitinases (DUBs) in the progression from UC to CAC remains incompletely understood. We identified ZUP1 as a markedly down-regulated deubiquitinase in UC and CAC by RNA sequencing, public dataset analyses, screening with multiple machine-learning algorithms, and validation in clinical specimens. Functionally, ZUP1 deficiency aggravated colitis-associated inflammation and barrier damage, and promoted the proliferation, migration, and invasion of colorectal cancer cells. Mechanistically, ZUP1 directly interacted with ERK1/2 and removed K63-linked ubiquitin chains from ERK1/2, thereby disrupting MEK1/2–ERK1/2 interaction and restraining ERK1/2 phosphorylation. In addition, ERK activation up-regulated c-JUN, which in turn bound to the ZUP1 promoter and repressed its transcription, forming a positive feedback loop. In conclusion, these findings identify ZUP1 as a previously unrecognized suppressor of UC and CAC progression and suggest that the ZUP1–ERK1/2–c-JUN axis may serve as a therapeutic target in UC and CAC.
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DOI
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Lin Xiao-mian,Luo Wu,Wang Heng,Li Rong-zhen,Huang Yi-shan,Chen Lian-kuai,Wu Xiao-ping
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.
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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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2022
·
IF 4.46
Xiu Xin,Haiqiong Chen,Fuhong Tian,Jingjing Li,Haoni Yan,Yige Yu,Feifei Ma,Huitao Li,Yiyan Wang,Xiaoheng Li,Yang Zhu,Ren-shan Ge
Perfluoroundecanoic acid (PFUnA), a perfluorinated compound , has environmental persistence, bioaccumulation , and potential toxicity. However, its effect on Leydig cell function remains unclear. Rats (age of 56 days) were gavaged with 0 (corn oil), 0.1, 0.5, 1, or 5 mg/kg/day PFUnA for 28 days. PFUnA significantly reduced serum testosterone levels as low as 0.5 mg/kg. PFUnA markedly decreased Leydig cell number as low as 0.1 mg/kg. PFUnA markedly reduced transcript levels of Star and Insl3 in the testes at 1 mg/kg after adjusting to Leydig cell number. It also reduced their protein levels. PFUnA significantly decreased the phosphorylation of AKT1 and mTOR as low as 0.1 mg/kg and the phosphorylation of ERK1/2 at 1 mg/kg and the phosphorylation of AKT1, AKT2, ERK1/2, and mTOR in Leydig cells at various concentrations (0.01–10 μM) after 24 h of in vitro treatment. In conclusion, PFUnA inhibits Leydig cell function possibly via AKT/ERK1/2/mTOR signaling pathways.
研究领域:
毒理学
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内分泌学
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生殖生物学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2019
·Vol. 44
·期 12
·2821-2831
·
IF 2.782
Zhai Ailing,Zhang Zeng,Kong Xiangjuan
Paeoniflorin (PF) has been reported to possess neuroprotective influences on cognitive dysfunction illness. In current research, we attempted to probe into the protective influences of PF against H 2 O 2 -induced damage and the underlying regulating mechanisms on hippocampal HT-22 cells. HT-22 cells were pretreated with PF, and then induced by H 2 O 2 . Afterwards, the influences of PF pretreatment were examined using CCK-8 assay, apoptosis assay, western blot and ROS assay, respectively. In addition, the expression of microRNA-135a (miR-135a) was analyzed and altered by qRT-PCR and cell transfection, respectively. After overexpression of miR-135a, the effects of miR-135a mimic on cell functions were detected again. Moreover, influences of H 2 O 2 , PF and miR-135a overexpression on JAK2/STAT3 and ERK1/2 signal pathways were further investigated. Further experiments verified that PF pretreatment alleviated H 2 O 2 -induced oxidative stress through increasing cell viability, inhibiting cell apoptosis, reducing ROS generation and activating JAK2/STAT3 and ERK1/2 pathways. Besides, expression of miR-135a was declined by PF pretreatment. Whereas, miR-135a mimic abrogated the protective effects triggered by PF pretreatment. These results indicated that PF can alleviate H 2 O 2 -induced oxidative stress by down-regulation of miR-135a via activation of JAK2/STAT3 and ERK1/2 pathways.
研究领域:
药理学
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神经科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Xiaoyong Dai,Yibo Hou,Ting Deng,Gaoyang Lin,Yuanxiong Cao,Guiyuan Yu,Wei Wei,Qing Zheng,Laiqiang Huang,Shaohua Ma
Triple-negative breast cancer (TNBC) is an aggressive cancer that poses a significant threat to women's health. Unfortunately, the lack of clinical targets leads the poor clinical outcomes in TNBC. Many cancers demonstrate overexpression of receptor for advanced glycation end products (RAGE), which can contribute to cancer progression. Despite the potential therapeutic value of blocking RAGE for TNBC treatment, effective peptide drugs have yet to be developed. In our study, we observed that RAGE was highly expressed in TNBC and was associated with poor disease progression. We subsequently investigated the antitumor effects and underlying mechanisms of the RAGE antagonist peptide RP7 in both in vitro and in vivo models of TNBC. Our study revealed that RP7 selectively binds to RAGE-overexpressing TNBC cell lines, including MDA-MB-231 and BT549, and significantly inhibits cell viability, migration, and invasion in both cell lines. Furthermore, RP7-treatment suppressed tumor growth in TNBC xenograft mouse models without inducing detectable toxicity in normal tissues. Mechanistically, RP7 was found to inhibit the phosphorylation of ERK1/2, IKKα/β, IKBα, and p65 to block the NF-κB pathway, prevent the entry of p65 into the nucleus, decrease the protein expression of Bcl-2 and HMGB1, and promote the release of cytochrome C from the mitochondria into the cytoplasm. These effects were observed to activate apoptosis and inhibit epithelial-mesenchymal transition (EMT) in TNBC cells. This study highlights RAGE as a candidate therapeutic target for TNBC treatment and suggests that the RAGE antagonist peptide RP7 is a promising anticancer drug for TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Xinyu Liu,Xiaofan Liu,Yuping Zhao,Yang Liu,Huimin Wang,Yi Li,Nan Ma,Hongchen Sun,Fermín E. González,Youliang Zhu,Junfeng Zhou,Yuewei Zhang,Ding Zhou,Xiaowei Xu
Insufficient nutrient and oxygen supply remains a critical barrier to cell survival and tissue regeneration in three-dimensional scaffolds. Here, we developed a self-supplying glucose/oxygen hydrogel (SGO-Gel) that intrinsically provides sustained metabolic support for dental pulp stem cells (DPSCs). The hydrogel was constructed by crosslinking oxidized dextran with phenylboronic acid-grafted carboxymethyl chitosan through dynamic Schiff-base and phenylboronic ester bonds, yielding an injectable, self-healing network capable of releasing glucose upon dextranase degradation. Polydopamine-coated calcium peroxide nanoparticles were incorporated to achieve controlled oxygen release while maintaining structural stability. SGO-Gel exhibited a uniform porous architecture that facilitated nutrient diffusion, as confirmed by molecular dynamics simulations. In vitro , the hydrogel significantly enhanced DPSCs survival under combined glucose starvation and hypoxia, maintaining viability above 70 % after 7 days compared to less than 30 % in control gels. Transcriptomic analysis revealed activation of the MAPK/Erk1/2 pathway and upregulation of VEGF, which was consistent with functional assays showing enhanced endothelial migration and tube formation. In an ectopic transplantation model, SGO-Gel promoted the formation of vascularized pulp-like tissue with abundant collagen deposition and odontoblast differentiation. Overall, SGO-Gel shifts the paradigm from passive scaffolds to metabolically active matrices, offering a promising strategy for dental pulp regeneration and broader tissue engineering applications where ischemia and limited vascularization remain key challenges.
研究领域:
组织工程
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再生医学
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干细胞生物学
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生物材料
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牙科研究
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产品关联
DOI
高影响因子
Annals of Translational Medicine
·
2020
·
IF 3.297
Li-Xuan Yang,Fang-Yu Chen,Hai-Long Yu,Pin-Yi Liu,Xin-Yu Bao,Sheng-Nan Xia,Yue Gu,Yun Xu,Xiang Cao
Background Based on accumulating evidence, excessive activation of microglia-mediated inflammatory responses plays an essential role in ischemic stroke. Poncirin (Pon) exerts anti-hyperalgesic, anti-osteoporotic and anti-tumor effects on various diseases. However, the roles of Pon in microglial activation and the underlying mechanism have not been elucidated. This study aimed to explore whether Pon inhibits lipopolysaccharide (LPS)-induced microglial neuroinflammation and protects against brain ischemic injury in experimental stroke in mice. Methods Primary microglia cells were prepared from the cerebral cortices of 1- to 2-day-old C57BL/6J mice. Murine BV2 cells and primary microglia were stimulated with LPS and the effects of a non-cytotoxic concentration of Pon on LPS-stimulated pro-inflammatory factors were measured using real-time PCR and enzyme-linked immunosorbent assays (ELISAs). Western blot analyses were used for mechanistic studies. In an in vivo study, 8-week-old male C57BL/6J mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). Pon (30 mg/kg, i.p.) or the same volume of saline was administered after the MCAO model was established, and the infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. We also evaluated animal behaviours, the expression of pro-inflammatory cytokines and microglial activation in the ischemic hemisphere. Results Pon prevented the release of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNF-α) in both BV2 cells and primary microglia stimulated with LPS. The inhibitory effects of Pon were associated with the regulation of the ERK1/2, JNK and nuclear factor kappa B (NF-κB) signaling pathways. In mice that underwent MCAO, Pon administration decreased the lesion size and improved neurological deficits. Furthermore, Pon attenuated the production of inflammatory cytokines mainly by restraining microglial activation after ischemic stroke. Conclusions Based on the findings from the present study, Pon provides neuroprotection through its anti-inflammatory effects on microglia and it may be a useful treatment for ischemic stroke.
研究领域:
神经科学
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药理学
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免疫学
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神经病学
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产品关联
DOI
PubMed
高影响因子
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