Journal of Advanced Research
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2025
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IF 13
Qu-Nan Wang,Chunzhi Wang,Yán Wāng
Introduction The extensive use of 6PPD in tire rubber has led to its increase in atmospheric tire wear particles. 6PPD reacts with ozone to form 6PPD-quinone (6PPD-Q), a respiratory toxicant enriched in tire and road wear particles. Objectives The aim of this study is to decipher the potential sensitive target organs and toxic actions by inhalation exposure to atmospheric 6PPD-Q. Methods This study employed a mouse inhalation exposure model to simulate environmental levels of 6PPD-Q at three concentrations of 0, 0.14, and 14 mg/m 3 . Using a 28-day exposure period followed by an equivalent recovery phase, we systematically evaluated the toxicological targets and effects of subacute exposure. Results The findings revealed that, compared to pulmonary, cardiovascular, and metabolic organ damage, 6PPD-Q-induced neurotoxicity was more persistent and irreversible, particularly characterized by prolonged anxiety-like behaviors. Histopathological analyses of the basolateral amygdala, using Nissl staining and markers of neuronal aging, indicated substantial neuronal degeneration linked to elevated oxidative stress, identifying this region as a critical target of 6PPD-Q neurotoxicity. Transcriptomic analysis uncovered that the expression of Egr1 , a transcription factor crucial for neuronal plasticity, was markedly dysregulated. Findings of significant downregulation at the gene level and an upward trend in protein expression suggest that Egr1 expression is influenced by translational efficiency, epigenetic modifications, and post-translational regulatory mechanisms. Egr1 dysregulation disrupted downstream networks involving solute carrier proteins and calcium-binding proteins, contributing to aberrant neurobehavioral outcomes. Notably, the elevation of Egr1 protein levels in the basolateral amygdala but not in the cerebral cortex highlights the region-specific nature of 6PPD-Q’s neurotoxic effects. Conclusion This study provides the first insights into the neurotoxicity and irreversibility of inhaled 6PPD-Q exposure, paving the way for future research into the long-term neurological consequences and regulatory mechanisms of 6PPD-Q.
研究领域:
毒理学
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神经科学
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环境健康
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PubMed
高影响因子
JOURNAL OF BONE AND MINERAL RESEARCH
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2026
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IF 6.5
Guo Xufei,Yan Lingyun,Niu Jiaxin,Ding Yuzhe,Nie Yongshuai,Chen Zhi,Yuan Guohua,Yang Guobin
Dentinogenesis is a highly coordinated process orchestrated by odontoblasts that is not only critical for tooth development but also essential for pulp vitality after injury. Although the signaling pathways regulating this process have been well characterized, it remains elusive how dentinogenesis is epigenetically regulated during tooth development and adulthood. Here, we show that nuclear receptor binding SET domain protein 1 (NSD1), a histone methyltransferase catalyzing the dimethylation of histone H3 at lysine 36 (H3K36me2), exhibits dynamic spatiotemporal expression patterns during odontoblast differentiation as well as injury response. Conditional knockout of Nsd1 in the odontoblasts of neonatal mice, driven by rAAV6-Col2.3-Cre, led to decreased dentin thickness, defective mineral deposition, and the downregulation of odontoblast differentiation markers. Consistently, Nsd1 deletion in adult mice impaired reactionary dentin formation after injury. Mechanistically, transcriptomic profiling of mouse dental papilla cells identified early growth response 1 (EGR1) as a key downstream target of NSD1, which in turn modulated the expression of many genes downregulated upon Nsd1 knockdown by RNA-seq analysis. The Egr1 locus was tightly enriched with H3K36me2, which controlled its expression and further activated Col1a1, an extracellular matrix component. Upon injury, the expression of NSD1/H3K36me2 and EGR1 was rapidly induced to facilitate reactionary dentinogenesis to protect the inner dental pulp. Collectively, our findings support a potential role for the NSD1/H3K36me2–EGR1 axis in initiating both primary and reactionary dentin matrix formation.
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JOURNAL OF HUMAN HYPERTENSION
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2020
·Vol. 35
·期 8
·696-708
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IF 2.26
Lv Lingchun,Shen Jiayi,Xu Jian,Wu Xiaoyan,Zeng Chunlai,Lin Li,Mao Wei,Wei Tiemin
Through previous literature studies, we found that miR-124-3p may be associated with hypertension. Therefore, we investigated the relationship between miR-124-3p and hypertension in Human Umbilical Vein Endothelial Cells (HUVECs) induced by angiotensin II (AngII). AngII-induced HUVECs model was constructed and the expression of miR-124-3p was detected by qRT-PCR. After transfected cells, apoptosis and ROS production were detected by flow cytometry, caspase-3 kit, and DCFH-DA staining. The target genes of miR-124-3p were predicted and verified by TargrtScan, Luciferase assay, qRT-PCR, and western blot. After silencing Early growth response factor 1 (siEGR1), its effects on apoptosis and ROS production were explored. Finally, the rescue experiments were conducted to explore the mechanism of miR-124-3p to reduce hypertension. MiR-124-3p was underexpressed in the cell model. In Ang II-induced HUVECs, the number of apoptosis increased, the content of caspase-3 was higher, and ROS production increased. However, these effects could be partially inhibited by miR-124-3p mimic. EGR1 was down-regulated by miR-124-3p, and siEGR1 was able to inhibit apoptosis and ROS production of cell model. In the final rescue experiments, miR-124-3p partially reversed the effect of Ang-II on the viability, migration, invasion and apoptosis and ROS production in HUVECs by down-regulating EGR1. MiR-124-3p inhibits Ang II-induced apoptosis and ROS production in HUVECs by down-regulating EGR1.
研究领域:
心血管研究
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分子生物学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Xiaotian Gao,Xiaoniao Chen,Luying Qiao,Yingtao Zhang,Xiaoling Liu,Sifan Yang,Yan Zheng,Xun Chen,Xu Wang,Ran Liu,Zheyi Dong,Qian Wang,Quan Hong
Ethnopharmacological relevance Formononetin (FMN) is a natural isoflavone found in several medicinal plants. Its effects on diabetic retinal and renal microvascular injury and EGR1/VEGF-related endothelial responses remain incompletely defined. Aim of the study To assess whether FMN attenuates early diabetes-associated retinal and renal injury and whether EGR1 is involved. Materials and methods Alloxan-induced diabetic rabbits received FMN orally at 25 mg/kg/day from Week 4 to Week 16 after pretreatment renal and OCT/OCTA assessment. Renal function, histopathology, retinal flat mounts, longitudinal OCTA, and tissue EGR1/VEGF expression were examined. High-glucose-treated retinal, renal microvascular, and umbilical vein endothelial cells were used for functional assays. EGR1 overexpression, VEGFA promoter reporter assays, SPR, docking, and molecular dynamics simulations were also performed. Results FMN lowered serum creatinine, blood urea nitrogen, and urinary albumin-to-creatinine ratio, and reduced renal histopathological injury. It also attenuated retinal capillary loss, retinal thinning, and OCTA abnormalities despite persistent hyperglycemia. Retinal and renal tissues from FMN-treated rabbits showed lower EGR1 and VEGF expression. In endothelial cells, FMN reduced EGR1 and VEGF expression, abnormal tube formation, permeability, invasion, ROS, and inflammatory mediator release, while increasing NO-related signals. EGR1 overexpression weakened several effects and increased VEGFA promoter activity through the predicted EGR1-binding sequence. SPR detected FMN–EGR1 binding with a K_D of 3.245 μM. Computational analyses provided structural context. Conclusions FMN attenuated early diabetes-associated retinal and renal injury and was linked to EGR1/VEGF-related endothelial responses. The data support EGR1 involvement but do not establish it as the sole target or mediator of FMN.
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CELL BIOLOGY INTERNATIONAL
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2026
·Vol. 50
·期 1
·e70127
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IF 3.1
Yiming Weng,Yanqiu Wang,Jun Xiang,Denglong Wu,Wei Le
Spermatogonial stem cells (SSCs) are essential for maintaining sperm production but are highly susceptible to damage from testicular ischemia-reperfusion (IR) injury, a common consequence of conditions like testicular torsion. This injury leads to oxidative stress, disruption of the blood-testis barrier (BTB), and germ cell death. While the transcription factor EGR1 is known to promote SSC survival in laboratory settings, its protective mechanisms within a living organism remained unclear. This study aimed to identify the downstream targets through which EGR1 confers protection against IR injury. Through bioinformatic analysis, a potential binding site for EGR1 was discovered in the promoter of the Nudt16L1 gene. A series of experiments, including chromatin immunoprecipitation and luciferase reporter assays, confirmed that EGR1 directly binds to this site and activates Nudt16L1 expression. In a mouse model of testicular IR injury, overexpression of EGR1 was found to alleviate tissue damage, improve sperm motility, and preserve the integrity of the BTB. Crucially, when Nudt16L1 was experimentally silenced, the protective benefits of EGR1 were lost. Conversely, overexpressing Nudt16L1 alone was sufficient to mimic EGR1's protective effects, reducing reactive oxygen species and preventing cell death in SSCs subjected to oxygen-glucose deprivation/reperfusion, an in vitro model of IR. In conclusion, this research identifies Nudt16L1 as a critical downstream effector of EGR1. The EGR1-Nudt16L1 signaling axis protects SSCs from IR injury by mitigating oxidative stress, maintaining BTB integrity, and inhibiting apoptosis. These findings highlight this pathway as a promising therapeutic target for preventing infertility resulting from testicular torsion and similar ischemic events.
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PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Du Ailin,Chen Yingying,Qiao Siyu,Dong Jiaxing,Li Yulin,Cao Bokai,Zhao Rongyu,Zhang Ruiling
Introduction: Chronic alcoholism is one of the most common neurological diseases in modern society. However, the key mechanisms underlying learning and memory impairments caused by chronic alcohol exposure remain unclear. In this study, a microRNA-messenger RNA (miRNA-mRNA) network was constructed to explore the potential function of key genes in chronic alcohol exposure, their effects on the hippocampus, and their mechanisms which facilitate brain injury in mice.Methods: The Morris water maze test was used to assess the learning ability of mice in each group. Mitochondrial ATPase activity and H2S levels in the hippocampi of mice were determined. Differentially expressed miRNAs and mRNAs in the mouse hippocampus were identified using second-generation sequencing. Using the TargetScan, miRTarBase, and miRDB databases, we predicted miRNA target genes and constructed a miRNA-mRNA regulatory network. Furthermore, using the Gene Ontology and KEGG databases we performed functional enrichment and protein-protein interaction analyses. Real-time quantitative polymerase chain reaction (qPCR) and other methods were employed to verify the mRNA expression of related genes.Results: The Morris water maze test revealed that mice exposed to chronic alcohol exhibited a significantly reduced learning ability compared to the control group (p < 0.05). Compared with the control group, the activity of mitochondrial ATPase in the hippocampal tissue of alcohol-treated mice was significantly decreased (p < 0.01), suggesting brain injury. In the model group, H2S significantly increased in the mice hippocampi (p < 0.01), indicating that chronic alcohol exposure could activate cystathionineβ-synthase (CBS) and catalyze the mass formation of H2S, suggesting brain injury. A total of 208 differentially expressed miRNAs and 377 differentially expressed mRNAs were screened through bioinformatic analysis. Enrichment analysis indicated that the main pathways were involved in neurodegeneration and regulation of the Wnt signaling pathway. The PCR detected a significant downregulation in the expressions of FOS and EGR1 genes.Discussion: Consequently, chronic alcohol exposure may regulate the expression of FOS and EGR1 in the hippocampus through miR-222-3p, miR-132-3p, miR-212-3p, and miR-191-5p, reduce the activity of hippocampal mitochondrial ATPase, activate CBS, catalyze the large amount of H2S formation, and destroy the mitochondrial structure, resulting in decreased learning ability. Our findings revealed valuable genes and miRNAs for the study of chronic alcohol exposure.
研究领域:
神经生物学
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分子生物学
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生物信息学
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2022
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IF 16.744
Weipan Peng,Shenghui Li,Yating zhang,Qiuting Zhang,Wenna Li,Houyu Han,Dianming Zhou,Sheng Wang,Jin Chang,Xiaoqun Gong
Tumors progression is usually characterized by proliferation, migration, and angiogenesis , and it leads to uncontrolled tissue growth and blocks the mechanism of apoptosis. Therefore, targeted angiogenesis and anti-apoptosis is considered promising therapeutic strategy for cancer prevention and treatment. Herein, we report a versatile and intelligent MnO 2 -PEI-DNAzymes (MnPDs) nanodevice for self-sufficient anti-tumor angiogenesis and pro-apoptosis synergistic gene silencing, coupling multi-target bimodal in situ imaging. Intracellularly, the multifunctional charge-reversal MnPDs undergo reduction and lysis by the overexpressed GSH, actualizing enhanced MR imaging and sufficient DNAzyme cofactors in tumor tissue, and enabling miRNA-155 and telomerase biomarkers dual-fluorescence imaging. Under the precise multimodal imaging, the dual DNAzymes enable self-sufficient Early growth response-1 (EGR1) and Survivin (SUR) mRNAs synergistic silencing, effectively inhibiting tumor angiogenesis and anti-apoptotic. Considering that accurate and efficient therapy has become a trend in cancer therapy, our proposed self-sustaining multifunctional nanodevice is promising for broad clinical applications.
研究领域:
癌症生物学
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纳米技术
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基因治疗
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分子成像
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生物医学工程
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高影响因子
ACS Nano
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2024
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IF 15.8
Jiayin Fu,Ning Zhang,Changfu Xu,Meng Zhao,Shaofei Wu,Shihui Xu,Xulin Hong,Meihui Wang,Guosheng Fu
Synthetic vascular grafts are promising conduits for small caliber arteries. However, due to restenosis caused by intimal hyperplasia, they cannot keep long patency in vivo. In this work, through single cell RNA sequencing, we found that thrombospondin-1 (THBS1) was highly expressed in the regenerated smooth muscle cells (SMCs) in electrospun polycaprolactone (PCL) vascular grafts. The expression of THBS1 by injured SMCs was confirmed in a balloon-induced vascular injury model. Downregulation of Thbs1 expression maintained contractile phenotypes of SMCs and reduced neointimal hyperplasia after vascular injury via inhibition of FGFR1/EGR1 signaling by decreasing THBS1 expression. THBS1 small interfering RNA (THBS1-siRNA) was then loaded into macrophage membrane (MM) hybrid lipid nanoparticles (Lipid NP@MM), which were used to modify PCL vascular grafts via polydopamine (PDA) coatings. Lipid NP@MM not only protected THBS1-siRNA from degradation but also improved its internalization by SMCs to decrease the level of THBS1 expression. PCL vascular grafts modified with PDA coatings and Thbs1-siRNA-loaded Lipid NP@MM showed significantly reduced intimal hyperplasia. Thus, the downregulation of THBS1 expression in regenerated SMCs in vascular grafts is a promising strategy to inhibit intimal hyperplasia during vascular graft regeneration in vivo.
研究领域:
生物材料
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组织工程
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血管生物学
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分子生物学
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纳米技术
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DOI
PubMed
高影响因子
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