CELLULAR SIGNALLING
·
2025
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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
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肺病学
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职业医学
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DOI
PubMed
高影响因子
Cell and Bioscience
·
2024
·Vol. 14
·期 1
·1-18
·
IF 6.1
Maimaiti Yasenjiang,Su Ting,Zhang Zhanying,Ma Lingling,Zhang Yuan,Xu Hong
This study investigates NADPH oxidase 4 (NOX4) involvement in iron-mediated astrocyte cell death in Alzheimer’s Disease (AD) using single-cell sequencing data and transcriptomes. We analyzed AD single-cell RNA sequencing data, identified astrocyte marker genes, and explored biological processes in astrocytes. We integrated AD-related chip data with ferroptosis-related genes, highlighting NOX4. We validated NOX4’s role in ferroptosis and AD in vitro and in vivo. Astrocyte marker genes were enriched in AD, emphasizing their role. NOX4 emerged as a crucial player in astrocytic ferroptosis in AD. Silencing NOX4 mitigated ferroptosis, improved cognition, reduced Aβ and p-Tau levels, and alleviated mitochondrial abnormalities. NOX4 promotes astrocytic ferroptosis, underscoring its significance in AD progression.
研究领域:
神经科学
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分子生物学
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基因组学
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神经退行性疾病
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PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2023
·Vol. 69
·期 9
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IF 1.6
Aili Xuan,Mei Yang,Qun Xia,Qian Sun
Asthma is a respiratory inflammatory disease, and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is involved in the progression of respiratory diseases. However, the role of NOX4 in asthma remains unclear. In the present study, we aimed to explore the effects of NOX4 on airway remodeling and inflammation. NOX4 expression was measured using immunocytochemistry (IHC), western blot, and real-time PCR (qPCR). Lung tissues were stained using the H&E assay. ELISA was used to examine the levels of airway remodeling-related indicators, and qPCR was used to detect airway inflammatory factors. The results indicated that NOX4 is highly expressed in lung tissues, bronchoalveolar lavage fluid (BALF), and serum of OVA-treated mice. Inhibition of NOX4 alleviated OVA-induced airway remodeling and inflammation. Similarly, TGF-β1 was also upregulated in BALF and serum OVA-induced mice. Inhibition of TGF-β1 signaling also improved airway remodeling and inflammation induced by OVA. Moreover, the downregulation of NOX4 inactivated the TGF-β1-Smad2/3 pathway, and TGF-β1 decreased Smad2/3 expression. Moreover, inhibition of the TGF-β1 was enhanced, while TGF-β1 reversed the effects on airway remodeling and inflammation induced by NOX4 inhibition. Taken together, the downregulation of NOX4 improves airway remodeling and inflammation via inactivation of the TGF-β1-Smad2/3 pathway in asthma mice, suggesting that NOX4 may be a therapeutic target for asthma.
研究领域:
呼吸系统疾病
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
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2024
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IF 3
Di Li,Xuanyi Che,Ningning Gao,Jing Li
Previous studies have shown that the development of age-related cataract (ARC) is involved in lens epithelium dysfunction, which is associated with abnormally expressed circular RNAs (circRNAs). The current work aims to probe the role of circSTRBP (hsa_circ_0088,427) in hydrogen peroxide (H 2 O 2 )-induced lens epitheliums. Lens epithelium tissues were harvested from ARC or normal subjects (n = 23). CircSTRBP, spermatid perinuclear RNA binding protein (STRBP), and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, cycle progression, and apoptosis were assessed using 5-ethynyl-2′-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and flow cytometry assays. Caspase 3 activity, reactive oxygen species (ROS), malondialdehyde (MDA), and Glutathione peroxidases (GSH-PX) levels were detected using corresponding kits. NOX4 protein level was determined using Western blot. The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and circSTRBP or NOX4 was assessed through RNA immunoprecipitation (RIP). CircSTRBP and NOX4 abundances were increased in lens epithelium samples from ARC patients and H 2 O 2 -treated SRA01/04 cells. CircSTRBP knockdown might abolish H 2 O 2 -triggered SRA01/04 cell proliferation repression and apoptosis and oxidative stress promotion. In mechanism, circSTRBP is bound with IGF2BP1 and improves the stability and expression of NOX4 mRNA in SRA01/04 cells. CircSTRBP facilitated H 2 O 2 -induced SRA01/04 cell apoptosis and oxidative stress through by enhancing NOX4 mRNA stability via recruiting IGF2BP1, providing novel insights for ARC progression and treatment.
研究领域:
分子生物学
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细胞生物学
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眼科学
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生物化学
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PubMed
高影响因子
Scientific Reports
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2017
·Vol. 7
·期 1
·1-13
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IF 4.259
Zhao Wenwen,Feng Haitao,Guo Shuhui,Han Yantao,Chen Xiuping
ICAM-1 overexpression and subsequent adhesion of leukocytes to endothelial cells play critical roles in the early stage of atherosclerosis. Danshenol A (DA) is an abietane-type diterpenoid isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. The mechanisms under its regulation of adhesion of molecular expression are explored. Here, the effect of DA on TNF-α-induced ICAM-1 expression was investigated in endothelial cells. TNF-α-induced ICAM-1 expression and subsequent adhesion of monocytes, as well as elevated reactive oxygen species (ROS) generation and NOX4 expression were all significantly reversed by DA, siNOX4 and NOX4 inhibitor GKT137831. Furthermore, TNF-α-induced ICAM-1 expression, which was increased via IKKβ/IκBα-mediated activation of NF-κB p65, was also inhibited by DA. Interestingly, NOX4 overexpression suppressed the ICAM-1 expression, and this finding may be ascribed to the activation of Nrf-2. Additionally, NF-κB inhibitor PDTC, siNOX4, or DA can decrease the TNF-α-induced ICAM-1 expression and suppress the adhesion of monocytes. In all, DA inhibited TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion to endothelial cells through the NOX4-dependent IKKβ/NF-κB pathway. Besides, NOX4 played dual role in regulating ICAM-1 expression via diverse signal pathway. This novel bioactivity will make DA a good candidate to be further explored for therapeutic or preventive application for atherosclerosis.
研究领域:
药理学
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心血管疾病
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
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IF 8.3
Meiqi Wang,Beixuan Yang,Xin Li,Huanhuan Ma,Xia Ou,Zeren Dawa,Fangle Liu,Chenchen Zhu,Chaozhan Lin
Background Nonalcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of fat in the liver, has emerged as a leading cause of chronic liver diseases and malignancies. However, there remains a scarcity of approved therapeutic interventions. Brunodelphinine A (BruA) is a diterpenoid alkaloid isolated from Delphinium brunonianum Royle. in our previous study. It was evaluated with strong activity of lipid-lowering. Nevertheless, its precise effects and mechanisms in the treatment of NAFLD remain unexplored. Purpose The present study aims to elucidate the effects of BruA against NAFLD and to investigate its potential pharmacological mechanism. Methods The lipid-lowering and anti-NAFLD effects of BruA were evaluated in the free fatty acid (FFA)-induced cell model and high-fat diet (HFD)-induced mice. Network pharology analysis combined with Non-targeted metabolomics study was used to explore the key mechanism of BruA. Furthermore, molecular docking and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of BruA on the NADPH oxidase 4 (NOX4). The core role of NOX4 in BruA in regulating nicotinamide adenine dinucleotide (NAD + )/Sirtuin 1 (SIRT1) and peroxisome proliferators-activated receptors (PPARs) signaling pathway to improve oxidative stress and lipid metabolic disorders was further focused, and such mechanism was evaluated in WT and NOX4 knockout mice or HepG2 cells. Results BruA dose-dependently reduced FFA-induced lipid accumulation and cell damage in vitro , and mitigated HFD-induced NAFLD in mice. At the metabolite level, BruA improved metabolic disorder in NAFLD mice focusing on the metabolism of arachidonic acid and linolenic acid, which has been considered as signs of oxidative stress, that positively correlated with NAFLD. BruA targeting inhibited NOX4 to mitigate reactive oxygen species (ROS)-mediated oxidative stress and prevent abnormal redox levels, thereby regulating NAD + /SIRT1 in protecting the liver from oxidative damage, and further affected downstream PPARs-related lipid metabolism regulation processes, thus alleviating hepatic lipid accumulation. Furthermore, NOX4 deficiency suppressed the protective effect of BruA in vitro and in vivo . Conclusion BruA improved oxidative stress and lipid metabolic disorders of NAFLD by regulating the NOX4-SIRT1-PPARs signaling axis in vivo and in vitro , and this regulation is targeting dependent on NOX4. For its mechanisms of antioxidant stress and lipid-lowering, there is great therapeutic potential for BruA in the treatment of period with elevated lipids and inflammation production in NAFLD.
研究领域:
药理学
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生物化学
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分子生物学
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药物化学
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细胞生物学
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代谢组学
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药物研发
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肝病学
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DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
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2023
·
IF 8.8
Si-Yu Gui,Xin-Chen Wang,Zhi-Hao Huang,Mei-Mei Li,Jia-Hao Wang,Si-Yin Gui,Gan-Hua Zhang,Yao Lu,Li-Ming Tao,Hai-Sheng Qian,Zheng-Xuan Jiang
Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of VCAM-1, HIF-1α, and VEGF, causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H 2 O 2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy.
研究领域:
药学
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纳米技术
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眼科学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2024
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IF 3.3
Jianfeng Ye,Cheng Qiu,Lexi Zhang
Renal ischemia-reperfusion (I/R) injury leads mainly to acute kidney injury. Leucine-rich alpha-2-glycoprotein 1 (LRG) is upregulated in kidney tissues of mice after renal I/R injury. However, its role in renal I/R injury has not been fully elucidated. A mouse model of renal I/R injury was constructed by unilateral renal pedicle clamping and reperfusion. Mice undergoing I/R procedures exhibited renal function impairment and increased LRG protein expression compared with mice receiving sham operations. Tail vein injection with lentivirus carrying shLRG decreased renal I/R injury-induced increase in caspase-3 activity, IL-1β and IL-18 concentrations, and ROS production. Furthermore, shRNA-mediated LRG knockdown in HK-2 cells protected against H/R-induced cell damage. LRG could upregulate the expression of NADPH oxidase 4 (NOX4). We also determined the increased NOX4 expression in kidney tissues of renal I/R-operated mice and H/R-treated HK-2 cells. NOX4 overexpression reversed the inhibitory role of LRG knockdown in HK-2 cell damage caused by H/R. Collectively, our findings demonstrate that LRG knockdown decreases the NOX4 expression, thereby alleviating renal I/R injury by inhibiting cell apoptosis, inflammation, and oxidative stress.
研究领域:
肾病学
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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 RECEPTORS AND SIGNAL TRANSDUCTION
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2020
·
IF 1.466
Chongxia Huang,Du Liang,Chongbo Huang,Baolin Li,Jiandong He,Ximou Huang
Cadmium (Cd) has a direct toxic effect on bones. Statins such as simvastatin have protective effects on various diseases, including on tissue injury. The current study revealed the efficacy of simvastatin on Cd-induced preosteoblast injury. Preosteoblast MC3T3-E1 cells were incubated with various doses of CdCl2 for 12 h, 24 h and 48 h, and then the cell cytotoxicity was assessed using MTT assay and flow cytometry, respectively. The expression level of Nox4 was assessed by Western blot and qRT-PCR. The morphological appearance of MC3T3-E1 cells was observed under a microscope. Cells exposed to CdCl2 (5 µM) were further treated by simvastatin at various doses, subsequently cell viability, apoptosis and the expression of Nox4 were measured. Furthermore, to confirm the protective effects of simvastatin on Cd-induced pre-osteoblast injury, functional rescue assays were performed after corresponding cell treatment by simvastatin (10−8 M), CdCl2 (5 µM), and overexpression of Nox4. Expressions of cell apoptosis-related markers were measured by Western blot and qRT-PCR. The results revealed that CdCl2 caused MC3T3-E1 cell injury because the cell viability was decreased and the apoptosis was increased. Nox4 expression was up-regulated with the increase of CdCl2 concentrations. Simvastatin increased the cell viability, relieved the cell apoptosis and Nox4 expression previously increased by CdCl2. The effects of CdCl2 on MC3T3-E1 cells and Nox4 expression could be attenuated by simvastatin, and promoted by Nox4 overexpression. The current study found that simvastatin protects Cd-induced preosteoblast injury via Nox4, thus, it can be used as a potential drug for treating cadmium-induced bone injury.
研究领域:
药理学
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毒理学
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细胞生物学
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DOI
PubMed
高影响因子
TOXICOLOGY
·
2026
·
IF 4.6
Jin Chen,Hanwen Hu,Jing Fu,Yaolin He,Hui Zhou,Jingwei Lei,Ming Huang,Jianqi Wang,Anfei Liu,Zhenzhong Liu
Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities—including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Jie-Ru Hong,Chen-Yu Zhang,Wen-Jing Zhong,Hui-Hui Yang,Jian‑Bing Xiong,Ping Deng,Nan-Shi-Yu Yang,Hui Chen,Ling Jin,Cha-Xiang Guan,Jia-Xi Duan,Yong Zhou
Alveolar epithelial cell (AEC) senescence is considered to be a universal pathological feature of many chronic pulmonary diseases. Our previous study found that epoxyeicosatrienoic acids (EETs), produced from arachidonic acid (ARA) through the cytochrome P450 cyclooxygenase (CYP) pathway, have significant negative regulatory effects on cellular senescence in AECs. However, the exact mechanisms by which EETs alleviate the senescence of AECs still need to be further explored. In the present study, we observed that bleomycin (BLM) induced enhanced mitophagy accompanied by increased mitochondrial ROS (mito-ROS) content in the murine alveolar epithelial cell line MLE12. While EETs reduced BLM-induced mitophagy and mito-ROS content in MLE12 cells, and the mechanism was related to the regulation of NOX4/Nrf2-mediated redox imbalance. Furthermore, we found that inhibition of EETs degradation could significantly inhibit mitophagy and regulate NOX4/Nrf2 balance to exert anti-oxidant effects in D-galactose-induced premature aging mice. Collectively, these findings may provide new ideas for treating age-related pulmonary diseases by targeting EETs to improve mitochondrial dysfunction and reduce oxidative stress.
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DOI
PubMed
高影响因子
Redox Biology
·
2018
·
IF 7.126
Dong Hou,Zhaojian Liu,Xiuhua Xu,Qiao Liu,Xiyu Zhang,Beihua Kong,Jian-Jun Wei,Yaoqin Gong,Changshun Shao
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.
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
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