AMERICAN JOURNAL OF CHINESE MEDICINE
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2019
·Vol. 47
·期 05
·1113-1131
·
IF 3.51
Li-Ying Peng,Lin An,Ning-Yuan Sun,Yi Ma,Xiao-Wei Zhang,Wen-Hua Liu,Bao-Lin Liu,Ping Li,Jun Chen
Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF- β 1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF- β 1/Smad3 signaling by downregulating protein kinase C delta (PKC- δ ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF- β 1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo , which might be associated with activation of Nrf2 pathway and inhibition of TGF- β 1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.
研究领域:
药理学
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肺科学
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分子生物学
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氧化应激研究
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 11
·5269-5282
·
IF 5.31
Jian Shen,Ganglei Li,Yu Zhu,Qingsheng Xu,Hengjun Zhou,Kangli Xu,Kaiyuan Huang,Renya Zhan,Jianwei Pan
The blood-brain barrier (BBB) damage is a momentous pathological process of ischaemic stroke. NADPH oxidases 4 (NOX4) boosts BBB damage after ischaemic stroke and its expression can be influenced by microRNAs. This study aimed to probe into whether miR-92b influenced the BBB damage after ischaemic stroke by regulating NOX4 expression. Here, miR-92b expression was lessened in the ischaemic brains of rats and oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs). In middle cerebral artery occlusion (MCAo) rats, miR-92b overexpression relieved the ameliorated neurological function and protected the BBB integrity. In vitro model, miR-92b overexpression raised the viability and lessened the permeability of OGD-induced BMECs. miR-92b targeted NOX4 and regulated the viability and permeability of OGD-induced BMECs by negatively modulating NOX4 expression. The transcription factor Foxo1 bound to the miR-92b promoter and restrained its expression. Foxo1 expression was induced by OGD-induction and its knockdown abolished the effects of OGD on miR-92b and NOX4 expressions, cell viability and permeability of BMECs. In general, our findings expounded that Foxo1-induced lessening miR-92b boosted BBB damage after ischaemic stroke by raising NOX4 expression.
研究领域:
神经科学
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分子生物学
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病理学
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高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2019
·
IF 5.657
Xiao-Xue Li,Sun-Kai Ling,Ming-Yue Hu,Yu Ma,Yuan Li,Pei-Lin Huang
The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an α-glucosidase inhibitor that suppresses postprandial hyperglycemia , however, the cardiovascular protection of acarbose has still remained controversial. NLRP3 inflammasome activation mediated tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. Given the anti-inflammatory property of acarbose, it was investigated that acarbose protected against vascular endothelial barrier dysfunction through inhibiting NLRP3 inflammasome in vascular endothelial cells in T2DM rats. The rat aortic endothelial cells (RAECs) were incubated with high glucose (HG, 30 mM) for 24 h in vitro. It was found that HG significantly induced the formation and activation of NLRP3 inflammasome, which was markedly blocked by acarbose treatment. Furthermore, acarbose blocked the Nox4-dependent superoxide (O 2 .- ) generation, which regulated NLRP3 inflammasome in RAECs. Importantly, we found that acarbose remarkably enhanced the junction protein expression of ZO-1 and VE-Cadherin and consequently abolished vascular hyperpermeability, which was associated with inhibiting NLRP3 inflammasome in RAECs. In vivo, acarbose intervention relieved vascular leakage in the heart of diabetic rats injected with Evans blue dye and the vasodilatory response to acetylcholine , which was accompanied with the restoration of ZO-1, VE-Cadherin, Nox4 and NLRP3 inflammasome in the aortal endothelium of diabetic rats. Taken together, our data indicated that acarbose ameliorated endothelial barrier dysfunction by directly inhibiting NLRP3 inflammasome which was dependent on inhibiting Nox4 oxidase-dependent O 2 .- production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.
研究领域:
药理学
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心血管科学
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糖尿病研究
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分子生物学
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PubMed
高影响因子
Current Research in Food Science
·
2022
·
IF 6.269
Xuan Chen,Liufeng Zheng,Bing Zhang,Zeyuan Deng,Hongyan Li
Oxidative stress is a potential factor in the promotion of endothelial dysfunction. In this research, flavonoids (quercetin, luteolin) combined with carotenoids (lycopene, lutein), especially quercetin-lycopene combination (molar ratio 5:1), prevented the oxidative stress in HUVEC cells by reducing the reactive oxygen species (ROS) and suppressing the expression of NADPH oxidase 4 (Nox4), a major source of ROS production. RNA-seq analysis indicated quercetin-lycopene combination downregulated inflammatory genes induced by H 2 O 2 , such as IL-17 and NF-κB. The expression of NF-κB p65 was activated by H 2 O 2 but inhibited by the quercetin-lycopene combination. Moreover, the quercetin and lycopene combination promoted the thermostability of Sirtuin 1 (SIRT1) and activated SIRT1 deacetyl activity. SIRT1 inhibitor EX-527 attenuated the inhibitory effects of quercetin, lycopene, and their combination on the expression of p65, Nox4 enzyme, and ROS. Quercetin-lycopene combination could interact with SIRT1 to inhibit Nox4 and prevent endothelial oxidative stress, potentially contributing to the prevention of cardiovascular disease.
研究领域:
药理学
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分子生物学
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细胞生物学
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心血管研究
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高影响因子
TOXICOLOGY LETTERS
·
2017
·
IF 3.858
Huaicheng Chen,Zongming Song,Shilong Ying,Xi Yang,Wei Wu,Qiufan Tan,Xin Ju,Wencan Wu,Xin Zhang,Jia Qu,Yi Wang
Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Müller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Müller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.
研究领域:
眼科学
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免疫学
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分子生物学
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药理学
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PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2018
·
IF 6.02
Qing Li,Jie Su,Shi-Jie Jin,Wei Wei,Xiao-dong Cong,Xiao-Xue Li,Ming Xu
Background Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in type 2 diabetes mellitus (T2DM). Therefore, there are great potential clinical implications in developing pharmacological interventions targeting endothelial insulin resistance. Our previous studies indicated that argirein which was developed by combining rhein with L -arginine by a hydrogen bond , could substantially relieved stress related exacerbation of cardiac failure and alleviated cardiac dysfunction in T2DM, which was associated with suppressing NADPH oxidase activity. However, it is unclear whether argirein treatment attenuates the vascular lesion and dysfunction in T2DM and its underlying mechanisms. Methods and results The rat aortic endothelial cells (RAECs) were used to treat with palmitic acid (PA), a most common saturated free fatty acid , which could induce insulin resistance. It was showed that argirein increased glucose uptake and glucose transporter-4 (Glut4) expression and reversed the phosphorylation of IRS-1-ser307 and AKT-ser473, consequently resulting in the increase of the production of eNOS and NO in PA-induced RAECs. We further found that argirein blocked the Nox4-dependent superoxide (O 2 -. ) generation, which regulated glucose metabolism in RAECs during PA stimulation. In vitro, argirein increased the release of endothelial NO to relieve the vasodilatory response to acetylcholine and insulin, and restored the expression of Nox4 and pIRS-1-ser307 in the aorta endothelium of high-fat diet (HFD)-fed rats following an injection of streptozocin (STZ). Conclusion These results suggested that argirein could improve endothelial insulin resistance which was attributed to inhibiting Nox4-dependent redox signaling in RAECs. These studies thus revealed the novel effect of argirein to prevent the vascular complication in T2DM.
研究领域:
药理学
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内分泌学
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心血管科学
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糖尿病研究
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2026
·
IF 7
Zenni Chen,Zifeng Zhuang,Shaozi Lin,Yuting Hao,Xiaokang Xie,Hongling Chen,Lan Lin,Yixuan Li,Lili Fan,Shiquan Chang,Guoping Zhao,Di Zhang
BackgroundSciatica causes severe pain and impaired mobility. Neuroinflammation is involved in the development of sciatica.PurposeThis study aimed to explore whether Gallic acid (GA) reduces neuroinflammation to relieve sciatica by regulating NOX4-mediated oxidative stress.MethodsAfter scRNA-seq analysis was performed, 32 SD (Sprague-Dawley) rats were randomly divided into 4 groups: sham operation, chronic constriction injury (CCI), CCI+mecobalamin, and CCI+GA groups. We conducted behavioral tests, ELISA, western blotting, and immunofluorescence analysis. In cell experiments, we conducted ROS measurement, flow cytometry, PCR, and western blotting.ResultsscRNA-seq analysis revealed that gene signatures related to the “inflammatory response” and “oxidative stress” were significantly enriched, with higher module scores observed specifically in M1 macrophages. In RAW264.7 cells, LPS stimulation significantly increased ROS generation and MDA levels and upregulated the expression of M1 macrophage markers, including IL-1β, iNOS, TNF-α, and CD32. In addition, LPS increased the protein expression of NOX4 and inflammatory mediators (TNF-α, IBA-1, IL-1β, COX-2, and iNOS) while reducing the levels of ATF4 and p-Nrf2. GA treatment reduced ROS generation and MDA levels; downregulated the mRNA expression of IL-1β, iNOS, TNF-α, and CD32; and increased CD206 mRNA expression. Similarly, GA decreased the protein levels of NOX4, TNF-α, IBA-1, IL-1β, COX-2, and iNOS but restored the expression of ATF4 and p-Nrf2. In CCI rats, GA significantly attenuated thermal hyperalgesia from Day 7 to Day 21, with thermal withdrawal thresholds recovering toward sham control levels. CCI markedly increased IL-8, COX-2, TNF-α, TGF-β, IL-6, and IL-1β levels in the sciatic nerve; increased IBA-1/CD32 coexpression; decreased IBA-1/CD206 coexpression; and markedly disrupted sciatic nerve architecture. These pathological changes were accompanied by elevated expression of IBA-1, NOX4, IL-1β, and iNOS, together with reduced ATF4 and p-Nrf2 levels. Notably, GA treatment largely reversed these CCI-induced alterations.ConclusionGA alleviated sciatica in a rat model, possibly through its ability to promote the polarization of proinflammatory M1 macrophages toward anti-inflammatory M2 macrophages via the regulation of NOX4-mediated oxidative stress.
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LIFE SCIENCES
·
2025
·
IF 5.1
Qian Chen,Huaxing Zhang,Yuhong Chen,Yangxuan Peng,Yuhan Yao,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xu Teng,Mingqi Zheng,Bing Xiao,Yuming Wu,Sheng Jin
Aims The present study aimed to investigate the direct link between trimethylamine N-oxide (TMAO) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Materials and methods Diastolic dysfunction is the main manifestation of HFpEF, so the “two-hit” mouse HFpEF model are used. After treated with high-fat diet (HFD) and N [w] -nitro-l-arginine methyl ester (L-NAME) for 8 weeks, the cardiac function, myocardial fibrosis, oxidative stress levels, and molecular alterations were assessed. Key findings The HFpEF mice displayed a declined diastolic function, characterized by an increase in the E/E' ratio, accompanied by a significant increase in plasma brain natriuretic peptide levels and cardiac fibrosis and down-regulation of SERCA2 expression, while, DMB treatment improved diastolic function. Subsequently, TMAO was injected intraperitoneally into the mice for 1 month and found that TMAO induced diastolic dysfunction. In addition, we found that either the HFD and L-NAME or TMAO treatment down-regulated Piezo1 expression, and the cardiomyocyte-specific Piezo1 knockout mice (Piezo1 ΔCM ) also had diastolic dysfunction. Moreover, the NOX4 expression was up-regulated and the reactive oxygen species levels were increased in the heart tissues of Piezo1 ΔCM or TMAO-treated mice, which was reversed by a Piezo1 activator (Yoda1) in the TMAO-treated mice. Yoda1 also reversed diastolic dysfunction in the HFpEF mice. Significance In conclusion, our data revealed that TMAO-induced oxidative stress injury by down-regulating Piezo1 to be involve in cardiac diastolic dysfunction of HFpEF. It should be noted that this preclinical study did not evaluate HFpEF-related symptoms such as exercise intolerance or pulmonary congestion, which warrant further validation.
研究领域:
心脏病学
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分子生物学
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药理学
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产品关联
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PubMed
高影响因子
Immunity Inflammation and Disease
·
2023
·Vol. 11
·期 4
·e820
·
IF 3.2
Mingfei Li,Huifang Wang,Yun Lu,Jinwen Cai
Introduction Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation that predominantly affects the lung and peripheral airways. Previous investigation has underlined the efficacy of luteolin in the treatment of inflammation-related symptoms. Accordingly, our study concentrates on unveiling the effect of luteolin on COPD. Methods Mice or A549 cells were treated with cigarette smoke (CS) to establish COPD models in vivo and in vitro. Then, the serum and bronchoalveolar lavage fluid of mice were harvested. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of damage. The inflammation and oxidative stress factors level were calculated via enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. The expressions of nuclear factor-kappa B (NF-κB) pathway-related factors were detected by Western blot. Results In in vivo experiments, CS treatment reduced the weight of mice and promoted lung tissue damage, while luteolin attenuated the effect of CS on the mice. Moreover, luteolin inhibited the inflammation factors level, oxidative stress, and NADPH oxidase 4 (NOX4)-mediated NF-κB signaling pathway in CS-induced COPD mice. Similar results were obtained in in vitro experiments that luteolin alleviated CS-induced inflammation, oxidative stress, and NOX4-mediated NF-κB signaling pathway activation in CS-treated A549 cells. Besides, NOX4 overexpression offset the impacts of luteolin on the CS-induced A549 cells. Conclusion Luteolin alleviates inflammation and oxidative stress in COPD via NOX4-mediated NF-κB signaling pathway, which provides a theoretical basis for the treatment of COPD with luteolin.
研究领域:
药理学
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肺病学
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分子生物学
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PubMed
高影响因子
Food Production Processing and Nutrition
·
2026
·Vol. 8
·期 1
·72
·
IF 6.3
Niu Ruge,Xu Zhongchi,Yang Wenli,Bao Tong,Xu Fengsheng,Zhou Wenqi,Zhang Long,Jia Qi,Wang Xiaolong,Chen Jiandong,Lin Xin
Radiotherapy is a standard treatment for thoracic malignancies, but it frequently leads to radiation‑induced heart disease (RIHD), a serious and dose‑limiting complication for which no targeted therapies are currently available. Total extracts from Abelmoschus manihot (L.) (TEA), known for their cardioprotective properties, are widely used in treating various ischemic heart diseases. Here, we identify ferroptosis driven by the NOX4/SLC7A11/GPX4 axis as a core mechanism of RIHD, with GPX4 serving as the non‑redundant downstream executor. TEA effectively modulates this axis; however, it lacks cardiac selectivity, which may compromise antitumor efficacy. To overcome this barrier, we developed, characterized, and evaluated a novel nanoplatform consisting of TEA‑loaded PLGA nanoparticles conjugated with a primary cardiomyocyte‑specific homing peptide (PCM), further integrated with low-intensity focused ultrasound (LIFU)‑triggered on‑demand release (TEA@PLGA‑PCM). This system achieves superior myocardial accumulation, effectively improves cardiac function, reverses pathological remodeling, and normalizes ferroptosis markers as well as NOX4/SLC7A11/GPX4 protein expression. In summary, we successfully constructed a novel nanoplatform that represents a promising strategy for integrated targeted delivery and synergistic therapy in RIHD management. Graphical
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JOURNAL OF CELLULAR BIOCHEMISTRY
·
2019
·Vol. 120
·期 10
·18509-18523
·
IF 3.448
Yujie Yao,Xueyuan Hu,Xiujing Feng,Yuan Zhao,Manyu Song,Chaoran Wang,Honggang Fan
Dexmedetomidine (DEX) prevents kidney damage caused by sepsis, but the mechanism of this effect remains unclear. In this study, the protective molecular mechanism of DEX in lipopolysaccharide (LPS)-induced acute kidney injury was investigated and its potential pharmacological targets from the perspective of inhibiting oxidative stress damage and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. Intraperitoneal injection of DEX (30 μg/kg) significantly improved LPS (10 mg/kg) induced renal pathological damage and renal dysfunction. DEX also ameliorated oxidative stress damage by reducing the contents of reactive oxygen species, malondialdehyde and hydrogen peroxide, and increasing the level of glutathione, as well as the activity of superoxide dismutase and catalase. In addition, DEX prevented nuclear factor-kappa B (NF-κB) activation and I-kappa B (IκB) phosphorylation, as well as the expressions of NLRP3 inflammasome-associated protein and downstream IL-18 and IL-1β. The messengerRNA (mRNA) and protein expressions of toll-like receptor 4 (TLR4), NADPH oxidase-4 (NOX4), NF-κB, and NLRP3 were also significantly reduced by DEX. Their expressions were further evaluated by immunohistochemistry, yielding results were consistent with the results of mRNA and protein detection. Interestingly, the protective effects of DEX were reversed by atipamezole-an alpha 2 adrenal receptor (α 2 AR) inhibitor, whereas idazoxan-an imidazoline receptor (IR) inhibitor failed to reverse this change. In conclusion, DEX attenuated LPS-induced AKI by inhibiting oxidative stress damage and NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF-κB pathway, mainly acting on the α 2 AR rather than IR.
研究领域:
药理学
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免疫学
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肾脏生理学
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分子生物学
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Lijun Fang,Linmao Lyu,Hongyu Zhong,Jiamao Lin,Pengtao Ren,Yu Wang,Yunhong Yin,Mengyu Zhang,Yiqing Qu
Idiopathic pulmonary fibrosis (IPF) is a kind of chronic and progressive interstitial lung disease of unclear aetiology. A key aspect of IPF is transforming growth factor-β1 (TGF-β1)-induced mitophagy dysfunction and senescence in lung fibroblasts. Mesenchyme homeobox 1 (MEOX1) is a critical transcription factor in the regulation of cell differentiation. However, the role of MEOX1 in the pathogenesis of lung fibrosis and mitophagy has not been clarified. In this study, RNA-sequencing analysis was employed to identify the differentially expressed genes in TGF-β1-treated lung fibroblasts and IPF lung tissue. In vivo , the mouse model of lung fibrosis was established by intratracheal injection of bleomycin (BLM), and fibroblast-specific knockdown of MEOX in mice was achieved by intratracheal injection of adeno-associated viruse-shMEOX1. And in vitro experiments were also carried out on human lung fibroblasts. Our results indicated that fibroblast-specific knockdown of MEOX1 protected mice from BLM-induced pulmonary fibrosis, connective tissue growth factor (CTGF) expression, and lung fibroblast activation, as well as mitophagy deficiency and senescence. In vitro , MEOX1 knockdown abolished TGF-β1-induced mitophagy deficiency by downregulating CTGF expression, thereby inhibiting senescence, over-activation and collagen production in lung fibroblasts. Furthermore, we also found that TGF-β1 upregulated the expression of MEOX1 through the NOX4-ROS-Smad pathway. In conclusion, MEOX1 knockdown may ameliorate pulmonary fibrosis by regulating mitophagy and senescence and may be a potential therapeutic target for IPF and other types of interstitial lung diseases.
研究领域:
分子生物学
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细胞生物学
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呼吸病学
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遗传学
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生物信息学
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病理学
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高影响因子
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