FASEB JOURNAL
·
2022
·Vol. 36
·期 9
·e22505
·
IF 5.834
Xia Wu,Xueliang Zhou,Songqing Lai,Jichun Liu,Jianwei Qi
The hallmark feature of Diabetes mellitus (DM) is hyperglycemia which can lead to excess production of reactive oxygen species (ROS) in the myocardium, contributing to diabetic cardiomyopathy (DCM). Nuclear factor erythroid2-related factor2 (Nrf2), a transcriptional activator, enhances its ability to resist oxidative stress by activating multiple downstream anti-oxidants, anti-inflammatory proteins, and detoxifying enzymes. However, the mechanism of Nrf2 signaling in HG-induced DCM is unclear. In this study, we used HG pretreated H9c2 cells as the experimental basis in vitro, and established a high fat-diet, streptozotocin (STZ) induced Type 2 diabetic rat model in vivo. Meanwhile, we used shRNA-Nrf2 and curcumin (CUR) (as an activator) to affect H9c2 cells, to verify the role of the Nrf2 signaling pathway in DCM. The results showed that the excessive production of ROS caused by HG, which could inhibit the activation of Nrf2-related signaling, resulting in a decrease in cell energy metabolism and an increase in cell apoptosis. Surprisingly, we found that the activation of the Nrf2 signaling pathway significantly increased cardiomyocyte viability, reduced ROS formation, increased antioxidant enzyme activity, and inhibited cardiomyocyte apoptosis. In conclusion, these findings conclusively infer that CUR activation of the Nrf2/HO-1 signaling pathway exerts myocardial protection by reducing ROS formation.
研究领域:
药理学
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心脏病学
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糖尿病研究
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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
BIOMEDICINE & PHARMACOTHERAPY
·
2025
·
IF 7.5
Yang Yu,Yurong Wang,Ziqi Yang,Zhanqiang Li,Dianxiang Lu,Xingmei Nan
Pulmonary hypertension is divided into five groups, and chronic exposure to hypoxia causes pulmonary hypertension in the third group -- high altitude pulmonary hypertension, which is commonly seen in patients with chronic obstructive pulmonary disease, sleep-disordered breathing, and interstitial lung disease. Its clinicopathological features include right heart overload and right ventricular hypertrophy, with severe patients potentially experiencing right heart failure or even death. The pathogenesis of high altitude pulmonary hypertension is complex; it includes oxidative stress, mitochondrial dysfunction, apoptosis, and pyroptosis. Pharmacological therapy may alleviate the condition if immediate descent to lower altitudes or supplemental oxygen is not possible. Herein, we preliminarily investigated the effect of methyleugenol on high altitude pulmonary hypertension through in vitro and in vivo experiments. Methyleugenol alleviated pulmonary arteriole constriction by acting on potassium ion channels, and inhibited the proliferation of pulmonary artery smooth muscle cells(PASMCs) by decreasing and reactive oxygen species levels, as well as inhibiting the expression of HIF-1α. The cardiac systolic function improved and mitochondrial structure of pulmonary artery smooth muscle cells in rats with high altitude pulmonary hypertension was significantly improved after methyleugenol gavage intervention, and malondialdehyde levels in serum of rats were decreased while those of superoxide dismutase and glutathione increased, suggesting that the reduction of oxidative stress may be one of the mechanisms to improve mitochondrial function. Western blot experiments showed that methyleugenol regulated the oxidative stress level in rats by activating Nrf2/HO-1 signaling pathway, activate p27Kip1, inhibit CDK4/CCND1/ p-ERK1/2 and inhibited HIF-1α/RASSF1/Ras axis to inhibit cell proliferation, thereby improving the occurrence and development of high altitude pulmonary hypertension in rats. The results of this study reveal that methyl eugenol has the potential to alleviate pulmonary vasoconstriction and remodeling in rat models of high-altitude pulmonary hypertension, providing a scientific basis for the application of this compound in improving pulmonary vascular remodeling.
研究领域:
药理学
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心血管病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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
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药理学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Hongliang Li,Yingmeng Hou,Shiyu Jia,Mingqian Tan,Haitao Wang
Fucoxanthin (Fx) has garnered significant interest due to its exceptional biological properties. However, its efficacy in enhancing food quality and human health is contingent upon the solubility of the compound in water and its physicochemical stability. Therefore, nanocarriers must be developed to enhance the stability and biocompatibility of Fx. In this study, oxidized paramylon and Fx self-assembled nanoparticles (Fx-OEP) were prepared via the anti-solvent method, with a loading rate of 82.47 % for Fx. The Fx-OEP exhibited robust storage and photostability. In vitro simulated digestion assays demonstrated that Fx-OEP effectively protected Fx from premature gastric release, while achieving a release efficiency of 72.17 % in the intestinal phase. Fx-OEP has the capacity to scavenge a range of reactive oxygen species (ROS) induced by cellular oxidative stress. Treatment with Fx-OEP resulted in a significant reduction in ROS accumulation in insulin-resistant HepG2 cells, which was attributed to the activation of the nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. This, in turn, activated insulin receptor substrate 1/glucose transporter type 4 (IRS1/GLUT4), promoting cellular glucose absorption and utilization. These findings indicate the potential of self-assembled nanoparticles based on oxidized paramylon as a new type of nanocarrier for delivering hydrophobic substances.
研究领域:
营养学
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药理学
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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
·
2022
·
IF 3.322
Zixin Li,Luchen Shan,Pei Yu
Nitroglycerin (NTG) is recommended as the first-line drug in angina pectoris though its prolonged use impacts nitroglycerin tolerance. In this study, we investigated the preventive effect of Tetramethylpyrazine (TMP), a famous Chinese medicine used for cardiovascular diseases, on NTG-induced tolerance and further explained the underlying mechanism of its action. The results revealed that pretreatment of TMP improved NTG-induced tolerance in vitro thoracic aorta rings and in rats. Proteomic analysis showed oxidative stress and ribosome proteins dyshomeostasis in NTG-tolerance vessels. TMP attenuated the oxidative stress by enhancing the protein expression of ALDH2 , Nrf2 and HO-1. In addition, TMP recovered the down-regulated expression of RpL10a induced by nitroglycerin. Therefore, TMP could prevent nitroglycerin tolerance in rats, which may be mediated by up-regulation of ALDH2 and Nrf2/HO-1 signaling pathway and involved in the restoration of ribosome homeostasis . These findings indicate the potential of TMP as a promising medicine for preventing the development of nitroglycerin-induced tolerance.
研究领域:
心血管药理学
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分子生物学
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药物动力学
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产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2023
·
IF 6.7
Pan Zejun,Hou Mingzhuang,Zhang Yijian,Liu Yang,Tian Xin,Hu Xiayu,Ge Xiaoyang,Zhao Zhijian,Liu Tao,Xu Yong,Yang Huilin,Liu Hao,Zhu Xuesong,He Fan
Treating articular cartilage defects in patients remains a challenging task due to the absence of blood vessels within the cartilage tissue. The regenerative potential is further compromised by an imbalance between anabolism and catabolism, induced by elevated levels of reactive oxygen species (ROS). However, the advent of tissue engineering introduces a promising strategy for cartilage regeneration, offering viable solutions such as mechanical support and controlled release of chondrogenic molecules or cytokines. In this study, we developed an antioxidant scaffold by incorporating natural silk fibroin (SF) and kartogenin (KGN)-loaded liposomes (SF-Lipo@KGN). The scaffold demonstrated appropriate pore size, connectivity, and water absorption and the sustained release of KGN was achieved through the encapsulation of liposomes. In vitro experiments revealed that the SF-Lipo@KGN scaffolds exhibited excellent biocompatibility, as evidenced by enhanced cell adhesion, migration, and proliferation of chondrocytes. The SF-Lipo@KGN scaffolds were found to stimulate cartilage matrix synthesis through the activation of the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) antioxidant signaling pathway. In vivo experiments demonstrated the effective promotion of articular cartilage regeneration by the SF-Lipo@KGN scaffolds, which enhanced extracellular matrix anabolism and restored the intrinsic redox homeostasis. Overall, this study successfully developed biomimetic KGN-loaded scaffolds that restore cartilage redox homeostasis, indicating promising prospects for cartilage tissue engineering.
研究领域:
组织工程
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再生医学
·
骨科
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产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE
·
2025
·
IF 2.8
Siqi Quan,Mengyuan Li,Zhouli Yue,Hui Liu,Shuaijun Peng,Roujia Guo,Xiaoyan Fang,Yucheng Li
Neuroinflammation and oxidative stress are major pathogenic drivers of depression, with the Keap1/Nrf2/HO-1 pathway serving as a key regulator of both processes. Formononetin (FMN) is a naturally occurring isoflavone with anti-inflammatory and antioxidant activities; however, its potential to exert antidepressant effects through activation of this pathway has not been investigated. In this study, lipopolysaccharide (LPS, 1 mg/kg, i.p.) was used to induce neuroinflammation and depressive-like behaviors in mice, and FMN (20 or 40 mg/kg) was administered for seven days prior to LPS challenge. FMN dose-dependently alleviated LPS-induced behavioral deficits, including reduced sucrose preference, decreased locomotor activity, and prolonged immobility in the tail suspension test. Hematoxylin-eosin (HE) and Nissl staining revealed that FMN markedly attenuated LPS-induced hippocampal neuronal damage. FMN also inhibited microglial activation, as evidenced by reduced Iba-1 expression, decreased NF-κB phosphorylation, and downregulation of both mRNA and protein levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Furthermore, LPS-induced lipid peroxidation was significantly attenuated, as indicated by lower levels of 4-hydroxynonenal (4-HNE). Molecular docking suggested a potential direct interaction between FMN and Keap1, while Western blot analysis confirmed that FMN downregulated Keap1 and upregulated Nrf2 and HO-1 protein expression. Collectively, these findings demonstrate that FMN alleviates LPS-induced neuroinflammation and depressive-like behaviors, likely through activating the Keap1/Nrf2/HO-1 pathway, supporting its potential as a preventive candidate for inflammation-associated depression.
研究领域:
神经药理学
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分子生物学
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精神病学
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炎症研究
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氧化应激
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Shan Luo,Yake Lan,Ruoqi Zhang,Zhongqiu Luan
Introduction Diabetic nephropathy (DN), as a complication of diabetes, is one of the major causes of end-stage renal disease. Licochalcone B (LCB), a flavonoid active component derived from licorice, is well known for its anti-inflammatory and antioxidant properties. However, the influence of LCB on DN remains unclear. This research investigated the effect of LCB on DN and elucidated the regulatory mechanism. Methods We employed male C57BL/6 mice to construct a DN mouse model induced by a high-fat diet (HFD)/streptozotocin (STZ). In vitro , a high glucose (HG)-induced injury model in HK-2 (human renal tubular epithelial) cells was used to further confirm the protective effects of LCB. Results LCB treatment (20 mg/kg and 40 mg/kg) decreased blood glucose levels, kidney injury, glycogen deposition, and collagen accumulation in the DN mice. Moreover, LCB at a dosage of 40 mg/kg reduced albumin, creatinine, and blood urea nitrogen levels by about 70.7%, 33.4%, and 45.6%, respectively, indicating an improvement in kidney function. In renal tissues, LCB suppressed oxidative stress and apoptosis in HFD/STZ-induced mice. Consistent with in vivo findings, LCB alleviated HG-induced oxidative stress and apoptosis in HK-2 cells. Transcriptome analysis revealed that LCB affects oxidative stress and renal function-related pathways to alleviate DN. Further mechanistic studies demonstrated that LCB treatment upregulates the expressions of heme oxygenase-1 (HO-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), suggesting activation of the Nrf2/HO-1 signaling pathway. Conclusion Taken together, this research demonstrates that LCB suppresses oxidative stress and apoptosis accompanied by modulating the Nrf2/HO-1 pathway to ameliorate DN, which provides a promising strategy for DN treatment.
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Zixu Li,Muge Xu,Yahan Zhang,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the aryl hydrocarbon receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or ferroptosis significantly attenuated these changes, highlighting the potential of AhR and ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR–NRF2/HO-1–ferroptosis–HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.
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DOI
PubMed
高影响因子
PLoS One
·
2016
·Vol. 11
·期 2
·e0149032
·
IF 3.057
Zhao Gao,Yu Han,Yunhui Hu,Xiaoyan Wu,Yongbin Wang,Xiaoqun Zhang,Jinjuan Fu,Xue Zou,Jun Zhang,Xiongwen Chen,Pedro A. Jose,Xi Lu,Chunyu Zeng
Both oxidative stress and inflammation are involved in the pathogenesis of contrast-induced nephropathy (CIN). Epigallocatechin-3-gallate (EGCG), a purified catechin from green tea, has antioxidant and anti-inflammatory effects. However, it is unknown whether or not EGCG is effective in treating CIN. Our present study found that intravenous administration of EGCG, either before or just after the establishment of CIN, had a protective effect, determined by normalization of serum creatinine and blood urea nitrogen levels, improvement in renal histopathological scoring and alleviation of apoptosis, accompanied by decreased oxidative stress and inflammation. Because EGCG is a potent inducer of the antioxidant heme oxygenase-1 (HO-1), we studied HO-1 signaling in CIN. HO-1 levels were increased in CIN; treatment with EGCG further increased HO-1 levels, accompanied by an increase in Nrf2, a regulator of antioxidant proteins. Interestingly, blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) prevented the protective effect of EGCG on CIN. ZnPP also blocked the ability of EGCG to increase the activity of an antioxidant (superoxide dismutase), and decrease markers of oxidative stress (myeloperoxidase and malondialdehyde) and inflammation (myeloperoxidase and IL-1β), indicating that HO-1 is the upstream molecule that regulates the EGCG-mediated protection. To determine further the role of HO-1 on the EGCG-mediated inhibition of inflammation, we studied the effect of EGCG on the NLRP3 inflammasome, an upstream signaling of IL-1β. EGCG down-regulated NLRP3 expression, which was blocked by ZnPP, indicating that HO-1 links EGCG with NLRP3. Therefore, EGCG, via up-regulation of HO-1, protects against CIN by amelioration of oxidative stress and inflammation.
研究领域:
药理学
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肾病学
·
氧化应激与炎症
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Rui Li,Jiaojiao Mou,Lei Zhao,Mengqiu Hu,Bin Wang,Yanying Sun,Jing Liu,Xiaohui Qi,Jie Yang
Intestinal barrier disruption and oxidative stress are the major pathological features during the ulcerative colitis (UC). The present research aimed to explore the amelioration property of fucoidan of Stichopus chloronotus (Fuc Sc) against dextran sulfate sodium (DSS) resulted UC. The findings from our study suggest that treating with Fuc-Sc improved the integrity of the Caco-2 monolayer through raising its TEER value, reducing LDH release, promoting the tight junction proteins (TJs) in Caco-2 cells, and shielding the cells from decreases of these proteins caused by H 2 O 2 . Besides, Fuc-Sc activated Nrf2/HO-1 pathway to facilitate the antioxidant activities of Caco-2 cells under oxidative stress through elevating the SOD and GSH, and reducing LDH and MDA. Furthermore, oral administration of Fuc-Sc attenuated DSS resulted body weights decrease, DAI score increase, colon length decrease, and structural damage of colon tissue. Fuc-Sc also promoted the barrier function and suppressed oxidative injury via activation of Nrf2/HO-1 signal pathway. Collectively, this research provided the theoretical foundation for fucoidan as a promising functional food for colitis.
研究领域:
营养学
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消化病学
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分子生物学
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DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 5
·1-14
·
IF 3.5
Zhao Hexiang,Yang Ping,Zhang Mou,Zheng Wenshu,Qi Renli,Zhu Xiaofeng,Li Jinghui,Li Shipeng
Reperfusion, while essential for restoring blood supply, paradoxically exacerbates neuronal damage through cerebral ischemia-reperfusion injury (CIRI). This study aimed to develop a reactive oxygen species (ROS)-responsive drug delivery system (DDS) loaded with edaravone (EDA) to enhance targeted therapy for CIRI. The stimuli-responsive DDS was synthesized using dextran (DEX) as the biocompatible carrier and benzeneboronic acid pinacol ester (BAPE) as the ROS-sensitive moiety. The physicochemical characteristics of the DEX-BAPE/EDA (DB/EDA) micelles were systematically evaluated. In vitro studies assessed the anti-inflammatory, antioxidant, and anti-apoptotic effects of DB/EDA. Moreover, the neuroprotective efficacy of DB/EDA in vivo was analyzed via behavioral tests, infarct volume measurement, ELISA assays of inflammatory cytokines and OS markers, and Western blot analysis of Nrf2-related pathways. Pharmacokinetics and biosafety were analyzed through plasma profiling and H&E staining. DB/EDA exhibited high stability, efficient drug encapsulation, and ROS-responsive drug release. Cellular uptake studies confirmed enhanced internalization of DB/EDA micelles in BV2 cells. In the oxygen-glucose deprivation/reoxygenation (OGD/R) model, DB/EDA significantly suppressed TNF-α, IL-1β, IL-6, and MDA, restored SOD levels, and attenuated apoptosis. In the middle cerebral artery occlusion/reperfusion (MCAO/R) mice, DB/EDA administration effectively improves cognition and mitigates neuronal damage. Mechanistically, DB/EDA activated the Nrf2/HO-1 pathway, amplifying antioxidant and anti-inflammatory responses. Pharmacokinetic analysis revealed prolonged circulation and increased brain accumulation, and histopathological analysis demonstrated the safety profile of DB/EDA. The ROS-responsive DB/EDA nano-micelles provided targeted EDA delivery to ischemic brain regions, alleviating CIRI via Nrf2 activation, suggesting that DB/EDA is a promising strategy for CIRI treatment. Graphical abstract
研究领域:
药剂学
·
神经科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）