Frontiers in Pharmacology
·
2023
·
IF 5.6
Sheng Mingyue,Chen Xun,Yu Yan,Wu Qi,Kou Junping,Chen Gangling
Backgrounds: The circadian clock protein Rev-erbα is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erbα plays a key role in the inflammation and oxidative stress, two pivotal mechanisms in the pathogenesis, progression, and recovery process of ischemic stroke. However, it remains inconclusive whether Rev-erbα activation is protective against ischemic brain damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of inflammatory and oxidative responses. Our study aimed to determine whether pharmacological activation of Rev-erbα by SR9009 protects against acute ischemic brain damage partly via Nrf2 pathway.Methods: Adult mice were pretreated with SR9009 or Nrf2 inhibitor all-trans-retinoic acid (ATRA) for 3 days prior to Sham or middle cerebral artery occlusion (MCAO) operation. After ischemia for 1 h and reperfusion for 24 h, the neurological function and cerebral infarction volume were determined, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and glutathione peroxidase (GSH-PX) activity in serum were detected by kit. The mRNA and/or protein level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), Period (Per)1, Brain and muscle arnt-like1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev-erbα, Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in cerebral cortex were detected by q-PCR and Western blot.Results: We confirmed that SR9009 activated Rev-erbα gene in the cerebral cortex under basal condition. At 24 h after reperfusion, SR9009 ameliorated acute neurological deficits, reduced infarct volume. Meanwhile, the inflammatory TNF-α, IL-1β, iNOS and MDA content levels were significant decreased, SOD and GSH-PX activity were obviously increased, which were markedly blunted (or abolished) by ATRA. SR9009 enhanced the induction of Nrf2 and its downstream target genes HO-1 and NQO1 after ischemic insult. In addition, we found that SR9009 restored Rev-erbα, Bmal1, Clock, Per1 genes expression in the cerebral cortex under ischemic condition.Conclusion: Taken together, Rev-erbα activation by SR9009 protects against ischemic stroke damage, at least, partly through Nrf2 pathway.
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Food & Function
·
2023
·Vol. 14
·期 4
·1884-1896
·
IF 6.1
Huiyi Li,Qiqing Weng,Shuai Gong,Weixian Zhang,Jiaqi Wang,Yuqiao Huang,Yuanjun Li,Jiao Guo,Tian Lan
Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects via the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg−1) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells in vitro. Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.
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Food & Function
·
2023
·Vol. 14
·期 2
·1087-1098
·
IF 6.1
Chengzhu Song,Dongning Li,Jie Zhang,Xiaoyan Zhao
Imatinib mesylate (IMA) belonging to the selective tyrosine kinase inhibitor family has been proven to induce cardiotoxic effects along with therapeutic strategies. Nrf2-dependent ferroptosis has been implicated in the cardiotoxicity induced by IMA. The present study was designed to investigate the protective effects of berberine hydrochloride (Ber) on cardiac injuries induced by IMA and to explore its potential mechanisms. In H9c2 cells, cell viability, the generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and labile iron pool (LIP) levels were measured. In a mouse model of IMA-induced cardiomyopathy, serum biomarkers and cardiac tissues were examined. A western blot assay was performed to evaluate the expression of ferroptosis-related proteins in vitro and in vivo. Our results indicated that Ber increased cell viability and MMP and decreased cellular ROS and iron levels in comparison to the IMA group of H9c2 cells. In mice, Ber significantly improved cardiac status and attenuated the level of ferroptosis biomarkers including malonaldehyde (MDA) and iron content. Additionally, Ber downregulated the expression of transferrin receptor (TfR) and P53 and upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1), ferritin heavy chain-1 (FTH1), and glutathione peroxidase 4 (GPX4) in H9c2 cells and mice. The present data indicated that Ber has the potential to protect against IMA-induced cardiotoxicity, partly via inhibiting Nrf2-dependent ferroptosis.
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Antioxidants
·
2021
·Vol. 11
·期 1
·38
·
IF 6.313
Zhiwei Qiu,Jinzhao He,Guangying Shao,Jiaqi Hu,Xiaowei Li,Hong Zhou,Min Li,Baoxue Yang
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specificPkd1knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library.In vitroexperiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner.In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.Keywords:obacunone;autosomal dominant polycystic kidney disease;NRF2;glutathione peroxidase;lipid peroxidation;MAPK;mTOR
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Yanan Hou,Xinming Li,Shoujiao Peng,Juan Yao,Feifei Bai,Jianguo Fang
The mechanisms underlying neurodegenerative diseases are not fully understood yet. However, an increasing amount of evidence has suggested that these disorders are related to oxidative stress. We reported herein that lipoamide (LM), a neutral amide derivative of lipoic acid (LA), could resist oxidative stress-mediated neuronal cell damage. LM is more potent than LA in alleviating hydrogen peroxide- or 6-hydroxydopamine-induced PC12 cell injury. Our results reveal that LM promotes the nuclear accumulation of NFE2-related factor 2 (Nrf2), following with the activation of expression of Nrf2-governed antioxidant and detoxifying enzymes. Notably, silencing Nrf2 gene annuls the protection of LM, which demonstrates that Nrf2 is engaged in this cytoprotection. Our findings suggest that LM might be used as a potential therapeutic candidate for oxidative stress-related neurological disorders.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2019
·Vol. 393
·期 1
·57-65
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IF 2.058
Zhai Jiajia,Li Zeping,Zhang Huifeng,Ma Louyan,Ma Zhengquan,Zhang Yi,Zou Jian,Li Mo,Ma Li,Li Xiaomiao
The present study has been designed and carried out to evaluate the potential of coptisine on diabetic nephropathy. Diabetes was induced in SD rats through one single intraperitoneal injection of streptozotocin (65 mg/kg) method, and then diabetic rats were orally administered with 25 mg/kg/day coptisine or 50 mg/kg/day coptisine for 8 weeks. Severe impairment of renal function in rats with diabetes was observed as indicated by increased urine protein excretion, kidney hypertrophy index, serum creatinine level, and blood urea nitrogen level. Oxidative stress damage was observed as indicated by increased levels of reactive oxygen species, malondialdehyde, and decreased levels of glutathione, superoxide dismutase, and catalase. However, these alterations in kidneys of rats with diabetes were alleviated by administration of coptisine. Furthermore, the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its targeted antioxidative genes heme oxygenase 1 and NADPH quinone oxidoreductase 1 in the diabetic kidneys were significantly increased after coptisine treatment. These results suggested that coptisine ameliorated oxidative renal injury in diabetic rats, and the possible mechanisms for the renoprotective effects of coptisine may be related to activation of the Nrf2 signaling pathway.
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Molecular Medicine Reports
·
2019
·Vol. 20
·期 2
·1017-1024
·
IF 1.851
Duzhen Zhang,Man Li
Puerarin is the major bioactive ingredient isolated from the dry root of Pueraria lobata, a plant used in traditional Chinese medicine. Puerarin has been used to treat diabetes and cataracts in China; however, its underlying mechanism of action remains unclear. The aim of the present study was to investigate the effectiveness and mechanism of puerarin in preventing cataracts in diabetic rats. Diabetes was induced by streptozocin (STZ) administration and rats were intraperitoneally injected with puerarin (25, 50 and 100 mg/kg). Blood glucose levels and cataract development were examined in the different experimental groups. In addition, the expression levels of markers associated with oxidative stress, including nuclear factor erythroid 2 like 2 (Nrf2) and heme oxygenase‑1 (HO‑1), were analyzed. The present results suggested that treatment with puerarin at 25, 50 and 100 mg/kg significantly reduced blood glucose levels and the incidence of cataract in STZ‑induced diabetic rats. Additionally, puerarin treatment reduced oxidative stress, restoring the levels of malondialdehyde and glutathione, and the activity of glutathione peroxidase. Furthermore, puerarin administration decreased the expression levels of retinal vascular endothelial growth factor and interleukin‑1β and increased the mRNA expression levels of Nrf2 and HO‑1, thus inhibiting oxidative stress. The present findings suggested that puerarin had hypoglycemic effects and that it prevented cataract development and progression in diabetic rats by reducing oxidative stress through the Nrf2/HO‑1 signaling pathway.
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Molecular Medicine Reports
·
2018
·Vol. 18
·期 4
·3691-3698
·
IF 1.922
Yan Zhou,Hanyang Liu,Jun Song,Liang Cao,Liming Tang,Chunjian Qi
Sinomenine (SIN), a pure alkaloid isolated from Sinomenium acutum, has been widely used in arthritis for its anti‑inflammatory effect, but little is known about the effect of SIN on human ulcerative colitis (UC). In the present study, the effect and mechanism of SIN was examined in a dextran sulfate sodium (DSS)‑induced murine colitis model, which mimics human UC. Oral administration of SIN significantly suppressed the elevated disease activity index and ameliorated colonic histological damage in a DSS‑induced colitis model. Tumor necrosis factor‑α, interleukin‑6 and inducible nitric oxide synthase levels were also reduced as detected by reverse transcription‑quantitative polymerase chain reaction. In addition, SIN reversed the decreased colon length and colonic superoxide dismutase activity. Furthermore, western blot analysis revealed that nuclear factor‑erythroid 2‑related factor 2 (Nrf2) and its downstream genes, heme oxygenase‑1 and NADP(H) quinone oxidoreductase 1 (NQO‑1), were markedly activated by SIN. The current results indicated that SIN alleviated DSS‑induced colitis in mice, which may be due to its antioxidant properties and was at least in part dependent on the Nrf2/NQO‑1 signaling pathway. Therefore, SIN may have potential applications as a protective drug for patients with UC.
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PHARMACEUTICAL CHEMISTRY JOURNAL
·
2018
·Vol. 52
·期 2
·95-102
·
IF 0.679
Xu Xiaoya,Chen Yajun,Zhang Min,Wang Dianlei,Wu Jie,Yao Zhaomin,Wu Qingqing,Fang Wei
The therapy of Huatanjiangqi capsule (HTJQ) has been used in the treatment of chronic obstructive pulmonary disease (COPD) clinically, with remarkable benefits. A lower functional activity of MRP1 is related to COPD development. However, the mechanism that contributes to MRP1 up-regulation by HTJQ was unclear. This study aimed to investigate the effects of HTJQ on the expression of Nrf2 and MRP1 in COPD rats. Rats were exposed to cigarette smoke plus lipopolysaccharide tracheal instillation to induce a COPD model. Then, Nrf2, HO-1, and MRP1 mRNA expression and their protein production in lung tissues were examined. The model group showed significant changes in the above assessments as compared to those of the control group ( p < 0.05). The lung function of model group treated with low/high dose of HTJQ was significantly strengthened (both p < 0.05), and the inflammatory cells and goblet cells were decreased in lung tissues. Treatment with low/high dose of HTJQ resulted in obvious increase in Nrf2, HO-1, and MRP1 mRNA and protein expression levels ( p < 0.05). HTJQ could up-regulate Nrf2 and MRP1 expression in lung tissues of COPD model rats. The mechanism by which HTJQ up-regulates MRP1 expression may be associated with Nrf2.
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Scientific Reports
·
2025
·Vol. 15
·期 1
·1-12
·
IF 3.9
Cheng Chunfang,Zhang Shasha,Chen Chong,Gong Yanchun,Ding Kaizhi,Li Guoyin,Jiang Wei,Zhang Zhenyu,He Bin,Hu Zhihong,Li Yuhua,Yao Lihua
Excessive exercise can lead to physical fatigue and disruption of the antioxidant system, resulting in neurological damage and cognitive decline. Cordycepin, the main component of Cordyceps militaris , has anti-inflammatory, antioxidant and neuroprotective effects. In this study, the anti-fatigue effect and potential mechanism of action of cordycepin were investigated using a forced exercise mouse model. The results showed that oral administration of cordycepin enhanced exercise endurance, increased liver and muscle glycogen content, and simultaneously decreased serum levels of lactic acid, lactate dehydrogenase, creatine kinase, and blood urea nitrogen ( p < 0.05). In addition, cordycepin had antioxidant effects, increasing superoxide dismutase activity and decreasing serum malondialdehyde (MDA) levels ( p < 0.01). In vitro experiments further demonstrated the antioxidant and anti-fatigue effects of cordycepin. Behavioral tests showed that the learning and memory ability of mice in the excessive exercise model group decreased to 40% compared with the control group. Cordycepin alleviated the learning and memory deficits in the over-exercised mice, significantly reduced the levels of fatigue metabolites and oxidative stress in vivo ( p < 0.05), and altered the levels of neurotransmitters levels ( p < 0.05). Furthermore, cordycepin modulated Keap1/Nrf2/HO-1-mediated oxidative stress and enhanced BDNF levels ( p < 0.05). These findings suggest that cordycepin can alleviate excessive exercise-induced fatigue by modulating the Keap1/Nrf2/HO-1 signaling pathway and BDNF expression, providing strong supporting evidence for the development of cordycepin-functional foods or anti-fatigue drugs.
研究领域:
运动生理学
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药理学
·
神经科学
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FOOD RESEARCH INTERNATIONAL
·
2024
·
IF 7
Xinya Qi,Lingling Tong,Hui Lian,Zilei Chen,Linhui Yang,Yang Wu,Suxing Jin,Dongsheng Guo
Here, a high molecular weight polysaccharide preparation from Ophiocordyceps gracilis was utilized as a stabilizer and dispersant to create nanocomposites based on selenium nanoparticles (GSP-1a-SeNPs). The NPs showed the highest stability at a selenium/polysaccharide mass ratio of 1:1, with no significant change after 28 days of storage at 4 ℃. The NPs exhibited a symmetrical spheroid structure with an average diameter of 85.4 nm. Next, the anti-inflammatory properties and mechanisms of the GSP-1a-SeNPs were examined in LPS-induced RAW264.7 cells, which efficiently internalized the NPs. In the anti-inflammatory assays, GSP-1a-SeNPs significantly reduced the production of pro-inflammatory cytokines, including TNF-α and IL-6, and lowered ROS levels by activating the Nrf2-Keap1 pathway. This pathway regulates selenoprotein expression, thereby balancing the immune microenvironment of RAW264.7 cells and mitigating inflammation. These results suggest that GSP-1a-SeNPs could serve as potential therapeutic agents or adjuvants for treating LPS-induced inflammation.
研究领域:
药理学
·
纳米医学
·
免疫学
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ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yishi Lu,Ziyue Zu,Nan Zhong,Yang Li,Xuan Sha,Shangyu Lu,Jie Zhang,Hanyao Sun,Xi Luo,Ziqing Xu,Feiyun Wu,Yuxia Tang,Shouju Wang
Autophagy blockade has emerged as a promising strategy to enhance the antitumor efficacy of pancreatic ductal adenocarcinoma (PDAC). However, autophagy inhibition in PDAC may induce compensatory macropinocytosis to maintain cellular homeostasis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, lysosomal-activated nanoreactors loaded with the NRF2 inhibitor ML385 (CPZI-Ms) are developed to spatiotemporally block autophagy and inhibit macropinocytosis. The nanoreactors, which preferentially accumulate in lysosomes, undergo degradation in the acidic lysosomal environment, triggering a Fenton-like reaction between the released Cu 2 ⁺ ions and H₂O₂ to generate hydroxyl radicals. This results in lysosomal membrane permeabilization, which further leads to not only lysosomal autophagy blockade, but also the leakage of Cu 2 ⁺ and ML385 into the cytoplasm. Cu 2 ⁺ induces extensive oxidative stress throughout the whole cell, while ML385 suppresses compensatory macropinocytosis response activated by autophagy blocking. As a result, the Panc02 cells become a “besieged fortress”, with impaired autophagic clearance and restricted nutrient uptake. In vivo, CPZI-Ms effectively suppress tumor growth in Panc02-bearing mice, offering a promising nanoplatform for enhancing cancer cell killing. Taken together, the present work provides an innovative anti-tumor insight by spatiotemporally blocking autophagic flux and inhibiting compensatory macropinocytosis.
研究领域:
肿瘤学
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药理学
·
纳米医学
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