INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 13
·7395
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IF 6.208
Xiaoqin Ding,Yan Chen,Lina Zhou,Ruoyun Wu,Tunyu Jian,Han Lyu,Yan Liu,Jian Chen
Bisdemethoxycurcumin (BDMC), a principal and active component of edible turmeric, was previously found to have beneficial effects on metabolic diseases. Chronic kidney disease (CKD) may benefit from its potential therapeutic use. Using a high-fat diet (HFD)-fed mouse model, we examined the effects of BDMC on renal injury and tried to determine how its associated mechanism works. A number of metabolic disorders are significantly improved by BDMC, including obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia and inflammation. Further research on renal histopathology and function showed that BDMC could repair renal pathological changes and enhance renal function. Moreover, decreased serum malondialdehyde (MDA), elevated superoxide dismutase (SOD) activity, and the inhibition of renal reactive oxygen species (ROS) overproduction revealed the alleviation of oxidative stress after BDMC administration. In addition, renal Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway was activated in BDMC-treated mice. In conclusion, these findings demonstrated BDMC as a potential therapy for HFD-induced CKD via the activation of the Keap1/Nrf2 pathway.Keywords:bisdemethoxycurcumin;chronic kidney disease;high-fat diet;Keap1/Nrf2 pathway;oxidative stress
研究领域:
药理学
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肾病学
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营养学
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DOI
PubMed
高影响因子
Current Research in Food Science
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2022
·
IF 6.269
Yong Chen,Jiajun Wang,Ziheng Jing,Jose M. Ordovas,Jing Wang,Lirong Shen
Demands for dietary supplements with anti-fatigue effects are growing fast due to increasing societal demands. Moreover, in highly physically active individuals, there are also significant needs for supplements to improve exercise performance. The present study evaluated the potential anti-fatigue and anti-oxidant effects of curcumin in mice using exhaustive swimming test. Male C57BL/6J mice were randomized into six groups: blank control (Rest), swimming control (Con), Vitamin C (Vc), low-dose curcumin (C 50 ), middle-dose curcumin (C 100 ), and high-dose curcumin (C 200 ). After a 4-week intervention, the mice in all groups except the Rest group were subject to an exhaustive swimming test. Then, mice were sacrificed to examine serum biochemical markers and fatigue-related enzymes. Moreover, the gene and protein expressions of signal transduction factors involved in the Nrf2/Keap1 signaling pathway were measured. The results indicated that curcumin significantly enhanced the exercise tolerance of mice in the exhaustive swimming test. Particularly, the swimming time of mice in the C 100 group was increased by 273.5% when compared to that of mice in the Con group. The levels of blood urea nitrogen, blood ammonia, lactic acid, creatine kinase and lactate dehydrogenase in the C 100 group were decreased by 13.3%, 21.0%, 18.6%, 16.7% and 21.9%, respectively, when compared to those of mice in the Con group. Curcumin alleviated exercise-induced oxidative stress and significantly enhanced the activities of superoxide dismutase, catalase and glutathione peroxidase by activating the Nrf2 signaling. These findings indicated that curcumin supplementation exerted remarkable anti-oxidant and anti-fatigue effects in mice, providing additional evidence supporting the use of curcumin as functional food, especially by those engaged in sports-related activities.
研究领域:
营养学
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运动生理学
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药理学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2023
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IF 7.2
Huihui Wang,Baoping Xie,Shuotao Shi,Rong Zhang,Qi Liang,Zhongqiu Liu,Yuanyuan Cheng
Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae . The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 7.3
Mingming Qi,Hui Zhong,Zhaoyan Cheng,Shujie Chen,Han Xiao,Jing Shang,Li Chen,Jianbo Sun
Activating Nrf2 through inhibiting Keap1 has been proven to alleviate oxidative stress and related diseases, including nonalcoholic fatty liver disease (NAFLD). Traditional Keap1 inhibitors could not avoid the “off-target” effects, but using proteolysis targeting chimera (PROTAC) technology to induce Keap1 degradation might be an effective strategy to find potential NAFLD improving agents. Thus, several PROTACs were designed and synthesized by harnessing CDDO as the Keap1 ligand in this study. PROTAC I-d exhibited optimal Keap1 degradation activity, which could increase the Nrf2 level and alleviate oxidative stress in free fatty acid-induced AML12 cells and the liver of mice fed with a methionine-choline-deficient diet. Moreover, compared with CDDO, PROTAC I-d displayed significant advantages in inhibiting hepatic steatosis, steatohepatitis, and fibrosis in the in vivo and in vitro models of NAFLD. In addition, PROTAC I-d also showed lower in vivo toxicity than CDDO. All these results suggested that PROTAC I-d might be a potential improving agent for NAFLD.
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
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2025
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IF 4
Yinpei Huang,Hailun Xie,Lian Liu,Heng Zhao,Bing Li,Feng Zhang
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal apoptosis, ultimately leading to progressive cognitive impairment. This study investigated the neuroprotective potential of a reactive oxygen species (ROS)-responsive nanotherapeutic, namely TPCD nanoparticles (TPCD NP), synthesized through the conjugation of Tempol and phenylboronic acid pinacol ester to β-cyclodextrin, in both in vivo and in vitro models. In rats, intravenous administration of TPCD NP improved memory performance as assessed by the Morris water maze test, and preserved hippocampal neuronal morphology. TPCD NP significantly reduced intracellular ROS content and malondialdehyde (MDA) levels while restoring antioxidant capacity, including superoxide dismutase (SOD) and glutathione (GSH). Apoptosis was attenuated, as evidenced by the downregulation of Bax and cleaved caspase-3, and the upregulation of Bcl-2 expression. Mechanistically, TPCD NP enhanced the nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2), suppressed Kelch-like ECH-associated protein 1 (KEAP1), and increased heme oxygenase-1 (HO-1) expression. The protective effects were abolished by ML385, a selective NRF2 inhibitor, confirming the essential role of NRF2 activation in mediating the antioxidant and anti-apoptotic effects of TPCD NP. In conclusion, TPCD NP attenuates oxidative stress and apoptosis induced by IH in the hippocampus by activating the NRF2/KEAP1/HO-1 pathway. These findings highlight TPCD NP as a promising therapeutic strategy for OSA-associated neurodegeneration.
研究领域:
医学
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Huimei Zhao,Haiyan Zhang,Jianyu Shi,Yanru Liu,Jingao Yu,Yuangui Yang,Jingyu Weng,Zhongxing Song,Rui Zhou,Hong Min,Jian Yao,Mei Wang,Zhen Zhang
Ethnopharmacological relevance Asthma is a chronic inflammatory airway disease. Current treatments have limited efficacy and often cause severe side effects. Wuwei Shaji Powder (WSP), a traditional Mongolian remedy, is used for treating chronic pulmonary diseases, but its efficacy against asthma and underlying mechanisms are still unclear. Aim of the study To investigate the therapeutic effect of WSP on asthma and elucidate its molecular mechanisms. Materials and methods An ovalbumin (OVA)-induced allergic asthma model was established in rats. Ferroptosis or apoptosis was induced in BEAS-2B cells using Erastin or CdCl 2 . Various techniques including histopathological staining, ELISA, Western blot, flow cytometry, and transmission electron microscopy were employed to assess WSP's effects and mechanisms. Results WSP alleviated OVA-induced allergic asthma in rats without the immunosuppressive side effects observed with dexamethasone. WSP suppressed ferroptosis in bronchial epithelial cells both in vivo and in vitro. It reduced thiol- and sulfonic-based oxidative stress through Keap1 S-sulfhydration, disrupted the Keap1-Nrf2 interaction, and promoted Nrf2 nuclear translocation. Notably, we discovered that CdCl 2 can induce ferroptosis in BEAS-2B cells, and WSP prevented both ferroptosis and apoptosis in these cells. Conclusion WSP alleviates OVA-induced allergic asthma by protecting bronchial epithelial cells from ferroptosis via S-sulfhydration of Keap1, providing new insights for its clinical application.
研究领域:
民族药理学
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呼吸系统疾病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nutrients
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2022
·Vol. 14
·期 15
·3102
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IF 6.706
Ning Li,Liuding Wen,Tiange Li,Huijie Yang,Mingwu Qiao,Tianlin Wang,Lianjun Song,Xianqing Huang,Mingming Li,Erkigul Bukyei,Fangyu Wang
Many researchers have found that Pb exposure can cause oxidative stress damage to the body’s tissue. Black soybean peptide (BSP) has a variety of physiological functions, especially in terms of oxidative stress. Nevertheless, the mitigation function of BSPs on Pb-induced oxidative stress damage in PC12 cells has not been clearly defined. In this study, cell viability was detected by CCK8. Oxidative stress indicators, such as ROS, GSH/GSSG, MDA, SOD, CAT, GPx, and GR, were tested with biochemical kit. Protein expression of Keap1, Nrf2, and TXNIP was measured by Western blot. Compared with the control group, Pb reduced the cell viability of PC12 cells. However, BSP treatment significantly increased the viability of PC12 cells induced by lead exposure (p< 0.05). Lead can enrich the contents of MDA and ROS, but decrease the amount of CAT, SOD, GR, GPx, and GSH/GSSG in PC12 cells, while BSP can alleviate it (p< 0.05). Lead can enhance the expression of Keap1 and TXNIP proteins, but reduce Nrf2 expression. In contrast, BSPs reversed this phenomenon (p< 0.05). BSPs can alleviate oxidative stress injury induced by lead in PC12 cells through the Keap1/Nrf2/TXNIP signaling pathway.Keywords:black soybean peptide;Pb;PC12 cells;Keap1/Nrf2/TXNIP;oxidative stress
研究领域:
毒理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2019
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IF 3.775
Maiquan Li,Weisu Huang,Fan Jie,Mengmeng Wang,Yongheng Zhong,Qi Chen,Baiyi Lu
Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2−related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton−anchored Kelch−like ECH−associated protein 1 (Keap1). The Keap1–Nrf2 protein–protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1–Nrf2 protein–protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D−QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1. The Nrf2 activation effect was tested on a H 2 O 2 −induced oxidative−injured cell model. Results showed that the 178 phytochemicals could be divided into high−, medium−, and low−total−score groups depending on their binding affinity with Keap1, and the high−total−score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1−Nrf2 interface. Compounds from high−total−score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators.
研究领域:
药理学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Foods
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2021
·Vol. 10
·期 11
·2765
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IF 4.35
Fanghua Guo,Rong Tsao,Chuyao Li,Xiaoya Wang,Hua Zhang,Li Jiang,Yong Sun,Hua Xiong
As a processing by-product, green pea hull (GPH) was found to be rich in phenolic components in our previous studies. In this study, UHPLC-LTQ-OrbiTrap-MS (Ultra performance liquid chromatography-linear ion trap orbitrap tandem mass spectrometry) technique was used to quantify polyphenols, and DSS (sodium dextran sulfate)-induced colitis mouse model was established to explore the effect of GPH extracts on colitis. The results showed that quercetin and its derivatives, kaempferol trihexanside and catechin and its derivatives were the main phenolic substances in the extract, reaching 2836.57, 1482.00 and 1339.91 µg quercetin/g GPH extract, respectively; GPH extracts can improved inflammatory status, repaired colonic function, regulated inflammatory factors, and restored oxidative balance in mice. Further, GPH extracts can activate Keap1-Nrf2-ARE signaling pathway, regulate downstream antioxidant protease and gut microbiota by increasing F/B value and promoting the growth ofLactobacillaceaeandLachnospiraceae, and improve the level of SCFAs (short-chain fatty acids) to relieve DSS-induced colitis in mice. Therefore, GPH may be a promising dietary resource for the treatment of ulcerative colitis.Keywords:polyphenols;colitis;UHPLC-LTQ-OrbiTrap-MS;GPH extracts;Keap1-Nrf2;gut microbiota
研究领域:
药理学
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营养学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Hongli Zhang,Ziyu Lan,Hui Wang,Haojie Yao,Ruiyan Zheng,Zijing Chen,Xiang Luo,Peng Wu,Yuanyuan Cheng,Zhongqiu Liu
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by a complex clinical syndrome. Pubescenoside A (PBA), a phenylpropanoid derived from Ilex pubescens , exhibits significant anti-inflammatory effects; however, the impact and underlying mechanism of PBA on UC remain unclear. Therefore, the aim of this study is to investigate the potential mechanism of PBA against UC using in vivo and in vitro experiments. Pubescenoside A effectively enhances weight loss in UC mice, decreases the disease activity index (DAI). Regarding colonic morphology, PBA ameliorates colorectal stenosis and shortening, reduces intestinal mucosal ulceration, diminishes inflammatory cell infiltration, and tends to normalize glandular arrangement. Furthermore, PBA effectively suppresses pro-inflammatory factors. Mechanism studies have shown that PBA can directly target Kelch Like ECH Associated Protein 1 (Keap1), subsequently promoting the interaction between Keap1 and DEAD-box RNA helicase 5 (DDX5) to enhance ubiquitination and degradation of DDX5, leading to a down-regulation of C-C motif chemokine ligand 3 (CCL3) expression. Additionally, PBA disrupts the Keap1/Nrf2 complex, facilitating Nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry to inhibit the Nuclear factor-κB (NF-κB) pathway. Importantly, in Gpt-lgr5-creERT2 Keap1 flox/flox mice, the anti-UC effect of PBA was attenuated. Our results indicated that PBA mitigated UC by targeting Keap1, thereby promoting the ubiquitination degradation of DDX5 and facilitating the nuclear entry of Nrf2.
研究领域:
药理学
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分子生物学
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免疫学
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胃肠病学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOFACTORS
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2021
·Vol. 48
·期 1
·190-203
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IF 6.113
Huijie Chen,Jianqing Chen,Xu Shi,Lu Li,Shiwen Xu
Bisphenol A (BPA) has caused serious pathologies in varying organs of humans and animals, especially reproductive organs. Naringenin (NRG) is a flavanone compound that has shown protective effects against several environmental chemicals through suppression of oxidative stress and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Herein, we described the discovery path of NRG inhibition on apoptosis in BPA exposed swine testis (ST) cells through targeting Kelch-like ech-associated protein (Keap1). We found that NRG could specifically bound to the active residues of DGR domain in Keap1, thereby activating Nrf2 signaling pathway, and then increasing the levels of SOD, GPx and CAT, and finally inhibiting oxidative stress and mitochondrial apoptosis induced by BPA in ST cells. Altogether, our results showed that NRG inhibits oxidative stress and mitochondrial apoptosis induced by BPA in ST cells by targeting Keap1/Nrf2 signaling pathway, indicating that NRG could serve as an antagonistic therapy against BPA.
研究领域:
毒理学
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生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Xingfang Zhang,Liang Gao,Jianv Wang,Wei Zhang,Dong Xu,Yanhua Wang,Tianlong Liu,Kai Gao,Zhen Ren,Yi Ding
β-Bisabolene, a bioactive sesquiterpene extracted from myrrh—a substance utilized for ischemic stroke treatment—has known therapeutic potential. Nevertheless, the exact mechanisms underlying its beneficial effects on ischemic stroke, along with its potential targets, remain to be fully elucidated. This study aimed to investigate the therapeutic potential of β-Bisabolene in ameliorating ischemic stroke, identify its potential targets and interactions, and explore the underlying pathways involved. Bioinformatics analyses, including network pharmacology and analysis of GEO transcriptomic datasets, were performed to predict the potential targets and mechanisms of β-Bisabolene in ischemic stroke treatment. Preliminary computational validation was achieved through molecular similarity comparisons, molecular docking studies, and molecular dynamics simulations. In vitro experiments were then conducted to confirm the protective effects of β-Bisabolene on microglia injured by oxygen‒glucose deprivation and to validate the findings from the bioinformatics analyses. The results revealed that β-Bisabolene reduces the levels of the proinflammatory cytokines TNF-α, IL-1β and NO; decreases reactive oxygen species levels; and decreases the expression of COX-2, P38, ERK and Keap1. Moreover, it increases the expression of Arg-1, Nrf2, NQO1 and HO-1. These effects are associated with improved survival rates of oxygen–glucose deprivation–damaged microglia. In conclusion, β-Bisabolene may exert anti-inflammatory and antioxidant effects to ameliorate microglial injury induced by ischemic stroke by antagonizing COX-2 and mediating the MAPK signaling pathway and Keap1/Nrf2 pathway. This study provides valuable insights into the therapeutic potential of β-Bisabolene for the treatment of ischemic stroke.
研究领域:
药理学
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神经科学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
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