NEUROTOXICITY RESEARCH
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2020
·Vol. 38
·期 1
·59-73
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IF 2.992
Wen Caiyan,Huang Cuiqin,Yang Mei,Fan Chongzhu,Li Qin,Zhao Jiayi,Gan Danhui,Li An,Zhu Lihong,Lu Daxiang
Oxidative stress is a potential pathological mechanism of Alzheimer’s disease (AD). Berberine (BBR) can improve antioxidative capacity and inhibit Aβ protein aggregation and tau protein hyperphosphorylation in AD, and stem cell therapy is also increasingly recognized as a therapy for AD. Bone marrow mesenchymal stem cells (BMSCs) have many advantages, as they exhibit antioxidant and anti-inflammatory activity and secrete a variety of neurotrophic factors, and play important roles in neurodegenerative disease treatment. In this study, we investigated the antioxidant effects of secretions from BMSCs pretreated with BBR on tert -butyl hydroperoxide ( t -BHP)–damaged neurons. We demonstrated that BBR can enhance BMSC viability and the secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both of which are vital neurotrophic factors that maintain neuronal growth. Moreover, conditioned medium from BBR-treated BMSCs (BBR-BMSC-CM) reduced reactive oxygen species (ROS) production, attenuated a decrease in the mitochondrial membrane potential, and ameliorated neuronal apoptosis by decreasing levels of the apoptotic proteins Bax/Bcl-2, cytochrome c, and cleaved caspase-3/caspase-3. In addition, increased synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) levels indicated that neuronal synaptic function was restored. Further study revealed that BBR-BMSC-CM activated the antioxidant proteins Keap1, Nrf2, and HO-1. In conclusion, our results showed that BBR-BMSC-CM attenuated apoptosis and oxidative damage in neurons by activating the Keap1-Nrf2-HO-1 signaling pathway. Taken together, these results also suggest BBR as a drug to stimulate the secretion of nutritional cytokines with the potential to treat AD.
研究领域:
神经科学
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药理学
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干细胞生物学
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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
Frontiers in Nutrition
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2022
·
IF 6.59
Chen Hui,Zheng Huizhen,Li Tiejun,Jiang Qihong,Liu Shulai,Zhou Xuxia,Ding Yuting,Xiang Xingwei
Oyster peptide (OP) has exhibited useful biological activities and can be used in multi-functional foods. OP has been reported to play a significant role in intestinal protection, but its specific mechanism is still not completely understood. The aim of this study was to analyze the potential effect of OP on oxidative damage of mice intestine induced by cyclophosphamide (Cy). The experimental results revealed that intragastric administration of OP significantly increased average bodyweight, improved ileum tissue morphology and villus structure, as well as increased the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in oxidized mice serum and liver. The content of malondialdehyde (MDA) in the mice serum and liver homogenate was found to be markedly decreased. Moreover, OP significantly increased the relative mRNA expression levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), quinone oxidoreductase (NQO1) and heme oxidase-1 (HO-1) in ileum. Western-blot results indicated that prior administration of OP significantly up-regulated the Nrf2 production in ileum, and substantially decreased then Keap1 gene expression. In conclusion, intake of OP was found to markedly improve intestinal oxidative stress in vivo, and this effect was primarily mediated through the simulation of antioxidant Nrf2-Keap1 signaling pathway. This study is beneficial to the application of peptide nutrients in the prevention or mitigation of intestinal oxidative damage.
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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免疫学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Xiaojue Xiang,Xu Lin,Qifang Wu,Xiaoming Zhang,Xueliang Fu,Linya Wu,Haibin Tong,Zhenyu Dai
Dendrobium officinale extract DOE ameliorates metabolic disorders and diabetic cardiomyopathy. • DOE reduced myocardial injury, fibrosis, and oxidative stress via activating NRF2 pathway. • Dendrobine was the principal cardioprotective alkaloid in DOE against diabetic cardiomyopathy . • Dendrobine directly targets KEAP1 Kelch domain to disrupt the KEAP1-NRF2 interaction . Background Dendrobium officinale Kimura et Migo is a prestigious traditional Chinese medicine historically used for treating "Xiao-Ke" (diabetes and its complications). However, the specific material basis and direct molecular targets responsible for its efficacy against diabetic cardiomyopathy (DCM) remain largely obscure. This study aimed to systematically investigate whether dendrobine, the characteristic active alkaloid of DO, serves as the principal cardioprotective component by directly targeting the KEAP1-NRF2 signaling axis. Methods The therapeutic effects of D. officinale extract (DOE) and dendrobine were evaluated in vivo using db/db mice and in vitro using high-glucose (HG)-challenged H9c2 cardiomyocytes. Cardiac pathological remodeling, lipid peroxidation, and systemic metabolic profiles were comprehensively assessed. The direct interaction between dendrobine and KEAP1 was definitively characterized using Co-Immunoprecipitation (Co-IP), Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), MicroScale Thermophoresis (MST), and 100-ns Molecular Dynamics (MD) simulations. Reverse pharmacological validation was performed using NRF2-specific siRNA and the inhibitor ML385. Results In vivo , DOE significantly ameliorated systemic insulin resistance, hyperlipidemia, and myocardial pathological remodeling in db/db mice while robustly suppressing myocardial oxidative stress (MDA, 4-HNE) by upregulating NRF2-driven antioxidant enzymes (HO-1, NQO1, GPX4). In vitro , dendrobine dose-dependently replicated these cardioprotective and antioxidative efficacies. Mechanistically, dendrobine promoted NRF2 nuclear translocation and initiated the downstream antioxidant cascade. Crucially, MST and CETSA revealed that dendrobine binds directly to KEAP1 with high affinity ( K d = 1.18 μM), functioning as a competitive protein-protein interaction (PPI) inhibitor to disrupt the KEAP1-NRF2 complex. MD simulations and mutagenesis validation pinpointed the Kelch domain of KEAP1 (specifically residue Arg415) as the binding pocket. Finally, silencing or inhibiting NRF2 abolished the anti-hypertrophic and cytoprotective effects of dendrobine, and the in vivo administration of dendrobine successfully recapitulated the metabolic regulation and KEAP1/NRF2-mediated cardioprotection of DOE in db/db mice. Conclusion Dendrobine, the principal alkaloid of D. officinale , effectively ameliorates diabetic cardiomyopathy by functioning as a novel, direct competitive inhibitor of the KEAP1-NRF2 interaction. This targeted disruption liberates NRF2 to restore myocardial redox homeostasis, highlighting dendrobine as a promising lead compound for DCM therapy. Download: Download high-res image (395KB) Download: Download full-size image
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DOI
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Wei Wu,Hui Han,Jingwangwei Liu,Min Tang,Xiaoyu Wu,Xiaojun Cao,Tiantian Zhao,Yujia Lu,Tingting Niu,Juanjuan Chen,Haimin Chen
As the most abundant marine carotenoid extracted from seaweeds, fucoxanthin (FUC) is considered to have excellent neuroprotective activity. However, the target of FUC for its neuroprotective properties remains largely unclear. Oxidative stress is one of the initiating factors causing neuronal cell loss and necrosis, and it is also an important inducement of Parkinson’s disease (PD). In the present study, the neuroprotective effect of FUC was assessed using a 6-hydroxydopamine- (6-OHDA-) induced neurotoxicity model. FUC suppressed 6-OHDA-induced accumulation of intracellular ROS, the disruption of mitochondrial membrane potential, and cell apoptosis through the Nrf2-ARE pathway. Keap1 as a repressor of Nrf2 can regulate the activity of Nrf2. Here, the biolayer interferometry (BLI) assay demonstrated that FUC specifically targeted Keap1 and inhibited the interaction between Keap1 and Nrf2. FUC bound to the hydrophobic region of Keap1 pocket and formed hydrogen bonding interactions with Arg415 and Tyr525. Besides, it also dose-dependently upregulated the expressions of antioxidant enzymes, such as nicotinamide heme oxygenase-1, glutamate-cysteine ligase modifier subunit, and glutamate-cysteine ligase catalytic subunit, in 6-OHDA-induced PC12 cells. In 6-OHDA-exposed zebrafish, FUC pretreatment significantly increased the total swimming distance of zebrafish larvae and improved the granular region of the brain tissue damage. These results suggested that FUC could protect the neuronal cells against 6-OHDA-induced injury via targeting Keap1.
研究领域:
神经科学
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药理学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
Current Computer-Aided Drug Design
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2024
·Vol. 21
·期 4
·503-516
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IF 1.5
Xiaoyan Meng,Xinming Yan,Peng Xue,Zhaoqing Xi
ObjectiveThis study utilized transcriptomic sequencing combined with cellular and animal models to explore the potential mechanisms of Xuebijing in treating sepsis-induced myocardial dysfunction, also known as sepsis-induced myocardial injury.MethodsWe investigated potential targets and regulatory mechanisms of XBJ injection using network pharmacology and RNA sequencing. The effects of XBJ on oxidative stress and apoptosis levels in human cardiac myocytes (AC16) and C57BL/6 mice exposed to lipopolysaccharide (LPS) were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), fluorescent probe, Fluorescent Quantitative Polymerase Chain Reaction (qPCR), Western Blot, Transmission Electron Microscopy, oxidative stress-related indicators detection kit, flow cytometry, and Immunohistochemistry (IHC).ResultsFirst, it was verified that XBJ can reduce the deformation of AC16 cardiomyocytes induced by LPS and the production and secretion of ROS (P <0.01). The transcriptome sequencing results showed that the TRIM16 gene was significantly increased after XBJ treatment, and the data of KEGG and GO analyses demonstrated that XBJ could inhibit the pathway expression of oxidative stress damage in AC16 cells, and PCR verified that XBJ could indeed increase the expression level of TRIM16 gene in AC16 cells (P <0.01). Basic animal and cell experiments showed that LPS could inhibit the expression of TRIM16 and NRF2 in cardiomyocytes (P <0.05) and promote the expression of Keap1 (P <0.01), while XBJ could significantly up-regulate the expression levels of TRIM16 and NRF2 (P <0.01) and inhibit the expression of Keap1 (P <0.01), thereby affecting the expression levels of downstream proinflammatory cytokines and alleviating LPS-induced oxidative stress damage. In addition, XBJ also inhibited the expression of the pro-apoptotic proteins Bax and c-caspase3 (P <0.01), promoted the expression of the anti-apoptotic protein Bcl2 (P <0.01), and reduced LPS-induced apoptosis by upregulating TRIM16.ConclusionOur comprehensive data demonstrated that TRIM16 is a key gene in the therapeutic action of Xuebijing in sepsis-induced myocardial dysfunction, protecting myocardial cells from injury through antioxidative stress and anti-apoptotic mechanisms.
研究领域:
医学
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分子生物学
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药理学
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DOI
高影响因子
Food & Function
·
2020
·Vol. 11
·期 4
·3043-3052
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IF 4.171
Wenli Yan,Guimei Lin,Rong Zhang,Zhen Liang,Wenjuan Wu
Two novel effective antioxidative tripeptides GWY and QWY were designed based on 3D-QSAR models. Their activities were confirmed by an improved TEAC assay. The experimental results showed that GWY and QWY possessed good antioxidant activity, equaling 3.32 mM TE and 2.97 mM TE respectively. This indicated that 3D-QSAR models possessed significant predictive capacity for drug design. In addition, molecular docking and molecular dynamics simulation were applied to reveal the potential molecular mechanism of antioxidant peptides. The result showed that GWY and QWY could enhance the stability of Keap1 by interacting with the key residues Arg415, Arg483, Arg380 and Ser555 in the active sites. Interestingly, the key residues were exactly the binding site of Nrf2 in the active pocket of Keap1. Thus, GWY and QWY could compete with Nrf2 for binding to Keap1. This demonstrated that the new tripeptides might have the ability to activate the signaling pathway Keap1–Nrf2–ARE and improve the antioxidant defense system of the body as well.
研究领域:
生物化学
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药物设计
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2020
·Vol. 24
·期 15
·8579-8588
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IF 4.486
Xing-He Xue,Ji-Xin Xue,Wei Hu,Fang-Ling Shi,Yang Yang
Osteoarthritis (OA) is a long-term and inflammatory disorder featured by cartilage erosion. Here, we describe nomilin (NOM), a triterpenoid with inflammation modulatory properties in variety of disorders. In this study, we demonstrated the latent mechanism of NOM in alleviating the progress of OA both in vitro and in vivo studies. The results showed that NOM pre-treatment suppressed the IL-1β–induced over-regulation of pro-inflammation factors, such as NO, IL-6, PGE 2 , iNOS, TNF-α and COX-2. Moreover, NOM also down-regulates the degradation of ECM induced by IL-1β. Mechanistically, the NOM suppressed NF-κB signalling via disassociation of Keap1-Nrf2 in chondrocytes. Furthermore, NOM delays the disease progression in the mouse OA model. To sum up, this research indicated NOM possessed a new potential therapeutic option in osteoarthritis.
研究领域:
药理学
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风湿病学
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炎症研究
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DOI
PubMed
高影响因子
Frontiers in Endocrinology
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2018
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IF 3.519
Ying Yin,Jin Jiye,Ye Li,Sun Pingping,Wang Hui,Wang Xiaodong
Hyperglycemia induces chronic inflammation and oxidative stress in cardiomyocyte, which are the main pathological changes of diabetic cardiomyopathy (DCM). Treatment aimed at these processes may be beneficial in DCM. Phloretin (PHL), a promising natural product, has many pharmacological activities, such as anti-inflammatory, anticancer, and anti-oxidative function. The aim of this study was to investigate whether PHL could ameliorate the high glucose-mediated oxidation, hypertrophy, and fibrosis in H9c2 cells and attenuate the inflammation- and oxidation-mediated cardiac injury. In this study, PHL induced significantly inhibitory effect on the expression of pro-inflammatory, hypertrophy, pro-oxidant, and fibrosis cytokines in high glucose-stimulated cardiac H9c2 cells. Furthermore, PHL decreased the levels of serum lactate dehydrogenase, aspartate aminotransferase, and creatine kinase-MB, and attenuated the progress in the fibrosis, oxidative stress, and pathological parameters via Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) pathway in diabetic mice. In additional, molecular modeling and immunoblotting results confirmed that PHL might obstruct the interaction between Nrf2 and Keap1 through direct binding Keap1, and promoting Nrf2 expression. These results provided evidence that PHL could suppress high glucose-induced cardiomyocyte oxidation and fibrosis injury, and that targeting Keap1/Nrf2 may provide a novel therapeutic strategy for human DCM in the future.
研究领域:
药理学
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心脏病学
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糖尿病
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULES
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2026
·Vol. 31
·期 12
·2157
·
IF 5.1
Beibei Chen,Liang He,Qi Huang,Yanbin Wang
Ganoderma lucidumspores protein (GLSP) holds significant potential for providing antioxidant peptides. We employed in silico enzymatic hydrolysis to generate small peptide fragments by specific proteins. Through fast computer screening and molecular docking with Keap1 receptor, we identified two potential antioxidant peptides, KAF (Lys-Ala-Phe) and NDSF (Asn-Asp-Ser-Phe), from 1171 candidates after efficient hydrolysis by pepsin and proteinase K. Molecular docking result showed both of them could bind onto the Leu557, Ala 510 and Val512 of bioactive pockets of Keap1 through hydrogen bonds and NDSF had lower docking energy (−85.6073 kcal/mol). The in vitro antioxidant validation indicated both of them could eliminate DPPH and ABTS radicals dramatically, and NDSF had a stronger scavenging capacity on DPPH (IC50= 35.1 μg/mL) and ABTS (IC50= 55.9 μg/mL), respectively. Quantitative chemical analysis further revealed that the key antioxidant active sites of NDSF were located at O18 of Ser amino side chain, and N9 of Lys terminal amino residue for KAF. Furthermore, in the cellular experiments, NDSF and KAF effectively increased the activities of antioxidant enzymes such as SOD, CAT, and GPx, while also reducing the level of MDA. Together, these findings highlight the potential ofGanoderma lucidumspore proteins as a source for the rapid identification of antioxidant peptides. The two selected peptides, therefore, s hold promising prospects for applications in functional foods and health products.
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Xingyu Chen,Wenqian Sun,Yanting Song,Shangong Wu,Shouqi Xie,Wen Xiong,Chengdong Peng,Yu Peng,Zhengxiang Wang,Sovan Lek,Christer Hogstrand,Mette Sørensen,Lei Pan,Dong Liu
The impact of cadmium (Cd) toxicity on fish liver injury has received much attention in recent years. Currently, autophagy, apoptosis and endoplasmic reticulum stress were reported in Cd exposed fish liver, and if there are other mechanisms (such as ferroptosis) and relevant signaling pathways involved in fish remains unknown. An experiment was conducted to investigate Cd toxicity in Channa argus (Cantor, 1842) exposed to 0, 1.0, and 2.0 mg Cd/L of water for 96 h. Cd disrupted the structure of mitochondria in the liver. Besides, Cd induced ferroptosis by significantly increasing the level of Fe 2+ , ROS, MDA and significantly decreasing the level of Ferritin, GSH, GSH-Px, GPX4, GST and SOD ( p < 0.05 in all cases). In addition, the mRNA expression of ferroptosis related genes, gpx4 and slc7a11 , were significantly downregulated by Cd. Moreover, Cd exposure significantly inhibited the Nrf2/Keap1 signaling pathway, one of the pathways involved in ferroptosis, by upregulating the mRNA levels of keap1a and keap1b , and downregulating the mRNA levels of nrf2 and its target genes ( ho-1 , nqo1 and cat ). Cd exposure also caused extensive accumulation of vacuoles and lipid droplets in liver, as well as an increase in triglyceride content. Cd significantly affected lipid metabolism related enzyme activity and gene expression, which were also regulated by Nrf2/Keap1 signaling pathway. In summary, these results indicate that ferroptosis is a mechanism in waterborne Cd exposed fish liver injury via the Nrf2/Keap1 signaling pathway and the Cd induced hepatic steatosis is also modulated by Nrf2/Keap1 pathway at the whole-body level in fish. These findings provide new insights into the fish liver injury and molecular basis of Cd toxicity.
研究领域:
环境毒理学
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鱼类生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Mengdi Zhang,Jindong Gao,Md. F. Kulyar,Wanhe Luo,Guodong Zhang,Xiaoqi Yang,Tianguang Zhang,Haihang Gao,Yuxuan Peng,Jiabin Zhang,Muhammad Altaf,Samah Attia Algharib,Donghai Zhou,Jianzhong He
Acute renal failure is a common clinical disease in canines, affecting antioxidant levels and decreasing the body's resistance. This study aims to explore the therapeutic mechanism of Nano-selenium in acute renal failure. The histopathological and imaging changes of kidney tissue were observed with the gene and protein expression levels of Keap1, Nrf2, HO-1, and NQO1 in the kidney. According to our findings, adding nano-selenium can effectively reduce the concentration of CRE and BUN in blood and kidney tissues. It increased the activity of GSH-PX and SOD by an effective reduction of MDA. Through pathological and imaging observations, it was found that adding nano-selenium could improve the kidney tissue structure of acute renal failure. The results of the RT-qPCR experiment showed that after the addition of nano-selenium, the mRNA expression of the Keap1 gene decreased significantly. In contrast, the mRNA expression of the Nrf2, HO-1, and NQO1 genes increased significantly. The experimental results were further verified by western blot and immunohistochemical analysis. Hence, the nano-selenium intervention improved kidney function and increased antioxidant levels in canines suffering from acute renal failure with the involvement of the Keap1-Nrf2/ARE signaling pathway.
研究领域:
兽医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2025
·
IF 9.8
Zaheer Abbas,Jing Zhang,Yucui Tong,Baseer Ahmad,Junyong Wang,Haosen Zhang,Zhenzhen Li,Xubiao Wei,Rijun Zhang,Dayong Si
The objective of this study was to isolate and characterize antioxidant peptides from mulberry leaves fermented with Bacillus subtilis H4 and Bacillus amyloliquefaciens LFB112. The results indicated that fraction F4 (<1 kDa) exhibited superior DPPH activity compared to the F1 (>10 kDa), F2 (3–10 kDa), and F3 (1–3 kDa) fractions, and cytoprotective effect against lipopolysaccharides (LPS)-induced oxidative stress in RAW264.7 cells. Three novel peptides, FRFDP, RFGG, and GPPLAFGGGP, were identified in the F4 fraction of the mulberry leaf ferment, and docking results showed that these peptides could form stable carbon (covalent) and hydrogen bonds to the active sites of Keap1, thus regulating the Keap1-Nrf2 pathway by blocking the Nrf2 binding sites on Keap1. These peptides significantly upregulated the mRNA expression of Nrf2 , HO-1 , and NQO1 , providing indirect evidence of their potential to enhance cellular antioxidant defense via the possible activation of Keap1-Nrf2 pathway. Furthermore, these peptides showed good DPPH and ABTS scavenging activities, indicating their potential as antioxidant peptides. This study offers valuable insights into the integration of these novel peptides in developing mulberry leaf ferment as a functional food and their potential use as a feed additive.
研究领域:
食品科学
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生物化学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）