CHEMISTRY & BIODIVERSITY
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2021
·Vol. 18
·期 4
·e2001007
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IF 2.408
Yan Zhao,Yu Wang,Min Zhang,Yugang Gao,Zhaowei Yan
Ginsenosides (20 S )-Rg3 and (20 R )-Rg3 are famous rare ginsenosides from red ginseng, and their configurations in C-20 are different. This study aimed to investigate the protective mechanism of ginsenosides (20 S )-Rg3 and (20 R )-Rg3 on H 2 O 2 -induced H9C2 cells and compare their activity. The results showed that the ginsenosides (20 S )-Rg3 and (20 R )-Rg3 could increase the cell activity and the levels of GSH-Px, SOD and CAT, and decrease activities of LDH, MDA and ROS. Further studies showed that ginsenosides (20 S )-Rg3 and (20 R )-Rg3 could prevent oxidative stress injury of H9C2 cells by H 2 O 2 through the Keap-1/Nrf2/HO-1 pathway. But the ML385 counteracts these effects. Interestingly, among these results, ginsenoside (20 R )-Rg3 was superior to (20 S )-Rg3, indicating that ginsenoside (20 R )-Rg3 have a stronger effect of antioxidative stress. This study reflected that ginsenoside (20 R )-Rg3 could be used as a potential Nrf2 activator and a safe effective Chinese herbal monomer in the treatment of cardiovascular disease.
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Frontiers in Pharmacology
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2020
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IF 4.225
Yao He,Sun Jingyu,Wei Jie,Zhang Xin,Chen Bing,Lin Yajun
Over recent years, an increasing number of studies have confirmed that the occurrence and development of vascular pathological changes are closely related to oxidative stress and the inflammatory response of the vascular endothelium. Kaempferol is the most common flavonoid compound found in fruits and vegetables. Our present research identified that kaempferol had the capability to protect the vascular endothelium in a mouse model of vascular injury and explored the specific mechanisms underlying these effects by investigating oxidative stress, the extent of cardiovascular injury, and inflammatory markers such as NF-κB, TNF-α, IL-6, and the Nrf2/HO-1 signaling pathway. Analysis showed that kaempferol reduced oxidative stress and inflammation mediated by H2O2 and paraquat, respectively, both in vitro and in vivo. Furthermore, kaempferol suppressed the levels of TNF-α and IL-6, and the activation of NF-κB, in aortic tissues and human umbilical vein endothelial cells (HUVECs). Finally, we observed that kaempferol corrected the levels of antioxidants and elevated the protein levels of Nrf2 and HO-1 in aortic tissues and HUVECs. Collectively, our findings prove that kaempferol protects blood vessels from damage induced by oxidative stress and inflammation and that the Nrf2/HO-1 signaling pathway plays a key role in mediating these effects.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2019
·
IF 3.571
Dongwen Hu,Tao Bao,Yang Lu,Hongming Su,Huihui Ke,Wei Chen
This study was aimed to investigate the protective effects of three different mulberry fruit polysaccharide fractions (MFP-I, MFP-II, and MFP-III) against palmitic acid (PA)-induced hepatocyte lipotoxicity and characterize the functional polysaccharide fraction using gel permeation chromatography, high-performance liquid chromatography, Fourier transform infrared spectroscopy, and nuclear magnetic resonance analyses. MFP-I, MFP-II, and MFP-III were isolated from mulberry fruit by stepwise precipitation with 30, 60, and 90% ethanol, respectively. MFP-II at 0.1 and 0.2 mg/mL dramatically attenuated PA-induced hepatic lipotoxicity, while MFP-I and MFP-III showed weak protection. It was demonstrated that MFP-II not only increased nuclear factor erythroid-2-related factor 2 (Nrf2) phosphorylation and its nuclear translocation, thereby activating the Nrf2/ARE signaling pathway, but also enhanced heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and γ-glutamate cysteine ligase gene expressions and promoted catalase and glutathione peroxidase activities, which protected hepatocytes against PA-induced oxidative stress and lipotoxicity. Further investigation indicated that the molecular weight of MFP-II was 115.0 kDa, and MFP-II mainly consisted of galactose (30.5%), arabinose (26.2%), and rhamnose (23.1%). Overall, our research might provide in-depth insight into mulberry fruit polysaccharide in ameliorating lipid metabolic disorders.
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CHEMICAL RESEARCH IN TOXICOLOGY
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2018
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IF 3.432
Zixuan Liu,Wenjing Dong,Bingwei Yang,Lu Peng,Xiaomin Xia,Lanxiang Pu,Na Zhang,Erqun Song,Yang Song
Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells. TCBQ upregulated the levels of GSH mainly by the following two ways: (i) Nrf2 activation induced the expression of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT); (ii) Nrf2 activation resulted in increased the expression of glutamylcysteine ligase. GSH is involved in cell antioxidant ability and protein thiol homeostasis, especially in the ER. Therefore, GSH has the ability to inhibit ER stress and promote cell survival. Our data showed that decreasing GSH levels exacerbated TCBQ-induced depletion of protein-SH, particularly in the ER. Conversely, increasing GSH levels attenuated TCBQ-induced protein damage, degree of ER stress, and cell death. These findings demonstrated that GSH-inhibited cells were vulnerable to TCBQ-induced ER stress and apoptosis. Overall, our results analyzed the relationships between Nrf2 and ER stress in response to TCBQ and showed that activation of Nrf2-GSH played a protective role against TCBQ-induced ER stress-associated neurotoxicity via regulating GSH synthesis and protein thiol homeostasis.
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FOOD CHEMISTRY
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2024
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IF 8.5
Kuiyou Wang,Kexin Huang,Xueqian Li,Hao Wu,Li Wang,Fengyu Bai,Mingqian Tan,Wentao Su
This study innovatively utilized kelp-derived nanocellulose and sodium caseinate (SC) to prepare fucoxanthin (Fx)-loaded nanoparticles, exploring their efficacy in reducing oxidative stress and inhibiting lipid accumulation. 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation produced well-dispersed, kelp-derived nanocellulose. When these celluloses were mixed with SC at varying mass ratios, the composite nanoparticles showed excellent stability. Specifically, at a TEMPO-oxidized kelp nanocellulose (TKNC) to SC mass ratio of 1:3, the encapsulation efficiency for Fx reached 82.2 %, with a retention of 56.12 % after 14 days of storage. In vitro , the nanoparticles demonstrated good biocompatibility and were efficiently absorbed by cells, significantly enhancing Fx bioavailability . This enhanced delivery efficiency alleviates oxidative stress by activating the Nrf2/HO-1/NQO1 signaling pathways and effectively inhibits lipid droplet formation induced by excessive free fatty acids (FFAs). Moreover, distribution studies in mice revealed effective accumulation of nanoparticles in the intestines and liver, indicating their potential for targeted drug delivery. These findings provide strong experimental support for the use of TKNC and SC as biocompatible materials in nanoparticles for drug delivery and treatment applications.
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Scientific Reports
·
2024
·Vol. 14
·期 1
·1-16
·
IF 3.8
Zhu Chunyang,Lu Yangyang,Wang Shasha,Song Jialin,Ding Yixin,Wang Yan,Dong Chen,Liu Jiani,Qiu Wensheng,Qi Weiwei
Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)—NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Jingjing Lin,Lu Deng,Ailin Qi,Hong Jiang,Di Xu,Yuehui Zheng,Zixuan Zhang,Xiaoman Guo,Beilei Hu,Peijun Li
Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo . We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.
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International Journal of Pharmacology
·
2026
·Vol. 22
·期 6
·
IF 0.7
Yachun Guo,Jiahui Zhang,Yanchao Li
Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, and novel therapeutic strategies are urgently needed to overcome treatment resistance. Cordycepin (Cor), a bioactive nucleoside isolated from Cordyceps militaris, exhibits antitumor activity in multiple malignancies. However, whether Cor induces ferroptosis in NSCLC cells and the underlying mechanisms remain unclear. Therefore, this study aimed to investigate the modulatory effects of Cor on ferroptosis in NSCLC cells and to elucidate the underlying molecular and network pharmacology mechanisms. Methods: Human NSCLC A549 cells were treated with Cor (25, 50, and 100 μM). Cell viability was assessed using Cell Counting Kit-8 assays. Ferroptosis involvement was evaluated using ferroptosis inhibitors (ferrostatin-1, deferoxamine, and liproxstatin-1) and other programmed cell death inhibitors. Intracellular reactive oxygen species (ROS), Fe2+ accumulation, lipid peroxidation, glutathione (GSH) levels, and ferroptosis-related proteins were measured using fluorescence probes, spectrophotometric assays, and western blotting. Network pharmacology, protein-protein interaction analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and molecular docking were performed to identify potential molecular targets. Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression was further examined by western blotting. Results: Cor inhibited A549 cell viability in a time- and dose-dependent manner (n = 6). Among the tested death inhibitors, only ferroptosis inhibitors significantly reversed Cor-induced cytotoxicity (p < 0.05, n = 3). Cor treatment elevated intracellular ROS levels, Fe2+ accumulation, and lipid peroxidation while reducing GSH content (p < 0.05, n = 3). At the protein level, Cor downregulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression but upregulated transferrin and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression (p < 0.05, n = 3). Database screening identified 28 mutual targets linked to Cor, NSCLC, and ferroptosis. Molecular docking confirmed that Cor spontaneously binds to the Nrf2 and HO-1 proteins encoded by the key pathway genes nuclear factor erythroid 2 like 2 (NFE2L2) and heme oxygenase 1 (HMOX1), which correlated with a significant, dose-dependent downregulation of Nrf2 and HO-1 protein expression (p < 0.05, n = 3). Conclusions: Cordycepin induces ferroptosis in A549 NSCLC cells, characterized by oxidative stress, iron accumulation, lipid peroxidation, and suppression of antioxidant defenses. The Nrf2/HO-1 pathway may contribute to this process and represents a potential therapeutic target for NSCLC.
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INFLAMMOPHARMACOLOGY
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2024
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IF 4.6
Li Ming-Jie,Xu Jing-Yi,Zhang Hua-Yue,Guo Min,Lan Meng-Ning,Kong Jie,Liu Shi-Wei,Zheng Hua-Jun
Alzheimer’s disease (AD) is a neurodegenerative disorder frequently accompanied by neuroinflammation and oxidative stress. The medicine and food homology (MFH) has shown potential for treating neuroinflammation and oxidative stress. This study aimed to provide a safe and efficient therapy for AD based on MFH. In this study, we develop a MFH formula consisting of egg yolk oil, perilla seed oil, raphani seed oil, cinnamon oil, and noni puree (EPRCN). To evaluate the ameliorative effects of EPRCN on AD-related symptoms, a mouse model of AD was constructed using intraperitoneal injection of scopolamine in ICR mice. Experimental results demonstrated that EPRCN supplement restored behavioral deficits and suppressed neuroinflammation and oxidative stress in the hippocampus of scopolamine-induced mice. An in vitro study was then performed using induction of Aβ (25–35) in glial (BV–2 and SW–1783) and neuron (SH–SY5Y) cell lines to examine the improvement mechanism of EPRCN on cognitive deficits. Multi-omics and in vitro studies demonstrated that these changes were driven by the anandamide (AEA)-Trpv1-Nrf2 pathway, which was inhibited by AM404 (an AEA inhibitor), AMG9810 (a Trpv1 inhibitor), and BT (an Nrf2 inhibitor). Consequently, EPRCN is an effective therapy on preventing cognitive deficits in mouse models of AD. In contrast to donepezil, EPRCN exhibits a novel modes action for ameliorating neuroinflammation. The mechanism of EPRCN on preventing cognitive deficits is mediated by improving neuroinflammation and oxidative stress via activating the AEA–Trpv1–Nrf2 pathway.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
·
IF 7.7
Kunfeng Zhang,Hao Chen,Yunbo Hao,Wensen Li,Yong Li,Wenna Zhang,Yan Chen
We identified Armillariella tabescens polysaccharide (PAT-W), a compound isolated from a Chinese medicinal mushroom , as a potential novel oral ulcer (OU) drug. In treating OU rats with PAT-W, especially in the high-dose group, oral mucous tissue TNF- α , IL-1 β , and IL-6 levels were markedly reduced, and pathological morphology and oxidative stress were effectively improved. Western blot analysis showed that the PAT-W channel ameliorated OU mucous tissue damage, which depends on the activation of the Nrf2/HO-1 antioxidant signaling pathway . Furthermore, high-throughput sequencing results showed that PAT-W regulated the maladjustment of the oral microbiota caused by OU. Therefore, based on the new viewpoint of activating the Nrf2/HO-1 pathway and regulating oral microbiota, PAT-W is expected to become a new natural drug for treating oral ulcers and improving patients' quality of life.
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ENVIRONMENTAL TOXICOLOGY
·
2024
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IF 4.4
Lei Huang,Jiayi Wang,Jieqin Yu,Mengxuan Bian,Xingdong Xiang,Guanjie Han,Weisin Chen,Ning Wang,Jun Ge,Shunyi Lu,Jian Zhang
Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.
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JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
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2024
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IF 3.3
Xi-you Li,Xiao-yuan Gu,Xiao-min Li,Jian-gang Yan,Xin-liang Mao,Qin Yu,Yu-lan Du,Hiroshi Kurihara,Chang-Yu Yan,Wei-xi Li
BACKGROUND Carnosine, a natural bioactive dipeptide derived from meat muscle, possesses strong antioxidant properties. Dexamethasone, widely employed for treating various inflammatory diseases, raises concerns regarding its detrimental effects on bone health. This study aimed to investigate the protective effects of carnosine against dexamethasone-induced oxidative stress and bone impairment, along with its underlying mechanisms, utilizing chick embryos and a zebrafish model in vivo , as well as MC3T3-E1 cells in vitro . RESULTS Our findings revealed that carnosine effectively mitigated bone injury in dexamethasone-exposed chick embryos, accompanied by reduced oxidative stress. Further investigation demonstrated that carnosine alleviated impaired osteoblastic differentiation in MC3T3-E1 cells and zebrafish by suppressing the excessive production of reactive oxygen species (ROS) and enhancing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, mechanistic studies elucidated that carnosine promoted the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby facilitating the transcription of its downstream antioxidant response elements, including heme oxyense-1 (HO-1), glutamate cysteine ligase modifier (GCLM), and glutamate cysteine ligase catalytic (GCLC) to counteract dexamethasone-induced oxidative stress. CONCLUSION Overall, this study underscores the potential therapeutic efficacy of carnosine in mitigating oxidative stress and bone damage induced by dexamethasone exposure, shedding light on its underlying mechanism of action by activating the NRF2 signaling pathway. © 2024 Society of Chemical Industry.
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