BIOMATERIALS
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2023
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IF 14
Shengjie Sun,Mian Yu,Liu Yu,Wenxin Huang,Meishu Zhu,Yanan Fu,Lingchen Yan,Qiang Wang,Xiaoyuan Ji,Jing Zhao,Meiying Wu
Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage , which is highly correlated with the upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream products, such as glutathione (GSH). Herein, to overcome this dilemma, we designed a versatile nanoadjuvant ( [email protected] ) to enhance the sensitivity of tumor cells to oxidative stress via Nrf2-specific small interfering RNA (siNrf2). The constructed [email protected] could significantly amplify photooxidative stress and achieve robust DNA oxidative damage, activating the stimulator of interferon genes (STING)-dependent immune-sensing to produce interferon-β (IFN-β). Additionally, [email protected] together with laser irradiation reinforced tumor immunogenicity by exposing or releasing damage-associated molecular patterns (DAMPs), showing the prominent adjuvant effect for promoting dendritic cell (DC) maturation and T-lymphocyte activation and even alleviating the immunosuppressive microenvironment to some extent.
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Drug Design Development and Therapy
·
2023
·
IF 4.8
Wei-guang Yang,Ao Sun,Rong Zhu,Nan Liu,Wei-jie He,Lin-lin Liu
Background Artemisinin (ART) is a safe and effective antimalarial drug. In recent years, antimalarial drugs have demonstrated a good therapeutic efficacy in IgA nephropathy, suggesting that this may become a new treatment option.Purpose We aimed to evaluate the effect and mechanism of artemisinin in IgA nephropathy.Methods In this study, CMap database was used to predict the artemisinin therapeutic effect for IgA nephropathy. A network pharmacology approach was applied to explore the unknown mechanism of artemisinin in IgA nephropathy. We used molecular docking to predict the binding affinity of artemisinin with the targets. A mouse model of IgA nephropathy was established to investigate the therapeutic effect of artemisinin on IgA nephropathy. In vitro, the cell counting Kit-8 assay was used to evaluate the cytotoxicity of artemisinin. Flow cytometry and PCR assays were used to detect the effects of artemisinin on oxidative stress and fibrosis in lipopolysaccharide (LPS)-stimulated mesangial cells. Western blot and immunofluorescence were used to detect the expression of pathway proteins.Results CMap analysis showed artemisinin may reverse the expression levels of differentially expressed genes in IgA nephropathy. Eighty-seven potential targets of artemisinin in the treatment of IgA nephropathy were screened. Among them, 15 hub targets were identified. Enrichment analysis and GSEA analysis indicated that response to reactive oxygen species is the core biological process. AKT1 and EGFR had the highest docking affinity with artemisinin. In vivo, artemisinin could improve renal injury and fibrosis in mice. In vitro, artemisinin attenuated LPS-induced oxidative stress and fibrosis promoted AKT phosphorylation and Nrf2 nuclear translocation.Conclusion Artemisinin reduced the level of fibrosis and oxidative stress with IgA nephropathy through the AKT/Nrf2 pathway, which provided an alternative treatment for IgAN.
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Food Bioscience
·
2023
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IF 5.2
Hengju Ge,Jiaxin Li,Yang Xu,Jiahong Xie,Naymul Karim,Fujie Yan,Jianling Mo,Wei Chen
Fructus Gardeniae (FG) is the dried ripe fruit of Gardenia jasminoides Ellis, having beneficial effects for human health. In this study, we discovered that the most relevant pathway influenced by Fructus Gardeniae extract (FGE) is lipid metabolism according to the analysis of network pharmacology. Furthermore, the protective effect of FGE against palmitic acid-induced lipotoxicity was investigated. In L02 cells, FGE significantly promoted cellular proliferation after being treated with palmitic acid , and reduced the accumulation of lipid droplets and triglyceride level . Palmitic acid led to an increase of ROS content, which was reduced by FGE. Additionally, FGE could facilitate Nrf2 localized to nuclear and followed by activating its downstream targets. ML385 (a Nrf2 inhibitor) treatment further proved that FGE attenuated lipotoxicity through regulating Nrf2/ARE pathway. Consequently, we demonstrated for the first time FGE could be regarded as potential functional food materials for hepatic protection.
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Journal of Cancer
·
2022
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IF 4.478
Kezhong Tang,Qing Chen,Yanmo Liu,Lantian Wang,Wenjie Lu
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2022
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IF 3.712
Haihua Zhang,Wuying Lang,Sufen Li,Chao Xu,Xiumin Wang,Yunyu Li,Zhiqiang Zhang,Tonglei Wu,Minshan Feng
Objective Corynoline is an active substance extracted from Corydalis bungeana Turcz and exerts a therapeutic effect in multiple diseases by alleviating inflammatory response. The present study sought to elucidate the role of corynoline in ulcerative colitis (UC).Methods The experimental colitis models were induced in BALB/c mice via receiving a drinking water supplemented with 3.5% (I) dextran sulfate sodium (DSS) ad libitum for 7 days.Results Corynoline administration inhibited body weight loss, colon shortening, disease activity index and colonic pathomorphological changes in DSS-treated mice. Besides, corynoline down-regulated the levels of pro-inflammatory interleukin (IL)-1β, IL-6 and tumor necrosis factor Alpha (TNF-α), as well as decreased myeloperoxidase (MPO) activity in the colon of DSS-treated mice. In addition, severe oxidative stress in the colonic tissues of DSS-treated was mitigated by corynoline treatment. However, these beneficial effects were reversed by a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 intervention. Further evidence confirmed that corynoline promoted Nrf2 nuclear migration and heme oxygenase-1 gene expression in the colonic tissues of UC mice. Besides, corynoline treatment restrained colonic nuclear factor-kappa B (NF-κB) activation as proved by the decrease in phosphorylation and nuclear translocation of NF-κB.Conclusions Corynoline ameliorates DSS-induced mouse colitis, which may provide a promising therapeutic strategy for UC treatment.
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FOOD AND CHEMICAL TOXICOLOGY
·
2022
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IF 5.572
Xue-Yan Dai,Shi-Yong Zhu,Jian Chen,Mu-Zi Li,Yi Zhao,Milton Talukder,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant. It has been determined that DEHP is involved in multiple health disorders. Lycopene (Lyc) is a natural carotenoid pigment , with anti-inflammatory and antioxidant properties. However, it is not clear whether Lyc can protect the spleen from DEHP-induced oxidative damage. A total of 140 mice were randomly divided into seven groups (n = 20) and continuously gavaged with corn oil, distilled water, DEHP (500 or 1000 mg/kg BW/day) and/or Lyc (5 mg/kg BW/day) for 28 days. Histopathological and ultrastructural results showed a DEHP-induced inflammatory response and mitochondrial injuries. Moreover, DEHP exposure induced redox imbalance, which resulted in the up-regulation of ROS activity and MDA content, and the down-regulation of T-AOC, T-SOD and CAT in the DEHP groups. Simultaneously, our results also demonstrated that DEHP-induced kelch-like ECH-associated protein 1 (Keap1) expression was downregulated, and the expression levels of P62, nuclear factor erythroid 2-related factor (NRF2) and their downstream target genes were up-regulated. However, the supplementary Lyc reverted these changes to normal levels. Together, Lyc prevented DEHP-induced splenic injuries by regulating the P62-Keap1-NRF2 signaling pathway. Hence, the protective effects of Lyc might be a therapeutic strategy to ameliorate DEHP-induced splenic damage.
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Journal of Functional Foods
·
2022
·
IF 5.223
Jinyuan Wang,Yinyan Yin,Nuo Xu,Bangyue Zhou,Tao Qin
In the bacterial infection of humans, sepsis is of great concern based on its high fatality rate. Correction of immune dysfunction by targeting dendritic cells (DCs) is a promising strategy for sepsis therapy. Royal jelly, a natural health product, is produced by worker bees for feeding queens. In the study, we evaluated whether royal jelly could attenuate LPS-induced immune dysfunction of DCs. We found that royal jelly reduced the expression levels of mature phenotype (MHCII, CD40, CD80, and CD86), activation marker (CD69), and inflammatory cytokines (TNF-α, IL-6, and IL-10) in LPS-induced DCs. In addition, royal jelly enhanced the endocytosis levels and abrogated allogeneic CD4 + T cell proliferation in LPS-induced DCs. Finally, we found that the Nrf2/HO-1 axis played a vital role in the inhibition of LPS-induced immune dysfunction of DCs by royal jelly. These results indicated that royal jelly had a potential application in sepsis therapy by regulating DC function.
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Drug Design Development and Therapy
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2022
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IF 4.319
Deshan Yao,Bo Shi,Sichuan Wang,Liuxiang Bao,Meng Tan,Hui Shen,Zhengang Zhang,Xin Pan,Yi Yang,Yong Wu,Kaizheng Gong
Background Oxidative stress and inflammatory reaction play critical roles in acute myocardial infarction (AMI). Isoliquiritigenin (ISL), a flavonoid monomer extracted from licorice, has been found to have antioxidant and anti-inflammatory effects in cancer studies. Here, we tested the effect and underlying mechanisms of ISL on ischemia-induced myocardial injury in a mouse AMI model. Methods Adult C57BL/6 mice were pre-treated by intraperitoneal injection of ISL and/or a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 for 3 days, respectively. Then, the AMI model was established by ligating the anterior descending branch of the left coronary artery. Myocardial oxidative stress status, inflammatory response, cardiac function and infarction size were assessed after 7th day of surgery. Results Compared with sham group, the reactive oxygen species (ROS) and malondialdehyde (MDA) level in AMI group were significantly increased. However, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) level were dramatically decreased. ISL treatment significantly reduced the myocardial infarction area, improved cardiac function, inhibited the production of ROS and MDA and reduced the consumption of SOD and GSH-Px. Interestingly, ISL could significantly increase nuclear Nrf2 and cytosolic heme oxygenase 1 (HO-1) level in the infarcted myocardium and reduce the oxidative stress after AMI. Also, ISL treatment dramatically inhibited the activation of myocardial NF-κB pathway and reduced the expression of pro-inflammatory factors in the AMI group. However, the administration of ML385 not only suppressed the Nrf2/HO-1 activation, the anti-oxidant and anti-inflammatory effects induced by ISL, but also attenuated the beneficial role of ISL on reducing infarct size and improving cardiac function in the mouse with AMI. Conclusion The results suggested that activation of Nrf2/HO-1 pathway has an essential role in ISL-induced cardiac protection by alleviating myocardial oxidative stress and inflammation response in mice with AMI.
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JOURNAL OF SURGICAL RESEARCH
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2022
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IF 2.417
Ming Deng,Ping Xie,Junqi Liu,Yan Zhou,Zhonghui Chen,Yonggang Ma,Jianwei Yang
Introduction α-Cyperone has anti-inflammatory activities, but its effects on spinal cord injury (SCI) remain obscure. Thus, this study attempts to investigate the effects and modulatory mechanisms of α-Cyperone on SCI. Materials and methods An SCI model was established in rats which were further treated with α-Cyperone. Basso-Beattie-Bresnahan (BBB) scoring was used to assess motor rehabilitation of rats modeled with SCI. The spinal cord tissues were collected, and the effect of α-Cyperone on the histopathology of rats modeled with SCI was detected by hematoxylin-eosin staining. Rat primary cortical neuron was stimulated with H 2 O 2 and further treated with α-Cyperone and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. The levels of Nrf2, interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), Akt, toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) were detected by immunofluorescence staining and western blotting . Results α-Cyperone elevated the BBB score and ameliorated the damage of spinal cord tissue in rats modeled with SCI. The levels of IL-6, Nrf2, NF-κB, TLR4, and TNF-α were upregulated, whereas that of Akt was downregulated in rats and cells modeled with SCI. Furthermore, α-Cyperone diminished the levels of IL-6, NF-κB, TLR4, and TNF-α, while augmenting those of Nrf2 and Akt in rats and cells modeled with SCI. ML385 inhibited the Nrf2 level that had been promoted by α-Cyperone in the nucleus and elevated the Nrf2 level that had been suppressed by α-Cyperone in the cytosol of cells modeled with SCI. ML385 increased the levels of IL-6, NF-κB, TLR4, and TNF-α that had been inhibited by α-Cyperone and decreased the Akt level that had been enhanced by α-Cyperone in cells modeled with SCI. Conclusions α-Cyperone suppressed SCI-induced inflammation and spinal cord tissue damage via activating Akt/Nrf2 and suppressing NF-κB pathways.
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LIPIDS
·
2022
·Vol. 57
·期 3
·153-162
·
IF 1.646
Danping Wang,Jinglong Chen,Huangbing Sun,Wenjing Chen,Xiaojing Yang
Oxidative stress is an important factor in the occurrence and development of liver disease. Medium-chain fatty acids (MCFAs) have potential antioxidant function, whereas the exact underlying mechanism of MCFA in oxidative injury of hepatocytes remains unclear. In our present study, three different MCFAs, 8-carbon octanoic acid (OA), 10-carbon capric acid (CA), and 12-carbon lauric acid (LA), have been performed to observe their protective action for hepatocyte under the H 2 O 2 challenge. The result showed that MCFA treatment significantly increased the cell viability, T-AOC, and expression of antioxidant-related genes in AML12 cells under oxidative stress condition, and reduced reactive oxygen species (ROS) production. Moreover, MCFA treatment significantly increased the protein expression of Nrf2 and the phosphorylation level of ERK1/2; LA treatment significantly promoted the Nrf2 nuclear translocation. With a further test, the rescue ability of MCFA was blocked by treating with the ERK inhibitor U0126. Overall, our data suggested that MCFA treatment has positive impact on protecting AML12 cells against oxidative stress through ERK1/2/Nrf2 pathway.
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BIOFACTORS
·
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.
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Antioxidants
·
2026
·Vol. 15
·期 9
·1183
·
IF 8.2
Junying Jiao,Ning Xu,Zhixuan Hong,Lei Chang,Derong Huang,Yang Yu,Zhendi Wang,Yibai Li,Jiaxin Yu,Juntao Guo,You Wang,Lirun Kuang,Yong Wang,Bei Yang,Rui Zhao,Yongyong Hou,Huihui Wang,Qiang Zhang,Ping Xu,Yuanyuan Xu,Jingbo Pi,Jingqi Fu
Hypercholesterolemia and hyperlipidemia are major contributors to the pathogenesis and progression of atherosclerosis and cardiovascular diseases (CVDs). Nuclear factor erythroid-derived 2-like 2 (NRF2) exerts antioxidant and anti-inflammatory effects while regulating glucose and lipid metabolism. However, the precise role and molecular mechanisms of NRF2 in hepatic cholesterol metabolism remain incompletely understood. Approach and Results: ApoE -knockout ( ApoE -KO) mice were crossed with hepatocyte-specific Nrf2 -knockout ( Nrf2 (H)-KO) mice to explore how NRF2 modulated cholesterol metabolism and the progression of atherosclerosis in vivo. Atherosclerotic lesion areas in Nrf2 (H)-KO; ApoE -KO mice were significantly reduced compared with control counterparts ( Nrf2 -LoxP; ApoE -KO). Total cholesterol and LDL-cholesterol levels in plasma of Nrf2 (H)-KO; ApoE -KO mice were significantly decreased, consistent with atherosclerotic phenotypes. Furthermore, hepatic triglyceride levels and cholesterol contents were increased in Nrf2 (H)-KO; ApoE -KO mice. The hepatic transcriptomic analysis highlighted lipid metabolism pathway alterations in Nrf2 (H)-KO; ApoE -KO mice, and carboxylesterase 1 ( Ces1s ) and lipocalin gene family member major urinary proteins ( Mups ) clusters markedly reduced expression in Nrf2 (H)-KO; ApoE -KO livers. Liver proteomics analysis corroborated the transcriptomic findings. The current findings suggest that NRF2-modulated CES1s and MUPs may regulate cholesterol metabolism in the ApoE -KO model. Conclusions: Hepatocyte-specific Nrf2 deficiency significantly reduced plasma cholesterol levels, thereby attenuating atherosclerotic plaque formation and progression in the ApoE -KO background. This study established NRF2 in hepatocytes as a potential therapeutic target for controlling hypercholesterolemia and preventing atherosclerosis development.
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