Emerging trends and hotspots of Nuclear factor erythroid 2-related factor 2 in nervous system diseases

BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.

Long non-coding RNA CDKN2B-AS1 promotes hepatocellular carcinoma progression via E2F transcription factor 1/G protein subunit alpha Z axis

BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its role in hepatocellular carcinoma(HCC)has not been fully deciphered.AIM To decipher the role of CDKN2B-AS1 in the progression of HCC.METHODS CDKN2B-AS1 expression in HCC was detected by quantitative real-time polymerase chain reaction.The malignant phenotypes of Li-7 and SNU-182 cells were detected by the CCK-8 method,EdU method,and flow cytometry,respectively.RNA immunoprecipitation was executed to confirm the interaction between CDKN2B-AS1 and E2F transcription factor 1(E2F1).Luciferase reporter assay and chromatin immunoprecipitation were performed to verify the binding of E2F1 to the promoter of G protein subunit alpha Z(GNAZ).E2F1 and GNAZ were detected by western blot in HCC cells.RESULTS In HCC tissues,CDKN2B-AS1 was upregulated.Depletion of CDKN2B-AS1 inhibited the proliferation of HCC cells,and the depletion of CDKN2B-AS1 also induced cell cycle arrest and apoptosis.CDKN2B-AS1 could interact with E2F1.Depletion of CDKN2B-AS1 inhibited the binding of E2F1 to the GNAZ promoter region.Overexpression of E2F1 reversed the biological effects of depletion of CDKN2B-AS1 on the malignant behaviors of HCC cells.CONCLUSION CDKN2B-AS1 recruits E2F1 to facilitate GNAZ transcription to promote HCC progression.

Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2-related factor 2 pathway

Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2（Nrf2）pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside（30 mg/kg）reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.

Interplay between nuclear factor erythroid 2-related factor 2 and inflammatory mediators in COVID-19-related liver injury

Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide.In addition to respiratory symptoms,COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases.Nuclear factor erythroid 2-related factor 2(NRF2)is a transcription factor that regulates the expression of antioxidant proteins,participating in COVID-19-mediated inflammation and liver injury.Here,we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury.Additionally,we describe some mechanisms and treatment strategies.

Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extending from simple steatosis to inflammation,fibrosis,cirrhosis,and hepatocellular carcinoma.Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD,progressing to liver fibrosis and cirrhosis.The nuclear factor erythroid 2-related factor 2(NRF2)is a master regulator of redox homeostasis.NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant,anti-inflammatory,and cytoprotective response.Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD development,from simple steatosis to inflammation,advanced fibrosis,and initiation/progression of hepatocellular carcinoma.NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes.Thus,modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies.This review outlined the current knowledge on the effects of NRF2 pathway,modulators,and mechanisms involved in the therapeutic implications of liver steatosis,inflammation,and fibrosis in MAFLD.

Keap1-nuclear factor rythroid 2-related factor 2 inhibitor NXPZ ameliorates Aβ1-42-induced cognitive dysfunction in mice

OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a widely concerned drug target.Recent research has identified that Nrf2 is involved in the pathology of Alzheimer disease(AD),whereas the mechanism is unknown.The purpose of this study is to figure out the role of Nrf2 in the pathologic process of AD through Nrf2-Keap1-ARE pathway and the effects of Keap1-Nrf2 inhibitor in AD mice models.METHODS Amyloid β^(1-42)(Aβ^(1-42))was injected into the bilateral hippocampus to induce the cognitive dysfunction in eight-week old male mice.The mice were treated with Keap1-Nrf2 inhibitor NXPZ of three doses as well as donepezil as a positive control by intragastric administration one time a day for one week.Several behavior tests were used to analyze the mice learning and memory ability.Additionally,we detected Nrf2 and Aβ in the plasma in mice with ELISA kits,as well as some factors related to oxidative stress in the hippocampus and cortex.The expression levels of Nrf2,Keap1,Tau and p-Tau were measured in the murine brain tissue with Western blotting.SH-SY5 Y cells were studied as an in vitro model to further clarify the mechanism.RESULTS The treatment of NXPZ ameliorated learning and memory dysfunction in AD mice in a dose-dependent manner,and the high dose group recovered better than the positive drug group.The plasma Nrf2 level was increased in a dose-dependent manner in the treatment groups;however,the plasma Aβ was decreased.What′ s more,superoxide dismutase(SOD) and glutathione reductase(GSSH) in the hippocampus and cortex were increased in the treatment group,while the malondialdehyde(MDA) was decreased,meaning that NXPZ treatment promoted expression of the anti-oxidative factors and inhibited the expression of the oxidative factors in the down-stream.Western blotting analysis of hippocampus and cortex showed up-regulated Nrf2,decreased Keap1 and decreased p-Tau in NXPZ treatment mice.In ex vivo experiments,when SH-SY5 Y cells were treated with Aβ,Nrf2 in the cytoplasm was increased,as well as the expression Nrf2 in the nuclear was decreased.The treatment of NXPZ increased nuclear Nrf2,decreased cytoplasm Nrf2,and decreased the expression of p-Tau.CONCLUSION Nrf2 has an important role in neuron function.Nrf2 activation by selective Keap1-Nrf2 inhibitor NXPZ may contribute to improve cognitive function in AD mice.The mechanism may be related to increased generation and release of Nrf2 induced by more disaggregation with Keap1,leading to more expression of anti-oxidative molecules to protect the damage caused by Aβ.These results indicates that Nrf2 may be a novel therapeutic target of AD and Keap1-Nrf2 inhibitor may be a novel medication for protecting the loss of learning and memory ability.

Upregulation of miR-34c after silencing E2F transcription factor 1 inhibits paclitaxel combined with cisplatin resistance in gastric cancer cells

BACKGROUND MicroRNA 34c(miR-34c)has been reported to be associated with malignant types of cancer,however,it remains unknown whether miR-34c is involved in chemoresistance in gastric cancer(GC).AIM To investigate the effect of miR-34c and its upstream transcription factor E2F1 on paclitaxel combined with cisplatin resistance in GC cells.METHODS Paired GC tissues and adjacent normal tissues were randomly sampled from 74 GC patients.miR-34c and E2F1 were detected by real-time quantitative PCR(qPCR)and Western blot.In addition,the drug resistance of GC cells to paclitaxel and cisplatin was induced by concentration gradient increasing methods,and changes in miR-34c and E2F1 during this process were measured.Furthermore,E2F1 and miR-34c overexpression or underexpression vectors were constructed and transfected into drug-resistant GC cells.MTT was employed to test the sensitivity of cells to paclitaxel combined with cisplatin,qPCR was adopted to detect the expression of miR-34c,Western blot was applied to detect the expression levels of E2F1,drug resistance-related proteins and apoptosis-related proteins,and flow cytometry was used for the determination of cell apoptosis and cell cycle status.RESULTS E2F1 was overexpressed while miR-34c was underexpressed in GC.After inducing GC cells to be resistant to paclitaxel and cisplatin,E2F1 expression increased while miR-34c expression decreased.Both silencing E2F1 and overexpressing miR-34c could increase the sensitivity of drug-resistant GC cells to paclitaxel combined with cisplatin,promote cell apoptosis and inhibit cell proliferation.Among which,silencing E2F1 could reduce the expression of drug resistance-related proteins and apoptosis-related proteins,while over-expression of miR-34c could upregulate the expression of apoptosis-related proteins without affecting the expression of MDR-1,MRP and other drug resistance-related proteins.Rescue experiments demonstrated that inhibiting miR-34c could significantly weaken the sensitization of drug resistant cells,and Si E2F1 to paclitaxel combined with cisplatin.CONCLUSION E2F1 inhibits miR-34c to promote the proliferation of GC cells and enhance the resistance to paclitaxel combined with cisplatin,and silencing E2F1 is conducive to improving the efficacy of paclitaxel combined with cisplatin in GC cells.

High glucose reduces Nrf2-dependent cRAGE release and enhances inflammasome-dependent IL-1βproduction in monocytes:the modulatory effects of EGCG

Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.

Hydrogen sulfide reduces oxidative stress in Huntington's disease via Nrf2

The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.

Lactobacillus plantarum J26 alleviates alcohol-induced oxidative liver injury by regulating the Nrf2 signaling pathway

Oxidative stress is one of the main ways to cause alcohol-induced liver injury,and alcoholic liver disease(ALD)has been a common health problem worldwide.Lactic acid bacteria(LAB)is also considered as a potential treatment to alleviate alcohol-induced liver injury.Lactobacillus plantarum J26 is a LAB isolated from Chinese traditional fermented dairy products with excellent probiotic effects.This study aimed to establish a mice model of alcoholic liver injury through acute-on-chronic alcohol feeding and to study the alleviating effect of pre-intake of L.plantarum J26 on alcohol-induced oxidative liver injury and focus on its potential mechanism of alleviating effect.The results showed that pre-intake of L.plantarum J26 could improve liver pathological changes,reduce lipid accumulation,increase mitochondrial ATP and mitochondrial(mtDNA)levels,and alleviate liver injury.In addition,pre-intake L.plantarum J26 can improve the level of short-chain fatty acids(SCFAs)in the intestines in mice,short chain fatty acids can be used as a signaling molecule activation of nuclear factor E2-related factor 2(Nrf2)signaling pathway to alleviate liver oxidative stress,and maintain mitochondrial homeostasis by regulating the expression of genes related to mitochondrial dynamics and autophagy,thereby reducing cell apoptosis to alleviate alcohol-induced oxidative liver injury.

Functionalized selenium nanoparticles ameliorated acetaminophen-induced hepatotoxicity through synergistically triggering PKCδ/Nrf2 signaling pathway and inhibiting CYP 2E1

Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.

Procyanidin A_1 and its digestive products alleviate acrylamide-induced IPEC-J2 cell damage through regulating Keap1/Nrf2 pathway

Our previous study has revealed that procyanidin A_(1)(A_(1))and its simulated digestive product(D-A,)can alleviate acrylamide(ACR)-induced intestine cell damage.However,the underlying mechanism remains unknown.In this study,we elucidated the molecular mechanism for and D-A_(1) to alleviate ACR-stimulated IPEC-J2 cell damage.ACR slightly activated nuclear factor erythroid 2-related factor 2(Nrf2)signaling and its target genes,but this activation could not reduce intestine cell damage.A_(1) and D-A_(1) could alleviate ACR-induced cell damage,but the effect was abrogated in cells transiently transfected with Nrf2 small interfering RNA(siRNA).Further investigation confirmed that A_(1) and D-A_(1) interacted with Ketch-like ECH-associated protein 1(Keapl),which boosted the stabilization of Nrf2,subsequently promoted the translocation of Nrf2 into the nucleus,and further increased the expression of antioxidant proteins,thereby inhibiting glutathione(GSH)consumption,maintaining redox balance and eventually alleviating ACR-induced cell damage.Importantly,there was no difference between A_(1) and D-A_(1) treated groups,indicating that A_(1) can tolerate gastrointestinal digestion and may be a potential compound to limit the toxicity of ACR.

IKBKE、YAP1和TEAD2在结直肠癌中的表达及临床意义

目的探讨核因子κb激酶亚基ε的抑制剂(IKBKE)、Yes相关蛋白1(YAP1)和转录增强结构域转录因子2(TEAD2)在结直肠癌(CRC)组织中的表达及其临床意义。方法收集2016年1月至2017年12月在蚌埠医科大学第一附属医院手术切除的142例CRC组织及对应癌旁组织,采用免疫组化法检测标本中IKBKE、YAP1和TEAD2的表达情况。分析3种蛋白在CRC组织中表达的相关性,分析蛋白阳性率与患者临床病理参数及预后的关系;绘制Kaplan-Meier生存曲线,比较这些蛋白不同表达情况患者的生存差异。采用Cox回归分析影响患者预后的危险因素。结果CRC组织中IKBKE、YAP1和TEAD2的阳性率均显著高于癌旁组织(65.5%比9.9%,73.9%比14.1%,66.9%比8.5%,均P<0.05)。IKBKE的表达与肿瘤的分化程度、浸润深度、淋巴结转移、肿瘤-淋巴结-远处转移(TNM)分期有关,YAP1和TEAD2的表达均与肿瘤的分化程度、浸润深度、淋巴结转移、远处转移及TNM分期有关。Spearman秩相关分析显示CRC组织中IKBKE与YAP1、TEAD2表达均呈正相关(均P<0.01)。Kaplan-Meier生存分析显示IKBKE、YAP1和TEAD2阳性表达组的总生存率降低。Cox回归分析显示IKBKE、YAP1和TEAD2阳性、肿瘤分化程度高、TNM分期高是CRC患者预后的独立危险因素。结论CRC中IKBKE、YAP1和TEAD2阳性表达与肿瘤的分化程度、TNM分期、转移等因素有关,可能成为CRC治疗的潜在靶点;检测这3个蛋白的表达有助于评估预后。

IGF_(2)BP_(1)调控lncRNA NEAT1在类风湿关节炎中的作用

目的:类风湿关节炎(rheumatoid arthritis,RA)是一种常见的全身性自身免疫疾病,可能导致关节变形和功能障碍。本研究旨在探索胰岛素样生长因子-2 mRNA结合蛋白1(insulin like growth factor 2 mRNA binding protein 1,IGF_(2)BP_(1))在RA中的表达水平,以及其对长链非编码RNA(long non-coding RNA,lncRNA)核丰富转录本1(nuclear paraspeckle assembly transcript 1,NEAT1)稳定性的影响和在RA发病机制中的作用。方法:通过GEO(Gene Expression Omnibus)数据库获取RA数据集,并将其分为正常对照组和RA组,使用R软件分析获取N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)相关的甲基化酶的表达量并进行差异分析。分析差异表达的m^(6)A甲基化酶与lncRNA NEAT1的相关性。通过在线网站ENCORI预测与lncRNA NEAT1结合的蛋白质,并与lncRNA NEAT1表达相关的m^(6)A甲基化酶取交集,从而获取关键基因。通过RNA蛋白质相互作用分析实验(RNA pull-down)验证在RA滑膜细胞中NEAT1与关键基因结合的情况。通过蛋白质印迹法验证关键基因在正常滑膜细胞和RA滑膜细胞中的表达水平。在RA滑膜细胞中转染关键基因的小干扰RNA,通过real-time RT-PCR检测NEAT1在滑膜细胞中的表达水平。结果:差异分析结果显示:与正常对照组相比,共有8个m^(6)A甲基化基因在RA组中存在差异表达,其中IGF_(2)BP_(1)、甲基转移酶样蛋白14(methyltransferase 14,N^(6)-adenosine-methyltransferase subunit,MEEEL14)与lncRNA NEAT1存在相关性;ENCORI预测结果显示:共有23个蛋白质能够与lncRNA NEAT1结合,与NEAT1共表达m^(6)A甲基化酶取交集,获得NEAT1相关m^(6)A甲基化蛋白IGF_(2)BP_(1)。蛋白质印迹法显示:与正常对照组相比,RA组中IGF_(2)BP_(1)蛋白在RA滑膜细胞中表达升高(P<0.05);RNA pull-down结果显示IGF_(2)BP_(1)蛋白与NEAT1结合;real-time RT-PCR的结果表明:敲减IGF_(2)BP_(1)可显著降低NEAT1 mRNA表达水平(P<0.01)。结论:IGF_(2)BP_(1)可能通过稳定lncRNA NEAT1表达参与RA发病,调控IGF_(2)BP_(1)水平可能是一种新的治疗RA的方法。

橙皮素调控Nrf2/ARE通路改善载脂蛋白E基因敲除小鼠动脉粥样硬化的实验研究

目的:基于核因子E2相关因子2(Nrf2)/抗氧化反应原件(ARE)通路探讨橙皮素对载脂蛋白E基因敲除(ApoE^(-/-))小鼠动脉粥样硬化(AS)的影响。方法:将48只ApoE^(-/-)小鼠用高脂饮食喂养12周后,采用左颈总动脉缩窄性套管法建立ApoE^(-/-)小鼠AS模型。模型制备成功后将ApoE^(-/-)小鼠随机分为模型组、橙皮素低剂量组、橙皮素高剂量组、鸦胆子苦醇组,每组12只。另取12只雄性C57BL/6J小鼠作为对照组,给予普通饲料喂养。橙皮素低、高剂量组小鼠分别给予50 mg/kg、100 mg/kg橙皮素灌胃,每日1次;鸦胆子苦醇组小鼠灌胃100 mg/kg橙皮素,隔天腹腔注射Nrf2抑制剂鸦胆子苦醇2 mg/kg,连续给药12周;对照组和模型组给予等量0.5%羧甲基纤维素钠灌胃。检测各组血清血脂水平以及丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)水平;油红O染色观察主动脉斑块形成和主动脉窦脂质沉积情况,并计算损伤面积百分比;荧光探针测定主动脉中活性氧(ROS)的生成;蛋白免疫印迹法(Western Blot)检测主动脉中Nrf2/ARE通路相关蛋白表达。结果:与对照组相比,模型组小鼠主动脉ROS增加,血清总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、氧化型低密度脂蛋白(ox-LDL)、MDA、主动脉斑块损伤和主动脉窦脂质损伤面积百分比、Kelch样环氧氯丙烷相关蛋白1(Keap1)的表达均明显升高,血清SOD、GSH-Px活性、主动脉Nrf2、还原型辅酶/醌氧化还原酶(NQO1)、血红素加氧酶1(HO-1)的表达明显降低,差异均有统计学意义(P<0.05);与模型组相比,橙皮素低、高剂量组小鼠ROS降低,血清TC、TG、LDL-C、ox-LDL、MDA水平、主动脉斑块损伤和主动脉窦脂质损伤面积百分比、Keap1均明显下降,HDL-C、SOD、GSH-Px活性、Nrf2、NQO1、HO-1的表达均明显升高,差异均有统计学意义(P<0.05);鸦胆子苦醇可逆转高剂量橙皮素减轻ApoE^(-/-)小鼠AS病变的作用。结论:橙皮素可能通过激活Nrf2/ARE通路,维持内皮细胞中的氧化还原平衡,减轻ApoE^(-/-)小鼠AS病变,具有较好的抗AS作用。

Dialogue between estrogen receptor and E2F signaling pathways: The transcriptional coregulator RIP140 at the crossroads

Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases.

红金消结胶囊联合米非司酮对子宫肌瘤患者卵巢功能及血清Ang-2、EGF、NF-κBp65水平的影响

目的探究红金消结胶囊联合米非司酮对子宫肌瘤患者卵巢功能及血清促血管生成素-2(Ang-2)、表皮细胞生长因子(EGF)、人核转录因子肽(NF-κBp65)水平的影响。方法便利选择2018年7月—2020年10月在邹城市人民医院接受医治的57例子宫肌瘤患者为研究对象,通过随机数表法将其分成对照组(29例)和治疗组(28例)。对照组采用米非司酮治疗,治疗组在对照组基础上联合使用红金消结胶囊治疗。两组患者的治疗周期1个月为1个疗程,均持续进行3个疗程。结果治疗组治疗后总有效率(89.29%)高于对照组(55.17%),差异有统计学意义(χ^(2)=8.211,P<0.01)。治疗后两组患者子宫体积和瘤体最大直径较治疗前均减小,且治疗组小于对照组,差异有统计学意义(t=2.996、9.089,P<0.05)。血清卵泡雌激素(FSH)、促黄体生成素(LH)、雌二醇(E_(2))、Ang-2、EGF、NF-κBp65水平均较治疗前下降,且治疗组低于对照组,差异有统计学意义(t=7.660、16.073、11.464、19.579、13.856、13.510,P<0.05)。结论红金消结胶囊联合米非司酮对子宫肌瘤患者具有缓解临床症状、延缓疾病进展、促进恢复子宫功能、改善疾病相关因子的作用。

Oxidative stress in retinal pigment epithelium degeneration:from pathogenesis to therapeutic targets in dry age-related macular degeneration

Age-related macular degeneration is a primary cause of blindness in the older adult population. Past decades of research in the pathophysiology of the disease have resulted in breakthroughs in the form of anti-vascular endothelial growth factor therapies against neovascular age-related macular degeneration;however, effective treatment is not yet available for geographical atrophy in dry agerelated macular degeneration or for preventing the progression from early or mid to the late stage of age-related macular degeneration. Both clinical and experimental investigations involving human agerelated macular degeneration retinas and animal models point towards the atrophic alterations in retinal pigment epithelium as a key feature in age-related macular degeneration progression. Retinal pigment epithelium cells are primarily responsible for cellular-structural maintenance and nutrition supply to keep photoreceptors healthy and functional. The retinal pigment epithelium constantly endures a highly oxidative environment that is balanced with a cascade of antioxidant enzyme systems regulated by nuclear factor erythroid-2-related factor 2 as a main redox sensing transcription factor. Aging and accumulated oxidative stress triggers retinal pigment epithelium dysfunction and eventually death. Exposure to both environmental and genetic factors aggravates oxidative stress damage in aging retinal pigment epithelium and accelerates retinal pigment epithelium degeneration in age-related macular degeneration pathophysiology. The present review summarizes the role of oxidative stress in retinal pigment epithelium degeneration, with potential impacts from both genetic and environmental factors in age-related macular degeneration development and progression. Potential strategies to counter retinal pigment epithelium damage and protect the retinal pigment epithelium through enhancing its antioxidant capacity are also discussed, focusing on existing antioxidant nutritional supplementation, and exploring nuclear factor erythroid-2-related factor 2 and its regulators including REV-ERBα as therapeutic targets to protect against age-related macular degeneration development and progression.

Nrf2与NF-κB对鼻咽癌患者放射性黏膜炎的交互作用及预测效能

目的 探讨核转录因子红系2相关因子2(Nrf2)与核因子κB(NF-κB)对鼻咽癌患者放射性黏膜炎的交互作用及预测效能。方法 选取2021年8月至2023年2月联勤保障部队第904医院与南通大学附属肿瘤医院收治的116例鼻咽癌患者作为研究对象,所有患者均行放疗治疗,根据放疗第3周放射性黏膜炎发生情况分为无症状组(0级)、轻度组(1~2级)、重度组(3~4级)。对比3组患者血清Nrf2、NF-κB水平。Spearman秩相关系数分析血清Nrf2、NF-κB水平与发生放射性黏膜炎的相关性。受试者工作特征曲线(ROC曲线)分析血清Nrf2、NF-κB水平对重度放射性黏膜炎发生风险的预测价值。分析重度放射性黏膜炎发生的影响因素及Nrf2与NF-κB对重度放射性黏膜炎发生的交互作用。结果 重度组血清Nrf2水平低于轻度组、无症状组,血清NF-κB水平高于轻度组、无症状组,轻度组血清Nrf2水平低于无症状组,血清NF-κB水平高于无症状组(P<0.05);放疗前血清Nrf2水平与放射性黏膜炎发生呈低度负相关(r=-0.452,P<0.001),放疗1周血清Nrf2水平与放射性黏膜炎发生呈中度负相关(r=-0.586,P<0.001),放疗3周血清Nrf2水平与放射性黏膜炎发生呈中度负相关(r=-0.620,P<0.001);放疗前血清NF-κB水平与放射性黏膜炎发生呈低度正相关(r=0.475,P<0.001),放疗1周血清NF-κB水平与放射性黏膜炎发生呈中度正相关(r=0.541,P<0.001),放疗3周血清NF-κB水平与放射性黏膜炎发生呈中度正相关(r=0.619,P<0.001);预防性用药、放疗1周血清Nrf2水平是重度放射性黏膜炎发生的独立保护因素,吸烟史、放疗剂量、放疗1周血清NF-κB水平是重度放射性黏膜炎发生的独立危险因素(P<0.05);血清Nrf2、NF-κB水平联合预测重度放射性黏膜炎发生的AUC值为0.829,大于血清Nrf2(Z=2.519,P=0.012)、NF-κB(Z=2.084,P=0.037)水平单独预测的AUC值(分别为0.730、0.764)(P<0.05);Nrf2与NF-κB对重度放射性黏膜炎发生存在拮抗作用(S<1),在重度放射性黏膜炎发生风险中,约31.6%是由二者交互作用所致。结论 鼻咽癌患者血清Nrf2、NF-κB水平变化及放射性黏膜炎发生发展关系密切,通过检测二者水平变化可为临床预测重度放射性黏膜炎的发生提供参考依据。

红景天苷通过NF-κB/Bcl-2信号通路对重症肺炎大鼠肺血管内皮细胞凋亡及IL-23、Th17表达的影响

目的:探讨红景天苷通过核转录因子(NF-κB)/B淋巴细胞瘤2(Bcl-2)信号通路对重症肺炎大鼠肺血管内皮细胞(PVECs)凋亡及白介素-23(IL-23)、辅助性T细胞17(Th17)表达的影响。方法:将50只大鼠随机分为假手术组、模型组、红景天苷组、抑制剂组、红景天苷+抑制剂组五组,每组10只。除假手术组外,均建立重症肺炎大鼠模型。造模成功后红景天苷组大鼠腹腔注射红景天苷(100 mg/kg);抑制剂组大鼠腹腔注射NF-κB抑制剂喹唑啉化合物(EVP4593)(5 mg/kg);红景天苷+抑制剂组大鼠腹腔注射红景天苷(200 mg/kg)+EVP4593(3 mg/kg);假手术组、模型组腹腔注射等容积的0.9%氯化钠溶液。所有大鼠持续干预7 d后使用酶联免疫吸附测定法(ELISA法)检测各组大鼠血清中白介素(IL)-17、IL-23,流式细胞术检测血清中Th17细胞比例,HE染色观察肺组织病理形态,免疫印记检测大鼠肺组织中NF-κB/Bcl-2蛋白表达。取肺组织进行PVECs培养并检测第2代PVECs的增殖率及凋亡率。结果:与假手术组相比,各建模组大鼠血清中IL-23、IL-17、Th17细胞比例,肺组织中NF-κB/Bcl-2蛋白表达以及PVECs凋亡率均明显升高,PVECs增殖率明显降低(P<0.05),肺组织病变严重;与模型组相比,红景天苷组、抑制剂组、红景天苷+抑制剂组大鼠血清中IL-23、IL-17、Th17细胞比例,肺组织中NF-κB/Bcl-2蛋白表达以及PVECs凋亡率均明显降低,PVECs增殖率明显升高(P<0.05),肺组织病变有所好转;与红景天苷组、抑制剂组相比,红景天苷+抑制剂组大鼠血清中IL-23、IL-17、Th17细胞比例,肺组织中NF-κB/Bcl-2蛋白表达以及PVECs凋亡率均明显降低,PVECs增殖率明显升高(P<0.05),肺组织形态基本恢复正常;红景天苷组与抑制剂组相比,血清中IL-23、IL-17、Th17细胞比例、肺组织中NF-κB/Bcl-2蛋白表达、PVECs凋亡/增殖率以及肺组织形态差异无统计学意义(P>0.05)。结论:红景天苷可通过降低NF-κB/Bcl-2水平调节重症肺炎大鼠IL-23/Th17平衡,并有效抑制PVECs凋亡。