BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells...BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation(H/R)-induced oxidative iniury are still unclear.METHODS: The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid(9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA-pretreated group(100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group(2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential(ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signif icant when P was <0.05.RESULTS: Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531.CONCLUSION: The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.展开更多
Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphol...Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.展开更多
Malignant melanoma is a common cancer of skin. Its incidence is growing rapidly in recent years, however, there is no effective therapy for this cancer. Retinoids are metabolites or derivatives of vitamin A. They are ...Malignant melanoma is a common cancer of skin. Its incidence is growing rapidly in recent years, however, there is no effective therapy for this cancer. Retinoids are metabolites or derivatives of vitamin A. They are essential for growth, differentiation, and maintenance of epithelial tissues. Previous studies showed that retinoids could inhibit growth of many kinds of malignant tumor cell lines and induce its apoptosis, including malignant melanoma cell lines. Some retinoids have therapeutic action to malignant melanoma, such as all-trans retinoic acid （ATRA） and 13-cis-RA. Retinoids take effects mainly through two kinds of nuclear receptors, retinoic acid receptor （RAR） and retinoic acid X receptor （RXR）. In this study, we have investigated the effects of diverse retinoids and receptor agonists in inhibiting proliferation and inducing apoptosis of human melanoma cell line A375.展开更多
All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodim...All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.展开更多
Retinoids mediate their actions via RARs(retinoic acid receptors)and RXRs(retinoid X receptors).Each classes of these nuclear retinoid receptor is further subdiviede into three species namelyα,βand γ.Recent studies...Retinoids mediate their actions via RARs(retinoic acid receptors)and RXRs(retinoid X receptors).Each classes of these nuclear retinoid receptor is further subdiviede into three species namelyα,βand γ.Recent studies demonstrate that ER-positive HBC cell lines are sensitive and ER-negative cell lines are resistant to growth inhibitory effects of retinoic acid(RA). In this study we look at the expresion of RARs and RXRs in 6 HBC cell lines, we found only RARαmRNA level was strong correlated with ER-status. To further inestigate the major role of RARαin retinoidmediated inhibition of growth, we transfected RARαcDNA in two RA-resistant ER-negative HBC cell lines.Analyses of different clonal populations of RARα transfectants from each cell line revealed growth inhibition by retinoids. Our results demonstrates that RARα Plays a major role in mediating retinoids inhibition of growth in HBC cells and adequate levels are required for such actions.展开更多
This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is ...This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is effective against human breast cancer BT-20 and MCF-7 cell lines. At the same time, compound L2 exerts its effect on human prostate cancer PC-3 and human breast cancer MDA-MB-231 and MCF-7 cell lines respectively. The retinoid ligands exert their pleiotropic action toward retinoic acid receptors (RARs) than their metal complexes but all compounds exhibit concentration-dependent.展开更多
Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in art...Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in artificial breeding.However,reproductive behavior at the level of genes is rarely reported,thus,the research on the genetic basis of behavior,reproduction,and artificial breeding was limited.We applied RNA-seq in different stages of reproduction to investigate the reason of rapid aging after spawning,pre-maturity,pre-spawning after maturity,and post-spawning.The retinoid X receptor(RXR)gene family in S.japonica was identified,and 1343–1452 differentially expressed genes(DEGs)in all 3 stages of reproductive life were identified from pairwise m RNA comparisons.Furthermore,through the GO term and KEGG analysis,S.japonica could handle neuronal development and network formation before maturity and have a functional degradation of neural communication,signal transduction,vision,and gene expression after spawning.Eight Sj RXRαs have been identified and they played different roles in growth development or reproduction.Therefore,the regulation of several channels and receptors is the intrinsic molecular mechanism of rapid aging after spawning in S.japonica.This study revealed the survival strategy and provided fundamental data on the level of genes for understanding the reproductive behavior and the reproduction of S.japonica.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defin...Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease.However,due to the its subtle nature and concurring events PDAC cure remains elusive.Nuclear receptors(NR)are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism,to growth and development.Given the nature of their ligands,NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases.There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages;nonetheless many aspects of their role are not fully understood.The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors,retinoic acid receptors,retinoid X receptor,androgen receptor,estrogen receptors and the orphan NR Nur,chicken ovalbumin upstream promoter transcription factorⅡand the liver receptor homologue-1 receptor to PDAC development,connections that could lead to the identification of novel therapies for this disease.展开更多
The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer ste...The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells(CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs(BCSCs) are likely to sustain the growth of the primary tumour mass, as wellas to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and proinflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the antiinflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.展开更多
The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among th...The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFkB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase- dependent manner.展开更多
目的探究视黄酸相关孤儿受体(RORγt)白细胞介素23(IL-23)通路调节辅助性T细胞17(Th17)在老年盐敏感性高血压发病中的作用。方法对内蒙古自治区的村民进行调查,2021年1月至2022年1月选取289例老年高血压患者作为研究对象,采用Sullivan...目的探究视黄酸相关孤儿受体(RORγt)白细胞介素23(IL-23)通路调节辅助性T细胞17(Th17)在老年盐敏感性高血压发病中的作用。方法对内蒙古自治区的村民进行调查,2021年1月至2022年1月选取289例老年高血压患者作为研究对象,采用Sullivan盐负荷试验将患者进行分组,盐敏感高血压患者103例作为研究组,非盐敏感高血压患者186例作为对照组,给予慢性盐负荷试验。结果研究组收缩压、舒张压、MAP、心率在D10、D17均显著高于对照组(P<0.01)。2组尿量、尿钠、尿钾、尿肌酐水平在基线D3比较无显著差异(P>0.05),D10与对照组比较,研究组尿钠[(315.32±57.21)mmol/24 h vs(226.64±58.53)mmol/24 h,P=0.000]、尿肌酐[(12.46±1.64)mmol/24 h vs(10.12±1.17)mmol/24 h,P=0.000]显著增高。2组Th17比例、IL-17A水平在D4、D5、D10逐渐上升,在D17下降,且研究组Th17比例、IL-17A水平在D4、D5、D10、D17均显著高于对照组(P<0.01)。结论Th17参与了盐敏感性高血压的发生,RORγt-IL-23受体信号通路可诱导Th17细胞分化。展开更多
目的:观察阿托伐他汀(Atorv)对链脲佐菌素(STZ)诱导的糖尿病高脂喂养载脂蛋白E敲除(apolipoprotein E knockout,ApoE-/-)小鼠动脉粥样硬化的影响,探讨阿托伐他汀在糖尿病合并高脂饮食条件下对抗动脉粥样硬化的机制。方法:C57小鼠8只作...目的:观察阿托伐他汀(Atorv)对链脲佐菌素(STZ)诱导的糖尿病高脂喂养载脂蛋白E敲除(apolipoprotein E knockout,ApoE-/-)小鼠动脉粥样硬化的影响,探讨阿托伐他汀在糖尿病合并高脂饮食条件下对抗动脉粥样硬化的机制。方法:C57小鼠8只作为对照,34只高脂喂养的ApoE-/-小鼠随机分为3组:ApoE-/-组、STZ-ApoE-/-组和STZ-ApoE-/-+Atorv组。STZ腹腔注射建立糖尿病动物模型,测定小鼠空腹血糖、血脂水平,HE染色图像分析测定胸主动脉斑块面积;免疫杂交检测主动脉及细胞内NADPH氧化酶亚基gp91phox蛋白水平;Fenton反应Griess显色法测定血清及胸主动脉匀浆上清液活性氧(ROS)水平。I型胶原酶消化法培养人脐静脉内皮细胞(HUVECs),流式细胞术检测内皮细胞内ROS的水平,光泽精分析法测定NADPH氧化酶活性。采用干扰RNA和质粒转染的方法评价类视黄醇X受体α(RXRα)在Atorv抑制氧化应激中的作用。结果:(1)与C57组相比,ApoE-/-组小鼠胸主动脉斑块面积显著增加[(215.88±34.19)μm2vs 0μm2,P<0.01],2组间空腹血糖水平无显著差异,血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、血清及胸主动脉ROS、胸主动脉gp91phox表达水平显著缩小(P<0.05);(2)与ApoE-/-组相比,STZ-ApoE-/-组胸主动脉斑块面积进一步增加[(314.13±35.72)μm2vs(215.88±34.19)μm2,P<0.05],血糖水平升高,血清TC、LDL-C、血清及胸主动脉ROS、胸主动脉gp91phox水平进一步增加(P<0.05);(3)与STZ-ApoE-/-组相比,STZ-ApoE-/-+Atorv组胸主动脉粥样斑块面积显著降低[(217.47±24.56)μm2vs(314.13±35.72)μm2,P<0.05],血糖、血清TG、HDL、TC、和LDL-C无显著变化,血清及胸主动脉ROS、胸主动脉gp91phox水平亦显著降低(P<0.05);(4)高糖(25 mmol/L)干预后,HUVECs内ROS含量、gp91phox蛋白水平及NADPH氧化酶活性明显增加(P<0.05),阿托伐他汀(10-8~10-6mol/L)显著降低高糖环境下HUVECs胞内ROS含量、gp91phox表达及NADPH氧化酶活性,且具有浓度依赖性;(5)将RXRαsiRNA转染至HUVECs之后,阿托伐他汀(10-6mol/L)对高糖环境下ROS生成及NADPH氧化酶活性的抑制效应显著减弱,RXRα质粒转染使RXRα过表达后,阿托伐他汀(10-6mol/L)抑制ROS生成及NADPH氧化酶活性的作用明显增强(P<0.05)。结论:阿托伐他汀通过抑制高糖环境下机体的氧化应激反应对抗动脉粥样硬化;核受体RXRα介导阿托伐他汀的抗氧化应激效应。展开更多
大黄素(emodin)对多种肿瘤细胞有较强的抑制增殖和诱导凋亡的作用,但其作用机制尚不清楚。本研究通过配体-受体竞争结合实验以及报告基因检测了大黄素对维甲酸X受体(retinoid X receptor alpha,RXRα)的结合和转录活性的调控,并研究了...大黄素(emodin)对多种肿瘤细胞有较强的抑制增殖和诱导凋亡的作用,但其作用机制尚不清楚。本研究通过配体-受体竞争结合实验以及报告基因检测了大黄素对维甲酸X受体(retinoid X receptor alpha,RXRα)的结合和转录活性的调控,并研究了大黄素对肺癌细胞H460和肝癌细胞SMMC-7721生长和凋亡的作用。结果发现,大黄素对两种癌细胞有很强的抑制增殖作用,加入RXRα的天然配体9-顺式视黄酸(9-cis-retinoid acid,9-cis-RA)共同处理可显著缓解这种抑制作用。大黄素能浓度依赖地引起两种癌细胞系的凋亡,使细胞核出现碎裂和染色质浓染。报告基因实验发现大黄素对RXRα同源和异源二聚体的转录激活有显著抑制作用。体外的配体竞争结合实验发现,大黄素不直接结合RXRα的配体结合区。蛋白质免疫印迹实验发现,大黄素不影响RXRα的蛋白表达。结果提示,大黄素具有诱导肺癌细胞H460和肝癌细胞SMMC-7721凋亡和抑制细胞生长的作用,大黄素抑制9-cis-RA对RXR转录激活作用以及9-cis-RA具有一定程度拮抗大黄素对肺癌细胞H460和肝癌细胞SMMC-7721的生长抑制作用,提示大黄素的抗癌作用可能与细胞内RXR的功能有关,并以RXR转录非依赖性的方式起作用。配体竞争结合实验结果提示大黄素可能间接作用于RXR。展开更多
基金supported by grants from the National Natural Science Foundation of China(81270282,81070176,30600242,81170192,81200163)Wenzhou Science Technology Bureau Foundation(Y20100010)Education Foundation of Zhejiang Province(Y200906376)
文摘BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation(H/R)-induced oxidative iniury are still unclear.METHODS: The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid(9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA-pretreated group(100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group(2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential(ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signif icant when P was <0.05.RESULTS: Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531.CONCLUSION: The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.
基金supported by Natural Sciences and Engineering Council of Canada Discovery Grant to RLC and GES
文摘Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.
基金This work was supported by a grant from the National NaturalScience Foundation of China (No.30070699).
文摘Malignant melanoma is a common cancer of skin. Its incidence is growing rapidly in recent years, however, there is no effective therapy for this cancer. Retinoids are metabolites or derivatives of vitamin A. They are essential for growth, differentiation, and maintenance of epithelial tissues. Previous studies showed that retinoids could inhibit growth of many kinds of malignant tumor cell lines and induce its apoptosis, including malignant melanoma cell lines. Some retinoids have therapeutic action to malignant melanoma, such as all-trans retinoic acid （ATRA） and 13-cis-RA. Retinoids take effects mainly through two kinds of nuclear receptors, retinoic acid receptor （RAR） and retinoic acid X receptor （RXR）. In this study, we have investigated the effects of diverse retinoids and receptor agonists in inhibiting proliferation and inducing apoptosis of human melanoma cell line A375.
文摘All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.
文摘Retinoids mediate their actions via RARs(retinoic acid receptors)and RXRs(retinoid X receptors).Each classes of these nuclear retinoid receptor is further subdiviede into three species namelyα,βand γ.Recent studies demonstrate that ER-positive HBC cell lines are sensitive and ER-negative cell lines are resistant to growth inhibitory effects of retinoic acid(RA). In this study we look at the expresion of RARs and RXRs in 6 HBC cell lines, we found only RARαmRNA level was strong correlated with ER-status. To further inestigate the major role of RARαin retinoidmediated inhibition of growth, we transfected RARαcDNA in two RA-resistant ER-negative HBC cell lines.Analyses of different clonal populations of RARα transfectants from each cell line revealed growth inhibition by retinoids. Our results demonstrates that RARα Plays a major role in mediating retinoids inhibition of growth in HBC cells and adequate levels are required for such actions.
文摘This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is effective against human breast cancer BT-20 and MCF-7 cell lines. At the same time, compound L2 exerts its effect on human prostate cancer PC-3 and human breast cancer MDA-MB-231 and MCF-7 cell lines respectively. The retinoid ligands exert their pleiotropic action toward retinoic acid receptors (RARs) than their metal complexes but all compounds exhibit concentration-dependent.
基金the National Key R&D Program of China(No.2019YFD0901204)the Hong Kong,Macao and Taiwan Science and Technology Cooperation Project(No.2014DFT30120)+2 种基金the Zhejiang Provincial Natural Science Foundation of China(No.Y14C190008)the National Natural Science Foundation of China(Nos.31101937,31872547)the Science Foundation of Donghai Laboratory(No.DH-2022KF0209)。
文摘Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in artificial breeding.However,reproductive behavior at the level of genes is rarely reported,thus,the research on the genetic basis of behavior,reproduction,and artificial breeding was limited.We applied RNA-seq in different stages of reproduction to investigate the reason of rapid aging after spawning,pre-maturity,pre-spawning after maturity,and post-spawning.The retinoid X receptor(RXR)gene family in S.japonica was identified,and 1343–1452 differentially expressed genes(DEGs)in all 3 stages of reproductive life were identified from pairwise m RNA comparisons.Furthermore,through the GO term and KEGG analysis,S.japonica could handle neuronal development and network formation before maturity and have a functional degradation of neural communication,signal transduction,vision,and gene expression after spawning.Eight Sj RXRαs have been identified and they played different roles in growth development or reproduction.Therefore,the regulation of several channels and receptors is the intrinsic molecular mechanism of rapid aging after spawning in S.japonica.This study revealed the survival strategy and provided fundamental data on the level of genes for understanding the reproductive behavior and the reproduction of S.japonica.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease.However,due to the its subtle nature and concurring events PDAC cure remains elusive.Nuclear receptors(NR)are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism,to growth and development.Given the nature of their ligands,NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases.There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages;nonetheless many aspects of their role are not fully understood.The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors,retinoic acid receptors,retinoid X receptor,androgen receptor,estrogen receptors and the orphan NR Nur,chicken ovalbumin upstream promoter transcription factorⅡand the liver receptor homologue-1 receptor to PDAC development,connections that could lead to the identification of novel therapies for this disease.
文摘The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells(CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs(BCSCs) are likely to sustain the growth of the primary tumour mass, as wellas to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and proinflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the antiinflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.
文摘The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFkB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase- dependent manner.
文摘目的探究视黄酸相关孤儿受体(RORγt)白细胞介素23(IL-23)通路调节辅助性T细胞17(Th17)在老年盐敏感性高血压发病中的作用。方法对内蒙古自治区的村民进行调查,2021年1月至2022年1月选取289例老年高血压患者作为研究对象,采用Sullivan盐负荷试验将患者进行分组,盐敏感高血压患者103例作为研究组,非盐敏感高血压患者186例作为对照组,给予慢性盐负荷试验。结果研究组收缩压、舒张压、MAP、心率在D10、D17均显著高于对照组(P<0.01)。2组尿量、尿钠、尿钾、尿肌酐水平在基线D3比较无显著差异(P>0.05),D10与对照组比较,研究组尿钠[(315.32±57.21)mmol/24 h vs(226.64±58.53)mmol/24 h,P=0.000]、尿肌酐[(12.46±1.64)mmol/24 h vs(10.12±1.17)mmol/24 h,P=0.000]显著增高。2组Th17比例、IL-17A水平在D4、D5、D10逐渐上升,在D17下降,且研究组Th17比例、IL-17A水平在D4、D5、D10、D17均显著高于对照组(P<0.01)。结论Th17参与了盐敏感性高血压的发生,RORγt-IL-23受体信号通路可诱导Th17细胞分化。
文摘目的:观察阿托伐他汀(Atorv)对链脲佐菌素(STZ)诱导的糖尿病高脂喂养载脂蛋白E敲除(apolipoprotein E knockout,ApoE-/-)小鼠动脉粥样硬化的影响,探讨阿托伐他汀在糖尿病合并高脂饮食条件下对抗动脉粥样硬化的机制。方法:C57小鼠8只作为对照,34只高脂喂养的ApoE-/-小鼠随机分为3组:ApoE-/-组、STZ-ApoE-/-组和STZ-ApoE-/-+Atorv组。STZ腹腔注射建立糖尿病动物模型,测定小鼠空腹血糖、血脂水平,HE染色图像分析测定胸主动脉斑块面积;免疫杂交检测主动脉及细胞内NADPH氧化酶亚基gp91phox蛋白水平;Fenton反应Griess显色法测定血清及胸主动脉匀浆上清液活性氧(ROS)水平。I型胶原酶消化法培养人脐静脉内皮细胞(HUVECs),流式细胞术检测内皮细胞内ROS的水平,光泽精分析法测定NADPH氧化酶活性。采用干扰RNA和质粒转染的方法评价类视黄醇X受体α(RXRα)在Atorv抑制氧化应激中的作用。结果:(1)与C57组相比,ApoE-/-组小鼠胸主动脉斑块面积显著增加[(215.88±34.19)μm2vs 0μm2,P<0.01],2组间空腹血糖水平无显著差异,血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、血清及胸主动脉ROS、胸主动脉gp91phox表达水平显著缩小(P<0.05);(2)与ApoE-/-组相比,STZ-ApoE-/-组胸主动脉斑块面积进一步增加[(314.13±35.72)μm2vs(215.88±34.19)μm2,P<0.05],血糖水平升高,血清TC、LDL-C、血清及胸主动脉ROS、胸主动脉gp91phox水平进一步增加(P<0.05);(3)与STZ-ApoE-/-组相比,STZ-ApoE-/-+Atorv组胸主动脉粥样斑块面积显著降低[(217.47±24.56)μm2vs(314.13±35.72)μm2,P<0.05],血糖、血清TG、HDL、TC、和LDL-C无显著变化,血清及胸主动脉ROS、胸主动脉gp91phox水平亦显著降低(P<0.05);(4)高糖(25 mmol/L)干预后,HUVECs内ROS含量、gp91phox蛋白水平及NADPH氧化酶活性明显增加(P<0.05),阿托伐他汀(10-8~10-6mol/L)显著降低高糖环境下HUVECs胞内ROS含量、gp91phox表达及NADPH氧化酶活性,且具有浓度依赖性;(5)将RXRαsiRNA转染至HUVECs之后,阿托伐他汀(10-6mol/L)对高糖环境下ROS生成及NADPH氧化酶活性的抑制效应显著减弱,RXRα质粒转染使RXRα过表达后,阿托伐他汀(10-6mol/L)抑制ROS生成及NADPH氧化酶活性的作用明显增强(P<0.05)。结论:阿托伐他汀通过抑制高糖环境下机体的氧化应激反应对抗动脉粥样硬化;核受体RXRα介导阿托伐他汀的抗氧化应激效应。
文摘大黄素(emodin)对多种肿瘤细胞有较强的抑制增殖和诱导凋亡的作用,但其作用机制尚不清楚。本研究通过配体-受体竞争结合实验以及报告基因检测了大黄素对维甲酸X受体(retinoid X receptor alpha,RXRα)的结合和转录活性的调控,并研究了大黄素对肺癌细胞H460和肝癌细胞SMMC-7721生长和凋亡的作用。结果发现,大黄素对两种癌细胞有很强的抑制增殖作用,加入RXRα的天然配体9-顺式视黄酸(9-cis-retinoid acid,9-cis-RA)共同处理可显著缓解这种抑制作用。大黄素能浓度依赖地引起两种癌细胞系的凋亡,使细胞核出现碎裂和染色质浓染。报告基因实验发现大黄素对RXRα同源和异源二聚体的转录激活有显著抑制作用。体外的配体竞争结合实验发现,大黄素不直接结合RXRα的配体结合区。蛋白质免疫印迹实验发现,大黄素不影响RXRα的蛋白表达。结果提示,大黄素具有诱导肺癌细胞H460和肝癌细胞SMMC-7721凋亡和抑制细胞生长的作用,大黄素抑制9-cis-RA对RXR转录激活作用以及9-cis-RA具有一定程度拮抗大黄素对肺癌细胞H460和肝癌细胞SMMC-7721的生长抑制作用,提示大黄素的抗癌作用可能与细胞内RXR的功能有关,并以RXR转录非依赖性的方式起作用。配体竞争结合实验结果提示大黄素可能间接作用于RXR。
