Antitumor Drugs That Target tRXRα/PI3K/AKT Signal Pathway

类视黄醇X受体（retinoidXreceptor，RXR），是核受体超家族中重要的一 类，参与了人体代谢、生长、发育、分化、死亡和免疫等几乎所有的生理调控。 其表达或功能异常与人体的许多疾病有关。最近有研究发现肿瘤细胞与癌组织中 存在截断型RXRα（tRXRα），但功能尚不明确。 通过动物实验我们发现tRXRα可以促进裸鼠移植瘤的生长，阐述了tRXRα 癌蛋白的促肿瘤生长作用。经筛选，我们获得了一个与tRXRα结合，且拮抗其 转录激活及促肿瘤生长活性的夹氧杂蒽类化合物CF-31。此化合物结构非常独 特，虽然没有经典配体结合tRXRα所必须的极性端，但却与tRXRα有很强的亲和力...Retinoid X receptor （RXR）α, a unique member of the nuclear receptor superfamily, plays a critical role in many biological processes. Altered expression and function of RXRα is implicated in the development of a number of diseases such as cancer. Consistently, proteolytic cleavage of RXRα （tRXRα） protein are often found in cancer cells and tumor tissues. However, the function and the underlying act...学位：理学博士院系专业：生物医学研究院_化学生物学专业学号：3052008015043

Chemical component in camellia cake against ultraviolet rays radiation damage on skin cells

目的分离纯化油茶粕中抗皮肤细胞紫外损伤活性成分。方法硅胶色谱和高效液相反相制备色谱纯化油茶粕正丁醇提取物,WESTErn-blOTTIng法检测纯化物质对uV照射HA CA T皮肤细胞Jnk、P38激活以及MMP-9的表达的影响。结果分离得到一单体化合物,经鉴定为kAEMPfErOl 3-O-{β-d-gluCOPyrAnOSyl-(1->2)-[α-l-rHAMnOPyrAnOSyl-(1->6)]-β-d-gluCOPyrAnOSIdE},且该化合物能够抑制HA CA T皮肤细胞uV照射后Jnk、P38激活以及MMP-9表达。结论油茶粕含有抗皮肤细胞紫外损伤活性成分,值得进一步开发。Objective To isolate the chemical component of camellia cake against ultraviolet rays radiation damage on skin cells.Methods Silica gel column chromatography and reverse phase preparative HPLC were used for the isolation of active compounds from the n-butanol extract of camellia cake.The effects of isolated compound on the activation of JNK and P38,and the protein expression of MMP-9 in UV irradiated Ha Ca J skin cells were determined by western blotting assay.Results A flavonoid glycoside was isolated from the camellia cake and identified as Kaempferol 3-O-{ β-D-glucopyranosyl-( 1-> 2)-[α-L-rhamnopyranosyl-( 1-> 6) ]-β-D-glucopyranoside} using NMR dada analysis.In addition,the isolated compound was showed to markedly inhibit the activation of JNK and P38,and MMP-9 protein expression in UV irradiated Ha Ca J skin cells.Conclusion The components in camellia cake might have significant activity on protecting skin from UV rays radiation damage,suggesting their potential development values.国家自然科学基金(No.81102332); 福建省厦门市科技计划项目(No.3502Z20123015

Effects of Diosmetin from Carbonized Cirsium japonicum on Apoptosis in Human MCF-7 Breast Cancer Cells and its Mechanisms

研究大蓟炭中香叶木素诱导人乳腺癌MCF-7细胞凋亡及其作用机制。采用硅胶和Sephadex; LH-20柱层析从大蓟炭中分离鉴定了三个黄酮类化合物,经NMR和MS鉴定他们的结构分别为香叶木素(1)、刺槐素(2)和柳川鱼黄素(3)。采用MT; S方法检测不同浓度的香叶木素对MCF-7的细胞活力的影响;流式细胞术检测不同浓度的香叶木素处理对MCF-7细胞凋亡的作用;Western; blot法检测香叶木素处理对细胞PARP、P-JNK等细胞凋亡相关蛋白表达的影响。MTS及流式细胞术结果显示香叶木素能显著抑制MCF-7的增殖并; 且诱导细胞凋亡;香叶木素可上调P-JNK促进细胞凋亡。结果表明香叶木素在体外实验能通过激活JNK细胞凋亡通路抑制MCF-7的增殖及促进细胞凋亡。To study the effects of diosmetin from carbonized Cirsium japonicum on; apoptosis in human MCF-7 breast cancer cells and its mechanisms. Three; flavonoids were isolated and purified from carbonized C. japonicum by; silica gel and Sephadex LH-20 chromatography methods. Their structures; were elucidated by NMR and MS spectroscopic data and identified as; diosmetin(1),acacetin(2) and pectolinarigenin(3). MTS assay was; performed to detect the viability of MCF-7 cells treated by different; concentrations of diosmetin. The cell apoptosis rate was further; analyzed by flow cytometry(FCM). Western blot assay was applied to; measure the apoptosis related protein expression levels of PARP,P-JNK.; Diosmetin treatment on MCF-7 cells significantly inhibited cell; proliferation and induced cell apoptosis. Diosmetin significantly; downregulated P-JNK and upregulated cleaved-PARP protein expression.; Diosmetin inhibited MCF-7 cell proliferation and induced cell apoptosis; by activation of JNK pathway in vitro.江西中医药大学校级科研项目; 国家自然科学基金; 江西省自然科学基

舒林酸衍生物K-80003与MEK抑制剂考比替尼联合用药对乳腺癌的效果研究

目的舒林酸衍生物K-80003是全球首个以类维甲酸受体的截断形式(该文简称tRXRα)为靶点的原创候选新药。本课题组前期研究发现,K-80003在抑制乳腺癌的同时,在乳腺癌细胞中可以激活p-ERK,因此该文试图将K-80003与已上市的MEK抑制剂考比替尼(cobimetinib,GDC-0973)联合使用,探究其对乳腺癌的抑制效果是否增强。方法采用Western blot法、MMTV-PyMT乳腺癌转基因小鼠模型、免疫组化染色等方法,检测K-80003与GDC-0973联合用药对乳腺癌细胞内ERK信号通路及肿瘤细胞凋亡水平的影响。结果 K-80003与GDC-0973联合使用可以更好地抑制p-ERK,并促进PARP切割,导致乳腺癌细胞凋亡,K-80003与GDC-0973联合使用相比于K-80003单药使用,对肿瘤细胞增殖的抑制作用有明显统计学意义。结论舒林酸衍生物K-80003与MEK抑制剂GDC-0973联合使用呈现一定的协同促进乳腺癌细胞凋亡作用。国家自然科学基金资助项目(No 91429306

视黄醇X受体小分子配体衍生物对宫颈癌细胞周期及细胞凋亡的影响

为筛选视黄醇X受体α(RXRα)配体XS-23的衍生物中作用于细胞周期的化合物,通过蛋白免疫印迹检测细胞周期G0/G1期检查点关键负调控因子p21 WAF1/CIP1(简称p21)、细胞M期周期蛋白Cyclin B1的表达水平,从中筛选到两个编号分别为05和06的化合物,可导致人宫颈癌HeLa细胞中p21表达上调和Cyclin B1表达下调.用流式细胞术和siRNA干扰技术检测化合物对细胞周期的影响及其RXRα依赖性,结果显示:化合物05和06可引起G0/G1期细胞比例显著增加,同时G2/M期细胞比例显著下降,且化合物05和06引起p21表达水平上调的作用在一定程度上依赖于RXRα.用Annexin V-FITC/PI试剂盒检测细胞凋亡率,同时检测聚腺苷二磷酸核糖聚合酶(PARP)切割蛋白水平及其RXRα依赖性,结果表明:化合物05和06均能够引起HeLa细胞凋亡率显著增加,并导致PARP切割且具有一定的RXRα依赖性.进而用计算机模拟的方法对化合物与RXRα进行分子对接,模拟化合物与RXRα可能的结合位点,结果显示化合物05和06可能与RXRα蛋白的helix12、helix3、helix4形成的表面区域结合.综上,筛选出的化合物05和06可能通过与RXRα表面结合,阻滞HeLa细胞周期于G0/G1期,最终诱导HeLa细胞凋亡.国家自然科学基金(91429306,81672749,U1405229

Measurement of integrated luminosity of data collected at 3.773 GeV by BESIII from 2021 to 2024

We present a measurement of the integrated luminosity e+e- of collision data collected by the BESIII detector at the BEPCII collider at a center-of-mass energy of Ecm = 3.773 GeV. The integrated luminosities of the datasets taken from December 2021 to June 2022, from November 2022 to June 2023, and from October 2023 to February 2024 were determined to be 4.995±0.019 fb-1, 8.157±0.031 fb-1, and 4.191±0.016 fb-1, respectively, by analyzing large angle Bhabha scattering events. The uncertainties are dominated by systematic effects, and the statistical uncertainties are negligible. Our results provide essential input for future analyses and precision measurements