GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines

BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.

Involvement of T-complex protein 1-ring complex/chaperonin containing T-complex protein 1(TRiC/CCT) in retrograde axonal transport through tau phosphorylation

The cytosolic chaperonin T-complex protein 1-ring complex(TRiC)or chaperonin containing T-complex protein 1(CCT)is essential in de novo folding of approximately 10%of the eukaryotic,newly translated polypeptides as well as misfolded proteins.There is a close link between the TRiC/CCT cytosolic chaperonin and neurodegenerative diseases(Lopez et al.,2015).A lot of research suggests that CCT plays neuroprotective roles in neurodegenerative diseases including Huntington’s disease(Lopez et al.,2015).Either overexpression of a single or all eight subunits(CCT1-8)or treatment of the substrate-binding apical domain of yeast CCT1(ApiCCT1)prevented mutant Huntingtin aggregation and improved cellular and neuronal functions(Zhao et al.,2016).Importantly,our recent study has demonstrated that both CCT and ApiCCT could reduce mutant Huntingtin level and enhance both anterograde and retrograde axonal transport of brain-derived neurotrophic factor.These results led to restoration of the trophic status of striatal neurons from a bacterial artificial chromosome transgenic mouse model of Huntington’s disease(Zhao et al.,2016).Axonal transport is regulated by many factors including microtubule-associated protein tau,which promotes tubulin polymerization and stabilizes microtubules.Impaired interaction between tau and microtubules plays a vital role in the pathogenesis of multiple neurodegenerative diseases(Wang and Mandelkow,2016).Interestingly,tau phosphorylation is also observed in brains of several Huntington’s disease mouse models and Huntington’s disease patients(Gratuze et al.,2016).In a recent study,we explored if CCT subunit has any effect on axonal transport in a tau-dependent pathway(Chen et al.,2018b).We focused on the retrograde axonal transport of brain-derived neurotrophic factor,as neurotrophic factor-mediated signaling in the form of signaling endosome is essential in both the developing and the mature nervous system and dysregulation of trafficking of neurotrophic factors is tightly linked to disorders of the nervous system(Chen et al.,2018a).We found that the expression of a single CCT subunit(CCT5)significantly promoted retrograde axonal transport of brain-derived neurotrophic factor in primary cortical neurons.Mechanically,CCT regulated the level of cyclin-dependent kinase 5(CDK5)/p35/p25 and,subsequently contributed to CCT-induced tau phosphorylation,which induced detachment of tau from microtubules(Chen et al.,2018b)(Figure 1).

Discovery of a small-molecule bromodomain-containing protein 4 inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer

OBJECTIVE To discover a small-molecule bromodomain-containing protein 4(BRD4)inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer and exploreits potential mechanisms.METHODS BRD4 interactors were analyzed by PPI network prediction and The Cancer Genome Atlas(TCGA)analysis.The interaction between BRD4 and AMPK was confirmed by co-immunoprecipitation assay.Novel BRD4 inhibitors were designed and synthesized based upon pharmacophore analysis of BRD4(1),then screened by antiproliferative activity and Alpha Screen of BRD4(1).The selectivity of the best candidate compound 8f was validated by co-crystallization,FRET assay and co-immuno precipitation assay.The mechanisms of 8f were investigated by fluorescence microscopy,electron microscopy,Western blotting,immunocytochemistry,si RNA and GFP-m RFP-LC3 plasmid transfections,as well as immunohistochemistry and immunofluorescence.Potential mechanisms were discovered by i TRAQ-based proteomics analysis and the therapeutic effect of 8f was assessed by xenograft breast cancer mouse and zebrafish models.RESULTS We identified that BRD4 interacted with AMPK,which was remarkably downregulated in breast cancer.We next designed and synthesized 49 candidate compounds,and eventually discovered a selective small-molecule inhibitor of BRD4(8f).Subsequently,8f was discovered to induce autophagyassociated cell death(ACD)by BRD4-AMPK interaction,and thus activating AMPK-m TOR-ULK1-modulated autophagic pathway in breast cancer cells.Interestingly,the i TRAQ-based proteomics analyses revealed that 8f induced ACD pathways,involved in HMGB1,VDAC1/2 and e EF2.Moreover,8f displayed a therapeutic potential on both xenograft breast cancer mouse and zebrafish models.CONCLUSION We discovered a novel small-molecule inhibitor of BRD4 that induces BRD4-AMPK-modulated ACD in breast cancer,which may provide a candidate drug for future cancer therapy.

Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development

Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.

Wheat Lysin-Motif-Containing Proteins Characterization and Gene Expression Patterns under Abiotic and Biotic Stress

Lysin motif(LysM)-containing proteins(LYPs)are important pattern recognition receptors in plants.However,the evolutionary history and characteristics of LYP genes remain largely unclear in wheat.In this study,62 LYPs were identified at genome wide in wheat.Based on phylogenetic and domain analysis,wheat LYPs were classified into 6 subgroups(group LysMe,LysMn,LYP,LYK,LysMFbox).Syntenic analysis showed the evolution of LYP genes in wheat.RNA-seq data showed that 22 genes were not expressed at any tissue or stress stimulation period.Some LYP and LYK genes were tissue-or stage-specific.The majority of TaLYK5s,TaLYK6s,TaLYP2s and TaLysMns genes were induced under chitin,flg22 and fungal treatment.qRT-PCR analysis showed that 4 genes were upregulated during Puccinia triticina infection with a peak at 18 h post inoculation.Our findings suggested that wheat LYPs may have specific roles in response to fungal infection and provided insights into the function and characteristics of wheat LYP genes.

An enriched environment increases the expression of fibronectin type Ⅲ domain-containing protein 5 and brain-derived neurotrophic factor in the cerebral cortex of the ischemic mouse brain

Many studies have shown that fibronectin type III domain-containing protein 5(FDNC5) and brain-derived neurotrophic factor(BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia;however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion(pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16–20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions(based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities(based on the spatial learning scores from the Morris water maze test 16–19 days after operation), and memory abilities(based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF(r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval Nos. 20160858 A232, 20160860 A234) on February 24, 2016.

Antitumor Active Protein-containing Glycans from the Body of Ganoderma tsugae

To explore the effects of traditional herbal medicine Ganoderrna tsugae（G, tsugae） on immunomodulatory and antitumor activities, the crude polysaccharides of G. tsugae were purified by filtration, diethylaminoethyl（DEAE） sepharose-fast flow chromatography and sephadex G-100 size-exclusion chromatography. Two main fractions, pro- tein-containing glyeans CSSLP-1 and CSSLP-2, were obtained via the gradient elution. The protein content, molecu- lar weight, and monosaccharide composition of the two fractions were analyzed. Furthermore, the influence of the protein-containing glycans from G. tsugae on the activation of human acute monocytic leukemia cell line（THP-l） and their antitumor activities to the human hepatocellular liver carcinoma cell（HepG-2） in vitro were evaluated. The re- sults indicate that CSSLP-1 and CSSLP-2 could increase the pinocytie activity of THP-1 cells and induce THP-1 cells to produce the eytokines of TNFa and IL-2, significantly. CSSLP-1 and CSSLP-2 also played an inhibiting effect on the cancer cell（HepG-2）. Moreover, the anti-proliferation activity of CSSLP-1 and CSSLP-2 increased with the par- ticipation of TNFa and IL-2 or other antitumor factors induced from THP-1 cells by G. tsugae protein-containing glycan fractions.

Flavin-Containing Monooxygenase (FMO) Protein Expression and Its Activity in Rat Brain Microvascular Endothelial Cells

The aim of this study was to examine whether flavin-containing monooxygenase (FMO) protein was expressed in cultured rat brain microvascular endothelial cells (BMECs), which constitute the blood-brain barrier (BBB), and whether N-oxide from the tertiary amine, d-chlorpheniramine, was formed by FMO in rat BMECs. BMECs were isolated and cultured from the brains of three-week-old male Wistar rats. The expression of FMO1, FMO2 and FMO5 proteins was confirmed in rat BMECs by western blotting analysis using polyclonal anti-FMO antibodies, but FMO3 and FMO4 proteins were not found in the rat BBB. Moreover, N-oxide of d-chlorpheniramine was formed in rat BMECs. The intrinsic clearance value for N-oxidation at pH 8.4 was higher than that at pH 7.4. Inhibition of N-oxide formation by methimazole was found to be the best model of competitive inhibition yielding an apparent Ki value of 0.53 μmol/L, suggesting that N-oxidation was catalyzed by FMOs in rat BMECs. Although FMO activity in rat BMECs was lower than that in SD rat normal hepatocytes (rtNHeps), we suggest that rat BMECs enzymes can convert substrates of exogenous origin for detoxification, indicating that BMECs are an important barrier for metabolic products besides hepatic cells.

Purification and Characteristics of Mn-containing Nitrogenase Component Ⅰ

A mutant UW 3, which is unable to fix N 2 in the presence of Mo (Nif -) but undergo phenotypic reversal to Nif + under Mo deficiency, was able to grow in Mo- and NH 3-deficient medium containing Mn, and the growth was accelerated by Mn at low concentration. A partly purified nitrogenase component Ⅰ protein separated from UW 3 grown in the Mn-containing medium was shown to contain Fe and Mn atoms (ratio of Fe/Mo/Mn: 10.41/0.19/1.00) with C 2H 2- and H +-reducing activity which almost equal to half of that of MoFe protein purified from wild-type mutant of Azotobacter vinelandii Lipmann. This protein was obviously different from MoFe protein in both absorption spectrum and circular dichroism, and the molecular weight of subunits in Mn-containing protein was close to that of α subunit in MoFe protein. The preliminary results indicated that the protein containing Mn might be a nitrogenase component Ⅰ protein.

葡萄VQ motif-containing蛋白家族基因鉴定及其在胁迫响应中的作用研究

本研究鉴定出18个葡萄VQ motif-containing蛋白家族成员。18个葡萄VQ motif-containing蛋白家族成员可分为6个亚家族,并包含2个孤儿VQ motif-containing蛋白基因。很多葡萄VQ motif-containing蛋白基因的表达不仅受到非生物胁迫及外源ABA处理的影响,也可能受到葡萄CBF4基因的调控,还会受到病毒感染或白粉病感染的影响。通过比较易感病品种‘赤霞珠’和抗病品种‘诺顿’感染白粉病后VQ motif-containing蛋白基因的表达变化发现,二者中大部分相同VQ motif-containing蛋白基因的表达趋势一致。但是,VIT_213s0156g00160和VIT_201s0011g01350的表达变化趋势在二者之间不同。VIT_208s0007g05180和VIT_208s0058g00690可以与葡萄WRKY33互作,部分葡萄VQ motif-containing蛋白还可以与多个Sigma70_r2结构域包含蛋白互作。此外,葡萄VQ motif-containing蛋白家族在进化历史中主要遭受纯化选择。

三阴性乳腺癌中KIAA1522表达和作用研究

目的分析三阴乳腺癌(TNBC)中KIAA1522激活对Wnt信号通路及促进肿瘤细胞转移的机制影响。方法该研究于2021年1月至2022年10月进行,收集唐山市人民医院手术治疗的三阴乳腺癌36例,TNBC癌组织依据有淋巴结转移(转移组)和无淋巴结转移(未转移组)分为两组,采用蛋白质印迹法和实时荧光定量逆转录PCR(RT-qPCR)法分别检测各组KIAA1522、含IQ模序的GTP酶活化蛋白1(IQGAP1)、β连环素(β-catenin)的蛋白及mRNA相对表达水平,免疫共沉淀法检测KIAA1522、IQGAP1分别与β-catenin的相互作用情况。结果转移组中KIAA1522、IQGAP1、β-catenin蛋白相对表达量(0.37±0.05、0.28±0.02、1.50±0.08)均高于未转移组(0.27±0.05、0.25±0.05、1.05±0.02)(P<0.05)。转移组中KIAA1522、IQGAP-1 mRNA相对表达量(0.95±0.03、1.08±0.10)高于未转移组(0.73±0.05、0.99±0.12)(P<0.05),两者呈正相关关系(r=0.55,P<0.05),β-catenin mRNA在二组中的相对表达量差异无统计学意义。免疫共沉淀显示在TNBC癌组织中KIAA1522蛋白与β-catenin蛋白无相互作用,而IQGAP1蛋白与β-catenin蛋白相互共沉淀。结论KIAA1522激活Wnt信号通路,促进TNBC肿瘤细胞的转移,机制可能与上调IQGAP1 mRNA,过表达的IQGAP1促进β-catenin蛋白累积并结合成蛋白复合物有关。

三结构域蛋白21对非酒精性脂肪性肝病的影响及机制研究

目的探讨三结构域蛋白21(tripartite motif containing protein 21,TRIM21)对游离脂肪酸(free fatty acid,FFA)诱导的肝细胞脂质沉积的影响,并探讨核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)及相关基因在该过程中的作用。方法用TRIM21敲低慢病毒及TRIM21过表达质粒分别感染及转染细胞,构建TRIM21基因干扰体外模型并使用qRT-PCR和Western blotting实验进行模型验证;验证FFA诱导非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)体外模型方法的可行性;干扰TRIM21表达后建立NAFLD体外模型,油红O染色检测细胞脂质沉积情况;DCFH-DA荧光探针检测细胞内活性氧水平;qRT-PCR检测Nrf2、Keap1、HO-1 mRNA表达水平;Western blottingting检测Nrf2、Keap1蛋白表达水平;免疫荧光检测Nrf2蛋白在细胞内的分布情况。结果(1)油红O染色结果表明:敲低TRIM21表达减少FFA诱导的肝细胞内脂质沉积(P<0.05),过表达TRIM21增加FFA诱导的肝细胞内脂质沉积(P<0.05)。(2)细胞内ROS水平检测结果显示:敲低TRIM21表达,胞内ROS水平降低(P<0.05),TRIM21过表达时胞内ROS水平升高(P<0.05)。(3)qRT-PCR检测结果显示:敲低TRIM21表达,Nrf2、Keap1、HO-1 mRNA表达增加(P<0.05),TRIM21过表达时,Nrf2 mRNA表达增加(P<0.01),Keap1、HO-1表达减少(P<0.05)。(4)Western blotting结果显示:敲低TRIM21表达,Nrf2蛋白表达减少(P<0.01),Keap1蛋白表达增加(P<0.001),TRIM21过表达时Nrf2蛋白表达增加(P<0.05),Keap1蛋白表达减少(P<0.0001)。(5)敲低TRIM21表达Nrf2免疫荧光染色平均荧光强度(细胞核/细胞质)较对照组增加(P<0.001),TRIM21过表达时Nrf2平均荧光强度较对照组减少(P<0.001)。结论干扰TRIM21表达可能通过调节Nrf2及相关蛋白来影响FFA诱导的细胞脂质沉积,进而影响NAFLD发生发展过程。

同步靶向马铃薯StRTP5a和StRTP5b基因RNA干扰载体的构建及遗传转化

植物免疫调控基因RTP5(Resistance to Phytophthora 5)编码一个含WD40结构域的蛋白,该基因负调控植物对疫霉的抗性。为获得沉默马铃薯中RTP5同源基因StRTP5a和StRTP5b的遗传材料,以便进一步探究StRTP5a和StRTP5b基因的生物学功能。以四倍体马铃薯品种‘Désirée’的cDNA为模板,扩增到靶向StRTP5a和StRTP5b基因的DNA片段,通过Gateway技术将目的片段重组至植物表达载体pHellsgate12,构建同步靶向StRTP5a和StRTP5b基因的目的表达载体pHells12-StRTP5a/b i,然后利用根癌农杆菌介导的遗传转化方法将目的表达载体转化至‘Désirée’中。经PCR和qPCR分析后,获得8株2个目的基因同时沉默的马铃薯株系,转化株系中StRTP5a和StRTP5b基因表达量同时降幅最高达70%以上。

miR-184-3p促进舌鳞状细胞癌生长的作用机制研究

目的探讨miR-184-3p通过抑制SET结构域蛋白2(SETD2)调节N-Myc原癌基因蛋白(MYCN)启动子的组蛋白H3第36位赖氨酸三甲基化(H3K36me3)修饰促进舌鳞状细胞癌(TSCC)发生、发展的机制。方法培养正常口腔上皮细胞系HOEC、TSCC细胞系(CAL27、SCC-4和SCC-9)。采用实时荧光定量聚合酶链反应法检测细胞miR-184-3p表达水平,细胞计数试剂盒8法检测细胞增殖能力,流式细胞术检测细胞凋亡率,克隆形成实验检测细胞克隆形成能力,划痕愈合实验检测细胞迁移能力,Transwell实验检测细胞侵袭能力,蛋白质印迹法检测SETD2、MYCN、H3K36me3表达水平。结果与HOEC细胞相比,TSCC细胞miR-184-3p表达上调,SETD2表达下调,MYCN表达上调,TSCC细胞增殖、迁移和侵袭能力增强,差异均有统计学意义(均P<0.05)。干扰CAL27、SCC-4细胞miR-184-3p表达后,H3K36me3表达上调,MYCN表达下调,细胞增殖、迁移和侵袭能力减弱;干扰CAL27细胞MYCN表达后,MYCN表达下调,细胞增殖、迁移和侵袭能力减弱,差异均有统计学意义(均P<0.05),而H3K36me3表达不变;干扰CAL27细胞MYCN表达,同时过表达miR-184-3p后,MYCN表达上调,细胞增殖、迁移和侵袭能力增强,H3K36me3表达下调,差异均有统计学意义(均P<0.05)。CAL27细胞过表达SETD2后,MYCN表达下调,H3K36me3表达上调,差异均有统计学意义(均P<0.05)。CAL27细胞过表达SETD2,同时过表达MYCN后,H3K36me3表达不变。结论在TSCC中高表达的miR-184-3p通过抑制SETD2调节MYCN启动子H3K36me3修饰促进TSCC细胞增殖、迁移和侵袭。

Eps15同源结构域蛋白2在结肠癌细胞侵袭、转移中的作用及其初步机制

目的探究Eps15同源结构域蛋白2(Eps15 homology domain-containing protein 2,EHD2)在结肠癌细胞中的作用及其分子机制。方法在SW620细胞系中构建过表达EHD2的细胞模型,检测EMT相关标志分子物的变化,研究过表达EHD2对细胞株的生物学行为包括转移、侵袭、增殖及凋亡的影响。最后运用异种移植肿瘤模型验证过表达EHD2对裸鼠体内结肠癌的发生及发展的影响。结果过表达EHD2会抑制结肠癌细胞的增殖、迁移、侵袭及促进凋亡;在裸鼠体内,过表达EHD2可以抑制裸鼠皮下肿瘤的生长;且EHD2与EMT相关标志物的表达呈正相关,推测EHD2通过抑制EMT途径抑制结肠癌的进展。结论EHD2可能作为抑癌基因通过EMT进程抑制结肠癌的侵袭和转移。

冠心病患者血清SCUBE1、αvβ3表达与PCI术后氯吡格雷敏感程度的关联性分析

目的分析信号肽-CUB-表皮生长因子结构域包含蛋白1(SCUBE1)、整合素αvβ3在冠心病(CHD)患者血清中的表达与经皮冠状动脉介入(PCI)术后氯吡格雷敏感程度的关联性。方法招募2022年3月至2023年9月三亚中心医院收治的CHD患者164例(CHD组),另选取同期健康体检者150名(对照组)。根据血小板聚集抑制率(IPA),将CHD患者分为低敏感组(41例,IPA<20%)和高敏感组(123例,IPA≥20%)。采用酶联免疫吸附试验检测对照组体检当天和CHD组PCI术前、术后即刻和术后48 h的血清SCUBE1、αvβ3水平。采用多因素logistic回归分析影响CHD患者PCI术后氯吡格雷敏感程度下降的因素。采用受试者工作特征(ROC)曲线分析CHD患者术前血清SCUBE1、αvβ3水平预测PCI术后氯吡格雷敏感程度下降的效能。结果CHD组PCI术前、术后即刻、术后48 h的血清SCUBE1、αvβ3水平均显著高于对照组(P<0.05),且术后血清SCUBE1、αvβ3水平均呈上升趋势,组内各时间点间比较差异有统计学意义(P<0.05)。低敏感组PCI术前、术后即刻、术后48 h的血清SCUBE1、αvβ3水平均高于高敏感组,差异有统计学意义(P<0.05)。多因素logistic回归分析结果显示,PCI术前较高的PLT[OR(95%CI)=2.693(1.182~6.134)]、MPV[OR(95%CI)=2.285(1.328~3.933)]、SCUBE1[OR(95%CI)=2.571(1.352~4.890)]和αvβ3[OR(95%CI)=3.254(1.113~7.340)]水平是促进PCI术后氯吡格雷敏感程度下降的独立危险因素(P<0.05)。ROC曲线分析结果显示,PCI术前血清SCUBE1、αvβ3水平均可有效预测CHD患者术后氯吡格雷敏感程度下降,且二者联合的预测效能更高[AUC(95%CI)=0.899(0.842~0.940)],灵敏度和特异度分别为72.61%和94.31%。结论CHD患者血清SCUBE1、αvβ3水平升高,且PCI术前血清SCUBE1、αvβ3水平可有效预测术后氯吡格雷敏感程度下降,值得临床医师关注。

血清SCUBE1、CLEC-2、UCP2对急性缺血性脑卒中患者静脉溶栓后预后不良的预测价值

目的分析血清信号肽-CUB-表皮生长因子结构域包含蛋白1(SCUBE1)、C型凝集素样受体-2(CLEC-2)、解偶联蛋白2(UCP2)对急性缺血性脑卒中(AIS)患者静脉溶栓(IVT)后预后不良的预测价值。方法选取2022年6月至2023年10月在该院接受IVT治疗的116例AIS患者为观察组,另选取同期在该院进行体检的116例健康者为对照组。根据改良Rankin量表(mRS)评分将患者分为预后良好组和预后不良组。采用酶联免疫吸附试验检测血清SCUBE1、CLEC-2、UCP2水平。采用多因素Logistic回归分析AIS患者IVT后预后不良的影响因素。绘制受试者工作特征(ROC)曲线分析血清SCUBE1、CLEC-2、UCP2对AIS患者IVT后预后不良的预测价值。结果观察组血清SCUBE1、CLEC-2水平高于对照组,血清UCP2水平低于对照组,差异均有统计学意义(P<0.05)。预后良好组有75例患者,预后不良组有41例患者。预后不良组梗死面积>4 cm~3患者比例、血清SCUBE1、CLEC-2水平高于预后良好组,血清UCP2水平低于预后良好组,差异均有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,血清SCUBE1、CLEC-2水平升高为AIS患者IVT后预后不良的危险因素(P<0.05),血清UCP2水平升高为AIS患者IVT后预后不良的保护因素(P<0.05)。ROC曲线分析结果显示,血清SCUBE1、CLEC-2、UCP2单独预测AIS患者IVT后预后不良的曲线下面积(AUC)分别为0.752、0.694、0.776,3项指标联合预测的AUC为0.861,3项指标联合预测的AUC大于SCUBE1、CLEC-2、UCP2单独预测的AUC(Z_(3项联合-SCUBE1)=2.358、Z_(3项联合-CLEC-2)=2.714、Z_(3项联合-UCP2)=2.591,P=0.018、0.007、0.010)。结论IVT后预后不良的AIS患者血清SCUBE1、CLEC-2水平升高,UCP2水平降低,3项指标联合检测对AIS患者IVT后预后不良有较高的预测价值。

非瓣膜性房颤合并急性心肌梗死患者血清MIP-1α,SCUBE1表达水平及其临床诊断价值

目的 探究非瓣膜性房颤(NVAF)合并急性心肌梗死(AMI)患者血清巨噬细胞炎症蛋白-1α(MIP-1α),信号肽-CUB-表皮生长因子结构域包含蛋白1(SCUBE1)表达水平及其临床诊断价值。方法 选取2021年4月-2023年5月在北大荒集团建三江医院收治的155例NVAF患者作为观察对象(观察组),根据是否合并AMI将患者分为未合并AMI组128例与合并AMI组27例,同时选取在本院健康检查的155名人员为对照组,比较各组血清MIP-1α、SCUBE1水平。受试者工作特征(ROC)曲线分析血清MIP-1α,SCUBE1对NVAF合并AMI的诊断价值。Logistic分析影响NVAF合并AMI的因素。结果 观察组血清MIP-1α、SCUBE1水平高于对照组(P<0.05)。合并AMI组左心室射血分数(LVEF)、左心房内径(LAD)、左心室舒张末期容积(LVEDV)显著低于未合并AMI组,血清MIP-1α和,SCUBE1水平、心房颤动(以下简称房颤)卒中风险评分(CHA2DS2-VASc)高于未合并AMI组(P<0.05)。ROC曲线分析显示,血清MIP-1α、SCUBE1水平辅助诊断NVAF患者合并AMI的曲线下面积(AUC)分别是0.819(95%CI:0.728~0.910)、0.784(95%CI:0.680~0.889),二者联合预测的AUC为0.917(95%CI:0.870~0.964),优于二者单独检测(Z=1.857、2.251, P<0.05)。Logistic分析显示,MIP-1α、SCUBE1是NVAF患者合并AMI的影响因素(P<0.05)。结论 NVAF合并AMI患者血清MIP-1α、SCUBE1水平升高,二者联合检测提高了对合并AMI的诊断效能,可能是NVAF合并AMI的潜在评估指标。

VEGFR3及APPL1在NSCLC组织及癌旁组织中的表达及与临床病理的关系分析

目的 分析血管内皮生长因子受体-3(VEGFR3)及磷酸酪氨酸衔接蛋白1(APPL1)在非小细胞肺癌(NSCLC)组织及癌旁组织中的表达及与临床病理的关系。方法 选取2019年1月至2020年12月在蚌埠医科大学第一附属医院收治的100例NSCLC患者为研究对象,并收集患者手术切除的NSCLC组织、癌旁组织。采用免疫组织化学法检测VEGFR3与APPL1表达,并分析VEGFR3与APPL1表达与患者临床病理的关系,以及VEGFR3与APPL1对NSCLC患者预后的预测价值。结果 NSCLC组织与癌旁组织中VEGFR3、APPL1阳性率比较差异有统计学意义(P<0.05)。VEGFR3阳性率在不同组织学类型、淋巴结转移情况、肿瘤浸润情况患者中比较差异有统计学意义(P<0.05);APPL1阳性率在不同组织学类型、肿瘤浸润情况患者中比较差异有统计学意义(P<0.05)。Spearman相关性分析显示,VEGFR3与APPL1表达之间呈正相关(r=0.330,P<0.05)。死亡组VEGFR3、APPL1相对表达量均高于存活组,差异有统计学意义(P<0.05)。受试者工作特征曲线分析显示,VEGFR3、APPL1相对表达量预测NSCLC患者预后的曲线下面积为0.843(95%CI:0.757~0.908)、0.799(95%CI:0.707~0.872)。结论 NSCLC患者VEGFR3及APPL1表达与其临床病理特征有关,VEGFR3和APPL1相对表达量对临床预估NSCLC患者预后具有重要价值。

Thioredoxin interacting protein,a key molecular switch between oxidative stress and sterile inflammation in cellular response

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.