简介：AbstractPsoriatic arthritis (PsA) is a type of chronic inflammatory arthritis which is associated with psoriasis. The early recognition and treatment for PsA are of critical importance. Janus kinase (JAK) inhibitors, as a kind of orally small molecules, have emerged as an encouraging class of drug in PsA treatment. This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA. There are three JAK inhibitors approved for use in autoimmune diseases, for example, tofacitinib, baricitinib, and upadacitinib, and only tofacitinib has been approved in PsA treatment. The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing. The efficacy and safety of these agents were briefly discussed. Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.

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简介：SulfatecanbeactivatedbyATPsulfurylaseandadenosine5-phosphosulfatekinase(APSK)invivo.RecentstudiessuggestedthatAPSKinArabidopsisthalianaregulatedthepartitionbetweenAPSreductionandphosphorylationanditsactivitycanbemodulatedbycellularredoxstatus.InordertostudyregulationofAPSKinrice(OsAPSK),OsAPSKIgenewasclonedanditsactivitywasanalyzed.OsAPSKIC36andC69werefoundtobetheconservedcounterpartsofC86andC119,whichinvolvedindisulfideformationinAtAPSK.C36A/C69AOsAPSK1doublemutationwasmadebysitedirectedmutagenesis.OsAPSKanditsmutantwereprokaryoticallyover-expressedandpurified,andthenassayedforAPSphosphorylationactivity.OsAPSK1activitywasdepressedbyoxidizedglutathione,whiletheactivityofitsmutantwasnot.Furtherstudiesinthecasethatoxidativestresswillfluctuateinvivo3'-phosphoadenosine-5'-phosphosulfatecontent,andallAPSKisoenzymeshavesimilarregulationpatternsarenecessarytobeperformed.

简介：Brassinosteroids(BR)是植物激素的一个主要的组调整植物生长和开发。BRI1，对质膜局部性的蛋白质，当BR受体和它被建议了，工作它的kinase活动在调整BR的植物生长和开发有一个必要角色。这里，我们报导隔离和bri1的新等位基因的分子的描述，bri1-301，哪个表演中等词法显型和减少的回答到在正常生长条件下面的BR。顺序分析从GG识别了二底的改变到，导致到在BRI1kinase领域的989I的989G的变换在。kinase活动的试管内试金证明bri1-301不向BRI1底层TTL和BAK1举办可检测的autophosphorylation活动或磷酸化活动。而且，我们的结果建议甚至与极其损害的kinase活动，bri1-301仍然在调整植物生长和开发保留部分功能，它提出BRI1kinase活动是否在高等植物为调停BR的生长和开发是必要的问题。

简介：Humanpolymorphonuclearleukocytes(PMN)havebeenreportedtocompletelylackofDNA-dependentproteinkinase(DNA-PK)whichiscomposedofKuproteinandthecatalyticsubunitDNA-PKcs,neededfornonhomologousend-joining(NHEJ)ofDNAdouble-strandbreaks.PromyelocyticHL-60cellsexpressavariantformofKuresultinginenhancedradiationsensitivity.ThisraisesthequestioniflowefficiencyofNHEJ,instrumentalforthecellularrepairofoxidativedamage,isanormalcharacteristicofmyeloiddifferentiation.HereweconfirmedthecompletelackofDNAPKinPMNproteinextracts,andtheexpressionofthetruncatedKu86variantforminHL-60.However,thisdegradationofDNA-PKwasshowntobeduetoaDNA-PK-degradingproteaseinPMNandHL-60.Inaddition,byusingaprotease-resistantwholecellassay,bothKu86andDNA-PKcscouldbedemonstratedinPMN,suggestingthepreviouslyreportedabsenceinPMNofDNA-PKtobeanartefact.ThelevelsofKu86andDNA-PKcsweremuchreducedinPMN,ascomparedwiththatofthelymphocytes,whereasHL-60displayedamarkedlyelevatedDNA-PKconcentration.Inconclusion,ourfindingsprovideevidenceofreduced,notdepletedexpressionofDNA-PKduringthematurestagesofmyeloiddifferentiation.

简介：SulfatecanbeactivatedbyATPsulfurylaseandadenosine5’-phosphosulfatekinase(APSK)invivo.RecentstudiessuggestedthatAPSKinArabidopsisthalianaregulatedthepartitionbetweenAPSreductionandphosphorylationanditsactivitycanbemodulatedbycellularredoxstatus.InordertostudyregulationofAPSKinrice(OsAPSK),OsAPSK1genewasclonedanditsactivitywasanalyzed.OsAPSK1C36andC69werefoundtobetheconservedcounterpartsofC86andC119,whichinvolvedindisulfideformationinAtAPSK.C36A/C69AOsAPSK1doublemutationwasmadebysitedirectedmutagenesis.OsAPSK1anditsmutantwereprokaryoticallyover-expressedandpurified,andthenassayedforAPSphosphorylationactivity.OsAPSK1activitywasdepressedbyoxidizedglutathione,whiletheactivityofitsmutantwasnot.Furtherstudiesinthecasethatoxidativestresswillfluctuateinvivo3’-phosphoadenosine-5’-phosphosulfatecontent,andallAPSKisoenzymeshavesimilarregulationpatternsarenecessarytobeperformed.

简介：AbstractBackground:Vascular endothelial dysfunction is considered a key pathophysiologic process for the development of acute lung injury. In this study, we aimed at investigating the effects of unfractionated heparin (UFH) on the lipopolysaccharide (LPS)-induced changes of vascular endothelial-cadherin (VE-cadherin) and the potential underlying mechanisms.Methods:Male C57BL/6 J mice were randomized into three groups: vehicle, LPS, and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received subcutaneous injection of 8 U UFH 0.5 h before LPS injection. The lung tissue of the mice was collected for assessing lung injury by measuring the lung wet/dry (W/D) weight ratio and observing histological changes. Human pulmonary microvascular endothelial cells (HPMECs) were cultured and used to analyze the effects of UFH on LPS- or tumor necrosis factor-alpha (TNF-α)-induced vascular hyperpermeability, membrane expression of VE-cadherin, p120-catenin, and phosphorylated myosin light chain (p-MLC), and F-actin remodeling, and on the LPS-induced activation of the phosphatidylinositol-3 kinase (PI3K)/serine/threonine kinase (Akt)/nuclear factor kappa-B (NF-κB) signaling pathway.Results:In vivo, UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes (neutrophil infiltration and erythrocyte effusion, alveolus pulmonis collapse, and thicker septum), decreased the lung W/D, and increased protein concentration (LPS vs. LPS + UFH: 0.57 ± 0.04 vs. 0.32 ± 0.04 mg/mL, P = 0.0092), total cell count (LPS vs. LPS + UFH: 9.57 ± 1.23 vs. 3.65 ± 0.78 × 105/mL, P= 0.0155), polymorphonuclear neutrophil percentage (LPS vs. LPS+ UFH: 88.05% ± 2.88% vs. 22.20% ± 3.92%, P = 0.0002), and TNF-α (460.33 ± 23.48 vs. 189.33 ± 14.19 pg/mL, P = 0.0006) in the bronchoalveolar lavage fluid. In vitro, UFH pre-treatment prevented the LPS-induced decrease in the membrane expression of VE-cadherin (LPS vs. LPS + UFH: 0.368 ± 0.044 vs. 0.716 ± 0.064, P = 0.0114) and p120-catenin (LPS vs. LPS + UFH: 0.208 ± 0.018 vs. 0.924 ± 0.092, P = 0.0016), and the LPS-induced increase in the expression of p-MLC (LPS vs. LPS + UFH: 0.972 ± 0.092 vs. 0.293 ± 0.025, P = 0.0021). Furthermore, UFH attenuated LPS- and TNF-α-induced hyperpermeability of HPMECs (LPS vs. LPS + UFH: 8.90 ± 0.66 vs. 15.84 ± 1.09 Ω·cm2, P = 0.0056; TNF-α vs. TNF-α + UFH: 11.28 ± 0.64 vs. 18.15 ± 0.98 Ω·cm2, P = 0.0042) and F-actin remodeling (LPS vs. LPS + UFH: 56.25 ± 1.51 vs. 39.70 ± 1.98, P = 0.0027; TNF-α vs. TNF-α + UFH: 55.42 ± 1.42 vs. 36.51 ± 1.20, P = 0.0005) in vitro. Additionally, UFH decreased the phosphorylation of Akt (LPS vs. LPS + UFH: 0.977 ± 0.081 vs. 0.466 ± 0.035, P = 0.0045) and I kappa B Kinase (IKK) (LPS vs. LPS + UFH: 1.023 ± 0.070 vs. 0.578 ± 0.044, P = 0.0060), and the nuclear translocation of NF-κB (LPS vs. LPS + UFH: 1.003 ± 0.077 vs. 0.503 ± 0.065, P = 0.0078) in HPMECs, which was similar to the effect of the PI3K inhibitor, wortmannin.Conclusions:The protective effect of UFH against LPS-induced pulmonary endothelial barrier dysfunction involves VE-cadherin stabilization and PI3K/Akt/NF-κB signaling.

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简介：房间有大量的控制维持他们的完整并且阻止随机切换到另外一个一个生物状态。RafKinase禁止的蛋白质(RKIP)，phosphatidylethanolamine绑定蛋白质(PEBP)的一个成员家庭，表明工作维持“yinyang”或生物系统的平衡的串联的调节的人的一个新类是代表性的。RKIP禁止地图kinase(Raf-MEK-ERK)，表明串联的G联合蛋白质的受体(GPCR)kinase和NFkappaB。因为RKIP指向依赖于它磷酸化的状态的不同家族ases，RKIP也行动集成多重环境刺激开始的串音。RKIP的损失或弄空导致正常细胞的壅滞和罐头的混乱导致象癌症那样的chromosomal畸形和疾病状态。因为RKIP和PEBP家庭以前被考察了，这分析的目标是提供更改并且加亮一些RKIP的唯一的特征在细胞的发信号的过程的规定使它成为一个批评播放器。

简介：Humanrhodopsinkinase(RK)andacarboxylterminus-truncatedmutantRKlackingthelast59aminoacids(RKC)wereexpressedinhumanembryonickidney293cellstoinvestigatetheroleofthecarboxylterminusofRKinrecognitionandphosphorylationofrhodopsin.RKC,likethewild-typeRK,wasdetectedinbothplasmamembranesandcytosolicfractions.TheCterminaltruncatedrhodopsinkinasewasunabletophosphorylatephoto-activatedrhodopsin,butpossesseskinaseactivitysimilartothewild-typeRKinphosphorylationofsmallpeptidesubstrate.ItsuggeststhatthetruncationdidnotdisturbthegrossstructuresofRKcatalyticdomain.OurresultsalsoshowthatRKCfailedtotranslocatetophoto-activatedrodoutsegments.Takentogether,ourstudydemonstratethecarboxylterminusofRKisrequiredforphosphorylationofphoto-activatedrhodopsinandstronglyindicatethatcarboxyl-terminusofRKmaybeinvolvedininteractionwithphoto-activatedrhodopsin.

简介：AbstractBackground:Topoisomerase II alpha (TOP2A) has been reported to play a crucial role in the tumorigenesis of various cancer types. However, the biological role of TOP2A in gallbladder cancer (GBC) remains unknown. The current study aimed to explore the function and potential mechanism of TOP2A in GBC.Methods:Based on Gene Expression Profiling Interactive Analysis data, we found TOP2A was significantly up-regulated in GBC tissues and resulting in shorter overall survival. Quantitative real-time polymerase chain reaction and immunohistochemistry were conducted to detect the expression of TOP2A in 45 pairs of GBC tissues and adjacent non-tumor tissues. In vitro, cell proliferation, migration, and invasion ability were examined by cell counting kit-8 and transwell assay, respectively. Epithelial-mesenchymal transition (EMT) related and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related markers were measured by Western blotting. Xenograft model assay was performed to evaluate the effect of TOP2A in vivo.Results:TOP2A was found up-regulated in GBC (tumor vs. normal, 12.62 vs. 0.34) and correlated with the late tumor node metastasis stage (P = 0.0032), present of lymph node metastasis (P = 0.0273), and poor prognosis in GBC patients (log-rank P = 0.028). In vitro and in vivo assays showed that knockdown of TOP2A notably inhibited cell proliferation, migration, invasion, EMT process, and tumor growth in GBC. In addition, TOP2A down-regulation significantly decreased the protein levels of phosphor (p)-PI3K, p-Akt, and p-mTOR.Conclusion:Our study demonstrates that TOP2A was overexpressed in GBC and associated with poor prognosis in GBC patients. TOP2A promotes GBC cell proliferation, migration, invasion, EMT process, and tumor growth through activating PI3K/Akt/mTOR signaling pathway, and may serve as a novel prognostic biomarker and therapeutic target for GBC.

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简介：瞄准：在与clinicopathological特征和成纤维细胞生长因素受体1的表示(FGFR1)和ephrinligands的关系在胃的癌症澄清Ephrin受体A4(EphA4)的表示和角色。方法：十一根胃的癌房间线，胃的腺癌的24个配对的外科的新鲜标本并且邻近非，肿瘤组织，74个常规修理福尔马林的、嵌入石蜡的肿瘤标本，和55个标本在组织上看到微数组(TMA)被分析。反向的transcription-PCR(RT-PCR)，即时RT-PCR，免疫组织化学，和房间生长试金被执行。结果：EphA4mRNA表示的Overexpression在8被观察(73%)11胃的癌症，房间排队并且10(42%)24胃的癌症纸巾。EphA4的Overexpression，由免疫组织化学分析了，在62被观察(48%)129胃的癌症纸巾。在蛋白质水平，在表示上的EphA4显著地与侵略和复发的深度被联系。在表示上的EphA4也在表示上与FGFR1被相关。有EphA4积极的癌症的病人比有显著地更短的全面幸存时期与EphA4否定的癌症做了那些(P=0.0008)。为ephrinligands的mRNAs是在在胃的癌症房间线和癌症纸巾的各种各样的联合的coexpressed。由在EphA4-overexpressing胃的癌症房间线的siRNA的EphA4表示的Downregulation在房间生长导致了重要减少。结论：我们的结果建议那在胃的癌症在EphA4的表示上起一个作用。

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简介：Gastrointestinal(GI)cancerisoneofthemostcommoncausesofcancer-relateddeathsworldwide.Tumormarkersarevaluableindetectingpost-surgicalrecurrenceorinmonitoringresponsetochemotherapy.PyruvatekinaseisoformM2(PKM2),aglycolyticenzymecatalyzingconversionofphosphoenolpyruvate(PEP)topyruvate,confersagrowthadvantagetothetumorcellsandenablesthemtoadapttothetumormicroenvironment.Inthisreview,wehavesummarizedcurrentresearchontheexpressionandregulationofPKM2intumorcells,anditspotentialroleinGIcarcinogenesisandprogression.Furthermore,wehavealsodiscussedthepotentialofPKM2asadiagnosticandscreeningmarker,andatherapeutictargetinGIcancer.

简介：Aim:Toidentifythegenesspecificallyexpressedinhumanadultandfetaltestesandspermatozoa.Methods:AhumantestiscDNAmicroarraywasestablished.ThenmRNAsofhumanadultandfetaltestisandspermatozoawerepurifiedandprobeswerepreparedbyareversetranscriptionreactionwithmRNAasthetemplate.Themicroarraywashybridizedwithprobesofadultandfetaltestesandspermatozoa.ThenucleicacidsequencesofdifferentiallyexpressedgenesweredeterminedandhomologiesweresearchedinthedatabasesofGenBank.Results:Anovelhumantestis-specificgene,PKH-T,wasidentifiedbyhybridizingadultandfetaltestisandspermatozoaprobeswithahumantestiscDNAmicroarray.ThecDNAofPKH-Twas1069bpinlength.ThecDNAsequenceofthisclonewasdepositedintheGenbank(AY303972)andPKH-TwasalsodeterminedasInterimGenSymbol(Unigene,HS.38041).PKH-TcontainedmostPKHconservedmotif.The239aminoacidsequencesdeducedfromthe719bpopenreadingframe(ORF)hadahomologywiththegenePKH(U89606).PKH-Twasspecificallyandstronglyexpressedinthetestis.ComparisonofthedifferentialexpressionsofPKHandPKH-Tintestesofdifferentdevelop-mentalstagesindicatedthatPKH-Twasexpressedintheadulttestisandspermatozoa,whilePKH,intheadult,fetalandagedtestes.PKH-ThadnoexpressioninthetestisofSertolicellonlyandpartiallyspermatogenicarrestpatients.Conclusion:PKH-Tisagenehighlyexpressedinadulthumantestisandspermatozoa.Itmayplayanimportantroleinspermatogenesisandcouldberelatedtomaleinfertility.

简介：Thetherapeuticeffectofherpessimplexvirusthymidinekinase/ganciclovir(HSV-tk/GCV)systemonhepatocellularcarcinomawasstudiedinthisexperiment.Thetk-containingretroviralrecombinantswereusedtoinfecthepatomacells(BEL-7402)andthecellsweretreatedwithganciclovir(0-100μg/ml).TheresultsshowedthatHSV-tkgenecouldbeefficientlytransferredinvitrointohepatomacellsandstablyexpressed.Thegrowthpotentialofthetk-containingcellswassignificantlyinhibitedbyGCV(P<0.01)ascomparedtothenon-tk-containingcells.TheantitumoreffectofHSV-tk/GCVsystemwasalsoproducedexvivointk-containingtumorofnudemiceascharacterizedbyamarkeddecreaseintumorgrowthafterGCVtreatmentcontrarytoaprogressiveenlargementofnon-tk-containingtumors.Althoughthehistologicalexaminationdemonstratedthattheefficiencyofthegenetransferwaslessthan30%,thekillingeffectofHSV-tk/GCVsystemonhepatocellularcarcinomawasstillsignificantlygenerated.ThegropermechanismofHSV-tkgenetherapyonhepatictumorreferredas“bystandereffect”intherapeuticapproachhasnotbeenfoundinthisstudyandrequiredtobeexploredfurther.

简介：胰岛素不仅在糖尿病中发挥重要的作用，在骨的代谢中也是关键的调节因子，胰岛素与胰岛素受体结合，促进胰岛素受体底物（IRS）发生酪氨酸磷酸化，进而激活PI3kinase／Akt通路。PI3kinase／Akt通路参与了多种细胞的增殖分化，越来越多的证据证明，PI3kinase／Akt通路在骨细胞的增殖、分化起重要作用。本文就PI3kinase／Akt通路对骨代谢的调节作一综述，希望能为骨代谢疾病患者种植牙的药物选择提供思路。

简介：Cancerevadeshostimmunesurveillancebyusingimmunecheckpoints,whichareinhibitorypathwayscrucialformaintainingself-tolerance1.Tumorcellsexpressmultipleinhibitoryligands,andtumor-infiltratinglymphocytes(TIL)expressavarietyofinhibitoryreceptors.InhibitoryreceptorscytotoxicT-lymphocyte-associatedprotein4(CTLA-4)andprogrammeddeath-1