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简介：HDAC和帽子是哪个的二种酶catalysedeacetylation和在优核质的histone的acetylation，其动态平衡在DNA为基因抄写和优核质的基因表示有精确规定水平。他们的Disbalance能在正常房间带增长和区别的混乱，然后导致肿瘤的开始。他们的异常功能是直接与各种各样的肿瘤的开始和前进有关例如promyelocytic白血病，Hodgkin淋巴瘤，结肠的癌症和gastral癌症。HDAC的禁止者被用于肿瘤的治疗。他们能制止HDAC的活动并且堵住deacetylation的混乱引起的基因表示的抑制。它的主要生物效果在导致肿瘤房间的区别躺着，逮捕在G0/G1的房间圆，激活房间apoptosis基因，提高化学治疗和放射性的治疗的敏感。到目前为止HDAC是在anticancer药research.Cellular与分子的免疫学的重要目标酶。2006；3(4):285-290。

简介：EfficientactivationofTlymphocytesthroughTcellreceptor(TCR)dependsontwosignals．Thefirstsignal(signalone)isderivedfromTCRinteractingwiththeMHC／antigenicpeptidecomplex，whichconfersantigenicspecificitytotheimmuneresponse．Thesecondsignal(signaltwo)isprovidedbytheengagementofTcellsurfacereceptorswiththeirspecificligandsonantigenpresentingcell(APC)[1]．Asthereisgrowingevidenceforbidirectionalcommunicationsandsocalled“reversesignaling”fortraditionallydefinedligands，thedistinctionbetweenreceptorsandligandsbecomeslessclear．Thesepairsofmoleculesshouldbeviewedascosignalingmoleculesfunctioningincellswhichwouldexpresseitherthereceptorsortheligands.

简介：AbstractEpigenetic regulation includes changes of DNA methylation and modifications of histone proteins and is essential for normal physiologic functions, especially for controlling gene expression. Epigenetic dysregulation plays a key role in disease pathogenesis and progression of some malignancies, including acute myeloid leukemia (AML). Epigenetic therapies, including hypomethylating agents (HMAs) and histone deacetylase (HDAC) inhibitors, were developed to reprogram the epigenetic abnormalities in AML. However, the molecular mechanisms and therapeutic effects of the two agents alone or their combination remain unknown. An overview of these epigenetic therapies is given here. A literature search was conducted through PubMed database, looking for important biological or clinical studies related to the epigenetic regimens in the treatment of AML until October 15th, 2019. Various types of articles, including original research and reviews, were assessed, identified, and eventually summarized as a collection of data pertaining the mechanisms and clinical effects of HMAs and HDAC inhibitors in AML patients. We provided here an overview of the current understanding of the mechanisms and clinical therapeutic effects involved in the treatment with HMAs and HDAC inhibitors alone, the combination of epigenetic therapies with intensive chemotherapy, and the combination of both types of epigenetic therapies. Relevant clinical trials were also discussed. Generally speaking, the large number of studies and their varied outcomes demonstrate that effects of epigenetic therapies are heterogeneous, and that HMAs combination regimens probably contribute to significant response rates. However, more research is needed to explore therapeutic effects of HDAC inhibitors and various combinations of HMAs and HDAC inhibitors.

简介：AbstractWith the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

简介：Sixnovelbenzoylphenylureachitininhibitorderivativesweresynthesizedintheyieldsof30%-50%fromthereadilyavailablestartingmaterialchlorothalonil1viasequentialfluorineexchange,aminolysis,hydrolysisandacylationreactions.

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简介：INTRODUCTIONItisaninterestingresearchareausingureaseinhibitorstocurbureaseactivityinsoil,todecreasetherateofureahydrolysisandtoincreasetherecoveryofureanitrogen(Zhou,1984;Guan,1985).Fewstudieshavebeenconductedontherelationshipbetweentheeffectivenessoftheinhibitorsappliedtoriceandtheenvironmentalconditionsandits

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：IAPs(inhibitorsofapoptosis)areafamilyofproteinscontainingoneormorecharacteristicBIRdomains.Theseproteinshavemultiplebiologicalactivitiesthatincludebindingandinhibitingcaspases,regulatingcellcycleprogression,andmodulatingreceptor-mediatedsignaltransduction.OurrecentstudiesfoundtheIAPfamilymembersXIAPandc-IAP1areubiquitinatedanddegradedinproteasomesinresponsetoapoptoticstimuliinTcells,andtheirdegradationappearstobeimportantforTcellstocommittodeath.InadditiontothreeBIRdomains,eachoftheseIAPsalsocontainsaRINGfingerdomain.Wefoundthisregionconfersubiquitinproteaseligase(E3)activitytoIAPs,andisresponsiblefortheauto-ubiquitinationanddegradationofIAPsafteranapoptoticstimulus.GiventhefactthatIAPscanbindavarietyofproteins,suchascaspasesandTRAFs,itwillbeofinteresttocharacterizepotentialsubstratesoftheE3activityofIAPsandtheeffectsofubiquitinationbyIAPsonsignaltransduction,cellcycle,andapoptosis.

简介：AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, generating new variants that pose a threat to global health; therefore, it is imperative to obtain safe and broad-spectrum antivirals against SARS-CoV-2 and its variants. To this end, we screened compounds for their ability to inhibit viral entry, which is a critical step in virus infection. Twenty compounds that have been previously reported to inhibit SARS-CoV-2 replication were tested by using pseudoviruses containing the spike protein from the original strain (SARS-CoV-2-WH01). The cytotoxicity of these compounds was determined. Furthermore, we identified six compounds with strong antagonistic activity against the WH01 pseudovirus, and low cytotoxicity was identified. These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2 (Delta) and B.1.1.529 (Omicron), the two most prevalent circulating strains. These assays demonstrated that two phenothiazine compounds, trifluoperazine 2HCl and thioridazine HCl, inhibit the infection of Delta and Omicron pseudoviruses. Finally, we discovered that these two compounds were highly effective against authentic SARS-CoV-2 viruses, including the WH01, Delta, and Omicron strains. Our study identified potential broad-spectrum SARS-CoV-2 inhibitors and provided insights into the development of novel therapeutics.

简介：在过去的年，histonedeacetylases(HDAC)的overexpression导致的肿瘤suppressor基因的epigenetic沉默在carcinogenesis起一个重要作用，这被发现了。因此，HDAC禁止者作为附件出现了自从他们能堵住特定的HDAC的活动，为多重人的癌症的治疗学的代理人恢复一些肿瘤suppressor基因的表示并且导致房间区别，生长拘捕和apoptosis。迄今为止，HDAC禁止者由导致房间死亡的精确机制充分还没被阐明了，单个HDAC禁止者的角色没被识别。而且，在癌症治疗的HDAC禁止者的实际使用，以及他们有另外的治疗学的策略的synergistic效果还有待于被评估。在这篇评论文章，我们简短在反癌症HDAC禁止者和他们的潜在的临床的值的开发的研究讨论最近的进展。

简介：AIMToinvestigatetheinfluenceofprotonpumpinhibitors（PPIs）exposureonthediagnosisofHelicobacterpylori（H.pylori）gastritisandintestinalmetaplasia.METHODS：ChronicPPIuseisassociatedwithmaskingofH.pyloriinfection.PatientswithH.pyloriinfectionarepredisposedtogastricandduodenalulcers,andlong-terminfectionwiththisorganismhasbeenassociatedwithgastricmucosalatrophyandseriouslong-termcomplications,suchasgastriclymphomaandadenocarcinoma.ThreehundredpatientsdiagnosedwithgastritisbetweenJanuary2008andApril2010wereincludedinourstudy.Thecomputerizedmedicaldatabaseofthesepatientswasreviewedretrospectivelyinordertoassesswhetherthetypeofgastritisdiagnosed（H.pylorivsnon-H.pylorigastritis）isinfluencedbyPPIexposure.H.pyloridensitywasgradedaslow,ifcorrespondingtomilddensityfollowingtheUpdatedSydneySystem,orhigh,ifcorrespondingtomoderateorseveredensitiesintheUpdatedSydneySystem.RESULTS：Patientswereequallydistributedbetweenmalesandfemaleswithamedianageatthetimeofdiagnosisof50yearsold（range：20-87）.ThehistologicaltypesofgastritiswereclassifiedasH.pylorigastritis（n=156,52%）andnon-H.pylorigastritis（n=144,48%）.Allpatientswithnon-H.pylorigastritishadinactivechronicgastritis.PatientswithnopreviousPPIexposureweremorelikelytobediagnosedwithH.pylorigastritisthanthosewithpreviousPPIexposure（71%vs34.2%,P〈0.001）.Intestinalmetaplasiawasmorelikelytobedetectedinthelatterpatients（1.4%vs6.5%,P=0.023）.MultivariateanalysishasalsodemonstratedthatinthepresenceofpreviousPPIexposure（OR=0.217,95%CI：0.123-0.385）,GERD（OR=0.317,95%CI：0.132-0.763,P=0.01）,alcoholintake（OR=0.396,95%CI：0.195-0.804,P=0.01）,thedetectionofH.pyloriwaslesslikely.ChronicuseofPPIsmaymaskH.pyloriinfectionspromotingthediagnosisofnon-H.pylorigastritisandleadstoasi

简介：Melanomaisthedeadliestformofskincancerandhasanincidencethatisrisingfasterthananyothersolidtumor.Metastaticmelanomatreatmenthasconsiderablyprogressedinthepastfiveyearswiththeintroductionoftargetedtherapy(BRAFandMEKinhibitors)andimmunecheckpointblockade(anti-CTLA4,anti-PD-1,andanti-PD-L1).However,eachtreatmentmodalityhaslimitations.Treatmentwithtargetedtherapyhasbeenassociatedwithahighresponserate,butwithshort-termresponses.Conversely,treatmentwithimmunecheckpointblockadehasalowerresponserate,butwithlongtermresponses.Targetedtherapyaffectsantitumorimmunity,andsynergymayexistwhentargetedtherapyiscombinedwithimmunotherapy.Thisarticlepresentsabriefreviewoftherationaleandevidenceforthepotentialsynergybetweentargetedtherapyandimmunecheckpointblockade.Challengesanddirectionsforfuturestudiesarealsoproposed.

简介：Activationofthephosphoinositide3kinase(PI3K)/Akt/mammaliantargetofrapamycin(mTOR)pathwayiscommoninbreastcancer.Thereispreclinicaldatatosupportinhibitionofthepathway,andphaseⅠtoⅢtrialsinvolvinginhibitorsofthepathwayhavebeenorarebeingconductedinsolidtumorsandbreastcancer.Everolimus,anmTORinhibitor,iscurrentlyapprovedforthetreatmentofhormonereceptor(HR)-positive,humanepidermalgrowthfactorreceptor2(HER2)-negativebreastcancer.Inthisreview,wesummarisetheefficacyandtoxicityfindingsfromtherandomisedclinicaltrials,withsimplifiedguidelinesonthemanagementofpotentialadverseeffects.Educationofhealthcareprofessionalsandpatientsiscriticalforsafetyandcompliance.WhilethereissomeclinicalevidenceofactivityofmTORinhibitioninHR-positiveandHER2-positivebreastcancers,thebenefitsmaybemorepronouncedinselectedsubsetsratherthanintheoverallpopulation.FurtherdevelopmentofpredictivebiomarkerswillbeusefulintheselectionofpatientswhowillbenefitfrominhibitionofthePI3K/Akt/mTOR(PAM)pathway.

简介：Brassinosteroid（BR）andgibberellin（GA）aretwopredominantplanthormonesthatregulateplantcellelongation.Mutantsdisruptthebiosynthesisofthesehormonesanddisplaydifferentdegreesofdwarfphenotypesinrice.Althoughtheroleofeachplanthormoneinpromotingthelongitudinalgrowthofplantshasbeenextensivelystudiedusinggeneticmethods,theirrelationshipisstillpoorlyunderstood.Inthisstudy,weusedtwospecificinhibitorstargetingBRandGAbiosynthesistoinvestigatetherolesofBRandGAingrowthofriceseedlings.Yucaizol,aspecificinhibitorofBRbiosynthesis,andTrinexapac-ethyl,acommerciallyavailableinhibitorofGAbiosynthesis,wereused.TheeffectofYucaizolonriceseedlingsindicatedthatYucaizolsignificantlyretardedstemelongation.TheIC50valuewasfoundtobeapproximately0.8μmol/L.Yucaizolalsoinducedsmallleafanglephenocopyinriceseedlings,similarlytoBR-deficientrice,whileTrinexapac-ethyldidnot.WhenYucaizolcombinedwithTrinexapac-ethylwasappliedtothericeplants,themixtureofthesetwoinhibitorsretardedstemelongationofriceatlowerdoses.OurresultssuggestthattheuseofaBRbiosynthesisinhibitorcombinedwithaGAbiosynthesisinhibitormaybeusefulinthedevelopmentofnewtechnologiesforcontrollingriceplantheight.

简介：gonadal睾丸激素合成的抑制首先代表标准为变形前列腺癌症的治疗的线治疗。在得阉割抵抗的前列腺癌症(CRPC)的病人的多数，然而，通过自己在肾上腺或在肿瘤以内生产的雄激素检测雄激素受体(AR)的坚持的激活是可能的。Abiraterone醋酸盐作为17α与活动作为双功能的细胞色素P450酶CYP17的一个不可逆的禁止者被开发；-hydroxylase和17,20-lyase。CYP17为从胆固醇的nongonadal雄激素的生产是必要的。基于与abiraterone和泼尼松对泼尼松在全面幸存(OS)显示出重要改进的阶段III试用，在2011的abiraterone的规章的赞同代表了指向AR为与CRPC在人改进结果是必要的原则的证明。17α的抑制；由abiraterone的-hydroxylase由于垂体的调停皮质醇的抑制的损失导致在上游的mineralocorticoids的累积促肾上腺皮质的荷尔蒙(ACTH)，为17,20-lyase为CYP17禁止者的开发向一个基本原理提供增加的特性(orteronel，galeterone和VT-464)没有外长的corticosteroids，那能潜在地被管理。在这篇文章，我们考察abiraterone和另外的CYP17禁止者的发展；有abiraterone的最近的研究在quality-of-life，反应的潜在的早预言者，并且关于另外的代理人的abiraterone的最佳的定序上通知我们的理解象药效果那样的临床的参数；并且提供卓见进抵抗机制给导致临床的试用，药联合设计了延长abiraterone利益或恢复abiraterone活动的CYP17禁止者的翻译研究结果。

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