New patented histone deacetylase inhibitors

Importance of the field: Following FDA approval of vorinostat in 2006, several novel HDAC inhibitors (HDACis) have entered clinical trials, and there are numerous published patent applications claiming novel HDACis which were optimized as potential drug candidates, designed for regional or systemic release, and created as dual or multifunctional inhibitors. Given the breadth and depth of recent reporting of novel HDACis, there has emerged a need to review the field from a chemist's perspective in one compact article.

Areas covered in this review: This review provides a summary of published patent applications claiming novel HDACis from 2007 until mid-2009, covering mainly classes I, II and IV anticancer HDACis including those that have recently advanced to the clinic.

What the reader will gain: Readers will rapidly gain an overview of the majority of HDACi scaffolds with representative structure–activity relationships; they will learn how these new compounds were created, how their drug like properties were improved and which companies are the main players in the field.

Take home message: Although competition in this field is intense, the future application of HDACis to treat human disease either as single agents or in combination with existing drugs holds real promise.     

原花青素对人胆管癌细胞QBC939抑制的体内外研究

目的研究原花青素(PC)体内外对人胆囊癌细胞的抑制作用。方法常规培养细胞,24 h后随机分为阳性对照组、空白对照组和PC组。MTT法检测PC对人胆囊癌细胞增殖的抑制作用;流式细胞术检测细胞凋亡率和细胞周期;建立QBC939细胞裸鼠异种移植瘤模型。将荷瘤裸鼠随机分为5组:阴性对照组、5-Fu阳性对照组及PC 3个剂量组,每日腹腔注射给药,每隔3 d测肿瘤大小;12 d后,处死裸鼠,剥瘤称重并计算抑瘤率。结果 PC 3个剂量组显著抑制QBC939细胞增殖,且呈时间和剂量依赖性;将细胞周期阻滞在S期,并诱导QBC939细胞凋亡;PC可抑制QBC939细胞裸鼠异种移植瘤的生长。结论 PC体内外均可抑制SHG-44细胞生长,并诱导肿瘤细胞凋亡。     

基于新型光敏剂的光动力治疗在胆管癌中的应用

目的：验证新型叶绿素类光敏剂———2-1-己氧乙基-2-去乙烯基卟吩e6三钠盐（ HCE6）,光动力疗法对于QBC939系胆管癌细胞的光动力治疗作用,并探讨其量效关系。方法 CCK-8检测652 nm不同激光光强度下不同浓度（0、0．3、0．5、1．0、15、2．0 mg· L－1）光敏剂HCE6光动力处理下细胞的增殖率,得出最适光动力剂量。建立QBC939系胆管癌细胞荷瘤裸鼠模型,光敏剂尾静脉注射0．5 mg· kg－1,24 h后接受激光治疗（激光剂量：120 J· cm－2,功率0．2 W,治疗20 min）,激光治疗后1、3、5、7、10 d观察实验组和对照组瘤体体积变化差异,并对比观察瘤体病理变化。结果在最适光照强度2．7 J· cm－2（功率0．9 W,PDT处理5 min）剂量,随着光敏剂浓度升高,细胞增殖率逐渐下降,最适完全抑制浓度为1．5 mg· L－1;超过这个浓度,细胞增值率变化无差异。荷瘤裸鼠模型实验中实验组和对照组有明显肿瘤体积差异（P＜0．05）,光动力治疗第10天,实验组与对照组体积差异明显（P＜0．05）,实验组瘤块体积（0．5±0．010）cm3,而对照组（2．25±0．015）cm3。接受PDT组与对照组比较肿瘤生长速度明显受限。结论体内外实验表明光敏剂HCE6对QBC939系人胆管癌细胞生长具有明显的抑制作用。     

华蟾素对人胆管癌细胞QBC939抑制作用研究

目的观察华蟾素体内外对人胆囊癌QBC939细胞的抑制作用。方法常规培养细胞,24 h后随机分为空白对照组和华蟾素组6个剂量组,分别于3个时相采用MTT法检测华蟾素对人胆囊癌细胞增殖的抑制作用;建立QBC939细胞裸鼠异种移植瘤模型,随机分为阴性对照组、5-Fu阳性对照组及华蟾素3个剂量组,每日腹腔注射给药,观察荷瘤裸鼠的一般活动状况及进食量;12 d后处死裸鼠,剥瘤称重并计算抑瘤率;取血,ELISA法检测血清中细胞因子IL-6、TNF-α和sVCAM-1含量。结果华蟾素6个剂量组对QBC939细胞的增殖均具有抑制作用,与对照组比较差异有统计学意义,并且随着剂量的增加和时间的延长,抑制率也增加;华蟾素腹腔注射给药可改善荷瘤裸鼠的一般活动状况,增加进食量;抑制荷瘤裸鼠移植瘤的生长,与对照组比较差异有统计学意义;提高血清TNF-α水平,降低IL-6和sVCAM-1水平,差异均有统计学意义。结论华蟾素体内外均可抑制胆囊癌QBC939细胞的生长,其体内抑瘤作用机制可能与上调裸鼠血清TNF-α细胞因子水平,下调IL-6和sVCAM-1水平有关。     

XAV939, a small molecular inhibitor,provides neuroprotective effects on oligodentrocytes

White matter tracts are composed of axons and myelinating oligodendrocytes. Oligodendrocytes are the myelinating cells in the central nervous system that allow formation of myelin and saltatory nerve conduction. Cerebral white matter is highly vulnerable to ischemic injury in adults and neonates. White matter injury in newborn brains results in cerebral palsy and cognitive disability. In this study, we found that XAV939, a small‐molecular inhibitor that stimulated β‐catenin degradation by stabilizing axin, protected against serum and glucose deprivation (SGD)‐induced cell death in oligodentrocyte cell line OLN‐93 cells in a concentration‐dependent manner. We further showed that XAV939 reduced caspase‐3 and caspase‐8 levels and increased the expression of phosphorylated Akt in SGD‐induced OLN‐93 cells. Our data demonstrate that XAV939 protects against neonatal hypoxic/ischemic injury. In summary, our results demonstrate that XAV939 confers neuroprotection against SGD‐induced injury in OLN‐93 cells via its antiapoptotic activity and the loss of oligodendrocytes and neurons in neonatal hypoxic/ischemic injury. © 2014 Wiley Periodicals, Inc.     

miR-939在人肺癌中的表达及对细胞周期的影响

目的:探讨miR-939在人肺癌细胞株A549中的表达及增强miR-939表达对肺癌细胞周期的影响。方法:提取15对肺癌、癌旁正常组织标本的RNA,用qPCR法检测miR-939的表达。将miR-939前体转染入A549中,实验分为三组,即前体转染组(P组)、转染试剂阴性对照组(N组)、转染试剂空白对照组(C组),分别以qPCR法检测miR-939前体转染后三组细胞内miR-939的表达水平。用MTT法测定细胞生长曲线。PI染色法检测转染后三组细胞周期变化情况。结果:相对肺癌癌旁正常组织,86.7%肺癌组织中miR-939呈低表达（P＜0.01）。P组中miR-939表达水平较N组、C组都显著升高（P＜0.01）。转染48h后,P组较N组、C组,G1期细胞百分比明显增多,S期细胞百分比明显减少(P＜0.05)。结论:miR-939在肺癌组织中呈低表达,上调A549细胞中 miR-939的表达,能够诱导细胞周期阻滞。提示miR-939在肺癌的发生发展过程中有可能起着重要作用。     

Assessment of unloading effects after open wedge high tibial osteotomy using quantitative bone scintigraphy

IntroductionWe evaluated changes in bone tracer uptake (BTU) in open wedge high tibial osteotomy (OWHTO) and determined if BTU correlates with clinical symptoms, postoperative alignment, or cartilage regeneration after OWHTO.Materials and methodsSeventy-five knees in 64 patients who underwent OWHTO for medial compartment osteoarthritis were enrolled in this retrospective study. All cases were assessed preoperatively and at plate removal using bone scintigraphy. Visual analog scale (VAS), Japanese Orthopedic Association (JOA) score, Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the weight-bearing line ratio (WBLR) were assessed preoperatively and at plate removal. In addition, cartilage regeneration was evaluated at plate removal. We assessed changes in BTU for the medial and lateral compartment after OWHTO and the correlations between BTU of the medial compartment and all other parameters were analyzed.ResultsPostoperatively, all outcome measures significantly improved: mean VAS 61.4 ± 18.3 to 9.5 ± 8.2, mean JOA score 65.1 ± 11.5 to 94.7 ± 6.0, mean OKS 29.4 ± 8.1 to 42.3 ± 4.1, mean KOOS 57.0 ± 14.3 to 83.7 ± 9.6, mean WBLR 22.8 ± 10.9 to 70.0 ± 9.4. Cartilage regeneration was observed in 53 knees (70.7%). BTU of the medial compartment significantly decreased after OWTHO, whereas no increased postoperative BTU was found in the lateral compartment. Postoperative BTU of the medial compartment significantly correlated with VAS, KOOS, and WBLR. No statistically significant associations were found between BTU and cartilage regeneration.ConclusionsOWHTO significantly decreased BTU of the medial compartment, which correlated with knee pain and postoperative mechanical alignment. Unloading effects of OWHTO led to pain relief after surgery, regardless of cartilage regeneration.     

National Health Insurance: A conceptual framework from conflicting typologies

In the path to universal health coverage, policymakers discuss different alternative health system’s financing schemes. Classical typologies have been posited, including models such as National Health Service, Social Health Insurance and Private Health Insurance. More recently, National Health Insurance (NHI) has been suggested as a separate model. Nevertheless, there are discrepancies regarding what defines an NHI model. The purpose of this article is to propose a comprehensive definition of an NHI model, aimed to disentangle the current discrepancies in the conceptualization and the scope of this type of arrangement. Based on the previous literature we identified some common characteristics across NHI definitions, namely universal coverage, pooling in a single fund and a purchasing function based on a single-payer financing mechanism. Areas of controversy were also identified. While some authors emphasized the importance of an effective separation between the purchaser and provider functions, others highlighted the relative importance of privately-owned provision to define a system like NHI-type. Based on empirical data, we suggest that the ownership is not a critical variable to distinguish an NHI from other models, and instead, suggest that a pivotal characteristic of the NHI is the single payer mechanism that is not integrated with the health providers.     

XAV939, a Wnt/β-catenin pathway modulator,has inhibitory effects on LPS-induced inflammatory response

Aim: In this study, we report the anti-inflammatory activity of XAV939, a modulator of the Wnt/β-catenin pathway.

Methods: WNT/β-catenin pathway and NF-κB signaling pathway were examined in LPS-stimulated human bronchial epithelial cells and effects of XAV939 on these pathways were analyzed. The effect of XAV939 was confirmed in human umbilical vein endothelial cells.

Results: LPS-induced expressions of pro-inflammatory genes IL-6, IL-8, TNF-α, IL-1β, MCP-1, MMP-9, iNOS and COX-2 were significantly and dose-dependently suppressed by XAV939. LPS-induced NF-κB signaling, such as IκB phosphorylation and degradation as well as nuclear translocation of NF-κB, was also suppressed by XAV939. Target DNA binding of NF-κB was significantly and dose-dependently suppressed by XAV939 during LPS-induced inflammatory response. The suppressive effects of XAV939 on NF-κB signaling, target DNA binding of NF-κB and pro-inflammatory gene expression were all rescued by over expression of β-catenin, which shows that the anti-inflammatory effect of XAV939 is mediated by the modulation of β-catenin, a central component of the WNT/β-catenin pathway.

Conclusion: The findings of this study showed that XAV939 exerts anti-inflammatory effects through the modulation of the Wnt/β-catenin pathway.