Type 1 reaction in leprosy: a model for a better understanding of tissue immunity under an immunopathological condition

Type 1 reaction (T1R) or reversal reaction is the leading cause of physical disabilities and deformities in leprosy. Leprosy patients, even after being considered cured and released from treatment, may suffer from reactional episodes for long periods of time. Early diagnosis is a great challenge for effectively treating and managing T1R. There is an urgent need to identify the most significant biomarkers to prevent recurrent T1R and to differentiate late T1R from relapse. T1R continues to be treated with corticosteroids and complications due to iatrogenic treatment remain frequent. This review aims to provide a framework from which to approach the great challenges that still persist in T1R management and debate key issues in order to reduce the distance between basic research and the clinic.     

PPARγ基因多态性与冠心病及其危险因素相关性研究概况

过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptors,PPARs）属于核激素受体家族。PPARs包括3个亚型即α亚型δ亚型和γ亚型,PPARγ2亚型有两个常见多态：C1431T和Pro12Ala。研究证实在人类PPARγ基因多态性与动脉粥样硬化的发生发展密切相关,可导致冠心病的发生发展,并与冠状动脉粥样硬化性心脏病多个危险因素,如2型糖尿病、高血压、肥胖、血脂异常、代谢综合征有关。因此PPARγ基因多态性不仅直接参与了冠心病发生发展的多个环节,并可通过增加冠心病的危险因素来进一步促进冠心病的发生与发展。临床通过测定PPARγ基因多态性有可能分析出发生2型糖尿病、高血压、代谢综合征、血脂异常、肥胖和冠心病发病的可能性和风险,发现与诊断冠心病的高危人群。     

γ-促分泌酶抑制剂阻断Notch信号对支气管哮喘模型小鼠气道炎症的影响

目的 研究γ-促分泌酶抑制剂阻断Notch信号对支气管哮喘(简称哮喘)模型小鼠气道炎症反应的影响,为哮喘治疗寻找新的药物提供理论基础.方法 制作小鼠哮喘模型,在小鼠激发阶段尾静脉注射γ-促分泌酶抑制剂MW167,采用RT-PCR方法检测小鼠肺T细胞IL-4 mRNA及IFN-γmRNA的表达,ELISA方法检测外周血清及BALF上清中IL-4及IFN-γ水平.结果 MW167注射组较哮喘组病理学改变减轻,而肝及肾无明显形态学改变,MW167阻断Notch信号后,MW167注射组小鼠肺T细胞IL-4 mRNA的表达较哮喘组减弱,而IFN-γ mRNA的表达增强(IL-4:0.119±0.045比0.414±0.214,P＜0.01; IFN-γ:0.459±0.205比0.170±0.050,P＜0.01);MW167注射组外周血清及BALF中IL-4的表达较哮喘组减弱[血清:(19.601±0.870) ng/L比(26.046±2.211) ng/L,P＜0.05;BALF:(75.077±14.438) ng/L比(113.478±8.628) ng/L,P＜0.01)];外周血清中及BALF中IFN-γ的表达较对照组增强[血清:(10.644±3.338) ng/L比(5.119±2.230) ng/L,P＜0.01]; BALF:(26.131±3.608) ng/L比(21.299±2.830) ng/L,P＜0.01].结论 静脉注射γ-促分泌酶抑制剂抑制了哮喘模型小鼠气道炎症,对哮喘有潜在的治疗价值.     

干扰素γ抑制转化生长因子β1诱导的A549细胞上皮-间充质转化及对ERK1/2和STAT3的作用

目的 探讨干扰素γ(IFN-γ)对转化生长因子β1(TGF-β1)诱导的A549细胞上皮-间充质转化(EMT)过程的作用及对胞外调节激酶1/2(ERK1/2)和信号转导和转录激活因子3(STAT3)的作用.方法 ①体外培养A549细胞,分为TGF-β1处理组(5 μg/L)、IFN-γ处理组(200 μg/L)和TGF-β1(5 μg/L)+ IFN-γ(10、100、200 μg/L)联合处理组.处理时间48 h,免疫荧光及Western blot方法检测各组细胞E-钙黏素( E-cadherin)、α-平滑肌肌动蛋白(α-SMA)、波形蛋白(vimentin)和纤维连接蛋白(fibronectin)的蛋白表达.②处理不同时间(5、30和60 min),Western blot方法检测各组细胞STAT3、p-STAT3和ERK1/2、p-ERK1/2的蛋白表达.结果 ①与TGF-β1单独处理组相比,IFN-γ(200 μg/L)+TGF-β1联合处理组vimentin和fibronectin的蛋白表达减低(P＜0.05),而α-SMA和E-cadherin蛋白表达无显著变化.②作用后5、30和60 min,IFN-γ(200 μg/L)+ TGF-β1联合处理组STAT3磷酸化水平显著升高(P＜0.01).作用后5、60 min,IFN-γ(200 μg/L) +TGF-β1联合处理组ERK1/2磷酸化水平升高(P＜0.05).结论 IFN-γ可在体外抑制TGF-β1诱导的A549细胞发生EMT,其机制可能与上调ERK1/2和STAT3信号通路有关.     

过氧化物酶体增殖物激活受体-γ在炎症性肠病中的表达及意义

目的 观察过氧化物酶体增殖物激活受体-γ(PPAR-γ)在炎症性肠病(IBD)中的表达,探讨其可能的意义.方法 采用免疫组织化学方法检测28例克罗恩病(CD)患者、38例溃疡性结肠炎(UC)患者及30例健康对照肠道组织中PPAR-γ蛋白的表达,并进一步分析PPAR-γ蛋白与IBD临床特征的关系.结果 PPAR-γ在UC患者中表达阳性率为34.21% (13/38),明显低于正常对照63.33%(19/30) 及CD患者60.71%(17/28)(P<0.05);PPAR-γ蛋白表达与UC疾病活动性明显相关(P<0.05),与UC严重程度、病变部位及CD临床特征无明显相关(P>0.05).结论 PPAR-γ蛋白在UC肠道组织中表达降低,且与疾病活动性明显相关.提示PPAR-γ可能在UC发生、发展中发挥重要作用.     

全自动精浆γ-L-谷氨酰转肽酶检测方法的建立及评价

目的:建立精浆γ-L-谷氨酰转肽酶(GGT)全自动检测方法并对其准确性、重复性和线性范围等进行评价。方法:利用速率法检测精浆GGT活性,并在全自动生化分析仪上建立检测参数,并评估该方法的试剂空白吸光度、准确性、重复性和线性范围,同时与目前临床上常用的精浆GGT检测化学比色法试剂盒(南京欣迪)进行比较。结果:试剂空白吸光度平均为0.047 6,空白吸光度变化率(△A/min)平均为0.000 168。3份高、中、低GGT活性的精浆样本重复测定10次的变异系数值分别为0.26%、4.83%和1.60%。采用比对试验的方法来评价准确性,40份精浆标本每个浓度点的相对偏差范围为-13.38%¹1.05%,均低于15%的要求。精浆GGT活性在29911.05%,均低于15%的要求。精浆GGT活性在299¹ 833 U/L范围时,具有良好的线性关系(r>0.99)。以精浆GGT检测化学比色法试剂盒作为对照试剂,全自动检测法作为试验试剂,两者对115例精浆样本的检测结果呈显著正相关(r=0.981,P<0.01),Kappa值为0.776(P<0.05),符合率为90.43%。结论:本研究建立的精浆GGT全自动检测法有较低的试剂空白,重复性和准确性较好,且与目前临床上使用的化学比色法有很好的一致性。该法操作简单、快速,精浆样本无需稀释,适合临床上大批量样本的检测筛查,大大节省了人力和试剂成本。     

早期帕金森病患者血浆谷氨酸、天冬氨酸和γ-氨基丁酸水平的改变及其诊断价值的研究

目的探索早期帕金森病(PD)患者血浆谷氨酸、天冬氨酸和γ-氨基丁酸(GABA)水平的改变及其潜在的早期诊断价值。方法选择病程3年的早期PD患者52例(早期PD组),年龄性别与PD组匹配的健康对照者52名(对照组),采用高效液相色谱-荧光检测法(HPLC-RF)检测所有研究对象的血浆谷氨酸、天冬氨酸和GABA水平,并量化分析两组间差异。运用受试者特征曲线(ROC)评价血浆氨基酸神经递质识别早期PD的能力。采用Spearman秩相关分析血浆氨基酸神经递质水平和早期PD患者临床特征的关联。结果早期PD组的血浆谷氨酸、天冬氨酸和GABA水平均明显低于对照组。ROC分析提示3种氨基酸均可以有较高的敏感度(76.9%~100%)和特异度(59.6%~100%)识别早期PD和健康者。相关性分析提示血浆天冬氨酸、GABA水平和早期PD患者的临床特征密切相关。结论血浆氨基酸神经递质水平下降是早期PD患者的外周生化基础的一部分,可以为PD的早期识别提供一些帮助。     

The mechanism of Arhalofenate in alleviating hyperuricemia―Activating PPARγ thereby reducing caspase-1 activity

Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to gout. Arhalofenate (Arha) has been proved to have uricosuric activity as an inhibitor of URAT1, organic anion transporter 4 (OAT4) and OAT10. However, the effects of Arha on HUA remain unknown. The objective of this study was to investigate whether Arha could alleviate HUA and uncovered the underlying mechanism in vitro. HK-2 cells were exposed to uric acid (UA) to simulate HUA in vitro. Then cells were treated with Arha, caspase-1 inhibitor Belnacasan (Beln), caspase-11 inhibitor Wedelolactone (Wede) and PPARγ inhibitor Mifobate, respectively. The alteration of cell proliferation, inflammation, pyroptosis and expression of related proteins were detected. Results showed that UA exposure inhibited cell viability and increased IL-1β and IL-18 generation in a concentration dependent manner. Meanwhile, UA activated the cleavage of gasdermin D (GSDMD), enhanced the protein expression of URAT1, OAT4, TLR4, caspase-1, and caspase-11 and reduced PPARγ expression. While the presence of Arha or Beln enhanced cell viability and inhibited cleavage of GSDMD. Wede slightly increased cell viability but failed to prevent GSDMD cleavage. The expression of related proteins except caspase-11was also recovered by Arha. Beln and Wede partially rescued related proteins level except PPARγ compared with model group. Besides, the co-treatment of Mifobate blunted the effects of Arha on cell viability and expression of GSDMD, TLR4, and caspase-1. In conclusion, Arha inhibited UA transport as well as preventing inflammation and pyroptosis via activating PPARγ thereby blocking caspase-1 activation of HUA in vitro.     

甘露聚糖肽联合斑蝥酸钠维生素B6治疗恶性胸腔积液的临床研究

目的探讨甘露聚糖肽联合斑蝥酸钠维生素B6治疗恶性胸腔积液的临床疗效。方法收集2016年1月—2017年1月在溧阳市人民医院进行治疗的恶性胸腔积液患者78例,根据用药的差别分为对照组(39例)和治疗组(39例)。对照组胸腔注入斑蝥酸钠维生素B6注射液,50 m L加入20 m L生理盐水,1次/周;治疗组在对照组的基础上胸腔注入甘露聚糖肽注射液,80 m L加入20 m L生理盐水,1次/周。两组患者均经过4周治疗。评价两组患者临床疗效,同时比较治疗前后两组患者胸水指标和KPS评分变化。结果治疗后,对照组和治疗组的临床总有效率分别为64.10%和84.62%。两组比较差异具有统计学意义(P0.05)。治疗后,两组癌胚抗原(CEA)、胰岛素样生长因子结合蛋白-2(IGFBP-2)、基质金属蛋白酶-9(MMP-9)水平均显著降低,干扰素-γ(IFN-γ)和白细胞介素-2(IL-2)水平显著增高,同组比较差异具有统计学意义(P0.05);且治疗组上述指标水平明显优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组KPS评分均升高(P0.05);且治疗组患者比对照组升高更明显(P0.05)。结论甘露聚糖肽联合斑蝥酸钠维生素B6治疗恶性胸腔积液可有效降低癌胚抗原水平,增强机体免疫功能,具有一定的临床推广应用价值。     

Bacteriomimetic poly-γ-glutamic acid surface coating for hemocompatibility and safety of nanomaterials

Poly-γ-glutamic acid (PGA), a major component of the bacterial capsule, is known to confer hydrophilicity to bacterial surfaces and protect bacteria from interactions with blood cells. We tested whether applying a bacteriomimetic surface coating of PGA modulates interactions of nanomaterials with blood cells or affects their safety and photothermal antitumor efficacy. Amphiphilic PGA (APGA), prepared by grafting phenylalanine residues to PGA, was used to anchor PGA to reduced graphene oxide (rGO) nanosheets, a model of hydrophobic nanomaterials. Surface coating of rGO with bacterial capsule-like APGA yielded APGA-tethered rGO nanosheets (ArGO). ArGO nanosheets remained stable in serum over 4?weeks, whereas rGO in plain form precipitated in serum within 5?minutes. Moreover, ArGO did not interact with blood cells, whereas rGO in plain form or as a physical mixture with PGA formed aggregates with blood cells. Mice administered ArGO at a dose of 50?mg/kg showed 100% survival and no hepatic or renal toxicity. No mice survived exposure at the same dose of rGO or a PGA/rGO mixture. Following intravenous administration, ArGO showed a greater distribution to tumors and prolonged tumor retention compared with other nanosheet formulations. Irradiation with near-infrared light completely ablated tumors in mice treated with ArGO. Our results indicate that a bacteriomimetic surface modification of nanomaterials with bacterial capsule-like APGA improves the stability in blood, biocompatibility, tumor distribution, and photothermal antitumor efficacy of rGO. Although APGA was used here to coat the surfaces of rGO, it could be applicable to coat surfaces of other hydrophobic nanomaterials.