甲状腺疾病患者血清可溶性细胞间黏附分子-1测定的临床意义

目的 探讨单纯甲状腺肿、格雷夫斯病（GD）和桥本甲状腺炎（HT）患者血清可溶性细胞间黏附分子-1（sICAM-1）的含量及其临床意义.方法 用放射免疫分析法检测单纯性甲状腺肿大100例、GD 250例、HT 50例及健康人对照组100例血清sICAM-1含量,进行比较分析.结果 健康人sICAM-1含量（170.43±34.23）μg/L和单纯性甲肿（182.48±40.05）μg/L差异无统计学意义（t=1.104,P＞0.05）;GD和HT的sICAM-1含量分别为（279.93±86.69）μg/L,（250.36±81.56）μg/L,均高于对照组（t=2.310,2.210,均P＜0.05）;三种方法治疗后sICAM-1含量[（178.95±59.78）μg/L,（185.65±53.25）μg/L,（259.41±71.46）μg/L）]均明显低于治疗前[（316.53±66.13）μg/L,（277.79±64.30）μg/L,（285.71±72.14）μg/L]（t=2.312,2.278,2.328,均P＜0.05）;GD停药复发患者血清sICAM-1为（329.34±90.47）μg/L,明显高于抗甲状腺药物治疗后甲状腺功能恢复正常的GD患者（251.92±77.75）μg/L（t=2.412,P＜0.05）.结论 血清sICAM-1含量可作为自身免疫性甲状腺疾病诊断的一个参考指标,并在临床评价Graves病的疗效、停药和复发等方面具有重要意义.     

可溶性细胞间黏附分子-1在白癜风中的临床意义

目的 探讨可溶性细胞间黏附分子-1(sICAM-1)水平与白癜风活动程度的关系和意义.方法 sICAM-1检测采用酶联免疫吸附试验(ELISA)方法.结果 (1)白癜风患者血清sICAM-1平均水平为769.80 ng/ml,显著高于正常对照组642.40 ng/ml(P＜0.001).(2)进展期白癜风患者血清sICAM-1平均水平为802.32 ng/ml,显著高于稳定期654.15 ng/ml(P＜0.001).(3)泛发型白癜风患者血清SICM-1平均水平为801.40 ng/ml,显著高于局限型675.45 ng/ml(P＜0.001).(4)稳定期和局限型白癜风患者血清sICAM-1水平与正常对照组差异无显著性(P均＞0.05).结论 sICAM-1可能参与白癜风的发病,与白癜风活动性和严重程度相关.     

Graves病患者治疗前后血清可溶性细胞间黏附分子-1变化的研究

目的:探讨Graves病(GD)患者血清可溶性细胞间黏附分子-1(sICAM-1)水平在治疗前后不同时期的变化及临床意义.方法:应用酶联免疫吸附测定法(ELISA)分别测定GD患者治疗前和抗甲状腺药物(ATD)治疗后3、6、12、18、24和30个月的血清sICAM-1水平,并与正常对照组相比,同时测定血清游离甲状腺素(FT4)、游离三碘甲状腺原氨酸(FT3)、超敏促甲状腺素(sTSH)与sICAM-1进行相关分析.结果:116例正常人sICAM-1为(125.27±29.55)μg/L,阳性率3.45%(4/116);初发GD患者295例为(236.68±72.74)μg/L,阳性率为75.59%(223/295),显著高于正常对照组(P<0.01);应用ATD系统治疗后,在3、6、12、18、24和30个月阳性率分别为78.42%(149/190)、63.01%(92/146)、53.91%(62/1151、30%(24/80)、18.52%(10/54)和13.64%(2/22);至30个月时与正常对照组相比较,血清slCAM-1水平及阳性率差异已无统计学意义(均P>0.05);初诊及治疗后各时期GD患者血清sICAM-1与FT3、FT4、sTSH间均无显著相关性(均P>0.05).结论:血清sICAM-1可反映GD患者的免疫损伤状态,其作为1个免疫指标对GD辅助诊断、疗效观察以及停药时机的确定有一定的临床意义.     

乌司他丁对多发伤并发脓毒症病人炎症状态及 T细胞亚群的影响

目的 探讨乌司他丁在多发伤并发脓毒症病人临床治疗中的应用效果.方法 回顾性分析2017年4月至2019年4月苏州第九人民医院收治的106例多发伤并发脓毒症病人病例资料,根据治疗方式的不同将所有病人分为两组,各53例.对照组仅予以抗感染等常规治疗,观察组在对照组基础上加用乌司他丁静脉滴注治疗,2次/天.两组均连续给药1周.比较两组病人炎症状态、T细胞亚群变化情况、血流动力学参数及临床治疗总有效率.结果 治疗后两组病人各血清炎性因子水平超敏C反应蛋白(hs-CRP)、血清肿瘤坏死因子α(TNF-α)、降钙素原及白细胞介素-6(IL-6)均有所降低,且观察组低于对照组[(20.85±3.06)mg/L比(38.16±4.27)mg/L,(21.94±3.18)mg/L比(33.05±4.16)mg/L,(0.71±0.32)g/L比(1.29±0.44)g/L,(215.63±28.49)ng/L比(279.14±36.85)ng/L,P<0.05];与治疗前相比,两组CD3+、CD4+、CD4+/CD8+均有所提高,CD8+均降低,且观察组CD3+(60.12±9.84)％比(47.08±7.35)％、CD4+(44.96±8.15)％比(44.96±8.15)％、CD4+/CD8+(1.59±0.83)比(1.17±0.69)指标高于照组,CD8+(27.04±5.39)％比(33.07±6.22)％指标低于对照组(P<0.05);治疗后两组病人心脏指数、每搏量指数(SVI)、全心舒张期末容积指数(GEDVI)、平均动脉压(MAP)及中心静脉压(CVP)均高于治疗前,心率低于治疗前,且观察组心脏指数、SVI、GED?VI、MAP及CVP指标高于对照组,心率指标低于对照组(P<0.05).观察组总有效率94.34％(50/53)与对照组总有效率90.57％(48/53)相比,差异无统计学意义(χ2=0.541,P=0.462).结论 将乌司他丁用于多发伤并发脓毒症病人治疗中可有效帮助其降低机体炎性反应,同时改善免疫功能及血流动力学参数,临床疗效确切.     

儿童难治性支原体肺炎白细胞介素 -8、白细胞介素 -17、 CD4-CD8比值与病情及预后的相关性研究

目的 研究白细胞介素-8(IL-8)、白细胞介素-17(IL-17)、CD4-CD8比值(CD4+/CD8+)水平与儿童难治性支原体肺炎(RMPP)病情及预后的相关性.方法 回顾性选取2017年1月至2019年7月在郑州大学附属儿童医院呼吸内科住院治疗的180例肺炎支原体肺炎(MPP)病儿中37例RMPP纳入RMPP组,其余143例普通MMP纳入轻型肺炎支原体肺炎(MMPP)组.比较两组病儿急性期IL-8、IL-17、CD4+/CD8+水平及其他实验室指标,logistic回归分析获得RMPP相关影响因素,绘制受试者工作特征(ROC)曲线分析logistic回归模型对RMPP的预测价值;依据支气管镜下表现评价预后,比较不同预后病人急性期血IL-8、IL-17、CD4+/CD8+水平.结果 RMPP组病儿IL-8[(85.69±37.48)ng/L比(39.44±17.17)ng/L]、IL-17[(2.27±0.61)ng/L比(1.64±0.95)ng/L]、白细胞计数(WBC)、中性粒细胞计数(Neu)、血小板计数(PLT)、C反应蛋白(CRP)、红细胞沉降率(ESR)、乳酸脱氢酶(LDH)、纤维蛋白原(Fib)、D-二聚体显著高于MMPP组,RMPP组病儿CD4+/CD8+(0.92±0.22)显著低于MMPP组CD4+/CD8+(1.49±0.37)病儿(P<0.05);logistic回归分析显示IL-8、CRP、D-二聚体是RMPP的独立危险因素,CD4+/CD8+是保护因素;logistic回归模型预测RMPP的曲线下面积(AUC)为0.992,临界值>0.136,灵敏度、特异度分别为100.00％、96.50％;IL-8、CD4+/CD8+、CRP、D-二聚体的AUC分别为0.847、0.901、0.768、0.828,临界值分别为>70.71 ng/L、≤1.26 ng/L、>37.95 mg/L、>1.62 mg/L;恢复期RMPP组中29例接受支气管镜检查,13例恢复期预后不良的RMPP病儿IL-8显著高于16例预后良好病儿,CD4+/CD8+显著低于预后良好病儿(P<0.001),但IL-17比较差异无统计学意义(P>0.05).结论 IL-8、CD4+/CD8+可作为预测RMPP病情、预后的灵敏指标,但IL-17与RMPP病情及预后的关系仍有待探究.     

益生菌联合四联疗法治疗青年人群幽门螺杆菌感染的临床疗效分析

目的 分析益生菌联合四联疗法对青年人群幽门螺杆菌感染的治疗效果。方法 90例幽门螺杆菌感染的青年患者,按照门诊就诊顺序分为对照组和观察组,每组45例。对照组用标准四联疗法治疗,观察组在对照组基础上联合使用益生菌治疗。对比两组幽门螺杆菌根除率、血清炎症因子、免疫功能、肠道菌群和胃蛋白酶原水平。结果 观察组幽门螺杆菌根除率为91.11%(41/45),明显高于对照组的71.11%(32/45),两组数据差异明显(P<0.05);用药后,两组患者C反应蛋白、肿瘤坏死因子-α和白细胞介素-6水平下降,观察组C反应蛋白(6.24±1.36)mg/L、肿瘤坏死因子-α(121.24±22.18)pg/ml、白细胞介素-6(5.54±1.12)pg/ml较对照组的(9.32±1.16)mg/L、(178.21±20.56)pg/ml、(8.16±1.27)pg/ml更低(P<0.05)。用药后,两组CD4+、CD4+/CD8+水平上升, CD8+水平下降,观察组CD4+(48.32±2.78)%、CD4+/CD8+(1.56±0.15)高于对照组的(46.21±3.54)%、(1.32±...     

细胞间黏附分子1在溃疡性结肠炎诊治中的临床意义

目的 探讨血清细胞问黏附分子1(ICAM-1)水平在溃疡性结肠炎(UC)中的临床意义.方法 收集30例UC患者(UC组)及30例正常者(C组)的血清,分别以ELISA法及免疫速率比浊法检测血清ICAM-1及C反应蛋白(CRP)水平.结果 UC组ICAM-1的水平明显高于C组(P<0.05);同一患者UC活动期ICAM-1高于缓解期(P<0.05);ICAM-1水平升高与UC疾病活动度的严重程度呈正相关(P<0.05),而与UC发生部位无关(P>0.05);ICAM-1与CRP有良好一致性(r=0.8).结论 UC患者血清ICAM-1水平升高与疾病活动度呈正相关,可作为UC疾病活动度和判断治疗效果的一个客观指标.     

胸腺肽α_1对小儿重症肺炎肿瘤坏死因子及白细胞介素-6的影响

目的:探讨胸腺肽α1对小儿重症肺炎肿瘤坏死因子及白细胞介素-6的影响。方法:选择2012年7月—2014年10月在妇幼保健院儿科接受治疗的重症肺炎患儿86例作为研究对象,86例重症肺炎患儿随机分成对照组和观察组两组,各43例。对照组患者接受重症肺炎的常规药物治疗。观察组在对照组治疗的基础上同时皮下注射胸腺肽α1。结果:观察组重症肺炎患儿的总有效率为95.35%高于对照组重症肺炎患儿的总有效率79.07%,差异具有统计学意义(χ2=5.108,P<0.05)。治疗后,观察组患儿的m HLA-DR水平(46.2±8.5)%高于对照组患儿的m HLA-DR水平(33.1%±3.5%,且观察组患儿IL-6水平(44.6±11.3)ng·L-1、TNF-α水平(42.4±11.7)ng·L-1低于对照组患儿的IL-6水平(67.1±22.5)ng·L-1、TNF-α水平(63.2±21.1)ng·L-1,差异具有统计学意义(P<0.01)。治疗后,观察组患儿CD3+水平(55.2±9.6)%、CD4+水平(53.4±9.9)%、CD4+/CD8+水平(2.5±1.2)%高于对照组患儿的CD3+水平(44.8±9.1)%、CD4+水平(42.5±9.5)%、CD4+/CD8+水平(1.7±0.8)%,且观察组患儿CD8+水平(24.6±3.1)%低于对照组患儿CD4+/CD8+水平(33.7±4.2)%,差异具有统计学意义(P<0.01)。治疗后,观察组患儿的MMF水平(1.72±0.29)L/s、PEF水平(2.14±0.28)L/s、PImax水平(83.41±8.23)%及PEmax水平(47.81±6.16)%高于对照组患儿的MMF水平(1.16±0.24)L/s、PEF水平(1.48±0.27)L/s、PImax水平(73.93±7.44)%及PEmax水平(39.23±5.76)%,差异具有统计学意义(P<0.01)。结论:胸腺肽α1治疗小儿重症肺炎能够减轻患儿局部炎症反应、提高免疫功能、改善肺功能,进而增强治疗效果。     

甲状腺疾病患者血清可溶性细胞间黏附分子-1测定的临床意义

Objective To explore the contents and clinical significance of soluble intracellular adhesion molecule-1 ( sICAM-1 ) in patients with single goitre,Graves'and Hashimoto disease. Methods The contents of sICAM-1 in 100 cases of simple goiter group, Graves disease (GD) group 250 cases, Hashimot group 50 cases and 100 normal control were examined by sICAM-1 Radioimmunoassay(RIA) method,and the results were analyzed. Results There were no significant difference of sICAM-1 contents between ( 170.43 ± 34. 23 ) μg/L in normal control group and ( 182.48 ± 40.05) μg/L in simple goiter group( t = 1. 104, P ＞ 0. 05 ); The contents of slCAM-1 in GD group and HT group [( 279.93 ± 86.69) μg/L、 (250.36 ± 81.56) μg/L] were higher than the control group( t = 2.310,2. 210, all P ＜0. 05) ;The sICAM-1 contents in 3 species.methods after treatment [( 178.95 ±59.78) μg/L, ( 185.65 ±53.25)μg/L, (259.41 ± 71.46) μg/L)] were significantly lower than before treatment [(316.53 ± 66.13) μg/L, (277.79±64.30)μg/L,(285.71 ±72.14)μg/L](t=2.312,2.278,2.328,all P ＜0.05);After the Graves'patients were treated and their thyroid function were normal,their serum sICAM-1 levels( 251.92 ± 77.75 )μg/L were lower than that( 329.34 ± 90.47 ) μg/L in relapse Graves'group( t= 2.412 ,P ＜ 0. 05). Conclusion sICAM-1 RIA can be used as a parameter in diagnosing autoimmune thyroid diseases and in evaluating effects of therapy,stopping medicine or the relapse of Graves' disease.     

巨噬细胞移动抑制因子和细胞间黏附分子 -1在慢性牙周炎合并动脉粥样硬化大鼠模型中的表达分析

目的 分析慢性牙周炎(CP)合并动脉粥样硬化(AS)大鼠血清及动脉组织中巨噬细胞移动抑制因子(MIF)以及细胞间黏附分子-1(ICAM-1)的表达.方法 24只成年雄性SD大鼠用随机数字表法分为四组,分别为正常对照(NC)组、CP组、AS组及CP+AS组,每组各6只.采用钢丝结扎双侧上颌第二磨牙联合口腔内接种牙龈卟啉单胞菌(P.gingivalis)建立牙周炎模型;高脂饮食、腹腔注射维生素D3联合左侧颈动脉球囊损伤法建立AS模型.四组分别接受相应的建模处理.12周后,组织病理学观察颈动脉组织的病理改变;体视显微镜下观察各组大鼠牙槽骨吸收面积;全自动生化分析仪检测大鼠血清血脂的表达水平;酶联免疫吸附测定(ELISA)和免疫组织化学法分析血清中和主动脉组织中MIF及ICAM-1的表达水平.结果 组织病理学检查发现:NC组颈动脉组织未见明显异常,CP组血管壁较NC组略增厚,AS组、CP+AS组颈主动脉组织中出现动脉粥样硬化斑块病变;AS组、CP+AS组血清三酰甘油、总胆固醇、低密度脂蛋白(LDL)水平较NC组、CP组明显升高(P<0.05),AS组、CP+AS组血清高密度脂蛋白(HDL)水平较NC组、CP组明显降低(P<0.05).两项检测结果提示AS模型建立成功.ELISA检测血清MIF表达水平,AS组(50.88±4.20)μg/L、CP+AS组(59.40±3.92)μg/L明显高于NC组(42.93±2.63)μg/L及CP组(45.57±2.59)μg/L(P<0.05),且CP+AS组表达水平最高(P<0.05);CP组(3.99±0.44)μg/L、AS组(4.19±0.89)μg/L、CP+AS组(6.77±1.47)μg/L血清ICAM-1表达水平明显高于NC组(1.33±0.25)μg/L(P<0.05),且CP+AS组表达水平最高(P<0.05),CP与AS组间差异无统计学意义(P>0.05).免疫组织化学法检测动脉组织中MIF表达(吸光度),AS组(0.127±0.011)、CP+AS组(0.152±0.022)明显高于NC组(0.096±0.010)、CP组(0.010±0.011)(P<0.05),且CP+AS组表达水平最高(P<0.05);AS组(0.183±0.025)、CP+AS组(0.197±0.033)动脉组织中ICAM-1表达(吸光度)明显高于NC组(0.133±0.012)、CP组(0.156±0.006)(P<0.05),AS组与CP+AS组间差异无统计学意义(P>0.05).结论 同CP组和AS组相比,CP+AS组血清及主动脉组织中MIF的表达水平及血清中ICAM-1的表达水平明显增高,提示慢性牙周炎可能通过升高炎性因子MIF及ICAM-1表达的方式促进AS病变的形成过程.     

1-甲基-1,2,3,4-四氢异喹啉的简易合成

目的制备1-甲基-1,2,3,4-四氢异喹啉。方法以苯乙胺为原料,经酰化反应得乙酰苯乙胺,在多聚磷酸的作用下环合得1-甲基-3,4-二氢异喹啉,经硼氢化钠还原得1-甲基-1,2,3,4-四氢异喹啉。结果反应总收率80%,比文献收率提高了10%,产物结构由1H-NMR光谱确证。结论经酰化、环合、还原三步反应制备1-甲基-1,2,3,4-四氢异喹啉的方法简单,原料便宜,处理容易,副产物较少。     

中等强度静磁场对THP-1细胞分泌炎症因子的影响

目的 观察中等强度静磁场对人单核细胞白血病细胞 THP-1 增殖和炎症因子肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、IL-8 分泌的影响。 方法 取对数生长期 THP-1 细胞, 分为对照组和磁场处理组, 利用 60 mT、200mT、400 mT 的静磁场分别作用细胞 18 h、24 h,、48 h 后, CCK-8 法检测细胞增殖情况。 另取细胞分为对照组、磁场处理组、脂多糖（LPS）活化组、LPS+磁场组。 利用 60 mT、200 mT、400 mT 的静磁场分别作用磁场处理组和 LPS+磁场组 18 h、24 h、48 h 后, 酶联免疫吸附试验（ELISA）检测各组 TNF-α、IL-6、IL-8 的水平。 结果 （1）与对照组相比, 3种强度磁场处理组对 THP-1 细胞增殖无明显影响（P > 0.05）。（2）各组 24 h 时 TNF-α、IL-6 水平较 18 h 升高, IL-8 则无明显变化。 而 48 h 与 24 h 相比较, TNF-α出现下降, IL-6 无明显变化, IL-8 出现升高。 3 个时点 LPS 活化组 TNF-α、IL-6、IL-8 水平较对照组及磁场处理组升高, 经过磁场处理后, LPS+磁场组 IL-6、IL-8、TNF-α水平均较 LPS活化组下降（P < 0.05）。 结论 静磁场对 THP-1 细胞释放炎症因子有一定抑制作用, 可为类风湿关节炎的治疗提供理论依据。     

Macrophage activation by factors released from acetaminophen-injured hepatocytes: potential role of HMGB1

Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1α and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1α and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1α or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity.     

儿童急性阑尾炎非手术治疗失败的相关危险因素分析

目的　分析儿童急性阑尾炎非手术治疗失败的危险因素，提高临床医师对该病的认识。方法　回顾性分析2013年1月—2018年12月我院儿科急性阑尾炎接受非手术治疗的158例患者资料，其中成功组110例，失败组48例。比较2组临床特征、实验室检查及腹部超声检查结果，采用Logistic回归分析儿童急性阑尾炎非手术治疗失败的危险因素。结果　成功组和失败组年龄、性别、腹痛时间、发热、呕吐、腹泻、腹胀、转移性右下腹痛及发病季节差异均无统计学意义（均P＞0.05）。实验室检查方面，2组患儿白细胞计数、中性粒细胞计数、淋巴细胞计数、C-反应蛋白比较差异无统计学意义（均P＞0.05）。腹部超声检查结果显示，失败组阑尾粪石（31.3% vs. 4.5%，χ2=21.555）和阑尾周围渗液（39.6% vs. 12.7%，χ2=14.587）发生率高于成功组（P＜0.01）；2组患者阑尾最大直径、阑尾壁厚度、腹腔淋巴结肿大比例比较差异均无统计学意义（P＞0.05）。Logistic回归分析结果发现阑尾粪石（OR=11.081，95%CI：3.567~34.421）、阑尾周围渗液（OR=5.196，95%CI：2.189~12.332）是儿童急性阑尾炎非手术治疗失败的危险因素。结论　阑尾粪石、阑尾周围渗液是儿童急性阑尾炎非手术治疗失败的危险因素，此类患者应引起临床医师重视，尽早采取手术治疗。     

Physiological factors affecting the expression of FMO1 and FMO3 in the rat liver and kidney

FMO1 and FMO3, the main FMOs described in the rat, are highly expressed in the liver and the kidney. The age, from 3 to 11 weeks, and gender-dependent expression of FMO1 and FMO3 in the rat liver and kidney were investigated. Based on the enzyme activities, protein levels and mRNA levels, this study demonstrates an important increase in the expression of the FMO3 in the liver of male rats during a period that corresponds to the acquisition of the sexual maturity. Rat liver FMO1 remains unchanged during this period of observation. The evolutions of both isoforms in the kidney of the male rat are similar to those observed in the liver. On the contrary, the important decrease in the total flavin-containing monooxygenase (FMO) activity observed in the liver of female rat is linked to a considerable decrease in the FMO1-dependent activity, FMO1 protein and FMO1 mRNA levels as a function of age. The expression of the FMO3 in the liver does not seem to be affected by the age of the female rat. Inversely, the expression of FMO1 in the female rat kidneys does not seem to be modified as a function of age while the expression of FMO3 is strongly increased.     

Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice

BACKGROUND AND PURPOSE: Neutrophil migration into tissues is involved in the genesis of inflammatory pain. Here, we addressed the hypothesis that the effect of CXC chemokines on CXCR1/2 is important to induce neutrophil migration and inflammatory hypernociception. EXPERIMENTAL APPROACH: Mice were treated with a non-competitive allosteric inhibitor of CXCR1/2, DF 2162, and neutrophil influx and inflammatory hypernociception were assessed by myeloperoxidase assay and electronic pressure meter test, respectively, in various models of inflammation. KEY RESULTS: DF 2162 inhibited neutrophil chemotaxis induced by CXCR1/2 ligands but had no effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF 2162 on CXCL-8-induced chemotaxis. Treatment with DF 2162 prevented influx of neutrophils and inflammatory hypernociception induced by CXCL1 in a dose-dependent manner. The compound inhibited neutrophil influx and inflammatory hypernociception induced by carrageenan, lipopolysaccharide and zymosan, but not hypernociception induced by dopamine and PGE(2). DF 2162 had a synergistic effect with indomethacin or the absence of TNFR1 to abrogate carrageenan-induced hypernociception. Treatment with DF 2162 diminished neutrophil influx, oedema formation, disease score and hypernociception in collagen-induced arthritis. CONCLUSIONS AND IMPLICATIONS: CXCR1/2 mediates neutrophil migration and is involved in the cascade of events leading to inflammatory hypernociception. In addition to modifying fundamental pathological processes, non-competitive allosteric inhibitors of CXCR1/2 may have the additional benefit of providing partial relief for pain and, hence, may be a valid therapeutic target for further studies aimed at the development of new drugs for the treatment of rheumatoid arthritis.     

Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A,polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women

Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P = 0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT + TC] vs. CC: P = 0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P = 0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low.     

Compounds from Sichuan and Melegueta peppers activate,covalently and non-covalently,TRPA1 and TRPV1 channels

Background and purpose:

Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations.

Experimental approach:

The structure–activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds'' aversive responses were measured in a taste brief-access test.

Key results:

For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH.

Conclusions and implications:

The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds.     

Discovery of CS-0777: A Potent,Selective, and Orally Active S1P1 Agonist

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