威灵仙注射液对骨关节炎关节液与软骨白介素-1水平的影响

目的 :探讨威灵仙注射液对骨关节炎模型动物的关节液和体外培养软骨细胞上清液白介素 1(IL 1β)水平的影响。方法 :体内实验 :建立骨关节炎动物模型 ,随机分为 3组 ,A威灵仙 (WLX)组 ,B盐水组 ,C空白对照组 ,A、B组分别注射威灵仙和生理盐水 ,C组不用药 ,另取同龄正常兔为正常对照D组 ,按设计分批处死动物 ,检测关节液中IL 1β的水平 ;体外实验 :分离培养软骨细胞 ,传代细胞分Ⅰ、Ⅱ组 ,Ⅰ组给予不同浓度威灵仙液刺激 ,Ⅱa组予不同浓度威灵仙液干预 2 4h再予脂多糖 (LPS)刺激 ,Ⅱb组先予LPS刺激 2 4h再予不同浓度威灵仙液干预 ,72h后收集上清液检测IL 1β水平。结果 :威灵仙注射液能够降低骨关节炎模型动物关节液与体外培养软骨细胞分泌IL 1β的水平。结论 :威灵仙注射液可以通过抑制白介素 1的水平对骨关节炎起防治作用。     

汉族人群白细胞介素-6基因多态性与骨关节炎易感性的相关性研究

目的:探讨汉族人群骨关节炎易感性与白细胞介素(IL)-6基因启动子区-174G/C基因多态性的相关性。方法:选取青岛大学附属医院2012年3月至2013年3月收治的膝关节内外侧间隙高度差1.5 mm以上、Kellgren-Lawrance评分为3~4分的汉族原发性膝关节骨关节炎患者448例,招募汉族528例健康志愿者作...     

CALM1基因及钙调素与骨关节炎

骨关节炎(OA)以进行性关节软骨丢失、骨赘形成等退行性变为主要特征。多功能受体蛋白钙调素(CaM)在真核细胞Ca~(2 )信号转导通路中发挥重要作用。关节软骨内Ca~(2 )-CaM信号对软骨细胞的分化形成具有重要作用;给予关节软骨适当的压力负荷刺激能诱导软骨基质合成增加,而这一反应似乎必须依赖于Ca~(2 )-CaM信号通路。软骨细胞内Ca~(2 )-CaM信号通路一旦发生异常,可能会引起软骨细胞分化形成、软骨细胞粘附能力、关节软骨修复及对压力负荷刺激的反应性等方面的异常,进而促进OA的发生、发展。近期研究表明,编码CaM的CaM基因之一CALM1的单核苷酸多态性与OA易感性相关,这一发现从基因和分子转录水平提示CaM及Ca~(2 )-CaM信号通路异常在OA发病机制中的作用。     

白介素-1在骨关节炎发病机制中的研究进展

骨关节炎(osteoarthritis,OA)是临床常见的关节病,严重影响患者的身体健康和生活质量,给家庭和社会带来了巨大的经济负担。OA的病因及发病机制至今尚未完全明确,但细胞因子在其发病机制的研究中越来越受到重视,尤以IL-1被认为是骨性关节炎发生发展中最核心的因子。近年来,许多临床试验把IL-1作为治疗骨关节炎的靶点,为OA的治疗提供新的方法。本文就IL-1参与OA软骨破坏的机制做一综述。     

白介素-18基因多态性与结直肠癌易感性的关系

目的探讨白介素-18（m-18）基因单核苷酸多态性及其单倍型与结直肠癌易感性之间的关系。方法以170例结直肠癌患者和160名健康对照者为研究对象,应用聚合酶链反应一限制性片段长度多态性（PCR-RFLP）的方法对IL．18基因-137G／C、-607C／A单核苷酸多态性进行基因分型,同时用SHEsis软件分析IL-18基因的连锁不平衡及单倍型频率。结果IL-18基因-607C／A多态性在结直肠癌患者和健康人群中的分布差异无统计学意义（P〉0．05）．而IL-18基因-137G／C多态性在两组人群中的分布差异有统计学意义（P〈0．05）。等位基因频率的相对风险分析显示．C等位基因携带者患结直肠癌的风险是G等位基因的1．814倍（OR=1．814,95％CI：1．246～2．642）。联合基因型分析显示,IL-18基因-137G／C、-607C／A单核苷酸多态性存在着强烈的连锁不平衡（ID＇｜=0．945）,-137C／-607A单倍型频率在结直肠癌患者中显著高于健康人群（P〈0．05）。-137C／-607A单倍型携带者显著增加了结直肠癌的发病风险（OR=1．637,95％CI：1．100～2．437）。结论IL—18基因-137G／C多态性和-137C／-607A单倍型与结直肠癌的发病具有相关性．其中-137C等位基因可能是结直肠癌的遗传易感基因。     

IGF-1基因5’端功能性SNP与中国汉族人群膝关节骨关节炎的相关性研究

背景：骨关节炎（osteoarthritis,OA）是最常见的关节炎,尤其在老年人群中发病率更高,它是包括遗传因素在内的多因素致病疾病。已有多项研究发现,许多基因与OA的易感性有密切关系。胰岛素样生长因子1（insulin likegrowth factor 1,IGF-1）可以促进软骨细胞合成软骨中的细胞外基质。IGF一1及其受体在软骨的发育及成年后重塑阶段均具有重要功能,并可能与OA的病因具有相关性。目的：IGF-1基因启动子区域-1245C／T位点（rs35767）单核苷酸多态性（single nucleotide polymorphisms,SNP）与膝关节OA的关系。方法：采用序列特异性引物PCR及探针法,检测中国汉族人群中具有临床症状且有影像学证据的524例原发性膝关节OA患者与540例健康对照者IGF-1基因启动子区域-1245C／T位点等位基因分布,分析-1245C／T位点等位基因与膝关节OA的相关性。结果：OA组与正常对照组比较,IGF-1基因启动子区域-1245C／T位点的基因型频率及等位基因频率分布无显著性差异（P=0．35、0．14）。按OA严重程度分组（中重度组患者均为K／L分级3、4级,轻度组为K／L分级2级）,中重度组与正常对照组比较,基因型分布无显著性差异（P=0．10）,等位基因频率分布有显著性差异（P=0．04）;但CC型与其它基因型（TT、TC）分布有显著性差异（P=0．03）。正常对照组中TT＋TC所占比例较中重度OA组多,OR=1．36,CI=[1．03,1．80]。逻辑回归分析示,上述差异为年龄、BMI及性别差异所致,与m35767的等位基因、基因型频率分布无显著相关性。结论：中国汉族人群的OA易感性与年龄、BMI、性别构成相关,与IGF-1基因启动子区域-1245C／T位点（rs35767）基因多态性可能无关。     

白介素-1β基因多态性与晚期膝骨关节炎易感性的关联性研究

目的探讨IL-1β基因的单核苷酸多态性和单体型与中国汉族人晚期膝骨关节炎（KOA）的易感性相关。方法采用病例对照研究,纳入120例中国汉族膝OA患者和130例年龄、性别匹配的健康对照者,用酶联免疫吸附测定法（ELISA）测定血清中IL-1β的水平,用聚合酶链反应和限制性片段长度多态性（PCR—RFLP）方法对IL-1β基因的-511C／T（rs16944）、＋3954C／T（rs114363）和-31C／T（rs1143627）位点进行单核苷酸多态性进行分析,并测序验证酶切结果。结果膝骨性关节炎患者组血清中白细胞介素1β水平明显高于健康对照组（t=-8．26,P〈0．01）,单核苷酸多态性分析显示：在膝OA患者组和健康对照组之间IL-1β-31C／T位点基因型分布和等位基因频率没有明显差异,该研究中没有发现IL-1β＋3954Tr基因型。膝OA患中的IL-1β-511TC、IL-1β＋3954CT基因型频率较健康对照组增加（P〈0．05,P〈0．05）,通过Logistic回归分析,IL-1β-511TC、IL-1β＋3954CT基因型与膝OA高风险发病率具有相关性（IL-1β-511TC,OR=1．842,95％CI=1．021—3．327,P〈0．05;IL-1β＋3954CT,OR=2．372,95％CI=1．022—5．509,P〈0．05）。此外,单体型分析显示与单体型TCC相比,单体型TCT和CCC与膝OA高风险发病率具有更强的相关性（TCT．OR=3．24,95％CI：1．50—7．00,P〈0．01;CCC．OR=6．07,95％CI：2．20—16．07,P〈0．01）。结论白细胞介素-1β基因的-511C／T（rs16944）和＋3954C／T（rs114363）位点多态性与中国汉族人膝OA的易感性相关。     

乳腺癌p21 WAF1基因多态性及其临床意义

目的探讨乳腺癌组织p21 WAF1基因多态性及其临床意义.方法采用聚合酶链反应单链构象多态性技术(PCR-SSCP)法检测100例乳腺癌组织p21 WAF1基因的结构变异,同时应用免疫组织化学SP法检测乳腺癌组织p21 WAF1的蛋白表达.结果 5%(2/40)的对照组组织出现多态性,18%(18/100)的乳腺癌组织出现两种多态性,两组间差异有显著性(x2=30.94,P＜0.05);p21 WAF1基因多态性与蛋白表达(r=0.576,P＜0.01)和组织学分级(r=0.360,P＜0.01)呈正相关.结论 p21 WAF1基因多态性在乳腺癌组织中明显增加;p21 WAF1基因多态性可能与促进细胞增殖和增强对癌的易感性有关.     

骨关节炎易感基因研究进展

骨关节炎(OA)是一种常见的关节退行性疾病,为基因相关性疾病。找到OA易感基因并明确其功能和作用机制。进而找到对OA的有效干预手段及治疗方法,具有很高的临床价值。对OA患者及正常人群的不同基因位点进行聚合酶链反应-限制性片段长度多态性与单核苷酸多态性检测,结合临床资料进行流行病学分析,以确定OA的易感基因。研究发现OA易感基因有分泌型卷曲相关蛋白-3基因、无孢蛋白基因和雌激素受体基因等。OA易感基因的功能和作用机制有待进一步研究。     

胃癌幽门螺杆菌感染与白细胞介素-1基因多态性的相关性研究

目的 探讨中国汉族人非贲门胃癌幽门螺杆菌（Hp）感染与白细胞介素（IL）-1基因多态性的关系，探讨宿主遗传因素对Hp感染在非贲门胃癌的作用。方法 采用病例对照研究和PCR-RFLP方法，检测143例非贲门胃癌患者和264例正常对照者的IL-1B和白细胞介素-1受体拮抗剂（IL-1 receptor antagonist，IL-1RN）双等位基因型分布。Hp感染通过检测血清HpAb-IgG。结果 Hp阳性非贲门胃癌患者IL．1B．511}T等位基因频率高于Hp阴性患者（60％VS46％，P=0．0342，OR=1．666，95％CI：1．045～2．656），也高于正常对照组（60％VS48％，P=0．0071，OR=1．665，95％CI：1．149～2．412），多因素logistic回归分析校正年龄和性别后，与携带IL-1B-511＊C／C基因型者比较，携带T／T基因型者胃癌风险升高3．01倍（OR=3．01，95％CI：1．27～7．11，P=0．012），携带IL．1B-511＊T等位基因者胃癌风险升高2．29倍（OR=2．29，95％CI：1．08～4．86，P=0．032）。结论 IL-1B-511＊T等位基因和Hp阳性胃癌相关，提示该等位基因在Hp阳性非贲门胃癌发病机制中可能起重要作用。     

Breast cancer risk associated with CYP1A1 genetic polymorphisms in Japanese women

Although several reports are available on the association between CYP1A1 polymorphisms and breast cancer risk in Caucasian women, it has never been reported in Japanese women. Since breast cancer incidence and clinicopathologic features of breast cancers are different between Japanese and Caucasian women, it is conceivable that the risk factors of breast cancer might also differ. In addition, a preliminary study has shown that the frequencies of the variant allele in the CYP1A1 gene are different among ethnic groups. Therefore, in the present study, we investigated the association of CYP1A1 polymorphisms with breast cancer risk in Japanese women. The association of two CYP1A1 polymorphisms, that is, 3' noncoding region (6235(T/C)) and codon 462 (Ile/Val), with breast cancer risk was analyzed by a case-control study (195 cases and 272 controls). Variant allele 6235C carriers at the 3' noncoding region polymorphism showed a significantly ( p < 0.01) reduced breast cancer risk (odds ratio 0.60; 95% CI 0.41–0.88) as compared with noncarriers, and variant allele 462Val carriers at the codon 462 polymorphism also showed a significantly ( p < 0.05) reduced risk (odds ratio 0.66; 95% CI 0.45–0.96) as compared with noncarriers. The relationship between the genetic polymorphisms and clinicopathologic characteristics of breast cancers was also investigated. Variant allele 6235C carriers showed a significantly ( p < 0.02) higher positivity of lymph node metastasis than noncarriers (54% versus 36%), and tumors measuring less than 2 cm were significantly ( p < 0.03) more frequently observed in variant allele 462Val carriers than noncarriers (50% versus 33%). These results suggest that the CYP1A1 polymorphisms would be useful for predicting breast cancer risk as well as some tumor characteristics in Japanese women.     

白细胞介素1B和1RN基因多态性与骨关节炎易感性的关系

目的在中国青岛地区膝骨性关节炎患者中,探讨白细胞介素-1B(-31C/T、-511C/T、＋3954C/T)及其拮抗基因IL-1RN基因多态性与骨关节炎易感性的关系。 方法采用病例对照研究,对就诊青岛市胶州中心医院经临床诊断为膝关节骨关节炎的216例患者和233例年龄、性别匹配的健康对照者,排除既往有膝关节外伤史、类风湿性关节炎及合并其他内科疾病的患者,以聚合酶链反应和限制性片段长度多态性(PCR-RFLP)方法检测IL-1B的－31C/T、－511C/T、＋3954 C/T位点及IL-1RN的多态性,采用logistic回归分析方法比较不同基因型与骨关节炎发病风险的关系。 结果骨关节炎组中IL-1B-511CT、IL-1B＋3954CT基因型频率明显高于对照组,与对照组差异有统计学意义(IL-1B-511CT χ²＝2.034,P＝0.026;IL-1B＋3954CT χ²＝5.526,P＝0.017),IL-1B＋3954C/T位点未发现TT基因型,通过logistic回归分析,结果显示与野生型的纯合子相比,杂合子-511CT、＋3954CT基因型与骨性关节炎高风险发病率具有相关性[IL-1B-511CT,OR＝1.89,95%CI(0.56,1.39),P＝0.026;IL-1B＋3954CT,OR＝2.51,95%CI(1.18,5.35),P＝0.017]。骨关节炎组和对照组在IL-1B-31C/T位点及IL-1RN基因型分布未见明显差异。 结论IL-1B-511TC、＋3954CT基因型人群可能增加对膝骨关节炎的易感性,而IL-1B-31C/T, IL-1RN*2基因多态性可能与膝骨关节炎遗传易感性不具相关性。     

Association of adiponectin gene polymorphisms with knee osteoarthritis

AIM To investigate the possible relationship of adiponectin(ADIPOQ) gene polymorphisms, plasma adiponectin, and the risk of knee osteoarthritis(OA).METHODS A total of 398 subjects, 202 knee OA patients and 196 healthy individuals, were enrolled in the case-control study. Genotyping at +45T/G(rs2241766) and +276G/T(rs1501299) loci was performed using polymerase chain reaction-restriction fragment length polymorphism. Plasma adiponectin levels were assessed using enzymelinked immunosorbent assay. OA severity was determined using the Kellgren-Lawrence(KL) grading system.RESULTS No significant associations were observed in the genotype distributions and allele frequencies at two loci of +45T/G and +276G/T polymorphisms in the ADIPOQ betweenknee OA patients and control subjects. There was a significant association between genotype distribution of +276G/T polymorphism and KL grade 2, 3 or 4(P = 0.037, P = 0.046, P = 0.016, respectively). At +45T/G locus, the percentage of GG genotype was notably greater in control subjects(13.40%) compared with OA subjects(1.70%)(P = 0.023). Plasma adiponectin was markedly decreased in OA subjects compared with control subjects(P = 0.03). Likewise, circulating adiponectin in OA subjects was notably lesser than that in control subjects in GG genotype of +45T/G(P = 0.029) and +276G/T polymorphisms(P = 0.012).CONCLUSION Polymorphisms +45T/G and +276G/T of the ADIPOQ gene might not be responsible for OA susceptibility among Thais.     

GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis

We investigated glutathione S-transferase (GST) P1I le (105) Val, T1, and M1 polymorphisms in 45 patients with documented cryptogenic cirrhosis and 56 healthy control subjects. Polymerase chain reaction-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Ile/Val and Val/Val GSTP1 genotypes were more frequent in the patients with cirrhosis (n = 39, 87%) than in the control subjects (n = 10; 18%) (odds ratio [OR] 34.04; 95% confidence interval [CI] 10.70 to 108.31, P < 0.001). Among these patients with cirrhosis, 16 were heterozygous and 23 were homozygous, whereas only one person in the control group was homozygous. The GSTM1 null genotype was also more prevalent in cirrhotic patients than in healthy control subjects (OR 6.83, 95% CI 2.53 to 18.42, P < 0.001). The rate of GSTT1 deletion did not show a significant difference between the two groups (OR 2.35, 95% CI 0.76 to 7.28, P = 0.111). To our knowledge, this is the first evidence that GSTP1 and GSTM1 polymorphisms may be related to the development of cirrhosis by unknown mechanisms. The significant association of cryptogenic cirrhosis with Val/Val GSTP1 genotype encoding a low detoxification activity protein implicates this polymorphism as a risk factor for the occurrence of the disease. Presented as an abstract at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 19–22, 2003 (Poster of Distinction).     

Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis

OBJECTIVE: Osteoarthritis (OA) is associated with increased levels of reactive nitrogen and oxygen species and pro-inflammatory cytokines, such as interleukin-1 (IL-1). Nitric oxide (NO) can mediate a number of the catabolic effects of IL-1 in articular cartilage. The aims of this study were to determine if OA cartilage shows evidence of DNA damage, and if IL-1 could induce DNA damage in non-OA cartilage by increasing NO or superoxide. METHODS: Articular chondrocytes were isolated from porcine femoral condyles and embedded in 1.2% alginate. The effects of 24h incubation with IL-1, the nitric oxide synthase 2 (NOS2)-selective inhibitor, the free radical scavenger superoxide dismutase (SOD), the NO donor NOC18, or the combined NO and peroxynitrite donor SIN-1 on DNA damage were tested, using the "comet" assay. NO production was measured using the Griess assay. The type of oxidative damage present was assessed using a modified comet assay. RESULTS: OA cartilage had significantly more DNA damage than non-OA cartilage (P<0.001). IL-1 caused an increase in DNA damage (P<0.01), which was associated with increased NO production (P<0.01). Both oxidative DNA strand breaks and base modifications of purines and pyrimidines were observed. IL-1-induced DNA damage was inhibited by an NOS2 inhibitor or by SOD (P<0.01). Furthermore, NOC18 or SIN-1 caused DNA damage (P<0.001). CONCLUSION: Our work shows chondrocytes in osteoarthritic cartilage exhibit DNA damage, and that IL-1 induces DNA damage and reactive oxygen and nitrogen species in non-OA chondrocytes in alginate.     

CYP1A1与GSTM1基因多态性与前列腺癌易感性的关系

目的　探讨CYP1A1、GSTM1基因多态性与前列腺癌遗传易感性的关系。　方法　采用寡核苷酸芯片对 83例前列腺癌患者和 115例正常对照的中国汉族人群基因组DNA进行CYP1A1、GSTM1基因多态性分析。　结果　GSTM1基因缺失型前列腺癌组占 5 7.8% ,对照组 4 1.7% ,差异有显著性意义 ( χ2 =4 .99,P =0 .0 2 5 ) ,GSTM1null基因型使患前列腺癌的危险度增加 1.9倍 ( 95 %CI=1.10～ 1.34)。GSTM1基因缺失型前列腺癌患者的平均年龄 [( 6 8.1± 8.3)岁 ]低于GSTM1未缺失的患者[( 71.9± 7.4 )岁 ,P =0 .0 31]。前列腺癌组CYP1A1基因的两个多态位点m1、m2基因型频率和等位基因的频率与对照组相比差异无显著性意义 (P >0 .0 5 )。　结论　中国汉族人群GSTM1基因多态性与前列腺癌的发生相关 ,可能是增加前列腺癌危险和发病年龄早的因素之一。CYP1A1基因m1和m2的基因多态与中国汉族人群前列腺癌的发生无相关性     

Interleukin‐17 and Toll‐like Receptor 10 genetic polymorphisms and susceptibility to large joint osteoarthritis

Primary osteoarthritis (OA) is the most common type of a joint disease. It has a polygenic risk inheritance pattern and affects older people. The etiology of this disease is not fully understood. The aim of this study was to investigate the associations between polymorphisms in pro‐inflammatory interleukin‐17 (IL17A and IL17F) and anti‐inflammatory Toll‐like Receptor 10 (TLR10) genes with the risk for development of advanced stage hip and knee primary OA in the Croatian population. A total of 500 OA patients and 597 controls were genotyped for IL17A SNP (rs2275913), IL17F SNPs (rs763780 and rs1889570), and TLR10 (rs11096957) genes. The allelic and genotypic frequencies of IL17F SNP (rs763780) showed statistically significant differences in comparisons of controls with hip—but not knee—OA patients. The major allele (T) of rs763780 was associated with the lower risk for developing hip OA (p = 7.9 × 10^?4, OR = 0.45, 95%CI = 0.27–0.74), whereas the minor allele (C) was associated with susceptibility to hip OA (p = 7.9 × 10^?4, OR = 2.24, 95%CI = 1.35–3.72). The genotype T/T was associated with the protection to hip OA (p = 3.9 × 10^?4, OR = 0.41, 95%CI = 0.24–0.70), and, lastly, the genotype T/C was associated with the higher risk to acquiring hip OA (p = 2.6 × 10^?4, OR = 2.50, 95%CI = 1.47–4.25). TLR10 SNP rs11096957 was found significantly associated with predisposition to hip OA (p = 0.04, OR = 1.41, 95%CI = 1.02–1.94) but not knee OA. Our findings suggest that hip OA in Croatian population might have a different genetic risk regarding the IL17 and TLR10 gene locus than knee OA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1684–1693, 2018.