马兜铃酸肾病研究进展

马兜铃酸肾病是近些年发现的药物性肾损害疾病 ,主要是指马兜铃酸引起的急、慢性肾小管 间质病变 ,可表现为急、慢性肾功能衰竭。本文就该病的由来、临床表现、发病机理、预防与治疗以及相关的中药作一综述。     

谷胱甘肽硫转移酶基因多态性与精子形成的研究进展

精子发生受到诸多有序基因的表达与调控,这些特异基因的遗传多态性可能影响精子的发生。谷胱甘肽硫转移酶是一组多功能同工酶,属于II相反应代谢的超家族酶系,其通过催化还原型谷胱甘肽与亲电物质发生轭合反应,降低该亲电物质的活性、加速其排泄,达到解毒的效果。研究发现,谷胱甘肽硫转移酶基因多态性与精子发生可能存在密切关系。     

马兜铃酸肾病最新研究进展

近年来有关马兜铃酸肾病的研究又取得较多突破性进展,本文重点从马兜铃酸代谢酶学、致病机制以及与巴尔干肾病的联系等方面的最新研究进展进行综述,并为今后的研究提出了新的方向.     

马兜铃酸肾病的发病机制

马兜铃酸诱导的肾小管上皮细胞转分化、坏死或凋亡等诸多因素在马兜铃酸肾病的肾间质纤维化过程中起重要作用,其确切机制尚待进一步研究。     

马兜铃酸肾病发病机制的研究进展

含马兜铃酸（AA）类成分中药导致的肾损害--马兜铃酸肾病近年受到国内外医药学界的广泛关注,其确切发病机制尚未阐明。本文总结了国内外近年来有关马兜铃酸肾病发病机制的研究概况。     

谷胱甘肽转硫酶基因多态性与湖北汉族人群溃疡性结肠炎的关系

目的 探讨谷胱甘肽转硫酶(GSTs)基因多态性与湖北汉族人群溃疡性结肠炎(UC)的关系.方法 回顾性分析2002年8月至2009年12月武汉大学中南医院、武汉大学人民医院、华中科技大学附属同济医院和协和医院收治的270例湖北汉族UC患者(UC组)及同期623例健康体检者(对照组)的临床资料.根据病变范围将UC患者分为远端UC组(229例)和广泛UC组(41例);根据病变严重程度将UC患者分为轻中度组(237例)和重度组(33例).采用聚合酶链反应检测GSTM1和GSTT1的基因多态性、采用限制性片段长度多态性聚合酶链反应检测GSTP1的基因多态性,并对GSTs基因型进行判定.将含有157 bp片段和480 bp片段者分别定义为GSTM1(+)和GSTT1(+),而无相应的扩增产物者分别定义为GSTM1(-)、GSTT1(-).采用x2检验对数据进行分析.结果 UC组和对照组中GSTM1(-)、GSTT1(-)和GSTP1纯合子突变型基因型(Val/Val)的分布频率分别为70.7%(191/270)、64.8%(175/270)、48.9%(132/270)和41.7%(260/623)、47.2%(294/623)、34.3%(214/623),两组比较,差异有统计学意义(x2=63.404,22.320,25.384,P＜0.05).进一步根据UC临床症状进行分层分析,远端UC组和广泛UC组中GSTT1(-)、GSTP1(Val/Val)的分布频率分别为71.6%(164/229)、57.6%(132/229)和31.7%(13/41)、29.3%(12/41),两组比较,差异有统计学意义(x2=24.528,9.609,P＜0.05).远端UC组与广泛UC组的GSTM1(-)基因型的分布频率分别为65.1%(149/229)和56.1%(23/41),两组比较,差异无统计学意义(x2=1.210,P＞0.05).远端UC组和广泛UC组中GSTT1(-)和GSTP1(Val/Val)的分布频率分别为71.6%(164/229)、31.7%(13/41)和57.6%(132/229)、29.3%(12/41),两组比较,差异有统计学意义(x2=24.528,9.609,P＜0.05).轻中度UC组和重度UC组中GSTM1(-)、GSTT1(-)、GSTP1(Val/Val)分布频率比较,差异无统计学意义(x2=0.623,1.884,3.403,P＞0.05).结论 突变的GSTs基因型与湖北汉族人群的UC发生明显相关.GSTs突变基因型可能与UC患者病情严重程度无关.

Abstract：

Objective To investigate the correlation between genetic polymorphisms of glutathione S-transferases (GSTs) and ulcerative colitis (UC) in Hubei Han population. Methods Genetic polymorphisms of GSTM1 and GSTT1 of 270 patients with UC (UC group) who were admitted to the Zhongnan Hospital, People's Hospital of Wuhan University, Tongji Hospital and Union Hospital of Huazhong University of Science and Technology from August 2002 to December 2009 and 623 healthy people ( control group) were detected by restriction fragment length polymorphism-polymerase chain reaction. All UC patients were allocated to distal UC group (n= 229) and extensive UC group (n =41 ) according to the location of the lesions; and all UC patients were also allocated to mild-moderate group (n = 237) and severe group (n = 33 ). The genetic polymorphisms of GSTP1 of these patients and healthy people were detected by polymerase chain reaction. The genotypes of GSTM1, GSTT1 and GSTP1 were also detected. GSTM1 and GSTT1 containing small DNA segments ( 157 bp and 480 bp) were defined as GSTM1 (+) and GSTT1 (+), otherwise, GSTM(-) and GSTT1 (-), respectively. All data were analyzed by chisquare test. Results The frequencies of GSTM1(-), GSTT1(-) and GSTP1 (Val/Val) were 70.7% (191/270),64.8% (175/270) and 48.9% (132/270) in the UC group, and 41.7% (260/623), 47.2% ( 294/623 ) and 34.3% (214/623) in the control group, with a significant difference between the two groups (x2 = 63. 404,22. 320, 25. 384, P ＜0.05 ). The frequencies of GSTT1 (-) and GSTP1 (Val/Val) were 71.6% (164/229) and 57.6% (132/229) in the distal UC group, which were significantly higher than 31.7% (13/41) and 29.3%( 12/41 ) in the extensive UC group ( x2 = 24.528, 9.609, P ＜ 0.05 ). The frequencies of GSTM1 (-) were 65.1%(149/229) in the distal UC group and 56.1% (23/41) in the extensive UC group, with no significant difference between the two groups ( x2 = 1. 210, P ＞ 0.05 ). The frequencies of GSTT1 (-) and GSTP1 ( Val/Val ) were 71.6%(164/229), 31.7% ( 13/41 ) in the distal UC group and 57.6% ( 132/229), 29.3% ( 12/41 ) in the extensive UC group, with a significant difference between the two groups ( x2 = 24. 528, 9. 609, P ＜ 0. 05 ). There was no significant difference in the frequencies of GSTM1 (-), GSTT1 (-), GSTP1 (Val/Val) in the mild-moderate group and the severe group( x2 = 0. 623, 1. 884, 3. 403, P ＞ 0. 05 ). Conclusions Variant genotypes of GSTs are significantly correlated with UC in Hubei Han population. The severity of UC may not be correlated with variant genotypes of GSTs.     

谷胱甘肽转硫酶基因多态性与湖北汉族人群溃疡性结肠炎的关系

Objective To investigate the correlation between genetic polymorphisms of glutathione S-transferases (GSTs) and ulcerative colitis (UC) in Hubei Han population. Methods Genetic polymorphisms of GSTM1 and GSTT1 of 270 patients with UC (UC group) who were admitted to the Zhongnan Hospital, People's Hospital of Wuhan University, Tongji Hospital and Union Hospital of Huazhong University of Science and Technology from August 2002 to December 2009 and 623 healthy people ( control group) were detected by restriction fragment length polymorphism-polymerase chain reaction. All UC patients were allocated to distal UC group (n= 229) and extensive UC group (n =41 ) according to the location of the lesions; and all UC patients were also allocated to mild-moderate group (n = 237) and severe group (n = 33 ). The genetic polymorphisms of GSTP1 of these patients and healthy people were detected by polymerase chain reaction. The genotypes of GSTM1, GSTT1 and GSTP1 were also detected. GSTM1 and GSTT1 containing small DNA segments ( 157 bp and 480 bp) were defined as GSTM1 (+) and GSTT1 (+), otherwise, GSTM(-) and GSTT1 (-), respectively. All data were analyzed by chisquare test. Results The frequencies of GSTM1(-), GSTT1(-) and GSTP1 (Val/Val) were 70.7% (191/270),64.8% (175/270) and 48.9% (132/270) in the UC group, and 41.7% (260/623), 47.2% ( 294/623 ) and 34.3% (214/623) in the control group, with a significant difference between the two groups (x2 = 63. 404,22. 320, 25. 384, P ＜0.05 ). The frequencies of GSTT1 (-) and GSTP1 (Val/Val) were 71.6% (164/229) and 57.6% (132/229) in the distal UC group, which were significantly higher than 31.7% (13/41) and 29.3%( 12/41 ) in the extensive UC group ( x2 = 24.528, 9.609, P ＜ 0.05 ). The frequencies of GSTM1 (-) were 65.1%(149/229) in the distal UC group and 56.1% (23/41) in the extensive UC group, with no significant difference between the two groups ( x2 = 1. 210, P ＞ 0.05 ). The frequencies of GSTT1 (-) and GSTP1 ( Val/Val ) were 71.6%(164/229), 31.7% ( 13/41 ) in the distal UC group and 57.6% ( 132/229), 29.3% ( 12/41 ) in the extensive UC group, with a significant difference between the two groups ( x2 = 24. 528, 9. 609, P ＜ 0. 05 ). There was no significant difference in the frequencies of GSTM1 (-), GSTT1 (-), GSTP1 (Val/Val) in the mild-moderate group and the severe group( x2 = 0. 623, 1. 884, 3. 403, P ＞ 0. 05 ). Conclusions Variant genotypes of GSTs are significantly correlated with UC in Hubei Han population. The severity of UC may not be correlated with variant genotypes of GSTs.     

马兜铃酸肾病的临床与慢性化机制的研究进展

含马兜铃酸类成分中药导致的肾脏损害一马兜铃酸肾病近年受到国内外医药学界的广泛关注。该病临床表现复杂多样,主要病理特点呈快速进展性肾间质纤维化,常导致慢性进行性肾衰竭;并且在我国该病属常见病、多发病,危害甚广。本文从马兜铃酸肾病的临床特征、致肾间质纤维化机制等方面做一综述。     

马兜铃酸肾病的临床及发病机制研究概况

近年来,有关中草药肾毒性的报道逐年增多,其中马兜铃酸肾病成为中草药不良反应的典型受到了广泛关注.该病起病隐匿,进展较快,预后不良,治疗尚无成熟方案.本文从临床与病理、发病机制及疾病的防治等方面时马兜铃酸肾病进行了论述.重点介绍了该病发生发展过程中的关键细胞因子和生长因子重要作用的研究.     

马兜铃酸肾病的临床及发病机制研究概况

近年来,有关中草药肾毒性的报道逐年增多,其中马兜铃酸肾病成为中草药不良反应的典型受到了广泛关注.该病起病隐匿,进展较快,预后不良,治疗尚无成熟方案.本文从临床与病理、发病机制及疾病的防治等方面时马兜铃酸肾病进行了论述.重点介绍了该病发生发展过程中的关键细胞因子和生长因子重要作用的研究.     

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).     

Association between GSTM1, GSTT1, and GSTP1 variants and the risk of end stage renal disease

Introduction: There are some evidences indicating DNA damage by oxidant and mutant agents has an essential role in the chronic renal failure and end stage renal disease (ESRD). To investigate the possible association of GSTs variants with ESRD, we investigated the frequency of GST- T1, M1, and P1 genotypes, and the level of malondialdehyde (MDA) in patients with ESRD.

Materials and methods: The present case-control study consisted of 136 ESRD patients treated with maintenance hemodialysis and 137 gender- and age-matched, unrelated healthy controls from the population of west of Iran. The GST- T1, M1, and P1 genotypes were determined in all individuals using multiplex-PCR and PCR-RFLP. The level of MDA was measured by high-performance liquid chromatography (HPLC).

Results: We found that GSTM1 and GSTT1 null genotypes (GSTT1?/GSTM1?) increased the risk of ESRD by 1.8 times (p?<?0.001) and the increased risk of ESRD for GSTM-null (T1+-M1?) genotype was 3.04 times (p?=?0.002). ESRD patients carriers the GST (GSTM1-null?+?GSTT1-null?+?GST-null) genotypes compared to GST normal genotype increased the risk of ESRD by 3.3 (p?<?0.001) times. ESRD patients carriers of GST-null, GSTM1-null, and GSTT1-null genotypes had greater MDA concentration compared with the same genotypes of control subjects. Our results indicated that the GST-null allele (GSTT1-null/GSTM1-null) is a risk factor for ESRD and carriers of this allele have high levels of MDA.

Conclusion: Our findings indicate that oxidative stress, impairment of the antioxidant system and abnormal lipid metabolism may play a role in the pathogenesis and progression of ESRD and its related complications. These data suggest that patients with ESRD are more susceptible to vascular diseases.     

慢性马兜铃酸肾病患者伴发泌尿系统肿瘤

目的探讨慢性马兜铃酸肾病患者伴发泌尿系肿瘤情况。方法回顾分析102例慢性马兜铃酸肾病患者中4例伴发泌尿系肿瘤患者的临床资料。结果(1)4例患者均有长期间断小剂量服含马兜铃酸药物史,并被确诊为慢性马兜铃酸肾病,慢性肾功能不全;(2)4例均有明显血尿,相差显微镜检查呈均一红细胞尿,其中2例有肉眼血尿;(3)膀胱镜检查、逆行尿路造影及手术证实,3例为膀胱乳头状移行细胞癌,1例为肾盂移行细胞癌。结论慢性马兜铃酸肾病患者若出现明显均一红细胞血尿时,即应高度警惕泌尿系肿瘤发生。     

Association of polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) with idiopathic azoospermia or oligospermia in Sichuan,China

The reported effects of the glutathione S-transferase (GSTs) genes (GSTM1, GSTT1, and GSTP1) on male factor infertility have been inconsistent and even contradictory. Here, we conducted a case-control study to investigate the association between functionally important polymorphisms in GST genes and idiopathic male infertility. The study group consisted of 361 men with idiopathic azoospermia, 118 men with idiopathic oligospermia, and 234 age-matched healthy fertile male controls. Genomic DNA was extracted from the peripheral blood, and analyzed by polymerase chain reaction and restriction fragment length polymorphism analysis. There was a significant association between the GSTP1 variant genotype (Ile/Val + Val/Val) with idiopathic infertility risk (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.11–2.11; P = 0.009). Similarly, a higher risk of infertility was noted in individuals carrying a genotype combination of GSTT1-null and GSTP1 (Ile/Val + Val/Val) (OR: 2.17; 95% CI: 1.43–3.31; P = 0.0002). These results suggest an increased risk of the GSTP1 variant genotype (Ile/Val + Val/Val) for developing male factor infertility. Our findings also underrate the significance of the effect of GSTM1 and/or GSTT1 (especially the former) in modulating the risk of male infertility in males from Sichuan, southwest China.     

慢性马兜铃酸肾病患者肾小管上皮细胞转分化的研究

目的探讨慢性马兜铃酸肾病。肾小管上皮细胞转分化与肾间质纤维化的关系。方法以慢性马兜铃酸肾病患者的肾组织为标本,作常规Masson染色化病理检查;用天狼星红组织化学(组化)染色检查胶原Ⅰ、Ⅲ表达;用免疫组化染色检查角蛋白(CK)、α-平滑肌肌动蛋白(α-SMA)、波形蛋白(Vim)及转化生长因子-β1(TGF-β1)表达。对结果进行定量或半定量分析。结果 肾间质Masson染色纤维化面积及胶原Ⅰ、Ⅲ面积,与肾小管间质α-SMA及Vim阳性表达面积呈显著正相关(P<0.05),与肾小管CK阳性表达面积呈显著负相关(P<0.05);病变过程中健存肾小管TGF-β1表达明显增强。结论慢性马兜铃酸肾病患者的肾小管上皮细胞可转分化为肌成纤维细胞,参与肾间质纤维化,而这细胞转分化很可能与其自身高表达TGF-β1相关。     

川芎嗪对马兜铃酸肾病大鼠肾间质微血管病变的干预研究

目的探讨川芎嗪对马兜铃酸肾病大鼠肾损害及肾间质微血管病变管周毛细血管（PTC）密度及血管内皮生长因子（VEGF）的变化。方法雄性Wistar大鼠98只分为4组,即模型组、川芎嗪组、苯那普利组各26只,按马兜铃酸（AA）20mg·kg^-1·d^-1灌胃关木通浸膏;对照组20只灌胃饮用水。2h后分组给药：对照组及模型组灌胃饮用水,川芎嗪50mg·kg^-1·d^-1;苯那普利1．8mg·kg^-1·d^-1。分别于4、8、12w末分别处死动物各6只,检测肾功能,肾脏病理,免疫组化观察FTC密度及VEGF表达。结果12w时模型组的血肌酐／体重水平明显升高（P〈0．01）,病理表现为弥漫性小管间质损害和灶性纤维化;模型组4w后出现中、重度肾血管病变,FTC密度明显下降;肾小管VEGF表达水平早期代偿性增高,以后逐渐降低并与FTC密度下降一致。川芎嗪组、苯那普利组的肾功能及小管间质病变程度较模型组降低（P〈0．01）;血管病变程度轻,FTC密度明显高于模型组,VEGF表达水平低于模型组。结论马兜铃酸可引起大鼠肾功能减退和肾小管间质损害,使肾间质微血管发生缺血性病变,川芎嗪可改善上述病变程度,并与调节VEGF表达有关。     

甘草酸及肾十方治疗慢性马兜铃酸肾病26例疗效观察

目的观察甘草酸及复方中药肾十方对慢性马兜铃酸肾病的疗效。方法26例符合慢性马兜铃酸肾病的患者,给予甘草酸二铵150mg加中药复方汤剂肾十方治疗3个疗程。观察治疗前后尿素氮（BUN）、血肌酐（SCr）、尿酶及24h尿蛋白排泄量,血红蛋白、红细胞压积。结果治疗后患者临床症状有显著改善,总有效率80.76％;BUN、SCr、尿N-乙酰葡萄胺酶（NAG）、β2-微球蛋白（β2-MG）均显著下降（P〈0．05）,血红蛋白、红细胞压积较治疗前升高（P〈0．05）。结论甘草酸及复方中药肾十方对慢性马兜铃酸肾病有确切的疗效。     

CIGALTl基因多态性与维吾尔族IgA肾病易感性的关联性分析

目的探讨β1,3-转移酶（C1GALTl）基因单核苷酸位点（SNP）rs9639031、rs5882115多态性与新疆维吾尔族IgA肾病（IgA ephropathy,IgAN）遗传易感性的关系。方法选取经肾活检明确诊断为IgAN的90例维吾尔族患者为实验组,以同期在同一医院体检的90例维吾尔族健康体检者作为对照组,2组的性别和年龄等相匹配。采集纳入研究对象的外周血,提取DNA,应用PCR法扩增C1GALT1因上2个SNP分别为rs9639031、rs5882115位点对应的基因片段;采用直接测序法检测2个SNP位点的基因型,分析rs9639031、rs5882115基因型及基因频率在2组间分布的差异,进一步分析C1GAT态性与IgAN发病的关系。结果（1）C1GALT1因SNPrs5882115中各基因型、等位基因频率在IgAN组与对照组的分布有显著性差异（基因型P=0．014,等位基因P=0．005）。IgAN组DI、Ⅱ型频率（32．2％、2．2％）较对照组（14．4％、1．1％）高,对照组DE）型频率（84．4％）较IgAN组（65．6％）高。单因素Logist回归分析显示,rs5882115多态性对IgAN患病风险可能有影响（P=0．005）,携带DI基因型的患病风险为携带DD基因型的2．874倍（OR=2．874,95％CI=1．3756．007）,而携带I等位基因的患病风险亦较携带D等位基因高（OR=2．469,95％CI=1．290～４.728）。（2）C1GALT1基因rs9639031中,IgAN组CC、CT、TT基因型及c、T等位基因频率分别为40．0％、42．2％、17．8％、61．1％、38．9％,对照组分别为32．2％、46．7oA、21．1％、55．6％、44．4％,但差异无统计学意义（P〉0．05）。结论C1GALTl基因上的SNP位点rs5882115多态性可能与维吾尔族IgAN发病风险有一定关系,但未发现C1GALT1基因上的SNP位点rs9639031多态性与维吾尔族IgAN发病风险的关联性。