基质金属蛋白酶及微血管密度和子宫内膜癌的关系

基质金属蛋白酶及其抑制剂在子宫内膜癌的侵袭和转移中发挥着重要的作用。肿瘤的新生血管对肿瘤的发生、发展、转移及预后有着重要作用。微血管密度是衡量血管生成的定量指标。基质金属蛋白酶抑制剂可抑制血管的生成和MMPs对细胞外基质的降解。现将他们与子宫内膜癌的关系综述如下。     

含人基质金属蛋白酶组织抑制因子-1重组腺病毒的构建与体外表达

从人肝癌组织中提取总RNA，RT—PCR合成hTIMP-1的全长cDNA，克隆到腺病毒载体AdEasy系统的穿梭质粒pAdTraek—CMV上，与骨架质粒pAdEasy-1在BJ5183受体菌中进行同源重组，成功构建含hTIMP-1全长eDNA的重组腺病毒载体，经293细胞的包装、扩增，生成含hTIMP-1基因的重组腺病毒AdhTIMP-1并实现体外表达，为进一步研究肝癌浸润和转移机理以及肝癌的基因治疗提供实验基础。     

Type IV collagenases in invasive tumors

Summary The matrix metalloproteinases appear to be elevated in tumors with metastatic potential, and may well be involved in penetration of the basement membrane and degradation of extracellular proteins including type IV collagen. An imbalance between the 72 kDa and 92 kDa type IV collagenases and the associated tissue inhibitors of these metalloproteinases (TIMPs) may therefore have a role in the invasive phenotype. Cultured tumor cells with invasive potential secrete both type IV collagenases, though in tumors there is some evidence that the 72 kDa form at least may be produced by stromal cells at the invading tumor front rather than primarily by the tumor cells themselves, while the 92 kDa form may be synthesized in macrophages near the front. These collagenases are elevated in invasive as compared within situ tumor components, but their specific roles and prognostic significance are not yet established.     

Expression of muscarinic acetylcholine receptors in hepatocytes from rat fibrotic liver

The pathological changes of parasympathetic nerve are considered as an independent prognostic factor of the survival rate of patients with chronic liver disease. The non-selective muscarinic acetylcholine receptors (mAchR) agonists and antagonists can affect the proliferation of hepatocytes and hepatic stellate cells, but the subtypes of mAchR expressions in HCs are still uncertain. Here, we investigate the expression of mAchR in hepatic fibrosis on rats. 3 ml/kg 40% carbon tetrachloride (CCL4) was given to induce hepatic fibrosis on rats and the hepatocytes were isolated. Compared to the normal state, the expression levels of m1, 3, 5 in fibrotic liver tissues or hepatocytes were obviously increased, while m2, 4 decreased. 10 μM pilocarpine or 10 μM acetylcholine could increase the alanine aminotransferase (ALT), hydroxyproline (Hyp), collagen I, III in the hepatocytes, and decreased albumin (ALB). They also changed the expressions of mAchR similarly as the fibrotic hepatocytes and livers. However, atropine could ameliorate the state of fibrotic hepatocytes. These data indicate that mAchR played an important role in the regulation of hepatic fibrosis process. Targeting mAchR would have therapeutic potential for hepatic fibrosis.     

甲氰咪胍在非酒精性脂肪性肝炎进展过程中对肝纤维化的影响

目的研究甲氰咪胍对金属蛋白酶组织抑制因子（TIMP）、基质金属蛋白酶（MMP）等纤维化相关指标的作用，探讨甲氰咪胍对NASH大鼠肝纤维化进展的影响。方法26只雄性SD大鼠随机分为正常饮食对照组（n=6）、高脂饮食模型组（n=10）和甲氰咪胍治疗组（n=10），实验时间12周。生化法检测血清AST、ALT、ALP、TBIL、肝组织1℃，放免法检测HA，RT-PCR法检测TIMP-1、TIMP-2、MMP2、MMP13 mRNA的表达。病理切片检查和Ⅰ型胶原免疫组化染色观察组织学改变。结果与模型组比较，治疗组大鼠肝功改善，HA水平下降，TIMP-1、TIMP-2、MMP2表达降低，但仍高于对照组，与模型组无显著差异，MMP13表达无降低。治疗组肝组织脂肪变改善，炎症减轻，Ⅰ型胶原沉积减少。结论甲氰咪胍具有一定抗纤维化的作用。     

金属蛋白酶类及其抑制剂在椎间盘退变中作用研究进展

椎间盘退变(intervertebral disc degeneration,IVDD)可导致多种脊柱相关疾病的发生.细胞外基质(extracellularmatrix,ECM)的降解被认为是IVDD的主要病理过程.基质金属蛋白酶(matrix metalloproteinases,MMPs)及含凝血酶敏感蛋白模体的解整合素样金属蛋白酶(a disintegrin and metalloproteinase with thrombospondin motif,ADAMTSs)是参与ECM降解的主要蛋白酶类.本文总结在IVDD中MMPs、ADAMTSs及金属蛋白酶组织抑制剂(tissue inhibitors of metalloproteinases,TIMPs)的基因表达调控相关研究.研究发现人IVDD中MMP-1、2、3、7、8、10、13,ADAMTS-1、4、5出现表达上调,TIMP-3下调、TIMP-1上调.MMPs、ADAMTSs的表达受多因素共同调节,包括机械应力、炎症、氧化应激等,部分参与P38途径.遗传因素也在MMP 1、2、3、9的表达中起重要作用.MMPs、ADAMTSs蛋白表达及酶活性的上调导致ECM降解,进一步导致IVDD的发展.未来的治疗将靶向于导致ECM病理降解的特定MMPs及ADAMTSs.     

基质金属蛋白酶与压力性尿失禁关系研究进展

女性压力性尿失禁的发病机制尚不明确,目前研究表明,胶原蛋白作为盆底支持组织细胞外基质的主要成份,在维持盆底支持组织的弹性和韧性中起重要作用.基质金属蛋白酶可降解盆底组织胶原,基质金属蛋白酶组织抑制物能与相应的基质金属蛋白酶特异性结合,抑制其降解作用,基质金属蛋白酶-基质金属蛋白酶组织抑制物家族功能异常可能造成盆底胶原组织降解增加,从而导致压力性尿失禁的发生.     

基质金属蛋白酶及其抑制物与子宫内膜异位症关系的研究

目的研究基质金属蛋白酶-2、3（MMP-2,3）、金属蛋白酶组织抑制物-2（TIMP-2）蛋白及其mRNA在正常子宫内膜、子宫内膜异位症（EMS）妇女正位及异位内膜的表达。方法采用免疫组织化学法半定量分析MMP-2、MMP-3、TIMP-2在正常子宫内膜、EMS妇女正位内膜及异位内膜的表达,使用实时荧光PCR法进行MMP-2、MMP-3、TIMP-2的mRNA的定量分析。结果MMP-2、MMP-3在EMS妇女异位内膜组阳性表达高于正常对照（P〈0．05）,TIMP-2在EMS妇女异位内膜组织阳性表达低于正常对照（P〈0．05）,而且MMP-2、MMP-3在异位内膜标本阳性染色范围有向间质浸润的趋势。在不同的组织学周期,MMP-2、MMP-3、TIMP-2的表达情况相似,差异不具有统计学意义。EMS妇女异位内膜的MMP-2、MMP-3、TIMP-2mRNA含量均高于正常对照（P〈0．05）。在不同的组织学周期,正常妇女子宫内膜组的MMP-2mRNA含量、EMS妇女正位内膜组的MMP-3mRNA含量的差异有统计学意义（P〈0．05）。结论EMS妇女的异位内膜具有更高的侵袭性可能与异位内膜MMP-2、MMP-3的过高表达及TIMP-2的低表达有关。     

Action mechanism of Yi Guan Jian Decoction on CCl4 induced cirrhosis in rats

Aim of study

To investigate action mechanism of Yi Guan Jian Decoction on cirrhosis induced by CCl₄ in rats.

Material and methods

CCl₄ (3 mL/kg) for the first time and then olive oil CCl₄ solution 50% (2 mL/kg) was administered hypodermically to rats twice each week for 12 weeks. At the end of 8th week, rats were randomly divided into CCl₄ control group (n = 10), Yi Guan Jian Decoction group (n = 9) and Xiao Chai Hu Decoction group (n = 9). Yi Guan Jian Decoction and Xiao Chai Hu Decoction were oral administrated per day respectively for 4 weeks, concomitantly continued CCl₄ administration. At 12th weekend, the rats were sacrificed for sampling and detection of liver function, histological changes of liver tissue, liver tissue hydroxyproline content and expression of α-SMA, CD68, MMP-13, TIMP-1, TIMP-2, Caspase-12, HGFα, MMP-2, MMP-9 and hepatocyte apoptotic index.

Results and conclusions

(1) Compared with that of normal rats, expression of α-SMA, CD68 and TIMP-1 in liver tissue of 8 week model group rats increases significantly (P < 0.01), moreover further increased in the 12 week of model group. However, MMP-13, HGFα, TIMP-2 content decreases gradually and the statistical difference is seen between each time point (P < 0.01). Activity of MMP-2, MMP-9, content of Caspase-12 and hepatocyte apoptotic index increased gradually at 4th, 8th, 12th week. (2) Compared to that of the same time point model group, activity of MMP-9 and contents of MMP-13, TIMP-2 and HGFα in Yi Guan Jian Decoction group improves significantly (P < 0.01), and activity of MMP-2 and contents of α-SMA, TIMP-1, Caspase-12 and hepatocyte apoptotic index decreases significantly (P < 0.01). This work suggests that Yi Guan Jian Decoction exerts significant therapeutic effect on CCl₄-induced cirrhosis in rats, through mechanism of inhibiting hepatocytes apoptosis and hepatic stellate cells activation, and regulating the function of Kupffer cell.

Ethnopharmacological relevance

This study investigates the mechanism of Yi Guan Jian against cirrhosis from aspect of heptocytes apoptosis and hepatic stellate cells activation. It suggest that although of unknown bioactive ingredients, mechanism of traditional Chinese medicine recipe against cirrhosis can be disclosed and of profound significance.     

基质金属蛋白酶及其抑制物在妇科领域中的研究进展

MMPs和TIMPs调节ECM的分解和合成 ,参与体内多种生理、病理过程。在子宫内膜中呈周期性变化 ,与月经形成和胚胎种植有关 ;在子宫内膜异位症异位内膜种植中的作用愈来愈受到关注 ;MMPs的异常升高参与妇科恶性肿瘤的侵袭和转移。