Correlation of Claudins6 (CLDN6) gene expression in meningioma tissue with the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of matrix metalloproteinase (TIMPs) and epithelial-mesenchymal transition (EMT) genes

Objective:To study the correlation of Claudins6 (CLDN6) gene expression in meningioma tissue with the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of matrix metalloproteinase (TIMPs) and epithelial-mesenchymal transition (EMT) genes.Methods:Meningioma tissue samples that were surgically removed in Yibin First People's Hospital between April 2014 and May 2017 were selected, normal arachnoid tissue samples that were collected from decompressive craniectomy in Yibin First People's Hospital during the same period were selected, and the expression of CLDN6, MMPs/TIMPs and EMT genes in tissues were determined.Results: CLDN6 protein expression in meningioma tissue was significantly lower than that in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue were significantly higher than those in normal arachnoid tissue while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly lower than those in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue with higher CLDN6 expression were significantly lower than those in meningioma tissue with lower CLDN6 expression while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly higher than those in meningioma tissue with lower CLDN6 expression. Conclusion: Lowly expressed CLDN6 gene in meningioma tissue can increase the hydrolysis activity of MMPs, induce epithelial-mesenchymal transition and thus promote the invasive growth of meningioma.

Placenta-derived mesenchymal stem cells attenuate secondary brain injury after controlled cortical impact in rats by inhibiting matrix metalloproteinases

Background:As a form of biological therapy,placenta-derived mesenchymal stem cells(PDMSCs)exhibit considerable promise in addressing the complex pathological processes of traumaticbrain injury(TBI)due to their multi-target and multi-pathway mode of action.Material&Methods:This study investigates the protective mechanisms and benefits of PDMSCs in mitigating the effects of controlled cortical impact(CCI)in rats and glutamate-induced oxidative stress injury in HT22 cells in vitro.Our primary objective is to provide evidence supporting the clinical application of PDMSCs.Results:In the in vivo arm of our investigation,we observed a swift elevation of matrix metalloproteinase-9(MMP-9)in the proximal cortex of injured brain tissues after CCI.PDMSCs,distinguished by their heightened expression of metalloproteinase tissue inhibitors-1 and-2(TIMP-1 and TIMP-2):were intravenously administered via the caudal vein.This intervention yielded significant reductions in the permeability of the blood-brain barrier(BBB):the extent of brain edema,the levels of inflammatory cytokines IL-1βand TNF-αin damaged brain tissue,and the activation status of microglia in CCI-afflicted rats.In the realm of in vitro experiments,PDMSC-conditioned media demonstrated substantial reductions in mortality rates and cleaved caspase-3 levels in glutamate-induced HT22 cells compared with conventional media.Notably,this advantage was negated upon the introduction of neutralizing antibodies targeting TIMP-1 and TIMP-2.Conclusion:Collectively,our findings underscore the potential of PDMSCs in alleviating oxidative stress injury and secondary brain injury in the pathological process of TBI.

Correlation of extracellular matrix metalloproteinase inducer expression with inflammatory response and MMPs/TIMPs in patients with myocardial infarction

Objective:To study the correlation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression with inflammatory response and matrix metalloproteinases (MMPs) /TIMPs in patients with myocardial infarction.Methods: The patients who were diagnosed with acute myocardial infarction and the patients who were diagnosed with stable angina pectoris in the Second People's Hospital of Juancheng County between March 2014 and December 2017 were selected as the AMI group and SAP group respectively, and the healthy volunteers who received physical examination during the same period were selected as the control group. Peripheral blood was collected to detect the expression of EMMPRIN, and serum was collected to determine the contents of inflammatory cytokines and MMPs/TIMPs. Results: Peripheral blood EMMPRIN expression as well as serum ICAM1, VCAM1, IL-1β, IL-17, MMP2, MMP8 and MMP9 contents of AMI group and SAP group were significantly higher than those of control group whereas TGF-β1, sFGL-2, TIMP1 and TIMP2 contents were significantly lower than those of control group and the changes of above indexes in AMI group were more significant than those in SAP group. Serum ICAM1, VCAM1, IL-1β, IL-17, MMP2, MMP8 and MMP9 contents of AMI group of patients with high EMMPRIN expression were significantly higher than those of patients with low EMMPRIN expression whereas TGF-β1, sFGL-2, TIMP1 and TIMP2 contents were significantly lower than those of patients with low EMMPRIN expression.Conclusion:The high EMMPRIN expression in peripheral blood of patients with myocardial infarction can aggravate the inflammatory response and destroy the balance of MMPs/TIMPs.

原发性肝癌患者血清CXCLs、MMPs及外周血炎性反应指标与治疗后短期预后的相关性

目的探究原发性肝癌患者血清CXC趋化因子配体(CXCLs)、基质金属蛋白酶(MMPs)及外周血炎性反应指标与治疗后短期预后的相关性。方法选取2021年9月—2023年9月首都医科大学附属北京佑安医院普外中心收治的原发性肝癌患者117例为研究对象,根据患者治疗后3个月预后情况分为短期预后不良组(n=27)和短期预后良好组(n=90)。检测患者血清CXCLs(CXCL2、CXCL8、CXCL9、CXCL13)、MMPs(MMP-2、MMP-7、MMP-9、MMP-14)水平及外周血炎性反应指标[中性粒细胞/淋巴细胞比值(NLR)、淋巴细胞/单核细胞比值(LMR)、系统免疫炎性指数(SII)];Spearman相关性分析差异性指标与原发性肝癌患者治疗后短期预后不良的相关性;多因素Logistic回归分析原发性肝癌患者治疗后短期预后不良的影响因素。结果短期预后不良组血清CXCL8、CXCL9、CXCL13水平均高于短期预后良好组(t/P=3.876/<0.001、4.779/<0.001、5.434/<0.001);短期预后不良组血清MMP-2、MMP-7、MMP-9、MMP-14水平均高于短期预后良好组(t/P=6.775/<0.001、5.376/<0.001、6.377/<0.001、6.565/<0.001);短期预后不良组SII高于短期预后良好组(t/P=5.569/<0.001);Spearman相关性分析表明,原发性肝癌患者肿瘤长径、多发肿瘤、合并肝硬化、CXCL8、CXCL9、CXCL13、MMP-2、MMP-7、MMP-9、MMP-14、SII与治疗后短期预后不良均呈正相关(r=0.286、0.209、0.200、0.415、0.417、0.420、0.459、0.383、0.493、0.442、0.440,P均<0.05);多因素Logistic回归分析结果显示,血清CXCL8、CXCL9、CXCL13、MMP-2、MMP-7、MMP-9、MMP-14水平及SII升高是原发性肝癌患者治疗后短期预后不良的独立危险因素[OR(95%CI)=1.021(1.009~1.063)、1.043(1.006~1.082)、1.087(1.011~1.170)、1.455(1.045~2.026)、1.096(1.001~1.201)、1.027(1.011~1.074)、1.128(1.083~1.295)、1.044(1.024~1.066)]。结论血清CXCLs、MMPs水平及SII高的原发性肝癌患者治疗后短期预后往往较差,密切监测血清CXCLs、MMPs水平及SII变化对于准确评估原发性肝癌患者预后具有一定临床意义。

颅内动脉瘤术后患者血清VEGFs、MMPs表达水平特征及对预后的预测效能

目的探讨颅内动脉瘤术后患者血清血管内皮生长因子(VEGFs)、基质金属蛋白酶(MMPs)水平特征及对预后的预测效能。方法选取2021年12月—2023年12月就诊于新疆维吾尔自治区人民医院神经外科的颅内动脉瘤术后患者121例作为研究对象,根据术后1个月预后情况将患者分为预后良好组(n=92)和预后不良组(n=29)。采用化学发光免疫测定法检测2组患者血清VEGFs、MMPs表达谱水平;Spearman相关性分析血清VEGFs、MMPs水平与颅内动脉瘤术后患者预后不良的相关性;Logistic回归分析颅内动脉瘤术后患者预后不良的危险因素;绘制受试者工作特征(ROC)曲线分析血清VEGFs、MMPs水平预测颅内动脉瘤术后患者预后不良的价值。结果预后不良组患者血清VEGF-1、VEGF-2、MMP-1、MMP-2、MMP-9水平均显著高于预后良好组患者(t/P=4.455/<0.001、3.982/<0.001、4.848/<0.001、5.702/<0.001、5.144/<0.001);血清VEGF-1、VEGF-2、MMP-1、MMP-2、MMP-9水平均与颅内动脉瘤术后患者预后不良呈显著正相关(r/P=0.338/<0.001、0.361/<0.001、0.383/<0.001、0.386/<0.001、0.331/<0.001);血清VEGF-1、VEGF-2、MMP-1、MMP-2、MMP-9水平升高均是颅内动脉瘤术后患者预后不良的独立危险因素[OR(95%CI)=1.142(1.011~1.372)、1.126(1.004~1.276)、1.027(1.002~1.052)、1.029(1.006~1.052)、1.026(1.006~1.047)];血清VEGF-1、VEGF-2、MMP-1、MMP-2、MMP-9水平独立及联合预测颅内动脉瘤术后患者预后不良的AUC分别为0.729、0.744、0.759、0.761、0.724、0.890,联合预测的效能大于各指标独立预测效能(Z/P=4.344/<0.001、4.185/<0.001、4.013/<0.001、4.010/<0.001、4.350/<0.001)。结论颅内动脉瘤术后患者血清VEGFs、MMPs表达水平与预后不良具有密切相关性。基于上述指标的联合预测模型对颅内动脉瘤术后患者不良预后有较高预测价值。

益景汤调控MMPs/TIMPs相关分子拮抗高糖诱导的iBRB模型基底膜损害

目的:观察益景汤拮抗高糖诱导的体外血-视网膜内屏障(iBRB)模型基底膜(BM)损害及机制。方法:分离、培养大鼠内皮细胞(ECs)和视网膜微血管周细胞(RMPs)构建体外iBRB模型,随机分成低糖组、高糖组、米诺环素组、益景汤组,分别予25 mmol/L葡萄糖、60 mmol/L葡萄糖、60 mmol/L葡萄糖+10μg/mL米诺环素、60 mmol/L葡萄糖+10%益景汤含药血清干预,各组干预12 h后终止孵育。采用Western blot法检测各组BM相关蛋白[Ⅳ型胶原(collagenⅣ,CⅣ)、层黏连蛋白(laminin,LN)]及MMPs/TIMPs相关蛋白(MMP-2、MMP-3、MMP-9、TIMP-1、TIMP-2)的表达。结果:与低糖组相比,高糖组、米诺环素组、益景汤组CⅣ蛋白表达增加,高糖组、米诺环素组LN蛋白表达增加(均P<0.05)。益景汤及米诺环素能够抑制高糖诱导的CⅣ、LN蛋白表达增加,益景汤组、米诺环素组与高糖组相比具有差异(均P<0.05)。与低糖组相比,高糖组、米诺环素组MMP-2、MMP-3、MMP-9蛋白表达增加(均P<0.05)。益景汤能够抑制高糖诱导的MMP-2、MMP-3、MMP-9蛋白表达增加,益景汤组与高糖组相比具有差异(均P<0.05)。低糖组、高糖组、米诺环素组、益景汤组各组之间TIMP-1、TIMP-2表达未见明显差异(均P>0.05)。结论:益景汤可能通过调控MMP-2、MMP-3、MMP-9、CⅣ、LN的表达,干预高糖介导的BM重塑,抑制iBRB的损害,从而干预DR。

膝骨关节炎患者膝关节液中TNF-α、ILs、MMPs、YKL-40的表达

目的研究膝骨关节炎(knee osteoarthritis,KOA)患者膝关节液中肿瘤坏死因子-α(TNF-α)、白介素(ILs)、基质金属蛋白酶(MMPs)、人甲壳质酶-40(YKL-40)的表达水平,及其与膝关节影像学Kellgren-Lawrence(K~L)分级之间的关系。方法选取100例行膝关节置换术的KOA患者,根据K~L标准将其分为KL~3级和KL~4级两组。在术前抽取患者的膝关节液,分别采用流式细胞小球微阵列术和ELISA方法检测膝关节液中TNF-α、IL-1β、IL-6、IL-8、IL-15和MMP-3、MMP-9、MMP-13、YKL-40的表达水平。采用两组间比较和单、多因素Logistic回归筛选KL~4的独立影响因素。选择Spearman法分析上述分子与K~L分级之间的相关性。结果100名KOA患者中男性25名,女性75名,平均年龄64.32岁,平均病程为8.98年。KL~3级55人、KL~4级45人。TNF-α、IL-1β、MMP-13、YKL-40在KL~3中表达较高,IL-6、IL-8、IL-15、MMP-3、MMP-9在KL~4中表达较高。IL-15、MMP-9在两组间的差异具有统计学意义(P<0.05)。单、多因素二元Logistic回归结果显示,IL-15[优势比(OR)=1.575,95%可信区间(95%CI):1.286~1.929,P<0.001]和MMP-9(OR=1.032,95%CI:1.008~1.056,P=0.01)是KL~4的独立危险因素。IL-15(r=0.220,P<0.05)、MMP-9(r=0.297,P<0.05)分别与K~L分级之间存在显著的正相关关系。结论KOA患者膝关节液中IL-15、MMP-9在KL~4级患者中高表达。IL-15和MMP-9是KL~4的独立危险因素,其水平与K~L分级之间存在正相关关系。IL-15与MMP-9有望为临床对该疾病的进展和评估提供参考。

The Role of Host-derived Dentinal Matrix Metalloproteinases in Reducing Dentin Bonding of Resin Adhesives

Dentin matrix metalloproteinases （MMPs） are a family of host-derived proteolytic enzymes trapped within mineralized dentin matrix, which have the ability to hydrolyze the organic matrix of demineralized dentin. After bonding with resins to dentin there are usually some exposed collagen fibrils at the bottom of the hybrid layer owing to imperfect resin impregnation of the demineralized dentin matrix. Exposed collagen fibrils might be affected by MMPs inducing hydrolytic degradation, which might result in reduced bond strength.Most MMPs are synthesized and released from odontoblasts in the form of proenzymes, requiring activation to degrade extracellular matrix components. Unfortunately, they can be activated by modem self-etch and etch-and-rinse adhe- sives. The aim of this review is to summarize the current knowledge of the role of dentinal host-derived MMPs in dentin matrix degradation. We also discuss various available MMP inhibitors, especially chlorhexidine, and suggest that they could provide a potential pathway for inhibiting collagen degradation in bonding interfaces thereby increasing dentin bonding durability.

大肠埃希氏菌诱导小鼠乳腺纤维化模型中瘦素及其受体、MMPs和TIMPs表达的研究

为探究Leptin、Ob-R、MMP-2、MMP-9、TIMP-1和TIMP-2对小鼠乳腺组织纤维化的作用,用奶牛乳腺炎大肠埃希氏菌感染小鼠乳腺后,分别于感染后1、3、7、14、21 d采集小鼠乳腺组织,应用免疫组化染色检测Leptin、Ob-R、MMP-2、MMP-9、TIMP-1和TIMP-2在小鼠乳腺组织细胞中的表达与分布,应用qPCR、Western blot方法检测小鼠乳腺组织中Leptin、Ob-R、MMP-2、MMP-9、TIMP-1和TIMP-2 mRNA转录水平和蛋白表达水平。结果显示,小鼠感染E.coli前期(1~7 d),Leptin、Ob-R、MMP-2、MMP-9、TIMP-1和TIMP-2主要在上皮细胞,炎性细胞中表达,感染后期(14~21 d)主要在上皮细胞、成纤维细胞和炎性细胞中表达。qPCR检测mRNA转录水平,E.coli感染1~14 d,Leptin、Ob-R、MMP-2和MMP-9的转录水平均显著上升,TIMP-2的mRNA转录水平极显著下降,感染后期(14~21 d)Leptin、Ob-R、MMP-2、TIMP-1和TIMP-2的mRNA转录水平与空白组相比无显著性差异,MMP-9mRNA转录水平极显著上升。Western blot检测蛋白表达水平,E.coli感染后1~14 d,Leptin、MMP-2、TIMP-1整体蛋白表达水平上升,TIMP-2蛋白表达水平下降,Ob-R在感染后7~14 d显著上升,MMP-9在3 d和14 d显著上升,感染后14~21 d,Ob-R、MMP-2、MMP-9呈上升趋势,Leptin呈下降趋势,TIMP-1、TIMP-2与对照组的蛋白表达水平基本持平。研究表明,通过E.coli建立的小鼠乳腺纤维化模型,能够刺激Leptin、Ob-R、MMP-2、MMP-9和TIMP-1表达,抑制TIMP-2表达。初步探究了乳腺纤维化与Leptin及其受体、MMPs和TIMPs的关系,为进一步探索纤维化的分子作用机理奠定了基础。

10-MDP钙盐对小鼠成纤维细胞L929增殖、凋亡及MMPs表达的影响

目的通过10-MDP钙盐对小鼠成纤维细胞L929的研究调查了不同浓度不同结构的10-MDP钙盐对牙周组织的影响。方法通过X射线衍射(X-Ray diffraction,XRD)对合成的三种不同比例10-MDP钙盐进行鉴定。使用CCK-8法检测10-MDP钙盐对小鼠成纤维细胞L929的细胞增殖毒性;流式细胞术检测细胞凋亡;蛋白免疫印迹实验检测细胞基质金属蛋白酶(matrix metalloproteinase,MMP)2、MMP9表达。结果XRD的结果证实三种合成方式均有不同结构10-MDP钙盐的产生;细胞增殖毒性CCK-8实验中仅有1.0 mg/mL MDP-1组在72 h后引起细胞增殖活性降低;各组培养72 h后均不诱导细胞凋亡;0.2 mg/mL和0.1 mg/mL MDP-2、MDP-1组均抑制L929细胞的MMP2和MMP9蛋白分泌。结论10-MDP钙盐可能对牙周组织中成纤维细胞没有细胞毒性作用,并且可以通过抑制MMP2、MMP9蛋白的分泌减少牙周组织破坏。

Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis

AIM:To assess expression of matrix metalloproteinases 2(MMP2)and MMP9 in gastric cancer,superficial gastritis and normal mucosa,and to measure metalloproteinase activity.METHODS:MMP2 and MMP9 mRNA expression was determined by quantitative real-time polymerase chain reaction.Normalization was carried out using three different factors.Proteins were analyzed by quantitative gelatin zymography(qGZ).RESULTS:18S ribosomal RNA(18SRNA)was very highly expressed,while hypoxanthine ribosyltransferase-1(HPRT-1)was moderately expressed.MMP2 was highly expressed,while MMP9 was not detected or lowly expressed in normal tissues,moderately or highly expressed in gastritis and highly expressed in cancer.Relative expression of 18SRNA and HPRT-1 showed no significant differences.Significant differences in MMP2 and MMP9 were found between cancer and normal tissue,but not between gastritis and normal tissue.Absolute quantification of MMP9 echoed this pattern,but differential expression of MMP2 proved conflictive.Analysis by qGZ indicated significant differences between cancer and normal tissue in MMP-2,total MMP-9,250 and 110 kDa bands.CONCLUSION:MMP9 expression is enhanced in gastric cancer compared to normal mucosa;interpretation of differential expression of MMP2 is difficult to establish.

Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia:a molecular docking study exploring possible neuroprotection

The main pathophysiology of cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Resveratrol has been reported to be one of the most potent chemopreventive agents that can inhibit cellular processes associated with ischemic stroke. Matrix metalloproteinases （MMPs） has been considered as a potential drug target for the treatment of cerebral ischemia. To explore this, we tried to investigate the inter-action of resveratrol with MMPs through molecular docking studies. At 30 minutes before and 2 hours after cerebral ischemia/reperfusion induced by occlusion of the middle cerebral artery, 40 mg/kg resveratrol was intraperitoneally administered. After resveratrol administration, neu-rological function and brain edema were significantly alleviated, cerebral infarct volume was signiifcantly reduced, and nitrite and malondialdehyde levels in the cortical and striatal regions were signiifcantly decreased. The molecular docking study of resveratrol and MMPs revealed that resveratrol occupied the active site of MMP-2 and MMP-9. The binding energy of the complexes was –37.848672 kJ/mol and –36.6345 kJ/mol for MMP-2 and MMP-9, respectively. In case of MMP-2, Leu 164, Ala 165 and Thr 227 were engaged in H-Bonding with resveratrol and in case of MMP-9, H-bonding was found with Glu 402, Ala 417 and Arg 424 residues. These ifndings collectively reveal that resveratrol exhibits neuroprotective effects on cerebral ischemia through inhibiting MMP-2 and MMP-9 activity.

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases(MMPs). Degradation of extracellular matrix(ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-teinase(TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK(reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2,-9 and-14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species(ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.

Expressions of matrix metalloproteinases 1 and 3 and their tissue inhibitors in the conjunctival tissue and fibroblasts cultured from conjunctivochalasis

AIM：To investigate the expression of matrix metalloproteinases 1 and 3（MMP-1 and MMP-3） and their tissue inhibitors of metalloproteinases 1 and 3（ TIMP-1 and TIMP-3） in the conjunctiva of eyes with conjunctivochalasis（CCh）.METHODS：The conjunctival tissue was obtained from the CCh patients and controls,the MMPs/TIMPs expression concentration was determined by enzyme-linked immunosorbent assay（ELISA） and immunofluorescence staining.The expression levels of MMPs/TIMPs in the CCh fibroblasts were determined by analyzing its concentration in the cellular supernatant that was abstracted from the in vitro cultured CCh fibroblasts.RESULTS：MMP-1 and MMP-3 levels determined by ELISA were both significantly higher in the CCh group than that in the control group（P= 0.042,0.022,respectively）,so was the levels of TIMP-1（P= 0.010）.No significant difference in the expression of TIMP-3 in conjunctiva was found between the two groups（P= 0.298）.The expression of MMP-1 and MMP-3 were both up-regulated significantly in the CCh group（P= 0.040,0.001,respectively） on immunofluorescence staining.MMP-1 and MMP-3 expression in the fibroblasts were both significantly higher in the CCh group than that in the control group（P= 0.027,0.001,respectively）,while neither the TIMP-1 nor TIMP-3 expression was significantly different between the two groups（P= 0.421,0.237,respectively）.CONCLUSION：The overexpression of MMP-1 and MMP-3 in conjunctival tissue and fibroblasts may play an important role in the pathogenesis and development of CCh.

Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury:A review

Matrix metalloproteinases(MMPs) are a family ofproteases using zinc-dependent catalysis to break down extracellular matrix(ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion(I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury.

Complex role of matrix metalloproteinases in angiogenesis

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and Promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly,TIMP-4 inhibit neovascularisation. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogehesis by converting plasndnogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide importal information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.

Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer

Matrix metalloproteinases(MMPs) are implicated in cancer development and progression and are associated with prognosis.Single-nucleotide polymorphisms(SNPs) of MMPs,most frequently located in the promoter region of the genes,have been shown to influence cancer susceptibility and/or progression.SNPs of MMP-1,-2,-3,-7,-8,-9,-12,-13 and-21 and of the tissue inhibitor of metalloproteinases(TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors.The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.

Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid

All-trans retinoic acid（ATRA） inhibits matrix metalloproteinase（MMP）-2 and MMP-9 in synovial fibroblasts, skin fibroblasts,bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells（HDPCs）. The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and-9 in HDPCs. The productions and messenger RNA（mRNA） expressions of MMP-2 and-9 were accessed by gelatin zymography and real-time polymerase chain reaction（PCR）, respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 mmol？L21ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs,which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.

Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage

A novel matrix metalloproteinase (MMP) was identified from leukocytes and found to be specifically expressedby peripheral blood leukocytes among 29 different tissuesexamined. Named leukolysin, it encodes for 562 residueswith a conserved MMP structure, i.e., pre-, pro-, catalytic , hinge- and hemopexin-like domains, but also a RXK/RRmotif, known for its role in MMP zymogen activation, anda C-terminal hydrophobic segment. Overall, leukolysindisplays the strongest homology to the newly identifiedMT-MMP subgroup with 45% and 39% identities to MT4and MT1-MMPs vs 30% and 31.5% to MMP1 and 3 respectively. Unlike MT4-MMP whose proteolytic activityremains undefined, a C-terminally truncated leukolysin isexpressed as a strong gelatinolytic species at 28 kDa whichis derived from a cell-associated 34 kDa proenzyme, presumably by furin or proprotein convertase mediated removal of the propeptide (-6 kDa). By green fluorescentprotein (GFP) tagging, the intracellular proenzyme is localized to granules throughout the cell, suggesting thatactivation occur immediately prior to secretion. Taken together, leukolysin may be part of the proteolytic arsenaldeployed by leukocytes during inflammatory responses.

不同方法联合放疗治疗薄型瘢痕疙瘩的疗效及对MMPs、HIF-1α、TGF-β1的影响

目的探讨不同方法联合放疗治疗薄型瘢痕疙瘩的疗效及对基质金属蛋白酶(MMPs)、缺氧诱导因子-1α(HIF-1α)及转化生长因子-β1(TGF-β1)的影响。方法回顾性选取2020年10月至2022年9月内蒙古医科大学附属肿瘤医院(内蒙古自治区肿瘤医院)整形外科收治的胸腹部瘢痕疙瘩患者62例(瘢痕疙瘩数94个),依据治疗方法不同分为激光联合放疗(LCR)组(30例,瘢痕疙瘩数47个)、手术联合放疗(SCR)组(32例,瘢痕疙瘩数47个)。LCR组行CO 2点阵LCR,SCR组行SCR。观察两组治疗12个月后临床疗效、复发情况。比较两组治疗前、治疗12个月后的患者与观察者瘢痕评估量表(POSAS)评分、温哥华瘢痕量表(VSS)评分、瘢痕组织基质金属蛋白酶(MMP)-2、MMP-9、HIF-1α、TGF-β1等细胞因子水平的变化。结果LCR组总有效率(93.62%)大于SCR组(76.60%),复发率(4.26%)小于SCR组(19.15%),差异均有统计学意义(P<0.05)。治疗12个月后,LCR组POSAS、VSS评分分别为(23.96±2.64)、(5.28±0.54)分,均低于SCR组[(33.96±3.59)、(6.55±0.68)分],差异均有统计学意义(P<0.05)。LCR组瘢痕组织MMP-2、MMP-9及HIF-1α、TGF-β1表达量分别为111.65±13.55、106.76±12.68、1.24±0.14、1.10±0.12,均低于SCR组(127.96±14.71、121.08±14.33、1.55±0.17、1.22±0.13),差异均有统计学意义(P<0.05)。两组不良反应发生率比较(38.30%vs.46.81%),差异无统计学意义(P>0.05)。结论LCR和SCR均可改善薄型瘢痕疙瘩症状,抑制瘢痕疙瘩复发,但LCR的治愈率更高,复发率更低,对瘢痕组织MMPs及HIF-1α、TGF-β1表达抑制作用更强,且安全性较高,值得临床推荐。