Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis

BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in early focal cerebral infarction following urokinase thrombolysis in rats

Activity of matrix metalloproteinase-9 increases following cerebral ischemia/reperfusion, and is associated with cerebral microvascular permeability, blood-brain barrier destruction, inflammatory cell infiltration and brain edema. Matrix metalloproteinase-9 also likely participates in thrombolysis. A rat model of middle cerebral artery infarction was established by injecting autologous blood clots into the internal carotid artery. At 3 hours following model induction, urokinase was injected into the caudal vein. Decreased neurological severity score, reduced infarct volume, and increased expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were observed in the cerebral cortex 24 hours after urokinase thrombolysis. These results suggest that urokinase can suppress damage in the acute-early stage of cerebral infarction.

Imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 may contribute to hemorrhage in cerebellar arteriovenous malformations

In this study, we determined the expression levels of matrix metalloproteinase-2 and -9 and matrix metalloproteinase tissue inhibitor-1 and -2 in brain tissues and blood plasma of patients undergoing surgery for cerebellar arteriovenous malformations or primary epilepsy （control group）. Immunohistochemistry and enzyme-linked immunosorbent assay revealed that the expression of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with cerebellar arteriovenous malformations than in patients with primary epilepsy. The ratio of matrix metalloproteinase-9 to matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with hemorrhagic cerebellar arteriovenous malformations compared with those with non-hemorrhagic malformations. Matrix metalloproteinase-2 and matrix metalloproteinase tissue inhibitor-2 levels were not significantly changed. These findings indicate that an imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-I, resulting in a relative overabundance of matrix metalloproteinase-9, might be the underlying mechanism of hemorrhage of cerebellar arteriovenous malformations.

Expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in malignant peripheral nerve sheath tumor

BACKGROUND： Matrix metalloproteinase-9 （MMP-9） can degrade collagen IV （the main structural ingredient of basilar membrane）, and it also plays an important role in tumor vascularization, tumor cell progression, formation of metastatic focus, etc. Tissue inhibitor of metalloproteinase-1 （T1MP-1） can bind with MMP-9 to form 1 ： 1 compound and inhibit its activity, and can negatively regulate the tumor progression and metastasis. OBJECTIVE： To analyze the relationship of MMP-9 and T1MP-1 expressions with the pathological grade, metastasis and prognosis of malignant peripheral nerve sheath tumor （MPNST）. DESIGN： An observational comparative experiment. SETTING： Heze Medical College. PARTICIPANTS： Fifty-eight surgical pathological samples, which were clearly diagnosed to be MPNST, were collected from the pathological laboratory archives in the Department of Pathology, Heze Municipal Hospital from January 1988 to December 2003. The MPNST pathological types were common tumor in 53 cases, malignant triton tumor in 2 cases, epithelial MPNST in 2 cases and MPNST with gland differentiation in 1 case. The pathological grade was grade 1 in 11 cases, grade 2 in 24 cases and grade 3 in 23 cases. Besides, the resected tumor samples of 20 patients with benign peripheral nerve tumor （10 cases of nerve sheath tumor and 10 cases of neurofibromatosis） and the normal peripheral nerves （by-products of some surgeries） of 5 patients were also collected. The samples were used with the approval of the patients. Rat-anti-human MMP-9, TIMP-1 monoclonal antibody and S-P kit were purchased from Fuzhou Maixin Biotechnology, Co.,Ltd. METHODS： The documented paraffin blocks were again prepared to sections of 5 lJ m. The expressions of MMP-9 and TIMP-1 in the samples were detected with mmunohistochemical S-P method. The relationships of the MPNST severity, recurrence, metastasis and survival rate with the expressions of MMP-9 and TIMP-1 were analyzed. MAIN OUTCOME MEASURES： Relationships of MMP-9 and TIMP-1 expressions with the MPNST severity and prognosis. RESULTS： ①Expressions of MMP-9 and TIMP-1 in three tissues： MMP-9 and TIMP-1 stainings were mainly observed in cytoplasm. Among the 58 MPNST patients, the MMP-9 expression was significantly higher than those in normal peripheral nerve and benign tumor （P 〈 0.05）, while the TIMP-1 expression in MPNST was lower than those in normal peripheral nerve and benign tumor （P 〈 0.05）. ②Relationship of MMP-9 and TIMP-1 expressions with the severity and prognosis of MPNST： The expressions of both proteins were observed in the four subtypes. The positive expression of MMP-9 in the MPNST patients of grades 2 - 3 was significantly higher than that in the MPNST patients of grade 1 （P 〈 0.05）, while the expression of MMP-9 was significantly lower than that in the MPNST patients of grade 1 （P 〈 0.05）. The metastatic rate was positively correlated with MMP-9 expression （r =1.696, P 〈 0.05）, but negatively correlated with TIMP-1 expression （r = - 2.125, P 〈 0.05）. CONCLUSION： MMP-9 and TIMP-1 are associated with MPNST pathological grades and metastasis, and can be used as the indicators for judging the severity and orognosis of MPNST.

Correlation of matrix metalloproteinase－2, －9, tissue inhibitor－1 of matrix metalloproteinase and CD44 variant 6 in head and neck cancer metastasis

This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The ex-pression of matrix metalloproteinase-2,-9 (MMP-2,MMP-9), tissue inhibitor-1 of matrix metalloprote inase(TIMP-1) , cell adhesion molecule 44 variant 6 (CD44v6) , HER2/neu and p53 was investigated in 154 pa-tients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP-2, MMP-9, TIMP-1,CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68. 18%, 98.05%,55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there wasclose positive relationship ( P < 0.05) between the expression of MMP-2 and MMP-9, TIMP-1 and CD44v6,HER2/neu and MMP-9, MMP-2 and p53. Up-regulation of MMP-2 was accompanied by advanced T stage( P < 0.01 ) . There was also a trend of MMP-2 expression being related with tumor metastasis. Increased ex-pression of HER2/neu was found in patients with tumor recurrence( P < 0.05 ) . The expression of TIMP-1 washigher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non-keratlnizing SCC than that in basaloid SCC ( P < 0.05 ) . These findings suggested that MMP-2 and MMP-9, HER2/neu andMMP-9, MMP-2 and p53 had a coordinate function in aggression of tumor; that MMP-2 had a more important function than MMP-9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker forpoor prognosis in HNSCC.

Expression of tissue inhibitor of metalloproteinase-1 in progression muscular dystrophy

Objective Tissue inhibitor of metalloproteinase-1 （TIMP-1） is a muhifunctional protein that has thc capacity to modify cellular activities and to modulate matrix turnover. This paper revealed the contributive role of TIMP-1 in progressive muscular dystrophy （PMD）. Methods We examined the expression and cellular localization of TIMP-1 protein using biopsied frozen muscle from patients with Duchenne muscular dystrophy （DMD）, Becker muscular dystrophy （BMD） , congenital muscular dystrophy （CMD） by immunohistochemistry, double immunofluorescence and Western blot analysis. Results The results of immunohistochemistry and double immunofluorescence showed that TIMP-1 was positive only in vascular endothelial cells of normal muscles. Immunohistochemistry and Western blot analysis showed that the staining intensity was distinctly increased in some dystrophic muscles of PMD for TIMP-1. Double immunofluorescence revealed that TIMP-1 strongly expressed in the regenerating muscle fibers, macrophages and macrophage infiltrating necrotic fibers. Some activated fibroblasts in endomysium and perimysium of DMD and CMD muscles were also positive for TIMP- 1. Conclusion The functional consequence of overexpression of TIMP-1 in the dystrophic muscles is unknown, but the elevated local expression of TIMP-1 in diseased muscles of PMD and their distinct distribution pattern provide evidence that TIMP-1 may participate in the pathogenesis of PMD.

多西他赛联合PD-1抑制剂对晚期非小细胞肺癌预后及血清MMP-9、TIMP-1水平的影响

目的探讨多西他赛联合程序性死亡受体1(PD-1)抑制剂对晚期非小细胞肺癌(NSCLC)预后及血清基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶组织抑制剂-1(TIMP-1)水平的影响。方法将90例晚期NSCLC患者随机分为研究组和对照组,每组45例。对照组给予多西他赛和顺铂治疗,研究组在对照组治疗基础上给予PD-1治疗,3周为1个治疗周期,共治疗6个周期。比较2组治疗后客观缓解率(ORR)、疾病控制率(DCR)、无进展生存期(PFS)、总生存期(OS),观察2组治疗期间不良反应发生情况及治疗前后血清MMP-9、TIMP-1水平的变化。结果研究组治疗后DCR、PFS、OS显著高于对照组(P<0.05);治疗期间2组不良反应发生率比较差异无统计学意义(P>0.05);2组治疗后血清MMP-9、TIMP-1水平较治疗前显著降低(P<0.05),且研究组降低较对照组更为显著(P<0.05)。结论多西他赛联合PD-1抑制剂对晚期NSCLC具有较好的疗效和预后,能够降低血清MMP-9、TIMP-1水平,降低肺癌细胞侵袭转移的能力,安全性良好。

CTA联合血清MMP-9、TIMP-1对脑梗死患者颈动脉斑块诊断价值

目的探究计算机断层扫描血管成像(CTA)联合血清基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶组织抑制剂-1(TIMP-1)对脑梗死患者颈动脉斑块诊断价值。方法选取2021年5月-2021年12月期间我院神经内科收治的140例脑梗死患者作为试验组研究对象,另选择同期至我院进行体检的健康者80例作为参照组。试验组患者均行CTA和数字减影血管造影(DSA),分析CTA诊断颈动脉斑块价值。试验组和参照组均接受血清MMF-9 TIMP-1检测。对比试验组与参照组的血清MMP-9、TIMP-1水平差异。在试验组中,以DSA为金标准,将患者分为斑块组和无斑块组,对比两组之间的血清MMP-9、TIMP-1水平差异,对CTA联合血清MMP-9、TIMP-1诊断颈动脉斑块的效果进行受试者特征曲线(ROC)分析。结果CTA检测结果显示存在颈动脉斑块者64例,无斑块组76例,CTA诊断颈动脉斑块敏感度为96.88%,特异性为97.37%,准确度为97.14%;试验组血清MMP-9水平显著高于参照组(P<0.05),TIMP-1水平显著低于参照组(P<0.05);斑块组血清MMP-9水平显著高于无斑块组(P<0.05),TIMP-1水平显著低于无斑块组(P<0.05);ROC曲线显示血清CTA、MMP-9、TIMP-1水平单独及联合诊断颈动脉斑块AUC值依次为0.979、0.835、0.812和0.993。结论CTA联合血清MMP-9、TIMP-1对脑梗死患者颈动脉斑块具有良好的诊断价值。

脑脊液基质金属蛋白酶9水平和基质金属蛋白酶9/基质金属蛋白酶组织抑制剂1比值与结核性脑膜炎病情严重程度的相关性及对预后的预测价值研究

目的 探讨脑脊液基质金属蛋白酶9(MMP-9)水平和MMP-9/基质金属蛋白酶组织抑制剂1(TIMP-1)比值与结核性脑膜炎病情严重程度的相关性及对预后的预测价值。方法 选择2021年1月至2023年2月在湖南省胸科医院住院的结核性脑膜炎患者72例为观察组,以同期住院的非肿瘤非感染性头痛患者52例为对照组。比较2组患者脑脊液MMP-9水平和MMP-9/TIMP-1比值。根据改良的英国医学研究理事会结核性脑膜炎分期标准将观察组患者分为Ⅰ期组、Ⅱ期组、Ⅲ期组,比较3组患者MMP-9水平和MMP-9/TIMP-1比值。根据预后情况将观察组患者分为预后良好组和预后不良组,比较2组MMP-9水平和MMP-9/TIMP-1比值,并以受试者工作特征(ROC)曲线法评估各指标对结核性脑膜炎的预后预测价值。结果 观察组MMP-9水平及MMP-9/TIMP-1比值均大于对照组[(96±21)μg/L比(50±12)μg/L、(1.21±0.33)比(0.67±0.15)](均P<0.05),但2组间TIMP-1水平比较差异无统计学意义(P>0.05)。不同严重程度结核性脑膜炎患者MMP-9水平及MMP-9/TIMP-1比值差异均有统计学意义,且均呈Ⅰ期<Ⅱ期<Ⅲ期(均P<0.05);不同严重程度结核性脑膜炎患者TIMP-1水平差异均无统计学意义(均P>0.05)。相关性分析结果显示,结核性脑膜炎病情严重程度与MMP-9水平及MMP-9/TIMP-1比值均呈正相关(r=0.861、P=0.012;r=0.731、P=0.008),与TIMP-1无相关性(r=0.220,P=0.063)。预后不良组患者MMP-9水平及MMP-9/TIMP-1比值均高于预后良好组(均P<0.05),2组TIMP-1水平差异无统计学意义(P>0.05)。ROC曲线分析结果显示,MMP-9水平、MMP-9/TIMP-1比值预测结核性脑膜炎患者预后不良的截断值分别为112.04μg/L、1.41,曲线下面积分别为0.803、0.905(均P<0.05)。结论 结核性脑膜炎患者脑脊液MMP-9水平、MMP-9/TIMP-1比值明显升高,且MMP-9水平、MMP-9/TIMP-1比值与结核性脑膜炎的病情严重程度呈正相关,并可用于预测患者预后。

CTA联合血清MMP-9、TIMP-1在缺血性脑卒中诊断中的应用

目的 探究CT血管成像(CTA)联合血清基质金属蛋白酶9(MMP-9)、金属蛋白酶组织抑制因子1(TIMP-1)在缺血性脑卒中诊断中的应用。方法 选取2021年5月至2022年5月期间张家口市第一医院神经内科收治的140例脑卒中患者作为研究组研究对象,均行CTA检查,以数字血管造影(DSA)为金标准,分析CTA对缺血性脑卒中诊断价值,另选择同期至此院进行体检的健康者80名作为对照组,比较两组患者血清MMP-9、TIMP-1水平。结果 140例患者,共检查463条头颈血管,经CTA诊断无狭窄236条、轻度狭窄66条、中度狭窄36条、重度狭窄46条、闭塞22条,与DSA对照CTA诊断缺血性脑卒中患者血管狭窄程度的灵敏度为81.25%,特异度为90.15%;CTA诊断轻度狭窄患者74例、中度16例、重度46、闭塞4例,与DSA对照CTA诊断灵敏度82.50%、特异度83.33%;研究组患者血清MMP-9、TIMP-1表达水平均显著高于对照组患者,差异有统计学意义(t=73.668、33.925,P<0.05),且研究组患者随着狭窄程度增加,血清MMP-9、TIMP-1水平逐渐上升,差异有统计学意义(F=13298.37、901.001,P<0.05);MMP-9以247.14 ng/mL为临界值,阳性53例,阴性87例;TIMP-1均值(239.21 ng/mL)为临界值,阳性53例,阴性87例;以CTA阳性为基础,MMP-9、TIMP-1任一指标阳性则定义为联合诊断阳性,结果显示联合诊断灵敏度为88.75%,特异度为80.00%。结论 CTA联合血清MMP-9、TIMP-1对缺血性脑卒中诊断效能较高,临床应在密切观察缺血性脑卒中患者CTA检查基础上联合MMP-9、TIMP-1水平检测。

Increased expression of matrix metalloproteinase-9 associated with gastric ulcer recurrence

AIM: To compare matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in gastric ulcer (GU) and chronic superficial gastritis (CSG). METHODS: This study enrolled 63 patients with GU and 25 patients with CSG. During upper gastroduodenal endoscopy, we took samples of gastric mucosa from the antrum and ulcer site from patients with GU, and samples of antral mucosa from patients with CSG. Mucosal biopsy tissues were cultured for 24 h, and the culture supernatant was measured for levels of MMP-9 and TIMP-1. After receiving eradication therapy for Helicobacter pylori (H. pylori ) and 8 wk proton-pump inhibitor therapy for GU, follow-up endoscopy examination was performed after 6 mo and whenever severe symptoms occurred. RESULTS: Levels of MMP-9 and TIMP-1 at the ulcer site or in the antrum were significantly higher in GU than CSG patients. MMP-9 levels at the ulcer site were significantly higher than in the antrum in GU patients, and had a significantly positive correlation with TIMP-1. MMP-9 levels were significantly higher in H. pylori -positive than H. pylori -negative GU and CSG patients. Levels of MMP-9 or TIMP-1 at the ulcer site were associated with the histological severity of activity and inflammation. About 57 GU patients were followed up, and seven had GU recurrence. H. pyloriinfection and MMP-9 levels were risk factors for the recurrence of GU adjusted for age and sex by multiple logistic regression analysis. CONCLUSION: MMP-9 may perform an important function in gastric ulcer formation and recurrence.

EPO、IL-1β、MMP-9/TIMP-1与烧伤患者瘢痕评分、创面愈合时间关系及对创面愈合质量的预测价值

目的:探讨促红细胞生成素(Erythropoietin,EPO)、白介素-1β(Interleukin-1β,IL-1β)、基质金属蛋白酶-9/基质金属蛋白酶抑制剂-1(Matrix metalloproteinase-9/Tissue inhibitor of metalloproteinase-1,MMP-9/TIMP-1)与烧伤患者瘢痕评分、创面愈合时间关系及对创面愈合质量的预测价值。方法:选取2018年5月-2021年1月笔者科室收治的113例深Ⅱ度烧伤患者,采用削痂植皮联合外用重组人粒细胞-巨噬细胞刺激因子治疗,根据创面愈合质量分为良好组(n=88)、不良组(n=25),比较两组基线资料及治疗前、治疗5 d、10 d后EPO、IL-1β、MMP-9/TIMP-1,应用Pearson分析治疗5 d、10 d后EPO、IL-1β、MMP-9/TIMP-1与温哥华瘢痕量表(Vancouver scar scale,VSS)、创面愈合时间关系,采用多因素Logistic回归方程分析创面愈合质量的相关影响因素,采用受试者工作特征曲线(Receiver operating characteristic,ROC)及ROC下面积(Area under the curve,AUC)分析治疗5 d、10 d后EPO、IL-1β、MMP-9/TIMP-1,预测创面愈合质量价值。结果:不良组创面愈合时间、VSS评分数值均高于良好组(P<0.05);不良组治疗5 d、10 d后EPO低于良好组,IL-1β、MMP-9/TIMP-1高于良好组,差异均有统计学意义(P<0.05);治疗5 d、10 d后EPO与VSS评分、创面愈合时间呈负相关(P<0.05);治疗5 d、10 d后IL-1β、MMP-9/TIMP-1与VSS评分、创面愈合时间呈正相关(P<0.05);将创面愈合时间、VSS评分控制后,治疗5 d、10 d后EPO、IL-1β、MMP-9/TIMP-1仍与创面愈合质量相关(P<0.05);治疗10 d后EPO、IL-1β、MMP-9/TIMP-1的AUC大于治疗5 d后,且EPO、IL-1β联合MMP-9/TIMP-1的AUC大于任一单一指标。结论:EPO、IL-1β、MMP-9/TIMP-1与烧伤患者瘢痕评分、创面愈合时间、创面愈合质量有关,联合检测能为临床预测创面质量提供有效参考,并有望成为促进创面愈合、提高愈合质量的一个干预靶点。

超脉冲CO_(2)激光联合磁敷疗法治疗浅表型增殖期婴幼儿血管瘤的临床效果及其对患儿血清EGFL7、HIF-1α、MMP9、TIMP-1水平的影响

目的探讨超脉冲CO_(2)激光联合磁敷疗法治疗浅表型增殖期婴幼儿血管瘤(IH)的临床效果及其对患儿血清表皮生长因子样结构域蛋白7(EGFL7)、缺氧诱导因子1α(HIF-1α)、基质金属蛋白酶9(MMP9)、组织金属蛋白酶抑制剂1(TIMP-1)水平的影响。方法将110例浅表型增殖期IH患儿随机分成观察组与对照组,各55例。观察组采用超脉冲CO_(2)激光联合磁敷疗法治疗,对照组采用单纯超脉冲CO_(2)激光治疗。比较两组患儿近期与远期治疗有效率,以及治疗前后的血清EGFL7、HIF-1α、MMP9、TIMP-1水平,观察两组患儿治疗期间不良反应的发生情况。结果观察组近期治疗有效率与远期治疗有效率均高于对照组(均P<0.05)。治疗后,两组患儿的血清EGFL7、HIF-1α、MMP9水平均低于治疗前,且观察组患儿的上述指标水平均低于对照组(均P<0.05);两组患儿的血清TIMP-1水平均高于治疗前,且观察组患儿的血清TIMP-1水平高于对照组(均P<0.05)。两组患儿治疗期间局部肿胀、局部红斑、色素沉着的发生率比较,差异均无统计学意义(均P>0.05)。结论相比于单纯超脉冲CO_(2)激光治疗,超脉冲CO_(2)激光联合磁敷疗法可提高浅表型增殖期IH患儿的治疗效果,安全性较高,其机制可能与调节血清EGFL7、HIF-1α、MMP9和TIMP-1水平有关。

血清TGF-β1、MMP-9和TIMP-1对子宫内膜息肉切除术后发生宫腔粘连的预测价值

目的:筛选子宫内膜息肉切除术后发生宫腔粘连的影响因素,并探讨血清转化生长因子β1(TGF-β1)、基质金属蛋白酶-9(MMP-9)和金属蛋白酶抑制因子-1(TIMP-1)水平在预测术后2年内发生宫腔粘连的诊断价值。方法:选择2016年1月至2019年6月在我院实施宫腔镜子宫内膜息肉切除术的患者341例,术后对所有患者均进行2年的随访,期间失访23例。术后2年出现宫腔粘连53例,为宫腔粘连组;未发生宫腔粘连患者265例,为非宫腔粘连组。采用酶联免疫吸附试验测定患者术前的血清TGF-β1、MMP-9和TIMP-1表达水平。通过单因素分析和多因素二元Logistics回归分析筛选出与宫腔镜子宫内膜息肉切除术后发生宫腔粘连相关的危险因素,采用受试者工作曲线(ROC曲线)分析血清TGF-β1、MMP-9和TIMP-1水平在预测子宫内膜息肉切除术后2年内发生宫腔粘连的诊断效能。结果:子宫内膜息肉切除术后2年内发生宫腔粘连与孕次、剖宫产史、刮宫史、内膜增生、盆腔炎史、多发息肉、血清TGF-β1、MMP-9和TIMP-1水平具有相关性(P<0.01),而与年龄、产次、引产史、宫内节育器史、绝经和体质量指数无相关性(P>0.05)。多因素回归分析发现孕次、盆腔炎史、血清TGF-β1和TIMP-1水平是术后2年内发生宫腔粘连的独立危险因素(P<0.05),而血清MMP-9水平是术后发生宫腔粘连的保护因子(P<0.05)。轻度粘连组、中度粘连组和重度粘连组患者术前的血清TGF-β1、MMP-9和TIMP-1水平差异均有统计学意义(P<0.01)。血清TGF-β1、MMP-9和TIMP-1水平在预测术后2年内发生宫腔粘连具有较高的联合诊断效能,联合检测的灵敏度为92.5%,特异度为79.6%,曲线下面积为0.932,均优于单个指标TGF-β1(Z=4.752,P<0.01)、MMP-9(Z=4.061,P<0.01)和TIMP-1(Z=3.709,P<0.01)。结论:孕次、盆腔炎史、血清TGF-β1、MMP-9和TIMP-1水平是子宫内膜息肉切除术后2年内发生宫腔粘连的影响因子,血清TGF-β1、MMP-9和TIMP-1水平在预测子宫内膜息肉切除术后2年内发生宫腔粘连具有重要的诊断价值,可为该类患者采取进一步干预措施提供理论依据。

针刺联合输卵管通液术治疗输卵管炎性不孕疗效观察及对血清MMP-9、TIMP-1的影响

目的观察针刺联合输卵管通液术治疗气滞血瘀型输卵管炎性不孕的临床疗效及对血清基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)、基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinase-1,TIMP-1)水平的影响。方法将69例气滞血瘀型输卵管炎性不孕患者随机分为针刺组(34例)和假针组(35例)。针刺组给予针刺联合输卵管通液术治疗;假针组给予输卵管通液术后针刺组穴位旁开1 cm非经非穴处进针,只刺破皮肤,不行针治疗。观察两组治疗前后中医证候和体征积分、输卵管通畅度及血清MMP-9和TIMP-1水平、MMP-9/TIMP-1比值变化,并比较两组中医证候、体征疗效及随访6个月内宫内妊娠率。结果假针组治疗后中医证候积分未见改变(P>0.05),针刺组治疗后低于治疗前和假针组(P<0.01)。两组治疗后体征积分降低(P<0.01),输卵管通畅情况呈现不同程度改善(P<0.05),血清MMP-9水平增高(P<0.01),血清TIMP-1降低(P<0.01),MMP-9/TIMP-1比值升高(P<0.01);针刺组治疗后优于假针组(P<0.01,P<0.05)。针刺组宫内妊娠率高于假针组(P<0.05)。结论针刺联合输卵管通液术治疗气滞血瘀型输卵管炎性不孕疗效显著,作用机制可能与升高MMP-9水平,降低TIMP-1水平,调节二者比值从而抑制纤维化过程有关。

芪地糖肾方对糖尿病肾病小鼠肾脏病变及血清Klotho、MMP-9/TIMP-1的影响

目的 探究芪地糖肾方对糖尿病肾病小鼠肾脏病变及血清Klotho、基质金属蛋白酶-9(MMP-9)/组织金属蛋白酶抑制剂-1(TIMP-1)的影响。方法 将36只14周龄db/db小鼠随机分为模型组、缬沙坦组、芪地糖肾方组,每组12只。选取12只14周龄db/m小鼠作为正常组。缬沙坦组给予10.29 g/kg缬沙坦水溶液灌胃,芪地糖肾方组给予3.33 g/kg芪地糖肾方颗粒水溶液灌胃,正常组及模型组给予等量的生理盐水灌胃,均1次/d,连续12周。免疫酶联吸附法检测尿微量白蛋白水平,计算12 h尿白蛋白水平;称小鼠体重、左肾重,计算肾重体重比值;免疫酶联吸附法检测血清Klotho、MMP-9、TIMP-1水平,计算MMP-9/TIMP-1;电镜、光镜下观察肾脏组织病理形态。结果 与正常组比较,模型组小鼠肾重体重比值、血清Klotho水平均明显降低(P均<0.05),12 h尿白蛋白水平及血清MMP-9、TIMP-1水平和MMP-9/TIMP-1均明显升高(P均<0.05),肾脏超微结构紊乱,肾小球基底膜明显增厚(P<0.05)。与模型组比较,芪地糖肾方组小鼠肾重体重比值明显升高(P<0.05),缬沙坦组升高不明显(P>0.05);缬沙坦组、芪地糖肾方组小鼠血清Klotho水平均明显升高(P均<0.05),12 h尿白蛋白水平及血清MMP-9、TIMP-1水平和MMP-9/TIMP-1均明显降低(P均<0.05),肾脏超微结构病变较轻,肾小球基底膜厚度均明显降低(P均<0.05)。结论 芪地糖肾方可明显减少糖尿病肾病小鼠尿蛋白,改善肾脏病变,其机制可能与调节血清Klotho及MMP-9/TIMP-1平衡有关。

视神经脊髓炎谱系疾病患者外周血TIMP1和MMP9及miR-363-5p的表达变化及其与血脑屏障破坏的关系

目的探讨视神经脊髓炎谱系疾病(NMOSD)患者外周血金属蛋白酶抑制剂1(TIMP1)mRNA及血浆TIMP1蛋白、基质金属蛋白酶9(MMP9)及miR-363-5p的表达变化及其与血脑屏障(BBB)破坏的关系。方法选取2019年9月至2021年11月河北医科大学第二医院收治的NMOSD患者30例,另选择健康体检者作为健康对照组10例。采用ELISA方法检测血浆TIMP1、MMP9的水平。采用qPCR法检测外周血单个核细胞(PBMC)TIMP1 mRNA和血浆miR-363-5p水平。根据脑脊液/血白蛋白商(Qalb)将NMOSD患者分为BBB正常组与BBB破坏组,分别比较NMOSD组与正常对照组以及BBB正常组与BBB破坏组TIMP1、MMP9及miR-363-5p表达差异,采用相关性分析评估其与BBB破坏的关系。采用双萤光素酶报告基因检测技术验证miR-363-5p与TIMP1靶向结合关系。通过慢病毒载体感染JURKA T细胞并分为4组:未转染miR-363-5p模拟物的正常对照组,转染miR-363-5p模拟物组,未转染miR-363-5p抑制剂的正常对照组,转染miR-363-5p抑制剂组。采用qPCR检测JURKA T细胞TIMP1 mRNA及MMP9 mRNA的表达,采用Western-blot技术检测JURKA T细胞TIMP1、MMP9蛋白表达的水平。结果(1)NMOSD组患者PBMC TIMP1 mRNA、血浆miR-363-5p、血浆TIMP1和MMP9蛋白水平高于健康对照组(P<0.01或P<0.05)。NMOSD组和健康对照组MMP9/TIMP1比值比较差异无统计学意义(P>0.05)。(2)NMOSD患者BBB破坏组MMP9/TIMP1比值高于BBB正常组(P<0.05)。NMOSD患者MMP9/TIMP1比值与Qalb呈中等正相关(r=0.505,P<0.01)。NMOSD患者血浆miR-363-5p与PBMC TIMP1 mRNA相对表达水平无相关性(r=-0.33,P>0.05),与血浆TIMP1蛋白表达水平呈中等负相关(r=-0.5157,P<0.01)。miR-363-5p可与TIMP13'UTR区结合,在JURKA T细胞中,转染miR-363-5p模拟物后TIMP1 mRNA和蛋白质表达水平下降(P<0.01,P<0.05)。结论NMOSD患者PBMC TIMP1 mRNA以及血浆TIMP1蛋白、MMP9蛋白、miR-363-5p表达升高;miR-363-5p可负调控JURKA T细胞TIMP1的表达;血浆MMP9/TIMP1比值升高可能在NMOSD患者BBB的破坏中发挥作用。

细胞间黏附分子-1、基质金属蛋白酶9及基质金属蛋白酶组织抑制物-1在非小细胞肺癌中的表达及与患者临床特征的关系

目的探讨细胞间黏附分子-1(ICAM-1)、基质金属蛋白酶9(MMP9)及基质金属蛋白酶组织抑制物-1(TIMP-1)在非小细胞肺癌(NSCLC)中的表达及与患者临床特征的关系。方法选取82例NSCLC患者,免疫组化法检测肿瘤组织及癌旁组织中ICAM-1、MMP9及TIMP-1的表达情况,并分析其与患者临床特征的关系,相关性分析采用Spearman等级相关分析。结果NSCLC患者肿瘤组织中ICAM-1、MMP9及TIMP-1阳性表达率均明显高于癌旁组织,差异均有统计学意义(P﹤0.01)。病理类型为腺癌、临床分期为Ⅲ~Ⅳ期、有淋巴结转移的NSCLC患者肿瘤组织中ICAM-1的阳性表达率均明显高于病理类型为鳞状细胞癌、临床分期为Ⅰ~Ⅱ期、无淋巴结转移的患者,差异均有统计学意义(P﹤0.01);临床分期为Ⅲ~Ⅳ期、有淋巴结转移的NSCLC患者肿瘤组织中MMP9、TIMP-1的阳性表达率均明显高于临床分期为Ⅰ~Ⅱ期、无淋巴结转移的患者,差异均有统计学意义(P﹤0.01)。Spearman相关分析显示,NSCLC患者肿瘤组织中ICAM-1的表达与MMP9的表达呈正相关(r=0.618,P﹤0.01),ICAM-1的表达与TIMP-1的表达呈正相关(r=0.584,P﹤0.01),MMP9的表达与TIMP-1的表达呈正相关(r=0.641,P﹤0.01)。结论ICAM-1、MMP9及TIMP-1在NSCLC患者肿瘤组织中阳性表达率高,且与NSCLC的发生发展密切相关。

Effects of Fengbaisan(丰白散) on the Expression of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Lung Tissue of Rats with Chronic Obstructive Pulmonary Disease

Objective： To observe effects of Fengbaisan （丰白散, FBS） on the expression of matrix metalloproteinase-9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1） in lung tissue of rats with chronic obstructive pulmonary disease （COPD） and to investigate the preventive and therapeutic mechanisms of FBS. Methods： The COPD rat model was established by cigarette smoke exposure and lipopolysaccharide （LPS） intra-tracheal dripping. The histopathological changes of lung tissue was observed via hematoxylin/eosin staining. The expression of MMP-9 and TIMP-1 in lung tissue was measured by reverse transcription polymerase chain reaction （RT-PCR） and immunohistochemistry. Results： The typical histopathological changes of COPD were displayed in the model group, Ambroxol Hydrochloride group and FBS group, and the pathological lesions in the FBS group were less than those in the model group. The expression of MMP-9 and TIMP-1 in the model group increased significantly compared with those in the normal group （P〈0.05）. After treatment for successive 28 days, the expression of MMP-9 and TIMP-1 in the FBS group decreased remarkably as compared with the model group （P〈0.05）. Conclusions： FBS can regulate MMP-9/TIMP-1 imbalance to prevent airway and lung parenchyma remodeling process via reducing the expression of MMP-9 and TIMP-1 in the lung tissue of COPD rats, and this may be a possible therapeutic mechanism of FBS on COPD. KEYWORDS chronic obstructive pulmonary disease, Fengbaisan, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, airway remodeling, Chinese medicine

Correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2

Background The relationship between the presence of metalloproteinases and thyroid cancer remains unknown, and many controversies still exist in this field. The objective of this study was to investigate the correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metall0Proteinase-2. Methods The correlations were studied bY detecting the levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloProteinase-1, and tissue inhibitor of metalloproteinase-2 by enzyme-linked immunosorbant assay and reverse-transcription polymerase chain reaction in the peripheral blood of 30 patients with papillary thyroid carcinoma, 27 patients with benign thyroid disease, and 25 hea !hy vo!unteers. Results The leve!s of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in the peripheral blood of patients with papillary thyroid carcinoma were significantly higher than those in the peripheral blood of patients with benign thyroid disease and healthy volunteers （P 〈0.05）. However, there were no significant differences between patients with benign thyroid disease and healthy volunteers （P 〉0.05）. The accuracy of detection by both enzyme-linked immunosorbant assay and reverse-transcription polymerase chain reaction in the papillary thyroid cancer group was 83.33%. Conclusions The levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in the peripheral blood are helpful in identifying thyroid carcinoma and aid in preoperative assessment.