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.

Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence

Objective This study aimed to explore the association of single nucleotide polymorphisms(SNP)in the matrix metalloproteinase 2(MMP-2)signaling pathway and the risk of vascular senescence(VS).Methods In this cross-sectional study,between May and November 2022,peripheral venous blood of151 VS patients(case group)and 233 volunteers(control group)were collected.Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway,assessed through carotid-femoral pulse wave velocity(cf PWV),and analyzed using multivariate logistic regression.The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction(MDR)and generalized multifactor dimensionality regression(GMDR)modeling.Results Within the multivariate logistic regression models,four SNPs were screened to have significant associations with VS:chemokine(C-C motif)ligand 2(CCL2)rs4586,MMP2 rs14070,MMP2rs7201,and MMP2 rs1053605.Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype,and those of the T/T genotype had a19.375-fold increased risk.CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions.Conclusion CCL2 rs4586,MMP-2 rs14070,MMP-2 rs7201,and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

Diagnostic value of matrix metalloproteinases 2, 7 and 9 in urine for early detection of colorectal cancer

BACKGROUND A noninvasive biomarker with high diagnostic performance is urgently needed for the early diagnosis of colorectal cancer(CRC).AIM To evaluate the diagnostic value of matrix metalloproteinases(MMPs)2,7 and 9 in urine for CRC.METHODS Of 59 healthy controls,47 patients with colon polyps and 82 patients with CRC were included in this study.Carcinoembryonic antigen(CEA)in serum and MMP2,MMP7,and MMP9 in urine were detected.The combined diagnostic model of the indicators was established by binary logistic regression.The receiver operating characteristic curve(ROC)of the subjects was used to evaluate the independent and combined diagnostic value of the indicators.RESULTS The MMP2,MMP7,MMP9,and CEA levels in the CRC group differed significantly from levels in the healthy controls(P<0.05).The levels of MMP7,MMP9,and CEA also differed significantly between the CRC group and the colon polyps group(P<0.05).The area under the curve(AUC)distinguishing between the healthy control and the CRC patients using the joint model with CEA,MMP2,MMP7 and MMP9 was 0.977,and the sensitivity and specificity were 95.10%and 91.50%,respectively.For early-stage CRC,the AUC was 0.975,and the sensitivity and specificity were 94.30%and 98.30%,respectively.For advanced stage CRC,the AUC was 0.979,and the sensitivity and specificity were 95.70%and 91.50%,respectively.Using CEA,MMP7 and MMP9 to jointly established a model distinguishing the colorectal polyp group from the CRC group,the AUC was 0.849,and the sensitivity and specificity were 84.10%and 70.20%,respectively.For early-stage CRC,the AUC was 0.818,and the sensitivity and specificity were 76.30%and 72.30%,respectively.For advanced stage CRC,the AUC was 0.875,and the sensitivity and specificity were 81.80%and 72.30%,respectively.CONCLUSION MMP2,MMP7 and MMP 9 may exhibit diagnostic value for the early detection of CRC and may serve as auxiliary diagnostic markers for CRC.

Integrin αvβ6 and matrix metalloproteinase 9 correlate with survival in gastric cancer

AIM: To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients.METHODS: Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ2 test and Fisher’s exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis.RESULTS: The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007).CONCLUSION: The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

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.

Combined Detection of Serum Matrix Metalloproteinase 9,Acetyl Heparinase and Cathepsin L in Diagnosis of Ovarian Cancer

Objective： To investigate the clinic values of combining test of serum matrix metalloproteinase 9 （MMP-9）, acetyl heparinase （Hpa） and Cathepsin L （CL） in diagnosis of ovarian cancer. Methods： Serum levels of MMP-9, Hpa and CL were detected in a total of 418 cases, including 217 cases with ovarian malignant tumor, 100 cases with ovarian benign tumor and 101 healthy controls, by using enzyme-linked immunosorbent assay （ELISA）. Their correlation with clinicopathologic feature of ovarian malignant tumor was analyzed and their diagnosis performance was evaluated by receiver operating characteristic （ROC）. The combined diagnosis model was established by logistic regression analysis. Results： The serum levels of MMP-9, Hpa and CL were significantly higher in patients with ovarian malignant tumor than in benign tumor and healthy control, the serum levels of CL and Hpa were higher in epithelial cancer than in non-epithelial tumor, and MMP-9, Hpa and CL were elevated in low grade and advanced stage compared to high grade and early stage. The sensitivity for diagnosis of ovarian malignant tumor from high to low was CL, Hpa and MMP-9, and the specificity was MMP-9, CL and Hpa. The united diagnosis model was established and showed the sensitivity and specificity of combined detection were 84.6% and 82.1%, respectively, which were significantly higher than a single tumor marker. Conclusion： Serum MMP-9, Hpa and CL were correlated with ovarian malignant tumor and the combined detection of which may be valuable for clinical diagnosis of ovarian malignant tumor.

Matrix metalloproteinase 9 level as an indicator for restenosis following cervical and intracranial angioplasty and stenting

Cervical and intracranial angioplasty and stenting is an effective and safe method of reducing the risk of ischemic stroke, but it may be affected by in-stent restenosis. The present study in-vestigated serum level of matrix metalloproteinase 9 as a predictor of restenosis after 40 patients underwent cervical and/or intracranial angioplasty and stenting. Results showed that resteno-sis occurred in 30% （3/10） of patients when the serum level of matrix metalloproteinase 9 at 3 days after surgery was 2.5 times higher than preoperative level. No restenosis occurred when the serum level of matrix metalloproteinase 9 at 3 days after surgery was not 2.5 times higher than preoperative level. Restenosis occurred in 12% （2/17） of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for more than 30 days after surgery, but only occurred in 4% （1/23） of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for less than 30 days after surgery. However, the differences observed were not statistically signiifcant （P 〉 0.05）. Experimental ifndings indicate that when the serum level of matrix metalloproteinase 9 is 2.5 times higher than preoperative level at 3 days after cervi-cal and intracranial angioplasty and stenting, it may serve as a predictor of in-stent restenosis.

Picroside Ⅱ down-regulates matrix metalloproteinase-9 expression following cerebral ischemia/reperfusion injury in rats

Studies have shown that Picroside Ⅱ attenuates inflammatory reactions following brain ischemia through the inhibition of the TLR-4-NF-KB signal transduction pathway, and ameliorates cerebral edema through the reduction of aquaporin-4 expression. Matrix metalloproteinase-9 （MMP-9）, located downstream of the TLR-4-NF-KB signal transduction pathway, can degrade the neurovascular matrix, damage the blood-brain barrier to induce cerebral edema, and directly result in neuronal apoptosis and brain injury, Therefore, the present study further observed MMP-9 expression in the brain tissues of rats with cerebral ischemia/reperfusion injury following Picroside Ⅱ treatment. Results demonstrated that Picroside Ⅱ significantly reduced MMP-9 expression in ischemic brain tissues, as well as neuronal apoptosis and brain infarct volume, suggesting Picroside Ⅱ exhibits neuroprotection by down-regulating MMP-9 expression and inhibiting cell apoptosis.

Expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in brain tissue of diabetic rats with ischemia reperfusion

Objective: To discuss the expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in the brain tissue of diabetic rats with ischemia reperfusion. Methods: A total of 60 male Wistar rats were randomly divided into the normal group, sham group, diabetic cerebral infarction group and single cerebral infarction group according to the random number table, with 15 rats in each group. The high sucrose diet and intraperitoneal injection of streptozotocin were performed for the modeling of diabetic rats, while the thread-occlusion method was employed to build the model of cerebral ischemia reperfusion. The immunohistochemical staining was performed to detect the expression of angiostatin, vascular endothelial growth factor(VEGF) and matrix metalloproteinase-9(MMP-9) in the brain tissue. Results: The expression of angiostatin after the reperfusion in the brain tissue of rats in the single cerebral infarction group and diabetic cerebral infarction group was increased 6 h after the reperfusion, reached to the peak on 1 d and then decreased gradually. The expression of angiostatin in the diabetic cerebral infarction group 6 h, 1 d, 3 d and 7 d after the reperfusion was significantly higher than that in the single cerebral infarction group(P<0.05). VEGF began to be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak at 6 h and then decreased gradually. The expression of VEGF in the diabetic cerebral infarction group at each time point after the reperfusion was significantly lower than that in the single cerebral infarction group(P<0.05). MMP-9 began to be be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak on 1 d and then decreased gradually. The expression of MMP-9 in the diabetic cerebral infarction group at each time point after the reperfusion was significantly higher than that in the single cerebral infarction group(P<0.05). Conclusions: The high glucose environment in which the diabetic cerebral infarction is occurred is to induce the formation of MMP-9 at first and then activate and increase the expression of angiostatin. Afterwards, the expression of VEGF is inhibited, resulting in the poor angiogenesis after cerebral infarction, which thus makes the injury of brain tissue after cerebral infarction even worse than the non-diabetes mellitus.

High matrix metalloproteinase-9 expression induces angiogenesis and basement membrane degradation in stroke-prone spontaneously hypertensive rats after cerebral infarction

Basement membrane degradation and blood-brain barrier damage appear after cerebral infarc- tion, severely impacting neuronal and brain functioning; however, the underlying pathogenetic mechanisms remain poorly understood. In this study, we induced cerebral infarction in stroke- prone spontaneously hypertensive rats by intragastric administration of high-sodium water （1.3% NaC1） for 7 consecutive weeks. Immunohistochemical and immunofluorescence assays demonstrated that, compared with the non-infarcted contralateral hemisphere, stroke-prone spontaneously hypertensive rats on normal sodium intake and Wistar-Kyoto rats, matrix metalloproteinase-9 expression, the number of blood vessels with discontinuous collagen IV expression and microvessel density were significantly higher, and the number of continuous collagen IV-positive blood vessels was lower in the infarct border zones of stroke-prone sponta- neously hypertensive rats given high-sodium water. Linear correlation analysis showed matrix metalloproteinase-9 expression was positively correlated with the number of discontinuously collagen IV-labeled blood vessels and microvessel density in cerebral infarcts of stroke-prone spontaneously hypertensive rats. These results suggest that matrix metalloproteinase-9 upregula- tion is associated with increased regional angiogenesis and degradation of collagen IV, the major component of the basal lamina, in stroke-prone spontaneously hypertensive rats with high-sodi- um water-induced focal cerebral infarction.

Huoxue Rongluo Tablet reduces matrix metalloproteinase-9 expression in infarcted brain tissue

Huoxue Rongluo Tablet was made of tall gastrodis tuber, dahurian angelica root, honeysuckle stem, grassleaf sweetflag rhizome, common flowering quince fruit, figwort root, red peony root and peach seed at a ratio of 3：2：6：2：3：3：3：3. Huoxue Rongluo Tablet is a well-established and common pre- scription for the treatment of cerebral infarction. In this study, a rat model of cerebral ischemia was established and the animals were intragastrically administered Huoxue Rongluo Tablet. This treat- ment reduced infarct volume, decreased matrix metalloproteinase-9 expression, and improved neurological function. Moreover, the effects of Huoxue Rongluo Tablet were better than those of buflomedil pyridoxal phosphate. These results indicate that Huoxue Rongluo Tablet is effective in treating cerebral infarction by regulating matrix metalloproteinase-9 protein expression.

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.

Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice

AIM: To study whether matrix metalloproteinase-9 (MMP-9) is a key factor in epithelial damage in the dextran sodium sulphate (DSS) model of colitis in mice.METHODS: MMP-9-deficient and wild-type (wt) mice were given 5% DSS in drinking water for 5 d followed by recovery up to 7 d. On d 5 and 12 after induction of colitis, gelatinases, MMP-2 and MMP-9, were measured in homogenates of colonic tissue by zymography and Western blot, whereas tissue inhibitor of metalloproteinases (TIMPs) were measured by reverse zymography. The gelatinolytic activity was also determined in supernatants of polymorphonuclear leukocytes (PMN) isolated from mice blood. Moreover, intestinal epithelial cells were stimulated with TNF-α to study whether these cells were able to produce MMPs. Finally, colonic mucosal lesions were measured by microscopic examination. RESULTS: On d 5 of colitis, the activity of MMP-9 was increased in homogenates of colonic tissues (0.24 ± 0.1 vs 21.3 ± 6.4, P < 0.05) and PMN from peripheral blood in wt (0.5 ± 0.1 vs 10.4 ± 0.7, P < 0.05), but not in MMP-9-deficient animals. The MMP-9 activity was also up-regulated by TNF-α in epithelial intestinal cells (2.5 ± 0.5 vs 14.7 ± 3.0, P < 0.05). Although colitis also led to increase of TIMP-1 activity, the MMP-9/TIMP-1 balance remained elevated. Finally, in the MMP-9-deficient colitic mice both the extent and severity of intestinal epithelialinjury were significantly attenuated when compared with wt mice. CONCLUSION: We conclude that DSS induced colitis is markedly attenuated in animals lacking MMP-9. This suggests that intestinal injury induced by DSS is modu-lated by MMP-9 and that inhibition of this gelatinase may reduce inflammation.

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.

Inhibitive effect of triptolide on invasiveness of human fibrosarcoma cells by downregulating matrix metalloproteinase-9 expression

Objective:To explore the molecular mechanisms of antitumor properties of triptolide,a bioactive component isolated from the Chinese herb Tripterygium wolfordii Hook F.Methods:Human fibrosarcoma HT-1080 cells were treated with different doses of triptolide for 72 h.Then the expression and activity of matrix metalloproteinase(MMP)-2 and -9 were measured and the invasiveness of triptolide-treated HT-1080 cells was compared with that of anti-MMP-9- treated HT-1080 cells.Results:18 nmol/L triptolide inhibited the gene expression and activity of MMP-9,but not those of MMP-2,in HT-1080 cells.In addition,both 18 nmol/L triptolide and 3μg/mL anti-MMP-9 significantly reduced the invasive potential of HT-1080 cells,by about 50%and 35%, respectively,compared with the control.Whereas there was no significant difference between the effect of 18 nmol/L triptolide and that of anti-MMP-9 on invasive potential of HT-1080 cells. Conclusions:These data suggest that triptolide inhibits tumor cell invasion partly by reducing MMP-9 gene expression and activity.

Alterations of glutathione S-transferase and matrix metalloproteinase-9 expressions are early events in esophageal carcinogenesis

AIM: To investigate the role of glutathione S-transferase (GST) and matrix metalloproteinase-9 (MMP-9) expres-sions in the development and progression of reflux es-ophagitis-Barrett’s metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.METHODS: GST and MMP-9 expressions were analyzed in 51 paraffin-embedded tissue samples by immunohisto-chemistry including patients with reflux esophagitis (n = 7), Barrett’s metaplasia (n = 14), Barrett and esophagi-tis (n = 8), Barrett and dysplasia (n = 7), esophageal adenocarcinoma (n = 8) and a control group without any histological changes (n = 7). Immunostaining was determined semiquantitatively. Statistical analysis with one-way ANOVA, LSD test and correlation analysis were performed. P value of < 0.05 was considered significant.RESULTS: GST expression was significantly higher while MMP-9 expression was significantly lower in control group compared to Barrett’s metaplasia and the other groups. No major changes were observed between Bar-rett, esophagitis, and Barrett and concomitant esophagi-tis. Barrett and concomitant dysplasia, and adenocarci-noma revealed a significant lower expression of GST and higher levels of MMP-9 compared to all other groups. Adenocarcinoma showed almost no expression of GST and significantly higher levels of MMP-9 than Barrett and concomitant dysplasia. Alterations of GST and MMP-9 were inversely correlated (r = - 0.82).CONCLUSION: Decreased GST and increased ex-pression of MMP-9 in Barrett’s metaplasia-dysplasia-adenocarcinoma sequence as compared to normal tissue suggest their association with esophageal tumorigenesis. Loss of GST and gain of MMP-9 in Barrett with dyspla-sia compared to non-dysplastic metaplasia indicate that these alterations may be early events in carcinogenesis. Quantification of these parameters in Barrett’s esopha-gus might be useful to identify patients at higher risk for progression to cancer.

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 expression of matrix metalloproteinase 2, 9 (MMP 2, MMP 9), tissue inhibitor 1 of matrix metalloproteinase (TIMP 1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients 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 was close 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 expression of HER2/neu was found in patients with tumor recurrence( P <0.05). The expression of TIMP 1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non keratinizing SCC than that in basaloid SCC( P <0.05). These findings suggested that MMP 2 and MMP 9, HER2/neu and MMP 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 for poor prognosis in HNSCC.

Mild hypothermia effects on matrix metalloproteinase-9 expression in the perihematomal region of rats following experimental intracerebral hemorrhage

BACKGROUND： Matrix metalloproteinase-9 （MMP-9） expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTIVE： To investigate the effects of mild hypothermia on MMP-9 expression and brain edema in the perihematomal region of experimental intracerebral hemorrhage rats. DESIGN, TIME AND SETTING： The randomized, controlled experiment was performed at the Central Laboratory of Shandong Provincial Hospital between May and September 2007. MATERIALS： Seventy-two, Wistar, male rats, 12-weeks old, were used for this study. Rabbit anti-MMP-9 primary antibody was purchased from Boster, China. METHODS： Wistar rats were equally and randomly divided into normothermia and mild hypothermia groups. The two groups each comprised control, 6-hour intracerebral hemorrhage, 24-hour intracerebral hemorrhage, 48-hour intracerebral hemorrhage, 72-hour intracerebral hemorrhage, and l-week intracerebral hemorrhage subgroups, with six rats in each subgroup. Rat models of intracerebral hemorrhage were established by injecting 100 μL of autologous blood into the rat caudate nucleus. Rats in the mild hypothermia group received four hours of local mild hypothermia immediately following the injection. lntracerebral temperature was maintained at （33 ± 0.5） ℃. Subsequently, intracerebral temperature was spontaneously recovered at 25 ℃. Rats in the control subgroup were not injected with autologous blood and received only with intracerebral hemorrhage. MAIN OUTCOME MEASURES： Brain water content and MMP-9 expression surrounding the hematoma region. RESULTS： MMP-9 expression increased at 6 hours, and brain edema reached a peak at 48 hours after intracerebral hemorrhage. MMP-9 expression was significantly decreased in the mild hypothermia group compared with the normothermia group at each time point （P 〈 0.05）. CONCLUSION： Mild hypothermia can significantly inhibit MMP-9 overexpression and relieve brain edema following intracerebral hemorrhage.

Clinical significance of matrix metalloproteinase-9 expression in esophageal squamous cell carcinoma

AIM: To evaluate the expression of matrix metalloproteinase-9 (MMP-9) and its clinical significance in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of MMP-9 in 208 cases of ESCC was detected by immunohistochemistry (IHC) and its clinical significance in ESCC especially the relationship with the clinicopathological parameters was analyzed. RESULTS: The percentage of positive cases for MMP-9 detected by IHC was 49.0%. MMP-9 was mainly expressed in the cytoplasm of cancer cells especially in the invasive front. Only weak expression was detected in the stromal cells and no expression in non-cancerous mucosa. The expression of MMP-9 was positively correlated with poorer differentiation (P= 0.001<0.01), existence of vessel permeation (P= 0.027<0.05) and lymph node metastasis (P=0.027<0.05). CONCLUSION: The expression of MMP-9 correlates with the cancer cell differentiation, vessel permeation and lymph node metastasis. It may be a novel biomarker for the diagnosis and treatment of ESCC.

TNF-α Up-regulates Matrix Metalloproteinase-9 Expression and Activity in Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease

To study the effects of tumor necrosis factor （TNF）-α on matrix metalloproteinase （MMP）-9 expression and activity in alveolar macrophages （AM） and to investigate the role of NF-κB in the induction, AM were collected from bronchoalveolar lavage fluid （BALF） of healthy subjects and patients with chronic obstructive pulmonary disease （COPD）. MMP-9 expression and activity were detected by semi-quantitative reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting and zymography. NF-κB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9 expression and activity induced by TNF-α in AM from healthy subjects or patients with COPD were significantly increased in a dose-dependent manner （P〈0.05）. NF-κB activity induced by TNF-α was significantly increased in AM from patients with COPD, and pyrrolidine dithiocarbamate （PDTC） and N-acetyl-L-cysteine （NAC） significantly inhibited the activation of NF-κB induced by TNF-α （P〈0.05）. The presents study suggested that the expression and activity of MMP-9 from AM can be induced by TNF-α, and TNF-α/NF-κB signal pathway may play an important role in the induction.