AIM: To investigate the signal transduction mechanism of matrix metalloproteinase-9(MMP-9) mediated-vascular endothelial growth factor(VEGF) expression and retinal neovascularization(RNV) in oxygen-induced retinopathy...AIM: To investigate the signal transduction mechanism of matrix metalloproteinase-9(MMP-9) mediated-vascular endothelial growth factor(VEGF) expression and retinal neovascularization(RNV) in oxygen-induced retinopathy(OIR) model.METHODS: C57BL/6J mice were divided into four groups:control group, OIR group, OIR control group(phosphatebuffered saline by intravitreal injection) and treated group[tissue inhibitor of matrix metalloproteinase-1(TIMP-1)by intravitreal injection]. OIR model was established in C57BL/6J mice exposed to 75% ±2% oxygen for 5d.m RNA level and protein expression of MMP-9, TIMP-1and VEGF were measured by real-time polymerase chain reaction and Western blotting, and located by immunohistochemistry.RESULTS: Levels of MMP-9 and VEGF in retina were significantly increased in animals with OIR and OIR control group. Levels of TIMP-1 in retina was significantly reduced in animals with OIR and OIR control group. Furthermore, a significant correlation was found between MMP-9 and VEGF. Intravitreal injection of TIMP-1 significantly reduced MMP-9 and VEGF expression of the OIR mouse model(all P <0.05).CONCLUSION: These results demonstrate that MMP-9-mediated up-regulation of VEGF promotes RNV in retinopathy of prematurity(ROP). TIMP-1 may be a potential target for the prevention and treatment of ROP.展开更多
BACKGROUND Tubular adenocarcinoma of the colon,which originates from the epithelium of the glands,is a major health concern worldwide.However,it is difficult to detect at an early stage.The lack of biomarkers is a mai...BACKGROUND Tubular adenocarcinoma of the colon,which originates from the epithelium of the glands,is a major health concern worldwide.However,it is difficult to detect at an early stage.The lack of biomarkers is a main barrier to the diagnosis and treatment of tubular adenocarcinoma.Neutrophil gelatinase-associated lipocalin(NGAL)is a secreted protein that induces the expression of matrix metalloproteinase-9(MMP-9)and is involved in various tumors.NGAL and MMP-9 have been reported to be associated with tumorigenesis and development.They may have potential as biomarkers for diagnosis of tubular adenocarcinoma of the colon.AIM To determine whether NGAL and MMP-9 can be used as potential biomarkers to indicate the progression of tubular adenocarcinoma of the colon.METHODS Samples were collected from surgically excised tissue from various patients.The content of pro-gastrin-releasing peptide(pro-GRP)in the serum was measured by an electrochemiluminescence immunoassay.The expression patterns of NGAL and MMP-9 and the relationship between NGAL and MMP-9 were examined by quantitative real-time PCR,Western blotting and immunohistochemical analysis.RESULTS In this study,we found that NGAL and MMP-9 can be used as biomarkers for the detection of tubular adenocarcinoma of the colon and that their combination improved diagnostic accuracy.By analyzing the expression of NGAL in tubular adenocarcinoma at different levels,we found that NGAL expression was significantly upregulated in primary tubular adenocarcinoma tissues compared with normal tissues.The upregulation of NGAL expression was strongly correlated with both the degree of differentiation and the disease stage(I–III),indicating that NGAL could serve as a diagnostic biomarker for tubular adenocarcinoma.When using NGAL as a biomarker for diagnosis,the accuracy was similar to that achieved with the widely used biomarker pro-GRP,suggesting that NGAL is reliable.Moreover,the expression of MMP-9 was also strongly correlated with the differentiation stage,demonstrating that MMP-9 could be used as a biomarker to indicate the progression of tubular adenocarcinoma of the colon.More importantly,the combination of NGAL and MMP-9 produced a more accurate diagnosis of tubular adenocarcinoma,and these results were further confirmed by immunohistochemical analysis of tissue sections.CONCLUSION Our study demonstrated that both NGAL and MMP-9 can be used as biomarkers for the diagnosis of colon tubular adenocarcinoma and that the results could be further improved by combining them.展开更多
<strong>Background:</strong> <span style="font-family:Verdana;">Invasive breast cancer is the most common type of malignancy in women worldwide. Matrix Metalloproteinase</span><spa...<strong>Background:</strong> <span style="font-family:Verdana;">Invasive breast cancer is the most common type of malignancy in women worldwide. Matrix Metalloproteinase</span><span style="font-family:""><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 is a member of degrading enzymes required for tumor metastasis.</span><b><span style="font-family:Verdana;"> Aim: </span></b><span style="font-family:Verdana;">To assess the prognostic significance of the Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression in invasive breast cancer and its association with the clinicopathological features.</span><b><span style="font-family:Verdana;"> Patients and Methods: </span></b><span style="font-family:Verdana;">Cross-sectional study was conducted at the Oncology and Nuclear Therapy Unit, Suez Canal University Hospital. The study involved 33 females that were registered between January 1</span><sup><span style="font-family:Verdana;">st</span></sup><span style="font-family:Verdana;">, 2008 and December, 31</span><sup><span style="font-family:Verdana;">st</span></sup><span style="font-family:Verdana;">, 2012. The eligible participants had a confirmed non-metastatic invasive ductal carcinoma, underwent surgery that their paraffin blocks containing tumor were available. The participants’ tissue specimens were immune stained for Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;">9 expression level in the hospital pathology lab. Survival analysis and correlation models were conducted to explore the association between Matrix Metalloproteinase</span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression level with clinicopathological parameters and survival.</span><b><span style="font-family:Verdana;"> Results</span></b><span style="font-family:Verdana;">: The mean age of participants was 51.2 ± 9.9 years. The mortality rate was 18.2%. The mean Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression was 5.42 (±3.37);57.6% showed high expression level. There was no significant correlation with clinicopathological features. Nottingham Prognostic Index was a significant predictor of mortality. Overall survival and disease-free survival were insignificantly different among cases with low and high MMP-9 expression.</span><b><span style="font-family:Verdana;"> Conclusion: </span></b><span style="font-family:Verdana;">Tissue Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;">9 expression level does not play a significant role in disease progression. However, Nottingham Prognosis Index is a significant predictor of mortality among studied breast cancer cases.</span></span>展开更多
BACKGROUND Matrix metalloproteinases(MMPs),including MMP-9,are an integral part of the immune response and are upregulated in response to a variety of stimuli.New details continue to emerge concerning the mechanistic ...BACKGROUND Matrix metalloproteinases(MMPs),including MMP-9,are an integral part of the immune response and are upregulated in response to a variety of stimuli.New details continue to emerge concerning the mechanistic and regulatory pathways that mediate MMP-9 secretion.There is significant evidence for regulation of inflammation by dimethyl sulfoxide(DMSO)and 3',5'-cyclic adenosine monophosphate(cAMP),thus investigation of how these two molecules may regulate both MMP-9 and tumor necrosis factorα(TNFα)secretion by human monocytes was of high interest.The hypothesis tested in this study was that DMSO and cAMP regulate MMP-9 and TNFαsecretion by distinct mechanisms.AIM To investigate the regulation of lipopolysaccharide(LPS)-stimulated MMP-9 and tumor necrosis factorαsecretion in THP-1 human monocytes by dimethyl sulfoxide and cAMP.METHODS The paper describes a basic research study using THP-1 human monocyte cells.All experiments were conducted at the University of Missouri-St.Louis in the Department of Chemistry and Biochemistry.Human monocyte cells were grown,cultured,and prepared for experiments in the University of Missouri-St.Louis Cell Culture Facility as per accepted guidelines.Cells were treated with LPS for selected exposure times and the conditioned medium was collected for analysis of MMP-9 and TNFαproduction.Inhibitors including DMSO,cAMP regulators,and anti-TNFαantibody were added to the cells prior to LPS treatment.MMP-9 secretion was analyzed by gel electrophoresis/western blot and quantitated by ImageJ software.TNFαsecretion was analyzed by enzyme-linked immuno sorbent assay.All data is presented as the average and standard error for at least 3 trials.Statistical analysis was done using a two-tailed paired Student t-test.P values less than 0.05 were considered significant and designated as such in the Figures.LPS and cAMP regulators were from Sigma-Aldrich,MMP-9 standard and antibody and TNFαantibodies were from R&D Systems,and amyloid-βpeptide was from rPeptide.RESULTS In our investigation of MMP-9 secretion from THP-1 human monocytes,we made the following findings.Inclusion of DMSO in the cell treatment inhibited LPSinduced MMP-9,but not TNFα,secretion.Inclusion of DMSO in the cell treatment at different concentrations inhibited LPS-induced MMP-9 secretion in a dosedependent fashion.A cell-permeable cAMP analog,dibutyryl cAMP,inhibited both LPS-induced MMP-9 and TNFαsecretion.Pretreatment of the cells with the adenylyl cyclase activator forskolin inhibited LPS-induced MMP-9 and TNFαsecretion.Pretreatment of the cells with the general cAMP phosphodiesterase inhibitor IBMX reduced LPS-induced MMP-9 and TNFαin a dose-dependent fashion.Pre-treatment of monocytes with an anti-TNFαantibody blocked LPSinduced MMP-9 and TNFαsecretion.Amyloid-βpeptide induced MMP-9 secretion,which occurred much later than TNFαsecretion.The latter two findings strongly suggested an upstream role for TNFαin mediating LPS-stimulate MMP-9 secretion.CONCLUSION The cumulative data indicated that MMP-9 secretion was a distinct process from TNFαsecretion and occurred downstream.First,DMSO inhibited MMP-9,but not TNFα,suggesting that the MMP-9 secretion process was selectively altered.Second,cAMP inhibited both MMP-9 and TNFαwith a similar potency,but at different monocyte cell exposure time points.The pattern of cAMP inhibition for these two molecules suggested that MMP-9 secretion lies downstream of TNFαand that TNFαmay a key component of the pathway leading to MMP-9 secretion.This temporal relationship fit a model whereby early TNFαsecretion directly led to later MMP-9 secretion.Lastly,antibody-blocking of TNFαdiminished MMP-9 secretion,suggesting a direct link between TNFαsecretion and MMP-9 secretion.展开更多
Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction and progressive expansion of the abdominal aortic wall. An AAA is typically defined as an enlargement of the abdominal aorta with ...Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction and progressive expansion of the abdominal aortic wall. An AAA is typically defined as an enlargement of the abdominal aorta with diameter ≥3 cm or ≥50% greater than the suprarenal diameter. The pathological changes associated with AAA include inflammatory cell infiltration, extracellular matrix (ECM) destruction and remodeling, and vascular smooth muscle cell loss. The matrix metalloproteinase (MMP) family of proteins plays an important role in initiation and progression of AAA. Since understanding the regulation of MMP-2 and MMP-9 in AAA is essential for treatment of AAA, this review summarized the regulatory mechanisms of MMPs to provide a reference for exploring novel therapeutic approaches.展开更多
BACKGROUND Alpha-L-fucosidase-1(FUCA1)has been demonstrated to play opposing regulatory roles in adenocarcinoma and non-adenocarcinoma.Moreover,recent studies reported that FUCA1 could decrease the invasion capability...BACKGROUND Alpha-L-fucosidase-1(FUCA1)has been demonstrated to play opposing regulatory roles in adenocarcinoma and non-adenocarcinoma.Moreover,recent studies reported that FUCA1 could decrease the invasion capability by downregulating matrix metalloproteinase 9(MMP-9)expression.However,the potential role and prognostic significance of FUCA1 in esophageal squamous cell carcinoma(ESCC)have not yet been explored.AIM To evaluate the status,association,and prognostic value of FUCA1 and MMP-9 expression in ESCC.METHODS Patients who underwent esophagectomy for ESCC between January 1,2014,and December 31,2014 at Sun Yat-Sen University Cancer Center were enrolled.The expression status of FUCA1 and MMP-9 in cancerous tissues was detected using immunohistochemistry.In addition,the expression profiles of the FUCA1 and MMP-9 genes in non-metastatic ESCC were extracted from The Cancer Genome Atlas(TCGA)database.RESULTS High expression of FUCA1 and MMP-9 was found in 90 patients(75.6%)and 62 patients(52.1%),respectively.In the high FUCA1 expression group,the constituent ratios of patients with stage III disease(61.1%vs 37.9%,P=0.029),lymphatic invasion(62.2%vs 31.0%,P=0.003),and high MMP-9 expression(60.0%vs 27.6%,P=0.002)were significantly higher than those in the low FUCA1 expression group.In Kaplan-Meier univariate analysis,advanced tumor-nodemetastasis stage(III,P=0.001),positive regional lymph node metastasis(N+,P=0.002),high FUCA1 expression(P=0.001),and high MMP-9 expression(P=0.002)were potential predictors of shorter overall survival(OS),which was similar to the results analyzed based on the TCGA database.Further Cox multivariate regression analyses still demonstrated that FUCA1 and MMP-9 expression levels were independent prognostic factors of OS[hazard ratio(HR):0.484,95%confidence interval(CI):0.239-0.979;P=0.044;and HR:0.591,95%CI:0.359-0.973,P=0.039,respectively].CONCLUSION FUCA1 cooperation with MMP-9 may have a major role in affecting the ESCC invasion and metastatic capability,and serve as a valuable prognostic biomarker in ESCC.展开更多
Objective To conduct a case-control study on the association of the nucleotide polymorphisms in the promoter region of the matrix metalloproteinase-9(MMP-9)gene with phenotype of esophageal cancer.Methods All subjects...Objective To conduct a case-control study on the association of the nucleotide polymorphisms in the promoter region of the matrix metalloproteinase-9(MMP-9)gene with phenotype of esophageal cancer.Methods All subjects were unrelated residents in northern regions of China.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)analysis was used to determine the MMP-9 genotypes.Results The overall distribution of genotypes in the patients was not different from that in the controls(OR=0.77,95% CI=0.45-1.34;P=0.36).There were no significant differences between the patients and the control subjects in terms of the distributions of sex and age,smoking status,alcohol dependence,pickled diet status,or history of environmental exposure.The patients were further examined with stratifications by age,sex,grade,depth of tumor invasion,lymphatic invasion,venous invasion and TNM staging.The results showed no pronounced association among the stratifications.Conclusion There is no significant association between the MMP-9 single nucleotide polymorphism genotypes and phenotype of esophageal cancer.展开更多
Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation ...Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.展开更多
Objective:Human Pygopus 2(Pygo2)was recently discovered to be a component of the Wnt signaling pathway required for b-catenin/Tcf-mediated transcription.But the role of Pygo2 in malignant cell proliferation and invasi...Objective:Human Pygopus 2(Pygo2)was recently discovered to be a component of the Wnt signaling pathway required for b-catenin/Tcf-mediated transcription.But the role of Pygo2 in malignant cell proliferation and invasion has not yet been determined.Methods:Lentivirus-mediated small interfering RNA(siRNA)and vector-based overexpression were used to study the function of Pygo2 in OS-RC-2 cells.The resulted cells were subject to Western blotting assay,MTT assay,colony formation and cell invasion assays.Furthermore,renal cell carcinoma(RCC)models were established in BALB/c nude mice inoculated with OS-RC-2 cells.Immunohistochemistry(IHC)staining of matrix metalloproteinase-7(MMP-7),matrix metalloproteinase-9(MMP-9)and vascular endothelial growth factor(VEGF)was performed in tumor tissue.Results:Pygo2 gene was successful knocked down and overexpressed in RCC OS-RC-2 cells by using an shRNA and overexpressing vector,respectively.Overexpression of Pygo2 effectively promoted cell proliferation,colony formation and invasion in vitro.Knockdown of Pygo2 obviously inhibited xenograft tumor growth in nude mice.In addition,overexpression of Pygo2 increased the levels of MMP-7,MMP-9 and VEGF in the xenograft tumors.Conclusion:Pygo2 has a role in promoting cell proliferation,invasion and metastasis,and may regulate angiogenesis via the Wnt/b-catenin signaling pathway.展开更多
Ds-echinoside A (DSEA),a non-sulfated triterpene glycoside,was isolated from the sea cucumber Pearsonothuria graeffei.In vitro and in vivo investigations were conducted on the effects of DSEA on tumor cell adhesion,mi...Ds-echinoside A (DSEA),a non-sulfated triterpene glycoside,was isolated from the sea cucumber Pearsonothuria graeffei.In vitro and in vivo investigations were conducted on the effects of DSEA on tumor cell adhesion,migration,invasion,and angiogenesis.In this study,we found that DSEA inhibited the proliferation of human hepatocellular liver carcinoma cells Hep G2,with a half-maximal inhibitory concentration (IC50) of 2.65 μmol/L,and suppressed Hep G2 cell adhesion,migration,and invasion in a dose-dependent manner.DSEA also reduced tube formation of human endothelial cells ECV-304 on matrigel in vitro and attenuated neovascularization in the chick embryo chorioallantoic membrane (CAM) assay in vivo.Immunocytochemical analysis revealed that DSEA significantly decreased the expression of matrix metalloproteinase-9 (MMP-9),which plays an important role in the degradation of basement membrane in tumor metastasis and angiogenesis.DSEA also increased the protein expression level of tissue inhibitor of metalloproteinase-1 (TIMP-1),an important regulator of MMP-9 activation.From the results of Western blotting,the expressions of nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) were found to be remarkably reduced by DSEA.These findings suggest that DSEA exhibits a significant antimetastatic activity through the specific inhibition of NF-κB-dependent MMP-9 and VEGF expressions.展开更多
The invasion and metastasis of breast cancer are supposed to involve several stages in which epithelial-mesenchymal transition(EMT)is regarded as the mechan-istic basis for the behavior of cancer cells.A series of fac...The invasion and metastasis of breast cancer are supposed to involve several stages in which epithelial-mesenchymal transition(EMT)is regarded as the mechan-istic basis for the behavior of cancer cells.A series of factors related to EMT are apparently involved in such process.The current study aimed to investigate the contributions of EMT and related factors in lymph node metastasis of breast cancer.The expressions of E-cadherin(E-Cad),N-cadherin(N-Cad),vascular endothelial cell growth factor(VEGF),matrix metalloproteinase-9(MMP-9),cyclooxygenase-2(COX-2),and CD34 were examined in 74 cases of breast cancer,including 39 cases with lymph node metastasis and 35 cases without lymph node metastasis by immunohistochemistry.Multivariable Cox proportional hazards model was used to analyze the patients’prognosis.The expressions of N-Cad,VEGF,MMP-9,and COX-2 in cases with lymph node metastasis were significantly higher than those without lymph node metastasis(P<0.05),while the E-Cad level was inversely related to status of lymph node metastasis(P<0.05).The metastasis rate of lymph node in the cases with EMT(lower E-Cad expression and higher N-Cad expression)was 78.3%,while that without EMT(higher E-Cad expression and lower N-Cad expression)was 11.1%.There was a statistical difference in the expression of COX-2 protein between histological grade I and grade II or III,respectively(P<0.05).In the cases with higher grade,the expression of E-Cad was decreased,while that of N-Cad was increased.Higher microvascular density(MVD)was also found to be significantly associated with lymphatic metastasis(P<0.05),and the cases with higher MVD had shorter survival time.This study indicates that EMT and expressions of VEGF,MMP-9 and COX-2,and MVD value are strongly correlated with lymph node metastasis in breast cancer.展开更多
Objective: To evaluate the effect of baicalin on subarachnoid hemorrhage(SAH) in rats and explore the potential mechanisms. Methods: Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin ...Objective: To evaluate the effect of baicalin on subarachnoid hemorrhage(SAH) in rats and explore the potential mechanisms. Methods: Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin at 10 or 50 mg/kg after 2 and 12 h of SAH. Neurological scores, brain water content, Evans-blue extravasation, and levels of glutathione peroxidase(GSH-Px), superoxide dismutase(SOD), myeloperoxidase(MPO), and malondialdehyde(MDA) were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2(Nrf2), NAD(P)H: quinone oxidoreductase 1(NQO1), matrix metalloproteinase-9(MMP-9), aquaporin 4(AQP4), occludin, and zonulaoccludens-1(ZO-1) were detected in the brain by Western blot. Heme oxygenase-1(HO-1) was detected by quantitative polymerase chain reaction, and tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) were assessed by enzyme-linked immunosorbent assay. Results: Baicalin attenuated EBI 24 h after SAH in rats(P<0.05). Baicalin elevated neurological scores, GSH-Px, SOD, and increased the expression of Nrf2, NQO1, HO-1, occludin, and ZO-1 in SAH rats(P<0.05 or P<0.01). Baicalin reduced MPO, MDA, and the expression of MMP-9, AQP4, TNF-α, and IL-1β(P<0.05 or P<0.01). Conclusion: Baicalin reduced SAH-induced EBI, partially via activation of the Nrf2/HO-1 pathway and inhibition of MMP-9 and AQP4.展开更多
基金Supported by National Natural Science Foundation of China (No.81371045)Science and Technology Project of Shenyang City, China (No.F13-220-9-37)
文摘AIM: To investigate the signal transduction mechanism of matrix metalloproteinase-9(MMP-9) mediated-vascular endothelial growth factor(VEGF) expression and retinal neovascularization(RNV) in oxygen-induced retinopathy(OIR) model.METHODS: C57BL/6J mice were divided into four groups:control group, OIR group, OIR control group(phosphatebuffered saline by intravitreal injection) and treated group[tissue inhibitor of matrix metalloproteinase-1(TIMP-1)by intravitreal injection]. OIR model was established in C57BL/6J mice exposed to 75% ±2% oxygen for 5d.m RNA level and protein expression of MMP-9, TIMP-1and VEGF were measured by real-time polymerase chain reaction and Western blotting, and located by immunohistochemistry.RESULTS: Levels of MMP-9 and VEGF in retina were significantly increased in animals with OIR and OIR control group. Levels of TIMP-1 in retina was significantly reduced in animals with OIR and OIR control group. Furthermore, a significant correlation was found between MMP-9 and VEGF. Intravitreal injection of TIMP-1 significantly reduced MMP-9 and VEGF expression of the OIR mouse model(all P <0.05).CONCLUSION: These results demonstrate that MMP-9-mediated up-regulation of VEGF promotes RNV in retinopathy of prematurity(ROP). TIMP-1 may be a potential target for the prevention and treatment of ROP.
基金Shandong Key Research and Development Plan,No.2016GSF201020.
文摘BACKGROUND Tubular adenocarcinoma of the colon,which originates from the epithelium of the glands,is a major health concern worldwide.However,it is difficult to detect at an early stage.The lack of biomarkers is a main barrier to the diagnosis and treatment of tubular adenocarcinoma.Neutrophil gelatinase-associated lipocalin(NGAL)is a secreted protein that induces the expression of matrix metalloproteinase-9(MMP-9)and is involved in various tumors.NGAL and MMP-9 have been reported to be associated with tumorigenesis and development.They may have potential as biomarkers for diagnosis of tubular adenocarcinoma of the colon.AIM To determine whether NGAL and MMP-9 can be used as potential biomarkers to indicate the progression of tubular adenocarcinoma of the colon.METHODS Samples were collected from surgically excised tissue from various patients.The content of pro-gastrin-releasing peptide(pro-GRP)in the serum was measured by an electrochemiluminescence immunoassay.The expression patterns of NGAL and MMP-9 and the relationship between NGAL and MMP-9 were examined by quantitative real-time PCR,Western blotting and immunohistochemical analysis.RESULTS In this study,we found that NGAL and MMP-9 can be used as biomarkers for the detection of tubular adenocarcinoma of the colon and that their combination improved diagnostic accuracy.By analyzing the expression of NGAL in tubular adenocarcinoma at different levels,we found that NGAL expression was significantly upregulated in primary tubular adenocarcinoma tissues compared with normal tissues.The upregulation of NGAL expression was strongly correlated with both the degree of differentiation and the disease stage(I–III),indicating that NGAL could serve as a diagnostic biomarker for tubular adenocarcinoma.When using NGAL as a biomarker for diagnosis,the accuracy was similar to that achieved with the widely used biomarker pro-GRP,suggesting that NGAL is reliable.Moreover,the expression of MMP-9 was also strongly correlated with the differentiation stage,demonstrating that MMP-9 could be used as a biomarker to indicate the progression of tubular adenocarcinoma of the colon.More importantly,the combination of NGAL and MMP-9 produced a more accurate diagnosis of tubular adenocarcinoma,and these results were further confirmed by immunohistochemical analysis of tissue sections.CONCLUSION Our study demonstrated that both NGAL and MMP-9 can be used as biomarkers for the diagnosis of colon tubular adenocarcinoma and that the results could be further improved by combining them.
文摘<strong>Background:</strong> <span style="font-family:Verdana;">Invasive breast cancer is the most common type of malignancy in women worldwide. Matrix Metalloproteinase</span><span style="font-family:""><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 is a member of degrading enzymes required for tumor metastasis.</span><b><span style="font-family:Verdana;"> Aim: </span></b><span style="font-family:Verdana;">To assess the prognostic significance of the Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression in invasive breast cancer and its association with the clinicopathological features.</span><b><span style="font-family:Verdana;"> Patients and Methods: </span></b><span style="font-family:Verdana;">Cross-sectional study was conducted at the Oncology and Nuclear Therapy Unit, Suez Canal University Hospital. The study involved 33 females that were registered between January 1</span><sup><span style="font-family:Verdana;">st</span></sup><span style="font-family:Verdana;">, 2008 and December, 31</span><sup><span style="font-family:Verdana;">st</span></sup><span style="font-family:Verdana;">, 2012. The eligible participants had a confirmed non-metastatic invasive ductal carcinoma, underwent surgery that their paraffin blocks containing tumor were available. The participants’ tissue specimens were immune stained for Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;">9 expression level in the hospital pathology lab. Survival analysis and correlation models were conducted to explore the association between Matrix Metalloproteinase</span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression level with clinicopathological parameters and survival.</span><b><span style="font-family:Verdana;"> Results</span></b><span style="font-family:Verdana;">: The mean age of participants was 51.2 ± 9.9 years. The mortality rate was 18.2%. The mean Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span><span style="font-family:Verdana;">9 expression was 5.42 (±3.37);57.6% showed high expression level. There was no significant correlation with clinicopathological features. Nottingham Prognostic Index was a significant predictor of mortality. Overall survival and disease-free survival were insignificantly different among cases with low and high MMP-9 expression.</span><b><span style="font-family:Verdana;"> Conclusion: </span></b><span style="font-family:Verdana;">Tissue Matrix Metalloproteinase</span></span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;">9 expression level does not play a significant role in disease progression. However, Nottingham Prognosis Index is a significant predictor of mortality among studied breast cancer cases.</span></span>
基金Supported by The University of Missouri-St.Louis,Alzheimer’s Association,No.NIRG-06-27267the Missouri Alzheimer’s and Related Disorders Research Program.
文摘BACKGROUND Matrix metalloproteinases(MMPs),including MMP-9,are an integral part of the immune response and are upregulated in response to a variety of stimuli.New details continue to emerge concerning the mechanistic and regulatory pathways that mediate MMP-9 secretion.There is significant evidence for regulation of inflammation by dimethyl sulfoxide(DMSO)and 3',5'-cyclic adenosine monophosphate(cAMP),thus investigation of how these two molecules may regulate both MMP-9 and tumor necrosis factorα(TNFα)secretion by human monocytes was of high interest.The hypothesis tested in this study was that DMSO and cAMP regulate MMP-9 and TNFαsecretion by distinct mechanisms.AIM To investigate the regulation of lipopolysaccharide(LPS)-stimulated MMP-9 and tumor necrosis factorαsecretion in THP-1 human monocytes by dimethyl sulfoxide and cAMP.METHODS The paper describes a basic research study using THP-1 human monocyte cells.All experiments were conducted at the University of Missouri-St.Louis in the Department of Chemistry and Biochemistry.Human monocyte cells were grown,cultured,and prepared for experiments in the University of Missouri-St.Louis Cell Culture Facility as per accepted guidelines.Cells were treated with LPS for selected exposure times and the conditioned medium was collected for analysis of MMP-9 and TNFαproduction.Inhibitors including DMSO,cAMP regulators,and anti-TNFαantibody were added to the cells prior to LPS treatment.MMP-9 secretion was analyzed by gel electrophoresis/western blot and quantitated by ImageJ software.TNFαsecretion was analyzed by enzyme-linked immuno sorbent assay.All data is presented as the average and standard error for at least 3 trials.Statistical analysis was done using a two-tailed paired Student t-test.P values less than 0.05 were considered significant and designated as such in the Figures.LPS and cAMP regulators were from Sigma-Aldrich,MMP-9 standard and antibody and TNFαantibodies were from R&D Systems,and amyloid-βpeptide was from rPeptide.RESULTS In our investigation of MMP-9 secretion from THP-1 human monocytes,we made the following findings.Inclusion of DMSO in the cell treatment inhibited LPSinduced MMP-9,but not TNFα,secretion.Inclusion of DMSO in the cell treatment at different concentrations inhibited LPS-induced MMP-9 secretion in a dosedependent fashion.A cell-permeable cAMP analog,dibutyryl cAMP,inhibited both LPS-induced MMP-9 and TNFαsecretion.Pretreatment of the cells with the adenylyl cyclase activator forskolin inhibited LPS-induced MMP-9 and TNFαsecretion.Pretreatment of the cells with the general cAMP phosphodiesterase inhibitor IBMX reduced LPS-induced MMP-9 and TNFαin a dose-dependent fashion.Pre-treatment of monocytes with an anti-TNFαantibody blocked LPSinduced MMP-9 and TNFαsecretion.Amyloid-βpeptide induced MMP-9 secretion,which occurred much later than TNFαsecretion.The latter two findings strongly suggested an upstream role for TNFαin mediating LPS-stimulate MMP-9 secretion.CONCLUSION The cumulative data indicated that MMP-9 secretion was a distinct process from TNFαsecretion and occurred downstream.First,DMSO inhibited MMP-9,but not TNFα,suggesting that the MMP-9 secretion process was selectively altered.Second,cAMP inhibited both MMP-9 and TNFαwith a similar potency,but at different monocyte cell exposure time points.The pattern of cAMP inhibition for these two molecules suggested that MMP-9 secretion lies downstream of TNFαand that TNFαmay a key component of the pathway leading to MMP-9 secretion.This temporal relationship fit a model whereby early TNFαsecretion directly led to later MMP-9 secretion.Lastly,antibody-blocking of TNFαdiminished MMP-9 secretion,suggesting a direct link between TNFαsecretion and MMP-9 secretion.
基金supported by the Natural Science Foundation of China (82070875,82070300).
文摘Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction and progressive expansion of the abdominal aortic wall. An AAA is typically defined as an enlargement of the abdominal aorta with diameter ≥3 cm or ≥50% greater than the suprarenal diameter. The pathological changes associated with AAA include inflammatory cell infiltration, extracellular matrix (ECM) destruction and remodeling, and vascular smooth muscle cell loss. The matrix metalloproteinase (MMP) family of proteins plays an important role in initiation and progression of AAA. Since understanding the regulation of MMP-2 and MMP-9 in AAA is essential for treatment of AAA, this review summarized the regulatory mechanisms of MMPs to provide a reference for exploring novel therapeutic approaches.
基金the Research Ethics Committee at the Sun Yat-Sen University Cancer Center(No.B2014-110)Shenzhen KeyMedical Discipline ConstructionFund, No. SZXK075and theSanming Project of Medicine inShenzhen, No. SZSM201612097.
文摘BACKGROUND Alpha-L-fucosidase-1(FUCA1)has been demonstrated to play opposing regulatory roles in adenocarcinoma and non-adenocarcinoma.Moreover,recent studies reported that FUCA1 could decrease the invasion capability by downregulating matrix metalloproteinase 9(MMP-9)expression.However,the potential role and prognostic significance of FUCA1 in esophageal squamous cell carcinoma(ESCC)have not yet been explored.AIM To evaluate the status,association,and prognostic value of FUCA1 and MMP-9 expression in ESCC.METHODS Patients who underwent esophagectomy for ESCC between January 1,2014,and December 31,2014 at Sun Yat-Sen University Cancer Center were enrolled.The expression status of FUCA1 and MMP-9 in cancerous tissues was detected using immunohistochemistry.In addition,the expression profiles of the FUCA1 and MMP-9 genes in non-metastatic ESCC were extracted from The Cancer Genome Atlas(TCGA)database.RESULTS High expression of FUCA1 and MMP-9 was found in 90 patients(75.6%)and 62 patients(52.1%),respectively.In the high FUCA1 expression group,the constituent ratios of patients with stage III disease(61.1%vs 37.9%,P=0.029),lymphatic invasion(62.2%vs 31.0%,P=0.003),and high MMP-9 expression(60.0%vs 27.6%,P=0.002)were significantly higher than those in the low FUCA1 expression group.In Kaplan-Meier univariate analysis,advanced tumor-nodemetastasis stage(III,P=0.001),positive regional lymph node metastasis(N+,P=0.002),high FUCA1 expression(P=0.001),and high MMP-9 expression(P=0.002)were potential predictors of shorter overall survival(OS),which was similar to the results analyzed based on the TCGA database.Further Cox multivariate regression analyses still demonstrated that FUCA1 and MMP-9 expression levels were independent prognostic factors of OS[hazard ratio(HR):0.484,95%confidence interval(CI):0.239-0.979;P=0.044;and HR:0.591,95%CI:0.359-0.973,P=0.039,respectively].CONCLUSION FUCA1 cooperation with MMP-9 may have a major role in affecting the ESCC invasion and metastatic capability,and serve as a valuable prognostic biomarker in ESCC.
基金supported by the Development Funding of Xi'an(No.YF07171/05/04/2007)
文摘Objective To conduct a case-control study on the association of the nucleotide polymorphisms in the promoter region of the matrix metalloproteinase-9(MMP-9)gene with phenotype of esophageal cancer.Methods All subjects were unrelated residents in northern regions of China.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)analysis was used to determine the MMP-9 genotypes.Results The overall distribution of genotypes in the patients was not different from that in the controls(OR=0.77,95% CI=0.45-1.34;P=0.36).There were no significant differences between the patients and the control subjects in terms of the distributions of sex and age,smoking status,alcohol dependence,pickled diet status,or history of environmental exposure.The patients were further examined with stratifications by age,sex,grade,depth of tumor invasion,lymphatic invasion,venous invasion and TNM staging.The results showed no pronounced association among the stratifications.Conclusion There is no significant association between the MMP-9 single nucleotide polymorphism genotypes and phenotype of esophageal cancer.
基金supported by the National Natural Science Foundation of China,Nos.81802232(to JXW),81801170(to YHT),82071284(to YHT),2019YFA0112000(to YHT)the Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)+1 种基金Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY)Science and Technology Commission of Shanghai,No.19441907900(to JFS).
文摘Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.
基金supported by grants(No.2011J01254)from Natural Science Foundation of Fujian Province.
文摘Objective:Human Pygopus 2(Pygo2)was recently discovered to be a component of the Wnt signaling pathway required for b-catenin/Tcf-mediated transcription.But the role of Pygo2 in malignant cell proliferation and invasion has not yet been determined.Methods:Lentivirus-mediated small interfering RNA(siRNA)and vector-based overexpression were used to study the function of Pygo2 in OS-RC-2 cells.The resulted cells were subject to Western blotting assay,MTT assay,colony formation and cell invasion assays.Furthermore,renal cell carcinoma(RCC)models were established in BALB/c nude mice inoculated with OS-RC-2 cells.Immunohistochemistry(IHC)staining of matrix metalloproteinase-7(MMP-7),matrix metalloproteinase-9(MMP-9)and vascular endothelial growth factor(VEGF)was performed in tumor tissue.Results:Pygo2 gene was successful knocked down and overexpressed in RCC OS-RC-2 cells by using an shRNA and overexpressing vector,respectively.Overexpression of Pygo2 effectively promoted cell proliferation,colony formation and invasion in vitro.Knockdown of Pygo2 obviously inhibited xenograft tumor growth in nude mice.In addition,overexpression of Pygo2 increased the levels of MMP-7,MMP-9 and VEGF in the xenograft tumors.Conclusion:Pygo2 has a role in promoting cell proliferation,invasion and metastasis,and may regulate angiogenesis via the Wnt/b-catenin signaling pathway.
基金Project supported by the National High-Tech R & D Program (863) of China (No. 2007AA091805)and the National Natural Science Foundation of China (Nos. 30972284 and 30871944)
文摘Ds-echinoside A (DSEA),a non-sulfated triterpene glycoside,was isolated from the sea cucumber Pearsonothuria graeffei.In vitro and in vivo investigations were conducted on the effects of DSEA on tumor cell adhesion,migration,invasion,and angiogenesis.In this study,we found that DSEA inhibited the proliferation of human hepatocellular liver carcinoma cells Hep G2,with a half-maximal inhibitory concentration (IC50) of 2.65 μmol/L,and suppressed Hep G2 cell adhesion,migration,and invasion in a dose-dependent manner.DSEA also reduced tube formation of human endothelial cells ECV-304 on matrigel in vitro and attenuated neovascularization in the chick embryo chorioallantoic membrane (CAM) assay in vivo.Immunocytochemical analysis revealed that DSEA significantly decreased the expression of matrix metalloproteinase-9 (MMP-9),which plays an important role in the degradation of basement membrane in tumor metastasis and angiogenesis.DSEA also increased the protein expression level of tissue inhibitor of metalloproteinase-1 (TIMP-1),an important regulator of MMP-9 activation.From the results of Western blotting,the expressions of nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) were found to be remarkably reduced by DSEA.These findings suggest that DSEA exhibits a significant antimetastatic activity through the specific inhibition of NF-κB-dependent MMP-9 and VEGF expressions.
文摘The invasion and metastasis of breast cancer are supposed to involve several stages in which epithelial-mesenchymal transition(EMT)is regarded as the mechan-istic basis for the behavior of cancer cells.A series of factors related to EMT are apparently involved in such process.The current study aimed to investigate the contributions of EMT and related factors in lymph node metastasis of breast cancer.The expressions of E-cadherin(E-Cad),N-cadherin(N-Cad),vascular endothelial cell growth factor(VEGF),matrix metalloproteinase-9(MMP-9),cyclooxygenase-2(COX-2),and CD34 were examined in 74 cases of breast cancer,including 39 cases with lymph node metastasis and 35 cases without lymph node metastasis by immunohistochemistry.Multivariable Cox proportional hazards model was used to analyze the patients’prognosis.The expressions of N-Cad,VEGF,MMP-9,and COX-2 in cases with lymph node metastasis were significantly higher than those without lymph node metastasis(P<0.05),while the E-Cad level was inversely related to status of lymph node metastasis(P<0.05).The metastasis rate of lymph node in the cases with EMT(lower E-Cad expression and higher N-Cad expression)was 78.3%,while that without EMT(higher E-Cad expression and lower N-Cad expression)was 11.1%.There was a statistical difference in the expression of COX-2 protein between histological grade I and grade II or III,respectively(P<0.05).In the cases with higher grade,the expression of E-Cad was decreased,while that of N-Cad was increased.Higher microvascular density(MVD)was also found to be significantly associated with lymphatic metastasis(P<0.05),and the cases with higher MVD had shorter survival time.This study indicates that EMT and expressions of VEGF,MMP-9 and COX-2,and MVD value are strongly correlated with lymph node metastasis in breast cancer.
基金Supported by the Project of Medical Innovation of Health and Family Planning Commision of Fujian Province of China (No. 2016-CX-18)the Natural Science Foundation of Fujian Province of China (No. 2017J01204)+3 种基金the Key Young Talents Cultivation Project of Health and Family Planning Commision of Fujian Province of China (No. 2016-ZQN-28)the Excellent Youth Scientific Research Personnel Cultivation Program of Fujian Province’s High School (No. 2016B026)the Clinical Key Subject (Neurosurgery) Foundation of Fujian Medical Universitythe Key Department (Neurosurgery) Foundation from Fujian Medical University Union Hospital,China。
文摘Objective: To evaluate the effect of baicalin on subarachnoid hemorrhage(SAH) in rats and explore the potential mechanisms. Methods: Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin at 10 or 50 mg/kg after 2 and 12 h of SAH. Neurological scores, brain water content, Evans-blue extravasation, and levels of glutathione peroxidase(GSH-Px), superoxide dismutase(SOD), myeloperoxidase(MPO), and malondialdehyde(MDA) were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2(Nrf2), NAD(P)H: quinone oxidoreductase 1(NQO1), matrix metalloproteinase-9(MMP-9), aquaporin 4(AQP4), occludin, and zonulaoccludens-1(ZO-1) were detected in the brain by Western blot. Heme oxygenase-1(HO-1) was detected by quantitative polymerase chain reaction, and tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) were assessed by enzyme-linked immunosorbent assay. Results: Baicalin attenuated EBI 24 h after SAH in rats(P<0.05). Baicalin elevated neurological scores, GSH-Px, SOD, and increased the expression of Nrf2, NQO1, HO-1, occludin, and ZO-1 in SAH rats(P<0.05 or P<0.01). Baicalin reduced MPO, MDA, and the expression of MMP-9, AQP4, TNF-α, and IL-1β(P<0.05 or P<0.01). Conclusion: Baicalin reduced SAH-induced EBI, partially via activation of the Nrf2/HO-1 pathway and inhibition of MMP-9 and AQP4.
