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-t...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.展开更多
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...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.展开更多
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 deter...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.展开更多
BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few s...BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.展开更多
The matrix metalloproteinases(MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins.Their canonical role in matrix r...The matrix metalloproteinases(MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins.Their canonical role in matrix remodelling is of significant importance in neural development and regeneration,but emerging roles for MMPs,especially in signal transduction pathways,are also of obvious importance in a neural context.Misregulation of MMP activity is a hallmark of many neuropathologies,and members of every branch of the MMP family have been implicated in aspects of neural development and disease.However,while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs,methodological constraints and complexities of the research models have impeded progress.Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms,and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology.展开更多
Objective:To study the effect of cell chemokine(CC motif)ligand 18(CCL18)on ovarian cancer proliferation and metastasis.Methods:This study first analyzed the effects of overexpression of CCL18 on the growth in a subcu...Objective:To study the effect of cell chemokine(CC motif)ligand 18(CCL18)on ovarian cancer proliferation and metastasis.Methods:This study first analyzed the effects of overexpression of CCL18 on the growth in a subcutaneous ovarian cancer xenografts mouse model.Real-time quantitative PCR was used to detect the expression of matrix metalloproteinases(MMPs)in xenografts tissues.Then,an ovarian cancer orthotropic xenografts model was used to access the effect of CCL18 on ovarian cancer metastasis.Results:Over expressing CCL18 in SKOV3 cells did not significantly promote the tumor growth of subcutaneous xenografts.But the mRNA levels of MMP1,MMP7,MMP11 and MMP15 were significantly increased(P <0.05).The mRNA level of MMP12 was not changed(P >0.05).In orthotopic xenografts ovarian cancer mouse model,metastasis appeared in more organs in CCL 18 overexpressed SKOV3 cells than GFP/SKOV3 cells.Conclusion:CCL18 increased the expression of MMPs in ovarian cancer cells and promoted metastasis of ovarian cancer cells in vivo.展开更多
AIM To study activation of extracellular signal-regulated kinase-1/2(ERK1/2) and pro-matrix metalloproteinases(pro-MMPs) secretion from isolated primary human ciliary muscle(h-CM) cells in response to bradykinin(BK) a...AIM To study activation of extracellular signal-regulated kinase-1/2(ERK1/2) and pro-matrix metalloproteinases(pro-MMPs) secretion from isolated primary human ciliary muscle(h-CM) cells in response to bradykinin(BK) and other agonists. METHODS Serum-starved h-CM cells were challenged with vehicle, BK agonists or antagonists. Cell lysates were evaluated for phosphorylated ERK1/2 using homogeneous timeresolved fluorescence technology based on a sandwich immunoassay. Rabbit polyclonal anti-pro-MMP antibodies were used to measure pro-MMPs using immunoblot analysis.RESULTS A 10 min incubation time using 5 × 104 h-CM cells/well was optimum condition for studying stimulation of ERK1/2 phosphorylation. BK(100 nmol/L) caused a 1.86 ± 0.26 fold(n = 3) increase in ERK1/2 phosphorylation above baseline. BK analogs, Met-Lys-BK and RMP-7(100 nmol/L), also stimulated ERK1/2 phosphorylation by 1.57 ± 0.04 and 1.55 ± 0.09 fold, respectively. However, DesArg9-Bradykinin, a B1 receptor-selective agonist(0.1-1 μmol/L), was essentially inactive. HOE-140 or WIN-64338(B2-antagonists) appreciably blocked phosphorylation of ERK1/2 induced by various BK agonists. Pre-treatmentof cells with a prostaglandin(PG) synthase inhibitor(bromfenac; 1 μmol/L) failed to alter kinin-induced ERK1/2 activation. BK and a non-peptide BK agonist(FR-190997)(10 nmol/L-1 μmol/L) also enhanced pro-MMPs secretion(pro-MMP-1 > pro-MMP-3 > pro-MMP-2; 1.45-1.75-fold over baseline) from h-CM cells. CONCLUSION These collective data suggest that B2 kinin receptors initiate signaling in h-CM cells by a relatively rapid mechanism(within minutes) involving ERK1/2 activation which in turn regulates MMPs production(within hours). The latter process does not involve PGs.展开更多
AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)w...AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)was prepared by subjecting human conjunctival fibroblasts to three cycles of freezing and thawing.The amounts of interleukin(IL)-1βand tumor necrosis factor(TNF)-αin NHCS were determined by enzyme-linked immunosorbent assays.HCFs exposed to NHCS or other agents in culture were assayed for the release of MMPs as well as for intracellular signaling by immunoblot analysis.The abundance of MMP m RNAs in HCFs was examined by reverse transcription and real-time polymerase chain reaction analysis.RESULTS:NHCS increased the release of MMP-1 and MMP-3 by HCFs as well as the amounts of the corresponding m RNAs in the cells.NHCS also induced activation of mitogen-activated protein kinase(MAPK)signaling pathways mediated by extracellular signal-regulated kinase(ERK),p38,and c-Jun NH2-terminal kinase(JNK)as well as elicited that of the nuclear factor(NF)-κB signaling pathway by promoting phosphorylation of the endogenous NF-κB inhibitor IκB-α.Inhibitors of MAPK and NF-κB signaling as well as IL-1 and TNF-αreceptor antagonists attenuated the NHCS-induced release of MMP-1 and MMP-3 by HCFs.Furthermore,IL-1βand TNF-αwere both detected in NHCS,and treatment of HCFs with these cytokines induced the release of MMP-1 and MMP-3 in a concentration-dependent manner.CONCLUSION:Alarmins,including IL-1βand TNF-α,produced by necrotic human conjunctival fibroblasts triggered MMP release in HCFs through activation of MAPK and NF-κB signaling.IL-1βand TNF-αare therefore potential therapeutic targets for the amelioration of corneal stromal degradation in severe ocular burns.展开更多
AIM:To observe changes in the content of matrix metalloproteinases(MMPs)in the corneal stroma after corneal cross-linking(CXL)in rabbits,and further explore the corneal pathophysiological process after CXL.METHODS:For...AIM:To observe changes in the content of matrix metalloproteinases(MMPs)in the corneal stroma after corneal cross-linking(CXL)in rabbits,and further explore the corneal pathophysiological process after CXL.METHODS:Forty-two rabbits(42 eyes)were randomly divided into seven groups.One group served as the control group,while the other six groups were treated with CXL.The concentrations of MMPs in corneal stroma were evaluated through parallel reaction monitoring at baseline and 3,7,15,30,90,and 180 d after treatment.RESULTS:The levels of MMP-2 in the corneal stroma of rabbits were 0.76±0.07,2.78±1.39,4.12±0.69,2.00±0.29,2.00±0.30,1.22±0.18,and 1.35±0.18(10^(-9)mol/g)at baseline and 3,7,15,30,90,and 180 d after treatment,respectively.The contents of tissue inhibitor of metalloproteinase-1(TIMP-1)were 1.83±0.26,7.94±0.58,6.95±2.64,3.81±0.48,3.07±0.92,1.72±0.19,and 1.69±0.74(10^(-9)mol/g),respectively.The ratios of MMP-2/TIMP-1 were 0.42±0.33,0.36±0.20,0.62±0.10,0.54±0.15,0.68±0.13,0.71±0.10,and 0.68±0.09,respectively.After CXL,the expression of MMP-2 and TIMP-1 in the rabbit corneal stroma was initially increased and subsequently decreased.The levels of MMP-2 remained higher than those recorded at baseline 180 d after treatment,but it was not statistically significant.The levels of TIMP-1 returned to baseline levels at 90 d after treatment.The ratio of MMP-2/TIMP-1 started to rise from 7 d after CXL.It was significantly higher than that calculated at baseline 30-180 d after CXL.The results for MMP-1,-3,-7,-9,-13,and TIMP-2 were negative.CONCLUSION:CXL can lead to changes in the content of MMP-2 and TIMP-1 in the rabbit corneal stroma.The ratio of MMP-2/TIMP-1 remains higher versus baseline,indicating that MMP-2 is involved in the corneal pathophysiological process after CXL.展开更多
Objective:To explore the expression levels of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)in ascites in ovarian tumor and provide a theoretical basis for the diagnosis and prognosis evaluatio...Objective:To explore the expression levels of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)in ascites in ovarian tumor and provide a theoretical basis for the diagnosis and prognosis evaluation of ovarian cancer ascites.Methods:ELISA was used to detect the levels of MMP-2 and MMP-9 in ascites samples from 73 cases of patients with malignant ovarian tumor,and RIA was used to detect the expression level of CA125 in the serum in these patients.Results:The expression levels of MMP-2 and MMP-9 in ascites in malignant ovarian tumor were higher than those in ascites in benign ovarian tumor(t=8.08,10.39,p<.01),and the difference was of statistical significance.The expression levels of MMP-2 and MMP-9 in patients with stage III and IV malignant ovarian tumors were higher than those in patients with stage I and II malignant ovarian tumors,and the difference was statistically significant(t=2.75,2.75,p<.05).There was no statistically significant difference in the expression levels of MMP-2 and MMP-9 among the patients with different pathological types,different histological grades,lymph node metastasis or not,different ascites volumes and different residual lesions(p>.05).The sensitivities of detecting MMP-2 and MMP-9 in ascites were 76.0%and 88.0%,respectively,which were significantly higher than those of ascites cytological examinations(χ^(2)=4.61,12.74,p<.05),but in comparison with serum CA125,there was no statistically significant difference(p>.05).The specificities of detecting MMP-2 and MMP-9 in ascites were 78.3%and 82.6%,respectively,which were significantly lower than those of ascites cytological examinations(χ^(2)=5.61,4.38,p<.05),but in comparison with serum CA125,there was no statistically significant difference(χ^(2)=1.64,2.68,p<.05).Conclusions:The levels of MMP-2 and MMP-9 in ascites may be markers for the differential diagnosis of benign and malignant ovarian lesions,and they are related to the prognosis in patients with malignant ovarian tumors.展开更多
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-sect...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.展开更多
Since the identification of matrix metalloproteinases(MMPs),a family of zincdependent endopeptidases,as being a driving factor for cancer progression and patient prognosis,MMPs have been studied extensively.Although e...Since the identification of matrix metalloproteinases(MMPs),a family of zincdependent endopeptidases,as being a driving factor for cancer progression and patient prognosis,MMPs have been studied extensively.Although early programs targeting MMPs were largely unsuccessful in clinical trials,they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression.As information regarding the structure and function of these proteinases is compiled and biotechnology evolves,tools to develop better inhibitors are within our grasp.Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent,have high binding affinities,and exhibit favorable pharmacokinetic profiles.More recently,advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field.In this review,we highlight the role of MMPs in cancer,clinical trials for MMP inhibitors,and novel approaches to targeting MMPs in cancer.展开更多
Objective: To examine the effect of brucine on the migration, invasion, adhesion and expressions of epithelial-to-mesenchymal transition(EMT) markers and matrix metalloproteinases(MMPs) in the highly metastatic breast...Objective: To examine the effect of brucine on the migration, invasion, adhesion and expressions of epithelial-to-mesenchymal transition(EMT) markers and matrix metalloproteinases(MMPs) in the highly metastatic breast cancer cell lines MDA-MB-231 and Hs578-T. Methods: MDA-MB-231 and Hs578-T cells were divided to 4 groups: the control group(0.1% DMSO), and 25, 50 and 100 μmol/L brucine groups. The cell viability was determined using a Cell Titer-Glo? luminescent cell viability. The scratch wound healing assay and tanswell migration assay were used to determine the migration ability of these cells treated by different concentrations of brucine. The proliferation rate, invasive potential and adhesive ability were respectively performed by colony formation assay, transwell invasion assay and adhension assay. The protein and m RNA expressions of EMT biomarkers, MMP-2 and MMP-9 were investigated by real-time reverse transcription polymerase chain reaction and Western blot. Results: Compared with the control group, brucine had little effect on cell viability or proliferation(P>0.05), but led to a dose-dependent decrease on migration, invasion, adhension of MDA-MB-231 and Hs578-T cells(P<0.01). Furthermore, brucine increased the protein and m RNA levels of EMT markers such as E-cadherin and β-catenin in MDA-MB-231 and Hs578-T cells, and decreased the protein and m RNA levels of mesenychmal markers such as vimentin and fibronectin, as well as the expressions of MMP-2 and MMP-9(all P<0.01). Conclusion: Brucine inhibited triple negative breast cancer cells metastasis potentially through EMT reversion and MMP-2 and MMP-9 inhibition.展开更多
OBJECTIVE:To study the effect of Lichong decoction(LD) on expression of matrix metalloproteinase-2(MMP-2) and metalloproteinase-2(TIMP-2) in a rat model of uterine leiomyoma(UL).METHODS:UL was induced in rats using ex...OBJECTIVE:To study the effect of Lichong decoction(LD) on expression of matrix metalloproteinase-2(MMP-2) and metalloproteinase-2(TIMP-2) in a rat model of uterine leiomyoma(UL).METHODS:UL was induced in rats using exogenous estrogen and progesterone.LD was administered(p.o.) for 4 weeks,and mifepristone(RU-486)used as a control.To observe the effect of LD on the uterine coefficient and uterine transverse diameter,a radioimmunoassay method was used to detect serum levels of sex hormones.Light microscopic analyses of pathologic changes in the tissues of UL rats were evaluated.Expression of the proteins of matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases(TIMPs) in uterine tissues was assessed by immunohistochemical staining and western blotting.RESULTS:A UL model in rats was established successfully.LD reduced uterine weight,uterine coefficient,and uterine transverse diameter compared with untreated controls.LD reduced levels of estradiol,progesterone,follicle-stimulating hormone,and luteinizing hormone in our UL models.LD improved the pathologic condition of uterine muscle.Expression of MMP-2 protein decreased to varying extents in LD-treated groups,but TIMP-2 levels were enhanced.LD appears to reduce MMP-2 expression and increase TIMP-2 expression in UL tissue.CONCLUSION:These data suggest that the mechanism of action of LD on ULs may involve reduction of MMP-2 expression and increase in TIMP-2 expression in rats.展开更多
The membrane-type matrix metalloproteinases(MT-MMPs),an important subgroup of the wider MMP family,demonstrate widespread expression in multiple tumor types,and play key roles in cancer growth,migration,invasion and m...The membrane-type matrix metalloproteinases(MT-MMPs),an important subgroup of the wider MMP family,demonstrate widespread expression in multiple tumor types,and play key roles in cancer growth,migration,invasion and metastasis.Despite a large body of published research,relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer.This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue,summarises the evidence for roles in prostate cancer progression,and examines the data relating to MT-MMP function in the development of bone metastases.Finally,the therapeutic potential of targeting MT-MMPs is considered.While MT-MMP inhibition presents a significant challenge,utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.展开更多
Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due...Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.展开更多
BACKGROUND Bariatric surgery is an efficient strategy for body weight and type 2 diabetes mellitus(T2 DM) management. Abnormal lipid deposition in visceral organs,especially the pancreas and liver, might cause beta-ce...BACKGROUND Bariatric surgery is an efficient strategy for body weight and type 2 diabetes mellitus(T2 DM) management. Abnormal lipid deposition in visceral organs,especially the pancreas and liver, might cause beta-cell dysfunction and insulin resistance. Extracellular matrix(ECM) remodeling allows adipose expansion, and matrix metalloproteinases(MMPs) play essential roles in ECM construction.MMP-2 and MMP-9 are the substrates of MMP-7. Different studies have reported that MMP-2,-7, and-9 increase in patients with obesity and metabolic syndromes or T2 DM and are considered biomarkers in obesity and hyperglycemia patients.AIMTo prospectively investigate whether MMP-2, MMP-7, and MMP-9 differ after two bariatric surgeries: Gastric bypass(GB) and sleeve gastrectomy(SG).METHODS We performed GB in 23 and SG in 19 obese patients with T2 DM. We measured body weight, waist circumference, body mass index(BMI), and serum concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood sugar(FBS),hemoglobin A1 c(Hb A1 c), C-peptide, homeostasis model assessments of insulin resistance, and MMP-2, MMP-7, and MMP-9 levels at baseline and at 3, 12, and 24 mo post-operation.RESULTS Twenty-three patients aged 44.7 ± 9.7 years underwent GB, and 19 patients aged40.1 ± 9.1 years underwent SG. In the GB group, BMI decreased from 30.3 ± 3.4 to24.4 ± 2.4 kg/m2, Hb A1 c decreased from 9.2% ± 1.5% to 6.7% ± 1.4%, and FBS decreased from 171.6 ± 65.0 mg/d L to 117.7 ± 37.5 mg/d L 2 years post-operation(P < 0.001). However, the MMP-2, MMP-7, and MMP-9 levels pre-and post-GB were similar even 2 years post-operation(P = 0.107, 0.258, and 0.466,respectively). The SG group revealed similar results: BMI decreased from 36.2 ±5.1 to 26.9 ± 4.7 kg/m2, Hb A1 c decreased from 7.9% ± 1.7% to 5.8% ± 0.6%, and FBS decreased from 138.3 ± 55.6 mg/d L to 95.1 ± 3.1 mg/d L(P < 0.001). The serum MMP-2,-7, and-9 levels pre-and post-SG were not different(P = 0.083,0.869, and 0.1, respectively).CONCLUSION Improvements in obesity and T2 DM induced by bariatric surgery might be the result of MMP-2,-7, or-9 independent pathways.展开更多
Objective:To determine the effect of Lentinula edodes extract on ultraviolet(UV)A and UVB-induced changes in matrix metalloproteinase(MMP)and type I procollagen expression using human immortalized HaCaT keratinocytes....Objective:To determine the effect of Lentinula edodes extract on ultraviolet(UV)A and UVB-induced changes in matrix metalloproteinase(MMP)and type I procollagen expression using human immortalized HaCaT keratinocytes.Methods:Lentinula edodes ethanol extract(LEE)was obtained by extraction with 80%ethanol for 4 h at 80℃.Effect of LEE on UVinduced alteration on the expression and production of MMPs and type I procollagen in keratinocytes was investigated using ELISA,RT-PCR,and Western blotting assay.To determine the underlying mechanism of LEE-mediated effects,mitogen-activated protein kinase(MAPK)and activator protein 1 signaling pathways were analysed by Western blotting assay.Results:LEE significantly inhibited the expression of MMP-1 and MMP-9 and increased the expression of type I procollagen in UVA and UVB-irradiated HaCaT keratinocytes.The phosphorylation levels of p38 were significantly inhibited by LEE whereas it did not affect c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation.Suppression of p38 phosphorylation was also accompanied by downregulation of UVA and UVB-induced increase in c-Fos.Conclusions:LEE effectively inhibits the expression of MMP-1 and MMP-9 and increases type I procollagen production through the p38 MAPK/c-Fos signaling pathway in UVA and UVB-irradiated HaCaT keratinocytes.This findings suggest that Lentinula edodes may be developed as a cosmetic material to suppress UV exposuremediated skin aging.展开更多
Various behaviors of cancer cells are strongly influenced by their interaction with extracellular matrices(ECM).We investigate how this interaction may be influenced if the cancer cells’ability of secreting matrix me...Various behaviors of cancer cells are strongly influenced by their interaction with extracellular matrices(ECM).We investigate how this interaction may be influenced if the cancer cells’ability of secreting matrix metalloproteinases(MMPs)to degrade ECM is inhibited by adding the MMP inhibitor.We useMDA-MB-231-GFP cells as model cells and use matrigel to mimic ECM.It is found that the added MMP inhibitor significantly reduces the migration speed of cancer cells covered by matrigel but has little influence on the migration persistence and shape factor of the cells and that with the MMP inhibitor added the presence of matrigel on the top has no influence on the migration speed of the cells but increases the cells’shape factor and migration persistence.展开更多
基金financially supported by the Key Research Projects of Ningxia Hui Autonomous Region of China under Grant No.2018BCG01002(to HCX).
文摘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.
基金Supported by the National Key Research and Development Program of China,No.2020YFC2004604 and 2020YFC2002700.
文摘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.
基金Supported by The National Council on Science and Technology (CONACYT:85675 and 79628)Institute of Public Health(POA: 2008-2010)Research Office of Veracruzana University and Public Education Secretariat(SEP-PROMEP-UV:PTC-319)
文摘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.
基金the National Council for Science and Technology,No.SALUD-2016-272579 and No.PAPIIT-UNAM TA200515.
文摘BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
文摘The matrix metalloproteinases(MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins.Their canonical role in matrix remodelling is of significant importance in neural development and regeneration,but emerging roles for MMPs,especially in signal transduction pathways,are also of obvious importance in a neural context.Misregulation of MMP activity is a hallmark of many neuropathologies,and members of every branch of the MMP family have been implicated in aspects of neural development and disease.However,while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs,methodological constraints and complexities of the research models have impeded progress.Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms,and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology.
基金supported by grants from the National Natural Science Foundation of China (No.81360341,81560428)National High Technology Research and Development Program (863Program)(No.2014AA020605)+3 种基金the Guangxi Nanning Qingxiu District Science and Technology Development Project (No.2015S14)the Guangxi Natural Science Foundation of China (No.2015GXNSFBA139147)Guangxi Health and Family Planning Commission Self-financing Project (No.Z2015622)2016 Guangxi University Young and Middle-aged Teachers’Basic Ability Support Project(No.KY2016YB073)
文摘Objective:To study the effect of cell chemokine(CC motif)ligand 18(CCL18)on ovarian cancer proliferation and metastasis.Methods:This study first analyzed the effects of overexpression of CCL18 on the growth in a subcutaneous ovarian cancer xenografts mouse model.Real-time quantitative PCR was used to detect the expression of matrix metalloproteinases(MMPs)in xenografts tissues.Then,an ovarian cancer orthotropic xenografts model was used to access the effect of CCL18 on ovarian cancer metastasis.Results:Over expressing CCL18 in SKOV3 cells did not significantly promote the tumor growth of subcutaneous xenografts.But the mRNA levels of MMP1,MMP7,MMP11 and MMP15 were significantly increased(P <0.05).The mRNA level of MMP12 was not changed(P >0.05).In orthotopic xenografts ovarian cancer mouse model,metastasis appeared in more organs in CCL 18 overexpressed SKOV3 cells than GFP/SKOV3 cells.Conclusion:CCL18 increased the expression of MMPs in ovarian cancer cells and promoted metastasis of ovarian cancer cells in vivo.
文摘AIM To study activation of extracellular signal-regulated kinase-1/2(ERK1/2) and pro-matrix metalloproteinases(pro-MMPs) secretion from isolated primary human ciliary muscle(h-CM) cells in response to bradykinin(BK) and other agonists. METHODS Serum-starved h-CM cells were challenged with vehicle, BK agonists or antagonists. Cell lysates were evaluated for phosphorylated ERK1/2 using homogeneous timeresolved fluorescence technology based on a sandwich immunoassay. Rabbit polyclonal anti-pro-MMP antibodies were used to measure pro-MMPs using immunoblot analysis.RESULTS A 10 min incubation time using 5 × 104 h-CM cells/well was optimum condition for studying stimulation of ERK1/2 phosphorylation. BK(100 nmol/L) caused a 1.86 ± 0.26 fold(n = 3) increase in ERK1/2 phosphorylation above baseline. BK analogs, Met-Lys-BK and RMP-7(100 nmol/L), also stimulated ERK1/2 phosphorylation by 1.57 ± 0.04 and 1.55 ± 0.09 fold, respectively. However, DesArg9-Bradykinin, a B1 receptor-selective agonist(0.1-1 μmol/L), was essentially inactive. HOE-140 or WIN-64338(B2-antagonists) appreciably blocked phosphorylation of ERK1/2 induced by various BK agonists. Pre-treatmentof cells with a prostaglandin(PG) synthase inhibitor(bromfenac; 1 μmol/L) failed to alter kinin-induced ERK1/2 activation. BK and a non-peptide BK agonist(FR-190997)(10 nmol/L-1 μmol/L) also enhanced pro-MMPs secretion(pro-MMP-1 > pro-MMP-3 > pro-MMP-2; 1.45-1.75-fold over baseline) from h-CM cells. CONCLUSION These collective data suggest that B2 kinin receptors initiate signaling in h-CM cells by a relatively rapid mechanism(within minutes) involving ERK1/2 activation which in turn regulates MMPs production(within hours). The latter process does not involve PGs.
基金Supported by the National Natural Science Foundation of China(No.81770889)the Natural Science Foundation of Guangdong Province(No.2018A030313428)。
文摘AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)was prepared by subjecting human conjunctival fibroblasts to three cycles of freezing and thawing.The amounts of interleukin(IL)-1βand tumor necrosis factor(TNF)-αin NHCS were determined by enzyme-linked immunosorbent assays.HCFs exposed to NHCS or other agents in culture were assayed for the release of MMPs as well as for intracellular signaling by immunoblot analysis.The abundance of MMP m RNAs in HCFs was examined by reverse transcription and real-time polymerase chain reaction analysis.RESULTS:NHCS increased the release of MMP-1 and MMP-3 by HCFs as well as the amounts of the corresponding m RNAs in the cells.NHCS also induced activation of mitogen-activated protein kinase(MAPK)signaling pathways mediated by extracellular signal-regulated kinase(ERK),p38,and c-Jun NH2-terminal kinase(JNK)as well as elicited that of the nuclear factor(NF)-κB signaling pathway by promoting phosphorylation of the endogenous NF-κB inhibitor IκB-α.Inhibitors of MAPK and NF-κB signaling as well as IL-1 and TNF-αreceptor antagonists attenuated the NHCS-induced release of MMP-1 and MMP-3 by HCFs.Furthermore,IL-1βand TNF-αwere both detected in NHCS,and treatment of HCFs with these cytokines induced the release of MMP-1 and MMP-3 in a concentration-dependent manner.CONCLUSION:Alarmins,including IL-1βand TNF-α,produced by necrotic human conjunctival fibroblasts triggered MMP release in HCFs through activation of MAPK and NF-κB signaling.IL-1βand TNF-αare therefore potential therapeutic targets for the amelioration of corneal stromal degradation in severe ocular burns.
基金Supported by Beijing Municipal Science and Technology Commission(No.Z151100004015217)。
文摘AIM:To observe changes in the content of matrix metalloproteinases(MMPs)in the corneal stroma after corneal cross-linking(CXL)in rabbits,and further explore the corneal pathophysiological process after CXL.METHODS:Forty-two rabbits(42 eyes)were randomly divided into seven groups.One group served as the control group,while the other six groups were treated with CXL.The concentrations of MMPs in corneal stroma were evaluated through parallel reaction monitoring at baseline and 3,7,15,30,90,and 180 d after treatment.RESULTS:The levels of MMP-2 in the corneal stroma of rabbits were 0.76±0.07,2.78±1.39,4.12±0.69,2.00±0.29,2.00±0.30,1.22±0.18,and 1.35±0.18(10^(-9)mol/g)at baseline and 3,7,15,30,90,and 180 d after treatment,respectively.The contents of tissue inhibitor of metalloproteinase-1(TIMP-1)were 1.83±0.26,7.94±0.58,6.95±2.64,3.81±0.48,3.07±0.92,1.72±0.19,and 1.69±0.74(10^(-9)mol/g),respectively.The ratios of MMP-2/TIMP-1 were 0.42±0.33,0.36±0.20,0.62±0.10,0.54±0.15,0.68±0.13,0.71±0.10,and 0.68±0.09,respectively.After CXL,the expression of MMP-2 and TIMP-1 in the rabbit corneal stroma was initially increased and subsequently decreased.The levels of MMP-2 remained higher than those recorded at baseline 180 d after treatment,but it was not statistically significant.The levels of TIMP-1 returned to baseline levels at 90 d after treatment.The ratio of MMP-2/TIMP-1 started to rise from 7 d after CXL.It was significantly higher than that calculated at baseline 30-180 d after CXL.The results for MMP-1,-3,-7,-9,-13,and TIMP-2 were negative.CONCLUSION:CXL can lead to changes in the content of MMP-2 and TIMP-1 in the rabbit corneal stroma.The ratio of MMP-2/TIMP-1 remains higher versus baseline,indicating that MMP-2 is involved in the corneal pathophysiological process after CXL.
文摘Objective:To explore the expression levels of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)in ascites in ovarian tumor and provide a theoretical basis for the diagnosis and prognosis evaluation of ovarian cancer ascites.Methods:ELISA was used to detect the levels of MMP-2 and MMP-9 in ascites samples from 73 cases of patients with malignant ovarian tumor,and RIA was used to detect the expression level of CA125 in the serum in these patients.Results:The expression levels of MMP-2 and MMP-9 in ascites in malignant ovarian tumor were higher than those in ascites in benign ovarian tumor(t=8.08,10.39,p<.01),and the difference was of statistical significance.The expression levels of MMP-2 and MMP-9 in patients with stage III and IV malignant ovarian tumors were higher than those in patients with stage I and II malignant ovarian tumors,and the difference was statistically significant(t=2.75,2.75,p<.05).There was no statistically significant difference in the expression levels of MMP-2 and MMP-9 among the patients with different pathological types,different histological grades,lymph node metastasis or not,different ascites volumes and different residual lesions(p>.05).The sensitivities of detecting MMP-2 and MMP-9 in ascites were 76.0%and 88.0%,respectively,which were significantly higher than those of ascites cytological examinations(χ^(2)=4.61,12.74,p<.05),but in comparison with serum CA125,there was no statistically significant difference(p>.05).The specificities of detecting MMP-2 and MMP-9 in ascites were 78.3%and 82.6%,respectively,which were significantly lower than those of ascites cytological examinations(χ^(2)=5.61,4.38,p<.05),but in comparison with serum CA125,there was no statistically significant difference(χ^(2)=1.64,2.68,p<.05).Conclusions:The levels of MMP-2 and MMP-9 in ascites may be markers for the differential diagnosis of benign and malignant ovarian lesions,and they are related to the prognosis in patients with malignant ovarian tumors.
基金supported by the Construction of Prevention and Treatment System of Geriatric Syndromes Focusing on Disability and Dementia(No.21-1-2-2-zyyd-nsh)。
文摘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.
基金supported in part by Baldwin Breast Cancer Foundation and National Cancer Institute(1R01CA166936 to J.C.).
文摘Since the identification of matrix metalloproteinases(MMPs),a family of zincdependent endopeptidases,as being a driving factor for cancer progression and patient prognosis,MMPs have been studied extensively.Although early programs targeting MMPs were largely unsuccessful in clinical trials,they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression.As information regarding the structure and function of these proteinases is compiled and biotechnology evolves,tools to develop better inhibitors are within our grasp.Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent,have high binding affinities,and exhibit favorable pharmacokinetic profiles.More recently,advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field.In this review,we highlight the role of MMPs in cancer,clinical trials for MMP inhibitors,and novel approaches to targeting MMPs in cancer.
基金Supported by the State Administration of Traditional Chinese Medicine of China(2009-No.30)
文摘Objective: To examine the effect of brucine on the migration, invasion, adhesion and expressions of epithelial-to-mesenchymal transition(EMT) markers and matrix metalloproteinases(MMPs) in the highly metastatic breast cancer cell lines MDA-MB-231 and Hs578-T. Methods: MDA-MB-231 and Hs578-T cells were divided to 4 groups: the control group(0.1% DMSO), and 25, 50 and 100 μmol/L brucine groups. The cell viability was determined using a Cell Titer-Glo? luminescent cell viability. The scratch wound healing assay and tanswell migration assay were used to determine the migration ability of these cells treated by different concentrations of brucine. The proliferation rate, invasive potential and adhesive ability were respectively performed by colony formation assay, transwell invasion assay and adhension assay. The protein and m RNA expressions of EMT biomarkers, MMP-2 and MMP-9 were investigated by real-time reverse transcription polymerase chain reaction and Western blot. Results: Compared with the control group, brucine had little effect on cell viability or proliferation(P>0.05), but led to a dose-dependent decrease on migration, invasion, adhension of MDA-MB-231 and Hs578-T cells(P<0.01). Furthermore, brucine increased the protein and m RNA levels of EMT markers such as E-cadherin and β-catenin in MDA-MB-231 and Hs578-T cells, and decreased the protein and m RNA levels of mesenychmal markers such as vimentin and fibronectin, as well as the expressions of MMP-2 and MMP-9(all P<0.01). Conclusion: Brucine inhibited triple negative breast cancer cells metastasis potentially through EMT reversion and MMP-2 and MMP-9 inhibition.
基金Supported by National Natural Science Fund(Study on the Action Mechanism of Inhibition of Uterine Leiomyoma of Regulation of Lichong Decoction for Ang-Tie-2 Transduction Pathway,No.81373812Research on the Regulating Mechanism of the Inhibitory Effect of Nourishing Healthy Qi and Eliminating Blood Stasis Chinese Medicine on Extracellular Matrix Metabolize in Uterine Leiomyoma,No.81073096)
文摘OBJECTIVE:To study the effect of Lichong decoction(LD) on expression of matrix metalloproteinase-2(MMP-2) and metalloproteinase-2(TIMP-2) in a rat model of uterine leiomyoma(UL).METHODS:UL was induced in rats using exogenous estrogen and progesterone.LD was administered(p.o.) for 4 weeks,and mifepristone(RU-486)used as a control.To observe the effect of LD on the uterine coefficient and uterine transverse diameter,a radioimmunoassay method was used to detect serum levels of sex hormones.Light microscopic analyses of pathologic changes in the tissues of UL rats were evaluated.Expression of the proteins of matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases(TIMPs) in uterine tissues was assessed by immunohistochemical staining and western blotting.RESULTS:A UL model in rats was established successfully.LD reduced uterine weight,uterine coefficient,and uterine transverse diameter compared with untreated controls.LD reduced levels of estradiol,progesterone,follicle-stimulating hormone,and luteinizing hormone in our UL models.LD improved the pathologic condition of uterine muscle.Expression of MMP-2 protein decreased to varying extents in LD-treated groups,but TIMP-2 levels were enhanced.LD appears to reduce MMP-2 expression and increase TIMP-2 expression in UL tissue.CONCLUSION:These data suggest that the mechanism of action of LD on ULs may involve reduction of MMP-2 expression and increase in TIMP-2 expression in rats.
文摘The membrane-type matrix metalloproteinases(MT-MMPs),an important subgroup of the wider MMP family,demonstrate widespread expression in multiple tumor types,and play key roles in cancer growth,migration,invasion and metastasis.Despite a large body of published research,relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer.This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue,summarises the evidence for roles in prostate cancer progression,and examines the data relating to MT-MMP function in the development of bone metastases.Finally,the therapeutic potential of targeting MT-MMPs is considered.While MT-MMP inhibition presents a significant challenge,utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.
文摘Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.
基金Supported by grants from MinSheng General Hospital,Taoyuan,Far Eastern Memorial Hospital-National Yang-Ming University Joint Research Program,No. 105DN15,No. 106DN15,and No. 107DN14 to Lee TH and Chen CY。
文摘BACKGROUND Bariatric surgery is an efficient strategy for body weight and type 2 diabetes mellitus(T2 DM) management. Abnormal lipid deposition in visceral organs,especially the pancreas and liver, might cause beta-cell dysfunction and insulin resistance. Extracellular matrix(ECM) remodeling allows adipose expansion, and matrix metalloproteinases(MMPs) play essential roles in ECM construction.MMP-2 and MMP-9 are the substrates of MMP-7. Different studies have reported that MMP-2,-7, and-9 increase in patients with obesity and metabolic syndromes or T2 DM and are considered biomarkers in obesity and hyperglycemia patients.AIMTo prospectively investigate whether MMP-2, MMP-7, and MMP-9 differ after two bariatric surgeries: Gastric bypass(GB) and sleeve gastrectomy(SG).METHODS We performed GB in 23 and SG in 19 obese patients with T2 DM. We measured body weight, waist circumference, body mass index(BMI), and serum concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood sugar(FBS),hemoglobin A1 c(Hb A1 c), C-peptide, homeostasis model assessments of insulin resistance, and MMP-2, MMP-7, and MMP-9 levels at baseline and at 3, 12, and 24 mo post-operation.RESULTS Twenty-three patients aged 44.7 ± 9.7 years underwent GB, and 19 patients aged40.1 ± 9.1 years underwent SG. In the GB group, BMI decreased from 30.3 ± 3.4 to24.4 ± 2.4 kg/m2, Hb A1 c decreased from 9.2% ± 1.5% to 6.7% ± 1.4%, and FBS decreased from 171.6 ± 65.0 mg/d L to 117.7 ± 37.5 mg/d L 2 years post-operation(P < 0.001). However, the MMP-2, MMP-7, and MMP-9 levels pre-and post-GB were similar even 2 years post-operation(P = 0.107, 0.258, and 0.466,respectively). The SG group revealed similar results: BMI decreased from 36.2 ±5.1 to 26.9 ± 4.7 kg/m2, Hb A1 c decreased from 7.9% ± 1.7% to 5.8% ± 0.6%, and FBS decreased from 138.3 ± 55.6 mg/d L to 95.1 ± 3.1 mg/d L(P < 0.001). The serum MMP-2,-7, and-9 levels pre-and post-SG were not different(P = 0.083,0.869, and 0.1, respectively).CONCLUSION Improvements in obesity and T2 DM induced by bariatric surgery might be the result of MMP-2,-7, or-9 independent pathways.
基金supported by the Ministry of Trade,Industry&Energy,Korea Institute for Advancement of Technology and Busan Institute For Regional Program Evaluation through the Encouragement Program for the Social and Economic Innovation Growth(project number,P0008724)
文摘Objective:To determine the effect of Lentinula edodes extract on ultraviolet(UV)A and UVB-induced changes in matrix metalloproteinase(MMP)and type I procollagen expression using human immortalized HaCaT keratinocytes.Methods:Lentinula edodes ethanol extract(LEE)was obtained by extraction with 80%ethanol for 4 h at 80℃.Effect of LEE on UVinduced alteration on the expression and production of MMPs and type I procollagen in keratinocytes was investigated using ELISA,RT-PCR,and Western blotting assay.To determine the underlying mechanism of LEE-mediated effects,mitogen-activated protein kinase(MAPK)and activator protein 1 signaling pathways were analysed by Western blotting assay.Results:LEE significantly inhibited the expression of MMP-1 and MMP-9 and increased the expression of type I procollagen in UVA and UVB-irradiated HaCaT keratinocytes.The phosphorylation levels of p38 were significantly inhibited by LEE whereas it did not affect c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation.Suppression of p38 phosphorylation was also accompanied by downregulation of UVA and UVB-induced increase in c-Fos.Conclusions:LEE effectively inhibits the expression of MMP-1 and MMP-9 and increases type I procollagen production through the p38 MAPK/c-Fos signaling pathway in UVA and UVB-irradiated HaCaT keratinocytes.This findings suggest that Lentinula edodes may be developed as a cosmetic material to suppress UV exposuremediated skin aging.
基金National Natural Science Foundation of China(Grant No.11774394)the Key Research Program of Frontier Sciences of Chinese Academy of Sciences(Grant No.QYZDB-SSW-SYS003)the K.C.Wong Education Foundation.
文摘Various behaviors of cancer cells are strongly influenced by their interaction with extracellular matrices(ECM).We investigate how this interaction may be influenced if the cancer cells’ability of secreting matrix metalloproteinases(MMPs)to degrade ECM is inhibited by adding the MMP inhibitor.We useMDA-MB-231-GFP cells as model cells and use matrigel to mimic ECM.It is found that the added MMP inhibitor significantly reduces the migration speed of cancer cells covered by matrigel but has little influence on the migration persistence and shape factor of the cells and that with the MMP inhibitor added the presence of matrigel on the top has no influence on the migration speed of the cells but increases the cells’shape factor and migration persistence.
