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

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BIOCELL 2024年第1期48卷 149-162页

作者： PING YANG YUANXIANG LAN ZHONG ZENG YAN WANG HECHUN XIA Department of Neurosurgery School of Clinical MedicineNingxia Medical UniversityYinchuanChina Key Laboratory of Ningxia Stem Cell and Regenerative Medicine General Hospital of Ningxia Medical UniversityYinchuanChina Department of Neurosurgery Xi’an International Medical Center HospitalXi’anChina

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.

关键词： Traumatic brain injury Mesenchymal stem cells Oxidative stress matrix metalloproteinases

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matrix metalloproteinases-2,-9 and tissue inhibitor of metallo-proteinase-1 in lung cancer invasion and metastasis

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Chinese Medical Journal 2005年第1期118卷 69-72页

作者： MINGShu-hong SUNTie-ying XIAOWei XUXiao-mao RespiratoryDepartment BeijingHospitalBeijing100730China RespiratoryDepartment QiLuHospitalShandongUniversityJinan250000China

Lung cancer is a major cause of death from malignant disease due to its high incidence, malignant behavior and lack of major advancements in treatment strategies. The ability to invade tissues and establish colonies at remote sites is a defining characteristic of malignant neoplasms. matrix metalloproteinases ( MMPs) are zinc proteinases that degrade compounds of extracellular matrix (ECM). These enzymes have been implicated in tumour invasion and metastasis through degrading many extracellular matrix proteins especially MMP-2 and MMP-9, which are regarded as markers of tumour invasion and metastasis.(1) The purpose of this study is to examine the role of MMP-9, MMP-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and MMP-9/TIMP-1 in tumour invasion and metastasis as well as the relationships between the mRNA expression of MMP-9 in white blood cells and MMP-9 levels in the plasma.

关键词： lung neoplasm matrix metalloproteinases metastasisRespiratory

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

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World Journal of Gastrointestinal Surgery 2023年第5期15卷 931-939页

作者： Liu Peng Xin Zhang Man-Li Zhang Tao Jiang Peng-Jun Zhang Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Interventional TherapyPeking University Cancer Hospital&InstituteBeijing 100142China Division of Medicine Innovation Research Chinese PLA General HospitalBeijing 100853China

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.

关键词： Colorectal cancer Early detection matrix metalloproteinases Urine Biomarker

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matrix metalloproteinases and their expression in mammary gland

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Cell Research 1998年第3期8卷 187-194页

作者： URIA JOSE A ZENA WERB(Department of Anatomy, University of California San Francisco, CA 94143-0452, USA) Department of Anatomy University of California San Francisco CA USA

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a key role in both normal and pathological processes involving tissue remodeling events. The expression of these proteolytic enzymes is highly regulated by a balance between extracellular matrix (ECM) deposition and its degradation, and is controlled by growth factors, cytokines, hormones, as well as interactions with the ECM macromolecules. Furthermore, the activity of the MMPs is regulated by their natural endogenous inhibitors, which are members of the tissue inhibitor of metalloproteinases (TIMP) family. In the normal mammary gland, MMPs are expressed during ductal development, lobulo-alveolar development in pregnancy and involution after lactation. Under pathological conditions, such as tumorigenesis, the dysregulated expression of MMPs play a role in tumor initiation, progression and malignant conversion as well as facilitating invasion and motastasis of malignant cells through degradation of the ECM and basement membranes. matrix metalloproteinases and their expression in mammary gland

关键词： matrix metalloproteinases ECM cancer progression mammary gland

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Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury

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Neural Regeneration Research 2014年第4期9卷 362-376页

作者： Linda L.Phillips Julie L.Chan Adele E.Doperalski Thomas M.Reeves Department of Anatomy and Neurobiology Virginia Commonwealth UniversityRichmondVAUSA

Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloproteinases. Importantly, these enzyme/substrate interactions can regulate degenerative and regenerative phases of synaptic plasticity, directing axonal and dendritic reorganization after brain insult. The present review first summarizes literature support for the prominent role of matrix metalloproteinases during neuroregeneration, followed by a discussion of data contrasting adaptive and maladaptive neuroplasticity that reveals time-dependent metalloproteinase/substrate regulation of postinjury synaptic recovery. The potential for these enzymes to serve as therapeutic targets for enhanced neuroplasticity after brain injury is illustrated with experiments demonstrating that metalloproteinase inhibitors can alter adaptive and maladaptive outcome. Finally, the complexity of metalloproteinase role in reactive synaptogenesis is revealed in new studies showing how these enzymes interact with immune molecules to mediate cellular response in the local regenerative environment, and are regulated by novel binding partners in the brain extracellular matrix. Together, these different examples show the complexity with which metalloproteinases are integrated into the process of neuroregeneration, and point to a promising new angle for future studies exploring how to facilitate brain plasticity.

关键词： neuroregeneration reactive synaptogenesis matrix metalloproteinases brain injury adaptive and maladaptive neuroplasticity metalloproteinase inhibition osteopontin lipocalin 2

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

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World Journal of Gastroenterology 2010年第12期16卷 1500-1505页

作者： Clara Luz Sampieri Sol de la Pea Mariana Ochoa-Lara Roberto Zenteno-Cuevas Kenneth León-Córdoba Institute of Public Health Veracruzana University Biomedical Sciences Doctoral Program Institute of Health SciencesVeracruzana University Dr.Miguel Dorantes Mesa Hospital

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.

关键词： Gastric cancer Superficial gastritis matrix metalloproteinases Quantitative real-time polymerase chain reaction Quantitative zymography

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Enhancement of matrix metalloproteinases 2 and 9 accompanied with neurogenesis following collagen glycosaminoglycan matrix implantation after surgical brain injury

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Neural Regeneration Research 2018年第6期13卷 1007-1012页

作者： Wei-Cherng Hsu Chun-Hsien Yu Woon-Man Kung Kuo-Feng Huang Department of Ophthalmology Taipei Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation School of Medicine Buddhist Tzu Chi University Department of Pediatrics Taipei Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Division of Neurosurgery Department of Surgery Taipei Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Department of Exercise and Health Promotion College of Education Chinese Culture University

Surgical brain injury may result in irreversible neurological deficits. Our previous report showed that partial regeneration of a traumatic brain lesion is achieved by implantation of collagen glycosaminoglycan（CGM）. matrix metalloproteinases（MMPs） may play an important role in neurogenesis but there is currently a lack of studies displaying the relationship between the stimulation of MMPs and neurogenesis after collagen glycosaminoglycan implantation following surgical brain trauma. The present study was carried out to further examine the expression of MMP2 and MMP9 after implantation of collagen glycosaminoglycan（CGM） following surgical brain trauma. Using the animal model of surgically induced brain lesion, we implanted CGM into the surgical trauma. Rats were thus divided into three groups：（1） sham operation group： craniotomy only;（2） lesion（L） group： craniotomy ＋ surgical trauma lesion;（3） lesion ＋ CGM（L ＋ CGM） group： CGM implanted following craniotomy and surgical trauma lesion. Cells positive for SOX2（marker of proliferating neural progenitor cells） and matrix metalloproteinases（MMP2 and MMP9） in the lesion boundary zone were assayed and analyzed by immunofluorescence and ELISA commercial kits, respectively. Our results demonstrated that following implantation of CGM after surgical brain trauma, significant increases in MMP2^＋/SOX2^＋ cells and MMP9^＋/SOX2^＋ cells were seen within the lesion boundary zone in the L ＋ CGM group. Tissue protein concentrations of MMP2 and MMP9 also increased after CGM scaffold implantation. These findings suggest that implantation of a CGM scaffold alone after surgical brain trauma can enhance the expression of MMP2 and MMP9 accompanied by neurogenesis.

关键词： collagen glycosaminoglycan matrix metalloproteinases surgical brain trauma neurogenesis neural regeneration

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Albumin Modulates the Production of matrix metalloproteinases-2 and -9 in Podocytes

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2009年第6期29卷 710-714页

作者：方展何方方陈珊孙希锋朱忠华张春 Department of Nephrology Union Hospital Tongji Medical College Huazhong University of Science and Technology

To investigate the effects of albumin on the production of matrix metalloproteinases-2 （MMP-2） and matrix metalloproteinases-9 （MMP-9）in podocytes. Podocytes were treated with bovine serum albumin （BSA） at the concentration of 0.1, 0.5, 1, 2 g/L, respectively. Conditioned media were harvested 12, 24, 48 and 72 h after the treatment. The expression of MMP-2 and MMP-9 was assayed by gelatin zymography, RT-PCR and Western blotting analysis. Our results showed that in comparison with the control group, BSA increased the expression of MMP-2 and MMP-9 mRNA and protein in a doseand time-dependent manner （P〈0.05）. Meanwhile, the enzymatic activities of MMP-2 and MMP-9 in the culture supernatants of podocytes were also increased （P〈0.05）. It is concluded that albumin up-regulated the expression of MMP-2 and MMP-9 at gene and protein levels in a time-and dose-dependent manner.

关键词： podocytes albumin matrix metalloproteinases glomerular basement membrane

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Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients

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World Journal of Hepatology 2021年第2期13卷 218-232页

作者： Moises Martinez-Castillo Abigail Hernandez-Barragan Ivonne Flores-Vasconcelos Marina Galicia-Moreno Dorothy Rosique-Oramas Jose Luis Perez-Hernandez Fatima Higuera-De la Tijera Eduardo E Montalvo-Jave Aldo Torre-Delgadillo Paula Cordero-Perez Linda Muñoz-Espinosa David Kershenobich Gabriela Gutierrez-Reyes Liver Pancreas and Motility LaboratoryUnit of Experimental MedicineSchool of MedicineGeneral Hospital of MexicoUniversidad Nacional Autonoma de MexicoMexico City 06726Mexico Department of Molecular Biology and Genomics Institute of Molecular Biology in Medicine and Gene TherapyHealth Science University CenterUniversity of GuadalajaraGuadalajara 06726Mexico Department of Gastroenterology General Hospital of Mexico“Dr.Eduardo Liceaga”Mexico City 06726Mexico Department of General Surgery General Hospital of Mexico“Dr.Eduardo Liceaga”School of MedicineUniversidad Nacional Autonoma de MexicoMexico City 06726Mexico Hepatology and Liver Transplant National Institute of Medical Sciences and Nutrition“Salvador Zubirán”Mexico City 06726Mexico University Hospital“Dr.JoséEleuterio González ”Autonomous University of Nuevo LeonMonterrey 06726Mexico

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.

关键词： Extracellular matrix matrix metalloproteinases Liver fibrosis Chronic hepatitis C Fibrogenesis Fibrolysis

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Targeting matrix metalloproteinases in cancer:Bringing new life to old ideas

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Genes & Diseases 2015年第1期2卷 26-34页

作者： Jillian Cathcart Ashleigh Pulkoski-Gross Jian Cao Department of Cellular and Molecular Pharmacology Stony Brook UniversityStony BrookNY 11794USA Department of Medicine/Cancer Prevention Stony Brook UniversityStony BrookNY 11794USA

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.

关键词： Cancer Inhibitors matrix metalloproteinases Metastasis MMPs

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