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

Background:As a form of biological therapy,placenta-derived mesenchymal stem cells(PDMSCs)exhibit considerable promise in addressing the complex pathological processes of traumaticbrain injury(TBI)due to their multi-target and multi-pathway mode of action.Material&Methods:This study investigates the protective mechanisms and benefits of PDMSCs in mitigating the effects of controlled cortical impact(CCI)in rats and glutamate-induced oxidative stress injury in HT22 cells in vitro.Our primary objective is to provide evidence supporting the clinical application of PDMSCs.Results:In the in vivo arm of our investigation,we observed a swift elevation of matrix metalloproteinase-9(MMP-9)in the proximal cortex of injured brain tissues after CCI.PDMSCs,distinguished by their heightened expression of metalloproteinase tissue inhibitors-1 and-2(TIMP-1 and TIMP-2):were intravenously administered via the caudal vein.This intervention yielded significant reductions in the permeability of the blood-brain barrier(BBB):the extent of brain edema,the levels of inflammatory cytokines IL-1βand TNF-αin damaged brain tissue,and the activation status of microglia in CCI-afflicted rats.In the realm of in vitro experiments,PDMSC-conditioned media demonstrated substantial reductions in mortality rates and cleaved caspase-3 levels in glutamate-induced HT22 cells compared with conventional media.Notably,this advantage was negated upon the introduction of neutralizing antibodies targeting TIMP-1 and TIMP-2.Conclusion:Collectively,our findings underscore the potential of PDMSCs in alleviating oxidative stress injury and secondary brain injury in the pathological process of TBI.

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

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

Metalloproteinases as mediators of inflammation and the eyes： molecular genetic underpinnings governing ocular pathophysiology

There are many vision threatening diseases of the eye affecting millions of people worldwide. In this article, we are summarizing potential role of various matrix metalloproteinases （MMPs）; the Zn （2＋）-dependent endoproteases in eye health along with pathogenesis of prominent ocular diseases such as macular degeneration, diabetic retinopathy, and glaucoma via understanding MMPs regulation in affected patients, interactions of MMPs with their substrate molecules, and key regulatory functions of tissue inhibitor of metalloproteinases （TIMPs） towards maintaining overall homeostasis.

Structure,expression,and developmental function of early divergent forms of metalloproteinases in Hydra

Metalloproteinases have a critical role in a broad spectrum of cellular processesranging from the break-down of extracellular matrix to the processing of signaltransduction-related proteins.These hydrolytic functions underlie a variety of mechanisms related to developmental processes as well as disease states.Structural analysis of metalloproteinases from both invertebrate and vertebrate species indicates that these enzymes are highly conserved and arose early during metazoan evolution.In this regard,studies from vari-ous laboratories have reported that a number of classes of metalloproteinases are found in hydra,a member of Cnidaria,the second oldest of existing animal phyla.These studies demonstrate that the hydra genome contains at least three classes of metalloproteinases to include members of the 1)astacin class,2)matrix met-alloproteinase class,and 3)neprilysin class.Functional studies indicate that these metalloproteinases play diverse and important roles in hydra morphogenesis and cell differentiation as well as specialized functions in adult polyps.This article will review the structure,expression,and function of these metalloproteinases in hydra.

Complex role of matrix metalloproteinases in angiogenesis

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and Promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly,TIMP-4 inhibit neovascularisation. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogehesis by converting plasndnogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide importal information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.

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

AIM:To assess expression of matrix metalloproteinases 2(MMP2)and MMP9 in gastric cancer,superficial gastritis and normal mucosa,and to measure metalloproteinase activity.METHODS:MMP2 and MMP9 mRNA expression was determined by quantitative real-time polymerase chain reaction.Normalization was carried out using three different factors.Proteins were analyzed by quantitative gelatin zymography(qGZ).RESULTS:18S ribosomal RNA(18SRNA)was very highly expressed,while hypoxanthine ribosyltransferase-1(HPRT-1)was moderately expressed.MMP2 was highly expressed,while MMP9 was not detected or lowly expressed in normal tissues,moderately or highly expressed in gastritis and highly expressed in cancer.Relative expression of 18SRNA and HPRT-1 showed no significant differences.Significant differences in MMP2 and MMP9 were found between cancer and normal tissue,but not between gastritis and normal tissue.Absolute quantification of MMP9 echoed this pattern,but differential expression of MMP2 proved conflictive.Analysis by qGZ indicated significant differences between cancer and normal tissue in MMP-2,total MMP-9,250 and 110 kDa bands.CONCLUSION:MMP9 expression is enhanced in gastric cancer compared to normal mucosa;interpretation of differential expression of MMP2 is difficult to establish.

The Role of Host-derived Dentinal Matrix Metalloproteinases in Reducing Dentin Bonding of Resin Adhesives

Dentin matrix metalloproteinases （MMPs） are a family of host-derived proteolytic enzymes trapped within mineralized dentin matrix, which have the ability to hydrolyze the organic matrix of demineralized dentin. After bonding with resins to dentin there are usually some exposed collagen fibrils at the bottom of the hybrid layer owing to imperfect resin impregnation of the demineralized dentin matrix. Exposed collagen fibrils might be affected by MMPs inducing hydrolytic degradation, which might result in reduced bond strength.Most MMPs are synthesized and released from odontoblasts in the form of proenzymes, requiring activation to degrade extracellular matrix components. Unfortunately, they can be activated by modem self-etch and etch-and-rinse adhe- sives. The aim of this review is to summarize the current knowledge of the role of dentinal host-derived MMPs in dentin matrix degradation. We also discuss various available MMP inhibitors, especially chlorhexidine, and suggest that they could provide a potential pathway for inhibiting collagen degradation in bonding interfaces thereby increasing dentin bonding durability.

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases(MMPs). Degradation of extracellular matrix(ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-teinase(TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK(reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2,-9 and-14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species(ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.

Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury:A review

Matrix metalloproteinases(MMPs) are a family ofproteases using zinc-dependent catalysis to break down extracellular matrix(ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion(I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury.

EXPRESSION OF mRNA FOR MEMBRANE-TYPE 1, 2, AND 3 MATRIX METALLOPROTEINASES IN HUMAN LARYNGEAL CANCER

To investigate correlation of expressions of membrane-type 1, 2, and 3 matrix metalloproteinases (MT1, MT2, and MT3-MMP) to the invasion and metastases in laryngeal cancer. Methods Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the mRNA level of MT1, MT2, and MT3-MMP in 24 patients with laryngeal cancer. The relationships of these three MT-MMP expressions to clinico-pathology were analyzed by statistics. Results The expressions of MT1, MT2, and MT3-MMP were significantly higher in laryngeal cancer tissues than those in para-tumorous tissues (P < 0.01) and had a close relationship with invasive depth (P < 0.05). But no significantly different expressions of these three MT-MMPs were found in different primary location and different histological grade of laryngeal cancer (P > 0.05). The expression of MT1-MMP was obviously higher in patients with metastatic lymph nodes than that in patients without metastatic lymph nodes (P < 0.05). Conclusion MT1, MT2, and MT3-MMP play an important role in the progression of laryngeal cancer, and MT1-MMP may serve as a reliable marker in estimating invasive and metastatic potency of laryngeal cancer. Suppressing expressions of MT1, MT2, and MT3-MMP early may inhibit the invasion and metastases of laryngeal cancer.

Matrix metalloproteinases and their expression in mammary gland

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

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

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.

Effect of heparin on high glucose induced proliferation and expression of matrix metalloproteinases in normal human mesangial cells

Background The pathogenesis of diabetic nephropathy (DN) is a complex pathophysiological process.Its precise mechanism is not fully known. In recent years it has been recognized that synthesis of various extracelluar matrix (ECM) components may increase, and that degradation of ECM may decrease in DN. It was reported heparin could inhibit mesangial cells proliferation in vitro. The main aim of this study is to explore whether heparin inhibits proliferation of mesangial cells grown in high glucose concentration and to measure the effect of heparin on matrix metalloproteinases (MMPs) expression in mesangial cells. Methods The medium contained either low glucose (5 mmol/L) or high glucose (25 mmol/L). The concentrations of heparin in the culture medium were 0, 25, 50,100, 200 or 400 μg/mL. A metabolic (WST-1) assay was used to measure mesangial cell proliferation and Western blot analysis was used to measure MMPs expression of mesangial cells. Results Normal human mesangial cell (NHMC) proliferation was higher in high glucose (HG) medium than in low glucose (LG) medium. They showed a 1.93 fold expansion after 72 h in high glucose in contrast to a 1.63 fold expansion in low glucose. In the presence of heparin, mesangial cells proliferation was inhibited, which was more obvious at high glucose concentrations than at low glucose concentrations. In high glucose, with heparin concentration of 50, 100, 200 and 400 μg/mL, the mesangial cells showed a 0. 61 fold, 0.52 fold, 0.52 fold and 0.41 fold reductions in cell number compared to cells grown without heparin. In low glucose, only concentrations of 200 μg/mL and 400 μg/mL showed reduction in cell number, namely 0.54 fold and 0.45 fold, when compared to cells grown without heparin. In Western blot analysis,MMP1, MMP2, MMP3 and MMP9 was expressed by mesangial cells expressed in both high and low glucose concentrations, which was more prominent in high glucose medium. Incubation of heparin further increased expression of MMP1, MMP2, MMP3 and MMP9. Conclusions This study suggests that glucose can accelerate mesangial cell proliferation while heparin can reduce proliferation, being more obvious at high glucose concentrations. Higher glucose concentrations led to increased MMP expression, which may take part in the regulation of mesangial matrix synthesis and degradation. Addition of heparin resulted in a corresponding increase in MMP expression, most notably at high glucose concentrations, indicating a potentially renoprotective role in DN.

Structure, expression, and developmental function of early divergent forms of metalloproteinases in Hydra

Metalloproteinases have a critical role in a broad spectrum of cellular processes ranging from the break-down of extracellulax matrix to the processing of signal transduction-related proteins. These hydrolyticfunctions underlie a variety of mechanisms related to developmental processes as well as disease states.Structural analysis of metalloproteinases from both invertebrate and vertebrate species indicates that theseenzymes are highly conserved and arose early during metazoan evolution. In this regard, studies from vari-ous laboratories have reported that a number of classes of metalloproteinases are found in hydra, a memberof Cnidaria, the second oldest of existing animal phyla. These studies demonstrate that the hydra genomecontains at least three classes of metalloproteinases to include members of the 1) astacin class, 2) matrix met-alloproteinase class, and 3) neprilysin class. Functional studies indicate that these metalloproteinases playdiverse and important roles in hydra morphogenesis and cell differentiation as well as specialized functionsin adult polyps. This article will review the structure, expression, and function of these metalloproteinasesin hydra.

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

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.

Expression of matrix metalloproteinases and tissue inhibitor metalloproteinases increases in X-irradiated rat ileum despite the disappearance of CD8a T cells

AIM： To investigate their expression and activity in the rat ileum after exposure to ionizing radiation along with that of the cellular effectors and molecular mediators involved in the regulation of MMPs. METHODS： Rats were exposed to a single 10-Gy dose of X-rays delivered to the abdomen. A combination of methods, such as zymography, immunohistochemistry and real time reverse transcriptase-polymerase chain reaction, were used to localize and quantify MMPs and the molecules involved in MMP activating and inhibitory pathways （plasmin/ plasminogen, TIMPs）, CD^8＋, as well as inflammatory （interleukin （IL）-1β, IL-8, tumor necrosis factor-s, TNF-α） and fibrogenic mediators （transforming growth factor- β1-3） within ileal tissue at 1, 3, and 7 d after irradiation. RESULTS： A marked increase in MMP-2 and -14 mRNA and protein levels associated with an increased activity of MMP-2 was observed in irradiated ileal tissue. MMP-2 and -14 expression was mainly observed in inflammatory, epithelial, and mesenchymal cells, whereas a slight increase in MMP-3 expression was detected in the few infiltrating macrophages at d i after irradiation. Conversely, MMP-1, -7, and -9 mRNA levels were not found to be affected by abdominal irradiation. Irradiation was found to induce disappearance of CD^8＋ cells. Furthermore, we have observed that TNF-α and IL-1β protein levels increased 6 h after irradiation, whereas those of IL-8 only increased after 3 d and was concomitant with neutrophil infiltration. In addition, the expressions of molecules involved in MMP activating and inhibitory pathways （urokinase-type plasminogen activator andtissue-type plasminogen activator; TIMP-1, TIMP-2, and plasminogen activator-inhibitor-i） were found to be increased after abdominal irradiation. CONCLUSION： This study showed that abdominal irradiation induces an acute remodeling of the ileum associated with an increased expression of MMPs and TIMPs that do not involve CD^8＋ T cells but involve mesenchymal and epithelial cells, although to a lesser extent, and probably even soluble inflammatory and fibrogenic mediators.

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

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.

Observation on In Situ Hybridization and Immunocytochemistry of Matrix Metalloproteinases in Rat Pancreas

In situ hybridization and immunocytochemical techniques were employed to examine the expression of matrix metalloproteinases 1 (MMP 1) and to identify the pattern of its distribution in rat pancreas. The results indicated that the signal of MMP 1 mRNA and MMP 1 positive immunoreaction were detected in some fiberoblasts around interlobular ducts and exocrine cell in margin acinus of some lobules, but the signal of MMP 1 mRNA and MMP 1 positive immunoreaction could not be detected in most of other acinus and islets of pancreas. It is concluded that the expression of MMP 1 in above cells of rat might play an important role in acinar proliferation and differentiation of rat pancreatic tissues.

Time-dependent matrix metalloproteinases and tissue inhibitor of metalloproteinases expression change in fusarium solani keratitis

AIM： To investigate matrix metalloproteinases（MMPs）and tissue inhibitor of metalloproteinases（TIMPs）expression during the progress of fusarium solani（F.solani） keratitis in a rat model.· METHODS： A rat model of F.solani keratitis was produced using corneal scarification and a hand-made contact lens. MMPs and TIMPs expressiond were explored in this rat model of F.solani keratitis using real-time polymerase chain reaction（PCR） and DIF.GM6001（400 μmol/m L） was used to treat infected corneas. The keratitis duration, amount and area of corneal neovascularization（CNV） were evaluated.·RESULTS： MMP-3 expression was 66.3 times higher in infected corneas compared to normal corneas. MMP-8,-9,and-13 expressions were significantly upregulated in the mid-period of the infection, with infected- to-normal ratios of 4.03, 39.86, and 5.94, respectively. MMP-2 and-7expressions increased in the late period, with the infected-to-normal ratios of 5.94 and 16.22, respectively.TIMP-1 expression was upregulated in the early period,and it was 43.17 times higher in infected compared to normal corneas, but TIMP-2,-3, and-4 expressions were mildly downregulated or unchanged. The results of DIF were consistent with the result of real-time PCR.GM6001, a MMPs inhibitor, decreased the duration of F.solani infection and the amount and area of CNV.·CONCLUSION： MMPs and TIMPs contributed into the progress of F.solani keratitis.

Matrix metalloproteinases in neural development:a phylogenetically diverse perspective

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.