Tissue Matrix Metalloproteinases Research Articles

N-Terminomic Identification of Intracellular MMP-2 Substrates in Cardiac Tissue.

Proteases are enzymes that induce irreversible post-translational modifications by hydrolyzing amide bonds in proteins. One of these proteases is matrix metalloproteinase-2 (MMP-2), which has been shown to modulate extracellular matrix remodeling and intracellular proteolysis during myocardial injury. However, the substrates of MMP-2 in heart tissue are limited, and lesser known are the cleavage sites. Here, we used degradomics to investigate the substrates of intracellular MMP-2 in rat ventricular extracts. First, we designed a novel, constitutively active MMP-2 fusion protein (MMP-2-Fc) that we expressed and purified from mammalian cells. Using this protease, we proteolyzed ventricular extracts and used subtiligase-mediated N-terminomic labeling which identified 95 putative MMP-2-Fc proteolytic cleavage sites using mass spectrometry. The intracellular MMP-2 cleavage sites identified in heart tissue extracts were enriched for proteins primarily involved in metabolism, as well as the breakdown of fatty acids and amino acids. We further characterized the cleavage of three of these MMP-2-Fc substrates based on the gene ontology analysis. We first characterized the cleavage of sarco/endoplasmic reticulum calcium ATPase (SERCA2a), a known MMP-2 substrate in myocardial injury. We then characterized the cleavage of malate dehydrogenase (MDHM) and phosphoglycerate kinase 1 (PGK1), representing new cardiac tissue substrates. Our findings provide insights into the intracellular substrates of MMP-2 in cardiac cells, suggesting that MMP-2 activation plays a role in cardiac metabolism.

Correlation Between HIF1-A Expression and Airway Remodeling in COPD.

Airway remodeling is a significant pathological characteristic of chronic obstructive pulmonary disease (COPD). In recent years, hypoxia-inducible factor 1-α (HIF-1α), a member of the hypoxia-inducible factor protein family, has gained attention. However, the potential correlation between HIF-1α and COPD airway remodeling remains unclear. This study explored the expression patterns of HIF-1α in patients with COPD and its association with airway remodelling. This investigation aims to furnish novel insights for the clinical identification of prospective therapeutic targets for ameliorating COPD-related airway remodelling. A total of 88 subjects were included, consisting of 28 controls and 60 COPD patients. Various staining methods were employed to observe the pathological changes in airway tissues. Immunohistochemistry was utilized to detect the expression of HIF-1α and MMP9 (matrix metalloproteinase 9) in airway tissues. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration in serum of HIF-1α and MMP9. Computed tomography (CT) airway parameters were measured in all participants to assess airway remodeling. The relationship between serum HIF-1α and MMP9 concentrations and airway parameters was analyzed. Staining of airway structures in COPD patients revealed significant pathological changes associated with airway remodelling, including mixed cilia and subepithelial fibrosis. The expression of HIF-1α and MMP9 was significantly higher in both human airway tissue and serum compared to controls. Chest CT scans exhibited typical imaging features of airway remodeling and increased airway parameters. The findings suggest a correlation between increased HIF-1α expression and COPD airway remodelling. This study provides novel evidence that HIF-1α may be a potential biomarker for airway remodelling in COPD patients.

Deciphering the role of wound healing genes in skin cutaneous melanoma: Insights into expression, methylation, mutations, and therapeutic implications.

Skin Cutaneous Melanoma (SKCM) is a form of cancer that originates in the pigment-producing cells, known as melanocytes, of the skin. Delay wound healing is often correlated with the occurrence of and progression of SKCM. In this comprehensive study, we investigated the intricate roles of two important wound healing genes in SKCM, including Matrix Metalloproteinase-2 (MMP2) and Matrix Metalloproteinase-9 (MMP9). Through a multi-faceted approach, we collected clinical samples, conducted molecular experiments, including RT-qPCR, bisulphite sequencing, cell culture, cell Counting Kit-8, colony formation, and wound healing assays. Beside this, we also used various other databases/tools/approaches for additional analysis including, UALCAN, GEPIA, HPA, MEXPRESS, cBioPortal, KM plotter, DrugBank, and molecular docking. Our results revealed a significant up-regulation of MMP2 and MMP9 in SKCM tissues compared to normal counterparts. Moreover, promoter methylation analysis suggested an epigenetic regulatory mechanism. Validations using TCGA datasets and immunohistochemistry emphasized the clinical relevance of MMP2 and MMP9 dysregulation. Functional assays demonstrated their synergistic impact on proliferation and migration in SKCM cells. Furthermore, we identified potential therapeutic candidates, Estradiol and Calcitriol, through drug prediction and molecular docking analyses. These compounds exhibited binding affinities, suggesting their potential as MMP2/MMP9 inhibitors. Overall, our study elucidates the diagnostic, prognostic, and therapeutic implications of MMP2 and MMP9 in SKCM, shedding light on their complex interplay in SKCM occurrence and progression.

Inhibition of heme oxygenase 1 alleviates thoracic aortic aneurysm via restoration of extracellular matrix

BackgroundThoracic aortic aneurysm (TAA) is a silent but life-threatening cardiovascular disease. Heme oxygenase 1 (HO-1) plays an important role in the cardiovascular diseases but is poorly understood in TAA. This study aims at investigating the role of HO-1 in TAA. MethodsSingle-cell RNA sequencing, Western blot and histological assay were performed to identify specific cellular expression of HO-1 in both human and β-aminopropionitrile (BAPN)-induced mice TAA. Zinc protoporphyrin (ZnPP), a pharmacological inhibitor of HO-1, was used to investigate whether inhibition of HO-1 could attenuate BAPN-induced TAA in rodent model. Histological assay, Western blot assay, and mRNA sequencing were further performed to explore the underlying mechanisms. ResultsSingle-cell transcriptomic analyses of 113,800 thoracic aortic cells identified an increase of HO-1(+) macrophage in aneurysmal thoracic aorta from BAPN-induced TAA mice and TAA patients. Histological assay verified HO-1 overexpression in clinical TAA specimens, which was co-localized with CD68(+) macrophage. HO-1(+) macrophage was closely associated with pro-inflammatory response and immune activation. Inhibition of HO-1 through ZnPP significantly alleviated BAPN-induced TAA in mice and restored extracellular matrix (ECM) in vivo. Further experiments showed that ZnPP treatment suppressed the expression of matrix metalloproteinases (MMPs) in aneurysmal thoracic aortic tissues from BAPN-induced TAA mice, including MMP2 and MMP9. Macrophages from myeloid specific HO-1 knockout mice displayed weakened pro-inflammatory activity and ECM degradation capability. ConclusionHO-1(+) macrophage subgroup is a typical hallmark of TAA. Inhibition of HO-1 through ZnPP alleviates BAPN-induced TAA in mice, which might work through restoration of ECM via suppressing MMP2 and MMP9 expression.

Insights into ascending aortic aneurysm: Interactions between biomechanical properties of the aortic wall and tissue biomarkers

BackgroundIt remains difficult to understand the association between the local mechanical properties of ascending thoracic aorta aneurysm (asTAA), its tissue, and its cellular and molecular changes. The purpose of our study was to investigate the relationship between biomechanical properties, histopathological findings, and tissue biomarkers of asTAA. MethodsIntraoperative asTAA samples from 30 patients were studied. All samples were examined histologically and underwent a tensile test. We determined the tensile strength (σв, MPa), the strain (ε, mm/mm˟%), and the area under the strength-strain curve (S) along with the concentrations of tissue matrix metalloproteinases (MMP-1 et al.) and their inhibitors, their interleukins (IL) -6 -10, and their tumor necrosis factor (TNF) -α. ResultsIt was found that 43.3 % of asTAA patients had atherosclerosis, 3.3 % had aortitis, and 53.3 % of patients had connective tissue dysplasia. Differences in the studied parameters between these subgroups were not found. Age correlated with ε (r = −0.49) and S (r = −0.54). ε was also associated with media fibrosis degree (r = −0.5), collagen/elastin ratio (r = −0.61), and IL-10 (r = 0.52). IL-10 correlated with collagen/elastin ratio (r = −0.58), TNF-α (r = 0.77), and MMP-1 (r = 0.71). ConclusionTissue IL-10 has a protective effect on the elastic structures of the aortic wall and is positively associated with the activity of MMP-1 and pro-inflammatory cytokines. IL-6 is associated with media fibrosis degree, and negatively affects strength-strain parameters of asTAA samples.

Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury.

Exercise training exerts protective effects against sepsis-associated multiple organ dysfunction. This study aimed to investigate whether aerobic exercise protected against sepsis-associated acute kidney injury (AKI) via modulating R-spondin 3 (RSPO3) expression. To investigate the effects of aerobic exercise on lipopolysaccharide (LPS)-induced AKI, LPS (20 mg/kg) was intraperitoneally injected after six weeks of treadmill training. To investigate the role of RSPO3 in LPS-induced AKI, wild-type (WT) or inducible endothelial cell-specific RSPO3 knockout (RSPO3EC-/- ) mice were intraperitoneally injected with 12 mg/kg LPS. RSPO3 was intraperitoneally injected 30 min before LPS treatment. Aerobic exercise-trained mice were more resistant to LPS-induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. Exercise training restored the LPS-induced decreases in serum and renal RSPO3 levels. Exercise or RSPO3 attenuated, whereas inducible endothelial cell-specific RSPO3 knockout exacerbated LPS-induced renal glycocalyx loss, endothelial hyperpermeability, inflammation, and AKI. Bioinformatics analysis results revealed significant increases in the expression of matrix metalloproteinases (MMPs) in kidney tissues of mice exposed to sepsis or endotoxaemia, which was validated in renal tissue from LPS-exposed mice and LPS-treated human microvascular endothelial cells (HMVECs). Both RSPO3 and MMPs inhibitor restored LPS-induced downregulation of tight junction protein, adherens junction protein, and glycocalyx components, thus ameliorating LPS-induced endothelial leakage. Exercise or RSPO3 reversed LPS-induced upregulation of MMPs in renal tissues. Increased renal expression of RSPO3 contributes to aerobic exercise-induced protection against LPS-induced renal endothelial hyperpermeability and AKI by suppressing MMPs-mediated disruption of glycocalyx and tight and adherens junctions.

Intervention of modified Shenling Baizhu San on peritoneal fibrosis induced by peritoneal dialysate with different sugar concentration in rats

To investigate the effect of modified Shenling Baizhu San on the pathological changes and extracellular matrix (ECM) in rats with peritoneal fibrosis induced by peritoneal dialysate fluid (PDF) with different sugar concentration and its mechanism. Seventy male Sprague-Dawley (SD) rats were randomly divided into control group, different sugar content PDF model groups and corresponding traditional Chinese medicine intervention groups, with 10 rats in each group. Peritoneal fibrosis model was reproduced by intraperitoneal injection of 100 mL×kg-1×d-1 PDF containing 1.5%, 2.5% and 4.25% sugar once a day for 8 weeks. The rats in the control group were given the same amount of normal saline. The rats in the traditional Chinese medicine intervention groups were treated with gavage of 10 mL/kg of modified Shenling Baizhu San (containing 2.014 g crude drug per liter) immediately after modeling. The PDF model groups and the control group were given the same amount of normal saline by gavage. After 8 weeks, the peritoneal ultrafiltration volume of rats in each group was measured. The peritoneal tissues were collected and stained with hematoxylin-eosin (HE), and the structural changes and thickness of the parietal peritoneum were observed under a light microscope. After Masson staining, the deposition of collagen fibers was observed under a light microscope. Western blotting was used to detect the protein expressions of E-cadherin, α-smooth muscle actin (α-SMA) and Vimentin, the main components of ECM in parietal peritoneum. The positive expressions of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-β1 (TGF-β1) were detected by immunohistochemical staining. Compared with the control group, PDF with different sugar contents could induce peritoneal fibrosis in rats, and the degree of fibrosis was gradually aggravated with the increase of sugar content, which was manifested as peritoneal thickening, increased collagen fiber deposition, decreased peritoneal ultrafiltration volume, down-regulated expressions of E-cadherin and MMP-9 in peritoneal tissue, and up-regulated expressions of α-SMA, Vimentin, TIMP-1 and TGF-β1, and the pathological changes and ECM accumulation in peritoneal tissues were more serious in 4.25% PDF model group. After the intervention of modified Shenling Baizhu San, compared with the corresponding PDF model groups, the peritoneal fibrosis of rats was improved to varying degrees, and the effect of the 4.25% PDF+traditional Chinese medicine intervention group was more significant, the parietal peritoneum was significantly thinner (μm: 101.86±16.01 vs. 140.65±10.13, P < 0.05), collagen fiber deposition was significantly reduced, peritoneal ultrafiltration volume was significantly increased (mL: -0.01±3.45 vs. -3.53±1.84, P < 0.05), the expressions of E-cadherin and MMP-9 in peritoneal tissues were significantly up-regulated [E-cadherin protein (E-cadherin/β-actin): 0.84±0.08 vs. 0.28±0.05, MMP-9 (A value): 0.60±0.15 vs. 0.37±0.01, both P < 0.05], and the expressions of α-SMA, Vimentin, TIMP-1 and TGF-β1 were significantly down-regulated [α-SMA protein (α-SMA/β-actin): 0.36±0.08 vs. 1.05±0.09, Vimentin protein (Vimentin/β-actin): 0.53±0.07 vs. 1.19±0.04, TIMP-1 (A value): 0.49±0.06 vs. 0.87±0.02, TGF-β1 (A value): 0.67±0.04 vs. 0.89±0.10, all P < 0.05]. The degree of peritoneal fibrosis gradually increased with the increase of PDF sugar content in rats. Modified Shenling Baizhu San can improve peritoneal fibrosis induced by PDF with different sugar contents in rats, and the mechanism is related to the changes in the expression of fibrosis markers and ECM accumulation.

A Blend of Tamarindus Indica and Curcuma Longa Extracts Alleviates Monosodium Iodoacetate (MIA)-Induced Osteoarthritic Pain and Joint Inflammation in Rats

Background and objective NXT15906F6 (TamaFlexTM) is a proprietary herbal composition containing Tamarindus indica seeds and Curcuma longa rhizome extracts. NXT15906F6 supplementation has been shown clinically effective in reducing knee joint pain and improving musculoskeletal functions in healthy and knee osteoarthritis (OA) subjects. The objective of the present study was to assess the possible molecular basis of the anti-OA efficacy of NXT15906F6 in a monosodium iodoacetate (MIA)-induced model of OA in rats. Methods Healthy male Sprague Dawley rats (age: 8–9 wk body weight, B.W.: 225–308 g (n = 12) were randomly assigned to one of the six groups, (a) vehicle control, (b) MIA control, (c) Celecoxib (10 mg/kg B.W.), (d) TF-30 (30 mg/kg B.W.), (e) TF-60 (60 mg/kg B.W.), and (f) TF-100 (100 mg/kg B.W.). OA was induced by an intra-articular injection of 3 mg MIA into the right hind knee joint. The animals received either Celecoxib or TF through oral gavage over 28 days. The vehicle control animals received intra-articular sterile normal saline. Results Post-treatment, NXT15906F6 groups showed significant (p < 0.05) dose-dependent pain relief as evidenced by improved body weight-bearing capacity on the right hind limb. NXT15906F6 treatment also significantly reduced the serum tumor necrosis factor-α (TNF-α, p < 0.05) and nitrite (p < 0.05) levels in a dose-dependent manner. mRNA expression analyses revealed the up-regulation of collagen type-II (COL2A1) and down-regulation of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13) in the cartilage tissues of NXT15906F6-supplemented rats. Cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) protein expressions were down-regulated. Decreased immunolocalization of NF-κβ (p65) was observed in the joint tissues of NXT15906F6-supplemented rats. Furthermore, microscopic observations revealed that NXT15906F6 preserved MIA-induced rats’ joint architecture and integrity. Conclusion NXT15906F6 reduces MIA-induced joint pain, inflammation, and cartilage degradation in rats.

Protective effects of Cu/Zn-SOD and Mn-SOD on UVC radiation-induced damage in NIH/3T3 cells and murine skin

Superoxide dismutase (SOD) is an antioxidant enzyme with multiple metal cofactors that can specifically clear reactive oxygen species (ROS), which plays an important role in a variety of ultraviolet-induced lesions. Therefore, SOD has the anti-ultraviolet radiation effect. The objective of this study was to compare the differences in the anti-ultraviolet radiation effect of SOD with distinct metal cofactors: Cu/Zn-SOD and Mn-SOD. SOD was first purified using hydrophobic interaction chromatography and ion-exchange chromatography. Second, the Methylthiazolyldiphenyl-tetrazolium bromide method and cell senescence kits were used to study the protective effect of SOD on ultraviolet-induced cell damage. Finally, the protective effect of SOD on ultraviolet -induced skin damage was histopathologically evaluated, and the expression levels of malondialdehyde (MDA) and matrix metalloproteinases (MMPs) in tissues were detected. The results showed that Cu/Zn-SOD was superior to Mn-SOD in promoting cell proliferation, alleviating cell damage, protecting skin structure, and regulating the expression levels of MDA and MMPs, and it has no side effects. In conclusion, Cu/Zn-SOD had a better anti-ultraviolet radiation effect than Mn-SOD, and it can be used in anti-aging and anti-ultraviolet skin-care products.

Complex studies on gene polymorphisms of MMP2, MMP3, MMP9 matrix metalloproteinases and TIMP1, TIMP2 tissue inhibitors of metalloproteinases in the patients with primary open-angle glaucoma

Abnormal expression of matrix metalloproteinases (MMP) in watery moisture in patients with glaucoma may affect regulation of intraocular pressure (IOP). MMP activity is regulated by tissue metalloproteinase inhibitors (TIMP). The imbalance between tissue metalloproteinase inhibitors and matrix metalloproteinases may contribute to the development of glaucoma. Genetic factors, including polymorphism of matrix metalloproteinase genes and their inhibitors genes, can regulate the level of their expression, thereby affecting susceptibility to disease. Our aim was to perform comprehensive analysis of the MMP2 (rs243865), MMP3 (rs3025058), MMP9 (rs3918242) polymorphisms, and TIMP1 (rs4898), TIMP2 (rs8179090) tissue inhibitor genes polymorphisms in the patients with stage II (advanced) primary open-angle glaucoma.99 patients (52 men and 47 women) with a verified diagnosis of stage II primary open-angle glaucoma were examined. The comparison group consisted of 100 age-matched persons (81 women and 19 men) without ophthalmic disorders. The single-nucleotide polymorphisms in promoter regions of MMP2, TIMP1, TIMP2 genes were analyzed by the TaqMan method, the MMP3 and MMP9 genes, by means of restriction fragment length polymorphism technique. Statistical evaluation was carried out using the specialized package of IBM SPSS Statistics 23 programs. The critical level of significance was assumed to be 0.05.The differences in the distribution of MMP2 rs243865 allelotypes with decreased frequency of TT genotype were found in the patient group and, vice versa, increased heterozygosity rates were revealed among them. In addition, the frequency of TIMP1 rs4898 heterozygous genotype was decreased in this group as compared to control sample. Four MMP/TIMP complex genotypes are positively associated with the development of pathology. Two of them were of bilocus type, i.e., MMP2-1306TC:TIMP2-418GG, and MMP3-11715A6A:TIMP1 372CC whereas two three-locus constellations were revealed, i.e., MMP2-1306TC:MMP9-1562CC:TIMP2- 418GG, and MMP3-11715A6A:MMP9-1562CC:TIMP1 372CC. There are nine MMP/TIMP complexes, the frequency of which in patients with glaucoma was significantly reduced when compared with control group.Polymorphism of regulatory regions of MMP2, MMP3, MMP9 genes and distinct gene variants of their inhibitors (TIMP1, TIMP2 genes) can be considered potential markers of the POAG development associated with an imbalance of MMP/TIMP activities.

Ex Vivo Analysis of an Association of Mechanical Strength of Dilated Ascending Aorta with Tissue Matrix Metalloproteinases and Cytokines.

We analyzed the associations of the mechanical strength of dilated ascending aorta wall (intraoperative samples from 30 patients with non-syndromic aneurysms) with tissue MMPs and the cytokine system. Some samples were stretched to break on an Instron 3343 testing machine and the tensile strength was calculated; others were homogenized and the concentrations of MMP-1, MMP-2, MMP-7, their inhibitors (TIMP-1 and TIMP-2), and pro- and anti-inflammatory cytokines were determined by ELISA. Direct correlations between aortic tensile strength and concentrations of IL-10 (r=0.46), TNFα (r=0.60), and vessel diameter (r=0.67) and an inverse correlation with patient's age (r=-0.59) were revealed. Compensatory mechanisms supporting the strength of the ascending aortic aneurysm are possible. No associations of MMP-1, MMP-7, TIMP-1, and TIMP-2 with tensile strength and aortic diameter were found.

Investigation of Matrix Metalloproteinase-2, Matrix Metalloproteinase-9, Tissue Matrix Metalloproteinase Inhibitor-1, and Tissue Matrix Metalloproteinase Inhibitor-2 levels in preeclamptic and eclamptic pregnancy

Investigation of Matrix Metalloproteinase-2, Matrix Metalloproteinase-9, Tissue Matrix Metalloproteinase Inhibitor-1, and Tissue Matrix Metalloproteinase Inhibitor-2 levels in preeclamptic and eclamptic pregnancy

TLR9 and Glioma: Friends or Foes?

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma.

Chlorogenic Acid-Conjugated Nanoparticles Suppression of Platelet Activation and Disruption to Tumor Vascular Barriers for Enhancing Drug Penetration in Tumor.

Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor-associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on FeIII -doped C3 N4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation- and platelet-inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition-assisted theranostics based on nanomedicines.

Factors of proteolysis in blood and urine as prognostic markers of progression of Alport syndrome in children

BACKGROUND. Alport syndrome is a rare hereditary kidney disease that causes progressive renal failure. There are significant differences in the progression of the disease between patients with Alport syndrome. Identifying patients with a high risk of rapid progression in order to optimally balance benefits and risks for prescribing therapy has become particularly important at this time. In this study, we wanted to assess whether the factors of proteolysis in blood and urine are associated with the nature of the course and to assess their prognostic value for children with Alport syndrome. THE AIM: To determine the level in blood serum and urinary excretion of MMP-2, MMP-3 and MMP-9 and their inhibitors TIMP-1 and 2, PAI-I, to show the relationship of their changes with the character of the course of Alport syndrome in children as an additional criterion for progression. PATIENTS AND METHODS. The study included 32 children with Alport syndrome. The level of MMP-2, MMP-3 and MMP-9 and their inhibitors TIMP-1 and 2, PAI-I, in blood serum and urine was determined by ELISA. A decrease in eGFR of ≥ 30 % at 2 years from baseline was chosen to indicate a progressive course of Alport syndrome. RESULTS. 28.1 % of children with Alport syndrome had a progressive course of the dis ease, 71.9 % had a slowly progressive course. The frequency of a decrease in MMP-9 and an increase in TIMP-1 both in blood (88.9 versus 43.5 % and 77.8 versus 21.7 %; p = 0.044 and 0.006, respectively) and in urine (100 versus 47, 8 % and 88.9 versus 30.4 %; 0.012 and 0.005, respectively) were statistically significantly more often detected in children with Alport syndrome with a progressive course of the disease than in a slowly progressive course. CONCLUSION. Type 9 matrix metalloproteinase and type 1 tissue matrix metalloproteinase inhibitor can be considered as risk factors for the progression of Alport syndrome in children.

Assessment of tissue expression of matrix metalloproteinase-9 level in patients with vitiligo and its relation to disease pattern, activity, and severity

Background Vitiligo is a common acquired depigmentary disorder characterized by milky-white cutaneous macules devoid of identifiable functional melanocytes of unknown origin. Several hypotheses have been advanced to explain the link between matrix metalloproteinase-9 (MMP-9) and vitiligo. Aim We aimed to compare the tissue expression of MMP-9 in vitiligo lesions with that of healthy controls. Patients and methods A case–control study was performed to evaluate MMP-9 levels by punch biopsies using an immunohistochemistry technique in lesional and nonlesional tissues of the same patient with vitiligo and in comparison with healthy controls. The study included 20 patients (10 patients with vitiligo and 10 healthy controls). Patients included were 18 years of age and older of both sexes, any duration, and any subtype. Results MMP-9 expression was found to be lower in the lesional skin of patients with vitiligo at the basal cell layer, follicular epithelium, and stromal cell layer when compared with nonlesional skin of the same patient with vitiligo and matched control individuals. Conclusion Tissue MMP-9 imbalance has a role in the etiopathogenesis of vitiligo. The low MMP-9 tissue expression may not facilitate the migration of melanoblasts. Tissue MMP-9 is a significant predictor of severity of vitiligo.

Matrix metalloproteinase-7 promotes chronic kidney disease progression via the induction of inflammasomes and the suppression of autophagy

Deposition of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and inflammation are crucial processes in chronic kidney disease (CKD) progression. The matrix metalloproteinases (MMPs) belong to a major enzyme group of proteinases that are involved in ECM degradation. MMP controls multiple biological processes, such as cell proliferation, EMT and apoptosis. The present study identified the roles of MMP7 in CKD progression. We demonstrated the transcriptional profiles of MMPs in kidney tissues of CKD patients in the Gene Expression Omnibus (GEO) data repository. MMP7 mRNA level was markedly upregulated in kidney tissues of CKD patients. MMP7 overexpression activated the NLRP3 and NLRP6 inflammasomes and increased fibrosis-related proteins in kidney cells. MMP7 inhibited oxidative stress-induced apoptosis and rapamycin-induced autophagy. We found that MMP7 expression in the kidney was increased in various CKD animal models. Knockdown of MMP7 affected renal function and renal fibrosis in a folic acid-induced CKD model. The inhibition of MMP7 decreased fibrosis and NLRP3 and NLRP6 inflammasomes and induced autophagy in kidney tissues. Taken together, these results provide insight into targeting MMP7 as a therapeutic strategy for CKD.

Matrix Metalloproteinases in Dental and Periodontal Tissues and Their Current Inhibitors: Developmental, Degradational and Pathological Aspects.

Objectives: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value. Design: The sections of this review discuss MMPs’ involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years. Results: 119 published papers, two textbooks and two doctoral theses were selected for preparing the current review. Conclusions: MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens.

Matrix Metalloproteinase-Targeted SPECT/CT Imaging for Evaluation of Therapeutic Hydrogels for the Early Modulation of Post-Infarct Myocardial Remodeling.

Following myocardial infarction (MI), maladaptive upregulation of matrix metalloproteinase (MMP) alters extracellular matrix leading to cardiac remodeling. Intramyocardial hydrogel delivery provides a vehicle for local delivery of MMP tissue inhibitors (rTIMP-3) for MMP activity modulation. We evaluated swine 10-14days following MI randomized to intramyocardial delivery of saline, degradable hyaluronic acid (HA) hydrogel, or rTIMP-3 releasing hydrogel with an MMP-targeted radiotracer (99mTc-RP805), 201Tl, and CT. Significant left ventricle (LV) wall thinning, increased wall stress, reduced circumferential wall strain occurred in the MI region of MI-Saline group along with left atrial (LA) dilation, while these changes were modulated in both hydrogel groups. 99mTc-RP805 activity increased twofold in MI-Saline group and attenuated in hydrogel animals. Infarct size significantly reduced only in rTIMP-3 hydrogel group. Hybrid SPECT/CT imaging demonstrated a therapeutic benefit of intramyocardial delivery of hydrogels post-MI and reduced remodeling of LA and LV in association with a reduction in MMP activation.

Effects of non-muscle myosin Ⅱ silenced bone marrow-derived mesenchymal stem cells transplantation on lung extracellular matrix in rats after endotoxin/lipopolysaccharide-induced acute lung injury

Effects of non-muscle myosin Ⅱ silenced bone marrow-derived mesenchymal stem cells transplantation on lung extracellular matrix in rats after endotoxin/lipopolysaccharide-induced acute lung injury