Exploring S100A8/A9, Neopterin, and MMP3 in Familial Mediterranean Fever.

Familial mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n=75), comprising from FMF patients during an attack (n=20), the same FMF patients during the attack-free period (n=14), patients with appendicitis (n=24), and healthy volunteers (n=17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (p-values: <0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (p-value: <0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (p-values: <0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (p-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging.

Mapping the Binding Sites of MMPs on Types II and III Collagens Using Triple-Helical Peptide Toolkits.

Libraries of triple-helical collagen-like peptides (Collagen Toolkits) have helped to define collagens II and III binding specificities of numerous collagen-binding proteins. Here I describe a simple solid-phase binding assay utilizing a biotin-streptavidin system to screen the Collagen Toolkits for binding of two distinct matrix metalloproteinases (MMPs) implicated in cancer: the collagenolytic MMP1 (collagenase 1) and the non-collagenolytic MMP3 (stromelysin 1). The screening revealed markedly disparate binding footprints of these MMPs on collagens II and III, in line with their distinct biological activities. Analogous screening of other potentially collagen-binding proteases may shed light on their inherent tissue retention capabilities and their pro- or anti-metastatic potential.

Induction of MMP-3 and MMP-9 expression during Helicobacter pylori infection via MAPK signaling pathways.

BACKGROUND AND AIMS: Helicobacter pylori (H. pylori)-induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP-3 and MMP-9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression. MATERIALS AND METHODS: C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp-3 and Mmp-9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES-1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP-3 and MMP-9 were determined via qPCR and Western blot, respectively. RESULTS: We observed transcriptional activation of Mmp-3 and Mmp-9 as well as aberrant MMP-3 and MMP-9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP-3 and MMP-9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho-p38 and increased phospho-ERK1/2 activity due to crosstalk between MAPK pathways. CONCLUSIONS: H. pylori colonization leads to the upregulation of MMP-3 and MMP-9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis.

Higher Content but Not Activity of Stromelysin-2 (MMP-10) in Comparison to Stromelysin-1 (MMP-3) in Human Renal Carcinoma.

Stromelysin-1 and stromelysin-2 (matrix metalloproteinase 3; MMP-3 and matrix metalloproteinase 10; MMP-10, respectively) are enzymes that activate other metalloproteinases. Apart from collagen, they also degrade elastin, fibronectin, gelatin and laminin. In carcinogenic processes, they are involved in angiogenesis and metastasis. Therefore, the aim of this study was to evaluate the DNA content, expression and activity of both stromelysines in cancers of human kidney. Renal carcinoma tissue samples were analyzed. Low- and high-grade cancer tissues were collected. Control material was collected from part of the kidney opposite to the tumor. DNA content, stromelysines content and stromelysin-1 and stromelysin-2 activity were measured using ELISA and Western blot methods. A higher content of deoxyribonucleic acid in low- and high-grade cancer tissues in comparison to the respective control tissue was observed. Both stromelysines were presented in control and cancer tissues in high-molecular-weight complexes. The content of MMP-10 was significantly higher in comparison to MMP-3 in all investigated tissues. Moreover, the content of stromelysin-2 was significantly higher in high-grade (G3) tissues compared to grade 2 (G2) kidney cancer. A significant decrease in the actual and specific activities of both stromelysines was observed with the increase in renal cancer grade. The presented results may indicate that the degradation of extracellular matrix increases with a higher grade of cancer. Moreover, the elevated content and decreased specific activity of stromelysin-2 in cancer tissue indicate that MMP-10 is mainly present in an inactive form in renal carcinoma. Detailed knowledge of the mechanism and participation of stromelysines in extracellular matrix degradation may be important in understanding the pathomechanism of renal cancer development. Therefore, the potential application of stromelysines in the monitoring or prognosis of kidney cancer should be discussed.

Expression of matrix metalloproteinase-3 and -10 is up-regulated in the periodontal tissues of aged mice.

OBJECTIVE: The present study was designed to investigate the whole transcriptome of periodontal tissues of both young and aged mice to identify the characteristic up-regulation of protease genes with aging and to localize their translated protein products in the periodontal tissues. BACKGROUND: The metzincin protease superfamily is composed of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs. Up-regulation of these extracellular matrix-degrading proteases has been implicated in senescence of tissues and organs, including the skin. However, few studies have investigated the expression profiles of these proteases and potential involvement in aging of periodontal tissues. METHODS: Periodontal tissues with the surrounding mandibular bones were collected from 50- and 10-week-old mice. Total RNA was extracted from the periodontal tissue and analyzed by cap analysis of gene expression (CAGE) to identify differentially expressed genes encoding the metzincin proteases. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the CAGE results, and the phenotypic expression of proteases involved in aging was localized via immunohistochemical analysis. RESULTS: The CAGE results showed that the expression levels of MMP-3, -10, and -12 were up-regulated at 50 weeks. Subsequent qRT-PCR analysis showed that the gene expression levels of MMP-3 and -10 were significantly increased with age. MMP-10 immunoreactivity was localized exclusively in the cementum and alveolar bone adjacent to the periodontal ligament and was stronger and broader in aged mice than young mice. MMP-3 immunoreactivity was localized in the periodontal ligaments at both 10 and 50 weeks. CONCLUSION: In the present study, we demonstrated that the expression of MMP-3 and -10 increased with aging and identified their characteristic localizations in aged periodontal tissues.

ST2 and galectin-3 as novel biomarkers for the prediction of future cardiovascular disease risk in preeclampsia.

The aim of this study was to investigate known cardiovascular disease (CVD) risk biomarkers galectin-3 (Gal-3) and human stromelysin-2 (ST2) levels in preeclampsia (PE) and normotensive pregnancies. A case-control study was conducted in a teaching and research hospital. We performed data analysis involving 45 pregnant women with PE and gestational week (GW) matched 35 normotensive pregnant women. The Gal-3 and ST2 levels were determined by using ELISA kit. Gal-3 values did not differ statistically between PE and control groups (535.1 ng/mL vs. 615.2 ng/mL) (p> .05). ST2 value in the PE group was statistically significantly lower than the control group (33.3 pg/mL vs. PE, 54.5 pg/mL, p ˂ .05). >34 GW patients (late-onset PE) had statistically significantly lower Gal-3 values than the ≤34 GW patients (early-onset PE) (507.1 ng/mL vs. 769.6 ng/mL, p ˂ .05). Late-onset PE patients had significantly lower ST2 values than early-onset patients (26.4 pg/mL vs. 57.9 pg/mL, p ˂ .05). We assume that low Gal-3 values in early-onset PE show a higher risk of cardiac fibrosis although both early and late-onset PE patients had an increased CVD risk later in life. We found the superiority of ST2 levels to Gal-3 levels in PE pregnancies for CVD risk assessment.Impact StatementWhat is already known about this subject? Preeclampsia (PE) in pregnancy is a known risk factor for future cardiovascular disease (CVD) and is also associated with increased mortality from ischaemic heart disease later in life. Studies that investigate patients with a higher risk for CVD in PE pregnancies are lacking.What do the results of this study add? We found different levels of two novel cardiac markers with PE and normotensive pregnancies, and also with early and late-onset PE pregnancies.What are the implications of these findings for clinical practice and/or further research? Different adaptive responses from patients during PE pregnancies via altered levels of cardiac markers could help clinicians to identify women with a higher risk of CVD.

Evaluation of Gene Polymorphism and Gingival Crevicular Fluid Levels of Matrix Metalloproteinase-3 in a Group of Turkish Periodontitis Patients.

INTRODUCTION: Periodontitis is characterized by the destruction of tooth-supporting tissues. Matrix metalloproteinases (MMPs) play a significant part in the degradation of collagen structure. The gingival crevicular fluid (GCF) levels of MMPs increase with the progression of periodontal inflammation. Polymorphisms can be responsible for high expression of MMPs and can exacerbate the breakdown of collagen structure. This study aims to investigate the effect of MMP-3 -1171 5A/6A polymorphism and the GCF levels of MMP-3 in a group of Turkish periodontitis patients. MATERIALS AND METHODS: Non-smoking, stage II grade A periodontitis (S II-Gr A) (n = 68) and stage II grade B periodontitis (S II-Gr C) (n = 64) patients were recruited. Healthy individuals (H) (n = 72) without signs of gingivitis or periodontitis served as the control. Venous blood was collected from participants to obtain DNA, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect polymorphism. GCF samples were taken to assess MMP-3 levels using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-3 -1179 5A/6A distribution showed no significant difference between the groups (p > 0.05). However, the MMP-3 GCF levels of the S II-Gr C group were higher than those of both the S II-Gr A and H groups (p < 0.05), and elevated MMP-3 levels were detected in S II-Gr A compared to H (p < 0.05). CONCLUSION: The MMP-3 GCF levels showed an association with periodontal tissue destruction, although single nucleotide polymorphism was not associated with the S II-Gr C and S II-Gr A groups in the Turkish population.

Cisatracurium attenuates LPS-induced modulation of MMP3 and junctional protein expression in human microvascular endothelial cells.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI) associated with hypoxemic lung damage and inflammation. Matrix metalloproteinase protein-3 (MMP3 or Stromelysin-1) is known to promote vascular injury in ALI/ARDS. Cisatracurium, a nicotinic neuromuscular blocker, is used in ARDS patients to decrease mechanical ventilator dyssynchrony, increase oxygenation, and improve mortality. However, the magnitude and the underlying mechanisms of these potential benefits of cisatracurium remains unclear. We investigated the effect of cisatracurium on lipopolysaccharide-induced MMP3 expression in human microvascular endothelial cells. In our results, cisatracurium treatment significantly decreased LPS-induced MMP3 expression and increased expression of cell junction proteins such as vascular endothelial cadherin (VE-cadherin) and claudin-5.

Pharmacological Inhibition of MMP3 as a Potential Therapeutic Option for COVID-19 Associated Acute Respiratory Distress Syndrome.

The high mortality of coronavirus disease 2019 (COVID-19) patients is due to their progression to cytokine-associated organ injuries, primarily the acute respiratory distress syndrome (ARDS). The uncertainties in the molecular mechanisms leading to the switch from the early virus infection to the advanced stage ARDS is a major gridlock in therapeutic development to reduce mortality. Previous studies in our laboratory have identified matrix metalloprotease-3 (MMP3) as an important mediator of bacterial lipopolysaccharide (LPS)-induced ARDS, particularly in the exudative phase. Our studies have also reported elevated plasma MMP3 activity levels in the ARDS patients and that inhibition of MMP3 can reduce the severity of LPS-induced ARDS in mice. Given these observations, targeting MMP3 could be a potential option to treat COVID-19 patients with ARDS, and measurement of MMP3 activity in the plasma may serve as a biomarker for the early detection of ARDS in COVID-19 patients.

Distinct effects of pharmacological inhibition of stromelysin1 on endothelial-to-mesenchymal transition and myofibroblast differentiation.

Endothelial-to-mesenchymal transition (EndMT) and fibroblast-to-myofibroblast (FibroMF) differentiation are frequently reported in organ fibrosis. Stromelysin1, a matrix metalloprotease-3 (MMP3) has been indicated in vascular pathologies and organ injuries that often lead to fibrosis. In the current study, we investigated the role of stromelysin1 in EndMT and FibroMF differentiation, which is currently unknown. In our results, whereas TGFß2 treatment of endothelial cells (ECs) induced EndMT associated with increased expression of stromelysin1 and mesenchymal markers such as α-smooth muscle actin (αSMA), N-cadherin, and activin linked kinase-5 (ALK5), inhibition of stromelysin1 blunted TGFß2-induced EndMT. In contrast, treatment of NIH-3T3 fibroblasts with TGFß1 promoted FibroMF differentiation accompanied by increased expression of αSMA, N-cadherin, and ALK5. Intriguingly, stromelysin1 inhibition in TGFß1-stimulated myofibroblasts further exacerbated fibroproliferation with increased FibroMF marker expression. Gene Expression Omnibus (GEO) data analysis indicated increased stromelysin1 expression associated with EndMT and decreased stromelysin1 expression in human pulmonary fibrosis fibroblasts. In conclusion, our study has identified that EndMT and FibroMF differentiation are reciprocally regulated by stromelysin1.

Maxing xiongting mixture regulates factors relevant to lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats / 中国组织工程研究

BACKGROUND: Hypoxic pulmonary hypertension is a key link in the progression from chronic obstructive pulmonary disease to cor pulmonale. Its severity is closely related to disease development and prognosis. Current treatments cannot prevent or reverse disease progression. Maxing Xiongting Mixture has significant effect on hypoxic pulmonary hypertension with the syndrome of intermingled phlegm and blood stasis. OBJECTIVE: To study how the Maxing Xiongting Mixture regulates relevant factors of lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats with the syndrome of intermingled phlegm and blood stasis. METHODS: Seventy Sprague-Dawley rats, 5 weeks old, were randomly divided into normal group (n=10) and model group (n=60), where acute cor pulmonale model was prepared by injecting 50 mg/kg monocrotaline solution (1%) intraperitoneally, followed by forced smoking and swimming 6 days a week lasting for 4 weeks. Except for 10 rats in the normal group, there were 46 model rats in the model group. According to the normal distribution of body mass, 40 rats were selected and randomly divided into 4 groups: model group, high-dose Maxing Xiongting Mixture group (MH), low-dose Maxing Xiongting Mixture group (ML) and fasudil group, with 10 rats in each group. Rats in MH and ML groups were respectively given Maxing Xiongting Mixture at 20 g/(kg·d) and 5 g/(kg·d), respectively and those in the fasudil group were given fasudil at a dose of 10 mg/(kg·d). Other groups were given equal amount of saline. Administration was given intraperitoneally and intragastrically, once a day for 14 days in total. RT-PCR was used to test the expression of factors related to lung reshaping and vascular remodeling, including RhoA, stromelysin 1 and tumor necrosis factor-α mRNAs. An approval for the study was obtained from the Ethics Committee of Chengdu University of Traditional Chinese Medicine (approval No. 2017-03). RESULTS AND CONCLUSION: Compared with the model group, the expressions of RhoA, stromelysin 1, and tumor necrosis factor-α mRNAs were significantly lowered in the MH group (all P 0.05). To conclude, Maxing Xiongting Mixture, which is similar to fasudil, intervenes lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats with the syndrome of intermingled phlegm and blood stasis by inhibiting the expressions of RhoA, stromelysin 1, and tumor necrosis factor-α mRNAs.

Matrilysins and Stromelysins in Pathogenesis and Diagnostics of Cancers.

Matrix metalloproteinases (MMPs) are endopeptidases which are widely studied in terms of their role in the physiological and pathological processes in the organism. In this article, we consider usefulness of matrilysins and stromelysins in pathogenesis and diagnostic of the most common malignancies in the world, e.g., lung, breast, prostate, and colorectal cancers. In all of the mentioned cancers, matrilysins and stromelysins have a pivotal role in their development and also may have diagnostic utility. Influence to the cancerous process is connected with specific dependencies between these enzymes and components of the extracellular matrix (ECM), non-matrix components like cell surface components. All the information provided below allows to take a closer look at matrilysins and stromelysins and their functions in the cancer development.

Thermal stability of human matrix metalloproteinases.

Matrix metalloproteinases (MMP) are key players in the remodelling of the extracellular matrix under physiological and pathological conditions. Thermodynamic parameters of human recombinant metalloproteinases of the active (rMMP2, 3, 7, 8 and 9) and latent (rPro-MMP2, 3 and 9) forms were obtained by differential scanning calorimetry (DSC). Temperature by itself does not result in autocatalysis of recombinant MMP. The transitions observed by DSC correspond to structural domains of the monomeric protein. In this study, we show the domain organization of these proteins, where the thermal transition (Tm) of the main component is observed at 71.3 °C (ProMMP-2); 74.8 °C (ProMMP-8); 80.0 °C (ProMMP-3); 92.6 °C (ProMMP-9) and 98.3 °C (ProMMP-7). For MMP-3, this main Tm is related to the catalytic domain (CD). The isolated recombinant CD of MMP-3 unfolds as a single transition at Tm 83.4 °C, matching the more stable domain observed in the full-length active form of rMMP-3. The denaturation profile of rProMMP-3 shows the main transition at Tm 80 °C, a less stable domain before the propeptide domain (PD) cleavage. Our results indicate that the structural stability of MMP and particularly their CD are not substantially altered after cleavage of the PD. We propose that the thermodynamic parameters obtained by DSC are relevant for the functional study of MMP, particularly to reveal their contribution in complex biological samples in health and disease.

Patients with acute respiratory distress syndrome exhibit increased stromelysin1 activity in the blood samples.

Enzyme activity analyses in the blood are expected to be reliable, non-invasive diagnostic as well as prognostic markers to reflect disease progression in acute lung injury (ALI). The objective of the current study was to evaluate the enzymatic activity of stromelysin1 (matrix metalloprotease-3) in the plasma/serum samples collected from ALI patients compared to the samples collected from healthy controls. Gene expression omnibus (GEO) database analysis indicated a correlation between increased stromelysin1 gene expression and the incidence of ALI in various animal models. Our analysis of patient plasma/serum samples from healthy controls and ALI patients revealed a significant, 3-fold increase in stromelysin1 activity in ALI plasma/serum compared to healthy subjects with no difference in stromelysin1 activity between the serum and plasma samples. Interestingly, no significant difference in stromelysin1 activity between non-smoking and smoking subjects was observed. These findings provide fundamental information on the potential reliability of stromelysin1 activity analysis, combined with other biomarkers in development, in blood samples for the early detection of ALI.

7­MEGA™ 500 regulates the expression of COX­2, MMP­3 and type 1 procollagen in UVB­irradiated human keratinocytes and dermal fibroblasts.

AlaskOmega® Omega 7 500, also known as Omega­7 fatty acid or 7­MEGA™, is a highly concentrated palmitoleic acid (C16:1). Little is known about how 7­MEGA regulates skin inflammation and wrinkle formation in cultured skin cells. The present study aimed to investigate the effects of 7­MEGA on the expression of cyclooxygenase­2 (COX­2), matrix metallopeptidase (MMP)­1/3 and type 1 procollagen, which are markers of skin inflammation and wrinkle formation, in ultraviolet B (UVB)­irradiated human dermal fibroblasts (HDFs) and keratinocytes (HaCaT). No toxicity was observed upon treatment of HDFs and HaCaT cells with 0.5­2.5 µl/ml 7­MEGA. The exposure of HaCaT cells to 10 mJ/cm2 UVB for 6 h resulted in increased protein and/or mRNA expression of COX­2 and MMP­3. Treatment of HaCaT cells with 2.5 µl/ml 7­MEGA suppressed the UVB­induced expression of COX­2 and MMP­3 in these cells. In addition, treatment with 2.5 µl/ml 7­MEGA attenuated the UVB­induced expression and phosphorylation levels of c­Fos and c­Jun, two components of the activator protein­1 (AP­1) transcription factor, in HaCaT cells. Exposure of HDFs to 60 mJ/cm2 UVB for 6 h significantly decreased the expression of type 1 procollagen protein, whereas treatment with 2.5 µl/ml 7­MEGA partially reversed the effects of UVB on the expression of type 1 procollagen protein. These results demonstrated for the first time that 7­MEGA regulated the expression of COX­2, MMP­3 and type 1 procollagen in UVB­irradiated skin cells. The present study suggested that 7­MEGA may serve as a novel agent against UVB­induced skin inflammation and damage.

Paralogues of Mmp11 and Timp4 Interact during the Development of the Myotendinous Junction in the Zebrafish Embryo.

The extracellular matrix (ECM) of the myotendinous junction (MTJ) undergoes dramatic physical and biochemical remodeling during the first 48 h of development in zebrafish, transforming from a rectangular fibronectin-dominated somite boundary to a chevron-shaped laminin-dominated MTJ. Matrix metalloproteinase 11 (Mmp11, a.k.a. Stromelysin-3) is both necessary and sufficient for the removal of fibronectin at the MTJ, but whether this protease acts directly on fibronectin and how its activity is regulated remain unknown. Using immunofluorescence, we show that both paralogues of Mmp11 accumulate at the MTJ during this time period, but with Mmp11a present early and later replaced by Mmp11b. Moreover, Mmp11a also accumulates intracellularly, associated with the Z-discs of sarcomeres within skeletal muscle cells. Using the epitope-mediated MMP activation (EMMA) assay, we show that despite having a weaker paired basic amino acid motif in its propeptide than Mmp11b, Mmp11a is activated by furin, but may also be activated by other mechanisms intracellularly. One or both paralogues of tissue inhibitors of metalloproteinase-4 (Timp4) are also present at the MTJ throughout this process, and yeast two-hybrid assays reveal distinct and specific interactions between various domains of these proteins. We propose a model in which Mmp11a activity is modulated (but not inhibited) by Timp4 during early MTJ remodeling, followed by a phase in which Mmp11b activity is both inhibited and spatially constrained by Timp4 in order to maintain the structural integrity of the mature MTJ.

Endothelial stromelysin1 regulation by the forkhead box-O transcription factors is crucial in the exudative phase of acute lung injury.

Enhanced vascular permeability is associated with inflammation and edema in alveoli during the exudative phase of acute respiratory distress syndrome (ARDS). Mechanisms leading to the endothelial contribution on the early exudative stage of ARDS are not precise. We hypothesized that modulation of endothelial stromelysin1 expression and activity by Akt1-forkhead box-O transcription factors 1/3a (FoxO1/3a) pathway could play a significant role in regulating pulmonary edema during the initial stages of acute lung injury (ALI). We utilized lipopolysaccharide (LPS)-induced mouse ALI model in vivo and endothelial barrier resistance measurements in vitro to determine the specific role of the endothelial Akt1-FoxO1/3a-stromelysin1 pathway in ALI. LPS treatment of human pulmonary endothelial cells resulted in increased stromelysin1 and reduced tight junction claudin5 involving FoxO1/3a, associated with decreased trans-endothelial barrier resistance as determined by electric cell-substrate impedance sensing technology. In vivo, LPS-induced lung edema was significantly higher in endothelial Akt1 knockdown (EC-Akt1-/-) compared to wild-type mice, which was reversed upon treatment with FoxO inhibitor (AS1842856), stromelysin1 inhibitor (UK356618) or with shRNA-mediated FoxO1/3a depletion in the mouse lungs. Overall, our study provides the hope that targeting FoxO and styromelysin1 could be beneficial in the treatment of ALI.

Narrowband ultraviolet B light treatment changes plasma concentrations of MMP-3, MMP-9 and TIMP-3 in psoriatic patients.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are thought to be associated with the pathogenesis and spread of psoriatic disease. This study was designed to investigate the plasma levels of MMP-3, MMP-9 and TIMP-3 in plaque psoriasis patients prior to and following a course of ultraviolet B narrowband treatment with respect to disease advancement. METHODS: Plasma samples of 49 patients suffering from plaque psoriasis and 40 healthy volunteers were evaluated. Concentrations of MMP-3, MMP-9 and TIMP-3 were determined using enzyme-linked immunosorbent assay, while Psoriasis Area and Severity Index was used to define disease advancement. RESULTS: Plasma levels of MMP-3, MMP-9 and TIMP-3 were significantly elevated in psoriasis patients compared to healthy individuals. A course of ultraviolet B narrowband treatment resulted in a significant decline in the studied metalloproteinases. Furthermore, the concentration of selected tissue inhibitors was negatively correlated with baseline Psoriasis Area and Severity Index score. CONCLUSION: Our research highlights the meaningful role of MMP-3, MMP-9 and TIMP-3 in psoriasis pathogenesis and clearance of disease symptoms. Furthermore, plasma levels of the analyzed metalloproteinases seem to be a valuable psoriasis biomarker.

Immunohistochemical Expression of Stromelysin-2 (St-2) In Patients with Oral Lichen Planus and Its Clinical Significance.

STATEMENT OF THE PROBLEM: Oral lichen planus (OLP) is a chronic inflammatory disorder with various clinical features; however, its pathogenesis is still unknown. In OLP, destruction of the basement membrane and migration of T-cell may be mediated by matrix metalloproteinases. PURPOSE: The aim of this study was to examine the role of stromelysin-2 (ST-2) expression in pathogenesis of OLP. MATERIALS AND METHOD: A retrospective analysis of 46 samples including 26 patients with OLP and 20 control patients with oral irritation fibroma was performed. All samples were stained employing immunohistochemistry method. After immunohistochemical staining for ST-2 marker and microscopic examination of the samples, the expression levels of ST-2 were evaluated. The data were analyzed by SPSS (V.21) and applying Mann-Whitney test. RESULTS: The strength of ST-2 expression was seen in most cases of OLP group, whereas control group did not show ST-2 expression. Mean expression of ST-2 in connective tissue was 1.7±1.10 and in the epithelium of the OLP samples was 1.6±1.06. Likewise, the ST-2 expression in connective tissue and epithelium of the OLP erosive lesions was significantly higher in comparison with reticular lesions (p< 0.05). CONCLUSION: According to the results of this study, we suggest that ST-2 may be involved in the formation of OLP lesions and it may play a key role in the transformation of reticular to erosive form of OLP.

Association of matrix metalloproteinase 3 and γ-glutamyltransferase 1 gene polymorphisms with the cardio-ankle vascular index in young Russians.

Specific gene polymorphisms are known to be associated with a different arterial physiology in the younger generation. The present study found that young Russians with the matrix metalloproteinase 3 6A/6A and γ-glutamyltransferase 1AA genotypes have lower levels of the cardio-ankle vascular index - a recent measure of arterial stiffness. This observation may serve as an additional tool for cardiovascular disease prevention in the young population.