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Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved. [ABSTRACT FROM AUTHOR]

Doxycycline is a drug that has been proposed to modify osteoarthritis (OA) progression, in addition to its role as an antibiotic. However, available evidence thus far comprises sporadic reports, with no consensus on its benefits. Hence, this review attempts to analyze the evidence available thus far on the role of doxycycline as a disease-modifying osteoarthritis drug (DMOAD) in knee osteoarthritis. The earliest evidence of doxycycline in OA appeared in 1991 when doxycycline was found to inhibit the type XI collagenolytic activity of extracts from the human osteoarthritic cartilage, and gelatinase and tetracycline were found to inhibit this metalloproteinase activity in articular cartilage in vivo, which could modify cartilage breakdown in osteoarthritis. Apart from the inhibition of cartilage damage by metalloproteinases (MMPs) and other cartilage-related mechanisms, doxycycline also affects the bone and interferes with many enzyme systems. The most significant finding after reviewing various studies was that doxycycline has a definitive role in structural changes in osteoarthritis progression and radiological joint space width, but its role in the improvement of clinical outcomes as a DMOAD has not been established. However, there is much of a gap and lack of evidence in this regard. Doxycycline, as an MMP inhibitor, has theoretical advantages for clinical outcomes, but the present studies reveal only beneficial structural changes in osteoarthritis and very minimal or nonexistent advantages in clinical outcomes. Current evidence does not favor the regular use of doxycycline for the treatment of osteoarthritis as an individual treatment option or in combination with others. However, multicenter large cohort studies are warranted to determine the long-term benefits of doxycycline. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation. [ABSTRACT FROM AUTHOR]

Tendinopathy is a common tendon disorder that causes pain, loss of strength and function, and local inflammation mainly characterized by hypoxia, collagen degradation, and extracellular matrix (ECM) disorganization. Generally, ECM degradation and remodeling is tightly regulated; however, hyperactivation of matrix metalloproteases (MMPs) contributes to excessive collagenolysis under pathologic conditions resulting in tendon ECM degradation. This review article focuses on the production, function, and signaling of matrikines for tendon regeneration following injury with insights into the expression, tissue compliance, and cell proliferation exhibited by various matrikines. Furthermore, the regenerative properties suggest translational significance of matrikines to improve the outcomes post-injury by assisting with tendon healing. [ABSTRACT FROM AUTHOR]

Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including metalloproteinases. The expression and activity of all metalloproteinases are under strict control, and their deregulation is often associated with diseases or chronic conditions, thereby being considered popular targets for developing new therapeutics. This review will highlight metalloproteinases of the MMP and ADAM families with functions in dermal homeostasis and give some insights into the mechanisms regulating their activity and expression. Furthermore, we discuss how the dysregulation of the most prominent family members affects dermal homeostasis by triggering disease development and influencing progression, focusing on cancer and aging. Here, recent discoveries and new approaches that target or exploit metalloproteinase activity in therapy are emphasized. The potential of naturally derived components in regulating metalloproteinase expression and activity in disease is discussed. [ABSTRACT FROM AUTHOR]

Because skin aging is so important in terms of looks, research into preventive and therapeutic treatments has proliferated. Ultraviolet (UV) radiation alters the extracellular matrix (ECM), stimulates matrix metalloproteinases (MMPs), while diminishes the elastin and collagen. MMPs are zinc-containing endo-peptidases that help to restore the ECM. The MMP families, based on substrate structure and specificity are: a) collagenases b) gelatinases c) stromelysins d) matrilysins and e) membrane type MMPs. Except for matrilysin, these enzymes contains haemopexin, propeptide and catalytic domains. Among the photoprotective strategies used to prevent and/or treat photoaging are topical sunscreens that work at the molecular level. We investigate photoaging mechanisms and plant bioactives. Skin photoaging is primarily caused by UV radiation from the sun, as it produces reactive oxygen species and disrupt DNA/cellular equilibrium, alter signal transduction pathways and inflammatory cascades, as well as immunosuppression and ECM restoration. Antiaging studies recently predicted the usage of natural chemicals from ancient civilizations. The sun protection factor and antioxidant properties of plants help prevent wrinkles and give the skin a youthful glow. Thus, the current study focuses on the development of anti-photoaging therapies that target specific MMPs connected to skin aging and wrinkle generation. We explored MMP suppressors or inhibitors found in plants. [ABSTRACT FROM AUTHOR]

Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 μM; p 〈0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and − 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer. [Display omitted] • Pancreatic cancer patients display higher expression of extracellular vesicle-associated proteins; • Calix[6]arene disturbs extracellular vesicle production in pancreatic cancer cells; • Calix[6]arene modulates miRNAs involved with vesicular trafficking. • Calix[6]arene disturbs Matrix Metalloproteinases 2 and 9 (MMP-2 and MMP-9) on cellular lineages and pancreatic tumor organoids. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum , has been shown to exert notable anti-inflammatory effects in previous studies, suggesting its potential effects in the treatment of OA. In this study, we revealed that the pretreatment of SW1353 human chondrocytes with SA before interleukin 1β (IL-1β) stimulation effectively decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, matrix metalloproteinases (MMPs; MMP3 and MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, type X collagen, and p62; increased the expression of type II collagen, ATG7, Beclin-1, and LC3; and increased the autophagic flux. Mechanistically, we found that SA suppressed the IL-1β-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Furthermore, the results of safranin O staining and toluidine blue staining of primary rat cartilage chondrocytes and a trauma-induced rat model of OA showed that SA alleviated progression of OA in vivo. Collectively, our research enhances understanding of the mechanism of protective effect of SA against the progression of OA, which involves amelioration of cartilage degeneration, thereby providing new evidence for the use of SA as a therapy to prevent the development of OA. [ABSTRACT FROM AUTHOR]

• miR-149 downregulation in rat model of MCAO. • miR-149 and Q10 lead to a decrease in MMP-2,9 levels following cerebral ischemia. • miR-149 and Q10 reduce IL-6 and TNF-α levels following brain ischemia. • miR-149 and Q10 reduce edema and tissue damage volume and increase BBB integrity in rat model of MCAO. The increase in some factors following cerebral ischemia, especially Matrix metalloproteinase (MMPs) and inflammatory factors lead to blood-brain barrier (BBB) damages, edema and neuronal death. Previous studies have shown that these molecules are miRNA-149−5p (miR-149) and Coenzyme (Co) Q10 targets. Therefore, in this study, the effect of mimic of miRNA-149−5p (mimic miR) and CoQ10 on the expression of metalloproteinase 1 and 2 and inflammatory cytokines following injury caused by cerebral ischemia is investigated. Cerebral ischemia was modeled by Middle Cerebral Artery Occlusion (MCAO). Male Wistar rats were randomly divided into 6 groups: sham (without surgery and treatment), control (MCAO), negative control (NC): MCAO + scrambled miR, vehicle: MCAO + Ethanole, first treatment: MCAO + mimic miR, second treatment: MCAO + Q10. Each group was divided into 6 subgroups to evaluate neurological defects, the volume of tissue damage using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, blood-brain barrier permeability using cerebral Evans Blue (EB) staining, edema by measuring the percentage of brain water, MMP-2,9 mRNA and miR-149−5p levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and the levels of IL-6 and TNF-α proteins using ELISA. The data obtained from this study showed that the use of mimic miR and Q10 increased the level of miR-149, decreased the extent of neurological defects and tissue damage, increased BBB integrity, decreased brain water percentage and also decreased the level of inflammatory cytokines and MMPs. It seems that the use mimic of miRNA-149−5p and Q10 can have a protective effect on the brain by reducing MMPs and inflammatory factors following cerebral ischemia and this could lead to a new treatment strategy to reduce the complications of cerebral ischemia. [ABSTRACT FROM AUTHOR]

Learning and memory are known to depend on synaptic plasticity. Whereas the involvement of plastic changes at excitatory synapses is well established, plasticity mechanisms at inhibitory synapses only start to be discovered. Extracellular proteolysis is known to be a key factor in glutamatergic plasticity but nothing is known about its role at GABAergic synapses. We reveal that pharmacological inhibition of MMP3 activity or genetic knockout of the Mmp3 gene abolishes induction of postsynaptic iLTP. Moreover, the application of exogenous active MMP3 mimics major iLTP manifestations: increased mIPSCs amplitude, enlargement of synaptic gephyrin clusters, and a decrease in the diffusion coefficient of synaptic GABAA receptors that favors their entrapment within the synapse. Finally, we found that MMP3 deficient mice show faster spatial learning in Morris water maze and enhanced contextual fear conditioning. We conclude that MMP3 plays a key role in iLTP mechanisms and in the behaviors that presumably in part depend on GABAergic plasticity. [ABSTRACT FROM AUTHOR]

Cell transplantation shows promise for repair of the injured nervous system, including spinal cord injury (SCI) and peripheral nerve injury (PNI). There are, however, still problems hampering these therapies moving from bench to bedside, and the methods need optimization. Three-dimensional (3D) cell culture systems are suggested to improve outcomes, bridging the gap between the in vitro and in vivo environments. In such constructs, cells are allowed to interact with each other and with the extracellular matrix (ECM) in 3D as they do in vivo. Transplanting cells in 3D constructs, rather than in suspension, is thought to promote cell survival and maintain important cellular behaviors. One such critical behavior is cell migration into and within the injury site. Understanding and controlling the migratory capability of 3D-cultured cells is therefore pivotal for developing better transplantation techniques. ECM remodelling can influence numerous cellular functions, including cell migration and matrix metalloproteinases (MMPs) are important enzymes for ECM modulation. Here, we discuss the idea of modulating MMPs to control cell migration in 3D culture systems, which can improve the therapeutic potential of cells transplanted in 3D. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the protective effects of chamazulene against IL-1β-induced rat primary chondrocytes and complete Freund's adjuvant (CFA)-induced osteoarthritic inflammation in rats. Oxidative stress markers, pro-inflammatory cytokines, and regulatory proteins were measured. Chamazulene significantly reverted (p < 0.05) the levels of lipid peroxidation and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) enzymes against IL-1β and CFA-induced oxidative stress. The levels of TNF-α and IL-6 were reduced (p < 0.05) in chamazulene treatment against IL-1β and CFA-induced inflammation. Western blot analysis results on the expressions of MMP-3, MMP-9, p65 NF-kβ, iNOS, and COX-2 showed chamazulene was able to protect the chondrocytes against IL-1β-induced osteoarthritic inflammation. Histopathology of rat hind ankle showed chamazulene significantly protected against CFA-induced osteoarthritic inflammation. Therefore, chamazulene can be recommended as a therapeutic agent for clinical trials against osteoarthritic inflammation. Reversal of osteoarthritic inflammation by chamazulene. [ABSTRACT FROM AUTHOR]

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles. [ABSTRACT FROM AUTHOR]

The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.

Abstract In the present study, we investigated the effects of the specific DPP-4 inhibitor vildagliptin on degradation of type II collagen and aggrecan, the main components of the articular extracellular matrix, in primary human chondrocytes. The results of our study reveal that vildagliptin reduced degradation of the articular extracellular matrix (ECM) by downregulating IL-1β-induced expression of matrix metalloproteinases-3 (MMP-3), matrix metalloproteinases-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). We also found that vildagliptin ameliorated IL-1β-induced activation of the JNK/AP-1 and nuclear factor-κB (NF-κB) pro-inflammatory signaling pathways by downregulating phosphorylation of JNK and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α (IκBα), activation of c-Fos/c-Jun, and nuclear translocation of p65. Our findings suggest that vildagliptin may serve as a novel treatment for excessive degradation of the articular ECM in osteoarthritis (OA). [ABSTRACT FROM AUTHOR]

Purpose: To compare the immunohistochemical expression of matrix metalloproteinases-2, -7, -9 and -26 and tissue inhibitors of metalloproteinases-1 and -2 in pleomorphic adenomas and adenoid cystic carcinomas of the minor salivary glands.Methods: Twenty cases of pleomorphic adenomas and 20 cases of adenoid cystic carcinomas were evaluated for the immunohistochemical expression of matrix metalloproteinases-2, -7, -9, and -26 and tissue inhibitors-1 and -2 in tumor parenchyma.Results: Most pleomorphic adenomas and adenoid cystic carcinomas showed high expression of matrix metalloproteinases and tissue inhibitors, predominantly located in the tumor cells. There was no statistically significant difference in the expression of the metalloproteinases-2 (p = 0.359), -7 (p = 0.081), and -26 (p = 0 553), as well as the tissue inhibitors-1 (p = 0.657), and -2 (p = 0.248) between the parenchyma of the studied tumors. Only matrix metalloproteinase-9 showed a significant difference in expression between the two tumors, with adenoid cystic carcinoma showing a more intense staining for this gelatinase (p = 0.041).Conclusions: The expression of the studied metalloproteinases suggests the involvement of these enzymes in the tissue remodeling process in pleomorphic adenomas and adenoid cystic carcinomas, but only MMP-9, significantly expressed in the adenoid cystic carcinomas, appears to be involved in the process of invasiveness and more aggressive behavior of these tumors. Additionally, results point that TIMPs-1 and -2 may have more complex functions besides metalloproteinase inhibition, which may be related to the pathogenesis and biological behavior of salivary gland tumors. [ABSTRACT FROM AUTHOR]

Objective To measure the effect of simulated human salivary esterases (SHSE) and metalloproteinases (MMP) inhibition on the integrity of restoration–tooth interfaces made from traditional or polyacid-modified resin composites bonded to human dentin by either total-etch or self-etch adhesives. Methods Resin–dentin specimens, made from traditional (Z250) or polyacid-modified (Dyract-eXtra) composites were bonded to human dentin using total-etch (TE-Scotchbond) or self-etch (SE-EasyBond) adhesives. TE was applied with or without the MMP inhibitor galardin. Specimens were incubated in phosphate-buffer or SHSE (37 °C/pH = 7.0) for up to 180 days, then suspended in a continuous flow biofilm fermenter cultivating biofilms of Streptococcus mutans UA159. Interfacial bacterial penetration, biofilm biomass and viability were measured by confocal laser scanning microscopy and biomarker dyes and used as interfacial biodegradation markers. Results All specimens showed increased biofilm penetration and biomass with time regardless of incubation condition. SHSE increased bacterial penetration in all experimental samples after 180 days (p < 0.05). Galardin reduced interfacial bacterial ingress and bacterial biomass vs. non-MMP-inhibited TE-bonded specimens (p < 0.05). TE interfaces showed lower interfacial bacterial biomass vs. SE after 90-day and 180-day (p < 0.05). Dyract-eXtra specimens showed lower bacterial cell viability within the interface vs. Z250 (p < 0.05). Significance The biodegradation of resin–tooth interfaces is accelerated by esterases, modulated by MMP inhibition and is dependent on the material’s chemistry and mode of adhesion. The in vitro bacterial growth model used in this study facilitates the elucidation of differences in interfacial integrity and biostability between different materials and techniques and is suitable for assessment of their performance prior to clinical evaluation. [ABSTRACT FROM AUTHOR]

The success of pregnancy depends on the maternal immune system’s ability to promote tolerance and host defense. This equilibrium is compromised in inflammatory and infectious impairment of placenta. Smoking during pregnancy exposes the fetus to severe complications which might result from an alteration in placenta macrophages (pMφ) functions. In this study, we assessed the effect of cigarette smoke extract (CSE) on the functions of third trimester pMφs.CSE inhibited particles uptake and the formation of multinucleated giant cells, a recently reported property of pMφs based on their ability to fuse in vitro. These alterations were associated with a CSE-induced abnormal activation of pMφs, which was characterized by an increased release of TNF, interleukin (IL)-33, and decreased IL-6 and IL-10 release. Furthermore, CSE enhanced the expression of metalloproteinase genes known to be involved in tissue remodeling. This effect of CSE on pMφs was specific because CSE affected circulating monocytes in a different way. Finally, we showed that nicotine affected in part the functional properties of pMφs. Taken together, these results showed that CSE modulated the functional activity of pMφs, which may compromise pregnancy. [ABSTRACT FROM AUTHOR]

Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a flavonoid compound exhibiting several beneficial biological activities, including neuroprotection, anti-cancer, antinociception, chondroprotection, anti-oxidation, and anti-inflammation. Our previous study demonstrated that eupatilin specifically activates peroxisome proliferator-activated receptor alpha (PPARα) through direct binding. The PPAR subfamily includes ligand-dependent transcription factors that consist of three isotypes: PPARα, PPARβ/δ, and PPARγ. All isotypes are involved in inflammation, epidermal proliferation/differentiation and skin barrier function. Among them, PPARα regulates lipid and glucose metabolism and skin homeostasis. In this study, we confirm that the ability of eupatilin as a PPARα activator significantly inhibited tumor necrosis factor-alpha (TNFα)-induced matrix metalloproteinase (MMP)-2/-9 expression and proteolytic activity in HaCaT human epidermal keratinocytes. Furthermore, we found that eupatilin subsequently suppressed IκBα phosphorylation, blocked NF-κB p65 nuclear translocation and down-regulated MAPK/AP-1 signaling via PPARα activation. Taken together, our data suggest that eupatilin inhibits TNFα-induced MMP-2/-9 expression by suppressing NF-κB and MAPK⁄AP-1 pathways via PPARα. Our findings suggest the usefulness of eupatilin for preventing skin aging. [ABSTRACT FROM AUTHOR]

HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients. [ABSTRACT FROM AUTHOR]

Quercetin, a flavone, is multifaceted, having anti-oxidative, anti-inflammatory, and anticancer properties. In the present study, we explored the effects of quercetin on the epithelial-- mesenchymal transition (EMT) and invasion of pancreatic cancer cells and the underlying mechanisms. We noted that quercetin exerted pronounced inhibitory effects in PANC-1 and PATU-8988 cells. Moreover, quercetin inhibited EMT and decreased the secretion of matrix metalloproteinase (MMP). Meanwhile, we determined the activity of STAT3 after quercetin treatment. STAT3 phosphorylation decreased following treatment with quercetin. We also used activating agent of STAT3, IL-6, to induce an increase in cell malignancy and to observe the effects of treatment with quercetin. As expected, the EMT and MMP secretion increased with activation of the STAT3 signaling pathway, and quercetin reversed IL-6-induced EMT, invasion, and migration. Therefore, our results demonstrate that quercetin triggers inhibition of EMT, invasion, and metastasis by blocking the STAT3 signaling pathway, and thus, quercetin merits further investigation. [ABSTRACT FROM AUTHOR]

Objective: We investigate the effects of bone morphogenetic protein-7 (BMP-7) on models with silica-induced and macrophage-mediated fibrosis and its possible mechanisms in vitro. Methods: Rat alveolar II epithelial (RLE-6TN) cells were incubated with the supernatant of mouse macrophage-like cells (RAW264.7) and treated with 0, 25, 50, and 100 μg/mL silica. Using Western blotting, the epithelial markers (surfactant proteins-C and E-cadherin) and the mesenchymal markers (fibronectin (FN) and viminten (Vim)) were detected. After neutralizing the BMP-7, the progress of fibrosis was assessed by the content of hydroxyproline (Hyp) and collagen I, III protein levels as well as the Smad signaling pathway proteins, including phosphorylated Smad1/5(P-Smad1/5) and phosphorylated Smad2/3(P-Smad2/3). Collagen I was also identified by immunofluorescence and pretreated with SB-431542, LDN-193189, or anti-BMP-7-neutralizing antibody. In addition, the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected using Western blotting. Results: The model of RLE-6TN cells was established successfully, the expressions of Vim, FN, MMP-2, and MMP-9 were upregulated, while the concentration of silica is increased. Neutralizing BMP-7 stimulated the decrease of P-Smad1/5 and the increase of P-Smad2/3, as well as the collagen I, collagen III, FN, and Hyp via Smad signaling pathway. Furthermore, pretreated with LDN-193189 or anti-BMP-7-neutralizing antibody, the expression of collagen I was increased, yet it was decreased with SB-431542 intervention. Conclusion: The activated BMP/Smad and suppressed transforming growth factor-β/Smad pathways could suppress silica-induced fibrosis via a MMP-dependent mechanism. BMP-7 is expected to be the optimized strategy of delaying the interstitial changes. [ABSTRACT FROM AUTHOR]

Purpose: Chronic low back pain has been associated with intervertebral disc (IVD) degeneration, which is characterized by the accumulation of extracellular matrix (ECM)-degrading proteases and inflammatory molecules in the degenerate tissue. IVD degeneration could be the outcome of natural organismal ageing and/or of the exposure of the disc to cumulative stressful environmental stimuli and is accompanied by an increased population of senescent cells in the tissue. On the other hand, senescent cells are known to secrete proteolytic enzymes and inflammatory molecules, which can contribute to ECM catabolism. The aim of this study was to investigate the transcriptional profile of selected metalloproteinases (MMPs) and inflammatory mediators in human nucleus pulposus IVD cells that became senescent using three different approaches: serial subculturing, exposure to ionizing radiation and p16INK4a overexpression.Methods: Gene expression was assessed using quantitative RT-PCR and protein levels were determined by western blot analysis. The proliferative potential of the cells, as well as the percentage of senescent cells in the population were estimated by nuclear BrdU incorporation and by senescence-associated β galactosidase staining, respectively.Results: All senescent cells showed a similar regulation of MMP-1, -2, -3, -9, interleukin (IL) 6, IL8 and interferon γ at the level of transcription, with only some quantitative differentiations observed in p16INK4a-overexpressing cells.Conclusions: Data described here suggest that senescent cells may have similar functions in IVD homeostasis, irrespective of the origin of senescence induction. [ABSTRACT FROM AUTHOR]

Purpose: To study the relationships between matrix metalloproteinases (MMP)-2, MMP-3, and tissue inhibitors of matrix metalloproteinases (TIMP)-1, TIMP-2, and TIMP-3 aqueous humor levels in patients with high myopia or cataract. Materials and Methods: MMPs and TIMPs protein levels in 65 aqueous humor samples collected from patients with high myopia or cataract during cataract or clear lens extraction surgery were measured with the Luminex xMAP Technology. The relationship between MMPs and TIMPs levels was analyzed with Spearman’s correlation test. Results: MMP-2 levels, but not MMP-3 levels, were increased in the aqueous humor from high-myopia patients. Levels of TIMP-1, -2, and -3 were positively and very significantly correlated with the MMP-2 levels (TIMP-1:r=0.626,p< 0.001; TIMP-2:r= 0.545,p< 0.001; TIMP-3:r= 0.439,p< 0.001). TIMP-2 and-3 levels did not significantly correlate with MMP-3 levels (TIMP-2:r= 0.175,p> 0.05; TIMP-3:r= 0.127,p> 0.05) and TIMP-1 levels only marginally correlated with MMP-3 levels (r= 0.278, 0.01

Periodontitis are infectious diseases characterized by immune-mediated destruction of periodontal supporting tissues and tooth loss. Matrix metalloproteinases (MMPs) are key proteases involved in destructive periodontal diseases. The study and interest in MMP has been fuelled by emerging evidence demonstrating the broad spectrum of molecules that can be cleaved by them and the myriad of biological processes that they can potentially regulate. The huge complexity of MMP functions within the 'protease web' is crucial for many physiologic and pathologic processes, including immunity, inflammation, bone resorption, and wound healing. Evidence points out that MMPs assemble in activation cascades and besides their classical extracellular matrix substrates, they cleave several signalling molecules--such as cytokines, chemokines, and growth factors, among others--regulating their biological functions and/or bioavailability during periodontal diseases. In this review, we provide an overview of emerging evidence of MMPs as regulators of periodontal inflammation. [ABSTRACT FROM AUTHOR]

Fangchinoline (FCL) is an active component isolated from the traditional medicinal plant Stephania tetrandra S. Moore, and has been reported to possess anti-cancer functions in several types of cancers; however, the effect of FCL on gastric cancer metastasis and its underlying molecular mechanisms remain unknown. The current study aimed to investigate the effect of FCL on the cell migration and invasion of human metastatic gastric cancer AGS cells and its mechanisms. Our study demonstrates that FCL dosage dependently suppressed the adhesion, migration and invasion capacities of human gastric cancer AGS cells without obvious cytotoxic effects. Reverse transcription-polymerase chain reaction and western blot assays demonstrated that FCL greatly inhibited the expression of matrix metalloproteinase (MMP)-2 and MMP-9 at both the mRNA and protein levels, while it significantly increased the expression of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP2 messenger RNAs. Our results also indicated that FCL repressed the phosphorylation of AKT in gastric cancer AGS cells. In summary, FCL may exert its anti-metastatic property in human gastric cancer cells in vitro by suppression of MMP-2 and MMP-9, increase of TIMP1 and TIMP2 genes, and inhibition of AKT phosphorylation. FCL may be a drug candidate for the treatment of gastric cancer metastasis. [ABSTRACT FROM AUTHOR]

We recently reported the expression of matrix metalloproteinase 20 (MMP20), hitherto thought to be tooth specific, in the metabolically active ductal epithelial cells of human salivary glands. Furthermore, our report indicated that MMP20 co-expressed and potentially interacts with dentin sialophosphoprotein (DSPP), a member of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs). Our earlier reports have shown the co-expression of three MMPs, MMP2, MMP3, and MMP9, with specific members of the SIBLING family: bone sialoprotein, osteopontin, and dentin matrix protein 1, respectively. This study investigated the expression of MMP20 and verified its co-expression with DSPP in human and monkey kidney sections and human mixed renal cells by IHC, in situ proximity ligation assay, and immunofluorescence. Our results show that MMP20 is expressed in all segments of the human and monkey nephron with marked intensity in the proximal and distal tubules, and was absent in the glomeruli. Furthermore, MMP20 co-expressed with DSPP in the proximal, distal, and collecting tubules, and in mixed renal cells. Consistent with other SIBLING–MMP pairs, the DSPP–MMP20 pair may play a role in the normal turnover of cell surface proteins and/or repair of pericellular matrix proteins of the basement membranes in the metabolically active duct epithelial system of the nephrons. [ABSTRACT FROM AUTHOR]

• Development of a functional gonad is an extensive tissue remodeling process. • Metalloproteases have critical roles in the remodeling process. • Few articles are available on metalloproteases in remodeling gonads. • This review is filling a knowledge gap. • Much remains to be discovered concerning roles of metalloproteases in gonad formation. • Determining enzymatic activities of metalloproteases is critical. Development of a functional gonad includes migration of primordial germ cells (PGCs), differentiations of somatic and germ cells, formation of primary follicles or spermatogenic cysts with somatic gonadal cells, development and maturation of gametes, and subsequent releasing of mature germ cells. These processes require extensive cellular and tissue remodeling, as well as broad alterations of the surrounding extracellular matrix (ECM). Metalloproteases, including MMPs (matrix metalloproteases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), are suggested to have critical roles in the remodeling of the ECM during gonad development. However, few research articles and reviews are available on the functions and mechanisms of metalloproteases in remodeling gonadal ECM, gonadal development, or gonadal differentiation. Moreover, most studies focused on the roles of transcription and growth factors in early gonad development and primary sex determination, leaving a significant knowledge gap on how differentially expressed metalloproteases exert effects on the ECM, cell migration, development, and survival of germ cells during the development and differentiation of ovaries or testes. We will review gonad development with focus on the evidence of metalloprotease involvements, and with an emphasis on zebrafish as a model for studying gonadal sex differentiation and metalloprotease functions. [ABSTRACT FROM AUTHOR]

EMMPRIN (extracellular matrix metalloproteinase inducer) is a widely expressed glycoprotein and a member of the immunoglobulin superfamily which exists in both a membrane-spanning and a soluble form. Homotypic interactions of EMMPRIN underlie its multiple roles in normal development and pathological situations such as viral infections, Alzheimer's disease and cancer. This study employed a recombinant soluble, fully glycosylated EMMPRIN domain (rhs EMN) as a tool to characterize the structural basis of EMMPRIN- EMMPRIN receptor ( EMNR) contacts and their functional effects on MCF-7 breast carcinoma cells. rhs EMN did not form dimers in solution but bound to surface EMMPRIN ( EMN) on MCF-7 cells with high affinity and was readily internalized. The interaction interface for the homotypic contact was localized to the N-terminal Ig domain. rhs EMN exerted a stimulatory effect on proliferation of MCF-7 cells whereas it reduced cell migration in a dose-dependent manner. These effects were accompanied by an upregulation of endogenous EMMPRIN as well as of matrix metalloproteinase-14 ( MMP-14), a membrane-bound protease involved in the extracellular release of soluble EMMPRIN, indicating a regulatory feedback mechanism. The proliferation-promoting activity of rhs EMN was mimicked by a novel functional antibody directed to EMMPRIN, underscoring that crosslinking of cell surface EMMPRIN ( EMNR) is crucial for eliciting intracellular signalling. Addressing malignancy-related signal transduction in HEK-293 cells, we could show that rhs EMN triggers the oncogenic Wnt pathway. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common arthritis and also one of the major causes of joint pain in elderly people. The aim of this study was to investigate the effects of pyrroloquinoline quinone (PQQ) on degenerated-related changes in osteoarthritis (OA). SW1353 cells were stimulated with IL-1β to establish the chondrocyte injury model in vitro. PQQ was administrated into SW1353 cultures 1 h before IL-1β treatment. Amounts of MMP-1, MMP-13, P65, IκBα, ERK, p-ERK, P38, and p-P38 were measured via western blot. The production of NO was determined by Griess reaction assay and reflected by the iNOS level. Meniscal-ligamentous injury (MLI) was performed on 8-week-old rats to establish the OA rat model. PQQ was injected intraperitoneally 3 days before MLI and consecutively until harvest, and the arthritis cartilage degeneration level was assessed. The expressions of MMP-1 and MMP-13 were significantly downregulated after PQQ treatment compared with that in IL-1β alone group. NO production and iNOS expression were decreased by PQQ treatment compared with control group. Amounts of nucleus P65 were upregulated in SW1353 after stimulated with IL-1β, while PQQ significantly inhibited the translocation. In rat OA model, treatment with PQQ markedly decelerated the degeneration of articular cartilage. These findings suggested that PQQ could inhibit OA-related catabolic proteins MMPs expression, NO production, and thus, slow down the articular cartilage degeneration and OA progression. Owing to its beneficial effects, PQQ is expected to be a novel pharmacological application in OA clinical prevention and treatment in the near future. [ABSTRACT FROM AUTHOR]

Obesity is characterized by hypertrophy of adipose tissue and chronic obstructive pulmonary disease (COPD) by lung damage; both diseases are associated with systemic low-grade inflammation. There are no animal models combining obesity and COPD; therefore, these diseases were induced simultaneously in rats to analyze their effects on the expression of inflammatory mediators and enzymes involved in lung tissue remodeling. Obesity was induced with sucrose (30%) for 4 months concomitant with tobacco smoke exposure (20 cigarettes/day, 5 days/wk) for the last 2 months. Were evaluated: body weight, abdominal fat, dyslipidemia, glucose tolerance test (GTT), histology, inflammatory mediators with qPCR and enzyme-linked immunosorbent assay, matrix metalloproteinases (MMP-2), MMP-9, MMP-12, TIMP-1 and TIMP-2 through qRT-PCR, and MMP-2 and MMP-9 by gelatin zymography. The rats on a sucrose diet exhibited increased body weight, abdominal fat, triglycerides, GTT, and plasma levels of insulin, adiponectin, leptin, resistin, IL-6, IL-1β, tumor necrosis factor-α (TNF-α) and IFN-γ, upregulated lung IL-6, IL-1β, TNF-α and IFN-γ, showing hyperplastic bronchial and alveolar epithelium. The animals exposed to sucrose and tobacco smoke exhibited decreased body weight, abdominal fat and plasma levels of leptin, resistin, IL-1β and IFN-γ, reducing inflammation but showing emphysematous lesions. Expression of gelatinases and MMP-12 augmented in the rats exposed to tobacco smoke alone or combined with sucrose. Zymography showed prominent gelatinases activity in all the experimental groups. These results suggest that simultaneous exposure to sucrose and tobacco smoke decreases inflammation but results in emphysematous lesions similar to those observed with tobacco smoke exposure, suggesting that obesity does not confer any protective effect against lung damage. [ABSTRACT FROM AUTHOR]

Aims Fibronectin ( FN) has attracted interest in cancer research, owing to its role in tumour progression. The aims of this study were to investigate the expression and clinical relevance of FN in breast cancer, and to explore its relationship with the expression of matrix metalloproteases ( MMPs) and their inhibitors ( TIMPs). Methods and results An immunohistochemical study was performed using tumours from 110 breast cancer patients, with tissue arrays and specific antibodies against FN, MMP-7, MMP-9, MMP-11, TIMP-1, and TIMP-2. The results indicated that FN expression was related to tumour size, histological grade, and MMP-9 expression. Tumours with high FN expression by tumour cells were significantly associated with a higher probability of metastasis, poorer overall survival, and expression of MMP-7, MMP-9, MMP-11, TIMP-1 and TIMP-2 by mononuclear inflammatory cells ( MICs). In addition, the combination of FN expression by tumour cells and MMP-11 by MICs was strongly associated with distant metastasis development. Conclusions Breast carcinomas with distant metastasis frequently have tumour cells expressing intracellular FN. There is a strong association between FN expression by tumour cells and MMP or TIMP expression by stromal MICs, and this may represent crosstalk that is of prognostic relevance in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: In the marine environment, manganese represents a potential emerging contaminant, resulting from an increased production of manganese-containing compounds. In earlier reports we found that the exposure of Paracentrotus lividus sea urchin embryos to manganese produced phenotypes with no skeleton. In addition, manganese interfered with calcium uptake, perturbed extracellular signal-regulated kinase (ERK) signaling, affected the expression of skeletogenic genes, and caused an increase of the hsc70 and hsc60 protein levels. Here, we extended our studies focusing on the temporal activation of the p38 mitogen-activated protein kinase (p38 MAPK) and the proteolytic activity of metalloproteinases (MMPs). We found that manganese affects the stage-dependent dynamics of p38 MAPK activation and inhibits the total gelatin-auto-cleaving activity of MMPs, with the exclusion of the 90–85 kDa and 68–58 kDa MMPs, whose levels remain high all throughout development. Our findings correlate, for the first time to our knowledge, an altered activation pattern of the p38 MAPK with an aberrant MMP proteolytic activity in the sea urchin embryo. [Copyright &y& Elsevier]

Many species belonging to the Scrophularia genus have been used since ancient times as folk remedies for many medical conditions such as scrofulas, scabies, tumors, eczema, psoriasis, inflammations. The aim of this study was to characterize the matrix metalloproteinases (MMPs) inhibitor compounds of the Scrophularia striata extract by bio-guide fractionation. The aerial parts of S. striata were collected and different extracts were sequentially prepared with increasingly polar solvents. The MMPs inhibitory activity of the crude extract and its fractions were evaluated by the Zymoanalysis method. The pure compounds were purified from the active fraction by chromatography methods. Chemical structures were deduced by nuclear magnetic resonance and mass spectrometry. Two active compounds (acteoside and nepitrin) were identified by bio-guide fractionation. The inhibitory effects of nepitrin and acteoside at 20 μg/mL were about 56 and 18 percent, respectivly. The inhibitory effects of acteoside at 80 μg/mL were increased to about 73 percent. In summary, the results suggest that nepitrin effectively inhibited MMPs inhibitory activity at low concentrations, whereas acteoside showed inhibition at high concentrations [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent studies supported the use of protein cross-linking agents during bonding procedures to inactivate endogenous dentin proteases, preventing dentin collagen degradation thus improving bond durability. The aim of this study was to evaluate the effect of a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-containing conditioner on the stability of the adhesive interface created by two etch-and-rinse adhesives. Methods: Human dentin was etched with 35% phosphoric acid, treated with 0.3M EDC-containing conditioner followed by a three-step or a two-step etch-and-rinse adhesive. Adhesives were applied to control specimens without EDC pre-treatment. Specimens were subjected to microtensile bond strength test and pulled to failure after 24h or 1 year of storage and interfacial nanoleakage expression was evaluated and quantified by light microscopy. Additionally, to investigate endogenous dentin matrix metalloproteinase activity a zymographic assay was performed on protein extracts obtained from phosphoric-acid-etched dentin powder with or without EDC treatment. Results: The use of the EDC-containing conditioner did not affect immediate bond strength to dentin but contributed to preserve the bond strength after 1 year (p <0.05) for both tested adhesives. No difference was found in the interfacial nanoleakage expression that increased after aging irrespective from the treatment. EDC pre-treatment inhibited dentin endogenous MMPs as assayed with the zymography. Significance: In conclusion, the results of the study provide proof that EDC can produce long-term inactivation of MMPs in acid-etched dentin matrices contributing to bond strength preservation over time. Future studies are needed to support the use of EDC in vivo. [Copyright &y& Elsevier]

Relaxin is a peptide discovered since 1926 by Hisaw. Belongs to the super family of structurally related hormones including: relaxin-1, -2 and -3 and insulin-like (INSL) peptides 3, 4, 5 and 6 and has important roles in follicle growth and ovulation, in implantation of the egg, preparation of the endometrium for implantation, in uterine growth in pregnancy, in inhibiting the myometrium contractile activity, in the procession of lactation and also exerts a protective effect in endometriosis. The relaxin family peptides produce their physiological effects by activating a group of four G protein-coupled receptors, relaxin family peptide receptors 1-4 (RXFP1-4). Relaxin regulates the expression of matrix metalloproteinase's (MMPs), a group of enzymes that degrade the extracellular matrix, essential for invasion of endometrial cells in peritoneum and also the expression of the vascular endothelial growth factor (VEGF), a glycoprotein with vasculogenic regulatory role in endometriosis by determining an excessive angiogenesis. MMPs and VEGF are both over expressed in the ectopic endometrial tissue of patients with endometriosis. Blocking the production of VEGF and MMPs appear to be effective and specific means of treatment in endometriosis. [ABSTRACT FROM AUTHOR]

Endometrial remodeling is a physiological process involved in the gynecological disease, endometriosis. Tissue remodeling is directed by uterine fibroblast production of matrix metalloproteinases (MMPs). Several MMPs are regulated directly by the protein extracellular matrix metalloproteinase inducer (EMMPRIN) and also by proinflammatory cytokines such as interleukin (IL)1-α/β. We hypothesized that human uterine epithelial cells (HESs) secrete intact EMMPRIN to stimulate MMPs. Microvesicles from HES cell-conditioned medium (CM) expressed intact EMMPRIN protein. Treatment of HES cells with estradiol or phorbyl 12-myristate-13-acetate increased the release of EMMPRIN-containing microvesicles. The HES CM stimulated MMP-1, -2, and -3 messenger RNA levels in human uterine fibroblasts (HUFs) and EMMPRIN immunodepletion from HES-cell concentrated CM reduced MMP stimulation (P < .05). Treatment of HUF cells with low concentrations of IL-1β/α stimulated MMP production (P < .05). These results indicate that HES cells regulate MMP production by HUF cells by secretion of EMMPRIN, in response to ovarian hormones, proinflammatory cytokines as well as activation of protein kinase C. [ABSTRACT FROM AUTHOR]

Abstract: Kahweol, a coffee-specific diterpene, is reported to have anti-cancer properties, although its precise chemopreventive mechanism remains unclear. The aim of our study was to determine the effect of kahweol on anti-metastatic activities and the possible mechanisms. Kahweol inhibited the migration and invasion ability of various cancer cells in vitro and decreased the secretion of metalloproteinase (MMP)-2, MMP-9, and VEGF in cancer cells via suppression of STAT3 activation. Kahweol also exhibited an inhibitory effect on lung metastasis in the experimental B16-F10 melanoma metastasis model. Moreover, kahweol inhibited migration and tube formation of endothelial cells in vitro, decreased the secretion of VEGF, and suppressed neovascularisation in Matrigel plugs in mice. Our findings demonstrate that kahweol inhibits metastasis through the disruption of STAT3-mediated transcription of the MMP and VEGF genes. [Copyright &y& Elsevier]

Aims: Receptor for advanced glycation endproducts (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with diff erent biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus. Methods: Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs). Results: Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137 ± 532 ng/l vs. 824 ± 309 ng/l, p < 0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p < 0.001) and HMGB1 concentrations were elevated in T2DM patients (p < 0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r = - 0.602, p < 0.002 and r = - 0.771, p < 0.001). Significant positive correlation was found between sRAGE and ICAM- 1, VCAM-1 or vWF (p < 0.01 to p < 0.001). Conclusion: We conclude that serum sRAGE and RAGE ligands concentrations refl ect endothelial dysfunction developing in diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: This study was aimed at searching noninvasive markers of the transition from mild to severe fibrosis stage in HCV patients undergoing hepatic fibrosis. Design and methods: Thirty-three patients affected by chronic HCV vs. twenty healthy donors were evaluated for the serum levels of several circulating matrix metalloproteinases (MMPs), TRAIL and β-NGF by multiplex biometric ELISA based immunoassay and anti- and pro-oxidant status (d-ROMs, BAP and NO) using a Diacron automated method. Results: HCV patients displayed increased expression levels of MMP-8, MMP-9, TRAIL and β-NGF, and an imbalance between pro- and antioxidant status, that contribute to liver fibrosis. Conclusions: Since the determination of these parameters represents a reliable and easily applicable method, these parameters are suggested as serum surrogate markers for HCV patients in the routine clinical practice. [Copyright &y& Elsevier]

Abstract: Whilst the majority of fractures heal normally, it is estimated that ∼10% of fractures exhibit some level of delayed or impaired healing. Although radiography is the primary diagnostic tool to assess the progression of fracture healing, radiographic features only qualitatively correlate with tissue level increases in mineral content and do not quantitatively measure underlying biological processes that are associated with the progression of healing. Specific metaloproteinases have been shown to be essential to processes of both angiogenesis and mineralised cartilage resorption and bone remodelling at different phases of fracture healing. The aim of this study was to determine the potential of using a simple urine based assay of the activity of two MMPs as a means of assessing the biological progression of fracture healing through the endochondral phase of healing. Using a standard mid-diaphyseal murine model of femoral fracture, MMP9 and MMP13 proteins and enzymatic activity levels were quantified in the urine of mice across the time-course of fracture healing and compared to the mRNA and protein expression profiles in the calluses. Both urinary MMP9 and MMP13 protein and enzymatic activity levels, assessed by Western blot, zymogram and specific MMP fluorometric substrate assays, corresponded to mRNA expression and immunohistologic assays of the proteins within callus tissues. These studies suggest that urinary levels of MMP9 and MMP13 may have potential as metabolic markers to monitor the progression of fracture healing. [Copyright &y& Elsevier]

Abstract: Objective: Previous studies have suggested that some functional polymorphisms in the matrix metalloproteinase (MMPs) genes are associated with the risk of periodontal disease. However, to date no study has investigated MMP8 gene variants in relation to chronic periodontitis (CP). The aim of this study was to analyse polymorphisms in the MMP8 gene and their associations with microbial composition and clinical manifestation of CP. Design: A total of 619 unrelated Czech subjects were included in the present study. Two polymorphisms [−799C/T (rs11225395) and +17C/G (rs2155052)] in the MMP8 gene were studied in 341 patients with CP and 278 unrelated non-periodontitis controls. Both polymorphisms were detected using the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) methods. Subgingival bacterial colonisation (occurrence of bacteria in subgingival pockets and gingival sulci) was investigated by a commercial semiquantitative kit in selected subjects (N =169). Results: Our results showed no differences in the allele and genotype frequencies of the MMP8 −799C/T and +17C/G polymorphisms between patients with CP and controls (p >0.05). Nevertheless, the haplotype T(−799)/C(+17) was significantly more frequent in patients with CP than in controls [43.7% vs. 37.6%, p <0.05, OR=1.273 (95% CI: 1.013–1.601)]. Despite significant differences determined in the occurrence of periodontal bacteria between patients with CP and non-periodontitis controls (from p <0.000001 to p <0.05), no significant relationships between periodontal pathogens, MMP8 polymorphisms and CP were found (p >0.05). Conclusions: Although none of the investigated SNPs in the MMP8 gene was individually associated with periodontitis, specific haplotype showed association with clinical manifestation of chronic periodontitis in a Czech population. [Copyright &y& Elsevier]

Abstract: Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. [Copyright &y& Elsevier]