Tissue-type plasminogen activator depletion affects the nasal mucosa matrix reconstruction in allergic rhinitis mice

Background: The present study was designed to assess the function of tissue plasminogen activator (t-PA) expression in allergic rhinitis. Methods: Age-matched t-PA gene knock out (t-PA-/-) and wild type (WT) mice were sensitised four times, and then challenged for six weeks with ovalbumin. The controls were treated with saline instead of ovalbumin. The structural change in the nasal mucosa was investigated with haematoxylin and eosin stain and van Gieson staining. u-PA (urokinase-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor) gene expression were measured by real time PCR. Matrix metalloproteinase-9 (MMP-9) expression was tested with Western blotting and with real time PCR. Results: After ovalbumin challenge for six weeks, compared with the WT group, t-PA depletion increased collagen deposition and gland hyperplasia. u-PA and PAI-1 gene expression increased both in t-PA-/- and in WT mice after ovalbumin treatment. MMP-9 expression decreased greatly after ovalbumin challenge in t-PA-/- mice. Conclusion: t-PA affects the nasal mucosa matrix reconstruction process in allergic rhinitis, with which MMP-9 is involved (AU)

Metaloproteinasas, matriz extracelular y cáncer / Metalloproteinases, extracellular matrix and cancer

Las metaloproteinasas de la matriz extracelular (MMP) estánimplicadas en procesos fisiológicos y patológicos e intervienen en larotura de la matriz extracelular (ECM). Las MMP constituyen unafamilia de endopeptidasas neutras dependientes de zinc, capaces dedegradar los componentes esenciales de la matriz. Los inhibidorestisulares endógenos de las MMP (TIMP), una clase de inhibidores delas MMP, reducen la degradación proteolítica excesiva de la ECM.La degradación de la ECM es crucial para el crecimiento tumoralmaligno, invasión, metástasis y angiogénesis. Se han descrito cambiosen las MMP y sus inhibidores durante la carcinogénesis y tambiénque unas y otros regulan las vías señalizadoras mediante larotura de otros sustratos que los de la matriz, tales como citoquinas,quimioquinas y factores de crecimiento. Como ciertas MMP limitanel crecimiento tumoral, su identificación e intervención terapéuticaen combinación con la quimioterapia convencional ha de proporcionarun medio para la terapia del cáncer(AU)

The extracellular matrix metalloproteinases (MMP) are involved in physiological and pathological processes, through the cleavage ofextracellular matrix (ECM) and non-matrix substrates. MMP are afamily of zinc-dependent neutral endopeptidases capable of degradingessentially all matrix components. Endogenous tissue inhibitors ofmetalloproteinases (TIMP), one kind of MMP inhibitors, reduce theexcessive proteolytic ECM degradation. Degradation of ECM is crucialfor malignant tumor growth, invasion, metastasis and angiogenesis.A variety of reports describe the correlated changes in MMP and TIMPduring the formation of cancer, and also that MMP and TIMP may actas regulators of signaling pathways through the cleavage of nonmatrixsubstrates, including cytokines, chemokines, and growthfactors. As certain MMP limit tumor growth, identification of properMMP in combination with conventional chemotherapy is expected toprovide a feasible approach for cancer therapy(AU)

Are adrenomedullin positive modulators novel matrix metalloproteinase inhibitors?

Las metaloproteasas de la matriz (MMPs) pertenecen a la familia de enzimasque contienen zinc y juegan un papel predominante en la degradación del tejidoconectivo. Por ello se consideran dianas terapéuticas para procesos de inflamacióny enfermedades malignas y degenerativas. Por otro lado, se ha demostrado recientementeque un miembro de esta familia, MMP-2, una colagenasa de tipo IV tambiénconocida como gelatinasa A, es capaz de degradar un péptido angiogénico denominadoadrenomedulina (AM) (1). AM es una hormona peptídica que desarrolla unpapel importante en diversas patologías como diabetes, hipertensión y cáncer. Seha identificado mediante un cribado de alto rendimiento (HTS) de la colección decompuestos del Instituto Nacional del Cáncer (NCI), una serie de moduladores coninteresante actividad hipotensora (2). El mecanismo de acción de estos moduladoreses desconocido y nosotros proponemos que pueden afectar a la biodisponibilidadde la AM en el torrente sanguíneo por medio de la inhibición de la actividad dela MMP-2. En este trabajo presentamos un estudio teórico que hace uso de técnicascomo mecánica molecular, docking y Cribado Virtual con el objetivo de demostraresa hipótesis. A continuación del estudio computacional se llevó a cabo la evaluaciónbiológica de algunos compuestos, permitiéndonos proponer un nuevo tipo deZBG que puede ser interesante para el diseño de nuevos inhibidores de MMPS, coninterés como agentes anticancerosos y antiangiogénicos

Matrix metalloproteinases (MMPs), are a family of structurally related zinccontaining enzymes that play a major role in the breakdown of connective tissueand therefore, are targets for therapeutic inhibitors in many inflammatory,malignant, and degenerative diseases. On the other hand, it has been recentlydemonstrated that one of these enzymes, MMP-2, a type IV collagenase, termedgelatinase A, cleaves the angiogenic peptide adrenomedullin (AM) (1). AM is apeptide hormone that plays a critical role in several diseases such as diabetes,hypertension and cancer. In a High Throughput Screening (HTS) carried out at theNational Cancer Institute (NCI), a series of AM modulators were identified, with aninteresting hypotensive activity (2). In order to shed light into the mechanism ofaction of these interesting compounds, we have hypothesized that they may be affecting the biodisponibility of AM in the blood stream by inhibiting the MMP-2protease activity. In the present work, we present a theoretical study, making useof molecular mechanics, docking and virtual screening techniques, with the aim ofdemonstrating this hypothesis. Biological evaluation of MMP-2 inhibition by someselected compounds, followed the computational work, leading us to propose astructurally new type of MMP-2 inhibitors, with possible interest as anticancer andantiangiogenic agents

Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031.

FR255031 (2-[(7S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxido-4-(2-pyridinylcarbonyl)hexahydro-1,4-thiazepin-7-yl]-N-hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type 1 MMP (MT1-MMP/MMP-14). FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of FR255031 and Trocade, an inhibitor of collagenase and MMP-14, on a rat collagen-induced arthritis (CIA) model. Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti-IIC antibody, and histological and radiographic scores were evaluated. FR255031 markedly inhibited cartilage degradation in a dose-dependent manner in the CIA model, but Trocade failed to prevent the degradation. FR255031 at a dose of 100 mg kg(-1) also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28. These results indicate that FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT-MMP, gelatinases are also involved in joint destruction in arthritis.

Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies.

COL-3 is an oral, lipophilic, tetracycline analog that has been administered to patients with metastatic cancer. Preliminary assessment of COL-3 in 35 patients with refractory metastatic carcinoma demonstrated apparent nonlinear pharmacokinetics with highly variable oral clearance (63.9% coefficient of variance [CV]). To elucidate possible sources of variability of COL-3 pharmacokinetics in vivo, in vitro plasma protein binding and in vitro metabolism were explored along with in vivo pharmacokinetics using compartmental modeling. The variability in the overall clearance and urinary excretion of COL-3 was also assessed. COL-3 had a long terminal half-life (median = 59.8 h), large apparent volume of distribution (median = 50.2 L), and low apparent clearance (median = 9.93 mL/min). Only adjusted ideal body weight decreased the variability in total apparent clearance. There was nonsaturable plasma protein binding of COL-3 (fu = 5.5%), with the majority of binding to albumin. The renal route of elimination is negligible, with 0.06% of unchanged COL-3 and 3.31% COL-3 glucuronide excreted in the first 6 days. COL-3 is not metabolized by phase I metabolism but does undergo glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and in vivo, as evidenced by COL-3 glucuronides in the urine (median = 13.6% of the total dose). COL-3 exhibits nonlinear pharmacokinetics, possibly due to dissolution rate-limited absorption.

CYP3A induction by N-hydroxyformamide tumor necrosis factor-alpha converting enzyme/matrix metalloproteinase inhibitors use of a pregname X receptor activation assay and primary hepatocyte culture for assessing induction potential in humans.

A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.