Clinical validation of an elastin-derived trifunctional peptide for skin regeneration.

Unlabelled: Aging is associated with progressive skin fragility, characterized in part by extracellular matrix (ECM) fragmentation. This degradation produces matrikines which have an impact on ECM rremodeling. Our group previously designed and characterized a trifunctional peptide (TFP), constituted of i) an elastokine motif (VGVAPG), able to increase the expression of matrix constituent through the stimulation of the elastin-binding protein receptor, ii) a tripeptide inhibiting matrix metalloproteinase-1 activity (GIL), and iii) a linker domain acting as a competitive substrate for urokinase (RVRL).

Regeneration of human dermis by a multi-headed peptide.

Skin aging is characterized by deterioration of the dermal collagen fiber network due to both decreased collagen expression and increased collagenolytic activity. We designed and evaluated in vitro and ex vivo the efficacy of a trifunctional peptide (TFP) to restore collagen and elastin fibers. TFP was constituted of an elastokine motif (VGVAPG)3, able to increase matrix constituent expression through the stimulation of the elastin-binding protein receptor, a GIL tripeptide occupying matrix metalloproteinase-1 subsites, and a RVRL linker domain acting as a competitive substrate for urokinase.

Elastin fragmentation and atherosclerosis progression: the elastokine concept.

Atherosclerosis is a progressive multifaceted inflammatory disease affecting large- and medium-sized arteries. Typical feature of this disease is the formation and build-up of atherosclerotic plaques characterized by vascular extracellular matrix degradation and remodeling. Many studies have documented degradation of native elastin, the main extracellular matrix protein responsible for resilience and elasticity of arteries, by local release of elastases, leading to the production of elastin-derived peptides (EDP).

Regulation of MMPs during melanoma progression: from genetic to epigenetic.

Melanoma is the most severe skin cancer characterized by a bad prognosis at metastatic stages due to resistance to most classical chemotherapies. Invasion of melanoma cells into the surrounding microenvironment locally and at distance of the primary tumour, is facilitated by expression of proteases that degrade the extracellular matrix. Matrix metalloproteinases (MMP) have been long thought as potential therapeutic targets as they are involved in several steps of tumour progression.

Neutrophil elastase as a target in lung cancer.

Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e.

Mechanical forces-induced human osteoblasts differentiation involves MMP-2/MMP-13/MT1-MMP proteolytic cascade.

Matrix metalloproteinase (MMP) family proteins play diverse roles in many aspects of cellular processes such as osteoblastic differentiation. Besides, mechanical forces that occur in 3D collagen gel promote the osteoblastic phenotype and accelerate matrix mineralization. Although MMPs have been involved in bone differentiation, the proteolytic cascades triggered by mechanical forces are still not well characterized.

Inhibition of stromelysin-1 by caffeic acid derivatives from a propolis sample from Algeria.

Stromelysin-1 (matrix metalloproteinase-3: MMP-3) occupies a central position in collagenolytic and elastolytic cascades, leading to cutaneous intrinsic and extrinsic aging. We screened extracts of a propolis sample from Algeria with the aim to isolate compounds able to selectively inhibit this enzyme. A butanolic extract (B (3)) of the investigated propolis sample was found to potently inhibit MMP-3 activity (IC (50) = 0.

The cell-elastin-elastase(s) interacting triade directs elastolysis.

Human elastases have been identified within serine, cysteine and metallopeptidase families. These enzymes are able to adsorb rapidly onto elastin, but they can also bind onto cell surface-associated proteins such as heparan sulfate proteoglycans, both interactions involving enzyme exosites distinct form active site. Immobilization of elastin at the cell surface will create a sequestered microenvironment and will favour elastolysis.

Inhibition of human leukocyte elastase, plasmin and matrix metalloproteinases by oleic acid and oleoyl-galardin derivative(s).

Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and human leukocyte elastase (HLE), plasmin and matrix metalloproteinase-2 (MMP-2), involved in the inhibitory capacity of fatty acid towards those proteases. The carboxylic acid group of the fatty acid was found to form a salt bridge with Arg(217) of HLE while unsaturation interacted with Phe(192) and Val(216) at the S(3) subsite, and alkyl end group occupied S(1) subsite. In keeping with the main contribution of kringle 5 domain in plasmin-oleic acid interaction [Huet E et al.

Post-translational proteolytic events influence LRP-1 functions.

The low-density lipoprotein receptor-related protein (LRP-1) is a membrane receptor displaying both endocytic scavenging and signaling functions. In this review, we briefly present post-translational proteolytic processes targeting this receptor and speculate on their possible influence on LRP-1 biological functions.

Trends in matrix metalloproteinase research from 1986-2007: a bibliometric study.

Using the SCI-expanded database, this study provides a quantitative description of the development of the research involving matrix metalloproteinase (MMP) over a period of 20 years. From 1986 to 2007 the scientific literature related to MMP increased sevenfold (397 papers in 1986-1987 and 2834 in 2006-2007). The number of countries participating in MMP-related research doubled during this period (33 in 1986-1987 to 67 in 2006-2007), and the USA continually remained the leader.

Role of the elastin receptor complex (S-Gal/Cath-A/Neu-1) in skin repair and regeneration.

Impaired elastic fiber assembly constitutes one major problem in skin wound healing. Recent data indicate that a ternary complex involving a splicing form of beta-galactosidase associated with cathepsin-A and neuraminidase-1 directs the transport of tropoelastin to the fibroblast plasma membrane and participates in the deposition of the elastin precursor onto a microfibrillar scaffold. In addition, this elastin receptor complex is ubiquitously expressed and also acts as a true receptor for elastin-derived peptides produced during the initial stage of wound repair following elastase-mediated proteolysis action.

Control of melanoma invasiveness by anticollagenolytic agents: a reappraisal of an old concept.

Collagen, the major constituent of human dermis, represents the main barrier against progression of melanoma cells. Several matrix metalloproteinases (MMPs), i.e.

TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival.

Besides its ability to inhibit MMP activity, TIMP-1 exhibits other biological functions. We earlier reported that TIMP-1 induced UT-7 erythroid cell survival through activation of the JAK2/PI 3-kinase/Akt pathway and we now aim to determine whether the TIMP-1 anti-apoptotic effect requires MMP involvement. We first show that proMMP-9 was expressed in UT-7 cells and associated with the cell plasma membrane.

Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity.

Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.

Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation.

Ceramides have been proposed as potential therapeutic strategy with regard to their ability to induce cell death. We previously demonstrated that C2-ceramide generated apoptosis in bronchocarcinoma BZR cells. We here investigated whether ceramides also target other molecules involved in cell-cell or cell-matrix interactions during cancer progression.

Collagen-binding domains of gelatinase A and thrombospondin-derived peptides impede endocytic clearance of active gelatinase A and promote HT1080 fibrosarcoma cell invasion.

Gelatinase A (matrix metalloproteinase-2, MMP-2) binds to several proteins through its collagen-binding domains (CBDs). Surface plasmon resonance analysis revealed a strong interaction between CBD123 and thrombospondin-1 (TSP-1), with a K(D) value of 2x10(-9) M. CBD123, as well as individual domains, behave as competitive inhibitors of the TSP-1-directed endocytic clearance of active MMP-2, but not of its latent form, by HT1080 fibrosarcoma cells.

Elastin receptor (spliced galactosidase) occupancy by elastin peptides counteracts proinflammatory cytokine expression in lipopolysaccharide-stimulated human monocytes through NF-kappaB down-regulation.

In inflammatory diseases, strong release of elastinolytic proteases results in elastin fiber degradation generating elastin peptides (EPs). Chemotactic activity for inflammatory cells was, among wide range of properties, the former identified biological activity exerted by EPs. Recently, we demonstrated the ability of EPs to favor a Th1 cytokine (IL-2, IFN-gamma) cell response in lymphocytes and to regulate IL-1beta expression in melanoma cells.

Simultaneous presence of unsaturation and long alkyl chain at P'1 of Ilomastat confers selectivity for gelatinase A (MMP-2) over gelatinase B (MMP-9) inhibition as shown by molecular modelling studies.

Structural analogues of Ilomastat (Galardin), containing unsaturation(s) and chain extension carrying bulky phenyl group or alkyl moieties at P'1 were synthesized and purified by centrifugal partition chromatography. They were analyzed for their inhibitory capacity towards MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14, main endopeptidases involved in tumour progression. Presence of unsaturation(s) decreased the inhibitory potency of compounds but, in turn increased their selectivity for gelatinases.

Elastin-elastases and inflamm-aging.

Degradation of elastin, the main amorphous component of elastic fibers, by elastases belonging to the serine, metallo, or cysteine families leads to the generation of elastin fragments, designated as elastokines in keeping with their cytokine-like properties. Generation of elastokines from one of the longest lived protein in human might represent a strong tissue repair signal. Indeed, they (1) exhibit potent chemotactic activity for leukocytes, (2) stimulate fibroblast and smooth muscle cell proliferation, and (3) display proangiogenic activity as potent as VEGF.

Beneficial influence of microsatellite instability on gelatinase-tissue inhibitors of metalloproteinase balance in colorectal cancer.

Background: Colorectal cancers (CRC) with high level of microsatellite instability (MSI-H) are characterized by lower metastasis propensity and better prognosis than their stable microsatellite (MSS) counterpart. It was hypothesized that the difference in cancer progression might be related to distinct gelatinase-tissue inhibitors of metalloproteinase (TIMPs) balance in MSI-H and MSS sporadic CRC.

Patients And Methods: Levels of gelatinase-A (MMP-2) and -B (MMP-9), TIMP-1 and -2 and membrane-type matrix metallo-proteinase-1 (MT1-MMP) were compared in tumors and normal mucosa from patients with MSI-H and MSS CRC.

Binding of elastin peptides to S-Gal protects the heart against ischemia/reperfusion injury by triggering the RISK pathway.

Elastin peptides (EPs) generated by hydrolysis of elastic fibers by elastinolytic enzymes display a wide spectrum of biological activities. Here, we investigated their influence on rat heart ischemia-mediated injury using the Langendorff ex vivo model. EPs, i.

The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit.

The binding of elastin peptides on the elastin receptor complex leads to the formation of intracellular signals but how this is achieved remains totally unknown. Using pharmacological inhibitors of the enzymatic activities of its subunits, we show here that the elastin peptide-driven ERK1/2 activation and subsequent pro-MMP-1 production, observed in skin fibroblasts when they are cultured in the presence of these peptides, rely on a membrane-bound sialidase activity. As lactose blocked this effect, the elastin receptor sialidase subunit, Neu-1, seemed to be involved.

Carbamylation differentially alters type I collagen sensitivity to various collagenases.

Carbamylation is a post-translational modification due to nonenzymatic binding of cyanate, a by-product of urea, on free amino groups of proteins. Post-translational modifications are known to induce alterations in structural and functional properties of proteins, thus disturbing protein-protein or cell-protein interactions. We report the impact of carbamylation on type I collagen sensitivity to enzymatic proteolysis.