382 research outputs found
Role of cathepsin S in basement remodelling and regulation of its enzymatic activity by glycosaminoglycans
No full textLe renouvellement de la membrane basale et de la matrice extracellulaire lors de processus physiologiques ou pathologiques (réparation tissulaire, angiogenèse, inflammation, cancer) fait intervenir de nombreuses protéases dont les cathepsines à cystéine. Après avoir étudié leur localisation dans l’épiderme à proximité de la jonction dermo-épidermique et leur sécrétion par les kératinocytes, nous avons montré la capacité de la cathepsine S à dégrader efficacement les principales protéines de la membrane basale (laminine, collagène IV, perlécan) et plus particulièrement le nidogène-1, qui est essentiel à l’organisation architecturale de la membrane basale via de multiples interactions avec les autres constituants. Parmi plusieurs glycosaminoglycanes présents dans la matrice extracellulaire, le chondroïtine 4-sulfate est capable de se complexer avec la cathepsine S, via trois sites potentiels de fixation dont un au niveau de son site actif, et d’inhiber son activité enzymatique de façon dose-dépendante. L’expression et l’activité de la cathepsine S au niveau de l’épiderme diminuent au cours du vieillissement cutané, alors que l’expression du nidogène-1 reste stable. La cathepsine S jouerait donc un rôle important aux côtés d’autres protéases dans le remodelage de la membrane basale.Basement membrane (BM) and extracellular matrix (ECM) turnover during physiological or pathological events (tissue repair, angiogenesis, inflammation, cancer) involves numerous proteases including cysteine cathepsins. Cathepsins expression in skin epidermis near dermal-epidermal junction and their secretion by keratinocytes were first analyzed. We showed that cathepsin S degrades efficiently main BM components (laminin, type IV collagen, perlecan) and particularly nidogen-1 that is essential for BM architecture. Among several glycosaminoglycans present in ECM, chondroïtin 4-sulfate is able to form a stable complex with cathepsin S. Three predicted binding sites including one closed to its active site were identified. Further, C4-S inhibits cathepsin S activity in a dose-dependent manner. The expression and activity of cathepsin S in epidermis are decreased upon skin aging while nidogen-1 expression remains unchanged. Cathepsin S besides other proteases may play an important role in BM remodeling
Role of cysteine cathepsis in the regulation of the antimicrobial peptide LL-37 during chronic lung inflammatory diseases
No full textLors de pathologies pulmonaires inflammatoires chroniques comme la mucoviscidose ou la BPCO, le déséquilibre de la balance protéases/antiprotéases aboutit à la dégradation du tissu pulmonaire et à l’inactivation des défenses antimicrobiennes. Les cathepsines à cystéine participent à l’inactivation protéolytique de peptides et protéines antimicrobiens (PAMs) pulmonaires comme le SLPI, la lactoferrine, et les β-défensines HBD-2 et -3 lors de l’emphysème ou de la mucoviscidose. Lors de cette thèse, nous avons étudié la capacité des cathepsines à cystéine B, K, L et S à hydrolyser le peptide LL-37, qui est un PAM important dans l’immunité innée pulmonaire. Seules les cathepsines K et S clivent le LL-37 et inactivent efficacement son activité antimicrobienne. A l’inverse, le LL-37 est un inhibiteur compétitif de la cathepsine L. D’autre part, l’expression pulmonaire de la cathepsine S est fortement augmentée chez les individus fumeurs atteints ou non de BPCO. La fumée de cigarette qui est une source importante de stress oxydatif induit une augmentation significative de l'expression et l'activité de la cathepsine S. Malgré un environnement oxydatif non favorable à l'activité des cathepsines, la cathepsine S parvient à hydrolyser le peptide LL-37 et pourrait ainsi augmenter le risque d’exacerbation lors de la BPCO.During chronic inflammatory lung diseases like cystic fibrosis or COPD, proteases/antiproteases imbalance leads to pulmonary tissue degradation and compromise antimicrobial barrier. Cysteine cathepsins are involved in the proteolytic inactivation of several lung antimicrobial peptides (AMPs) such as SLPI, lactoferrin and β- defensins -2 and -3 during emphysema or cystic fibrosis. During this thesis, we studied the ability of cathepsins B, K, L and S to degrade LL-37, which is an important AMP in lung immunity. Only cathepsins K and S degrade readily LL-37 and inactivate its antimicrobial property. Conversely, LL-37 is a competitive inhibitor of cathepsin L. Beside, lung expression of human cathepsin S is significantly increased in smokers with or without COPD compared to non-smokers. Cigarette smoke that is a major source of oxidative stress significantly increases the expression and activity of cathepsin S. Despite an unfavorable oxidative environment, cathepsin S retains its proteolytic activity toward LL-37 and thus could participate to COPD exacerbation
Regulation of cathepsin V by heparan sulfate in mucopolysaccharidosis
No full textLes mucopolysaccharidoses (MPS) de types I, II et III représentent un groupe de maladies génétiques rares dites de surcharges lysosomales, caractérisées par une accumulation importante d'héparane sulfate (HS). Les patients atteints de MPS présentent un dysfonctionnement multiviscéral progressif et une durée de vie limitée principalement due à de fortes atteintes cardiorespiratoires. Les mécanismes moléculaires contribuant à l'altération de la fonction respiratoire sont peu connus. Des dépôts anormaux de collagène et d'élastine au niveau du parenchyme pulmonaire chez les patients MPS peuvent être liés à cette altération de la fonction respiratoire. Les cathepsines à cystéine sont des protéases lysosomales (11 chez l'homme) impliquées dans la dégradation et le renouvellement des protéines, dont la majorité sont exprimées de manière ubiquitaire dans les tissus humains. Leur activité protéolytique incontrôlée est associée à des pathologies inflammatoires pulmonaires (emphysème, fibrose, asthme) et à certaines maladies osseuses (ostéoporose, polyarthrite rhumatoïde). Parmi les cathepsines, la cathepsine V est méconnue au niveau pulmonaire. L'activité protéolytique de certaines cathepsines apparentées à la cathepsine V étant étroitement contrôlée par des glycosaminoglycanes (GAGs), notre hypothèse est que l’accumulation excessive des GAGs, en particulier HS, peut empêcher les activités physiologiques des cathepsines, nécessaires à l’homéostasie pulmonaire, et plus particulièrement l’activité élastinolytique de la cathepsine V dans les poumons des patients atteints de MPS.Mucopolysaccharidoses (MPS) types I, II and III represent a group of rare genetic diseases known as lysosomal storage disorders, characterized by a significant accumulation of heparan sulfate (HS). Patients with MPS have progressive multiviscular dysfunction and a limited lifespan, mainly due to severe cardiorespiratory impairment. The molecular mechanisms contributing to the impairment of respiratory function are poorly understood. Abnormal deposits of collagen and elastin in the pulmonary parenchyma in MPS patients may be related to this impaired lung function. Cysteine cathepsins are lysosomal proteases (11 in humans) involved in protein degradation and turnover, the majority of which are ubiquitously expressed in human tissues. Their uncontrolled proteolytic activity is associated with pulmonary inflammatory pathologies (emphysema, fibrosis, asthma) and certain bone diseases (osteoporosis, rheumatoid arthritis). Among cathepsins, cathepsin V is poorly known in human lung. Since the proteolytic activity of some cathepsin V-related cathepsins is tightly controlled by glycosaminoglycans (GAGs), our hypothesis is that excessive accumulation of GAGs, particularly HS, may inhibit the physiological activities of cathepsins, necessary for pulmonary homeostasis, and more specifically the elastinolytic activity of cathepsin V in the lungs of patients with MPS
Contrôle de l'activité protéolytique des protéases à cystéine de trypanosomes
No full textTOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF
Reversible inhibition of cathepsin L-like proteases by 4-mer pseudopeptides
No full textAbstractA library of 121 pseudopeptides was designed to develop reversible inhibitors of trypanosomal enzymes (cruzain from Trypanosoma cruzi and congopain from Trypanosoma congolense). The peptides share the framework: Cha-X1-X2-Pro (Cha=cyclohexyl-alanine, X1 and X2 were phenylalanyl analogs), based on a previous report [Lecaille, F., Authié, E., Moreau, T., Serveau, C., Gauthier, F. and Lalmanach, G. (2001) Eur. J. Biochem. 268, 2733–2741]. Five peptides containing a nitro-substituted aromatic residue (Tyr/Phe) and one a 4-chloro-phenylalanine at the X1 position, and 3-(2-naphthyl)-alanine, homocyclohexylalanine or 3-nitro-tyrosine (3-NO2-Tyr) at the X2 position, were selected. They inhibited congopain more effectively than cruzain, except Cha-4-NO2-Phe-3-NO2-Tyr-Pro which bound the two parasitic enzymes similarly. Among this series, Cha-3-NO2-Tyr-HoCha-Pro and Cha-4-NO2-Phe-3-NO2-Tyr-Pro are the most selective for congopain relative to host cathepsins. No hydrolysis occurred upon prolonged incubation time with purified enzymes. In addition introduction of non-proteogenic residues in the peptidyl backbone greatly enhanced resistance to proteolysis by mammalian sera
particleShear: Discrete Python particle simulation with digital rheology and stress tensor evaluation
No full textparticleShear: Python package for particle shear simulation
This package provides a discrete particle simulation kit for having multiple spheres interacting. The spheres (i.e. 2D circles) interact by mutual elastic repulsion and tangential friction upon contact, but can also be crosslinked together. In addition to the elementary implementation of the interacting particles, it is also possible to define rheological experiments where the spheres are exposed to sinusoidally varying displacement conditions on the boundaries. We paid particular attention to avoid pitfalls that generate asymmetric stress tensors.
Acknowledgement: Thanks from the author go to Fabien Bonini and Joé Brefie-Guth for package testing, and to Daniel Lyobenov for initial help with simulation setup.
This repository archives the releases of the source code hosted at https://github.com/tbgitoo/particleShear. The package is available through the Python package server (see https://pypi.org/project/particleShear/1.0.2/). It can be installed automatically in python via
pip3 install particleShear
In some installations, the command may also be pip install particleShear; the minimal version of Python is 3.
Revisiting the S2 specificity of papain by structural analogs of Phe
No full textAbstractPapain characteristically has a strong preference for encoded l-aromatic amino acids (Phe>Tyr) at P2 position. We re-examined papain S2 specificity using structural analogs of Phe, in fluorogenic substrates of the series: dansyl-Xaa-Arg-Ala-Pro-Trp (Xaa=P2 residue). Kinetic analyses showed that the S2 pocket accommodates a broad spectrum of Phe derivatives. Papain is poorly stereoselective towards Dns-(d/l)-Phe-Arg-Ala-Pro-Trp and binding is not critically affected by replacement of the benzyl ring by the non-aromatic lateral chain of cyclohexylalanine. The Km was significantly improved by mono- and di-chlorination of Phe, or by its substitution by an electronegative group-like NO2, but the specificity constant was unchanged. Shortening or lengthening the side chain by adding or removing a methylene group impairs the P2/S2 interactions significantly, as do constrained structural analogs of Phe. Incorporation of benzyl-substituted phenylalanyl amino acid could help to design peptide-derived inhibitors with greater affinity and bioavailability
Optimizing construction of scheduled data flow graph for on-line testability
No full textThe objective of this work is to develop a new methodology for behavioural synthesis using a flow of synthesis, better suited to the scheduling of independent calculations and non-concurrent online testing. The traditional behavioural synthesis process can be defined as the compilation of an algorithmic specification into an architecture composed of a data path and a controller. This stream of synthesis generally involves scheduling, resource allocation, generation of the data path and controller synthesis. Experiments showed that optimization started at the high level synthesis improves the performance of the result, yet the current tools do not offer synthesis optimizations that from the RTL level. This justifies the development of an optimization methodology which takes effect from the behavioural specification and accompanying the synthesis process in its various stages. In this paper we propose the use of algebraic properties (commutativity, associativity and distributivity) to transform readable mathematical formulas of algorithmic specifications into mathematical formulas evaluated efficiently. This will effectively reduce the execution time of scheduling calculations and increase the possibilities of testability
Dataset: Stability of hemicarbonate under cement paste-like conditions
No full textData, and scripts (analysis, plots) to go with the publication:
Stability of hemicarbonate under cement paste-like conditions
Fabien Georget (a,1,∗), Barbara Lothenbach (b) , William Wilson (a,c) , Franco Zunino (a) Karen L. Scrivener (a)
a: aboratory of Construction Materials, LMC, EPFL-STI-IMX, Station 12, CH-1015
Lausanne, Switzerland
b: Empa, Concrete & Asphalt Laboratory, Dübendorf, Switzerland
c: Sherbrooke University, Sherbrooke, Quebec, Canada
1: current address: Institute of Building Materials Research, RWTH Aachen, Aachen, Germany
* corresponding author
To be submitted to Cement and Concrete Researc
Antimicrobial proteins and peptides in human lung diseases: A friend and foe partnership with host proteases
No full text- …
