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PubMed1997

The salivary lipocalin von Ebner's gland protein is a cysteine proteinase inhibitor.

The lipocalins make up a heterogeneous superfamily of proteins. Although showing almost no sequence homology, they share very similar secondary and tertiary structures. Their ability to bind hydrophobic ligands is well established, but the physiological function of most lipocalins remains unclear. The lipocalin from the human Von Ebner's Gland of the tongue (VEGh) contains three sequence motifs corresponding with the papain-binding domains of cystatins, a family of naturally occurring cysteine proteinase inhibitors. We found that VEGh inhibited papain activity to a similar extent as salivary cystatin S. Furthermore, synthetic peptides derived from VEGh and cystatin C, comprising these three motifs, inhibited papain, too. We conclude that VEGh is a physiological inhibitor of cysteine proteinases and therefore can play a role in the control of inflammatory processes in oral and ocular tissues.

Amino Acid Sequence↗

PubMed2005

A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping.

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.

Adolescent↗

PubMed2000

Intracellular degradation of histidine-rich glycoprotein mutants: tokushima-1 and 2 mutants are degraded by different proteolytic systems.

We reported the first case of a congenital histidine-rich glycoprotein deficiency (HRG Tokushima) in which substitution of Gly85 with Glu (G85E) in the first cystatin domain resulted in intracellular degradation and a low plasma level of HRG [Shigekiyo, T. et al. (1998) Blood 91, 128-133]. Recently, we identified the gene mutation of a second case of HRG deficiency as a Cys223 to Arg (C223R) mutation in the second cystatin domain. To investigate the molecular and cellular bases of these deficiencies, we expressed these HRG mutants in baby hamster kidney (BHK) cells. Pulse-chase experiments in the absence and presence of various proteinase inhibitors revealed that, while wild-type HRG was completely secreted during 4-h chase periods, both the G85E and C223R mutants were only partially secreted and primarily degraded within the cells. The intracellular degradation of the C223R mutant was almost completely inhibited in the presence of a proteasome inhibitor, lactacystin, carbobenzoxy-leucyl-leucyl-leucinal or N-acetyl-leucyl-leucyl-norleucinal, resulting in increased secretion of the C223R mutant, and thus implicating the proteasome system in this degradation process. In contrast, the sum of the amounts of the G85E mutant inside and outside the cells decreased during the chase periods even in the presence of the proteasome inhibitor, carbobenzoxy-leucyl-leucyl-leucinal or N-acetyl-leucyl-leucyl-norleucinal, although proteasome-specific inhibitor lactacystin and one of the cysteine protease inhibitors, E-64-d, prevented the intracellular degradation. These results suggested that intracellular degradation of G85E HRG occurred to some extent through a hitherto unknown mechanism. Similar studies involving recombinant mutants in which Gly85 or Cys223 was replaced with several other amino acids revealed that proteins with mutations leading to the destruction of the predicted b-sheet structure of the cystatin domains were eliminated by the intracellular quality control system.

Amino Acid Sequence↗

PubMed1999

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.

Aged↗

PubMed2004

The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.

Prevention of contrast agent-induced nephropathy is of crucial importance for a number of diagnostic studies. N-Acetylcysteine (NAC) was recently reported to decrease serum creatinine levels in this setting, and its administration before radiocontrast medium administration has been widely recommended. The objective of this prospective study was to investigate whether there are effects of NAC on serum creatinine levels that are independent of alterations in GFR. Volunteers with normal renal function who did not receive radiocontrast medium were studied. Fifty healthy volunteers completed the study protocol. NAC was administered orally at a dose of 600 mg every 12 h, for a total of four doses. Surrogate markers of renal function, such as serum creatinine, urea, albumin, and cystatin C levels, were measured and estimated GFR (eGFR) was assessed immediately before the administration of NAC and 4 and 48 h after the last dose. There was a significant decrease in the mean serum creatinine concentration (P < 0.05) and a significant increase in the eGFR (P < 0.02) 4 h after the last dose of NAC. The cystatin C concentrations did not change significantly. In several studies, a protective effect of NAC on renal function after radiocontrast medium administration has been postulated. This is the first study to demonstrate an effect of NAC on creatinine levels and eGFR, surrogate markers of renal injury, without any effect on cystatin C levels. Before renoprotective effects of NAC against contrast agent-induced nephropathy are considered, the direct effects of NAC on creatinine levels, urea levels, and eGFR should be assessed.

Acetylcysteine↗

PubMed1996

Purification and structural characterization of bovine cathelicidins, precursors of antimicrobial peptides.

Cathelicidins are a novel family of antimicrobial peptide precursors from mammalian myeloid cells. They are characterized by a conserved N-terminal region while the C-terminal antimicrobial domain can vary considerably in both primary sequence and length. Four cathelicidins, proBac5, proBac7, prododecapeptide and proBMAP-28, have been concurrently purified from bovine neutrophils, using simple and rapid methodologies. The correlation of ES-MS data from the purified proteins with their cDNA-deduced sequences has revealed several common features of their primary sequence, such as the presence of N-terminal 5-oxoproline (pyroglutamate) residues and two disulfide bridges in a 1-2, 3-4 arrangement. The N-terminal domains of the cathelicidins present one or two Asp-Pro bonds, which are particularly acid-labile in proBac5 and proBac7, but stable in prododecapeptide. This suggests that the spatial organization around these bonds may vary in different cathelicidins, and favour hydrolysis in some cases. An unexpected feature of the prododecapeptide is that it exists as dimers formed by three possible combinations of its two isoforms. The isolation of a truncated, monomeric form of this protein, lacking the cysteine-containing antimicrobial dodecapeptide, indicates that dimerization occurs via disulfide bridge formation at the level of the C-terminal domain and that the dodecapeptide is likely released as a dimer from its precursor. Sequence-based secondary structure predictions and CD results indicate for cathelicidins a 30-50% content of extended conformation and <20% content of alpha-helical conformation, with the alpha-helical segment placed near the N-terminus. Finally, similarity searching and topology-based structure prediction underline a significant sequential and structural similarity between the conserved N-terminal domain of cathelicidins and cystatin-like domains, placing this family within the cystatin superfamily. When assayed against cathepsin L, unlike the potent cystatin inhibitors, three of the four cathelicidins show only a poor inhibitory activity (Ki = 0.6-3 microM).

Amino Acid Sequence↗

PubMed2004

Specific cysteine protease inhibitors act as deterrents of western flower thrips, Frankliniella occidentalis (Pergande), in transgenic potato.

In this study, the effects of the accumulation of cysteine protease inhibitors on the food preferences of adult female western flower thrips, Frankliniella occidentalis (Pergande), were investigated. Representative members of the cystatin and thyropin gene families (stefin A, cystatin C, kininogen domain 3 and equistatin) were expressed in potato (Solanum tuberosum) cv. Impala, Kondor and Line V plants. In choice assays, a strong time- and concentration-dependent deterrence from plants expressing stefin A and equistatin was observed. Cystatin C and kininogen domain 3 were not found to be active. All tested inhibitors were equally or more active than stefin A at inhibiting the proteolytic activity of thrips, but, in contrast with stefin A, they were all expressed in potato as partially degraded proteins. The resistance of cysteine protease inhibitors against degradation in planta by endogenous plant proteases may therefore be relevant in explaining the observed differences in the deterrence of thrips. The results demonstrate that, when given a choice, western flower thrips will select plants with low levels of certain cysteine protease inhibitors. The novel implications of the defensive role of plant cysteine protease inhibitors as both deterrents and antimetabolic proteins are discussed.

Journal Article↗

PubMed2005

The Cockcroft-Gault formula should not be used in children.

BACKGROUND: Although designed for adults, the Cockcroft-Gault formula was recently proposed for use in children > or =13 years of age. METHODS: We compared the feasibility of the Cockcroft-Gault formula against the standard pediatric Schwartz formula and a novel cystatin C-based formula. Our patient cohort included 262 children aged 1 to 18 years with various renal pathologies, who underwent a 99-technetium diethylenetriaminepentaacetate ((99)Tc DTPA) glomerular filtration rate (GFR) renal scan. Calculations were performed in Systeme International (SI) units using published constants and recalculated constants from our patient population. Agreement was assessed using Bland and Altman analysis. RESULTS: Published and recalculated constants for the Cockcroft-Gault formula were 1.23 and 0.96, respectively, for boys, and 1.05 and 0.90, respectively, for girls. The published and recalculated constants for the Schwartz formula were 48 and 49.9, respectively, for boys > or =13 years old, and 38 and 46.2, respectively, for all girls and for boys <13 years old. Using published constants, there was agreement between GFR and Cockcroft-Gault formula in boys > or =13 years old (average bias 5.0 +/- 23.5%) while there was an average error of -19.0%+/- 36.4% for all ages. Similarly, the average bias with Schwartz for boys > or =13 years old was -6.8 +/- 24.0% and for all patients was -12.8 +/- 24.2%. Using recalculated constants, the average bias with Cockcroft-Gault in boys > or =13 years old was -19.8 +/- 23.5% and for all patients was -38.5 +/- 35.2%. Similarly, the average bias with Schwartz for boys < or =13 years old was -1.1 +/- 24.3% and for all patients was 3.0 +/- 24.0%. The novel cystatin C-based GFR calculations showed an average error of -4.9 +/- 20.3% in the adolescent boys and 2.4 +/- 20.4% for all ages. CONCLUSION: Cockcroft-Gault formula showed the worst agreement with GFR, regardless of using published or recalculated constants. The cystatin C-based approach resulted in the least error, and should be used for estimation of GFR.

Adolescent↗

PubMed2006

Analysis of bronchoalveolar lavage fluid proteome from systemic sclerosis patients with or without functional, clinical and radiological signs of lung fibrosis.

Lung fibrosis is a major cause of mortality and morbidity in systemic sclerosis (SSc). However, its pathogenesis still needs to be elucidated. We examined whether the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) might have a protective or a causative role in the lung fibrogenesis process. For this purpose we compared the BALF protein profile obtained from nine SSc patients with lung fibrosis (SScFib+) with that obtained from six SSc patients without pulmonary fibrosis (SScFib-) by two-dimensional gel electrophoresis (2-DE). Only spots and spot-trains that were consistently expressed in a different way in the two study groups were taken into consideration. In total, 47 spots and spot-trains, corresponding to 30 previously identified proteins in human BALF, showed no significant variation between SScFib+ patients and SScFib- patients, whereas 24 spots showed a reproducible significant variation in the two study groups. These latter spots corresponded to 11 proteins or protein fragments, including serum albumin fragments (13 spots), 5 previously recognized proteins (7 spots), and 4 proteins (3 spots) that had not been previously described in human BALF maps, namely calumenin, cytohesin-2, cystatin SN, and mitochondrial DNA topoisomerase 1 (mtDNA TOP1). Mass analysis did not determine one protein-spot. The two study groups revealed a significant difference in BALF protein composition. Whereas levels of glutathione S-transferase P (GSTP), Cu-Zn superoxide dismutase (SOD) and cystatin SN were downregulated in SScFib+ patients compared with SScFib- patients, we observed a significant upregulation of alpha1-acid glycoprotein, haptoglobin-alpha chain, calgranulin (Cal) B, cytohesin-2, calumenin, and mtDNA TOP1 in SScFib+ patients. Some of these proteins (GSTP, Cu-Zn SOD, and cystatin SN) seem to be involved in mechanisms that protect lungs against injury or inflammation, whereas others (Cal B, cytohesin-2, and calumenin) seem to be involved in mechanisms that drive lung fibrogenesis. Even if the 2-DE analysis of BALF did not provide an exhaustive identification of all BALF proteins, especially those of low molecular mass, it allows the identification of proteins that might have a role in lung fibrogenesis. Further longitudinal studies on larger cohorts of patients will be necessary to assess their usefulness as predictive markers of disease.

Bronchoalveolar Lavage Fluid↗

PubMed2006

Do cathepsins play a role in abdominal aortic aneurysm pathogenesis?

Between 1998 and 1999 we suggested a role for cysteine proteases, particularly cathepsins S and K, in atherosclerosis and abdominal aortic aneurysm (AAA) formation. We also demonstrated the presence and activity of cathepsins S, K, and L in atherosclerotic and aneurysmal lesions in humans. Features unique to this family of extracellular enzymes indicate its likely participation in these vascular diseases. As very potent elastolytic enzymes, cathepsins are strong candidates as key participants in aneurysm development. Importantly, cathepsins express very high elastolytic activity in AAA due to reciprocal correlation with cystatin C, their most abundant endogenous inhibitor. Two opposite processes coexist in aneurysmal tissue: overexpression of elastolytic cathepsins, and severe suppression of cystatin C, probably due to differentially regulated expression and secretion of cathepsins and their inhibitors in response to inflammatory cytokines. Involvement of cathepsins in microvessel formation, a pathophysiological marker of human AAA, and programmed cell death (apoptosis), increases the likelihood of cathepsin participation in AAA formation and growth. We also summarize here results obtained in our and other laboratories that demonstrated reduced atherosclerosis and AAA in in vivo models using mice lacking different cathepsins. Deficiency of cysteine protease inhibitor cystatin C in atherosclerosis-prone ApoE-null mice leads to the development of specific features of AAA such as thinning of the tunica media and aortic dilatation. Taken together, such findings in humans in vitro with different cell types and in vivo in genetically altered mice demonstrate the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during atherosclerosis and aortic aneurysm formation.

Animals↗

PubMed2004

Human cathepsin F: expression in baculovirus system, characterization and inhibition by protein inhibitors.

Recombinant full-length human procathepsin F, produced in the baculovirus expression system, was partially processed during the purification procedure to a form lacking the N-terminal cystatin-like domain and activated with pepsin. Active cathepsin F efficiently hydrolyzed Z-FR-MCA (kcat/Km=106 mM(-1) s(-1)) and Bz-FVR-MCA (kcat/Km=8 mM(-1) s(-1)), whereas hydrolysis of Z-RR-MCA was very slow (kcat/Km<0.2 mM(-1) s(-1)). Cathepsin F was rapidly and tightly inhibited by cystatin C, chicken cystatin and equistatin with Ki values in the subnanomolar range (0.03-0.47 nM), whereas L-kininogen was a less strong inhibitor of the enzyme (Ki=4.7 nM). Stefin A inhibited cathepsin F slowly (kass=1.6 x 10(5) M(-1) s(-1)) and with a lower affinity (Ki=25 nM). These data suggest that cathepsin F differs from other related endopeptidases by considerably weaker inhibition by stefins.

Animals↗

PubMed1998

Clinical features and genetics of progressive myoclonus epilepsy of the Univerricht-Lundborg type.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type is the most common cause of progressive myoclonus epilepsy worldwide. Typical features include onset at the age of 6-15 years, stimulus-sensitive myoclonus, tonic-clonic seizures, a progressive course and characteristic electroencephalographic findings with an exceptionally high sensitivity to photic stimulation. With modern anticonvulsive therapy the symptoms are relatively well controlled, and the disease may not always progress. Previously, no biochemical or pathological marker existed for the diagnosis of Unverricht-Lundborg disease. The positional cloning strategy was applied to identify the genetic defects that are responsible for this disease. The underlying gene encodes cystatin B, a cysteine protease inhibitor. The major mutation worldwide is an unstable expansion of a dodecamer minisatellite repeat unit in the promoter region of the cystatin B gene. In addition, five 'minor' mutations have been described. In the majority of patients, a reduced level of the cystatin B gene product seems to be the primary mechanism in the pathology, but the pathogenetic mechanisms are yet unknown. The molecular genetic findings have made a specific diagnosis possible and are the basis for understanding the molecular pathogenesis of the disease. This understanding may lead to the development of specific therapies for Unverricht-Lundborg disease.

Adolescent↗

PubMed2001

Structural studies of cysteine proteases and their inhibitors.

Cysteine proteases (CPs) are responsible for many biochemical processes occurring in living organisms and they have been implicated in the development and progression of several diseases that involve abnormal protein turnover. The activity of CPs is regulated among others by their specific inhibitors: cystatins. The main aim of this review is to discuss the structure-activity relationships of cysteine proteases and cystatins, as well as of some synthetic inhibitors of cysteine proteases structurally based on the binding fragments of cystatins.

Amino Acid Motifs↗

PubMed2002

Newly identified proteins in human nasal lavage fluid from non-smokers and smokers using two-dimensional gel electrophoresis and peptide mass fingerprinting.

Human nasal lavage fluids (NLFs) were analyzed with two-dimensional gel electrophoresis (2-DE) and proteins were identified with peptide mass fingerprinting using matrix-assisted laser desoption/ionization time of flight mass spectrometry. In some cases, the identification was verified by analysis of post-source decay fragmentation spectra. Many of the identified proteins were new forms or fragments of previously found proteins (e.g. albumin, lactoferrin, cystatin, calgranulin, von Ebners gland protein and palate lung nasal epithelium clone), while others were proteins that have previously been indicated by 2-DE image matching or immunoblots (e.g. apolipoprotein AI, lysozyme C, and Clara cell secretory protein). Some new proteins, not shown before in 2-DE patterns of NLF were also found, e.g. mammaglobin B, (2)-microglobulin and immunoglobulin J chain. Of the identified NLF proteins many appear to be involved in inflammatory and immune responses. A study was therefore conducted to investigate if the levels of these proteins were changed in smokers compared to nonsmokers. It was found that NLF from smokers contained decreased levels of Clara cell secretory protein, and increased proportions of a truncated variant of lipocortin-1, three acidic forms of alpha(1)-antitrypsin, and one phosphorylated form of cystatin S. Furthermore, NLF from smokers contained increased proportions of a new variant of palate lung nasal epithelium clone (PLUNC), a recently identified airway irritation marker. The results demonstrate that 2-DE of NLF may be used to assess alterations of proteins or post-translationally modified proteins in smokers. Clara cell secretory protein (CC 16, CC 10) and lipocortin-1 are two anti-inflammatory, phospholipase A(2) inhibitory proteins, and alpha(1)-antitrypsin and cystatin S are two proteinase inhibitors. Changed levels of these proteins may therefore be of importance to the airway inflammation caused by smoking. The results also support the notion that PLUNC is involved in inflammatory responses in the upper airways.

Case-Control Studies↗

PubMed2004

New antimicrobial peptide active against Gram-positive pathogens.

BACKGROUND & OBJECTIVES: Human and animal cystatins have been shown to inhibit the replication of certain viruses and bacteria, though it is not directly demonstrated that the effects are due to protease inhibitory capacity of the cystatins. We report antibacterial properties of a novel antimicrobial peptidyl derivative, (2S)-2-(N(alpha)-benzyloxycarbonyl-arginyl-leucylamido)-1-[(E)-cinnamoylamido]-3- methylbutane, structurally based upon the aminoterminal segment of the inhibitory centre of the human cysteine protease inhibitor, cystatin C. METHODS: Clinical isolates of group A, B, C and G streptococci were collected. The antibacterial activity of Cystapep 1 derivative was tested by agar well diffusion method. RESULTS: Cystapep 1, displayed antibacterial activity against several clinically important Gram-positive bacteria. It displayed minimal inhibitory and bactericidal concentrations of about 16 microg/ml for both Staphylococcus aureus and Streptococcus pyogenes. In radial agar diffusion assays, groups A, B, C and G streptococci as well as staphylococci were generally susceptible to the action of Cystapep 1, whereas pneumococci and enterococci were less susceptible. No activity against Gram-negative bacteria was observed. INTERPRETATION & CONCLUSION: Cystapep 1 also showed high activity against methicillin-resistant Staph. aureus (MRSA) and multi-antibiotic resistant coagulase negative staphylococci (CNS), suggesting its mechanism of action to be different from most currently used antibiotics.

Anti-Bacterial Agents↗

PubMed2005

Effect of rofecoxib on the glomerular filtration rate, proteinuria and the renin-angiotensin-aldosterone system in elderly subjects with chronic renal impairment.

UNLABELLED: Considering the increasing popularity and prescribing of specific COX-2 inhibitors, a new class of NSAIDs lacking gastrointestinal side effects, the evaluation of their effects on renal function has become very important. OBJECTIVE: The aim of the study was to evaluate the effect of rofecoxib on GFR, proteinuria and the renin-angiotensin-aldosterone system (RAAS) in elderly patients with chronic renal impairment under controlled conditions of water and salt intake. SUBJECTS: There were ten patients (average age 67 years, range 53 - 80 years) with analgesic or vascular nephropathy (average GFR 54 ml/min/1.73 m2, range 30 - 79 ml/min/ 1.73 m2) given 25 mg rofecoxib daily for seven days under balanced conditions of water and sodium metabolism (salt intake 6 - 8 g/24 hours). METHODS: The effect of rofecoxib on GFR measured using inulin clearance (C(in)), creatinine clearance (C(Cr)) serum cystatin C concentration (S(cystatin)), tubular creatinine secretion (using the ratio C(Cr)/C(in)), 24-hour urinary excretion of albumin (U(alb)V) and prostaglandins (U(PGE2)V and U(PGF2alpha)V), basal and stimulated plasma renin activity (PRA) and serum aldosterone concentration S(aldosterone) was evaluated before and on Day 7 during rofecoxib treatment. RESULTS: Rofecoxib did not significantly change C(in), C(Cr), S(cystatin), C(Cr)/C(in) and U(alb)V. However, U(PGE2)V and U(PGF2alpha)V were decreased during rofecoxib administration (p = 0.059 and p = 0.024, respectively). Rofecoxib attenuated the stimulated rise of PRA and S(aldosterone) (p = 0.019 and p = 0.008, respectively). CONCLUSIONS: Short-term rofecoxib administration was not associated with significant change in GFR in elderly patients with moderate chronic renal impairment under conditions of balanced salt and water metabolism despite significant attenuation of RAAS activity. Since the C(Cr)/C(in) ratio did not change in our study, we assume rofecoxib to have no influence on creatinine tubular secretion.

Aged↗

PubMed1988

Human cathepsin B and cysteine proteinase inhibitors (CPIs) in inflammatory and metabolic joint diseases.

Synovial fluid of patients with different inflammatory and metabolic joint diseases contains low-molecular CPIs (stefins and cystatins) and high-molecular CPIs (kininogens). An additional inhibitory fragment with a molecular mass of about 20 kDa, which is a part of the kininogen molecule, has been detected. Cathepsin B and cystatin C were determined by ELISA test in 47 patients with rheumatoid arthritis, seronegative spondylarthritis, osteoarthritis, undifferentiated arthritis and gout. A significantly higher amount of cathepsin B was found in patients with rheumatoid arthritis. The elevation of cathepsin B was accompanied by an increased amount of cystatin C.

Amino Acid Sequence↗

PubMed1995

Identification of an endothelial cell binding site on kininogen domain D3.

High and low molecular mass kininogen, two multidomain plasma proteins, bind to endothelial cells, platelets, and neutrophils in the intravascular compartment. The specific cell attachment site on their common heavy chain is mediated by domain-3, a cystatin-like structure with inhibitory capacity for papain-like proteinases (Jiang, Y., Müller-Esterl, W., and Schmaier, A. H. (1992) J. Biol. Chem. 267, 3712-3717). In this report, the domain-3 cell binding site is determined by an antibody-directed strategy. The epitope of monoclonal antibody HKH15, which binds to domain-3 and blocks the binding of kininogens to platelets and endothelial cells, was mapped using seven synthetic peptides, which span the entire domain-3 sequence. One peptide, LDC27, specifically bound to HKH15. Fine mapping of the epitope of HKH15 revealed that a minimal 13-residue segment in LDC27, named CNA13, is the antibody binding site. LDC27 and CNA13 inhibited biotinylated high molecular mass kininogen binding to endothelial cells with apparent IC50 values of 60.3 +/- 12 and 113.3 +/- 63.7 microM, respectively. Carboxymethylated papain and affinity-purified anti-LDC27 polyclonal antibodies also inhibited the binding of biotinylated high molecular mass kininogen to endothelial cells with an apparent IC50 of 1.04 microM and 59 nM, respectively. Biotinylated LDC27 itself directly bound to endothelial cells, and domain-3 inhibited biotinylated LDC27 binding to human umbilical vein endothelial cells with an IC50 of 41 nM. Using the crystalline structure of cystatin to computer model domain-3, LDC27 and CNA13 were located in the second hairpin loop of the reactive site of cystatin-like proteins (Bode, W., Engh, R., Musil, D., Thiele, U. Huber, R., Karshikov, A., Brzin, J., Kos, J., and Turk, V. (1988) EMBO J. 7, 2593-2599). These results indicate that the major endothelial cell attachment site on kininogen domain-3 is located on its carboxyl-terminal portion and that it overlaps its cysteine protease inhibitory region.

Amino Acid Sequence↗