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At least 721 records · Page 40Linked to original sources
PubMed1994

Latency of cathepsin B secreted by human colon carcinoma cells is not linked to secretion of cystatin C and is relieved by neutrophil elastase.

The lysosomal cysteine proteinase cathepsin B is shown to be secreted by ten human colon carcinoma cell lines and to accumulate in culture media as a latent enzyme. The cell lines also secrete a physiological inhibitor of cathepsin B, cystatin C. A significant correlation was found between secretion of the latent enzyme and the inhibitor (r = 0.755, P < 0.01). The aim of the present study was to modulate the respective secretion of the two antagonists to test whether or not latency of cathepsin B was due to the concomitant secretion of the inhibitor. SW480 colon carcinoma cells were treated with the acidotropic agent ammonium chloride, phorbol 12-myristate 13-acetate, and the inflammatory cytokines TGF-beta, TNF-alpha, and IL-1 beta. Ammonium chloride significantly increased latent cathepsin B levels without affecting the constitutive secretion of cystatin C. Phorbol 12-myristate 13-acetate induced a 4- to 5-fold increase in secreted latent cathepsin B, but did not alter significantly the accumulation of cystatin C in media. The cytokines, TGF-beta, TNF-alpha, and IL-1 beta, had no major effect on the expression of these two antagonists. Latent cathepsin B released from human carcinoma cells could be efficiently activated by neutrophil elastase at neutral pH. It is concluded that latent cathepsin B is a true proenzyme rather than an enzyme-inhibitor complex. In addition, our data from neutrophil elastase activation experiments indicate that a proteolytic system for activation of the tumor cell-secreted latent enzyme may exist in vivo.

Adenocarcinoma↗
PubMed2004

A sol particle homogeneous immunoassay for measuring serum cystatin C.

OBJECTIVES: We have developed a sol particle immunoassay (SPIA) for measuring serum cystatin C, an endogenous marker of glomerular filtration rate (GFR). DESIGN AND METHODS: We used colloidal gold particles coated with anti-cystatin C antibodies. RESULTS: The assay was linear in the range 0.2 to 8 mg/L and showed good correlation between theoretical and obtained values. The within and between-day coefficients of variation (CV) varied from 1.1 to 1.6% and 0.4 to 1.0%, respectively. Analytical recovery was 95.7 to 103.7%. No interference could be detected from bilirubin (up to 200 mg/L), hemoglobin (up to 3 g/L), chyle (up to 5,000 FTU), rheumatoid factor (up to 1,000 IU/mL) or anticoagulants. Serum samples (n = 101), from which turbidity had been removed, were measured either with our assay or with Dako Cystatin C PET kits, using a Model 7070 Hitachi automatic clinical analyzer. Comparing these two methods, the calculated linear regression equation and the correlation coefficient were y = 0.986 x -0.153 and r = 0.995, respectively. CONCLUSIONS: Our new SPIA assay is a fully automated, homogeneous immunoassay that can readily be used in conjunction with various commercial analyzers that are currently available. The assay is sensitive, precise and suitable for clinical use and appears to offer advantages over other GFR markers such as creatinine.

Biomarkers↗
PubMed2006

Enhanced cystatin C and lysosomal protease expression following 6-hydroxydopamine exposure.

6-Hydroxydopamine (6-OHDA) is a selective neurotoxin used to induce apoptosis in catecholamine-containing neurons. Although biochemical products and reactive oxygen species (ROS) of 6-OHDA have been well documented, the activation of cellular pathways following exposure are not well understood. Apoptosis in PC12 (Pheochromocytoma) cells was induced by 6-OHDA in a dose (10-150 microM) and time-dependent (24-72 h) manner compared to experimental controls (no treatment). PC 12 cells exposed to 50 microM 6-OHDA demonstrated the involvement of caspase 3 and lysosomal protease alterations. Following 6-OHDA exposure, the caspase 3-like inhibitor Ac-DEVD-CHO significantly decreased 6-OHDA induced cell death. In addition, alterations in expression of the lysosomal cysteine and aspartic proteases, cathepsin B (CB) and cathepsin D (CD) and the endogenous cysteine protease inhibitor cystatin C were observed utilizing immunocytochemical analysis at 24, 48, and 72 h following 6-OHDA exposure. Furthermore, CB and CD and cystatin C immuno-like reactivity was more pronounced in TUNEL positive cells. Moreover, Western blot analysis confirmed a significant increase in protein expression for CB and CD at 72 h and a temporal and concentration dependent increase in cystatin C in response to 6-OHDA. Cells treated with pepstatin A, an inhibitor for CD, showed a significant decrease in cell death, however, CA-074ME, a specific inhibitor for CB, failed to protect cells from 6-OHDA induced cell death. Thus, these results suggest that apoptosis induced by 6-OHDA exposure is mediated in part through caspase 3 activation and lysosomal protease CD.

Animals↗
PubMedDate not supplied

Glomerular filtration rate estimation in renal transplant patients based on serum cystatin-C levels: comparison with other markers of glomerular filtration rate.

PURPOSE: The assessment of glomerular filtration rate (GFR) is the most commonly used test of renal function. Cystatin-C, a cysteine protease inhibitor, which can be measured by light-scattering immunoassay, possesses many of the attributes required of the ideal GFR marker. Conversely, many endogenous markers that are widely used for the estimation of GFR such as serum creatinine (SCr) are not ideal. The present study was undertaken to evaluate the clinical application of serum cystatin-C (CysC) as a new marker of GFR in renal transplant patients. METHODS: Eighteen patients (9 men) were enrolled in the study (mean age: 46.35, range: 31-67 years) to measure serum CysC levels and compare them, with SCr, creatinine clearance (CCr), as well as the Cockcroft-Gault equation (CG) or the MDRD as indicator of GFR. Spearman's correlation coefficient was used to determine the relationship between CysC and other markers. RESULTS: There was a significant negative correlation between serum CysC and CCr (r = -0.768). Moreover, the CysC level was negatively correlated with CG (r = -0.854), positively correlated with SCr (r = 0.629), and negatively correlated with MDRD (r = -0.604). CONCLUSIONS: These results indicate that measurement of serum cystatin-C was useful and accurate to estimate GFR in renal transplant patients. The recent literature confirms our data although there are concerns about nonrenal influence on this test. Although serum CysC can generally be recommended as a marker for GFR, our study is still in progress seeking to validate the conclusions in a larger number of patients.

Adult↗
PubMed2003

Fate of cystatin C lacking the leader sequence in RPE cells.

The study made use of transiently transfected RPE cells expressing mature cystatin C (lacking the 26 amino acids leader sequence of the precursor cystatin C) fused to enhanced green fluorescent protein (EGFP) and, in control transfections, EGFP on its own. The findings demonstrate that 'leaderless' cystatin C is not processed through the secretory pathway of RPE cells. Since a polymorphism in the leader sequence has recently been associated with increased risk for development of exudative age-related macular degeneration (AMD), the present findings lend support to the hypothesis that impairment of function of the leader sequence may contribute to the aetiology of exudative AMD.

5' Untranslated Regions↗
PubMed1998

The high alkaline fraction on isoelectric focusing of cerebrospinal fluid is cystatin C.

A high alkaline fraction with a pI of 9.2 is sometimes seen on isoelectric focusing patterns of cerebrospinal fluid. The appearance of this fraction mainly depends on the type of concentrators used to prepare the cerebrospinal fluid samples, prior to isoelectric focusing. The amino acid sequence of the high alkaline fraction showed sequence identity to cystatin C, a cysteine protease inhibitor with a pI of 9.2-9.3 and a molecular mass of 13.4 kDa. In addition, on Western blot the high alkaline fraction was recognized by an antibody, directed against cystatin C. Taken together, the present findings demonstrate that the high alkaline fraction is cystatin C.

Amino Acid Sequence↗
PubMed1999

Expression of cathepsin B and cystatin C in human colorectal cancer.

Cathepsin B is a matrix protease that may be associated with colorectal carcinoma invasion and progression. In this study, we investigated the localization of cathepsin B in cancerous and noncancerous tissues of 80 patients with colorectal cancer including 25 cases with liver metastasis. In addition, the expression of cystatin C, one of several cathepsin B inhibitors, was compared with that of cathepsin B in the same samples to reveal one of the regulation mechanisms of cathepsin B. The cancer cells in the advancing edge of the tumors often exhibited the strongest immunostaining of cathepsin B, and stromal cells and normal epithelial cells adjacent to the tumors were also positive for cathepsin B. The percentage of cathepsin B-positive cases was significantly larger in the group with liver metastases than in the group without liver metastases. In the group without liver metastases, the cancer cells and stromal cells more frequently exhibited cathepsin B immunoreactivity in Dukes' A cases than in Dukes' B and C cases. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) confirmed cathepsin B synthesis in the cancer and proximal epithelial cells. There was an average 3.7-fold increase in cathepsin B mRNA levels in the cancerous tissues compared with that of noncancerous tissues, and Dukes' A tumors exhibited the highest expression level. Conversely, cystatin C mRNA levels were similar in all samples, and tended to show an inverse correlation with the cathepsin B levels. In conclusion, cathepsin B expression by human colorectal cancers and surrounding noncancerous cell components may contribute to both local invasion at the early stage and remote metastasis without influence of cystatin C.

Adenocarcinoma↗
PubMed2001

Cystatin C, beta 2-microglobulin, and retinol-binding protein as indicators of glomerular filtration rate: comparison with plasma creatinine.

BACKGROUND: The aim of this study was to assess the diagnostic accuracy of plasma levels of three low-molecular weight proteins cystatin C, beta 2-microglobulin, and retinol-binding protein, as indicators of impairment of glomerular filtration rate in comparison with plasma creatinine. METHODS: Glomerular filtration rate (GFR) was measured in 110 patients (51 M and 59 F, aged 18--79 years); creatinine (Creat), cystatin C (Cys), beta 2-microglobulin (beta 2M), and retinol-binding protein (RBP) were determined on the same day. The correlation coefficients between the different markers and GFR were determined. Receiver-operating characteristics (ROC) analysis was performed to assess their diagnostic accuracy. Furthermore, the relationship between plasma levels of the examined markers of GFR and body weight, height, fat-free mass (FFM) and body cell mass (BCM) was determined. FFM and BCM were calculated by means of total body electrical impedance measurement. RESULTS: Serum concentrations of Cys, beta 2M and RBP increase progressively with the reduction of GFR. The magnitude of the increase in blood levels of Creat and beta 2M was higher than the increase of Cys, and much more than that of RBP, in particular in patients with GFR<20 ml/min/1.73 m(2). The correlation coefficients between GFR and 1/plasma concentrations were 0.647 for Creat, 0.651 for Cys, 0.731 for beta 2M, and 0.406 for RBP. ROC analysis indicated that the accuracy of beta 2M and Cys, as indicators of different degrees of GFR impairment (<80, <60, and <40 ml/min per 1.73 m(2)), was similar to that of Creat, while the diagnostic accuracy of RBP resulted significantly lower than that of Creat for any level of GFR. In patients without renal failure (GFR>40 ml/min per 1.73 m(2)), plasma concentrations of Creat were positively correlated with body weight (P<0.01), height (P<0.01), FFM (P<0.001) and BCM (P<0.001). Serum concentrations of RBP resulted correlated with FFM (P<0.05) and BCM (P<0.05), while no correlation was found between anthropometric data and Cys and beta 2M. CONCLUSION: Cystatin C and beta 2-microglobulin have a diagnostic accuracy very similar to that of creatinine, while retinol-binding protein is not an adequate marker of glomerular filtration.

Adolescent↗
PubMed1997

G to C transversion at a splice acceptor site causes exon skipping in the cystatin B gene.

Several mutations have been described in the proteinase inhibitor cystatin B gene from individuals affected with progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1). One of these mutations, a 1925G-->C transition at the 3'-splice acceptor site of the intron 1, was postulated to lead to inappropriate splicing of a primary transcript of the cystatin B gene in EPM1 patients. In an effort to understand the expression of the 1925G-->C mutation, the sequence of cystatin B mRNA transcripts from lymphoblastoid cell lines of heterozygous patients carrying the mutation were analyzed. RT-PCR of total mRNA showed two main products: the apparently normal transcript and an aberrant, 102 bp shorter transcript. Direct PCR sequencing showed that the aberrant transcript is a consequence of exon 2 skipping.

Cell Line↗
PubMed2001

Role of cystatin C and cysteine proteinases in the development of mouse LS-lymphosarcoma.

The growth of LS-lymphosarcoma in CBA mice was accompanied by a decrease in the content of the major extracellular inhibitor cystatin C in the tumor, plasma and, to a lesser extent, in tissues not involved in tumor process (liver and spleen). Cyclophosphamide in a dose of 50 mg/kg prolonged the life-span of animals and decreased tumor size by 80%. Cathepsin B and L activities in the tumor tissue increased by 3 and 7 times, respectively. Cystatin C content in the tumor tissue, spleen, and plasma also increased. Cystatin C assay in tumor tissue and plasma helps to predict the rate of tumor growth and to evaluate the efficiency of antitumor therapy.

Animals↗
PubMed2003

Cystatin C and cysteine proteinases during the development and therapy of Lewis lung adenocarcinoma in mice.

We measured plasma cystatin C concentration and activity of cathepsins B and L in tumor tissue as possible markers for the efficiency of antitumor therapy and prognostic criteria for Lewis lung adenocarcinoma in mice. Plasma cystatin C concentration markedly decreased in mice with tumors. During successive therapy the increase in plasma cystatin C concentration correlated with the degree of inhibition of tumor growth. Activities of cathepsins B and L in the liver increased in animals with tumors. In mice receiving successive antitumor therapy activities of cathepsins B and L increased in tumor tissue, but decreased in the liver (compared to untreated animals).

Animals↗
PubMedDate not supplied

Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C. Dissociation of antiproteolytic and antibacterial effects.

Cysteine protease-inhibiting proteins of the cystatin superfamily can inhibit the replication of certain viruses and bacteria. The inhibitory centre of human cystatin C, the most widely distributed human cystatin, comprises three peptide segments. The present work describes the synthesis and antibacterial activity of 27 new peptidyl derivatives or cyclopeptides based upon the aminoterminal segment Arg8-Leu9-Val10-Gly11. Fourteen of the new compounds displayed antibacterial activity against from 1 up to 9 of 17 clinically important bacterial species tested. Antiproteolytic activity of a compound was usually not required for its antibacterial capacity. Peptidyl diazomethanes generally had a very narrow antibacterial spectrum, inhibiting only Streptococcus pyogenes, whereas cyclopeptides and peptidyl derivatives of the general structure X-Arg-Leu-NH-CH(iPr)-CH2-NH-Y had a much wider spectrum. The most potent of these substances displayed approximately equal minimal inhibitory and bactericidal concentrations of about 20 microg/ml for both Staphylococcus aureus and S. pyogenes and were devoid of antiproteolytic activity. Several of the new substances could protect mice against lethal intraperitoneal challenge with S. pyogenes. Though their target remains to be disclosed, the group of substances here reported might be promising for the development of antibacterial drugs and the discovery of novel principles of action.

Anti-Bacterial Agents↗
PubMed1998

Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice.

Loss-of-function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as Unverricht-Lundborg disease (EPM1). The primary cellular events and mechanisms underlying the disease are unknown. We found that mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in the human disease. The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis. This mouse model of EPM1 provides evidence that cystatin B, a non-caspase cysteine protease inhibitor, has a role in preventing cerebellar apoptosis.

Amino Acid Sequence↗
PubMed2006

A neurosphere-derived factor, cystatin C, supports differentiation of ES cells into neural stem cells.

Although embryonic stem (ES) cells are capable of unlimited proliferation and pluripotent differentiation, effective preparation of neural stem cells from ES cells are not achieved. Here, we have directly generated under the coculture with dissociated primary neurosphere cells in serum-free medium and the same effect was observed when ES cells were cultured with conditioned medium of primary neurosphere culture (CMPNC). ES-neural stem cells (NSCs) could proliferate for more than seven times and differentiate into neurons, astrocytes, and oligodendrocytes in vitro and in vivo. The responsible molecule in CMPNC was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, which turned out to be cystatin C. Purified cystatin C in place of the CMPNC could generate ES-NSCs efficiently with self-renewal and multidifferentiation potentials. These results reveal the validity of cystatin C for generating NSCs from ES cells.

Animals↗
PubMed1990

Binding of cystatin C to C4: the importance of sense-antisense peptides in their interaction.

Hydropathic anticomplementarity of amino acids indicates that peptides derived from complementary DNA strands may form amphiphilic structures and bind one another. By using this concept, we have found that the antisense peptide Ser-Tyr-Asp-Leu complementary to the segment Gln-Ile-Val-Ala-Gly (residues 55-59) in cystatin C (an inhibitor of cysteine proteases) is located at positions 611-614 of the beta chain of human C4, the fourth component of complement. Here we describe and characterize the specific interaction between cystatin C and C4 by ligand affinity chromatography and ELISA. Interaction between the two native proteins was mimicked on replacement of one of them with the corresponding sense-antisense peptide coupled to a carrier protein, and the binding was inhibited by these synthetic peptides in solution. Through the interaction with C4, cystatin C may play a regulatory role in complement activation that might be of particular importance at tissue sites where both proteins are produced by macrophages.

Amino Acid Sequence↗
PubMed1996

Folding-related dimerization of human cystatin C.

With the aim to improve our understanding of the structural basis for protein self-association and aggregation, in particular in relationship to protein refolding and amyloid formation, folding-related processes for human cystatin C have been studied. Using NMR spectroscopy together with chromatographic and electrophoretic methods, a self-association process resulting in dimer formation for protein samples treated with denaturing agents as well as for samples subjected to low pH or high temperature conditions could be studied with amino acid resolution. In all three cases, the dimerization involves properly folded molecules and proceeds via the reactive site of the inhibitor, which leads to complete loss of its biological activity. This dimerization process has potential relevance for amyloid formation by the brain hemorrhage-causing Leu58-Gln variant of cystatin C. The results also indicate that cystatin C dimerization and inactivation may occur in acidified compartments in vivo, which could be relevant for the physiological regulation of cysteine proteinase activity.

Amino Acid Sequence↗
PubMed2001

Serum cystatin C is a better marker for preeclampsia than serum creatinine or serum urate.

Altered renal function is an essential component of the pathophysiological process in preeclampsia. The kidneys play a significant part in the turnover of most low molecular weight substances such as creatinine, urate and cystatin C. The present work was undertaken to investigate if the serum levels of these components are altered in characteristic ways in preeclampsia, and can be used to assist in the diagnosis of this condition. The serum levels were therefore determined in samples from 100 healthy women at term as well as in 45 samples of patients with preeclampsia (diastolic blood pressure >90 mmHg; urinary albumin excretion >300 mgL(-1)). The levels of all three components were significantly higher in samples from preeclamptic patients with the mean+SD being 1.55+/-0.29 vs. 1.05+/-0.19 mg L(-1) for cystatin C, 70+/-23 vs. 56+/-9.7 micromol L(-1) for creatinine, and 413+/-128 vs. 305+/-61 micromol L(-1) for urate. Receiver operating characteristic analysis demonstrated that the serum level of cystatin C had a superior diagnostic accuracy for preeclampsia compared to those of serum urate and creatinine and that the diagnostic accuracy of serum urate was better than that of serum creatinine.

Case-Control Studies↗
PubMed2006

Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension.

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.

Adult↗