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PubMed1993

Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum.

Bunina bodies (BBs), small eosinophilic intraneuronal inclusions in the remaining lower motor neurons, are the only pathologically specific hallmark of amyotrophic lateral sclerosis (ALS). During immunohistochemical examinations of spinal cords of patients with ALS, we noted that BBs were positive for anti-cystatin C (CC) serum. Immunoelectron microscopically, many small deposits of immunoperoxidase products were seen in the cytoplasms and dendrites of the anterior horn cells. Some immunoperoxidase products exhibited a tubular or vesicular pattern, but no rough endoplasmic reticula, mitochondria, lipofuscin granules or nuclei were detected. The presence of BBs, especially in the periphery, was marked. In an adult cat, CC was mainly localized in the medial aspects of Golgi apparatus and in lysosomes in the anterior horn cells of the spinal cord. BBs may represent an abnormal accumulation of unknown proteinous material associated with the Golgi apparatus.

Adrenal Medulla↗
PubMed1989

High-level expression of active human cystatin C in Escherichia coli.

Expression of the human cysteine proteinase inhibitor, cystatin C (CysC) in the cytoplasm of Escherichia coli was studied using a cDNA fragment encoding the cysteine proteinase inhibitor controlled by the phage lambda pR/cI857 system. The yield of CysC was low, probably due to proteolytic degradation. By fusing the cysC cDNA to a DNA fragment encoding the signal peptide of the E. coli outer membrane protein A, it was possible to produce a substantial amount of CysC in the periplasm. The processing of the signal peptide was shown to be quantitative and to result in CysC with the correct N-terminal amino acid. Yields higher than 1000 micrograms CysC/ml can be obtained by initiating the product formation at a moderate temperature (40 degrees C) late in an optimized fermentation process. A method that gives selective extraction of the periplasmic proteins and at the same time stabilizes CysC has been used.

Bacteriophage lambda↗
PubMed1993

Efficient production of biologically active human salivary cystatins in Escherichia coli.

Different Escherichia coli expression systems were used for expression of cDNA clones encoding the human salivary cysteine proteinase (CysP) inhibitors, cystatins SN and S (CsnSN and CsnS). These included pOTSNco12 that expresses foreign sequences as authentic (nonfusion) proteins, and pGEX-2T that directs the synthesis of foreign polypeptides as fusion proteins with glutathione S-transferase (GST). The pOTS vector produced low levels of recombinant CsnSN (reCsnSN) that was localized in the soluble fraction, but not easily purified. The pGEX vector, on the other hand, produced much higher yields of the fusion protein, GST::CsnSN, that was localized almost entirely in the insoluble protein fraction. Solubilized and refolded GST::CsnSN inhibited the CysP, papain, more efficiently than chicken egg white Csn, indicating that the recombinant product was biologically active and that the GST carrier did not interfere with the biological activity. The pGEX-2T vector was subsequently used for the large-scale production of reCsnSN and reCsnS that were cleaved from the GST by thrombin and purified by DE-52 cellulose chromatography. ReCsnSN inhibited papain almost as efficiently as salivary CsnSN, while the reCsnS showed lower inhibitory activity as compared to both salivary CsnS and reCsnSN.

Amino Acid Sequence↗
PubMed1995

Structural organization, expression and chromosomal mapping of the mouse cystatin-C-encoding gene (Cst3).

Cystatin C (CstC) is a potent cysteine-proteinase inhibitor. The structure of the mouse CstC-encoding gene (Cst3) was examined by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of 5' flanking and 1.7 kb of its 3' flanking region. The sequence revealed that the overall organization of the gene is very similar to those of the genes encoding human CstC and other type-2 Cst, with two introns at positions identical to those in the human gene. The promoter area does not contain typical TATA or CAAT boxes. Two copies of a Sp1-binding motif, GGGCGG, are present in the 5' flanking region within 300 bp upstream from the initiation codon. A hexa-nucleotide, TGTTCT, which is a core sequence of the androgen-responsive element (ARE), is found in the promoter region. This region also contains a 21-nucleotide sequence, 5'-AGACTAGCAGCTGACTGAAGC, which contains two potential binding sites for the transcription factor, AP-1. The mouse Cst3 mRNA was detected in all of thirteen tissues examined by Northern blot analysis. Cst3 was mapped in the mouse to a position on distal chromosome 2.

Amino Acid Sequence↗
PubMed1994

Biological activities and secondary structures of variant forms of human salivary cystatin SN produced in Escherichia coli.

Using an Escherichia coli expression system, pGEX-2T, that expresses foreign sequences as fusion proteins with a glutathione S-transferase (GST) carrier, we have produced several recombinant human salivary cystatin SN (reCsnSN) variants. These include a N-terminal-truncated form (aa 17-121), a C-terminal-truncated form (aa 1-102) and two deletion mutants (delta 12-16 and delta 56-60). A large amount of the insoluble fusion protein (approx. 15 mg/l) was produced in each case. These were solubilized with urea and refolded by dialysis. The GST carrier was then cleaved with thrombin and the reCsn variants (except delta 56-60) were purified by anion-exchange chromatography. The CysP inhibitory activities against papain, and bovine and human cathepsin B, and secondary structures of the reCsnSN variants were determined and compared to natural salivary CsnSN. The full-length reCsnSN, the N-truncated and the delta 12-16 variants inhibited the CysP activity of papain and displayed circular dichroism (CD) spectra similar to that of natural CsnSN. On the other hand, the delta 56-60 mutant and the C-truncated variant exhibited very little inhibitory activity towards papain. The CD spectrum of the C-truncated variant indicated a change in the secondary structure (e.g., a decrease in beta-sheet and an increase of an alpha-helical content). Neither, the natural nor the full-length reCsnSN or the delta 12-16 mutant exhibited any inhibitory activity towards bovine and human cathepsin B.

Amino Acid Sequence↗
PubMed2006

Expression of Cystatin C in the rat endometrium during the peri-implantation period.

Endometrial receptivity for embryo implantation in the rat is a transient state occurring on day 5 of pregnancy or pseudopregnancy and is controlled by estrogen and progesterone. To identify genes potentially involved in receptivity, a uterine cDNA library was screened. An interesting pattern for Cystatin C (Cst3) expression was discovered with a peak in abundance just prior to embryo implantation (day 4 of pregnancy) followed by a significant drop the following day when implantation is initiated. Histology localized Cst3 mRNA and CST3 protein to the glandular epithelium on day 4 of pregnancy suggesting that it is secreted into the uterine lumen at this time. In ovariectomized rats endometrial Cst3 mRNA levels decreased within 3h of treatment with estradiol; this effect was inhibited by the anti-estrogen, ICI 182, 780. The data suggest that the endometrial expression of the cysteine protease inhibitor, Cst3, is modulated by estrogen during the peri-implantation period.

Animals↗
PubMed2003

Serum cystatin C is sensitive to small changes in thyroid function.

BACKGROUND: Serum cystatin C (CysC) is a novel marker for kidney function. The impact of mild thyroid dysfunction on CysC has never been investigated. METHODS: CysC was determined at the time of diagnosis of subclinical hypo- and hyperthyroidism, and when TSH returned into the normal range in 40 consecutive patients with mild thyroid dysfunction. RESULTS: Twenty-six patients with subclinical hypothyroidism and 14 patients with subclinical hyperthyroidism were included. In patients with subclinical hypothyroidism median (range) TSH was 7.8 (4.3-26.7) mU/l (reference 0.27-4.2) at diagnosis and decreased to 2.3 (0.36-4.0) mU/l following treatment with levothyroxine. Mean (+/-S.D.) CysC increased from 0.88+/-0.23 mg/l (reference 0.63-1.33) in the hypothyroid state to 1.01+/-0.21 mg/l when TSH normalized (p<0.001). In patients with subclinical hyperthyroidism, median TSH at diagnosis was 0.08 (0.001-0.26) mU/l and increased to 1.6 (0.28-4.0) mU/l in the euthyroid state. CysC declined from 1.04+/-0.29 mg/l at diagnosis of subclinical hyperthyroidism to 0.91+/-0.25 mg/l when TSH normalized (p<0.05). CONCLUSIONS: Mild thyroid dysfunction significantly alters CysC levels. Therefore, thyroid function has to be considered when CysC is used as a marker of kidney function.

Adolescent↗
PubMed2004

Relationship between plasma Cystatin C and creatinine in chronic renal diseases and Tx-transplant patients.

OBJECTIVES: Glomerular filtration rate (GFR) is the best overall index of renal function in health and disease. Recently, Cystatin C (Cyst C), a low molecular weight protein freely filtered through the glomerulus, and almost completely reabsorbed and catabolized by tubular cells, has been proposed as a new and very sensitive serum marker of change in GFR. This study investigated the relationship between Cyst C and creatinine (CR) in renal disease patients. METHODS: Serum Cyst C was determined by particle-enhanced immunoturbidimetry using the Cyst C PET-kit. The results could be obtained within 1 h. Cuvettes were washed before the Cyst C assay as recommended. Serum CR, BUN and albumin were determined by auto-analyzer. RESULTS: A strong correlation was observed between Cyst C and CR (P = 0.001, r = 0.764 and P = 0.0001, r = 0.888, respectively) in prehemodialysis (pre-HD) and kidney transplantation (Tx-kidney), whereas there was a weak correlation in continuous ambulatory peritoneal dialysis (CAPD) (P = 0.05, r = 0.535). CONCLUSION: These findings suggest that serum Cyst C may be considered as a sensitive predictive parameter for reduced GFR. It is of value for the laboratory diagnosis of chronic renal failure and should be preferentially used for CR clearance.

Adult↗
PubMed2005

Cystatin C as a marker of GFR--history, indications, and future research.

OBJECTIVE: To summarize recent knowledge on the small molecular weight protein cystatin C (cys-C) and its use as a marker of the glomerular filtration rate (GFR). METHODS: A multinational expert meeting was held in April 2002 in Marburg, Germany. Contributors summarized their main findings. CONCLUSIONS: Cys-C is at least equal if not superior to serum creatinine as a marker of GFR. The independence from height, gender, age, and muscle mass is advantageous. Select patient groups such as children, the elderly, and patients with reduced muscle mass benefit in particular.

Adolescent↗
PubMed2005

The relation between serum MDA and cystatin C levels in chronic spinal cord injury patients.

OBJECTIVES: The assessment of renal function is particularly important in patients with spinal cord injury (SCI). Creatinine (Cr) is known to be unsuitable as a marker of renal function in SCI because of muscle wasting. Although cystatin C (cys-C) is more reliable than Cr, its expression may be affected by oxidative stress accompanying SCI. The aim of the study was to estimate the cys-C levels in SCI patients with normal functioning kidneys. The prooxidant/antioxidant state in plasma of the patients and controls was measured, and any correlations between these parameters and cys-C were determined. DESIGN AND METHODS: Blood samples from 41 chronic SCI patients and 13 controls were obtained. Serum Cr was assayed by the Cobas Integra 400 autoanalyzer and cys-C by particle-enhanced immunoturbidimetry. Heparinized plasma was used for biochemical determinations of vitamin E, total antioxidant status (TAS) and malondialdehyde (MDA). RESULTS: Cr, TAS and MDA levels were significantly lower in SCI patients compared to the controls (P = 0.007, P = 0.019, P = 0.000, respectively), whereas no difference was seen in cys-C and vit E concentrations. Body mass indices (BMI) of SCI patients were less than those of the controls (P = 0.03). No correlation existed between cys-C and MDA in SCI patients and controls. Cys-C levels were independent from the body mass indices of subjects. CONCLUSION: In our study, although BMI and MDA were both affected in SCI patients, cys-C levels were unchanged. Therefore, the measurement of cys-C appeared to be of value for the follow-up of renal function in SCI. The low MDA levels observed in these patients suggest that various adaptation mechanisms may be relevant for subjects undergoing prolonged stress situations.

Adolescent↗
PubMed2006

Protein therapy for Unverricht-Lundborg disease using cystatin B transduction by TAT-PTD. Is it that simple?

In this work we analysed the characteristics of the cell-permeable peptide TAT-PTD fused to cystatin B (CSTB) to evaluate its potential for protein therapy of Unverricht-Lundborg (UL) epilepsy. TAT-PTD-CSTB does not penetrate the cells despite initial evidence of time and concentration-dependent transduction. Therefore, it cannot be used as a form of replacement of the intracytoplasmic protein missing in UL. Importantly, we discuss precautions to avoid false-positive results when working with TAT-PTD for protein therapy of neurological diseases.

Blood-Brain Barrier↗
PubMed2005

Improved estimation of GFR by serum cystatin C in patients undergoing cardiac catheterization.

Clinical assessment of glomerular filtration rate (GFR) mainly relies on single determinations of serum creatinine (crea) which is commonly insensitive to mild renal dysfunction. Serum cystatin C (cysC) has been proposed as an alternative endogenous marker of GFR showing higher correlation to standard clearance methods such as inulin or iohexol clearance. We compared serum crea and cysC levels in n=127 patients undergoing cardiac catheterization. The clearance of the iodinated contrast dye iopromide served as reference method for GFR. Serum cysC was determined by a particle-enhanced immunonephelometric method. CysC showed higher non-parametric correlation (r=0.805) to the iopromide clearance compared to crea (r=0.652) and to the estimated GFR according to the Cockcroft-Gault formula (r=0.690), which underestimated true GFR systematically. Receiver operating curves revealed a greater area-under-the-curve (AUC) for cysC (0.957 vs. 0.801, p<0.05). At a cut-off level of >1.3 mg/l cysC exhibited an 88% sensitivity and a 96% specificity for detecting renal dysfunction which was defined as an iopromide clearance less than 80 ml/min/1.73 m2; best values for crea were 63% for sensitivity and 80% for specificity at a cut-off of >1.2 mg/dl. In conclusion, cysC detected reduced GFR more reliably and at an earlier stage in patients undergoing cardiac catheterization allowing a better identification of patients with renal dysfunction and those at risk for contrast damage.

Adult↗
PubMed2005

Cell-specific expression of the epm1 (cystatin B) gene in developing rat cerebellum.

Cystatin B (cystB) is an anti-protease implicated in EPM1, a degenerative disease of the central nervous system. This work analyzes the pattern of expression of cystB in developing and adult cerebellum, identifying the cystB positive cells by double immune-fluorescence microscopy using specific cell markers. In primary glial cells, cystB is found in progenitor and differentiated oligodendrocytes as well as in astrocytes. In the cerebellum, only oligodendrocyte progenitors express cystB. In myelin-producing cells, cystB synthesis is strongly down-regulated and the protein is not detectable. Astrocytes and Bergmann glia express cystB at all the developmental stages analyzed both in the cell body and in the fibers. Most neurons of developing and adult rat cerebellum do not express detectable amounts of cystB, with the exception of the Purkinje cells and of some cells of the differentiated molecular layer. In human cerebellum, cystB is present in Purkinje cells and Bergmann glial fibers only. cystB is also found in the cortical neurons of the dentate gyrus of the hippocampus. In rat cerebellum, cystB forms a complex with a number of proteins, two of which are specific to the nervous system. The cellular co-localization of cystB and its partners in developing and adult cerebellum is also shown.

Aging↗
PubMed2005

Cystatin C and apoe polymorphisms in Italian Alzheimer's disease.

Recent studies have reported a genetic association between the 73 G/A polymorphism within exon 1 of the cystatin C gene and Alzheimer's disease (AD) with conflicting results. To further investigate the proposed association and to clarify the role of CST3 as risk factor for AD, we analyzed the genotype and allele frequency distribution of CST3 G73A and apolipoprotein (ApoE) gene polymorphisms in 243 Italian patients with AD and 186 controls. Patients with AD were consecutively collected among the outpatients from the Neurology Department at the University of Florence. All 429 subjects were genotyped for CST3 and ApoE polymorphisms. After stratification according to age, the GG frequency resulted slightly higher in younger (<65 years) cases, but far from statistically significant. There was also no evidence of a statistical interaction between CST3 and ApoE polymorphisms. In conclusion, our data suggest that the CST3 genetic variant is not a susceptibility factor in AD, nor mitigate the effect of the ApoE varepsilon4 allele in the risk of developing AD.

Aged↗
PubMed2006

Recovery after a traumatic brain injury depends on diurnal variations effect of cystatin C.

Many studies indicate that the hour of the day at which the onset of stroke occurs is very important in patient recovery. Furthermore, multiple studies have been conducted which show that ischemia in rats produces different magnitudes of injury depending on the hour of the day at which it was induced. Using a traumatic brain injury (TBI) model, we analyzed the effect of the time of day on the recovery of rats and obtained a higher survival rate if TBI was induced at 01:00 h as compared with TBI induced at 13:00 h. We also analyzed the effect of the protease inhibitor cystatin C (CC) on the recovery of rats from TBI and found that it increased mortality and bleeding, and that these effects were more pronounced at 13:00 h.

Analysis of Variance↗
PubMed2006

Potential participation of cystatin C in rapid eye movement sleep (REMS) modulation.

It has been hypothesized that proteins modulate rapid eye movement sleep (REMS). Studies have shown an increase in the liberation of proteins in the mesencephalic reticular formation of cats during REMS. It has also been determined that protein-synthesis inhibitors diminish REMS and that protease-inhibitors increase this sleep phase. These and other studies support the importance of "di novo" protein molecules in sleep, and in particular, in REMS regulation. In this context, it is important to determine the role of endogenous proteases and their endogenous inhibitors in sleep regulation. In this study, we found that Cystatin C (CC), an endogenous protease inhibitor, diminishes wakefulness and increases REMS. We have also found an increase in CC expression after REMS deprivation and a tendency to decrease after a 2 h period of REMS rebound. We further showed that REMS deprivation increases the expression of Cathepsin H (CH), a protease inhibited by CC. These results suggest that naturally occurring protease-inhibitors enhance REMS, perhaps by facilitating the availability of proteins.

Animals↗
PubMed2005

Cystatin C as a marker of renal function in kidney transplant patients.

INTRODUCTION: Serum creatinine (sCr) is the most commonly used biochemical parameter for gauging kidney function, but, due to its limitations, it is not the ideal marker for glomerular filtration rate (GFR). Cystatin C (sCyC) appears to be an endogenous marker of GFR. AIM: To assess the use of sCyC as a marker of renal function in kidney transplant patients, we compared it with sCr and with creatinine clearance either in a 24-hour urine or calculated using the Cockroft-Gault formula. METHODS: Among 78 patients (62.8% men, 37.2% women) undergoing kidney transplantation (average age 44.87 +/- 13.37 years) we determined at 2, 5, 7, 15, and 30 days, and 6, 12 and 18 months after kidney transplantation: sCr (using the Jaffé colorimetric method), sCyC (immunonephelometry), creatinine clearance with a 24-hour urine, creatinine clearance using the Cockroft-Gault formula. RESULTS: During the first 30 days following transplantation, there was a progressive decline in sCr levels. sCyC increased up to the fifth day, coinciding with the highest doses of steroids, and then decreased. At 6, 12, and 18 months, there was a correlation between sCyC and sCr, creatinine clearance in a 24-hour urine or calculated with the Cockroft-Gault formula (R = 0.859; R = -0.713, and R = -0.684, respectively, P < .001.) CONCLUSIONS: sCyC is an endogenous marker of GFR. Its limitations relate to its being affected by the high doses of steroids in the first days following transplantation. In the 18-month posttransplant period, it correlated with creatinine clearance in a 24-hour urine or calculated by the Cockroft-Gault formula.

Adult↗
PubMed2006

Assessment of glomerular filtration rate in renal transplant patients using serum cystatin C.

AIM: Serum cystatin C (SCysC) has been proposed as a better marker of glomerular filtration rate (GFR) than serum creatinine (Scr). However, few data are available in renal transplant patients, especially, during the early postoperative phase. METHODS: Thirty-nine renal transplant patients (22 men/17 women) were recruited for determination of SCysC and Scr before operation, at 1 week and at 4 weeks after operation. SCysC was determined by particle-enhanced turbidimetric immunoassay. Creatinine clearance (Ccr) was calculated using the Cockcroft-Gault formula. RESULTS: SCysC and Scr levels significantly decreased with the recovery of allograft function. SCysC showed a significant correlation with Scr and Ccr. The relationship between SCysC and Scr showed a positive correlation (r = .849 preoperation, and r = .940 postoperation). The relationship between SCysC and Ccr revealed a negative correlation (r = .857 preoperation, and r = .876 postoperation). At the Ccr level of 50 to 80 mL/min/1.73 m(2), the correlation between SCysC and Ccr (r = .778) was significantly better than that between Scr and Ccr (r = .553; P = .032). The concentration of SCysC was not affected by age, gender, height, body weight, hemoglobin, serum protein, glucose, or mycophenolate mofetil or azathioprine dosage. However, corticosteroids slightly increased the level of SCysC and cyclosporine (CsA) decreased it. The area under the curve of the receiver operating characteristic curve for SCysC and Scr are 0.964 and 0.915, respectively (P < .05). CONCLUSION: Although the concentration may be slightly influenced by prednisolone and CsA, SCysC is more sensitive than Scr to detect early and moderate deterioration of GFR in adult renal transplant recipients.

Biomarkers↗