Abstract:We recently demonstrated the presence of matrix metalloproteinases (MMPs)-1, -2, and -3 in AA amyloid deposits, which lead us to speculate that MMPs may participate in amyloidogenesis by either processing the precursor protein, or by degrading the amyloid deposits. Here we investigated this theory by determining the ability of MMP-1, -2, and -3 to degrade human acute-phase serum amyloid A (SAA) and human AA amyloid fibril proteins (AFPs). The following in vitro degradation experiments were performed: using eit… Show more
“…22,29 Moreover, des-R variants of SAA showed a differential susceptibility to matrix metalloproteinase (MMP) digestion than to that of intact SAA; MMPs suggested as being contributory factors to amyloid deposit formation in reactive amyloidosis. 30 Haptoglobin, as with SAA, is an acute-phase protein produced by the liver. Its functions are well characterized and are reviewed by Wassell.…”
The molecular analysis of serum is an important field for the definition of potential diagnostic markers or disease-related protein alterations. Novel proteomic technologies such as the mass spectrometric-based surface-enhanced laser desorption/ionization (SELDI) ProteinChip s technique facilitate a rapid and reproducible analysis of such protein mixtures and affords the researcher a new dimension in the search for biomarkers of disease. Here, we have applied this technology to the study of a cohort of serum samples from wellcharacterized renal cell carcinoma patients for the identification of such proteins by comparison to healthy controls. We detected and characterized haptoglobin 1 a and serum amyloid a-1 (SAA-1) as disease related, in addition to an as-yet-unidentified marker of 10.84 kDa. Of particular note is the detection of multiple variants of SAA-1 in multiplex that have not been described in the sera of cancer patients. SAA-1 is detected as full-length protein, des-Arginine and des-Arginine/des-Serine variants at the N terminus by SELDI. In addition, we could also detect a low-abundant variant minus the first five N-terminal amino acids. Such variants may impact the function of the protein. We conclude the technique to be a reproducible, fast and simple mode for the discovery and analysis of marker proteins of disease in serum.
“…22,29 Moreover, des-R variants of SAA showed a differential susceptibility to matrix metalloproteinase (MMP) digestion than to that of intact SAA; MMPs suggested as being contributory factors to amyloid deposit formation in reactive amyloidosis. 30 Haptoglobin, as with SAA, is an acute-phase protein produced by the liver. Its functions are well characterized and are reviewed by Wassell.…”
The molecular analysis of serum is an important field for the definition of potential diagnostic markers or disease-related protein alterations. Novel proteomic technologies such as the mass spectrometric-based surface-enhanced laser desorption/ionization (SELDI) ProteinChip s technique facilitate a rapid and reproducible analysis of such protein mixtures and affords the researcher a new dimension in the search for biomarkers of disease. Here, we have applied this technology to the study of a cohort of serum samples from wellcharacterized renal cell carcinoma patients for the identification of such proteins by comparison to healthy controls. We detected and characterized haptoglobin 1 a and serum amyloid a-1 (SAA-1) as disease related, in addition to an as-yet-unidentified marker of 10.84 kDa. Of particular note is the detection of multiple variants of SAA-1 in multiplex that have not been described in the sera of cancer patients. SAA-1 is detected as full-length protein, des-Arginine and des-Arginine/des-Serine variants at the N terminus by SELDI. In addition, we could also detect a low-abundant variant minus the first five N-terminal amino acids. Such variants may impact the function of the protein. We conclude the technique to be a reproducible, fast and simple mode for the discovery and analysis of marker proteins of disease in serum.
“…Furthermore, SAA may modulate adhesion of tumor cells to platelets and enhance plasminogen activation, both of which are involved in ECM degradation and tissue remodeling processes. Indeed, another important approach to SAA influencing ECM, has been verified by an increasing number of studies, is that it can stimulate the production of MMPs (Stix et al, 2001;Lee et al, 2005). This partially explains the value of SAA level as a monitor of metastatic dissemination in several solid tumor and the relationship with prognosis.…”
Purpose: To investigate the prognostic value of serum amyloid A (SAA) in patients with hepatocellular carcinoma (HCC) undergoing surgery. Materials and Methods: Preoperative serum samples of 328 patients with HCC who underwent curative resection and of 47 patients with benign liver lesion were assayed. Serum levels of SAA were measured by enzyme-linked immunosorbent assay and its correlations with clinicopathological characteristics and survival were explored. Results: Levels of SAA were significantly higher in patients with HCC than those with benign liver lesion. There were strong correlations between preoperative serum SAA level and tumor size and more advanced BCLC stage. On univariate analysis, elevated SAA was associated with reduced disease-free survival and overall survival (p=0.001 and 0.03, respectively). Multivariate analyses showed that serum SAA level was an independent prognostic factor for overall survival (hazard ratio 2.80, p=0.01). Conclusions: High SAA serum level is a novel biomarker for the prognosis of HCC patients.
“…Our study supports the MMP-mediated degradation of A, as both MMP-2 and MMP-3 were up-regulated in response to CQ⅐Cu 2ϩ treatment, and inhibition of these metalloproteases prevented the loss of secreted A. Whether other MMPs (40) and proteases (i.e. aminopeptidases) are also involved in the loss of A induced by CQ⅐Cu 2ϩ is not known.…”
Biometals play an important role in Alzheimer disease, and recent reports have described the development of potential therapeutic agents based on modulation of metal bioavailability. The metal ligand clioquinol (CQ) has shown promising results in animal models and small phase clinical trials; however, the actual mode of action in vivo has not been determined. We now report a novel effect of CQ on amyloid -peptide (A) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu 2؉ or Zn 2؉ resulted in an ϳ85-90% reduction of secreted A-(1-40) and A-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted A was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu 2؉ . MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu 2؉ also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of A-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of A deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.
Alzheimer disease (AD)4 is characterized by progressive neuronal dysfunction, reactive gliosis, and the formation of amyloid plaques in the brain. The major constituent of AD plaques is the amyloid -peptide (A), which is cleaved from the membrane-bound amyloid precursor protein (APP) (1). Aggregated or oligomeric A can induce neurotoxicity through pathways involving free radical production and increased neuronal oxidative stress (2). Among the factors capable of promoting A aggregation in vivo, recent evidence supports a central role for biometals such as Cu 2ϩ and Zn 2ϩ in this process (3). An important factor in controlling A accumulation in AD patients is the activity of A-degrading enzymes. Recent studies have identified several candidate proteases that may contribute to catabolism of A in the brain. Neprilysin, insulin-degrading enzyme, angiotensin-converting enzyme, and matrix metalloproteases (MMPs) have all demonstrated A-degrading activity in vitro and/or in vivo (4 -6). Reduced activity of these or other A-degrading proteases with age may play a role in promoting accumulation and deposition of A in AD patients. Development of strategies to enhance clearance of A may lead to novel therapeutic treatments for AD patients.Promoting A clearance may be achieved through modulating metal sequestration or metal-protein interactions. 5-Chloro-7-iodo-8-hydroxyquinoline or clioquinol (CQ), a disused antibiotic, has received considerable attention as a potential metal ligand in AD and Parkinson disease patients (7-9). Preliminary studies revealed that CQ rapidly and potently dissolved aggregates of synthetic or AD brain-derived A in vitro (10). In subsequent animal studies, a 9-week oral treatment with CQ resulted in a 49% reduction of...
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