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PubMed1987

Lysosomal and non-lysosomal peptidyl hydrolases of the bloodstream forms of Trypanosoma brucei brucei.

African trypanosomes have thiol-dependent proteolytic activity that resembles some of the cathepsin-like activity found in mammalian lysosomes [Lonsdale-Eccles, J. D. & Mpimbaza, G. W. N. (1986) Eur. J. Biochem. 155, 469-473]. Here we show that this activity is found in lysosome-like organelles which we have isolated (density = 1.082 g/cm3 in Percoll) from bloodstream forms of Trypanosoma brucei brucei. They are approximately 250 nm in diameter, are bounded by a single limiting membrane, and contain acid phosphatase. The predominant proteolytic and peptidolytic activity of these organelles has a pH optimum about 6.0, exhibits latency, and has the characteristics of mammalian cathepsin L (and possibly cathepsin H) with respect to its hydrolysis of small fluorogenic peptidyl substrates such as benzyloxycarbonyl-phenylalanyl-arginyl-7-amido-4-methylcoumarin. This substrate appears to be a good marker for trypanosomal lysosomes. The cathepsin-L-like activity is inhibited by the thiol-protease inhibitors, E-64, cystatin, leupeptin and mercurial compounds. The proteolytic activity of the lysosome-like fraction is observed as a single band of activity with an approximate molecular mass of 27 kDa when measured after electrophoresis in the fibrinogen-containing sodium dodecyl sulphate/polyacrylamide gels. The addition of mammalian serum to this purified fraction, or to whole trypanosome homogenates, results in the appearance of additional bands of activity, with a concomitant increase in the total observed proteolytic activity. The serum of some species of animal (e.g. goat and guinea pig) appear to lack the ability to generate this new and increased activity, while rat, rabbit, human and bovine sera exhibit varying capacities to generate the new activity, the cow being the most effective. The apparent molecular masses of the new bands of activity are different for each mammalian species, suggesting that the activator is a species-specific molecule or class of molecules. We also show that Trypanosoma brucei contains soluble peptidolytic activity with an alkaline pH optimum. It is inhibited by the serine-protease inhibitor diisopropylfluorophosphate, but not by inhibitors such as phenylmethylsulphonyl fluoride, alpha 1-antitrypsin, or aprotinin. Nor is it inhibited by the thiol-protease-specific inhibitors E-64 or cystatin, although it is susceptible to inhibition by tosyllysylchloromethane, leupeptin, HgCl2 and p-chloromercuribenzoate. This enzymic activity has a preference for arginyl residues in the primary binding site (the P1 position), as also does the activity from the lysosomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2004

Engineered multidomain cysteine protease inhibitors yield resistance against western flower thrips (Frankliniella occidentalis) in greenhouse trials.

Western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), cause very large economic damage on a variety of field and greenhouse crops. In this study, plant resistance against thrips was introduced into transgenic potato plants through the expression of novel, custom-made, multidomain protease inhibitors. Representative classes of inhibitors of cysteine and aspartic proteases [kininogen domain 3 (K), stefin A (A), cystatin C (C), potato cystatin (P) and equistatin (EIM)] were fused into reading frames consisting of four (K-A-C-P) to five (EIM-K-A-C-P) proteins, and were shown to fold into functional inhibitors in the yeast Pichia pastoris. The multidomain proteins were expressed in potato and found to be more resistant to degradation by plant proteases than the individual domains. In a time span of 14-16 days, transgenic potato plants expressing EIMKACP and KACP at a similar concentration reduced the number of larvae and adults to less than 20% of the control. Leaf damage on protected plants was minimal. Engineered multidomain cysteine protease inhibitors thus provide a novel way of controlling western flower thrips in greenhouse and field crops, and open up possibilities for novel insect resistance applications in transgenic crops.

Journal Article↗

PubMed2004

N-acetylcysteine in the prevention of radiocontrast-induced nephropathy: clinical trials and end points.

N-acetylcysteine (NAC) has been suggested to prevent radiocontrast-induced nephropathy (RCIN) in patients with a reduced renal function. However, clinical studies have not been demonstrating this effect consistently. Also, reviews and meta-analyses dealing with the question of prevention of RCIN by NAC have been controversial. Nearly all investigators used serum creatinine as surrogate end point of their trials, and changes in serum creatinine concentrations are thought to reflect the extent of renal injury as primary outcome. In a recent study, an effect of NAC on creatinine values and estimated glomerular filtration rate without any effect on cystatin C levels has been shown in volunteers with a normal renal function. Therefore, before renal protective effects of NAC in RCIN are proposed, any direct effects of NAC on creatinine, urea, and estimated glomerular filtration rate should be addressed. In future trials, the glomerular filtration rate should preferentially be measured directly, or at least additional markers of the renal function (e.g., serum cystatin C) have to be assessed. Furthermore, additional 'hard' end points, i.e., hospital morbidity, mortality, or dialysis dependency, should be considered in the design of future studies of RCIN.

Acetylcysteine↗

PubMed2006

Destabilizing role of cathepsin S in murine atherosclerotic plaques.

OBJECTIVE: Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization. METHODS AND RESULTS: Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques. CONCLUSIONS: These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.

Animals↗

PubMed2005

Proteinase and growth factor alterations revealed by gene microarray analysis of human diabetic corneas.

PURPOSE: To identify proteinases and growth factors abnormally expressed in human corneas of donors with diabetic retinopathy (DR), additional to previously described matrix metalloproteinase (MMP)-10 and -3 and insulin-like growth factor (IGF)-I. METHODS: RNA was isolated from 35 normal, diabetic, and DR autopsy human corneas ex vivo or after organ culture. Amplified cRNA was analyzed using 22,000-gene microarrays (Agilent Technologies, Palo Alto, CA). Gene expression in each diabetic corneal cRNA was assessed against pooled cRNA from 7 to 9 normal corneas. Select differentially expressed genes were validated by quantitative real-time RT-PCR (QPCR) and immunohistochemistry. Organ cultures were treated with a cathepsin inhibitor, cystatin C, or MMP-10. RESULTS: More than 100 genes were upregulated and 2200 were downregulated in DR corneas. Expression of cathepsin F and hepatocyte growth factor (HGF) genes was increased in ex vivo and organ-cultured DR corneas compared with normal corneas. HGF receptor c-met, fibroblast growth factor (FGF)-3, its receptor FGFR3, tissue inhibitor of metalloproteinase (TIMP)-4, laminin alpha4 chain, and thymosin beta(4) genes were downregulated. The data were corroborated by QPCR and immunohistochemistry analyses; main changes of these components occurred in corneal epithelium. In organ-cultured DR corneas, cystatin C increased laminin-10 and integrin alpha(3)beta(1), whereas in normal corneas MMP-10 decreased laminin-10 and integrin alpha(3)beta(1) expression. CONCLUSIONS: Elevated cathepsin F and the ability of its inhibitor to produce a more normal phenotype in diabetic corneas suggest increased proteolysis in these corneas. Proteinase changes may result from abnormalities of growth factors, such as HGF and FGF-3, in DR corneas. Specific modulation of proteinases and growth factors could reduce diabetic corneal epitheliopathy.

Aged↗

PubMedDate not supplied

Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer.

Cathepsins B, H and L have been shown to participate in processes of tumor growth, vascularization, invasion and metastasis. Their levels in tumor tissue extracts can provide useful clinical information to predict disease-free and overall survival in breast, lung, colorectal, brain and head and neck cancer patients. Recently we have found that both cysteine cathepsins and their endogenous protein inhibitors stefins and cystatin C can also predict prognosis when measured extracellularly. In melanoma and colorectal cancer patients high serum levels of cathepsins B and H correlated with shorter survival. Similarly, increased extracellular levels of stefins A and B and cystatin C correlated significantly with high risk of adverse outcome in cancer patients. However, the cathepsin B/cystatin C complex was found to be less abundant in sera of patients with malignant tumors than in those with benign diseases or in healthy controls, suggesting an imbalance between the enzyme and its inhibitor in cancer patients.

Biomarkers, Tumor↗

PubMed2006

Lymph node status as a guide to selection of available prognostic markers in breast cancer: the clinical practice of the future?

Prognosticators evaluating survival in breast cancer vary in significance in respect to lymph node status. Studies have shown e.g. that HER2/neu immunohistochemistry or HER2/neu gene amplification analysis do perform well as prognosticators in lymph node positive (LN +) patients but are less valuable in lymph node negative (LN -) patients. We collected data from different studies and tried to evaluate the relative significance of different prognosticators in LN+/LN- patient groups. In LN+ patients HER2/neu and E-cadherin immunohistochemistry were the statistically most significant prognosticators followed by proliferation associated features (mitotic counts by SMI (standardised mitotic index) or MAI (mitotic activity index), or S-phase fraction). Bcl-2 immunohistochemistry was also significant but p53 and cystatin A had no significance as prognosticators. In LN- patients proliferation associated prognosticators (SMI, MAI, Ki-67 index, PCNA immunohistochemistry, S-phase fraction) are especially valuable and also Cathepsin D, cystatin A, and p53 are significant, but HER2/neu or bcl-2, or E-cadherin less significant or without significance. We find that in studies evaluating single prognosticators one should distinguish between prognosticators suitable for LN+ and LN- patients. This will allow the choice of best prognosticators in evaluating the prospects of the patient. The distinction between LN+ and LN- patients in this respect may also be of special value in therapeutic decisions.

Journal Article↗

PubMed2005

The role of androgens in sertoli cell proliferation and functional maturation: studies in mice with total or Sertoli cell-selective ablation of the androgen receptor.

The role of androgens in the proliferation and maturation of Sertoli cells (SC) and the development of their capacity to support spermatogenesis remains poorly understood. We evaluated these functions in complete androgen receptor knockout (ARKO) and SC-selective androgen receptor knockout (SCARKO) mice. Compared with controls, ARKO mice exhibited a progressive reduction in SC number/testis, whereas SCARKOs showed minor changes, suggesting that androgen effects on SC number are not mediated via direct action on SCs. Immunoexpression of anti-Mullerian hormone (AMH), p27(kip1), GATA-1, and sulfated glycoprotein-2, which changes according to SC maturational status, occurred normally in ARKOs and SCARKOs. Functional capacity of SCs to support spermatogonia was similar in SCARKOs and controls, whereas ARKOs showed reduced capacity with age. SC capacity to support total germ cells revealed major deficits in ARKO and SCARKO adults, particularly with respect to postmeiotic germ cells. Using quantitative RT-PCR, the expression of SC markers was compared in d 50 testes. In ARKOs, expression of Pem, fatty acid binding protein, platelet-derived growth factor-A, and transferrin were all significantly reduced, whereas FSH receptor and AMH were increased. In SCARKOs, there were modest reductions in expression of cystatin-related gene highly expressed in testis and epididymis (cystatin-TE) and claudin-11, whereas expression of Pem, fatty acid binding protein, and platelet-derived growth factor-A was markedly reduced, highlighting these as potentially androgen-regulated SC genes that merit further study. In conclusion, androgen action is not required for maturation-dependent changes in immunoexpression of the SC markers AMH, p27(kip1), GATA-1, and sulfated glycoprotein-2 but is essential for expression of other SC genes, the attainment of normal SC number, and the support of meiotic and postmeiotic germ cell development.

Androgens↗

PubMed2003

Potential utility of various protease inhibitors for improving the intestinal absorption of insulin in rats.

The aim of the investigation was to study the effects of protease inhibitors on the absorption of insulin in-situ from closed small and large intestinal loops in rats and to investigate the mechanism of various protease inhibitors in different intestinal loops. The intestinal absorption of insulin was evaluated by its hypoglycaemic effect and serum insulin level in the presence or absence of luminal contents. No marked hypoglycaemic effect was observed after administration of insulin alone in either region in the presence or absence of luminal contents. A significant hypoglycaemic effect of insulin was obtained in the large intestinal loop in the presence or absence of luminal contents when insulin was co-administered with bacitracin (20, 30 mM), sodium glycocholate (20, 40 mM), bestatin (29 mM), leupeptin (21 mM) and cystatin (0.8 mM). In contrast, there was no hypoglycaemic effect in the small intestinal loop in the presence of luminal contents following small intestinal co-administration of insulin with these protease inhibitors. The effectiveness of protease inhibitors was susceptible to their categories, concentrations and activity of proteolytic enzymes in different regions. The degree of improving insulin absorption in intestine was in the order of leupeptin>sodium glycocholate>bacitracin>bestatin>cystatin. At the same time, the percutaneous enhancement effect was observed in the presence of either sodium glycocholate or bacitracin. These results suggest that protease inhibitors could increase the insulin efficacy more effectively in the large intestine than in the small intestine.

Animals↗

PubMed2000

Native and acid-denatured L-lactate dehydrogenase are different in the lysosomal proteinases involving in their overall degradation.

When native and (LDH) acid-denatured lactate dehydrogenase were incubated with total lysosomal enzymes in vitro, amino acids from their degradation were produced at various acidic pH. The pH profile in the overall degradation of native LDH was markedly different from that of acid-denatured LDH. Disappearance of the 35-kDa subunit of native LDH was markedly suppressed by a low level of cystatin alpha as well as by a general cysteine proteinase inhibitor, N-(L3-trans-carboxyoxirane-2-carbonyl)-L-leucine-3-methylbutylamid e (E-64-c). On the other hand, the degradation of acid-denatured LDH was only slightly suppressed by these inhibitors. It was concluded that at least a part of the proteinases involved in the overall degradation of native LDH is different from the proteinases involved in the degradation of acid-denatured form and a role of a cystatin alpha-sensitive cysteine proteinase is critical in the lysosomal degradation of native LDH, but not in that of acid-denatured form.

Cysteine Endopeptidases↗

PubMed2003

Diverse enzymatic specificities of digestive proteases, 'intestains', enable Colorado potato beetle larvae to counteract the potato defence mechanism.

In response to insect attack, high levels of proteinase inhibitors are synthesised in potato leaves. This can cause inefficient protein digestion in insects, leading to reduced growth, delayed development and lower fecundity. It has been suggested that Colorado potato beetle overcomes this defence mechanism by inducing the production of a set of cysteine proteases that are resistant to potato proteinase inhibitors. Experiments with gut extracts showed that these proteases have unusual inhibition profiles as they are not inhibited by most of the cystatins but are strongly inhibited by thyropins. In this study we have isolated three cysteine proteases from adapted guts of Colorado potato beetle larvae, named intestains 1, 2 and 3, the first cysteine proteases known to be involved in extracellular protein digestion. The N-terminal sequences suggest their classification into the papain family. Intestains differ in substrate specificities and inhibitory profiles. Their substrate specificities suggest that intestains 1 and 2 are general digestive enzymes, while intestain 3 has a more specific function. The inhibitory profile of intestain 1 is similar to that of proteases of the papain family. However, the Ki values for the interaction of intestain 2 with the same set of inhibitors are several hundred fold higher, which would enable the enzyme to circumvent the potato defence mechanism characterised by high concentrations of protease inhibitors in attacked potato leaves. A further, different strategy of the Colorado potato beetle to avoid potato defence is exhibited by intestain 3, which is able to cleave off the N-terminus of model cystatin and thus inactivate the inhibitor. These results suggest that the Colorado potato beetle combines different strategies to counteract plant defence mechanisms.

Amino Acid Sequence↗

PubMed2003

Inhibition of intraperitoneal tumor growth of human ovarian cancer cells by bi- and trifunctional inhibitors of tumor-associated proteolytic systems.

Several proteolytic systems are involved in (anti)adhesive, migratory, and proteolytic processes, necessary for tumor progression and metastasis. We analyzed whether multifunctional inhibitors of different tumor-associated proteolytic systems reduce tumor growth and spread of human ovarian cancer cells in vivo. Bifunctional inhibitors are composed of the N-terminal domain of either the human matrix metalloproteinase inhibitors TIMP-1 or TIMP-3 and the cysteine protease inhibitor chicken cystatin (chCysWT); trifunctional inhibitors are composed of N-TIMP-1 or -3 and a chicken cystatin variant harboring the uPAR binding site of uPA, chCys-uPA19-31, which in addition to its inhibitory activity toward cysteine proteases interferes with the interaction of the serine protease uPA with its receptor. OV-MZ-6#8 cancer cells, stably transfected with plasmids expressing the multifunctional inhibitors, displayed similar proliferative and adhesive features as the vector-transfected control, but showed significant reduction in their invasive behavior in vitro. The cell lines expressing the multifunctional inhibitors were inoculated into the peritoneum of nude mice. Expression of three of the four inhibitor variants (N-hTIMP-1-chCysWT, N-hTIMP-1-chCys-uPA19-31, and N-hTIMP-3-chCysWT) resulted in a significant reduction of tumor burden compared to the vector-control cell line. These compact and small inhibitors may represent promising agents for gene therapy of solid malignant tumors.

Animals↗

PubMed1992

Effects of lamb age, muscle type, and 24-hour activity of endogenous proteinases on postmortem proteolysis.

The objectives of this study were to examine the amount of postmortem proteolysis in three different lamb muscles at different ages and to determine whether a relationship exists between the extent of myofibrillar degradation and certain endogenous proteinase activities. Wether lambs were slaughtered at 8 (n = 6) and 26 (n = 6) wk of age. Samples were taken from the longissimus (LM), gluteus medius (GM), and supraspinatus (SS) muscles for determining myofibrillar fragmentation index (MFI) at 1 and 7 d postmortem, cathepsins B and B + L, cystatin(s), mu- and m-calpain and calpastatin 24-h activities, and muscle fiber type and area. Muscle samples were removed for SDS-PAGE analysis at 0, 1, and 7 d postmortem. The SS muscle consisted of more (P less than .05) oxidative fibers, whereas no age effects (P greater than .10) were observed for fiber type. The younger lambs had higher (P less than .01) cathepsins B and B + L, cystatin, and calpastatin 24-h activities but less (P less than .01) m-calpain activity than did the 26-wk-old lambs. Within each age, the SS muscle had the highest (P less than .05) mu-calpain, m-calpain, and calpastatin specific activities. The MFI values and SDS-PAGE results indicate that less proteolysis occurred in the SS muscle. Samples from 26-wk-old lambs tended to have greater MFI values at 1 and 7 d postmortem, especially for the LM and GM muscles. From these results, it seems that less postmortem proteolysis occurs in younger and more oxidative muscles and this may be attributed to the greater calpastatin 24-h activity.

Age Factors↗

PubMed1989

Systemic and cerebral amyloidosis.

Two types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) have been described: the Icelandic type (HCHWA-I), and the Dutch type (HCHWA-D). Both are autosomal-dominant forms of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes leading to an early death. In spite of their clinico-pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA-I, the amyloid protein is a degradation product of Cystatin C variant (gamma trace), a normal serum protein and an inhibitor of cysteine proteases. The amyloid protein is the expression of a genetic aberration, since it has been demonstrated that a point mutation occurred in the Cystatin C gene. On the other hand the amyloid protein in HCHWA-D type has very recently been shown to be related to Alzheimer's disease (AD) and Down's syndrome (DS) beta-protein. However, the complete sequence of HCHWA-D beta-protein obtained from leptomeninges was three residues shorter (39 instead of 42) than that reported for the insoluble plaque amyloid of AD. The distinct enzymatic cleavage at the carboxyl end of the beta protein is consistent with the concept that the amyloid fibrils derive from a larger precursor by specific and partial degradation. The difference may reflect a particular type of proteolysis that occurs in the vessel wall and not in the brain parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗

PubMed1999

The molecular genetic bases of the progressive myoclonus epilepsies.

Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.

Chromosome Mapping↗

PubMed1999

Saliva and dental caries.

A study of saliva and its tooth-protective components reveals at least four important functions of saliva: (1) buffering ability, (2) a cleansing effect, (3) antibacterial action, and (4) maintenance of a saliva supersaturated in calcium phosphate. Several salivary constituents subserve one or more of these functions. Research has yielded important information about organic and inorganic secretory products. It is also clear that saliva as a unique biologic fluid has to be considered in its entirety to account fully for its effects on teeth. Saliva is greater then the sum of its parts. One reason for this is that salivary components display redundancy of function, each often having more than one function. This redundancy, however, does not imply that proteins that share functional roles all contribute to the same degree. For instance, when comparing proteins that inhibit calcium phosphate precipitation, statherin and acidic proline-rich proteins are most potent, whereas histatins, cystatins, and mucins appear to play lesser roles. The complex interaction between proteins is another major factor contributing to saliva's function. In this regard, heterotypic complexes of various proteins have been shown to form on hydroxyapatite. Mucin binding to other salivary proteins, including proline-rich proteins, histatins, cystatins, and statherin, is well documented. The complexes, whether adsorbed to the tooth surface or in saliva, have important implications for bacterial clearance, selective bacterial aggregation on the tooth surface, and control of mineralization and demineralization. Finally, proteolytic activity of saliva generates numerous products whose biologic activities are often different from their parent compounds. Fluoride is another important component of saliva that is discussed separately in other articles in this issue. The ability of saliva to deliver fluoride to the tooth surface constantly makes salivary fluoride an important player in caries protection largely by promoting remineralization and reducing demineralization. Some key properties of salivary components discussed in this article are listed in Table 1. Saliva is well adapted to protection against dental caries. Saliva's buffering capability; the ability of the saliva to wash the tooth surface, to clear bacteria, and to control demineralization and mineralization; saliva's antibacterial activities; and perhaps other mechanisms all contribute to its essential role in the health of teeth. The fact that the protective function of saliva can be overwhelmed by bacterial action indicates the importance of prevention and therapy as in other infectious diseases. The knowledge of functional properties of saliva as well as those of its separate components may permit a better assessment of dental caries susceptibility. Future research is essential to characterize more fully salivary components and their interactions and how these affect the caries process. With such knowledge, the use of modified oral molecules as therapeutic agents may become a reality. Equally intriguing is the prospect of influencing the secretion of salivary components by greater knowledge and control over the secretory processes responsible for the delivery of those components.

Anti-Bacterial Agents↗

PubMed2002

Interaction of collagen-related genes and susceptibility to betel quid-induced oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity. It is a collagen-related disorder induced by betel quid chewing, a habit that is common in Taiwan. However, the cumulative exposure to betel quids varies in OSF patients. It seems that there is individual susceptibility to betel quid-induced OSF. This study compared the association of OSF and polymorphisms of six collagen-related genes, collagen 1A1 and 1A2 (COL1A1 and COL1A2), collagenase-1 (COLase), transforming growth factor beta1 (TGF-beta1), lysyl oxidase (LYOXase), and cystatin C (CST3), between patients with low and high exposure to betel quids. A total of 166 patients with OSF from a medical center and 284 betel quid chewers who were free of OSF and oral cancer, from the same hospital and five townships, were recruited. PCR-based restriction fragment length polymorphism assays were used to determine the genotypes of the six collagen-related genes situated on different chromosomes. We found that the genotypes associated with the highest OSF risk for collagen 1A1, collagen 1A2, collagenase-1, transforming growth factor beta1, lysyl oxidase, and cystatin C were CC, AA, TT, CC, AA, and AA, respectively, for the low-exposure group, and TT, BB, AA, CC, GG, and AA, respectively, for the high-exposure group. A trend was noted for an increased risk of OSF with increasing number of high-risk alleles for those with both high and low exposures for betel quid. The cell selection mechanism of oral fibroblasts is proposed to explain the effect of the modification of cumulative betel quid exposure on the risk profiles of collagen-related genes. These results imply that susceptibility to OSF could involve multigenic mechanisms modified by the betel quid-exposure dose.

Adult↗

PubMed2003

Effects of HDL3 on the expression of matrix-degrading proteases in human endothelial cells.

Modified lipoproteins have been suggested to modulate the expression of matrix-degrading proteases in the vascular wall. Since oxidized high density lipoprotein (HDL) has been found in atheromatous plaques and receptors for modified HDL are present on endothelial cells, we investigated the role of native and oxidized HDL3 on the expression of 35 proteases and their inhibitors in human endothelial cells using microarray analysis. Matrix metalloproteinase (MMP)-1, -2, -10, -13 and -14, tissue inhibitor of MMP (TIMP)-1, -2 and -3, cathepsin B and D, and cystatin C were expressed under basal conditions, of which MMP-10 and cystatin C expression have not been described before in endothelial cells. Native HDL3 increased MMP-1 and MMP-14 expression and decreased MMP-13 expression, whereas oxidized HDL3 increased PAI-1 and MMP-1 expression. The expression pattern was confirmed by quantitative real-time PCR. In summary, a large repertoire of matrix-degrading proteases is expressed in endothelial cells, an expression that can be modulated by native and oxidized HDL3.

Endopeptidases↗