Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The high resistance of bacterial spores to heat has been repeatedly postulated to be due to stabilization of spore biopolymers by metal chelate compounds. Binding of calcium dipicolinic acid (Ca(II)-DPA) with spore proteins and amino acids has been discussed in the literature, but equilibrium data are generally lacking. By means of potentiometric pH titrations at 25 degrees C and an ionic strength of 1.0 (KNO(3)), the formation of Ca(II)-DPA (1:1 and 1:2) chelates and the interactions of Ca(II)-DPA chelate with a mole of each of three typical amino acids viz., cysteine, alanine, and glycine has been investigated. Analysis of the potentiometric data indicates that calcium and DPA forms 1:1 and 1:2 chelates with log K(ML1) = 4.39 +/- 0.01 and log K(ML2) = 2.25 +/- 0.01. In the presence of an equimolar amount of each of the amino acids under consideration, the Ca(II)-DPA chelate forms mixed ligand (ternary) chelate yielding the following stepwise stability constants: log K(1) = 4.17 +/- 0.01, log K(2) = 0.78 +/- 0.01 for cysteine, log K(1) = 4.06 +/- 0.01, log K(2) = 0.65 +/- 0.01 for alanine, and log K(1) = 4.30 +/- 0.02, log K(2) = 0.11 +/- 0.01 for glycine. Methods for calculating the stability constants of the mixed ligand system have been developed. On the basis of the potentiometric equilibrium data, possible structures for the various calcium chelate species are discussed. The data suggest that the differences in heat resistance of various strains of bacterial spores may conceivably be related to the differences in composition and stability of coordination complexes in the spore.
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PMID:Mixed chelates of Ca(II)-pyridine-2,6-dicarboxylate with some amino acids related to bacterial spores. 571 54

Transcripts for the alpha 1 chain of mouse type XVIII collagen were found to be heterogeneous at their 5'-ends and to encode three variant N-terminal sequences of the ensuing 1315-, 1527-, or 1774-residue collagen chains. The variant mRNAs appeared to originate from the use of two alternate promoters of the alpha 1(XVIII) chain gene, resulting in the synthesis of either short or long N-terminal non-collagenous NC1 domains, the latter being further subject to modification due to alternative splicing of the transcripts. As a result, the 1527- and 1774-residue polypeptides share the same signal peptide, and the lengths of their NC1 domains are 517 or 764 amino acid residues, respectively, while the 1315-residue polypeptide has a different signal peptide and a 301-residue NC1 domain. The longest NC1 domain was strikingly characterized by a 110-residue sequence with 10 cysteines, which was found to be homologous with the previously identified frizzled proteins belonging to the family of G-protein-coupled membrane receptors. Thus, it is proposed that the cysteine-rich motif, termed fz, represents a new sequence motif that can be found in otherwise unrelated proteins. Tissues containing mainly one or two NC1 domain mRNA variants or all three NC1 domains were identified, indicating that there is tissue-specific utilization of two alternate promoters and alternative splicing of alpha 1(XVIII) transcripts.
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PMID:Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins. 787 42

Recently, fragments of extracellular proteins, including endostatin, were defined as a novel group of angiogenesis inhibitors. In this study, human plasma equivalent hemofiltrate was used as a source for the purification of high molecular weight peptides (10-20 kDa), and the isolation and identification of circulating human endostatin are described. The purification of this C-terminal fragment of collagen alpha1(XVIII) was guided by MALDI-MS and the exact molecular mass determined by ESI-MS was found to be 18 494 Da. N-terminal sequencing revealed the identity of this putative angiogenesis inhibitor and its close relation to mouse endostatin. The cysteine residues 1-3 and 2-4 in the molecule are linked by disulfide bridges. In vitro biological characterization of the native protein demonstrated no anti-proliferative activity on different endothelial cell types. These data indicate that human endostatin, which is a putative angiogenesis inhibitor, is present in the circulation.
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PMID:Isolation and characterization of the circulating form of human endostatin. 945 95

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
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PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis and suppresses neovascularization and tumor growth. However, the inhibitory mechanism of endostatin in human endothelial cells has not been characterized yet. Electron microscopic analysis revealed that endostatin induced formation of numerous autophagic vacuoles in endothelial in 6 to 24 h after treatment. Moreover, there was only a 2- to 3-fold increase in intracellular reactive oxygen species after endostatin treatment. Endostatin-induced cell death was not prevented by antioxidants (vitamin C, vitamin E, or propyl gallate) or caspase inhibitors, suggesting that the increase of oxidative stress or the activation of caspases may not be the crucial factors in the anti-angiogenic mechanism of endostatin. However, the cytotoxicity of endostatin was significantly reduced by 3-methyladenine (a specific inhibitor of autophagy) and serine and cysteine lysosomal protease inhibitors (leupeptin and aprotinin). Taken together, these results suggest that in human endothelial cells: (1) endostatin predominantly causes autophagic, rather than apoptotic, cell death, (2) endostatin-induced autophagic cell death occurs in the absence of caspase activation and through an oxidative-independent pathway, and (3) endostatin-induced "autophagic cell death" or "type 2 physiological cell death" is regulated by serine and cysteine lysosomal proteases.
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PMID:Endostatin induces autophagic cell death in EAhy926 human endothelial cells. 1279 83

Human type XVIII collagen was found to be expressed as three variants, termed NC1-303, NC1-493 and NC1-728, differing in their N-terminal non-collagenous domains (NC1). The corresponding gene was found to be approximately 105 kb in size and contain 43 exons. The short variant is derived from utilization of an upstream promoter associated with the first two exons of the gene. The two other variants are derived from a downstream promoter and alternative splicing of exon 3, resulting in 192 residues of shared sequences characterized by a putative approximately 30 residue conserved coiled-coil motif and 235 residues of sequences specific to NC1-728. The NC1-728 variant has a conserved cysteine-rich domain homologous with the ligand-binding part of the frizzled proteins. A polyclonal antibody specific to the NC1-728 variant was generated, and immunostaining of fetal tissues revealed staining in lung and skeletal muscle. Human serum contained 173- and 144-kDa alpha1(XVIII) chains corresponding to the NC1-728 and NC1-493 variants, respectively. A 200-kDa polypeptide was detected in cells transfected with a cDNA construct corresponding to the full-length NC1-728 variant, and EBNA-293 cells endogenously synthesizing low amounts of type XVIII collagen had a 45-kDa fragment in their culture medium that corresponded to most of the NC1 domain of the NC1-728 variant, suggesting processing of the N-terminal frizzled-containing domain.
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PMID:Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif. 1461 89

The cysteine protease cathepsin S is highly expressed in malignant tissues. By using a mouse model of multistage murine pancreatic islet cell carcinogenesis in which cysteine cathepsin activity has been functionally implicated, we demonstrated that selective cathepsin S deficiency impaired angiogenesis and tumor cell proliferation, thereby impairing angiogenic islet formation and the growth of solid tumors, whereas the absence of its endogenous inhibitor cystatin C resulted in opposite phenotypes. Although mitogenic vascular endothelial growth factor, transforming growth factor-beta1, and the anti-angiogenic endostatin levels in either serum or carcinoma tissue extracts did not change in cathepsin S- or cystatin C-null mice, tumor tissue basic fibroblast growth factor and serum type 1 insulin growth factor levels were higher in cystatin C-null mice, and serum type 1 insulin growth factor levels were also increased in cathepsin S-null mice. Furthermore, cathepsin S affected the production of type IV collagen-derived anti-angiogenic peptides and the generation of bioactive pro-angiogenic gamma2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
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PMID:Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. 1636 41

The primary leaves from corn seedlings grown for 6 days were harvested, frozen with liquid N(2) and extracted in a Tris buffer (pH 8.5, 250 millimolar) containing 1 millimolar dithiothreitol, 10 millimolar cysteine, 1 millimolar EDTA, 20 micromolar flavin adenine dinucleotide and 10% (v/v) glycerol. Nitrate reductase (NR) in the crude extract was stable for several days at 0 degrees C and for several months at -80 degrees C. The enzyme was purified using (NH(4))(2)SO(4) fractionation, brushite-hydroxyl-apatite chromatography and blue-sepharose affinity chromatography. The enzyme was eluted from the blue-sepharose column with a linear gradient of NADH (0-100 micromolar) or with 0.3 molar KNO(3). About 10% of the original activity was recovered with NADH (NADH-NR). It had a specific activity of about 60 to 70 units (micromoles NO(2) (-) per minute per milligram protein). A sequential elution with NADH followed by KNO(3) (0.3 molar) or KCl (0.3 molar) yielded 2 peaks. Rechromatography of each peak gave two peaks again. These results indicate that we are dealing with two forms of the same enzyme rather than two different NR proteins. The two NRs had different molecular weights as judged by chromatography on Toyopearl. The NADH-NR was more sensitive than the NO(3) (-)-NR to antibody prepared against barley leaf NR. In Ouchterlony assays a single precipitin line, with completely fused boundaries, was observed.
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PMID:Characterization of Nitrate Reductase from Corn Leaves (Zea mays cv W64A x W182E) : Two Molecular Forms of the Enzyme. 1666 12

Clinical studies demonstrate a positive correlation between the extent of matrix metalloproteinase (MMP) activation and malignant progression of precancerous lesions. Therefore, identification of effective, well-tolerated MMP inhibitors represents a rational chemopreventive strategy. A variety of agents, including proteinases and thiol-oxidizing compounds, activate MMPs by initiating release of the propeptide's cysteine sulfur "blockage" of the MMP active site. Despite the importance of the propeptide's cysteine thiol in preserving MMP latency, limited studies have evaluated the effects of reduced thiols on MMP function. This study investigated the effects of two naturally occurring nonprotein thiols, i.e., glutathione (GSH) and N-acetylcysteine (NAC), on activation, function, and cellular-extracellular matrix interactions of the basement-membrane-degrading gelatinase, MMP-9. Our results reveal that NAC and GSH employ protein S-thiolation to inhibit organomercurial activation of pro-MMP-9. Gelatinase activity assays showed that GSH and NAC significantly inhibited MMP-9 but not MMP-2 function, implying isoform structural specificity. Immunoblot analyses, which suggested GSH interacts with MMP-9's active-site Zn, were corroborated by computational molecular modeling. Cell invasion assays revealed that NAC enhanced endostatin's ability to inhibit human cancer cell invasion. Collectively, these data demonstrate that nonprotein thiols suppress MMP-9 activation and function and introduce the prospect for their use in chemopreventive applications.
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PMID:Reduced nonprotein thiols inhibit activation and function of MMP-9: implications for chemoprevention. 1701 78

Collagen XVIII is a heparan sulphate proteoglycan which is expressed ubiquitously in different basement membranes throughout the body. Its C-terminal fragment, endostatin, has been found to inhibit angiogenesis and tumor growth by restricting endothelial proliferation and migration and inducing apoptosis of endothelial cells. Collagen XVIII has three variants, of which the shortest one is found in most vascular and epithelial BM structures, whereas the longer variants are found especially in the liver. The longest or frizzled variant has a cysteine-rich domain in its N-terminus that has been shown to inhibit Wnt signaling in vitro. The presence of collagen XVIII homologues in organisms such as C. elegans, Xenopus laevis, zebrafish and chick suggests a fundamental role for this BM collagen. Mutations in the collagen XVIII gene lead to the Knobloch syndrome, which is characterized by high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele. Mice lacking collagen XVIII also show several ocular abnormalities. This suggests that in physiological conditions collagen XVIII is mostly needed for the proper development of the eye. Moreover, it appears to be needed for the structural stability of basement membranes in several other organs, and increasing evidence shows its importance for other organs in non-physiological situations such as atherosclerosis, glomerulonephritis or other type of tissue damage. This review focuses on clarifying the roles of collagen XVIII and its variants and domains in various physiological and pathological conditions.
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PMID:The multiple functions of collagen XVIII in development and disease. 2116 48


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