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C Cerami

Publications and source records attributed to C Cerami.

10 recordsLinked to original sources
PubMed2000

Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury.

Erythropoietin (EPO), recognized for its central role in erythropoiesis, also mediates neuroprotection when the recombinant form (r-Hu-EPO) is directly injected into ischemic rodent brain. We observed abundant expression of the EPO receptor at brain capillaries, which could provide a route for circulating EPO to enter the brain. In confirmation of this hypothesis, systemic administration of r-Hu-EPO before or up to 6 h after focal brain ischemia reduced injury by approximately 50-75%. R-Hu-EPO also ameliorates the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate. Given r-Hu-EPO's excellent safety profile, clinical trials evaluating systemically administered r-Hu-EPO as a general neuroprotective treatment are warranted.

Animals↗
PubMed1997

Tobacco smoke is a source of toxic reactive glycation products.

Smokers have a significantly higher risk for developing coronary and cerebrovascular disease than nonsmokers. Advanced glycation end products (AGEs) are reactive, cross-linking moieties that form from the reaction of reducing sugars and the amino groups of proteins, lipids, and nucleic acids. AGEs circulate in high concentrations in the plasma of patients with diabetes or renal insufficiency and have been linked to the accelerated vasculopathy seen in patients with these diseases. Because the curing of tobacco takes place under conditions that could lead to the formation of glycation products, we examined whether tobacco and tobacco smoke could generate these reactive species that would increase AGE formation in vivo. Our findings show that reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke in a form that can rapidly react with proteins to form AGEs. This reaction can be inhibited by aminoguanidine, a known inhibitor of AGE formation. We have named these glycation products "glycotoxins." Like other known reducing sugars and reactive glycation products, glycotoxins form smoke, react with protein, exhibit a specific fluorescence when cross-linked to proteins, and are mutagenic. Glycotoxins are transferred to the serum proteins of human smokers. AGE-apolipoprotein B and serum AGE levels in cigarette smokers were significantly higher than those in nonsmokers. These results suggest that increased glycotoxin exposure may contribute to the increased incidence of atherosclerosis and high prevalence of cancer in smokers.

Animals↗
PubMed1996

High-performance liquid chromatographic method for guanylhydrazone compounds.

A high-performance liquid chromatographic method has been developed for a series of aromatic guanylhydrazones that have demonstrated therapeutic potential as anti-inflammatory agents. The compounds were separated using octadecyl or diisopropyloctyl reversed-phase columns, with an acetonitrile gradient in water containing heptane sulfonate, tetramethylammonium chloride, and phosphoric acid. The method was used to reliably quantify levels of analyte as low as 785 ng/ml, and the detector response was linear to at least 50 micrograms/ml using a 100 microliters injection volume. The assay system was used to determine the basic pharmacokinetics of a lead compound, CNI-1493, from serum concentrations following a single intravenous injection in rats.

Animals↗
PubMed1994

Structural and functional properties of region II-plus of the malaria circumsporozoite protein.

During feeding, infected mosquitos inject malaria sporozoites into the host circulation. Within minutes, the parasites are found in the liver where they initiate the first stage of malaria infection. All species of malaria sporozoites are uniformly covered by the circumsporozoite protein (CS), which contains a conserved COOH-terminal sequence called region II-plus. We have previously shown that region II-plus is the parasite's hepatocyte-binding ligand and that this ligand binds to heparan sulfate proteoglycans (HSPGs) on the hepatocyte membrane. Using a series of substituted region II-plus peptides, we show here that the downstream basic amino acids as well as the interdispersed hydrophobic residues are required for binding of CS to hepatocyte HSPGs. We also show that this positively charged stretch of amino acids must be aggregated in order to bind to the receptor. On the basis of this information, we have synthesized a multiple antigen peptide that mimics the hepatocyte-binding ligand. This construct inhibits both CS binding to HepG2 cells in vitro as well as CS clearance in mice.

Amino Acid Sequence↗
PubMed1994

Rapid clearance of malaria circumsporozoite protein (CS) by hepatocytes.

The circumsporozoite protein (CS) covers uniformly the plasma membrane of malaria sporozoites. In vitro, CS multimers bind specifically to regions of the hepatocyte plasma membrane that are exposed to circulating blood in the Disse space. The ligand is in the region II-plus of CS, an evolutionarily conserved stretch of the protein that has amino acid sequence homology to a cell adhesive motif of thrombospondin. We have now found that intravenously injected CS constructs bind rapidly to the basolateral surface of hepatocytes, provided that the recombinant proteins contain region II-plus, and that they are aggregated. Significant amounts of CS were not retained in any other organ. The striking parallelism between these in vitro and in vivo findings with the target specificity of malaria sporozoites, reinforces the hypothesis that the attachment of the parasites to hepatocytes is via region II-plus of CS.

Amino Acid Sequence↗
PubMed1993

Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes.

During feeding by infected mosquitoes, malaria sporozoites are injected into the host's bloodstream and enter hepatocytes within minutes. The remarkable target cell specificity of this parasite may be explained by the presence of receptors for the region II-plus of the circumsporozoite protein (CS) on the basolateral domain of the plasma membrane of hepatocytes. We have now identified these receptors as heparan sulfate proteoglycans (HSPG). The binding of CS to the receptors is abolished by heparitinase treatment, indicating that the recognition of region II-plus is via the glycosaminoglycan chains. We have purified and partially characterized the CS-binding HSPGs from HepG2 cells. They have a molecular weight of 400,000-700,000, are tightly associated with the plasma membrane, and are released from the cell surface by very mild trypsinization, a property which the CS receptors share with the syndecan family of proteoglycans.

Amino Acid Sequence↗
PubMed1992

The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of Plasmodium falciparum sporozoites.

Minutes after injection into the circulation, malaria sporozoites enter hepatocytes. The speed and specificity of the invasion process suggest that it is receptor mediated. We show here that recombinant Plasmodium falciparum circumsporozoite protein (CS) binds specifically to regions of the plasma membrane of hepatocytes exposed to circulating blood in the Disse space. No binding has been detected in other organs, or even in other regions of the hepatocyte membrane. The interaction of CS with hepatocytes, as well as sporozoite invasion of HepG2 cells, is inhibited by synthetic peptides representing the evolutionarily conserved region II of CS. We conclude that region II is a sporozoite ligand for hepatocyte receptors localized to the basolateral domain of the plasma membrane. Our findings provide a rational explanation for the target cell specificity of malaria sporozoites.

Amino Acid Sequence↗
PubMed1992

Binding of malarial circumsporozoite protein to sulfatides [Gal(3-SO4)beta 1-Cer] and cholesterol-3-sulfate and its dependence on disulfide bond formation between cysteines in region II.

Region II of the malaria circumsporozoite (CS) protein is highly conserved between the CS proteins of different species of malaria. Amino acid sequences homologous to that of region II are found in thrombospondin, properdin, von Willebrand factor and a few other proteins. We show here that the native CS protein from the rodent parasite Plasmodium berghei, and recombinant Plasmodium vivax and Plasmodium falciparum CS proteins containing region II, but not recombinant proteins lacking region II, specifically bind to sulfatides and cholesterol-3-sulfate. The binding is abolished following reduction and alkylation of the proteins. Region II contains 2 cysteines separated by only 3 amino acids, S(N), V, T, and these are the only cysteines present in our recombinant proteins. Therefore, our findings strongly suggest that the region II cysteines are linked by a disulfide bond forming a small peptide loop. We also present evidence that the recognition of sulfatides, cholesterol-3-sulfate, or other cross-reactive sulfated macromolecules by region II may be required during sporozoite invasion of liver cells. Antibodies to a peptide representing region II react with live sporozoites and with sporozoites fixed with glutaraldehyde, indicating that this region is exposed on the surface of the parasites. Furthermore, we have found that the sulfatide and cholesterol-3-sulfate recognition by the CS proteins, and the invasion of hepatocytes by P. berghei sporozoites, are specifically inhibited by dextran sulfate.

Amino Acid Sequence↗
PubMed1987

Advanced glycosylation endproducts on erythrocyte cell surface induce receptor-mediated phagocytosis by macrophages. A model for turnover of aging cells.

Glucose can react nonenzymatically with amino groups of proteins to form covalent Amadori products. With time these adducts undergo further rearrangements to form irreversible advanced glycosylation endproducts (AGE), which accumulate with protein age. A specific AGE, 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI), has been identified on proteins in vivo. We have recently shown that a macrophage receptor specifically recognizes and internalizes proteins modified by AGE such as FFI, thus preferentially degrading senescent macromolecules. Reasoning that cellular turnover may be mediated by macrophage recognition of AGE-membrane proteins, we prepared human RBCs with FFI attached chemically. Human monocytes were incubated with either FFI-RBCs, IgG-opsonized RBCs, or PBS-treated RBCs. Erythrophagocytosis of FFI-RBCs was significantly higher than that of PBS-RBCs (55 vs. 4%; p less than 0.0025) and almost as high as that of IgG-RBCs (70%), and was competitively inhibited by AGE-BSA. AGE-RBCs were also prepared by incubating RBCs with various sugars. Human monocytes showed a 15% ingestion of glucose-RBCs, and a 26% ingestion of glucose-6-phosphate-RBCs, compared to 6% for PBS-RBCs. Similarly, diabetic mouse RBCs were phagocytosed by nearly three times more cells (21%) than normal mouse RBCs when exposed to syngeneic mouse macrophages. This phagocytosis was competitively inhibited (70%) by addition of excess AGE-BSA. The in vivo half-life of 51Cr-labeled mouse FFI-RBCs injected into syngeneic mice was reduced to 7 d, as compared to a half-life of 20 d for the controls. These data suggest that the macrophage receptor for the removal of glucose-modified proteins may also mediate the endocytosis of RBCs with AGE formed on their surface, and thus be responsible in part for the removal of some populations of aging cells.

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