heparitin-sulfate and Chemical-and-Drug-Induced-Liver-Injury

Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Europe; Heparitin Sulfate; Humans; Liver; Liver Failure, Acute; Mice; Mice, Inbred C57BL

In this study, we carried out an immunohistochemical investigation of time-dependent alterations in the distribution of proteoglycans, and the proliferation profiles of hepatocytes and fat-storing cells (FSCs) in the livers of rats intoxicated with D-galactosamine (GalN). The proliferative cells were analyzed by proliferative cell nuclear antigen (PCNA) staining. In untreated rats, heparan sulfate, dermatan sulfate, and chondroitin/chondroitin sulfate were detected within the portal spaces and the central veins, and, with the exception of chondroitin, also within the reticular fibers. After administration of GalN, the number of PCNA-positive cells (FSCs and hepatocytes) and FSCs increased, reaching maximal on the 2nd and 3rd days, respectively. Heparan sulfate showed complicated changes. Dermatan sulfate decreased in portal spaces from the 2nd to the 3rd day, and in reticular fibers from 12 h to the 6th day. Chondroitin/chondroitin sulfate staining was observed from 2 h to the 6th day in the sinusoidal endothelia, which suggests that the sinusoidal endothelia may produce chondroitin/chondroitin sulfate transiently during liver damage as part of the mechanism of regeneration. Heparan sulfate and chondroitin/chondroitin sulfate were detected in necrotic regions, but dermatan sulfate was not. These observations suggest that heparan sulfate and chondroitin/chondroitin sulfate are involved in cell proliferation or morphogenesis and that the dermatan sulfate plays a role in the differentiation or functional maintenance of cells in liver regeneration.

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Dermatan Sulfate; Disease Models, Animal; Extracellular Matrix; Galactosamine; Heparitin Sulfate; Immunohistochemistry; Liver; Liver Diseases; Male; Microscopy, Electron; Proliferating Cell Nuclear Antigen; Proteoglycans; Rats; Rats, Sprague-Dawley

67Ga uptake of the liver began to elevate from the 1st day and reached a maximum at the 2nd day of treatment with thioacetamide (TIAA). Incorporation of 3H-thymidine into the liver DNA fraction was reached a maximum at the 1.5th day, and the value was 5.7 times of the control. The uronic acid content and 35S incorporation in the 1.2 M NaCl-soluble fraction which contained predominantly heparan sulfate (HS), were both peaked at the 2nd day. These patterns were in good agreement with that of 67Ga uptakes in the liver treated with TIAA. Pretreatment of aminoacetonitrile, an inhibitor of fibrosis, was effective in lowering the elevated uptake of 67Ga in TIAA-treated rat liver. Uptake of the 67Ga in the TIAA-treated liver was also inhibited when they were treated with cycloheximide, an inhibitor of protein synthesis. On the other hand no significant inhibition was observed in the cytosine arabinoside-treated-TIAA rats. These results suggest that HS may be involved in the 67Ga uptake in damaged liver, and that relation between 67Ga uptake and cell proliferation is secondary.

Topics: Acetamides; Animals; Cell Differentiation; Chemical and Drug Induced Liver Injury; Cycloheximide; Cytarabine; DNA; Gallium Radioisotopes; Heparitin Sulfate; Liver; Male; Rats; Thioacetamide; Thymidine

Topics: 2-Acetylaminofluorene; Animals; Carbon Tetrachloride Poisoning; Cations; Chemical and Drug Induced Liver Injury; Gallium Radioisotopes; Glycosaminoglycans; Heparitin Sulfate; Liver; Male; Rats; Tissue Distribution

Administration of a single dose of D-galactosamine to rats causes time-dependent, biphasic changes of total glycosaminoglycan synthesis in liver. A rapidly occurring inhibition is followed by a significantly enhanced (greater than 2 fold) production of 35S-labeled glycosaminoglycans in later stages of injury. Degree and duration of the inhibitory phase are dose-dependent; 50% inhibition is reached at 80 mg/kg and maximum inhibition (nearly 80%) at about 300 mg/kg body weight 2 h after injection of D-galactosamine. The hepatotoxin impairs preferentially the production of heparan sulfate, whereas that of chondroitin sulfate and dermatan sulfate is diminished only slightly and for a rather short period of time. The synthesis of the latter, however, is more stimulated than that of heparan sulfate in later stages of injury. The specific radioactivity of 35S-labeled 3'-phosphoadenosine-5'-phosphosulfate (PAPS) did not change significantly during the course of acute liver damage. Glycosaminoglycan synthesis in regenerating liver was nearly unaffected by D-galactosamine. Uridine at the dose applied partially reversed D-galactosamine-inhibited synthesis of proteoheparan sulfate. In accordance with the labeling studies the content of glucosamine-containing glycosaminoglycans in treated liver decreased, whereas that of galactosamine-containing glycosaminoglycans slightly increased, resulting in a nearly 50% reduction of the glucosamine/galactosamine ratio 5 h after administration of D-galactosamine. Ion exchange chromatographic studies of 35S-labeled specific types of glycosaminoglycans from normal and galactosamine-injured liver revealed only minor structural differences.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chondroitin; Chondroitin Sulfates; Dermatan Sulfate; Galactosamine; Glycosaminoglycans; Heparitin Sulfate; Hepatectomy; Liver; Liver Regeneration; Male; Polysaccharides; Rats

The synthesis of glycosaminoglycans in slices from normal and acutely injured rat liver was studied. The rates of incorporation of [14C]-glucosamine into specific types of glycosaminoglycans varied markedly; nearly 90% was incorporated into a fraction containing predominantly heparan sulfate and far less if any heparin; about 9.5% was incorporated into chondroitin 4-and 6-sulfate, and only 0.2% of the radioactivity was found in hyaluronic acid. The rate of synthesis of a fraction having several of the characteristics of keratan sulfate comprised only 0.3% of the synthesis of total glycosaminoglycans. No [14C]hexosamine was incorporated into dermatan sulfate. Following acute hepatic injury, the synthesis of glycosaminoglycans was stimulated by 80 to 100%, and the proportions of various types changed. If calculated on the basis of the specific activity of the precursors of glycosaminoglycans, which was found to be strongly reduced in injured liver, the maximum enhancement of total glycosaminoglycan synthesis was 6.6-fold 5 days after onset of liver injury.

Topics: Acetamides; Animals; Chemical and Drug Induced Liver Injury; Glucosamine; Glycosaminoglycans; Heparin; Heparitin Sulfate; In Vitro Techniques; Liver; Liver Diseases; Male; Rats; Thioacetamide

The extractable and nonextractable collagen and glycosaminoglycuronans (GAG) were estimated and characterized in 32 dried, defatted human livers obtained at necropsy. 10 had normal livers. 22 of the 32 livers were from patients who drank in excess: 5 had fatty livers, 7 had alcholic hepatitis, and 10 had cirrhosis. Livers with alcoholic hepatitis or cirrhosis had significantly increased total and 1 N NaCl-extractable collagen. Only alcoholic hepatitis livers had significantly increased Tris-buffer-extractable GAG, but the amino acid composition of these GAG (proteoglycans) was no different from that of normal livers. The major fraction of these GAG had isoelectric pH (pI)

Topics: Alcoholism; Amino Acids; Chemical and Drug Induced Liver Injury; Chondroitin; Chromatography, Gel; Collagen; Connective Tissue; Dialysis; Fatty Liver; Glucosamine; Glycoproteins; Glycosaminoglycans; Heparitin Sulfate; Hexosamines; Humans; Hyaluronic Acid; Hydroxyproline; Isoelectric Focusing; Liver; Liver Cirrhosis