Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy

The mechanism of IgA deposition in the kidneys in IgA nephropathy is unknown, Mesangial IgA is of the IgA I subclass, and since no consistent antigenic target for the IgA I has been described, we have investigated the glycosylation of the molecule, as a potential non-immunological abnormality which may contribute to its deposition. IgA 1 is rich in carbohydrate, carrying N-linked moieties in common with IgG, but also O-linked sugars, which are rare in serum proteins, and not expressed by IgG or lgA2, Lectin binding assays were designed to examine the expression of terminal galactose on the N-linked carbohydrate chains of purified serum IgG and IgAI, and the O-linked sugars of IgAI and C1 inhibitor (one of the very few other serum proteins with O-linked glycosylation). No evidence was found for abnormalities of N-linked glycosylation of either isotype in IgA nephropathy compared with matched controls. However, in IgA nephropathy, reduced terminal galactosylation of the hinge region O-linked moieties was demonstrated; this was not seen in C1 inhibitor, which showed normal or increased galactosylation of the O-linked sugars. This abnormality of IgA1 has considerable implications for the pathogenesis of IgA nephropathy, since the O-linked sugars lie in an important functional location within the IgA1 molecule, close to the ligand of Fc receptors. Changes in the carbohydrates in this site may therefore affect interactions with receptors and extracellular proteins, leading to anomalous handling of the IgA1 protein in this condition, including failure of normal clearance mechanisms, and mesangial deposition.     

n,n′-二乙酰-L-胱氨酸对半乳糖胺联用脂多糖引起小鼠免疫性肝衰竭的作用

目的研究n,n′-二乙酰-L-胱氨酸(DiNAC)对免疫性肝衰竭的治疗作用。方法观察DiNAC对Balb/C小鼠由半乳糖胺联用脂多糖引起免疫性肝衰竭的作用。半乳糖胺/脂多糖攻击6 h后，小鼠血清ALT，AST和外周血T细胞亚群分别用全自动生化仪、流式细胞仪测定，并用光镜观察肝组织病理切片，统计半乳糖胺/脂多糖攻击24 h后的小鼠存活率。结果给肝衰竭小鼠ip DiNAC(50，200，800 mg·kg^-1)，能明显阻止小鼠血清ALT和AST活力增高，使肝组织损害减轻及提高小鼠存活率，并呈剂量依赖关系；DiNAC能增强免疫性肝衰竭小鼠外周血CD4⁺,CD8⁺,Th1和Th2 T淋巴细胞的增殖分化。结论DiNAC对免疫性肝衰竭动物有明显的治疗作用，这一作用与其免疫调节有关。     

Synthesis and biological properties of antitumor-active conjugates of ADR with dextran

Three kinds of polymeric adriamycin (ADR) conjugates of dextran were synthesized, namely a dextran–Gly-Leu-Gly-ADR (DGLGA) conjugate with a lysosomally degradable tripeptide spacer group, a dextran–Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga) conjugate with a targeting moiety of galactosamine on DGLGA, and a dextran–C₆H₁₀-ADR (DC₆A) conjugate with a hexamethylen spacer group. The content of the ADR moiety in the polymeric-drug conjugate was about 3 mol%. Enzyme hydrolysis of DGLGA and DC₆A was carried out by incubation with papain. The total amount of ADR released after 48 h was 43 mol% for DGLGA and less than 1 mol% for DC₆A. In an in vitro cytotoxicity experiment, the DGLGA-Ga conjugate has higher cytotoxic efficacy than the other conjugates for incubation with Hep-3B cells and consequently, the capability of targeting hepatoma cells of the galactosamine residue was determined. In contrast, for the incubation with SiHa cells of these conjugates, there was no significant cytotoxicity effect. The in vivo cytotoxic efficacy of each conjugate (20 mg ADR equiv./kg) against CT-26 mice colon cells implanted subcutaneously in Balb-C mice was studied. The DGLGA conjugate generated the best therapeutic effect with the presence of long-term survival (LTS) at day 50 (2/6).     

Hepatoprotective effects of Taiwan folk medicine: Alternanthera sessilis on liver damage induced by various hepatotoxins

The hepatoprotective effects of the Taiwanese herb ‘Horngtyan-wu’ (Alternanthera sessilis (L.) DC.) were investigated in three kinds of experimental animal model. Acute hepatitis was induced by various chemicals such as carbon tetrachloride (31.25 μL/kg, i.p.) or acetaminophen (paracetamol; 600 mg/kg, i.p.) in mice and D(+)-galactosamine (188 mg/kg, i.p.) in rats. When treated with A. sessilis (300 mg/kg, p.o.) at 2, 6 and 10 h, a reduction in elevation of serum glutamate oxaloacetic transaminase (SGOT) and glutamate pyruvic transaminase (SGPT) levels could be observed at 24 h after administration of the three hepatotoxins. These serological observations were also confirmed by histopathological examinations including centrilobular necrosis, eosinophilic bodies, pyknotic nuclei, microvesicular degeneration of hepatocytes and others. The liver microscopic examination showed a noted improvement in groups receiving A. sessilis. All pharmacological and histopathological effects were compared with observations using the hepatoprotective Chinese herb, Bupleurum chinense (Family Umbelliferae). It was confirmed that A. sessilis has hepatoprotective effects against liver injuries induced by hepatotoxins with different mechanisms.     

朱砂莲提取物(A_(1015))对D-氨基半乳糖胺肝损伤模型小鼠DNA合成作用的影响

目的　研究朱砂莲提取物 (A10 15)对D 氨基半乳糖胺(D Gl)肝损伤模型小鼠DNA合成作用的影响。方法　采用D Gl造模 ,3 H TdR参入法测定小鼠肝细胞DNA合成 ,并与肝细胞再生因子进行比较。观察了A10 15的剂量曲线和时间曲线。结果和结论　朱砂莲提取物 (A10 15)抵抗D Gl造成的肝组织坏死和促进肝脏细胞DNA合成作用的最适剂量为 2 5mg·kg-1体重。试验还提示A10 15的抗肝中毒作用2 0 0 1-12 -2 6收稿 ,2 0 0 2 -0 3 -0 6修回1 华西医科大学基础部药理学教研室 ,成都　 610 0 41作者简介 :刘碧崇 ,女 ,3 7岁 ,副研究员 ,博士。研究方向 :微生物药物与中药研究。Tel:0 2 8 43 780 40 ,Fax :0 2 8 43 3 3 2 18,E mail:huanggen @mail sc cninfo net;王浴生 ,男 ,81岁 ,教授 ,博士生导师。研究方向 :抗生素与中药药理不强于肝细胞再生因子     

Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and d‐galactosamine in mice

This study was designed to investigate the influence of 2‐methyl‐6‐phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d‐ galactosamine (d‐ GalN)‐induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 µg kg^?1 LPS and 500 mg kg^?1 d‐ GalN. MPEP (1, 5 and 25 mg kg^?1) was administered intraperitoneally 1 h before LPS/d‐ GalN injection. Twenty‐four hours after administration of LPS/d‐ GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/d‐ GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S‐transferase activity was increased by administration of LPS/d‐ GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg^?1, was effective in protecting against the decrease in catalase activity caused by LPS/d‐ GalN administration in mice. The histological data showed that sections of liver from LPS/d‐ GalN‐exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and d‐ GalN in mice was demonstrated. Copyright © 2009 John Wiley & Sons, Ltd.     

Protection against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage by Melothria maderaspatana extract

The aqueous extract of Melothria maderaspatana is used by traditional medical practitioners to treat jaundice in man. The effect of Melothria maderaspatana extract on damage induced in freshly isolated rat hepatocytes by D-galactosamine and tert-butyl hydroperoxide (TBH) has been investigated. On incubation of hepatocytes with galactosamine or TBH in the presence of the plant extract, a significant dose-dependent protection against hepatocyte damage was observed, with maximum protection at a concentration of 500 μg/mL. At this concentration the galactosamine-induced release of lactate dehydrogenase (LDH) and aspartate amino-transferase (AST) were reduced by 40.7% ± 4.2% and 37.7% ± 6.1% respectively, compared with control incubations. The TBH-induced lipid peroxidation (estimated from malondialdehyde production) was decreased by 26.0 ± 3.7% together with a 38.4% ± 4.4% and 40.8 ± 7.6% reduction in the release of cellular LDH and AST respectively into the incubation medium. On post-treatment with the plant extract the protective activity was found to decrease with increase in time of exposure of the cells to either of the toxins. The direct protective effects of Melothria extract on hepatocytes support the use of this plant as a herbal remedy.     

齐墩果醇酸对化学物质致小鼠急性肝损伤的保肝作用(英文)

目的:评价齐墩果醇酸(OA)对急性肝损伤的保肝作用.方法:小鼠sc OA 200 μmol·kg~(-1)三天,然后给予肝毒物.通过病理组织学观察及测定血清丙氨酸转氨酶和艾杜糖醇脱氢酶活性来估价肝损伤.结果:OA能明显减轻四氯化碳,溴苯,醋氨酚,速尿,硫代乙酰胺,鬼笔毒环肽,秋水仙硷,氯化镉,D—半乳糖胺和内毒素等所致小鼠急性坏死性肝损伤,降低这些肝毒物所引起的血清转氨酶和艾杜糖醇脱氢酶的升高,但对氯仿,二甲亚硝氨,鹅膏菌索和烯丙醇的毒性无作用.结论:OA能减轻多种化学物质(但并非全部)引起的肝损伤.其保肝机制可能是多方面的.