Fibrate for treatment of primary biliary cirrhosis

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and γ-guanosine 5'-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.     

Perinatal lung development following maternal exposure to methylmercuric chloride

Mercury ingested from dietary sources has potent neurotoxic and teratogenic effects. Initial studies have shown that mercury may also affect fetal lung development. Since these pulmonary effects may play a role in subsequent neonatal morbidity and mortality due to compromising of the development of the lung, mercury effects in fetal and neonatal lung were investigated. Methylmercuric chloride (MMC), 1,000 ppm (15 mg/kg of body weight), was administered via an intragastric tube to timed-pregnant Swiss/Webster mice on day 9 of gestation. Lungs from fetuses on gestational day 18 and from neonates on days 1, 5, or 10 after birth were studied. Significant changes in MMC-exposed lungs compared to controls occurred at postnatal day 1. At this time, lung weight per gram body weight increased, phospholipid content per gram of lung or per microgram of DNA decreased, while DNA per gram of lung increased. Methylmercury appears to have delayed lung maturation. Cuboidal epithelial cells in alveolar tubules contained conspicuous glycogen deposits, and differentiation of alveolar type II cells was adversely affected. These results suggest that prenatal exposure to methylmercury may be detrimental to lung development, specifically to the initiation of surfactant synthesis, by delaying the normal pattern of maturation of the alveolar type II cells within the lungs. Pediatr Pulmonol. 1994; 17:11–21 . © 1994 Wiley-Liss. Inc.     

3''''-甲基-4-二甲氨基偶氯苯对大鼠肝脏磷脂代谢的影响

探讨3'—甲基—4—二甲氨基偶氮苯（3'－Me－DAB）诱发大鼠肝癌过程中肝脏磷脂代谢的变化。用3'－Me－DAB诱发Wistar大鼠肝癌，同时辅以低胆碱饮食，TLC分离磷脂组分，Rouser法测定第6、9、12、16、20周肝脏中总磷脂及各磷脂组分含量。结果：发现诱癌组总磷脂和磷脂酸胆碱（PC）的含量不断下降，且两者变化一致；鞘磷脂（SM）在3'—Me—DAB加普通饮食组（A组）诱癌早期即迅速增高，超过对照组约1倍，并一直维持至肝癌形成，而在3'—Me—DAB加低胆碱饮食组（B组）虽然早期也升高，但当第20周肿瘤发生转移时降至对照组以下；溶血磷脂酰胆碱（LPC）仅在B组晚期出现下降。不含胆碱基因的磷脂组分：磷脂酰乙醇胺（PE）、磷脂酰丝氨酸（PS）和磷脂酰肌醇（PI）在3'—Me—DAB诱癌晚期均降低，B组尤为明显。缩醛磷脂的含量在整个诱癌过程中未见明显变化。结论：3'－Me－DAB诱发大鼠肝癌过程中主要影响PC和SM的代谢，表现为PC降低，SM增高。低胆碱饮食能缯强3'—Me—DAB对大鼠肝脏磷脂代谢的影响。     

Homology Models of the C Domains of Blood Coagulation Factors V and VIII: A Proposed Membrane Binding Mode for FV and FVIII C2 Domains

ABSTRACT: We present homology models of the C domains of coagulation factors V (FV) and VIII (FVIII). Using a threading approach, we identified the binding domain of galactose oxidase as an appropriate template for each C domain. The C1 and C2 domains of FV associate to form an elongated cylinder of 80Å long and 30Å diameter. The folding unit is a β-sandwich with a long axis of 40Å and a diameter of 30Å. The current model allows us to propose a membrane binding mode for the C2 domains of FV and FVIII with three major characteristics: 1) solvent-exposed hydrophobic side chains from three loops at one end of the β-sandwich are buried in the hydrophobic layer of the outer phospholipid leaflet; 2) a crown of positively charged residues is located in the polar zone of the phospholipid head groups; and 3) the long axis of the β-sandwich of the C2 domain is perpendicular to the plane of the membrane. This proposal satisfies experimentally observed characteristics of membrane binding for the C2 domain and the light chain of FVa.     

肌醇磷脂代谢与输精管平滑肌收缩之间的关系

对牛精子中分离的一种蛋白激酶C(PKC)大分子抑制剂对大白鼠输精管平滑肌肌醇磷脂代谢的影响进行了研究。大白鼠输精管平滑肌细胞放入Lock's液中孵育1h,用~(32)P(无载体)标记磷脂,加入去甲肾上腺素后,在不同的时间终止反应。磷脂分析的结果显示去甲肾上腺素使磷脂的代谢增强;如在加入去甲肾上腺素的同时加入牛精子中分离的大分子抑制剂或氯丙嗪,则肌醇磷脂和磷脂酰胆碱的代谢都受到抑制     

Binding of cardiolipin to polystyrene beads: evidence for a lamellar phase orientation

Summary. The association of cardiolipin with polystyrene beads was studied using ³¹P-NMR and electron microscopy. In the presence and absence of fetal calf serum, cardiolipin appeared to bind to the polystyrene beads in lamellar phase as assessed by ³¹P-NMR imaging. Electron microscopic analysis revealed an even coating of phospholipid about the beads with extensive micelle binding. Cardiolipin-coated beads challenged with ACA-positive sera followed by immunogold indicated antibody bound to micelles associated with the bead. Studies conducted with ACA IgG purified from patient sera indicated that some ACA bound to CL beads in the absence of a source of ACA cofactor (i.e. gelatin-blocked beads), some ACA required β₂-GPI for binding (i.e. no binding in the presence of β₂-GPI-depleted plasma), whereas other ACA which showed negliglible binding with gelatin-blocked beads, showed enhanced binding in the presence of /?₂-GPI-depleted plasma. The data indicate that: (1) cardiolipin binds to polystyrene beads in lamellar phase, (2) ACA bind to phospholipid micelles bound directly to the polystyrene beads, and (3) ACA differ between individuals displaying varying phospholipid and phospholipid/cofactor substrate specificities.     

Biochemical transmethylation of lipids and neuropeptidergic stimulation of pituitary hormone secretion

S-adenosyl-l-methionine-dependent methylation of membrane phosphatidylethanolamine to phosphatidylcholine has been shown to exist in a number of tissues including pituitary gland and to play important roles in receptor-mediated functions. The possible role of this phospholipid methylation reaction in pituitary hormone secretion has been studied. To this end, the ability of thyrotropin-releasing hormone (TRH) to release thyrotropin (TSH) and prolactin and the ability of luteinizing hormone-releasing hormone (LH-RH) to release luteinizing hormone (LH) were evaluated after inhibition of pituitary phospholipid methylation. Both TRH and LH-RH stimulated the release of their corresponding pituitary hormone in a dose-dependent manner and this stimulatory effect was inhibited in the presence of phospholipid methylation inhibitors. Non-specific stimulation of TSH release by 55 mM KCl or 0.1 mM veratridine, however, was not affected by the methylation inhibitors. The data suggest that phospholipid methylation may participate in receptor-mediated release of pituitary hormones.     

Effects of maternal essential fatty-acid deficiency on neonatal rat brain

Female weanling rats were raised to sexual maturity on either a normal stock diet or an essential fatty-acid (EFA) deficient diet, and then bred. Brain weight and lipid composition of the offspring from these animals were measured as part of an investigation into factors contributing to the early death of EFA-deficient progeny. Lactation failure does not seem to be an adequate explanation of the early deaths since the dead EFA-deficient offspring frequently have milk in their stomachs. Maternal behavior including nesting was lacking, however, in EFA-deficient dams. The EFA-deficient brains weighed less than normal neonatal brains, and frequently had subdural hemorrhaging. Relative to body weight, however, some “sparing” of the brain was apparent. Total brain sterol concentration was not measurably different, but fatty-acid composition of total brain lipid and phospholipid was. The EFA-deficient offspring had relatively less arachidonate and other EFA-related fatty acids, while the proportion of trienoic acids, principally 20:3 and 22:3 was increased considerably. In phosphatidyl ethanolamine, the proportion of 16:0 was particularly elevated in the EFA-deficient brains. The results are discussed in relation to the integrity of myelin and the synthesis of prostaglandins, as possible factors in the premature death of EFA-deficient progeny.     

Effect of polychlorinated biphenyls (PCBs) administration on phospholipid biosynthesis in rat liver

The effect of PCBs or phenobarbital on the biosynthesis of phospholipids in hepatic endoplasmic reticulum of rats was studied by the intraperitoneal injection of [³²P]orthophosphate, [Me?¹⁴ C]choline or [2?³H]glycerol. Significant increases in liver microsomal phospholipid content after the administration of either PCBs or phenobarbital indicated the actual proliferation of endoplasmic reticulum membranes. The rate of both [³²P] and [¹⁴C] incorporations into microsomal choline-containing phospholipids, such as phosphatidylcholine, sphingomyelin and lysophosphatidylcholine, was reduced to one fifth by PCBs administration compared with control animals. The incorporation of [³²P]orthophosphate into phosphatidylethanolamine or other phospholipid classes was less or not affected, respectively, by PCBs administration. The specific inhibitory effect of PCBs on the incorporation into cholinecontaining phospholipids was not observed when [2?³-H]glycerol was used as a precursor. Phenobarbital administration, however, increased significantly the rate of [³²P] incorporation into liver phospholipids, especially phosphatidylcholine. It is suggested that the increase in microsomal phospholipid content by PCBs administration is not due to the stimulation of synthesis but to the inhibition of the catabolism of membrane phospholipids and that the increase in content caused by phenobarbital is due at least in part, to the stimulation of synthesis. The possible site(s) of PCBs-induced inhibition of phospholipid biosynthesis in rat liver is discussed.     

Binding specificity of lupus anticoagulants and anticardiolipin antibodies

Antiphospholipid antibodies have been found to be strongly associated with syndromes characterised by spontaneous arterial and venous thromboses, recurrent miscarriage, immune thrombocytopenia, and occasionally neurological manifestations. These antibodies can be detected using solid phase immunoassays, and by their effect on prolonging phospholipid dependent clotting tests. This latter phenomenon is termed the lupus anticoagulant (LA). The relationship between anticardiolipin antibodies (ACA) and the LA activity of plasma was investigated in 14 patients. Plasma of these patients exhibited both LA activity and high levels of ACA. The patients included 7 with systemic lupus erythematosus, 6 without and 1 chlorpromazine induced lupus anticoagulant. 7 patients had a history of thrombosis and 7 did not, despite high antibody levels. Plasma was incubated in a serial fashion with solid phase cardiolipin and the residual ACA level and LA activity were monitored using a solid phase enzyme linked immunoassay, and the kaolin clotting time (KCT) and activated partial thromboplastin time (APTT) respectively. There was no correlation between baseline ACA levels and parameters of LA activity (dKCT or dAPTT) in contrast to previous reports. However, there was a concurrent reduction in both LA and ACA levels over 24 hours during incubation with cardiolipin in all patients. The rate of reduction of both parameters was highly correlated (r = 0.99. p < 0.001). The relative reduction of LA activity versus ACA level varied between patients, and may represent different affinities for phospholipid in thromboplastin versus phospholipid in solid phase. Thus, despite the lack of concordance between LA and ACA in many patients, the two activities can be removed concurrently , suggesting similar binding specificities of the antibodies. The incomplete concordance could be explained by varying affinities for different structural presentations of the lipid antigen.