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L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy 总被引:2,自引:0,他引:2
Hepatic encephalopathy (HE) is a common neuropsychiatric complication of liver disease affecting about 20-30% patients with cirrhosis. HE may only affect quality of life (e.g. impairments in attention; coordination; driving ability), but in some patients this progresses to coma and death; defining mortality in those with acute liver failure. HE is thought to occur through accumulation of ammonia as a by-product of protein metabolism. In liver failure ammonia accumulates to toxic levels, resulting in ammonia-associated brain swelling. Presently, there is no proven therapy for HE though recent studies suggest that during liver failure, ammonia removal by skeletal muscle (by conversion to glutamine) can be manipulated; also that ammonia and amino acid metabolism should be viewed in terms of their interorgan relationship. This led us to develop a novel concept for ammonia removal. Preliminary studies provide the proof of concept that the combination of L-ornithine (amino acid) with phenylactetate, as L-ornithine phenylacetate (OP), reduces toxic levels of ammonia by (1) L-ornithine acting as a substrate for glutamine synthesis from ammonia in skeletal muscle and (2) phenylacetate excreting the ornithine-related glutamine as phenylacetylglutamine in the kidneys. As both L-ornithine and phenylacetate are already available for human use, data showing its usefulness in ammonia lowering could translate quickly into providing the much needed therapy for HE patients. 相似文献
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Michael R. Narkewicz Simon Horslen Regina M. Hardison Benjamin L. Shneider Norberto Rodriguez-Baez Estella M. Alonso Vicky L. Ng Mike A. Leonis Kathleen M. Loomes David A. Rudnick Philip Rosenthal Rene Romero Girish C. Subbarao Ruosha Li Steven H. Belle Robert H. Squires 《Clinical gastroenterology and hepatology》2018,16(11):1801-1810.e3
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Christine Schulze 《European journal of pharmaceutics and biopharmaceutics》2011,77(3):376-383
The alveolar lining fluid (ALF) covering the respiratory epithelium of the deep lung is the first biological barrier encountered by nanoparticles after inhalation. We here report for the first time significant differences for metal oxide nanoparticles to the binding of surfactant protein A (SP-A), the predominant protein component of ALF. SP-A is a physiologically most relevant protein and provides important biological signals. Also, it is involved in the lung’s immune defence, controlling e.g. particle binding, uptake or transcytosis by epithelial cells and macrophages. In our study, we could prove different particle-protein interaction for eight different nanoparticles, whereas particles of the same bulk material revealed different adsorption patterns. In contrast to other proteins as bovine serum albumin (BSA), SP-A does not seem to significantly deagglomerate large agglomerates of particles, indicating different adsorption mechanisms as in the well-investigated model protein BSA. These findings may have important consequences for biological fate and toxicological effects of inhaled nanomaterials. 相似文献
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Hirofumi Uto Akio Ido Kazunori Kusumoto Satoru Hasuike Kenji Nagata Katsuhiro Hayashi Toshiya Yamagishi Eiichi Gohda Hirohito Tsubouchi 《Hepatology research》2005,33(4):272-276
Measurement of serum human hepatocyte growth factor (HGF) by enzyme-linked immunosorbent assay (ELISA) is useful for the early diagnosis and prediction of prognosis of patients with acute liver failure (ALF). This ELISA methodology, however, is neither rapid nor convenient for use at the bedside. In this study, we have developed a rapid semi-quantitative immunochromatographic (IC) assay and evaluated its usefulness in assessing patients with acute hepatic injury. Only 100mul of serum is required; the assay can be easily completed in 20min. The values obtained using this novel assay correlated well with the values obtained using the standard ELISA protocol. In addition, the values obtained in the IC assay correlated with clinical course; increased serum HGF levels were associated with an increased frequency of ALF and death. These results indicate that this rapid semi-quantitative IC assay for HGF is useful for the early diagnosis of ALF and prediction of clinical outcome in acute hepatic injury. 相似文献
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《European journal of medical genetics》2017,60(8):426-432
BackgroundAcute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes.Methods and ResultsWe here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3–11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele.ConclusionThe multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency. 相似文献
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目的探讨骨髓间充质干细胞(bonemarrow mesenchymal stemcells,BMSC)-肝细胞共培养上清治疗大鼠急性肝衰竭(acute liver failure,ALF)的疗效,为其临床应用提供实验依据。方法分别利用肝细胞、BMSC、BMSC-肝细胞培养上清治疗腹腔注射D-氨基半乳糖胺(D-gal)诱导的大鼠ALF模型,观察各治疗组动物的l周存活率,肝功能和肝组织病理改变。结果肝细胞、BMSC及两者共培养上清治疗组大鼠存活率显著高于对照组(P〈0.01),其中共培养上清治疗组大鼠存活率最高达80%;各治疗组ALT、AST、TBIL较治疗前均显著降低(P〈0.01),共培养上清治疗组下降最明显;各治疗组肝脏病理组织学损害明显减轻,对照组损害加重。培论BMSC-肝细胞共培养上清能更有效的救治大鼠ALF模型,有望为ALF的治疗提供了新的治疗途径。 相似文献
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Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, activates the innate immunity system through a receptor complex of myeloid differentiation 2 (MD-2) and toll-like receptor 4 (TLR4). MD-2 directly recognizes the lipid A domain of LPS, which triggers MD-2/TLR4-mediated cellular response aimed at eliminating the invaded pathogen. However, excess production of inflammatory mediators is harmful to host tissue and this can cause septic death in extreme cases. MD-2 represents an attractive therapeutic target of inflammatory and immune diseases in human. In particular, eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site, and it ameliorates various inflammatory conditions due to infection or sterile organ injury. In this review, we outline the recent advances in the structure biology of ligand interaction with MD-2/TLR4, and highlight the MD-2-directed LPS antagonists, which are natural and synthetic chemicals, under development to treat inflammatory diseases. 相似文献
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Case studies covering carbonaceous nanomaterials, metal oxide and metal sulphate nanomaterials, amorphous silica and organic pigments were performed to assess the Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). The usefulness of the DF4nanoGrouping for nanomaterial hazard assessment was confirmed. In two tiers that rely exclusively on non-animal test methods followed by a third tier, if necessary, in which data from rat short-term inhalation studies are evaluated, nanomaterials are assigned to one of four main groups (MGs). The DF4nanoGrouping proved efficient in sorting out nanomaterials that could undergo hazard assessment without further testing. These are soluble nanomaterials (MG1) whose further hazard assessment should rely on read-across to the dissolved materials, high aspect-ratio nanomaterials (MG2) which could be assessed according to their potential fibre toxicity and passive nanomaterials (MG3) that only elicit effects under pulmonary overload conditions. Thereby, the DF4nanoGrouping allows identifying active nanomaterials (MG4) that merit in-depth investigations, and it provides a solid rationale for their sub-grouping to specify the further information needs. Finally, the evaluated case study materials may be used as source nanomaterials in future read-across applications. Overall, the DF4nanoGrouping is a hazard assessment strategy that strictly uses animals as a last resort. 相似文献