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L Sclafani P Shimm J Edelman E Seifter S M Levenson A A Demetriou 《JPEN. Journal of parenteral and enteral nutrition》1986,10(2):184-187
We have previously shown that supplemental vitamin E has a cytoprotective effect in the liver of rats with chronic CCL4-induced liver cirrhosis. In this study, we hypothesized that vitamin E would have a protective effect in acute liver injury induced by D-galactosamine. D-Galactosamine-induced injury has been thought to be due to a synergistic direct toxic effect and presence of intestinal bacteria and/or endotoxins. D-Galactosamine was used to induce acute "hepatitis" (1.5-2.0 g/Kg body weight, ip). Rats were placed on either standard chow or the same chow supplemented with vitamin E (300 mg DL-alpha-tocopherol/Kg diet) and 6 days later were given D-galactosamine. There was significantly improved early (5-day) survival and late (14-day) survival in the vitamin E-supplemented group. The vitamin E beneficial effect was manifested also by decreased liver fat and collagen content and decreased SGPT level. Because bacterial endotoxins have been implicated as playing a role in the pathogenesis of D-galactosamine hepatitis, the same experiment was carried out using germ-free and conventional rats. There was significantly improved survival in both the germ-free and conventional vitamin E-supplemented groups both at 5 and 14 days. There was no significant difference between conventional and germ-free rats with or without vitamin E supplementation. In summary (a) vitamin E improves the early fat and collagen accumulation in the liver, decreases SGPT level, and improves survival in the D-galactosamine experimental model of acute liver injury in both conventional and germ-free rats; and (b) D-galactosamine toxicity is probably not mediated through intestinal bacteria and/or endotoxins. 相似文献
3.
Detry O Arkadopoulos N Ting P Kahaku E Margulies J Arnaout W Colquhoun SD Rozga J Demetriou AA 《Transplantation》1999,67(5):767-770
During orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF), some patients develop cerebral injury secondary to intracranial hypertension. We monitored intracranial pressure (ICP) and cerebral perfusion pressure (CPP) before and during OLT in 12 FHF patients undergoing transplantation. All four patients who had normal ICP preoperatively maintained normal ICP/CPP throughout OLT. During OLT, four of the eight patients with pretransplant intracranial hypertension had six episodes of ICP increase. These episodes of intracranial hypertension occurred during failing liver dissection (n=3) and graft reperfusion (n=3). At the end of the anhepatic phase, the ICP was lower than the preoperative ICP in all patients, and was below 15 mmHg in all but one patient. These data suggest that in FHF patients who develop intracranial hypertension before OLT, dissection of the native liver and graft reperfusion are associated with a risk of brain injury resulting from intracranial hypertension and cerebral hypoperfusion. 相似文献
4.
Huang ZM Chinen M Chang PJ Xie T Zhong L Demetriou S Patel MP Scherzer R Sviderskaya EV Bennett DC Millhauser GL Oh DH Cleaver JE Wei ML 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(2):553-558
Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents. 相似文献
5.
Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Polycystic kidney disease (ADPKD) is a condition with an autosomal dominant mode of inheritance and adult onset. Two forms of the disease, ADPKD1 and ADPKD2, caused by mutations in PKD1 and PKD2, respectively, are very similar, except that ADPKD1 patients run a more severe course. At the cellular level, ADPKD1 was first shown to be recessive, since somatic second hits are perhaps necessary for cyst formation. The near identical phenotype had suggested that ADPKD1 and ADPKD2 might have a similar pathogenesis and that the two gene products, poly- cystins 1 and 2, are part of a common developmental pathway. Work in transgenic mice showed that somatic loss of Pkd2 expression is necessary for renal cyst formation, and recently we showed that somatic mutations inactivating the inherited healthy allele were present in 9 of 23 cysts from a human ADPKD2 kidney, supporting a two-hit loss-of-function model for ADPKD2 cystogenesis. Here, we provide the first direct genetic evidence that polycystins 1 and 2 do interact, perhaps as part of a larger complex. In cystic DNA from a kidney of an ADPKD1 patient, we showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a trans -heterozygous state with mutations in both genes. One mutation in PKD1 is of germinal nature and the mutation in the PKD2 gene is of somatic nature. The implications of such a situation are enormous, not only for ADPKD, but also for many other conditions with phenotypic heterogeneity and age-dependent penetrance. 相似文献
6.
Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure. 总被引:15,自引:0,他引:15
O Detry N Arkadopoulos P Ting E Kahaku F D Watanabe J Rozga A A Demetriou 《The American surgeon》1999,65(10):934-938
Patients with acetaminophen-induced fulminant hepatic failure (FHF) who meet the King's College Hospital criteria have a high mortality risk (>90%) if they do not undergo liver transplantation. We have developed a treatment strategy for these patients based on the use of an extracorporeal bioartificial liver (BAL) support system. In this study, we report the results of the clinical application of BAL support in patients with acetaminophen-induced FHF. All patients were admitted to a dedicated surgical intensive care unit. They were evaluated for urgent liver transplantation and received the standard medical measures, including N-acetylcysteine administration and intracranial pressure monitoring. Moreover, they underwent daily 6-hour BAL treatments. Eight patients were treated. Three patients were bridged to liver transplantation, and five patients recovered without a transplant. All patients experienced neurological and metabolic improvement after treatments with the BAL support system. The BAL support system seems to improve the outcome of high-risk patients with acetaminophen-induced FHF, even in the absence of liver transplantation. Avoiding liver transplantation is particularly important in an era of organ shortage and high cost of transplants. 相似文献
7.
Immediate early genes and p21 regulation in liver of rats with acute hepatic failure 总被引:10,自引:0,他引:10
Hui TT Mizuguchi T Sugiyama N Avital I Rozga J Demetriou AA 《American journal of surgery》2002,183(4):457-463
It has been observed that liver regeneration in acute hepatic failure (AHF) is suppressed [Eguchi et al. Hepatology 1996;24(6):1452-9]. The molecular mechanism regulating this inhibition is not known. We previously reported that in AHF rats, hepatocyte proliferation was significantly impaired with elevation in serum IL-6, TGF-beta1, and HGF [Kamohara et al. Biochem Biophys Res Commun 2000;273(1):129-35]. Following either 70% partial hepatectomy (PH) or liver injury, quiescent mature hepatocytes are "primed" to re-enter the cell cycle. The process of "priming" appears to be triggered by extracellular cytokines (IL-6 and TNF-alpha) and is characterized by expression of immediate early genes. Under the stimulation of growth factors such as HGF, "primed" hepatocytes exit the G1 phase of the cell cycle. G1-associated cyclins and their inhibitors play a pivotal role in G1/S cell cycle transition. Here, we demonstrate that immediate early gene (i.e. c-myc, c-fos) expression and AP-1 activity are preserved in AHF rat livers despite absence of hepatocyte proliferation. In contrast, p21 mRNA and protein are both over-expressed in AHF livers compared to livers from rats undergoing PH; this elevation leads to inhibition in Cdk2 activity, resulting in G1 cell cycle arrest and inhibition of regeneration. 相似文献
8.
During and after transplantation the kidney experiences a variety of insults that result in functional impairment and structural damage. These changes are mediated or influenced by hormones, cytokines, enzymes and growth factors, which are excreted by endothelial, graft parenchymal as well as by graft infiltrating cells. This review evaluates the pathophysiological role of vasoactive substances (for example, the vasoconstrictors angiotensin II and endothelin, as well as vasodilators such as nitric oxide, adrenomedullin and atrial natriuretic peptide) in kidney transplantation and summarizes recent reports that indicate that targeting vasoactive substances may represent effective therapeutic strategies for the achievement of long-term allograft survival. 相似文献
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