Steatohepatitis induced by intragastric overfeeding in mice.

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice.

A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results.

In Part 1 of our work (1), four nanoparticles were synthesized specifically for the purpose of identifying design constraints to guide next generation gene delivery to the liver. The four nanoparticles are Gal-50 and Gal-140 (galactosylated 50 and 140 nm nanoparticles) and MeO-50 and MeO-140 (methoxy-terminated 50 and 140 nm nanoparticles). All four particles have the same surface charge, and Gal-50 and Gal-140 have the same surface galactose density (ca.

Microarray analysis of gene expression in the liver during the urinary ethanol cycle in rats fed ethanol intragastrically at a constant rate.

The regulation of gene expression in the liver of ethanol fed rats was studied using microarray analysis. The changes in gene expression were compared between pair-fed controls and rats fed ethanol intragastrically at a constant rate for 1 month. The rats fed ethanol were sacrificed at low and high urinary ethanol levels (UAL) during the UAL cycle in order to compare the effects of high and low blood alcohol levels (BAL).

T cell leukemia-1 modulates TCR signal strength and IFN-gamma levels through phosphatidylinositol 3-kinase and protein kinase C pathway activation.

A signaling role for T cell leukemia-1 (TCL1) during T cell development or in premalignant T cell expansions and mature T cell tumors is unknown. In this study, TCL1 is shown to regulate the growth and survival of peripheral T cells but not precursor thymocytes. Proliferation is increased by TCL1-induced lowering of the TCR threshold for CD4(+) and CD8(+) T cell activation through both PI3K-Akt and protein kinase C-MAPK-ERK signaling pathways.

Modifications in P62 occur due to proteasome inhibition in alcoholic liver disease.

P62 is capable of binding the polyubiquitin chain that targets proteins for degradation by the proteasome through its ubiquitin associated domain (UBA). Immunostaining of hepatocytes from human liver with alcoholic hepatitis showed colocalization of ubiquitin and P62 in Mallory bodies. Rats fed ethanol chronically and their controls showed that P62 is colocalized with the proteasome in hepatocytes as shown by confocal microscopy.

CYP2E1 inhibition enhances mallory body formation.

Mallory body (MB) formation is a complex phenomenon seen in chronic liver disease. CYP2E1 may play a role in preventing MB formation since it is involved in the elimination of toxic drugs and chemicals. When mice were fed with diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) for 10 weeks, Mallory bodies (MBs) developed in the liver at the end of this period.

The p105/50 NF-kappaB pathway is essential for Mallory body formation.

To determine if nuclear factor-kappaB (NF-kB) plays a role in Mallory body (MB) formation, quantitative real-time RT-PCR assay was used to measure liver NF-kappaB1/p105 mRNA levels in 4 different groups of mice. Group 1: mice given IP saline for 15 weeks; group 2: mice fed diethyl 1,4-dihydro-2,4,6,-trimethyl-3,5-pyridinedicarboxylate (DDC) for 10 weeks when MBs were formed; group3: mice fed DDC 10 weeks, then withdrawn 5 weeks when MBs disappeared; group 4: mice fed DDC 10 weeks, withdrawn 4 weeks, then fed DDC+chlormethiazole (CMZ) for 1 week when MBs again formed. The mRNA for p105 NF-kappaB expression was significantly increased in the livers of mice treated with DDC (group 2) and DDC+CMZ (group 4) compared with the control livers (group 1) as well as the drug-withdrawal livers (group 3).

The role of laminin-integrin signaling in triggering MB formation. An in vivo and in vitro study.

It is still unclear as to how hepatocytes perceive external factors and transduce the signals which initiate MB formation. To investigate this phenomenon, the model of MB formation in liver in vivo and in primary culture of hepatocytes derived from drug-primed mice was used. Control mice were fed the control diet (group 1).

The unique simultaneous occurrence of granular cell tumor, gastrointestinal stromal tumor, and gastric adenocarcinoma.

Granular cell tumors are generally benign oncocytoid lesions of schwannian origin that are often incidental findings in many locations. Gastrointestinal stromal tumors occur in older adults and express the c-Kit protein (CD117). Both of these tumors have been described in association with many other entities; however, they have never been reported to occur jointly.

A phagocytic cell line markedly improves survival of infected neutropenic mice.

Disseminated candidiasis is a frequent infection in neutropenic patients, in whom it causes 50% mortality, despite antifungal therapy. As the duration of neutropenia is the strongest predictor of survival in neutropenic patients with invasive fungal infections, neutrophil transfusions are a logical, therapeutic option. However, significant technical barriers have prevented the clinical use of neutrophil transfusions.

The effect of ethanol-induced CYP2E1 on proteasome activity: the role of 4-hydroxynonenal.

Previous studies have shown that the induction of P450 cytochrome 2E1 (CYP2E1) is associated with the loss of proteasomal activities. To correlate the loss of proteasomal activity with CYP2E1 induction, ethanol was fed intragastrically for 1, 3, 7, and 15 days. The maximum induction of CYP2E1 (3.

Animal models of alcoholic liver disease--focus on the intragastric feeding model.

The use of animal models has contributed to greater understanding of how alcoholic liver disease (ALD) develops, and of how the severity of liver injury is influenced by factors other than alcohol, such as nutrition, oxygen deprivation (as occurs with sleep apnea or smoking), and gene regulation. This article focuses on the use of one animal model in particular, the intragastric feeding model in rats. This model allows scientists to rigorously control an animal's consumption of both alcohol and dietary nutrients and is providing important information on the mechanisms of injury of alcoholic liver disease.

Fatal fat embolism following amphotericin B lipid complex injection.

A case of amphotericin B lipid complex induced fatal fat embolism is described. A 41-year-old Caucasian man with AIDS was undergoing treatment for cryptococcal meningitis with amphotericin B. His course was complicated by renal failure necessitating a change in therapy to amphotericin B lipid complex (Abelcet).

The effect of rotenone on the urinary ethanol cycle in rats fed ethanol intragastrically.

Chronic ethanol ingestion alters mitochondrial function in the liver including inhibition of complex I of the electron transport chain. This leads to a shift in the NAD/NADH ratio to the reduced state when blood ethanol levels are high. Rotenone also inhibits complex I and induces a reduced state.

Drug-induced increased mitochondrial biogenesis in a liver biopsy.

Oncocytic changes seen in hepatocytes in patients receiving highly active antiretroviral therapy (HAART) are a result of mitochondrial damage. This is the first report that provides the electron microscopy illustration of mitochondrial proliferation as a result of the HAART drug Stavudine (Zerit) hepatotoxicity. The drug's effect on mitochondrial DNA replication leads to depleted mitochondrial-encoded proteins and configurational defects of the mitochondrial inner membrane leading to reduced and abnormal cristae, which house the electron transport chain and elementary bodies.

Liver hypoxia and lack of recovery after reperfusion at high blood alcohol levels in the intragastric feeding model of alcohol liver disease.

The purpose of this study was to test for the presence of liver hypoxia and recovery after reperfusion when blood alcohol levels (BAL) are high. Male rats were fed ethanol intragastrically at a constant rate for 1 month. The pO(2) levels were then measured on the liver surface of these rats, in vivo during laparatomy under isoflurane anesthesia.

p62 is involved in the mechanism of Mallory body formation.

p62 is a scaffolding protein that binds to polyubiquitin. It is involved in the degradation of proteins by the proteasome. To determine if p62 is critical in the development of Mallory bodies (MBs), primary culture hepatocytes from drug-primed mice were studied and the results were compared with normal hepatocytes.

Catecholamines are involved in the mechanism of the urinary alcohol level cycle in rats fed ethanol intragastrically at a constant rate.

Studies have indicated that blood alcohol levels cycle exists when ethanol is fed continuously using the intragastric feeding rat model of early alcoholic liver disease. The aim of the present study was to determine the role played by catecholamines in the pathogenesis of the blood alcohol cycling observed when ethanol is fed at a constant rate. The rats were tested at the peaks and troughs of the urinary alcohol level (UAL) cycle and the results were compared with controls.

Costello syndrome with pancreatic islet cell hyperplasia.

A 3-month-old boy with Costello syndrome (CS) developed respiratory distress and fatal arrhythmias. An autopsy showed cardiac hypertrophy, mild coarctation of the aorta, and pancreatic islet cell hyperplasia. To our knowledge, this is the first report of a pancreatic abnormality in CS.

Melanocytic differentiation in a solid pseudopapillary tumor of the pancreas.

Solid pseudopapillary tumor of the pancreas (SPT) is an uncommon neoplasm of low malignant potential, generally occurring in young women. The tumor is indolent, usually with long survival, even in the presence of extension into adjacent organs and metastases. Pathological features include solid, cellular, and cystic regions and degenerative pseudopapillae formation.

The role of hypoxia in the pathogenesis of alcoholic liver disease.

Research on alcohol-induced liver hypoxia in experimental and clinical alcoholic liver disease (ALD) over a span of 20 years is reviewed. The data has repeatedly supported a role for hypoxia in the pathogenesis of ALD but little attention has been given to this phenomenon in a clinical setting where intervention strategies could be developed. Liver hypoxia, particularly when blood alcohol levels are high, has been documented in vivo in rats fed ethanol continuously at a constant rate for prolonged periods.

Hyperphosphorylation of rat liver proteasome subunits: the effects of ethanol and okadaic acid are compared.

In experimental alcoholic liver disease, protein degradation by the ATP-ubiquitin-proteasome pathway is inhibited. Failure of the proteasome to eliminate cytoplasmic proteins leads to the accumulation of oxidized and otherwise modified proteins. One possible explanation for the inhibition of the proteasome is hyperphosphorylation of proteasome subunits.

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A.

Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma.