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Ali Canbay

Publications and source records attributed to Ali Canbay.

17 recordsLinked to original sources
PubMed2006

[Specific therapy in acute liver failure].

Acute liver failure is defined as hepatic insufficiency (icterus and coagulopathy), hepatorenal syndrome and encephalopathy, associated with a high mortality. A number of conditions can cause this sudden severe liver failure, which finally triggers a multi-organ response. Its etiology shows considerable geographic variation, with viral hepatitis being the most common cause worldwide, whilst drugs, especially acetaminophen-induced hepatotoxicity, form the most common precipitant in many developed countries. The essential feature of a wide variety of agents is apoptosis and/or necrosis of liver cells which is associated with liver injury and insufficiency. Based on new experimental data, the identification of target molecules involved in apoptosis may offer new therapeutic options and improvement of prognosis scores in patients with acute liver failure.

Animals↗
PubMed2006

Changes in the expression of plasma membrane calcium extrusion systems during the maturation of hippocampal neurons.

Spatial and temporal control of intracellular calcium signaling is essential for neuronal development and function. The termination of local Ca2+ signaling and the maintenance of basal Ca2+ levels require specific extrusion systems in the plasma membrane. In rat hippocampal neurons (HNs) developing in vitro, transcripts for all isoforms of the plasma membrane Ca2+ pump and the Na/Ca2+ exchanger, and the major nonphotoreceptor Na+/Ca2+,K+ exchangers (NCKX) were strongly upregulated during the second week in culture. Upregulation of plasma membrane calcium ATPases (PMCAs)1, 3, and 4 mRNA coincided with a splice shift from the ubiquitous b-type to the neuron-specific a-type with altered calmodulin regulation. Expression of all PMCA isoforms increased over 5-fold during the first 2 weeks. PMCA immunoreactivity was initially concentrated in the soma and growth cones of developing HNs. As the cells matured, PMCAs concentrated in the dendritic membrane and often colocalized with actin-rich dendritic spines in mature neurons. In the developing rat hippocampal CA1 region, immunohistochemistry confirmed the upregulation of all PMCAs and showed that by the end of the second postnatal week, PMCAs1, 2, and 3 were concentrated in the neuropil, with less intense staining of cell bodies in the pyramidal layer. PMCA4 staining was restricted to a few cells showing intense labeling of the cell periphery and neurites. These results establish that all major Ca2+ extrusion systems are strongly upregulated in HNs during the first 2 weeks of postnatal development. The overall increase in Ca2+ extrusion systems is accompanied by changes in the expression and cellular localization of different isoforms of the Ca2+ pumps and exchangers. The accumulation of PMCAs in dendrites and dendritic spines coincides with the functional maturation in these neurons, suggesting the importance of the proper spatial organization of Ca2+ extrusion systems for synaptic function and development.

Alternative Splicing↗
PubMed2006

Non-alcoholic fatty liver disease in HIV-positive patients predisposes for acute-on-chronic liver failure: two cases.

Non-alcoholic fatty liver disease is a prominent feature in HIV-positive patients. We present two patients with long-lasting HIV-infection who suffered from this disease, as induced by highly active anti-retroviral therapy (HAART). The patients developed acute-on-chronic (AOC) liver failure after either (case 1) acute infection with hepatitis A virus (HAV) or (case 2) methamphetamine abuse ('Ecstasy'). Approximately 1 week after visiting an area endemic for HAV, case 1, a male patient, presented with icterus, elevated liver transaminases and HAV IgM. Previous examinations had demonstrated normal liver transaminase activities while hepatic steatosis had been suspected. He developed complications associated with liver failure including renal failure as well as pleural and pericardial effusions. Case 2, a second male patient, developed both liver failure and lactic acidosis 24 h after methamphetamine abuse. Both patients suffered from fatty liver in the pre-acute stage as indicated by ultrasound examination. After developing symptoms of liver failure, HAART was discontinued in both patients. Follow-up visits demonstrated that the patients recovered clinically with almost normalized laboratory parameters. In HIV infection, HAART-induced hepatopathological alterations may exist despite the absence of relevant laboratory parameters. These patients are likely to develop AOC liver failure when subjected to acute risk factors such as hepatitis viruses and narcotics or other drugs. In patients treated with HAART, we thus highly recommend hepatitis A and B virus vaccinations, and close monitoring of liver parameters.

Acute Disease↗
PubMed2005

Apoptosis and fibrosis in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease is becoming an increasingly common medical problem in the developed countries which, unfortunately, still is associated with the lack of any effective treatment. However, recent data favor a model in which a pathologically increased rate of hepatocytic apoptosis and the subsequent induction and upregulation of inflammation and fibrosis in the liver provide both a rationale for the pathogenesis of nonalcoholic fatty liver disease, as well as a clue for designing first effective therapeutic strategies. In order to illuminate this context, this article focuses on the pathogenesis and possible new therapeutic options in nonalcoholic fatty liver disease.

Animals↗
PubMed2004

Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.

Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to examine the cellular mechanisms involved in free fatty acid (FFA)-mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor kappa B-dependent tumor necrosis factor alpha expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated "dysmetabolic syndrome." In conclusion, these data support a lipotoxic model of FFA-mediated lysosomal destabilization.

Animals↗
PubMed2003

The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse.

Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for alpha-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-beta and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by alpha-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.

Animals↗
PubMed2003

Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1.

Bile acids up-regulate death receptor 5 (DR5)/TRAIL-receptor 2 (TRAIL-R2) expression thereby sensitizing hepatocytes to TRAIL-mediated apoptosis. However, the precise mechanism by which bile acids enhance DR5/TRAIL-R2 expression is unknown. Although several bile acids enhanced DR5/TRAIL-R2 expression, deoxycholic acid (DCA) was the most potent. DCA stimulated JNK activation and the JNK inhibitor SP600125 blocked DCA-induced DR5/TRAIL-R2 mRNA and protein expression. Reporter gene analysis identified a 5'-flanking region containing two Sp1 binding sites within the DR5/TRAIL-R2 promoter as bile acid responsive. Sp1 binding to one of the two sites was enhanced by DCA treatment as evaluated by electrophoretic mobility shift assays and chromatin immunoprecipitation studies. JNK inhibition with SP600125 also blocked binding of Sp1 to the DR5/TRAIL-R2 promoter. Finally, point mutations of the Sp1 binding site attenuated promoter activity. In conclusion, Sp1 is a bile acid-responsive transcription factor that mediates DR5/TRAIL-R2 gene expression downstream of JNK.

Anthracenes↗
PubMed2003

Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.

BACKGROUND & AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction. METHODS: Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis. RESULTS: TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls. CONCLUSIONS: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.

Adult↗
PubMed2003

Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice.

BACKGROUND/AIMS: Hepatic steatosis sensitizes the liver to injury and inflammation by unclear mechanisms. Because Fas has been linked to liver injury and inflammation, Fas expression and sensitization to Fas signaling was examined in models of hepatic steatosis. METHODS: Mice were fed a carbohydrate diet while control animals received standard chow. Sensitization to Fas was examined following administration of Jo2 antibody. For the in vitro experiments, HepG2 cells were incubated with or without a mixture of long chain fatty acids (2:1 oleate:palmitate). Sensitization of the cells to Fas was examined using the CH11 antibody. RESULTS: Mice fed a high caloric diet developed hepatic steatosis, hyperlipidemia, insulin resistance, and hyperleptinemia, all features of the human syndrome. Fas expression in hepatocytes was increased as compared to lean animals and was coupled to cytotoxic signaling. Indeed, hepatocyte apoptosis, liver injury and chemokine generation were all accentuated in obese animals following administration of Jo-2, a Fas agonist. Hep G2 cells cultured in the presence of free fatty acids also developed 'cellular steatosis', upregulated Fas expression and were more sensitive to apoptosis by a Fas agonist. CONCLUSIONS: Collectively, these data implicate Fas as a link between obesity associated fatty liver and increased susceptibility to liver damage.

Animals↗
PubMed2003

Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.

Hepatocyte apoptosis by death receptors, hepatic inflammation, and fibrosis are prominent features of liver diseases. However, the link between these processes remains unclear. Our aim was to ascertain whether engulfment of apoptotic bodies by Kupffer cells promotes hepatic inflammation and fibrosis. Isolated murine Kupffer cells efficiently engulfed apoptotic bodies generated from UV-treated mouse hepatocytes. Engulfment of the apoptotic bodies, but not latex beads, stimulated Kupffer cell generation of death ligands, including Fas ligand, and tumor necrosis factor alpha (TNF-alpha). Both apoptotic body phagocytosis and death ligand generation were attenuated by gadolinium chloride, a Kupffer cell toxicant. Kupffer cells isolated from 3-day bile duct-ligated (BDL) mice were phenotypically similar to apoptotic body-"fed" Kupffer cells with enhanced death ligand expression; inhibition of hepatocyte apoptosis with a caspase inhibitor prevented this Kupffer cell activation. Consistent with a role for Kupffer cells in liver inflammation and fibrosis, gadolinium chloride attenuated neutrophil infiltration and markers for stellate cell activation. In conclusion, these findings support a model of cholestatic liver injury where Kupffer cell engulfment of apoptotic bodies promotes inflammation and fibrogenesis.

Animals↗
PubMed2003

Apoptotic body engulfment by a human stellate cell line is profibrogenic.

Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-beta (TGF-beta), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in alpha-smooth muscle actin (primary cells), TGF-beta1, and collagen alpha1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-beta1 and collagen alpha1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen alpha1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway.

Apoptosis↗
PubMed2003

Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis.

Although a lysosomal, cathepsin B-dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb-/- versus Ctsb+/+ animals. Likewise, R-3032 (a Ctsb inhibitor) also reduced these parameters in BDL WT mice. Both genetic and pharmacologic inhibition of Ctsb in the BDL mouse reduced (a). hepatic inflammation, as assessed by transcripts for CXC chemokines and neutrophil infiltration, and (b). fibrogenesis, as assessed by transcripts for stellate cell activation and sirius red staining for hepatic collagen deposition. These differences could not be ascribed to alterations in cholestasis. These findings support a prominent role for the lysosomal pathway of apoptosis in tissue injury and link apoptosis to inflammation and fibrogenesis. Ctsb inhibition may be therapeutic in liver diseases.

Alanine Transaminase↗
PubMed2002

Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.

BACKGROUND & AIMS: Hepatocyte apoptosis and fibrosis are both features of liver injury. However, the potential mechanistic link between these 2 processes remains obscure. Our aim was to ascertain if Fas-mediated hepatocyte apoptosis promotes liver fibrogenesis during extrahepatic cholestasis. METHODS: Wild-type and Fas-deficient lymphoproliferation (lpr) mice underwent bile duct ligation. Liver injury was assessed by quantitating hepatocyte apoptosis with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and determining serum ALT values. mRNA expression was quantitated using real-time polymerase chain reaction technology. Liver fibrosis was assessed by digital image analysis of Sirius red-stained sections. RESULTS: In 3-day bile duct ligated (BDL) animals, TUNEL-positive hepatocytes and serum ALT values were reduced in lpr versus wild-type animals. Likewise, hepatic mRNA transcripts for alpha-smooth muscle actin and platelet-derived growth factor receptor-beta (initiation phase of stellate cell activation) and transforming growth factor beta1 mRNA, collagen 1alpha, and tissue inhibitor of matrix metalloproteinases (perpetuation phase of stellate cell activation) were also reduced in 3-day BDL wild-type mice compared with lpr mice. Finally, in 3-week BDL mice, immunoreactivity for alpha-smooth muscle actin and Sirius red staining for collagen were significantly less in lpr compared with wild-type animals. CONCLUSION: Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. These observations suggest that inhibition of Fas-mediated apoptosis may be a therapeutic antifibrogenic strategy in cholestatic liver diseases.

Actins↗
PubMed2002

Cholestasis increases tumor necrosis factor-related apoptotis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes the liver to TRAIL-mediated cytotoxicity.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potential chemotherapeutic agent for cancer, is not thought to be hepatotoxic. We have recently demonstrated, however, that bile acids increase TRAIL-R2/DR5 expression in a human liver cell line and render these cells susceptible to TRAIL-mediated apoptosis. These data suggest TRAIL may be hepatotoxic in cholestasis. The aim of this study was to directly assess TRAIL hepatotoxicity in bile duct-ligated mice, a model of extrahepatic cholestasis. Bile duct-ligated mice (3 days) were used for these studies. TRAIL-R2/DR5 expression was assessed by real-time and immunoblot analysis. The TRAIL death-inducing signaling complex (DISC) was evaluated by immunoprecipitation and immunoblot techniques. Bile duct ligation increased both liver TRAIL-R2/DR5 mRNA and protein expression (>10-fold). Following TRAIL administration (60 microg/mouse, i.v.) to bile duct ligation (BDL) mice, terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive hepatocytes, liver tissue caspase 3-like activity, and serum alanine aminotransferase values increased significantly compared with vehicle-treated BDL mice. The effect of TRAIL on the liver was direct, as the TRAIL DISC (Fas-associated death domain and procaspase 8 protein) was detected in liver tissue. TRAIL-mediated hepatocyte apoptosis in bile duct-ligated mice was associated with significant hepatotoxicity, as assessed by histopathology, although there was no animal mortality. In conclusion, these data define conditions under which TRAIL is hepatotoxic.

Alanine Transaminase↗
PubMedDate not supplied

Serum C3 complement concentrations correlate with liver function in patients with liver cirrhosis.

BACKGROUND/AIMS: The aim of this study was to investigate whether C3 and C4 serum complement concentrations have prognostic relevance for patients with liver cirrhosis. METHODOLOGY: Serum complement concentrations of C3 and C4 were measured in 69 patients with liver cirrhosis and correlated with the Child-Pugh score. RESULTS: C3 concentrations were 1.06+/-0.21 g/L in patients with Child-Pugh A liver cirrhosis and significantly lower in Child-Pugh B (0.78+/-0.24 g/L) and even lower Child-Pugh C (0.49+/-0.14 g/L) (p=0.006 B vs. A, p<0.001 C vs. B). Patients with consecutive hepatorenal syndrome (HRS) had the lowest C3 concentrations (0.44+/-0.05 g/L (Child-Pugh C +HRS) vs. 0.54+/-0.06g/dL (Child-Pugh C -HRS); p<0.05). C4 concentrations were 0.21+/-0.08 in Child-Pugh A and significantly lower in Child-Pugh B (0.11+/-0.04) and Child-Pugh C (0.09+/-0.04) patients (p<0.001). There was a negative correlation between C3 (r = -0.81, p<0.001) and C4 (r = -0.51, p<0.05) concentrations and the Child-Pugh score. CONCLUSIONS: Serum complement concentrations of C3 and C4 correlate negatively with the Child-Pugh score in patients with liver cirrhosis. C3 concentrations are lower in those Child-Pugh C cirrhosis patients with consecutive development of HRS.

Bacterial Infections↗
PubMedDate not supplied

Overweight patients are more susceptible for acute liver failure.

BACKGROUND/AIMS: To determine a potential correlation of gender, age, and/or body mass index (BMI) with the development of acute-on-chronic liver failure (AOC). METHODOLOGY: A retrospective 2.5-year study employed 34 patients (65% females and 35% males, aged 37.9 +/- 12.6 years) fulfilling established criteria for acute liver failure (ALF). Patients were subdivided into ALF (n = 18) and AOC (n = 16) groups, according to a history of prior chronic liver disease. Causes of liver failure included drug toxicity (52.9%), viral hepatitis (26.5%), and acute excessive ethanol abuse (11.8%). all anamneses were thoroughly reviewed. Throughout the course of the study, the patients were monitored for established clinical signs and laboratory parameters indicating acute liver injury. Gender, age, and BMI were correlated with the clinical outcome. RESULTS: Twelve patients (35.3%) received an orthotopic liver allograft, with one re-transplantation. Six patients (17.6%), including two transplanted individuals, died in the course of the study. Of all parameters evaluated, BMIs were significantly higher in AOC vs. ALF (p < 0.002), revealing values of > 25 in 62.5% of the AOC patients. When subjected to acute risk factors, elevated BMI clearly coincided with a higher rate of AOC. Importantly, half of all patients initially classified as ALF by employing current criteria thus suffered from AOC coinciding with increased mortality. CONCLUSIONS: Generally, these results call for a reduction of the BMI. Specifically, our findings argue for a closer BMI monitoring of patients at risk of developing chronic liver disease.

Adult↗