Search results for "cholestasis"
showing 10 items of 71 documents
Fluorescent benzofurazan-cholic acid conjugates for in vitro assessment of bile acid uptake and its modulation by drugs.
2009
One of the most common mechanisms of hepatotoxicity is drug-induced cholestasis. Hence, new approaches for screening the cholestatic potential of drug candidates are desirable. In this context, we describe herein the use of synthetic 4-nitrobenzo-2-oxa-1,3-diazole (NBD) fluorescent conjugates of cholic acid (ChA) at positions 3alpha, 3beta, 7alpha, and 7beta for in vitro assessment of bile acid uptake. All the conjugates show a strong absorption band between 400 and 550 nm and have a fluorescence quantum yield of approximately 0.45, with an emission maximum centered at approximately 530 nm. After their photophysical characterization, 3alpha-, 3beta-, 7alpha-, and 7beta-NBD-ChA were used to …
Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions
2011
Chronic cholestasis is characterizedby mitochondrial dysfunction, associated with loss of mitochondrialmembrane potential, decreased activities of respiratory chaincomplexes, and ATP production. Our aim was to determine themolecular mechanisms that link long-term cholestasis to mitochondrialdysfunction. We studied a model of chronic cholestasis inducedby bile duct ligation in rats. Key sensors and regulators of theenergetic state and mitochondrial biogenesis, mitochondrial DNA(mtDNA)-to-nuclear DNA (nDNA) ratio (mtDNA/nDNA) relativecopy number, mtDNA deletions, and indexes of apoptosis (BAX,BCL-2, and cleaved caspase 3) and cell proliferation (PCNA) wereevaluated. Our results show that long…
A Model‐Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs
2021
We present a generic workflow combining physiology-based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology-based bile acid model of glycochenodeoxycholic acid. The simulated drug-induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholest…
Liver failure caused by light chain deposition disease associated with multiple myeloma.
2012
Acute liver failure is an unusual complication in multiple myeloma. Here, we report a case of multiple myeloma with light chain deposition disease (LCDD) that presented with progressive jaundice due to intrahepatic cholestasis. Diagnosis was made after liver biopsy that showed deposition of kappa light chains occupying perisinusoidal spaces. The patient developed encephalopathy and liver failure and died despite prompt initiation of dexamethasone therapy. The current prognosis of multiple myeloma patients with liver failure due to LCDD is dismal. New therapeutic strategies might improve this condition.
TIMP expression in toxic and cholestatic liver injury in rat.
1997
Abstract Background/Aims: Hepatic fibrosis is a dynamic pathological process with a net accumulation of extracellular matrix proteins. Recent evidence suggests that besides their increased synthesis, inhibition of matrix degradation plays a significant role. ECM degradation occurs via metalloproteinases which are inhibited in situ by specific tissue inhibitors of metalloproteinases (TIMPs). The aim of our studies was to determine the expression of TIMPs during toxic liver injury and cholestatic liver injury leading to fibrosis. Methods: We examined the expression of TIMP-1, -2 and -3 in two different rat models for liver injury (intraperitoneal CCl 4 injection and bile duct ligation) by Nor…
Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis
2002
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology. Although the primary defect affects cholangiocytes, cholestatic injury of hepatocytes may promote further liver damage. Since down-regulation of hepatocellular organic anion transporters is implicated in the molecular pathogenesis of cholestasis, expression of these transporters was determined in a novel rat model, which closely resembles human PSC.Hepatic protein and mRNA expression of basolateral (Ntcp, Oatp1, 2 and 4) and canalicular (Mrp2, Bsep) organic anion transporters were analyzed 1, 4 and 12 weeks after induction of experimental PSC by 2,4,6-trinitrobenzenesulfonic acid (TNBS).Specific down-re…
Disease and patient characteristics in NP-C patients: findings from an international disease registry.
2013
Abstract Background Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterized by progressive neurodegeneration and premature death. We report data recorded at enrolment in an ongoing international NP-C registry initiated in September 2009 to describe disease natural history, clinical course and treatment experience of NP-C patients in clinical practice settings. Methods The NPC Registry is a prospective observational cohort study. Participating sites are encouraged to evaluate all consecutive patients with a confirmed diagnosis of NP-C, regardless of their treatment status. All patients undergo clinical assessments and medical care as determined by their physicians. D…
Recent insights into the relationship between inflammatory liver diseases and atherosclerosis.
2011
Atherosclerosis is a dynamic process in the human body. Many studies have evaluated atherosclerosis and its relationship with other systems in the body. Our perception of its pathogenesis is evolving with the introduction of new players in the game. It is no longer possible to consider the atherosclerosis as an independent process, unaffected by the liver and its function. Although several tasks performed by the liver, such as lipid metabolism, have been implicated in the pathogenesis of atherosclerosis, the role of other disorders of the liver (autoimmune diseases, viral hepatitis, and cirrhosis) are not fully understood. In this review, the most commonly encountered inflammatory liver di…
Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways.
2021
Treatment of β-lactamase positive bacterial infections with a combination of amoxicillin (AMOX) and clavulanic acid (CLAV) causes idiosyncratic drug-induced liver injury (iDILI) in a relevant number of patients, often with features of intrahepatic cholestasis. This study aims to determine serum bile acid (BA) levels in amoxicillin/clavulanate (A + C)-iDILI patients and to investigate the mechanism of cholestasis by A + C in human in vitro hepatic models. In six A + C-iDILI patients, significant elevations of serum primary conjugated BA definitely demonstrated A + C-induced cholestasis. In cultured human Upcyte hepatocytes and HepG2 cells, CLAV was more cytotoxic than AMOX, and, at subcytoto…
Liver-specific p38α deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice
2012
p38α mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor β, tumor necrosis factor-α, interleukin-1β, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38α-deficient cells. Our aim was to assess the role of p38α in the progression of biliary cirrhosis induced by chronic cholestasis as an experimental model of chronic inflammation associated with hepatocyte proliferation, apoptosis, oxidative stress, and fibrogenesis. Cholestasis was induced in wildtype and liver-specific p38α knockout mice by…