153 research outputs found
Human Kupffer cells recognition and phagocytosis of apoptotic peripheral blood lymphocytes.
No full textTargeting of naproxen covalently linked to HSA to sinusoidal cell types of the liver
No full textWe have coupled the anti-inflammatory drug naproxen (Nap) covalently to human serum albumin (HSA) to deliver this drug selectively to non parenchymal cell types of the liver during endotoxin induced hepatic inflammation. Liver endothelial cells and Kupffer cells play an important role in the pathogenesis of acute and chronic inflammatory liver diseases. Targeting Nap to these cells might increase the efficacy of this drug in the treatment of these diseases and reduce its side effects. During acute inflammation in male rats, induced by endotoxin, livers showed an increased uptake of Nap when coupled to HSA as compared to free Nap. 3 hours after administering 24 mg/kg Nap(23)-HSA 28% of the dose was found in the liver versus 1.1% of a therapeutic dose of 50 mg/kg Nap (pIn conclusion, during endotoxin induced inflammation the distribution of Nap as a Nap(23)-HSA conjugate to the liver is enhanced as compared to free Nap. Moreover, Nap liberated from the albumin carrier by proteolytic degradation exhibits a longer residence time in the liver, as compared to free Nap.</p
Targeting of naproxen covalently linked to HSA to sinusoidal cell types of the liver
No full textWe have coupled the anti-inflammatory drug naproxen (Nap) covalently to human serum albumin (HSA) to deliver this drug selectively to non parenchymal cell types of the liver during endotoxin induced hepatic inflammation. Liver endothelial cells and Kupffer cells play an important role in the pathogenesis of acute and chronic inflammatory liver diseases. Targeting Nap to these cells might increase the efficacy of this drug in the treatment of these diseases and reduce its side effects. During acute inflammation in male rats, induced by endotoxin, livers showed an increased uptake of Nap when coupled to HSA as compared to free Nap. 3 hours after administering 24 mg/kg Nap(23)-HSA 28% of the dose was found in the liver versus 1.1% of a therapeutic dose of 50 mg/kg Nap (pIn conclusion, during endotoxin induced inflammation the distribution of Nap as a Nap(23)-HSA conjugate to the liver is enhanced as compared to free Nap. Moreover, Nap liberated from the albumin carrier by proteolytic degradation exhibits a longer residence time in the liver, as compared to free Nap.</p
Targeting of naproxen covalently linked to HSA to sinusoidal cell types of the liver
No full textWe have coupled the anti-inflammatory drug naproxen (Nap) covalently to human serum albumin (HSA) to deliver this drug selectively to non parenchymal cell types of the liver during endotoxin induced hepatic inflammation. Liver endothelial cells and Kupffer cells play an important role in the pathogenesis of acute and chronic inflammatory liver diseases. Targeting Nap to these cells might increase the efficacy of this drug in the treatment of these diseases and reduce its side effects. During acute inflammation in male rats, induced by endotoxin, livers showed an increased uptake of Nap when coupled to HSA as compared to free Nap. 3 hours after administering 24 mg/kg Nap(23)-HSA 28% of the dose was found in the liver versus 1.1% of a therapeutic dose of 50 mg/kg Nap (pIn conclusion, during endotoxin induced inflammation the distribution of Nap as a Nap(23)-HSA conjugate to the liver is enhanced as compared to free Nap. Moreover, Nap liberated from the albumin carrier by proteolytic degradation exhibits a longer residence time in the liver, as compared to free Nap.</p
Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis
No full textGenetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa=0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. Conclusion: Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC
The role of activated hepatic stellate cells in capsule formation in hepatocellular carcinoma and colorectal metastases to the liver
No full textTumour encapsulation is associated with improved sur vival in patients with hepatocellular carcinoma (HCC), however the origin of the tumour capsule is unclear. This study examined the role of activated hepatic stellate cells (HSC) in tumour capsule formation in HCC
Targeting of liposomes to sinusoidal liver cells:Massive uptake by liver endothelial cells via a scavenger receptor mediated process
No full textHuman serum albumin (HSA) derivatized with cis-aconitic anhydride (Aco-HSA) was covalently coupled to liposomes (Aco-HSA-Lip). Aco-HSA-Lip were cleared from the blood and taken up by the liver within 30 minutes after injection into a rat. In the liver especially endothelial cells and to a lesser extent Kupffer cells were responsible for this uptake, which could be inhibited by preinjection with poly inosinic acid. Binding and competition experiments with cultured liver endothelial and Kupffer cells revealed that the uptake of Aco-HSA-Lip was mediated by scavenger receptors. Aco-HSA-Lip may prove to be useful drugcarriers for various liver or liver endothelium associated disorders.</p
Endotoxin detoxification by alkaline phosphatase in cholestatic livers
No full textIncreased expression of alkaline phosphatase (AP) in the liver is a hallmark of cholestasis but the pathophysiological role of this is not clear. We argue that deprotonation of carboxyl groups at the active site of the enzyme may be a prerequisite for optimal AP activity. Such a creation of negative charged groups can he achieved at high pH levels, but may also be directly provided by exposure of AP to polyanionic molecules. Endotoxin is a phosphorylated substance with multiple negatively charged residues. Phosphate groups determine many biological activities of this molecule. Therefore, we tested whether AP is able to dephosphorylate endotoxin at a physiological pH level. Phosphatase activity was histochemically studied in livers from normal and bile duct ligated rats as well as in the intestine. Enzyme activity was studied at pH 9.0 according to standard procedures and at pH 7.3 using endotoxin from E.coli as substrate. Furthermore the effect of AP upon the toxicity of endotoxin was assessed in vivo. In these studies, endotoxin preparations were administered intradermally to endotoxin sensitisized rats. Part of these preparations were pretreated with AP with or without the AP inhibitor levamisole (n=6 per group). Subsequently, the dermis was removed and neutrophil influx was measured.Our results show that hepatic and intestinal AP is endowed with endotoxin dephosphorylating activity at pH 7.4. Experiments also demonstrate that endotoxin pre-incubated with AP induced a much lower neutrophil influx as compared to endotoxin pre-incubated with vehicle (p <0.05). This effect was inhibitable by levamisole (p <0.025). Since cholestasis is associated with an increased delivery of endotoxin to the liver, endotoxin dephosphorylation may reflect an important function of this enzyme.</p
Targeting of liposomes to sinusoidal liver cells:Massive uptake by liver endothelial cells via a scavenger receptor mediated process
No full textHuman serum albumin (HSA) derivatized with cis-aconitic anhydride (Aco-HSA) was covalently coupled to liposomes (Aco-HSA-Lip). Aco-HSA-Lip were cleared from the blood and taken up by the liver within 30 minutes after injection into a rat. In the liver especially endothelial cells and to a lesser extent Kupffer cells were responsible for this uptake, which could be inhibited by preinjection with poly inosinic acid. Binding and competition experiments with cultured liver endothelial and Kupffer cells revealed that the uptake of Aco-HSA-Lip was mediated by scavenger receptors. Aco-HSA-Lip may prove to be useful drugcarriers for various liver or liver endothelium associated disorders.</p
Expression of iNOS during development of liver fibrosis in rats
No full textIncreased expression of the enzyme inducible Nitric Oxide Synthase (iNOS) has been observed in models of acute liver inflammation. Since in recent reports an influence of Nitric Oxide radicals (NO) on fibrosis was proposed, we studied the hepatic expression of iNOS after bile duct ligation, a model of chronic liver inflammation leading to fibrosis. Using a polyclonal antibody against iNOS, we investigated iNOS expression with Western blot analysis and immunohistochemical methods. Using Western Blot analysis, we demonstrated the induction of iNOS in the first and second week after ligation. Immunohistochemistry confirmed these results. One day after ligation of the bile duct, the inflammatory cells in the portal areas of the liver started to express iNOS. Four days after ligation, groups of hepatocytes became also iNOS positive. In addition, a typical pattern of MOS staining was found in these fibrotic livers. Cells around necrotic areas showed a clear expression and were identified as hepatocytes and inflammatory cells. After seven days the expression of iNOS gradually declined and virtually no staining was observed after two weeks. In conclusion, the enzyme iNOS is expressed in hepatocytes and inflammatory cells of bile duct ligated livers, especially in the early stage of fibrosis. In the later stages of the fibrotic process, when collagen accumulation increases, the expression of the enzyme disappeared.</p
- …
