Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of dietary oligosaccharides on the hepatotoxic action of D-galactosamine (GalN) were investigated in this study. Male Wistar rats fed with 20% casein diets containing 10% oligosaccharide or D-galactose (Gal) for 2 weeks were injected with GalN (1,900 mg/kg of body weight), and the plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the hepatic glycogen concentration were examined 20 hours after the injection. The plasma AST and ALT activities in experiment 1 for the Gal + neomycin (NEO) group were significantly lower than those for the control (C), NEO, raffinose (RAF) + NEO and galacto-oligosaccharide (GA-LO) + NEO groups. In experiment 2, these activities were significantly lower in the Gal, Gal + NEO and RAF groups than in the RAF + NEO group when the groups were treated with GalN. On the other hand, in respect of the hepatic glycogen concentration in experiment 1, that of the Gal + NEO group was higher than that of the C, NEO, RAF + NEO or GALO + NEO groups. In experiment 2, this parameter was significantly higher in the Gal, Gal + NEO and RAF groups than in the RAF + NEO group after the GalN treatment. As a result, it is suggested that the GalN-hepatitis-suppressive effects of indigestible oligosaccharides such as RAF or GALO is mediated by the action of intestinal bacteria.
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PMID:Effect of indigestible oligosaccharides on the hepatotoxic action of D-galactosamine in rats. 975 56

Out of a prospective series of 142 consecutive episodes of hypoxic (ischemic) hepatitis (HH), we identified 17 episodes associated with an acute exacerbation of chronic respiratory failure (CRF) without left cardiac failure. In the aim to evaluate the role of arterial hypoxemia in the pathogenesis of HH associated with respiratory failure, these 17 episodes of HH (study group) were hemodynamically compared with a control group of 17 episodes of HH associated with congestive heart failure (CHF) (control group 1) and a group of 16 episodes of acute respiratory failure (ARF) not complicated by HH (control group 2). Arterial hypoxemia was significantly more severe in the study group (arterial blood tension in O2 [PaO2], 34 mm Hg) than in control group 1 (PaO2, 70 mm Hg; P <.0001) and control group 2 (PaO2, 45.5 mm Hg; P =.002). The role of arterial hypoxemia, however, appeared weakened by comparable degrees of systemic hypotension and liver passive congestion in episodes of HH associated with CRF and episodes of HH associated with CHF. Finally, the causative role of arterial hypoxemia emerged from hemodynamic measurements of cardiac index (CI), systemic vascular resistances (SVR), and oxygen transport: systemic hypotension in HH associated with CHF (control group 1) was the result of a fall in CI (median, 2. 33 L/min. m2; range, 1.21-3.14 L/min. m2) associated with high SVR (median, 2,492 dyn. s/cm5. m2; range, 1,382-4,053 dyn. s/cm5. m2), whereas in HH associated with respiratory failure (study group), systemic hypotension was the result of a fall in SVR (median, 1,053 dyn. s/cm5. m2; range, 646-3,148 dyn. s/cm5. m2), resulting in high CI (median, 4.23 L/min. m2; range, 1.9-5.32 L/min. m2) (P =.0087 and. 0038 for cardiac index and SVR, respectively). Moreover, measurements of oxygen transport in patients with HH associated with respiratory failure showed low values of O2 delivery (DO2) (median, 376 mL/min. m2; range, 253-427 mL/min. m2) as a result of extreme arterial hypoxemia despite high CI. In conclusion, these hemodynamic results and additional measurements of hepatic blood flow (HBF) by the method of galactose clearance at a low concentration suggest that in the setting of HH associated with respiratory failure, the liver is not "ischemic," despite hypotension, but rather "hypoxic" as a result of the combination of severe arterial hypoxemia and elevated central venous pressure (CVP).
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PMID:Hypoxic hepatitis caused by acute exacerbation of chronic respiratory failure: a case-controlled, hemodynamic study of 17 consecutive cases. 991 19

Gut-derived lipopolysaccharide (LPS) may contribute to hepatocellular necrosis in alcoholic hepatitis through neutrophil sequestration in hepatic sinusoids. It is well known that the female has a greater susceptibility to alcoholic liver injury than the male. The aim of the present study was to investigate the effect of long-term ethanol consumption on ability of the liver to produce cytokine-induced neutrophil chemoattractant-1 (CINC-1), the most potent neutrophil-chemokine in rats, after LPS administration. Furthermore, we aimed to evaluate the gender difference in this ability. Male and female rats were pair-fed a liquid diet containing 36% of the total calories as ethanol or dextrose for 6 to 8 weeks. They were given LPS intravenously, and chemokine mRNA expression in the liver was evaluated after 2 and 6 hr. To study the organ or chemokine specificity, CINC-1 mRNA expression in the spleen and monocyte chemoattractant protein (MCP)-1 mRNA level were also determined. Serum ALT activity started to increase between 2 and 6 hr. Female rats fed an ethanol diet showed significantly higher ALT activity 6 hr after LPS injection than the male rats. CINC-1 mRNA expressions in the liver after 2 and 6 hr were significantly higher in the ethanol-fed group, compared with the pair-fed control. Female rats fed an ethanol diet showed a significantly higher level of CINC-1 mRNA in the liver than the male rats 2 hr after LPS injection. CINC-1 levels in the liver homogenates paralleled closely its mRNA expression, whereas its concentrations in sera did not correlate with those in the liver. Neither CINC-1 mRNA expression in the spleen nor MCP-1 mRNA expression in the liver was affected by ethanol feeding or gender. An additional experiment using the gonadectomized rats fed an ethanol diet showed that gonadectomy totally abolished the gender difference in CINC-1 mRNA of the liver. We conclude that CINC-1 induction in the liver may be responsible for LPS-induced hepatitis in the ethanol-fed rats, and that the difference in ability to produce CINC-1 between males and females is one important factor that may partly account for the gender difference of alcoholic liver disease.
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PMID:Effect of long-term ethanol consumption on ability to produce cytokine-induced neutrophil chemoattractant-1 in the rat liver and its gender difference. 1023 81

A polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.
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PMID:Development of a hepatocyte-specific prostaglandin E(1) polymeric prodrug and its potential for preventing carbon tetrachloride-induced fulminant hepatitis in mice. 1045

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E(1)(PGE(1)) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-L-lysine (PLL) and poly-L-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE(1) conjugate synthesized with activated PGE(1) by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE(1) during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE(1) to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE(1) was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE(1)-Gal-HZ-PLGA conjugate labeled with [(111)In] or [(3)H]PGE(1) rapidly accumulated in the liver parenchymal cells. In addition, the PGE(1) conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE(1) indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE(1) to hepatocyte utilizing galactose recognition.
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PMID:Design of polymeric prodrugs of prostaglandin E(1) having galactose residue for hepatocyte targeting. 1051 58

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1 (PGE1) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. Although galactosylated poly-L-glutamic acid with a ethylene diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its PGE1 conjugate synthesized by the carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE1 during conjugation and lack of release in the tissue. In order to overcome these problems, PGE1 was conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells after intravenous injection. In addition, PGE1 conjugate effectively inhibited the increase of GPT level in plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte utilizing galactose recognition.
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PMID:Design of polymeric prodrugs of PGE1 for cell-specific hepatic targeting. 1075 41

A novel polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using lactosylated poly(L-glutamic hydrazide) (Lac-NH-PLGA) as a targetable carrier to hepatocytes. Poly(L-glutamic hydrazide) (PLGA-HZ) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by coupling with lactose via a hydrazone linkage. Then the lactosylated PLGA-HZ was reduced by sodium cyanoborohydride (NaBH(3)CN) in order to make the linkage irreversible (Lac-NH-PLGA). Finally, PGE(1) was bound to hydrazide moieties remaining in Lac-NH-PLGA without any condensing agent under weakly acidic conditions (pH 5) where PGE(1) would be chemically most stable at room temperature (PGE(1) conjugate). The PGE(1) conjugate prepared was sufficiently water-soluble in spite of the hydrophobic nature of its backbone (-NH-CH-CO-) and PGE(1) itself. After intravenous injection in mice, the [111In]PGE(1) conjugate rapidly accumulated in the liver, whereas [111In]PLGA-HZ did not, suggesting the involvement of a galactose-specific mechanism in the uptake of the [111In]PGE(1) conjugate. Fractionation of liver cells revealed that the [111In]PGE(1) conjugate was preferentially taken up by liver parenchymal cells. The pharmacological activity was examined in mice with fulminant hepatitis induced by intraperitoneal injection of carbon tetrachloride. Intravenous injection of the PGE(1) conjugate at a dose of 1 mg (0.065 mg PGE(1))/kg effectively inhibited the increase in plasma glutamic pyruvic transaminase (GPT) activity compared with that of free PGE(1) at a dose of 0.065 or 0.65 mg/kg. These results suggest that the PGE(1) conjugate is an excellent prodrug for the treatment of fulminant hepatitis.
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PMID:Synthesis and pharmacological activity of a novel water-soluble hepatocyte-specific polymeric prodrug of prostaglandin E(1) using lactosylated poly(L-glutamic hydrazide) as a carrier. 1172 89

The asialoglycoprotein receptor (ASGP-R) on mammalian hepatocytes provides a unique means for the development of liver-specific carriers, such as liposomes, recombinant lipoproteins, and polymers for drug or gene delivery to the liver, especially to hepatocytes. The abundant receptors on the cells specifically recognize ligands with terminal galactose or N-acetylgalactosamine residues, and endocytose the ligands for an intracellular degradation process. The use of its natural ligand, i.e. asialofetuin, or synthetic ligands with galactosylated or lactosylated residues, such as galactosylated cholesterol, glycolipids, or galactosylated polymers has achieved significant targeting efficacy to the liver. There are several examples of successful targeted therapy for acute liver injury with asialofetuin-labeled and vitamin E-associated liposomes or with a caspase inhibitor loaded in sugar-carrying polymer particles, as well as for the delivery of a new antiviral agent, 9-(2-phosphonylmethoxyethyl)adenine. Liposome-mediated gene delivery to the liver is more difficult than to other organs, such as to lungs. It is still in its infancy due to difficulties in solving general issues, such as the circulatory stability of liposome-DNA complexes, and lysosomal or endosomal degradation of plasmid DNA. In spite of these existing concerns, several new approaches offer some reason for optimism, for example; intravenous injection of asialofetuin- or galactosylated cholesterol-labeled cationic liposomes has led to high transgene expression in the liver. In addition, specific antisense oligonucleotides against woodchuck hepatitis viruses incorporated into sialoorosomucoid-poly-L-lysine significantly inhibited viral replication in the liver. Finally, galactosylated polymers are promising for gene delivery, but require further studies to verify their potential applications.
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PMID:Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications. 1186 Dec 24

The novel antiviral protein cyanovirin-N (CV-N) was initially discovered based on its potent activity against the human immunodeficiency virus (HIV). Subsequent studies identified the HIV envelope glycoproteins gp120 and gp41 as molecular targets of CV-N. More recently, mechanistic studies have shown that certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) found on the HIV envelope glycoproteins comprise the specific sites to which CV-N binds. Such selective, carbohydrate-dependent interactions may account, at least in part, for the unusual and unexpected spectrum of antiviral activity of CV-N described herein. We screened CV-N against a broad range of respiratory and enteric viruses, as well as flaviviruses and herpesviruses. CV-N was inactive against rhinoviruses, human parainfluenza virus, respiratory syncytial virus, and enteric viruses but was moderately active against some herpesvirus and hepatitis virus (bovine viral diarrhea virus) strains (50% effective concentration [EC(50)] = approximately 1 micro g/ml) while inactive against others. Remarkably, however, CV-N and related homologs showed highly potent antiviral activity against almost all strains of influenza A and B virus, including clinical isolates and a neuraminidase inhibitor-resistant strain (EC(50) = 0.004 to 0.04 micro g/ml). When influenza virus particles were pretreated with CV-N, viral titers were lowered significantly (>1,000-fold). Further studies identified influenza virus hemagglutinin as a target for CV-N, showed that antiviral activity and hemagglutinin binding were correlated, and indicated that CV-N's interactions with hemagglutinin involved oligosaccharides. These results further reveal new potential avenues for antiviral therapeutics and prophylaxis targeting specific oligosaccharide-comprised sites on certain enveloped viruses, including HIV, influenza virus, and possibly others.
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PMID:Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin. 1287 14

Hepatoprotective activity-guided fractionation of the MeOH extract of Equisetum arvense L. (Equisetaceae) resulted in the isolation of two phenolic petrosins, onitin (1) and onitin-9-O-glucoside (2), along with four flavonoids, apigenin (3), luteolin (4), kaempferol-3-O-glucoside (5), and quercetin-3-O-glucoside (6). Among these, compounds 1 and 4 exhibited hepatoprotective activities on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells, displaying EC(50) values of 85.8 +/ -9.3 microM and 20.2 +/- 1.4 microM, respectively. Silybin, used as a positive control, showed the EC(50) value of 69.0 +/- 3.3 microM. Compounds 1 and 4 also showed superoxide scavenging effects (IC(50) = 35.3 +/- 0.2 microM and 5.9 +/- 0.3 microM, respectively) and DPPH free radical scavenging effect (IC(50) of 35.8 +/- 0.4 microM and 22.7 +/- 2.8 microM, respectively). These results support the use of this plant for the treatment of hepatitis in oriental traditional medicine.
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PMID:Hepatoprotective and free radical scavenging activities of phenolic petrosins and flavonoids isolated from Equisetum arvense. 1550 69


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