lipid-a and Liver-Diseases

A broad spectrum of infectious liver diseases emphasizes the need of microparticles for targeted delivery of immunomodulatory substances to the liver. Microcapsules (MCs) are particularly attractive for innovative drug and vaccine formulations, enabling the combination of antigen, drugs, and adjuvants. The present study aimed to develop microcapsules characterized by an enhanced liver deposition and accelerated uptake by nonparenchymal liver cells (NPCs). Initially, two formulations of biodegradable microcapsules were synthesized from either hydroxyethyl starch (HES) or mannose. Notably, HES-MCs accumulated primarily in the liver, while mannose particles displayed a lung preference. Functionalization of HES-MCs with anti-CD40, anti-DEC205, and/or monophosphoryl lipid A (MPLA) enhanced uptake of MCs by nonparenchymal liver cells in vitro. In contrast, only MPLA-coated HES-MCs promoted significantly the in vivo uptake by NPCs. Finally, HES-MCs equipped with MPLA, anti-CD40, and anti-DEC205 induced the secretion of TNF-α, IL-6 by Kupffer cells (KCs), and IFN-γ and IL-12p70 by liver dendritic cells (DCs). The enhanced uptake and activation of KCs by MPLA-HES-MCs is a promising approach to prevent or treat infection, since KCs are exploited as an entry gate in various infectious diseases, such as malaria. In parallel, loading and activating liver DCs, usually prone to tolerance, bears the potential to induce antigen specific, intrahepatic immune responses necessary to prevent and treat infections affecting the liver.

Topics: Animals; Antigens, CD; Capsules; CD40 Antigens; Dendritic Cells; Drug Delivery Systems; Female; Interferon-gamma; Interleukin-6; Kupffer Cells; Lectins, C-Type; Lipid A; Liver; Liver Diseases; Mice; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Nanoparticles; Phagocytosis; Receptors, Cell Surface; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Nelumbo nucifera Gaertn is widespread and a popular food in central and southern Taiwan. It has also been reported to possess different therapeutic effects, but the effects of N. nucifera leaf on lipid metabolism and liver function remain unclear. In this study, a high fat diet was used to induce hyperlipidemia, hypercholesterolemia, and fatty liver in hamster. The effects of flavonoid-enriched N. nucifera leaf extract supplement and two lipid-lowing drugs, silymarin and simvastatin, on the disorders induced by high fat diet were investigated. The results showed that a 10-week application of a high fat diet to hamsters led to significant increases of body weight, plasma lipid derivatives (triglyceride, total cholesterol, and lipoproteins), lipid peroxidation, and liver damage markers (plasma aspartate aminotransferase and alanine aminotransferase). Interestingly, flavonoid-enriched N. nucifera leaf extract supplement effectively ameliorated the high fat diet-induced lipid metabolic disorders as significantly as silymarin and simvastatin did. Moreover, the flavonoid-enriched supplement alleviated the high fat diet-induced accumulation of lipids in liver, the findings showing distinguishing mechanisms from the effects of silymarin and simvastatin. These results suggested that the flavonoid-enriched N. nucifera leaf extract supplement may significantly improve the high fat diet-induced abnormal blood lipids and liver damage as significantly as the common drugs. Consequently, it is suggested that the flavonoid-enriched N. nucifera leaf extract supplement is beneficial for the improvement of lipid metabolisms and the alleviation of liver damage in high fat diet treatment.

Topics: Animals; Cricetinae; Dietary Fats; Flavonoids; Hypercholesterolemia; Hyperlipidemias; Lipid A; Lipid Peroxidation; Liver; Liver Diseases; Mesocricetus; Nelumbo; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Leaves

An enzyme-linked immunosorbent assay (ELISA) to quantitate anti-lipid A antibodies in sera has been developed. The sensitivity of the ELISA was improved when the antigen (lipid A) was immobilized at pH 2.0, presumably by enhanced solid-phase adsorption of lipid A which is presumed to be aggregated at low pH. This was also verified by solid-phase immunoradiometry in which a four-fold improvement in the signal-to-noise ratio was observed when antigen coating was performed at pH 2.0 as compared to coating at pH 9.6. The enhanced sensitivity permitted the use of low concentrations of lipid A (10 micrograms/ml) for antigen coating of microtiter plates. The assay was able to clearly detect differences in IgG anti-lipid A levels between patients with chronic liver disease and normal controls.

Topics: Animals; Autoantibodies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Humans; Hydrogen-Ion Concentration; Immunoglobulin G; Immunoradiometric Assay; Lipid A; Liver Diseases; Rabbits; Sensitivity and Specificity

Topics: Animals; Antigen-Antibody Complex; Cholestasis; Endotoxins; Hepatitis A; Hepatitis, Alcoholic; Humans; Immunoglobulin M; Kupffer Cells; Limulus Test; Lipid A; Liver; Liver Diseases; Rats

Treatment of rabbits, rats, and mice with D-galactosamine increased their sensitivity to the lethal effects of lipopolysaccharide several thousand fold. The susceptibility of the animals was highest when the lipopolysaccharide was injected together with galactosamine and decreased successively when injection was carried out 1, 2, and 3 hr later. Sensitization was absent when the lipopolysaccharide was administered 1 hr before or 4 hr after galactosamine. The onset of lethality after treatment with galactosamine and lipopolysaccharide occurred faster than with lipopolysaccharide alone; usually all animals died 5-9 hr later. The galactosamine-induced sensitization to lipopolysaccharide could be reversed by uridine which is known to inhibit the early biochemical alterations induced by the amino sugar in the hepatocytes. Although galactosamine is known to exhibit hepatotoxic activity inducing ultimate necrosis of the hepatocytes, the data so far suggests that the sensitization to lipopolysaccharide is related only to the early metabolic effects of the hexosamine.

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Synergism; Endotoxins; Female; Galactosamine; L-Iditol 2-Dehydrogenase; Lipid A; Lipopolysaccharides; Liver Diseases; Male; Mice; Rabbits; Rats; Salmonella; Time Factors; Uridine

Topics: Embolism; Fats; Lipid A; Lipid Metabolism; Liver; Liver Diseases