lactoferrin and Chemical-and-Drug-Induced-Liver-Injury

Topics: Animals; Chemical and Drug Induced Liver Injury; Humans; Lactoferrin; Liver; Mice; NF-E2-Related Factor 2; Oxidative Stress

The primary objective of this research was to create injectable delivery formulations using Lactotransferrin (LTF) peptide-loaded dextran nanoparticles coated with docosahexaenoic acid. These nanoparticles, designated as LLDDNP, underwent a lyophilization process. The study encompassed a comprehensive investigation, including physicochemical characterization, in vivo assessment of biomarkers, and an examination of immune response through cytokine modulation. The zeta potential of LLDDNP was - 24.5 ± 12 mV, while their average particle size was 334.9 z.d.nm. The particles exhibited a conductivity of 2.10 mS/cm, while their mobility in the injectable dosage form was measured at - 3.65 µm cm/Vs. The scanning electron microscopy investigation, the lyophilization processes resulted in discrete particles forming particle aggregations. However, transmission electron microscopy analysis revealed that LLDDNP is spherical and smooth. The thermogram showed that about 95% of LLDDNP's weight was lost at 270 °C, indicating that the particles are extremely thermal stable. The XRD analysis of LLDDNP exhibited clear and distinctive peaks at 2θ angles, specifically at 9.6°, 20.3°, 21.1°, 22°, 24.6°, 25.2°, 36°, and 44.08°, providing compelling evidence of the crystalline nature of the particles. According to proton NMR studies, the proton dimension fingerprint region of LLDDNP ranges from 1.00 to 1.03 ppm. The in vitro release of LTF from LLDDNP was found to follow zero-order kinetics, with a commendable R

Topics: Chemical and Drug Induced Liver Injury; Cytokines; Dextrans; Docosahexaenoic Acids; Humans; Lactoferrin; Protons

Acetaminophen-induced liver injury (AILI) is a significant health problem and represents the most frequent cause of drug-induced liver failure in the United States. The development and implementation of successful therapeutic intervention strategies have been demanding, due to significant limitations associated with the current treatment for AILI. Lactoferrin (Lac), a glycoprotein present in milk, has been demonstrated to possess a multitude of biological functions. Our study demonstrated a profound protective effect of Lac in a murine model of AILI, which was not dependent on its iron-binding ability, inhibition of acetaminophen (APAP) metabolism, or a direct cytoprotective effect on hepatocytes. Instead, Lac treatment significantly attenuated APAP-induced liver sinusoidal endothelial cell dysfunction and ameliorated hepatic microcirculation disorder. This protective effect of Lac appeared to be dependent on hepatic resident macrophages (Kupffer cells [KCs]).. Collectively, our data indicate that Lac, through activation of KCs, inhibited APAP-induced liver sinusoidal endothelial cell damage and improved hepatic congestion, thereby protecting against AILI. These findings reveal the significant therapeutic potential of Lac during AILI and other types of liver diseases.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Endothelial Cells; Lactoferrin; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microcirculation

Liver diseases, caused by viral infection, autoimmune conditions, alcohol ingestion or the use of certain drugs, are a significant health issue, as many can develop into liver failure. Lactoferrin (Lac) is an iron-binding glycoprotein that belongs to the transferrin family. Owing to its multiple biological functions, Lac has been evaluated in a number of clinical trials to treat infections, inflammation and cancer.. The present study aims to reveal a profound hepatoprotective effect of Lac, using a mouse model of Concanavalin A (Con A)-induced hepatitis, which mimics the pathophysiology of human viral and autoimmune hepatitis.. C57Bl/6J mice were injected with bovine Lac following Con A challenge. The effects of Lac on interferon (IFN)-gamma and interleukin (IL)-4 expression were determined. The roles of Lac on T-cell apoptosis and activation, and leukocytes infiltration were examined.. The data demonstrated that the protective effect of Lac was attributed to its ability to inhibit T-cell activation and production of IFN-gamma, as well as to suppress IL-4 production by hepatic natural killer T cells.. These findings indicate a great therapeutic potential of Lac in treating in treating inflammatory hepatitis and possibly other inflammatory diseases.

Topics: Animals; Cattle; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytokines; Disease Models, Animal; Flow Cytometry; Hepatitis; Immunohistochemistry; Interferons; Interleukin-4; Lactoferrin; Liver; Male; Mice; Mice, Inbred C57BL; Probability; Random Allocation; Th1 Cells

Polyethylene glycol (PEG) is attached to proteins in order to increase their half-life in circulation and reduce their immunogenicity in vivo. The present study was conducted to examine whether two different sizes of PEGylated bovine lactoferrin (40k-PEG-bLf and 20k-PEG-bLf) would enhance the protective effect of native bLf on liver injury induced by carbon tetrachloride (CCl(4)) in rats. Silymarin, a known hepatoprotective drug was used as a positive control. Compared to native bLf, the treatment of PEGylated bLf more markedly prevented the elevation of serum levels of hepatic enzyme markers and inhibited fatty degeneration and the hepatic necrosis induced by CCl(4). 40k-PEG-bLf showed a more significant suppressive effect on CCl(4)-induced hepatic injury than 20k-PEG-bLf. The treatment with PEGylated bLf elevated serum SOD activity reduced by CCl(4) more significantly than native bLf. 40k-PEG-bLf enhanced serum SOD activity more significantly than 20k-PEG-bLf. Immunohistochemical study showed that the PEGylation of bLf enhanced its intracellular transportation to hepatocytes. The increases in intracellular transportation of the PEGylated bLf in order were: 40k-PEG-bLf>20k-PEG-bLf>native bLf. These findings suggested that the mechanism of the enhancement of hepatoprotective effect by PEGylated bLf was associated with an increase in the intracellular transportation of PEGylated bLf in hepatocytes.

Topics: Animals; Apoptosis; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Fatty Liver; Hepatocytes; Immunohistochemistry; Lactoferrin; Lipid Peroxidation; Liver; Male; Necrosis; Polyethylene Glycols; Protective Agents; Rats; Rats, Wistar; Silymarin; Superoxide Dismutase

It is known that lactoferrin is one of the functional proteins contained in mammalian milk and that it plays an important role in the immune system. In this study, we prepared multi-lamellar liposomal bovine lactoferrin composed of egg yolk phosphatidylcholine and phytosterol for oral delivery, and examined any resulting anti-inflammatory effects. Oral pretreatment of liposomal lactoferrin exhibited more suppressive effects than did non-liposomal lactoferrin on CCl4-induced hepatic injury in rats as well as on lipopolysaccharide-induced TNF-alpha production from mouse peripheral blood mononuclear leukocytes. Further investigation revealed that the liposomalization did not exert influence on the absorbability of lactoferrin to the venous blood or lymph following an intraduodenal administration in rats. Furthermore, there was no significant difference exhibited between the antigenicity of liposomal and non-liposomal lactoferrin, which was measured using the passive cutaneous anaphylaxis reaction following oral sensitization to them in guinea pigs. These results suggest that liposomal lactoferrin might act more effectively than conventional lactoferrin in the intestinal site, which is regarded as an active site of orally administered lactoferrin, although the biological mechanism is not fully understood yet. Consequently we propose that liposomal lactoferrin could be a novel active constituent useful for preventive and therapeutic treatment of inflammatory diseases.

Topics: Absorption; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Drug Carriers; Guinea Pigs; Intestinal Absorption; Jugular Veins; Lactoferrin; Liposomes; Lymph; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Phosphatidylcholines; Phytosterols; Rats; Rats, Wistar