lactoferrin and Hepatitis-C

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes/ macrophages. In turn, LPS-activated monocytes/ macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12 are the major mediators. Before therapy (To) and at the end of 6-month interferon (IFN)-alpha/Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients. At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg/ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg/ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg/ml). In terms of serum cytokine concentration, at T6 IFN-gamma levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values. The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity. In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration. Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

Topics: Autoantibodies; Cytokines; Drug Therapy, Combination; Endotoxemia; Hepatitis C; Humans; Interferon-alpha; Lactoferrin; Lipopolysaccharides; Ribavirin

Hepatitis C virus infection and interferon treatment have shown to be risk factors for sleep disorder health-related quality of life.. To determine whether the effects of resveratrol on sleep disorders were associated with different tests in subjects with chronic hepatitis C treated with Peg-IFN-α and RBV.. In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis received Pegylated-Interferon-α2b (1.5 mg/kg per week), Ribavirin and placebo (. The comparison between Group A and Group B showed significant differences after six months in C-reactive protein (. Supplementation with Resveratrol decreased General Health Questionnaire score and reduced sleep disorders in patients treated with Peg-IFN-α and RBV.

Topics: Acetylcysteine; Adult; Alanine Transaminase; Antiviral Agents; Aspartate Aminotransferases; Blood Glucose; Body Mass Index; C-Reactive Protein; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Lactoferrin; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Quality of Life; Recombinant Proteins; Resveratrol; Ribavirin; Sleep Wake Disorders; Stilbenes; Surveys and Questionnaires

Hepatitis C virus (HCV) is a major public-health problem with 130-170 million individuals chronically infected worldwide. In order to halt the epidemic, therapy against HCV will need to be both effective and widely available. Studies focusing on safe and affordable natural product active against HCV have revealed the antiviral activity of the human Lactoferrin (hLF) protein which binds and neutralizes the circulating virion. In the current study, investigation of hLF activity on the HCV subgenomic replicon system, which is independent from viral entry and shedding, revealed a distinct antireplicative activity of hLF against HCV. Hepatocellular uptake of hLF was confirmed and correlated with qualitative HCV staining reduction. Quantitative dose-response inhibition assays confirmed an hLF-mediated and dose-dependent HCV replication reduction reaching up to 60%. The in cellulo anti-HCV activity of hLF was additive to both Ribavirin and Interferon-α-2b. Further investigation of hLF activity against the essential viral proteins involved in HCV genome replication revealed an inhibitory activity against the HCV ATPase/Helicase NS3 protein but not against the HCV RNA-dependent RNA polymerase (NS5B protein). NS3 inhibition was mediated by a direct and specific interaction between hLF and an allosteric binding site on NS3. Taken together, our findings reveal a new antiviral mechanism of action by which hLF inhibits intracellular HCV replication.

Topics: Allosteric Site; Hepacivirus; Hepatitis C; Humans; Immunity, Innate; Lactoferrin; Protein Binding; Viral Nonstructural Proteins; Virus Replication

Hepatitis C virus (HCV) is a serious worldwide health risk and, to date, no effective treatments to prevent progression to chronic infection have been discovered. To combat the disease, Egyptian patients often use traditional medicines, for instance, camel milk, which contains lactoferrin. Currently, lactoferrin is one of the primary biopharmaceutical drug candidates against HCV infection. Camel lactoferrin (cLf) purification and biochemical and immunological characterization have shown its similarity to human and bovine lactoferrin, and crossreacts with the anti-human lactoferrin antibody. Incubation of human leukocytes with cLf then infected with HCV did not prevent the HCV entry into the cells, while the direct interaction between the HCV and cLf leads to a complete virus entry inhibition after seven days incubation. Our results suggest that the cLf may be one of the camel milk components having antiviral activity. In conclusion, we have demonstrated the potential for cLf to inhibit HCV entry into human leukocytes with more efficiency than human or bovine lactoferrin.

Topics: Animals; Antiviral Agents; Camelus; Genotype; Hepacivirus; Hepatitis C; Humans; Lactoferrin; Leukocytes, Mononuclear

Lactoferrin (Lf) expression has been immunohistochemically investigated in 117 formalin-fixed paraffin-embedded liver bioptic samples obtained from an equal number of patients affected by chronic hepatitis (HCV = 76; HBV = 17; HBV + HDV = 14; cryptogenetic = 10); in addition, 10 autoptic specimens of normal liver were studied as control. The Lf immunoreactivity was evaluated by an intensity-distribution (ID) score. The Lf immunoexpression was observed in 88 out of 117 (75%) cases of chronic hepatitis; interestingly, all liver specimens from HBV hepatitis showed a constant Lf reactivity with the highest ID-score, whereas the evidence of Lf was encountered in 54/76 (71.1%) HCV as well as in 11/14 (78.6%) HDV chronic hepatitis, thus documenting a variable degree of Lf immunostaining in relation to different viruses. Moreover, in 6/10 (60%) cases of cryptogenetic hepatitis Lf immunoexpression was documented, whereas all normal liver controls were unreactive. In HCV specimens, the Lf nuclear immunoreactivity appeared to increase with the progression of the disease, with a greater expression in genotype 1. In contrast, no relationship among Lf ID-scores and different stages or grades of HBV, HDV or cryptogenetic hepatitis was encountered. This fact may suggest a role for Lf as an unspecific defensive agent in chronic inflammatory liver diseases, similarly to that elsewhere reported in other inflammatory tissue injuries.

Topics: Adult; Aged; Cell Nucleus; Coloring Agents; Cytoplasm; Female; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis C; Hepatitis, Chronic; Hepatitis, Viral, Human; Hepatocytes; Humans; Immunohistochemistry; Lactoferrin; Liver; Male; Middle Aged

Decreased tear volume in patients with chronic hepatitis C has been reported in the literature. Lactoferrin is abundantly present in human tears, the main source of which is the acini of the lacrimal glands. In this study tear lactoferrin levels were measured to investigate the dry eye condition of patients with chronic hepatitis C.. Lactoferrin in tears/fluid was measured by a radial immunodiffusion assay in 42 patients with chronic hepatitis C. The rate of lacrimal secretion was determined by the cotton thread test. Rose bengal staining of the ocular surface was also performed.. Only three patients out of 42 complained of dry eye sensation and, in 31 patients, six showed positive results on the rose bengal staining test of the ocular surface. The lactoferrin concentration of tear fluid in the chronic hepatitis C group (1.42 (SD 0.56) mg/ml) was significantly lower than in the control group (1.90 (0.62) mg/ml; p <0.00048). The cotton thread test results in the chronic hepatitis C group (12.9 (5. 5) mm) were significantly lower than in the control group (17.9 (5. 3) mm; p<0.00048). Also, in the chronic hepatitis C group, tear lactoferrin concentration correlated with the results of the cotton thread test (r = 0.35, p<0.05).. Chronic hepatitis C patients showed both decreased tear volume, and decreased tear lactoferrin concentration. These findings suggest that there may be dysfunction of the lacrimal glands in patients with chronic hepatitis C, which may account for the mild dry eye.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Dry Eye Syndromes; Female; Hepatitis C; Humans; Lactoferrin; Male; Middle Aged; Tears