ABSTRACT
AIMS: We investigated the effects of globin digest (GD) and its active ingredient Trp-Thr-Gln-Arg (WTQR) on galactosamine/lipopolysaccharide (GalN/LPS)-induced liver injury in imprinting control region (ICR) mice. MAIN METHODS: The effects of WTQR and GD on the liver injury were examined by measuring the survival rate, serum aminotransferase activities, hepatic components, antioxidant enzyme activities, histopathological analysis, serum levels and hepatic gene expression of tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2), and nitric oxide (NO) or inducible nitric oxide synthase (iNOS), and nuclear factor-kappa B (NF-κB) p65 content in GalN/LPS-treated ICR mice. RAW264 mouse macrophages were used to confirm the anti-inflammatory effects of WTQR and GD on the macrophages. KEY FINDINGS: WTQR and GD increased the survival rate, suppressed the serum aminotransferase activities, serum levels and hepatic gene expression of TNF-α, MIP-2, and NO or iNOS, and nuclear NF-κB p65 content in GalN/LPS-treated mice; decreased the oxidized glutathione content, increased the superoxide dismutase activity, and decreased the histopathological grade values of the hepatocyte necrosis and lobular inflammation in GalN/LPS-injured liver; and suppressed the release levels and gene expression of TNF-α, MIP-2, and NO or iNOS, and nuclear NF-κB p65 content in LPS-stimulated RAW264 macrophages. WTQR and GD may improve the antioxidant defense system and inflammatory status in GalN/LPS-injured liver. SIGNIFICANCE: These findings indicate that WTQR and GD have hepatoprotective effects on GalN/LPS-induced liver injury in ICR mice.
Subject(s)
Chemical and Drug Induced Liver Injury/drug therapy , Globins/administration & dosage , Oligopeptides/administration & dosage , Peptide Fragments/administration & dosage , Analysis of Variance , Animals , Antioxidants/metabolism , Cell Line , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemokine CXCL2/blood , Chemokine CXCL2/genetics , Galactosamine/administration & dosage , Galactosamine/adverse effects , Globins/chemistry , Hepatocytes/drug effects , Hepatocytes/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/adverse effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Macrophages/metabolism , Male , Mice , Mice, Inbred ICR , NF-kappa B/analysis , NF-kappa B/metabolism , Nitric Oxide/blood , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Peptide Fragments/chemistry , Survival Rate , Transaminases/blood , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/geneticsABSTRACT
AIMS: We investigated the effect of globin digest (GD) on the liver injury and hepatic gene expression profile in galactosamine (GalN)-induced liver injury. MAIN METHODS: The effect of GD on the liver injury was examined by measuring the activities of serum transferases and hepatic antioxidant enzymes, histopathological analysis, gene expression profile, and proteins of the peroxisome proliferator-activated receptor alpha (PPARα) and met proto-oncogene (c-Met) in SD rats at 24 h after GalN administration. The effect of GD on the expression of PPARα and its target gene in AML-12 mouse hepatocytes was also examined. KEY FINDINGS: GD suppressed the elevated activities of serum transferases in GalN-induced liver injury in SD rats. The thiobarbituric acid reactive substance content in GalN-injured liver was a decreasing tendency by GD. GD suppressed the increased oxidized glutathione content, and increased the decreased protein, reduced glutathione contents, and catalase activity in GalN-injured liver. GD may improve the antioxidant defense system and protein synthesis in GalN-injured liver. GD suppressed the elevated expression of the genes related to the inflammation, and decreased the histopathological grade value of inflammatory cell infiltration in GalN-injured liver. GD increased the expression of PPARα protein in GalN-injured liver, and also increased the expression of PPARα and its target gene in AML-12 hepatocytes. The total and phosphorylated c-Met proteins in GalN-injured liver were the increasing tendencies by GD. SIGNIFICANCE: These findings indicate that GD has the hepatoprotective effect on GalN-induced liver injury in SD rats.
Subject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Gene Expression Regulation/drug effects , Globins/pharmacology , Animals , Antioxidants/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Galactosamine/toxicity , Hepatocytes/drug effects , Hepatocytes/metabolism , Male , Mice , PPAR gamma/drug effects , PPAR gamma/genetics , Phosphorylation/drug effects , Proto-Oncogene Proteins c-met/drug effects , Proto-Oncogene Proteins c-met/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
AIMS: Leu-Ser-Glu-Leu (LSEL) is the main active ingredient of globin digest (GD) that has an anti-diabetic effect. Here, we investigated the anti-diabetic effect of LSEL for the first time. MAIN METHODS: The anti-diabetic effects of GD and LSEL in ICR mice, streptozotocin (STZ)-induced diabetic mice and KK-Ay mice were examined. KEY FINDINGS: GD and LSEL suppressed the elevation of blood glucose in an oral glucose tolerance test (OGTT) in ICR mice, STZ-induced diabetic mice and KK-Ay mice as well as in an oral sucrose tolerance test in ICR mice and in an insulin tolerance test (ITT) in KK-Ay mice. GD and LSEL decreased the blood glucose levels in the basal state in STZ-induced diabetic mice and KK-Ay mice. Furthermore, GD and LSEL elevated the serum insulin levels in an OGTT in ICR mice and KK-Ay mice and promoted the use of insulin in an ITT in KK-Ay mice. GD and LSEL increased the translocation or expression of the glucose transporter 4 in the muscle of ICR mice, STZ-induced diabetic mice and KK-Ay mice and increased the expression of the uncoupling protein 2 (UCP2) in the muscle of ICR mice. SIGNIFICANCE: These results indicate that GD and LSEL control blood glucose through the promotion of glucose uptake in the muscle of the mice. The acceleration of glucose uptake by GD and LSEL may be controlled by the promotion of insulin secretion and the up-regulation of UCP2 expression. GD and LSEL seem to be useful for lowering the incidence of hyperglycemia.
