Paeoniae radix alba polysaccharides obtained via optimized extraction treat experimental autoimmune hepatitis effectively.

The extraction process of Paeoniae radix alba polysaccharides (PRAP) was optimized as the liquid-solid ratio of 10.65 mL/g, the extraction time of 2.10 h, and the 2 extraction repetitions through a response surface methodology. The chemical profiles of the obtained PRAP were characterized by measuring the contents of total carbohydrates, total phenolics, uronic acid and protein, and by analyzing the FT-IR spectrum and monosaccharide composition. To determine the therapeutic effects of PRAP on experimental autoimmune hepatitis (EAH), we established an EAH mice model. After treated with PRAP, liver and spleen injuries were reduced, and hepatocyte regeneration and liver function were improved. Further study of the mechanism by which PRAP treats EAH showed that PRAP significantly inhibited oxidative stress in the livers of EAH model mice. More importantly, PRAP inhibited immune inflammatory reactions in EAH model mice, including the hepatic infiltration of inflammatory CD4+ and CD8+ T cells, as well as overexpression of inflammatory cytokines IL-2, IL-6 and IL-10, via inhibition of the NF-κB signaling pathway.

Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis.

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are to describe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote disease progression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.

Metabolic profile of liver damage in non-cirrhotic virus C and autoimmune hepatitis: A proton decoupled 31P-MRS study.

PURPOSE: To study liver 31P MRS, histology, transient elastography, and liver function tests in patients with virus C hepatitis (HCV) or autoimmune hepatitis (AIH) to test the hypothesis that 31P MR metabolic profile of these diseases differ. MATERIALS AND METHODS: 25 patients with HCV (n=12) or AIH (n=13) underwent proton decoupled 31P MRS spectroscopy performed on a 3.0T MR imager. Intensities of phosphomonoesters (PME) of phosphoethanolamine (PE) and phosphocholine (PC), phosphodiesters (PDE) of glycerophosphoethanolamine (GPE) and glycerophosphocholine (GPC), and γ, α and ß resonances of adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide phosphate (NADPH) were determined. Liver stiffness was measured by transient elastography. Inflammation and fibrosis were staged according to METAVIR from biopsy samples. Activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and thromboplastin time (TT) were determined from serum samples. RESULTS: PME had a stronger correlation with AST (z=1.73, p=0.04) and ALT (z=1.77, p=0.04) in HCV than in AIH patients. PME, PME/PDE, PE/GPE correlated positively and PDE negatively with inflammatory activity. PE, PC and PME correlated positively with liver function tests. CONCLUSION: 31P-MRS suggests a more serious liver damage in HCV than in AIH with similar histopathological findings. 31P-MRS is more sensitive in detecting inflammation than fibrosis in the liver.

Hepatoprotective effect of DT56a is associated with changes in natural killer T cells and regulatory T cells.

OBJECTIVE: To determine the metabolic and immunological effects of the oral administration of DT56a, an enzymatic isolate of soybeans. METHODS: DT56a was orally administered to mice in three animal models: leptin deficiency, high-fat diet (HFD) supplementation and immune-mediated hepatitis. Liver damage and immunological status were assessed. RESULTS: Oral administration of DT56a to leptin-deficient (ob/ob) and HFD mice led to a significant reduction in serum triglyceride (TG) and total cholesterol (TC) levels. DT56a-treated mice in both models exhibited a significant reduction in hepatic levels of TG and marked alleviation of glycemic control as indicated by significant decreases in fasting blood glucose levels and glucose tolerance tests. The levels of liver enzymes were reduced. These metabolic effects were associated with altered distributions of regulatory T (Tregs) and natural killer T (NKT) cells. DT56a suppressed the immune-mediated liver damage induced by concanavalin A indicated by decreased liver enzymes and serum interferon-γ levels and by improved histology and decreased hepatic apoptosis. Oral administration of DT56a also alleviated immune-mediated hepatitis and affected Tregs and NKT cells. CONCLUSIONS: Oral administration of DT56a promotes a hepatoprotective effect associated with an alteration in the distribution of Tregs and NKT cells.

Efficacy of MK615 for the treatment of patients with liver disorders.

AIM: To investigate the hepatoprotective effect of MK615, a Japanese apricot extract, in an animal model, and its clinical therapeutic effect. METHODS: Wistar rats were administered physiological saline (4 mL/kg) or MK615 solution (4 mL/kg) for 7 d. On the sixth d, acute hepatic injury was induced by administering a single intraperitoneal injection (ip) of D-galactosamine hydrochloride (D-GalN) (600 mg/kg). Plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined, and liver tissues were used for histopathological analysis. Fifty-eight patients with liver disorders [hepatitis C (n = 40), non-alcoholic fatty liver disease (n = 15), and autoimmune liver disease (n = 3)] were orally administered commercially available Misatol ME-containing MK615 (13 g/d) daily for 12 wk. Blood and urine were sampled immediately before and 6 wk, 12 wk, and 16 wk after the start of intake to measure various biochemical parameters. The percentage change in ALT and AST levels after 12 wk from the pre-intake baseline served as a primary endpoint. RESULTS: D-GalN effectively induced acute hepatic injury in the rats. At 48 h after the ip injection of D-GalN, the plasma levels of ALT (475.6 ± 191.5 IU/L vs 225.3 ± 194.2 IU/L, P < 0.05) and AST (1253.9 ± 223.4 IU/L vs 621.9 ± 478.2 IU/L, P < 0.05) in the MK615 group were significantly lower than the control group. Scattered single cell necrosis, loss of hepatocytes, and extensive inflammatory cell infiltration were observed in hepatic tissue samples collected from the control group. However, these findings were less pronounced in the group receiving MK615. At the end of the clinical study, serum ALT and AST levels were significantly decreased compared with pre-intake baseline levels from 103.5 ± 58.8 IU/L to 71.8 ± 39.3 IU/L (P < 0.05) and from 93.5 ± 55.6 IU/L to 65.5 ± 34.8 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 26 (45%) of the 58 patients, while 25 (43%) patients exhibited similar AST level reductions. The chronic hepatitis C group exhibited significant ALT and AST level reductions from 93.4 ± 51.1 IU/L to 64.6 ± 35.1 IU/L (P < 0.05) and from 94.2 ± 55.5 IU/L to 67.2 ± 35.6 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 20 (50%) of the 40 patients. ALT levels in both the combined ursodeoxycholic acid (UDCA) treatment and the UDCA uncombined groups were significantly lower after Misatol ME administration. MK615 protected hepatocytes from D-GalN-induced cytotoxicity in rats. Misatol ME decreased elevated ALT and AST levels in patients with liver disorders. CONCLUSION: These results suggest that MK615 and Misatol ME are promising hepatoprotective agents for patients with liver disorders.

[Effects of interferon-alpha combined with saikosaponin on serum T lymphocyte subgroups and hepatic cytokines in mice with immune hepatic injury].

OBJECTIVE: To observe the effects of interferon-alpha combined with saikosaponin on serum T lymphocyte subgroups and hepatic cytokines in mice with immune hepatic injury. METHODS: The mice were randomly divided into five groups, i. e., the normal control group, the model group, the interferon group, the saikosaponin group, and the interferon combined saikosaponin group. Corresponding medication was given to mice in respective groups for two days. Peripheral blood was collected 8 and 24 h after concanavalin A (Con A) was injected. Serum lymphocyte subgroups, tumor necrosis factor alpha (TNF-alpha), levels of interleukin 18 (IL-18) and IL-10, activities of alanine aminotransferase (ALT) and aspartate transaminase (AST) were detected. Pathological changes of the liver tissue were observed. RESULTS: (1) Compared with the normal control group, serious inflammation and necrosis was significant in the liver tissue of the model group. The serum levels of ALT and AST obviously increased. Meanwhile, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios and the hepatic IL-10 level obviously decreased (P < 0.01). The levels of IL-18 and TNF-alpha significantly increased (P < 0.05, P < 0.01). (2) Compared with the model group, dot and lamellar necrosis was dispersedly seen in the liver tissue in the three medication groups. The serum activities of ALT and AST significantly decreased (P < 0.01). Meanwhile, the peripheral blood CD4+ T cell and CD8+ T cell ratios, as well as the hepatic IL-10 level obviously increased (P < 0.01, P < 0.05). The levels of IL-18 and TNF-alpha significantly decreased (P < 0.05, P < 0.01). (3) In the interferon combined saikosaponin group, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios increased more obviously than those of the interferon group. The 8- and 24-h IL-18 levels were obviously lower than those of the interferon group, while the 24-h TNF-alpha level significantly decreased more than that of the interferon group (P < 0.05). CONCLUSION: Interferon-alpha combined saikosaponin could effectively play a role in fighting against the immune hepatic injury.

Spots, blots, peaks and chips: proteomic approaches in autoimmune diseases.

During the past five years, investigations employing a variety of proteomic technologies have yielded a wealth of information on a number of autoimmune disorders. Animal models of autoimmune disease have been examined and have provided clues that can be useful in elucidating molecular pathways and mechanisms that play a role in autoimmune disorders. Human sera and body fluids have been analyzed and have resulted in the identification of autoantibodies that can be used as diagnostic markers in specific autoimmune diseases, and proteomic fingerprints of tissues and body fluids have resulted in the identification of individual proteins or patterns of protein expression that are deregulated in autoimmune diseases. The information provided by these proteomic studies are of diagnostic and therapeutic potential. This review provides an overview of the approaches used in the proteomic analyses of autoimmune disease.