Melatonin-selenium nanoparticles inhibit oxidative stress and protect against hepatic injury induced by Bacillus Calmette-Guérin/lipopolysaccharide in mice.

Melatonin-selenium nanoparticles (MT-Se), a novel complex, were synthesized by preparing selenium nanoparticles in melatonin medium. The present investigation was designed to determine the protective effects of MT-Se against Bacillus Calmette-Guérin (BCG)/lipopolysaccharide (LPS)-induced hepatic injury in mice. In BCG/LPS-induced hepatic injury model, MT-Se administered (i.g.) at doses of 5, 10, or 20 mg/kg to BCG/LPS-treated mice for 10 days, significantly reduced the increase in plasma aminotransferase, reduced the severe extent of hepatic cell damage and the immigration of inflammatory cells. The MT-Se particles also attenuated the increase in the content of thiobarbituric acid-reactive substances and enhanced the decrease in reduced activities of superoxide dismutase and glutathione peroxidase (GPx). However, treatment with MT-Se suppressed the increase in nitric oxide levels both in plasma and liver tissue. Furthermore, supplementation with MT-Se at the dose of 10 mg/kg (composed of 9.9 mg/kg melatonin and 0.1 mg/kg selenium) had great capability to protect against hepatocellular damage than a similar dose of melatonin (10 mg/kg) or selenium (0.1 mg/kg) alone. This effect may relate to its higher antioxidant efficacy in decreasing lipid peroxidation and increasing GPx activity. These results suggest that the mode of MT-Se hepatic protective action is, at least in part, related to its antioxidant properties.

Melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress.

Melatonin is reported to exhibit a wide variety of biological effects, including antioxidant and anti-inflammatory. Evidence shows the important role of oxidative stress in the etiopathogenesis of hepatic fibrosis. The aim of this study was to investigate the protective effects of administration of melatonin in rats with carbon tetrachloride-induced fibrosis for 6 weeks. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examinations. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione peroxidase (GSH-px) and superoxide dismutase (SOD) levels were evaluated in tissue homogenates by spectrophotometry. The nuclear factor-kappaB (NF-kappaB) in liver tissue was examined by immunohistochemistry. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) concentrations in Kupffer cells (KCs) culture supernatants were measured with ELISA. The rats injected subcutaneously with CCl4 for 6 weeks resulted in hepatic fibrotic changes increased hydroxyproline and MDA levels, and decreased GSH-px and SOD levels, whereas melatonin reversed these effects. Furthermore, melatonin inhibited the expression of NF-kappaB in liver tissue and decreasing production of proinflammatory cytokines such as TNF-alpha and IL-1beta from KCs in fibrotic rats. These present results suggest that melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress and proinflammatory cytokines production.

Melatonin-selenium nanoparticles protects liver against immunological injury induced by bacillus Calmette-Guerin and lipopolysaccharide.

AIM: Melatonin-selenium nanoparticle (MT-Se), a novel complex, was synthesized by preparing selenium nanoparticles in a melatonin medium. The present investigation was designed to determine the protective effects of MT-Se against immunological liver injury in mice induced by bacillus Calmette-Guerin (BCG)/lipopolysaccharide (LPS). METHODS: The model of immunological liver injury in mice was prepared. The levels of alanine aminotransferase, aspartate amino-transferase, nitric oxide (NO) in serum, malondialdehyde content, superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) activities in a liver homogenate were assayed by spectrophotometry. The content of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) were determined by ELISA. The splenocyte proliferation was assayed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction. Meanwhile, a hepatic pathological examination was observed. RESULTS: In the BCG/LPS-induced hepatic injury model, MT-Se administered at doses of 5, 10, or 20 mg/kg to the BCG/LPS-treated mice for 10 d significantly reduced the increase in serum aminotransferase, reduced the severe extent of hepatic cell damage and the immigration of inflammatory cells. It also attenuated the increase in the content of thiobarbituric acid-reactive substances and enhanced the decrease in activities of SOD and GSH-px. In contrast, the treatment with MT-Se suppressed the increase in NO level in both the serum and liver tissue. Furthermore, MT-Se significantly lowered an increase in TNF-alpha and IL-1beta levels in the liver and inhibited the production of TNF- alpha and IL-1beta by peritoneal macrophages. A downregulation effect of MT-Se on splenocyte proliferation was also observed. CONCLUSION: MT-Se showed a hepatic protective action on immunological liver injury in mice.

Effects of total glucosides of peony on immunological hepatic fibrosis in rats.

AIM: To study the effects of total glucosides of peony (TGP) on immunological hepatic fibrosis induced by human albumin in rats. METHODS: Sixty adult male Sprague-Dawley rats were randomly divided into: Normal group, model group, TGP (60 and 120 mg/kg) treatment groups and colchicines (0.1 mg/kg) treatment group. On the day before the rats were killed, those in TGP or colchicine groups received TGP or colchicine as above from the first day of tail vein injection of human albumin. The rats in normal and model groups were only administered with the same volume of vehicle. At the end of the 16th wk, rats in each group were killed. Blood and tissue specimens were taken. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO), content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were measured by biochemical methods. Serum procollagen type III (PC III) and laminin (LN) were determined by radioimmunoassay. Liver collagen level was determined by measuring hydroxyproline content in fresh liver samples. Hepatic tissue sections were stained with hematoxylin-eosin and examined under a light microscope. RESULTS: Histological results showed that TGP improved the human albumin-induced alterations in the liver structure, alleviated lobular necrosis and significantly lowered collagen content. The antifibrotic effect of TGP was also confirmed by decreased serum content of LN and PCIII in TGP-treated group. Moreover, the treatment with TGP effectively reduced the hydroxyproline content in liver homogenates. However, the level of ALT and AST increased in fibrotic rat but had no significance compared with normal control, whereas the ratio of A/G decreased without significance. TGP had no effect on level of ALT, AST and the ratio of A/G. Furthermore, TGP treatment significantly blocked the increase in MDA and NO, associated with a partial elevation in liver total antioxidant capacity including SOD and GSH-px. CONCLUSION: TGP has beneficial effects on hepatic fibrosis in rats by inhibition of collagen synthesis and decreasing oxidative stress.

Protective effect of melatonin against liver injury in mice induced by Bacillus Calmette-Guerin plus lipopolysaccharide.

AIM: To investigate the effects and mechanisms of melatonin on immunological liver injury in mice. METHODS: A model of liver injury was induced by tail vein injection of Bacillus Calmette Guerin (BCG) and lipopolysaccharide (LPS) in mice. Kupffer cells and hepatocytes were isolated and cultured according to a modified two-step collagenase perfusion technique. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and nitric oxide (NO), content of malondiadehyde (MDA), activity of superoxide dismutase (SOD), were measured by biochemical methods. Tumor necrosis factor-alpha (TNF-alpha) activity was determined by RIA. Interleukin (IL)-1 activity was measured by thymocyte proliferation bioassay. Hepatic tissue sections were stained with hematoxylin and eosin and examined under a light microscope. RESULTS: Immunological liver injury induced by BCG+LPS was successfully duplicated. Serum transaminase (ALT, AST) activities were significantly decreased by melatonin (0.25, 1.0, 4.0 mg/kg bm). Meanwhile, MDA content was decreased and SOD in liver homogenates was upregulated. Furthermore, pro-inflammatory mediators (TNF-alpha, IL-1, NO) in serum and liver homogenates were significantly reduced by melatonin. Histological examination demonstrated that melatonin could attenuate the area and extent of necrosis, reduce the immigration of inflammatory cells. In in vitro experiment, TNF-alpha was inhibited at the concentrations of 10(-8)-10(-6) mol/L of melatonin, while IL-1 production of Kupffer cells induced by LPS (5 microg/mL) was decreased only at the concentration of 10(-6) mol/L of melatonin, but no effect on NO production was observed. Immunological liver injury model in vitro was established by incubating hepatocytes with BCG- and LPS-induced Kupffer cells. Activities of ALT, TNF-alpha, IL-1, and MDA in supernatant were significantly increased. Melatonin had little effect on the level of ALT, but reduced the content of TNF-alpha and MDA at concentrations of 10(-7)-10(-5) mol/L and decreased the content of IL-1 at concentrations of 10(-6)-10(-5) mol/L. CONCLUSION: Melatonin could significantly protect liver injury in mice, which was related to free radical scavenging, increased SOD activity and pro-inflammatory mediators.