Protection Against Concanavalin A‐Induced Murine Liver Injury by the Organic Germanium Compound, Propagermanium

Abstract

Propagermanium (3-oxygermylpropionic acid polymer) is an organic germanium compound that activates the immune system. In this study, we investigated the action of propagermanium on T-cell-mediated murine hepatic injury induced by concanavalin A (Con A). Oral administration of propagermanium inhibited the development of liver injury about 10 h after ConA injection. Histological analysis demonstrated that propagermanium attenuated the extent of liver damage compared with controls, reducing infiltration by leucocytes, especially CD11b-positive cells. Infiltration by CD4-positive cells was not affected. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma are crucial for the development of hepatitis in this model. Propagermanium treatment induced significant inhibition of subsequent TNF-alpha production about 10 h after Con A injection, without affecting IFN-gamma, interleukin (IL)-10, IL-4 and IL-12 production. This effect on TNF-production coincided with the inhibition of aminotransferase activity late in the progression of Con A-induced liver injury. These facts suggest that this compound affects the macrophages (Mphi) function in the liver sinusoid. Therefore, Mphi were cultured with liver sinusoidal endothelial cells (SEC) and the effect of propagermanium on TNF-alpha production in the presence of IFN-gamma was determined. TNF-alpha production was reduced significantly in the coculture of Mphi and SEC when Mphi was treated with propagermanium. These results might explain the mechanisms by which propagermanium inhibits Con-A-induced liver injury. That is, propagermanium improves hepatitis through mechanisms including the reduced production of TNF-alpha, without modification of Th1- and Th2-cell function.

C-C Chemokine Receptor 2 Inhibitor Improves Diet-Induced Development of Insulin Resistance and Hepatic Steatosis in Mice

“…This concentration of propagermanium in the feeding chow results in an approximate dose of 5 mg/kg and 50 mg/kg body weight per day in each mouse, respectively, adjusted for previous measurement of food intake. This dose had no significant effect on normal mice 20) and caused no deaths in this study. The IC50 value for propagermanium inhibition of CCR2 is 0.52 g/mL 21) .…”

“…The molecular mechanism of the action of propagermanium has been explained by its targeting glycosylphosphatidylinositol-anchored proteins that are closely associated with CCR2 and the resulting blockade of MCP-1/CCR2-mediated signaling 21) . Many animal studies have shown that propagermanium improves liver injury 20,23) , atherosclerosis 24) and diabetic nephropathy 25,26) by reducing monocyte/macrophage infiltration into the lesion. In this study we demonstrated that inhibition of CCR2 C D function by propagermanium treatment reduced macrophage infiltration into adipose tissue in DIO mice as well as db/db mice 17) .…”

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

“…Some previous reports help us understand our results. Ishiwata et al 56 showed that mice treated with propagermanium (the organic germanium compound) were resistant to ConA-induced hepatitis, while CD4 + T-cell liver infiltration remained unchanged. Recently, Wolf et al 57 indicated that TNFR1 À/À and TNFR2 À/À mice were resistant to ConA-induced hepatitis, while infiltration of CD4 + T cells in liver also remained unchanged.…”

Advances in Effect of Germanium or Germanium Compounds on Animals—A Review

“…For instance, Ge-132, has a strong activity on inducing the generation of exogenous IFN in chickens [116] [126] [127]. The propagermanium can improve hepatitis through reducing the gereration of TNF-α [128]. The levels of IFN-γ, IL-1α, IL-1β, and IL-4 gene expression were also significantly increased after treated with germanium biotite [118].…”