IFN-γ inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.

BACKGROUND & AIMS: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. METHODS: We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSIONS: IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.

Effects of particle morphology, pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement.

Naproxen (Nap) is a commonly used drug for antiphlogosis and analgesia, but its dissolution rate in water is quite low. In this work, the dissolution behavior of Nap after loading in mesoporous silica materials was investigated in a simulated intestinal fluid (pH=6.8). The results indicated that the pore sizes, morphologies and surface chemical groups of the mesoporous silica were significant factors on the dissolution behavior of Nap. The physical state of encapsulated Nap was affected by the pore sizes of mesoporous silica, which influenced its dissolution rate. Amorphous Nap exhibited a higher dissolution rate than crystallized Nap, even though the larger pore size could facilitate its diffusion from the matrix. The effect of the morphology of mesoporous silicas on the dissolution of Nap can be ascribed to the length of pore channels, that the longer channel showed a longer diffusion pathway of Nap. Moreover, the release rate of Nap from functionalized mesoporous materials was effectively controlled compared with that of unmodified materials.