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Moniliformediquinone as a potential therapeutic agent, inactivation of hepatic stellate cell and inhibition of liver fibrosis in vivo

View Article: PubMed Central - PubMed

ABSTRACT

Background: Moniliformediquinone (MFD), a phenanthradiquinone in Dendrobium moniliforme, was synthesized in our laboratory. Beyond its in vitro inhibitory effects on cancer cells, other biological activity of MFD is unknown. The purpose of the present study was to investigate the effects of MFD on hepatic fibrogenesis in vitro and in vivo.

Methods: Hepatic stellate HSC-T6 was cultured. Cell viability assay and western blot analyses were performed. Male ICR mice were evaluated on CCl4-induced hepatotoxicity using both histological examination and immunohistochemical staining.

Results: First, in vitro study showed that the synthesized MFD effectively attenuated the expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and type I collagen (COL-1), which modulated the hepatic fibrogenesis. Furthermore, MFD reduced the phosphorylation of p65 NFκB in HSC-T6 cells. In vivo, liver fibrosis was induced by CCl4 twice a week for 10 weeks in mice. The administration of the MFD was started after 1 week of CCl4 thrice-weekly; the MFD significantly reduced plasma aspartate transaminase (AST) and lactose dehydrogenase (LDH) as well as hepatic hydroxy-proline, α-SMA, and COL-1 expression in CCl4-treated mice. Pathological analysis showed that the MFD alleviated CCl4-induced hepatic inflammation, necrosis and fibrosis. These results suggest that MFD possesses therapeutic potential for liver fibrosis.

Conclusions: The synthesized MFD exhibits anti-fibrotic potential by inactivation of HSCs in vitro and decreases mouse hepatic fibrosis in vivo. Further investigation into their clinical therapeutic potential is required.

No MeSH data available.


a Chemical structure of moniliformediquinone (MFD). b Effect of MFD on cell viability of HSC-T6 cells. HSC-T6 cells were treated with MFD (0–2.5 μM) for 24 and 48 h. MTT assays were performed to assess cell viability. The data represent mean ± SD of three independent experiments. *P < 0.01 versus the control
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Fig1: a Chemical structure of moniliformediquinone (MFD). b Effect of MFD on cell viability of HSC-T6 cells. HSC-T6 cells were treated with MFD (0–2.5 μM) for 24 and 48 h. MTT assays were performed to assess cell viability. The data represent mean ± SD of three independent experiments. *P < 0.01 versus the control

Mentions: Accordingly, hepatotoxins cause liver damage characterized by varying degrees of hepatocyte degeneration and cell death, such as ethanol, acetaminophen, and carbon tetrachloride (CCl4). For instance, CCl4 impairs hepatocytes directly by altering the permeability of the plasma, lysosomal, and mitochondrial membranes. In addition, CCl4-induced liver fibrosis shows many characteristics with human fibrosis of different etiologies [10]. Furthermore, CCl4-induced hepatic injury has been extensively used in animal models to evaluate the therapeutic potential of drugs. On the other hand, plants of the Dendrobium genus (Orchidaceae) are used in traditional herbal medicines in Asia, and studies have shown that they contain a wide variety of medicinal properties [11–13]. Moniliformediquinone (2,6-dimethoxy-1,4,5,8-phenanthradiquinone; MFD) (Fig. 1), collected by Chang et al. has been isolated from stems of Dendrobium monilifore (L.) Sw. in Taiwan and has been found to have anti-inflammation and anticancer effects [14]. In addition, our previous study of synthesized MFD showed that synthesized MFD could induce in vitro and in vivo antitumor activity through a glutathione-involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer [15]. Other biological activities of MFD are unknown. In the present study, the anti-hepatic fibrosis potential of synthesized MFD was evaluated using HSC-T6, an activated HSC cell line, and a mouse model of CCl4-induced hepatic injury. Further study aimed to investigate the effect of synthesized MFD on the expression of activated HSC-T6 markers and fibrosis-related proteins and its relationship with the expression of TGF-β1, α-SMA, and COL-1. Finally, pathological analysis showed that the synthesized MFD could possess therapeutic potential for liver fibrosis.Fig. 1


Moniliformediquinone as a potential therapeutic agent, inactivation of hepatic stellate cell and inhibition of liver fibrosis in vivo
a Chemical structure of moniliformediquinone (MFD). b Effect of MFD on cell viability of HSC-T6 cells. HSC-T6 cells were treated with MFD (0–2.5 μM) for 24 and 48 h. MTT assays were performed to assess cell viability. The data represent mean ± SD of three independent experiments. *P < 0.01 versus the control
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Fig1: a Chemical structure of moniliformediquinone (MFD). b Effect of MFD on cell viability of HSC-T6 cells. HSC-T6 cells were treated with MFD (0–2.5 μM) for 24 and 48 h. MTT assays were performed to assess cell viability. The data represent mean ± SD of three independent experiments. *P < 0.01 versus the control
Mentions: Accordingly, hepatotoxins cause liver damage characterized by varying degrees of hepatocyte degeneration and cell death, such as ethanol, acetaminophen, and carbon tetrachloride (CCl4). For instance, CCl4 impairs hepatocytes directly by altering the permeability of the plasma, lysosomal, and mitochondrial membranes. In addition, CCl4-induced liver fibrosis shows many characteristics with human fibrosis of different etiologies [10]. Furthermore, CCl4-induced hepatic injury has been extensively used in animal models to evaluate the therapeutic potential of drugs. On the other hand, plants of the Dendrobium genus (Orchidaceae) are used in traditional herbal medicines in Asia, and studies have shown that they contain a wide variety of medicinal properties [11–13]. Moniliformediquinone (2,6-dimethoxy-1,4,5,8-phenanthradiquinone; MFD) (Fig. 1), collected by Chang et al. has been isolated from stems of Dendrobium monilifore (L.) Sw. in Taiwan and has been found to have anti-inflammation and anticancer effects [14]. In addition, our previous study of synthesized MFD showed that synthesized MFD could induce in vitro and in vivo antitumor activity through a glutathione-involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer [15]. Other biological activities of MFD are unknown. In the present study, the anti-hepatic fibrosis potential of synthesized MFD was evaluated using HSC-T6, an activated HSC cell line, and a mouse model of CCl4-induced hepatic injury. Further study aimed to investigate the effect of synthesized MFD on the expression of activated HSC-T6 markers and fibrosis-related proteins and its relationship with the expression of TGF-β1, α-SMA, and COL-1. Finally, pathological analysis showed that the synthesized MFD could possess therapeutic potential for liver fibrosis.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Moniliformediquinone (MFD), a phenanthradiquinone in Dendrobium moniliforme, was synthesized in our laboratory. Beyond its in vitro inhibitory effects on cancer cells, other biological activity of MFD is unknown. The purpose of the present study was to investigate the effects of MFD on hepatic fibrogenesis in vitro and in vivo.

Methods: Hepatic stellate HSC-T6 was cultured. Cell viability assay and western blot analyses were performed. Male ICR mice were evaluated on CCl4-induced hepatotoxicity using both histological examination and immunohistochemical staining.

Results: First, in vitro study showed that the synthesized MFD effectively attenuated the expression of transforming growth factor-&beta;1 (TGF-&beta;1), connective tissue growth factor (CTGF), &alpha;-smooth muscle actin (&alpha;-SMA), and type I collagen (COL-1), which modulated the hepatic fibrogenesis. Furthermore, MFD reduced the phosphorylation of p65 NF&kappa;B in HSC-T6 cells. In vivo, liver fibrosis was induced by CCl4 twice a week for 10&nbsp;weeks in mice. The administration of the MFD was started after 1&nbsp;week of CCl4 thrice-weekly; the MFD significantly reduced plasma aspartate transaminase (AST) and lactose dehydrogenase (LDH) as well as hepatic hydroxy-proline, &alpha;-SMA, and COL-1 expression in CCl4-treated mice. Pathological analysis showed that the MFD alleviated CCl4-induced hepatic inflammation, necrosis and fibrosis. These results suggest that MFD possesses therapeutic potential for liver fibrosis.

Conclusions: The synthesized MFD exhibits anti-fibrotic potential by inactivation of HSCs in vitro and decreases mouse hepatic fibrosis in vivo. Further investigation into their clinical therapeutic potential is required.

No MeSH data available.