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A Novel Matrine Derivative WM130 Inhibits Activation of Hepatic Stellate Cells and Attenuates Dimethylnitrosamine-Induced Liver Fibrosis in Rats.

Xu Y, Peng Z, Ji W, Li X, Lin X, Qian L, Li X, Chai X, Wu Q, Gao Q, Su C - Biomed Res Int (2015)

Bottom Line: This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM.On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression.In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.

ABSTRACT
Activation of hepatic stellate cells (HSCs) is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient of Sophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50) and 34 μM (half IC50). The expression of α-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf) were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

No MeSH data available.


Related in: MedlinePlus

WM130 inhibited the migration and invasion of HSC-T6 cells. (a) The migration ability of HSC-T6 cells was analyzed by a scratch motility assay. WM130 68 μM group revealed a less migration distance during the treatment period of  0–48 h, compared with the control group or M19 group. (b) The effect of WM130 on inhibiting invasion of HSC-T6 cells was examined by transwell chamber assay. Invasive ability of HSC-T6 cells was quantified by counting the number of stained cells under microscopy (at 200x magnification). ∗p < 0.05, ∗∗p < 0.01 versus Control group; ##p < 0.01 versus M19 68 μM group.
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fig3: WM130 inhibited the migration and invasion of HSC-T6 cells. (a) The migration ability of HSC-T6 cells was analyzed by a scratch motility assay. WM130 68 μM group revealed a less migration distance during the treatment period of  0–48 h, compared with the control group or M19 group. (b) The effect of WM130 on inhibiting invasion of HSC-T6 cells was examined by transwell chamber assay. Invasive ability of HSC-T6 cells was quantified by counting the number of stained cells under microscopy (at 200x magnification). ∗p < 0.05, ∗∗p < 0.01 versus Control group; ##p < 0.01 versus M19 68 μM group.

Mentions: HSC-T6 cell motility was observed by wound healing assay to investigate the function of WM130. Twenty-four h after scratching, HSC-T6 cells treated with WM130 or M19 had healed the wound to a less extent than the cells in the control group. The results indicated that the migration activity of HSC-T6 cells treated with WM130 was markedly inhibited (Figure 3(a)).


A Novel Matrine Derivative WM130 Inhibits Activation of Hepatic Stellate Cells and Attenuates Dimethylnitrosamine-Induced Liver Fibrosis in Rats.

Xu Y, Peng Z, Ji W, Li X, Lin X, Qian L, Li X, Chai X, Wu Q, Gao Q, Su C - Biomed Res Int (2015)

WM130 inhibited the migration and invasion of HSC-T6 cells. (a) The migration ability of HSC-T6 cells was analyzed by a scratch motility assay. WM130 68 μM group revealed a less migration distance during the treatment period of  0–48 h, compared with the control group or M19 group. (b) The effect of WM130 on inhibiting invasion of HSC-T6 cells was examined by transwell chamber assay. Invasive ability of HSC-T6 cells was quantified by counting the number of stained cells under microscopy (at 200x magnification). ∗p < 0.05, ∗∗p < 0.01 versus Control group; ##p < 0.01 versus M19 68 μM group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488526&req=5

fig3: WM130 inhibited the migration and invasion of HSC-T6 cells. (a) The migration ability of HSC-T6 cells was analyzed by a scratch motility assay. WM130 68 μM group revealed a less migration distance during the treatment period of  0–48 h, compared with the control group or M19 group. (b) The effect of WM130 on inhibiting invasion of HSC-T6 cells was examined by transwell chamber assay. Invasive ability of HSC-T6 cells was quantified by counting the number of stained cells under microscopy (at 200x magnification). ∗p < 0.05, ∗∗p < 0.01 versus Control group; ##p < 0.01 versus M19 68 μM group.
Mentions: HSC-T6 cell motility was observed by wound healing assay to investigate the function of WM130. Twenty-four h after scratching, HSC-T6 cells treated with WM130 or M19 had healed the wound to a less extent than the cells in the control group. The results indicated that the migration activity of HSC-T6 cells treated with WM130 was markedly inhibited (Figure 3(a)).

Bottom Line: This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM.On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression.In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.

ABSTRACT
Activation of hepatic stellate cells (HSCs) is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient of Sophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50) and 34 μM (half IC50). The expression of α-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf) were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

No MeSH data available.


Related in: MedlinePlus