Abstract
Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.
Highlights
Medicinal plants have long been recognized as important sources of pharmaceutical drugs
A recent investigation showed that cannabidiol such as anandamide (AEA), naturally occurring compounds found in the Cannabis sativa plant, induces cell death of activated hepatic stellate cells (HSCs) by activating cannabinoid receptor (CBR) [4,5]
To evaluate the cytotoxic effects of BDMC and curcumin on activated HSCs, we examined the pro-apoptotic effect of BDMC on HSC-T6 cells, reflected as altered cell integrity, using MTT assay
Summary
Medicinal plants have long been recognized as important sources of pharmaceutical drugs. A recent investigation showed that cannabidiol such as anandamide (AEA), naturally occurring compounds found in the Cannabis sativa plant, induces cell death of activated HSCs by activating CBRs [4,5]. These receptors are known to exist as two subtypes, named CBR1 and CBR2 [6]. Curcumin is known to increase CBR1 expression, which can induce cell death of activated HSCs at higher doses. Both CBR1 and CBR2 are expressed in the liver. BDMC could be a promising candidate for treatments that would resolve liver fibrosis
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