Bisdemethoxycurcumin Induces Apoptosis in Activated Hepatic Stellate Cells via Cannabinoid Receptor 2

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.

Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

“…[24][25][26][27] Thus, the oxidative stress induced by ROS contributes to neuronal cell death in the brain. [24][25][26][27] Similar to these findings, we detected significantly high ROS levels in HT-22 cells after treatment with TG. On the contrary, inhibition of ROS generation by betulin was comparable with that caused by TUDCA, after treatment with TG ( Figure 2b).…”

“…Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, CO, and iron. 26 HO-1 has received considerable attention for the potential neuroprotective effects in cell death models. 27,28 We used hemin, an HO-1 inducer, and SnPP, an HO-1 inhibitor, to investigate whether HO-1 is involved in ER stress-induced cytotoxicity in HT-22 cells by assessing the cell viability by measuring the ROS levels (Figure 3a and b).…”

Curcuminoids combined with gefitinib mediated apoptosis and autophagy of human oral cancer SAS cells in vitro and reduced tumor of SAS cell xenograft mice in vivo

“…Our previous study also showed that DMC induced the apoptosis of human lung cancer NCI‐H460 cells through the mitochondrial‐dependent pathway . BDMC inhibited adipogenesis in 3T3‐L1 preadipocytes and it had the potential to prevent obesity and induced cell apoptosis in human laryngeal carcinoma cells, activated hepatic stellate cells, and lung cancer NCI‐H460 cells . In human fibrosarcoma cells, DMC or BDMC had higher anti‐metastasis potency than that of CUR via the differentially downregulation of ECM degradation enzymes …”

Active Turnover of Heme in Hibernation Period in Mammals

“…Animal tissues were lysed with radioimmunoprecipitation assay (RIPA) buffer [1 × PBS, 1% (v/v) Non-idet P-40 (NP-40), 0.5% (w/v) sodium deoxycholate, 0.1% (w/v) sodium dodecyl sulfate (SDS), 0.1 mg/mL phenylmethylsulfonyl fluoride (PMSF), 30 µl/mL aprotinin, and 1 mM sodium orthovanadate (Na 2 VO 3 )], and homogenized by sonication (Lee et al, 2015). Total tissue lysates were centrifuged and the resulting supernatants were collected.…”