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  • The Bcl and Bcl xL genes contain the CRE binding

    2022-01-25

    The Bcl-2 and Bcl-xL genes contain the CRE binding site in their promoter regions for CREB and CBP to bind to, so CREB phosphorylation was shown to up-regulate these anti-apoptotic genes, Bcl-2 and Bcl-xL [[29], [30], [31]]. Bcl-2 and Bcl-xL prevent the activation of caspases and the release of mitochondrial apoptogenic factors, including cytochrome c into the Terbinafine mg [32,33]. Here we demonstrated that O-1602 and Abn-CBD up-regulated Bcl-2 and Bcl-xL protein and mRNA levels in MIN6 cells. In addition, Bcl-2 and Bcl-xL expressions were decreased in our ER stress model, interestingly O-1602 and Abn-CBD prevented these decreases. This suggested that GPR55 agonists protected from ER stress-induced apoptosis via the up-regulation of Bcl-2 and Bcl-xL. Therefore, our study provided a novel mechanism of CREB-Bcl-2/Bcl-xL in mediating the anti-apoptotic effects by GPR55 agonists in β-cells. Caspases are synthesised as inactive forms (pro-caspases), and are activated in response to cell death stimuli and contributed to apoptosis [34,51]. Apoptosis is initiated through cell-intrinsic and cell-extrinsic pathways [51]. The cell-extrinsic pathway is occurred when an extracellular stimulus binds to the plasma membrane “death receptor” and activates initiator caspases (caspases-8/-10). On the other hand, the cell-intrinsic pathway is occurred in the mitochondria and it involves the release of cytochrome c into the cytoplasm. Cytochrome c binds with apoptotic protease activating factor 1 (Apaf-1) to form the apoptosome complex, and this complex recruits Terbinafine mg and cleaves pro-caspase-9 (initiator caspase) into caspase-9 [[52], [53], [54]]. The activation of initiator caspases activates effector caspases, such as caspase-3, which is the final step of apoptosis. Our results demonstrated that caspase-9 was activated in response to our ER stress model, and O-1602 and Abn-CBD prevented the cleavage of caspase-9. In addition, caspase-12 was shown to cleave pro-caspase-9 in vitro, and caspase-12 is activated in response to ER stress [35,36]. We also demonstrated that caspase-12 was activated in response to our ER stress model, and this activation was significantly decreased by O-1602 and Abn-CBD. Taken together, this suggested that GPR55 agonists protected from ER stress-induced apoptosis through caspase-9- and caspase-12-dependent pathways. Preserving and enhancing β-cell function are emerging therapies for T2DM, and in the present study, we focused on the study of GPR55 activation on ER stress-induced β-cell apoptosis. GPR55 was shown to play a role in the regulation of glucose and energy homeostasis, especially in metabolism [[14], [15], [16],19,20,42]. GPR55 agonism was able to increase glucose-induced insulin secretion in isolated human and mouse islets of Langerhans, and clonal beta BRIN-BD11 cells [[16], [17], [18], [19],42]. Moreover, O-1602 increased insulin secretion in islets from wild-type mice, but not in GPR55 knockout mice [16,19], this suggested a role of GPR55 in insulin secretion. In addition, studies showed that GPR55 agonists improved glucose tolerance in mice and non-fasted NIH Swiss mice [16,17]. Furthermore, a study characterised the role of GPR55 in energy balance and insulin sensitivity by using GPR55 knockout mice [55]. GPR55 knockout mice had similar glucose tolerance with wild-type mice, and they had significantly higher insulin resistance and basal insulin levels. Recently, a study also confirmed that GPR55 knockout mice had impaired insulin sensitivity in adipose tissue, skeletal muscle and liver [20]. This suggested that GPR55 plays a critical role in insulin sensitivity and glucose homeostasis. Besides, we observed that two GPR55 agonists, O-1602 and Abn-CBD, protected from ER stress-induced β-cell apoptosis through CREB pathway. Consistent with this, a recent study also showed that GPR55 agonists could increase β-cell proliferation and decrease cytokine-induced caspase-3/7 activity in human and mouse islets [42], suggesting that GPR55 agonists could improve β-cell survival. Taken together, our study together with other studies suggested that GPR55 could be a therapeutic target for T2DM [[15], [16], [17],20].