Neuroprotective Effects of Omentin-1 Against Cerebral Hypoxia/Reoxygenation Injury via Activating GAS6/Axl Signaling Pathway in Neuroblastoma Cells

Abstract

Ischemic stroke is characterized by insufficient blood supply to brain tissue and is associated with increased morbidity and mortality in adults worldwide. Growth arrest-specific protein 6 (GAS6) is a vitamin K-dependent protein and is widely expressed in the central nervous system. The biological functions of GAS6 are mediated by the interaction with TAM (Tyro3, Axl and Mertk) receptors, including cell survival and proliferation, immune regulation and apoptosis. Omentin-1, also known as intelectin-1 (ITLN-1), is a novel adipocytokine that is involved in a variety of biological events, such as insulin resistance, endothelial dysfunction, programmed cell death and metabolic disorders. Our previous study has found that omentin-1 act as a novel regulator of vascular and anti-apoptotic response in cerebral ischemia. However, the specific molecular mechanism of omentin-1’s protective effect on cerebral ischemia-reperfusion injury (IRI) is still unclear. First, the toxicity of recombinant human omentin-1 (rh-omentin) was assessed and a safe concentration was chosen for the next experiments. Then, rh-omentin exerted neuroprotection against hypoxia/reoxygenation (H/R) injury in N2a cells, indicated by increased cell viability, decreased LDH, ROS generation, and cell apoptotic rate. Furthermore, the similar protective effect was observed in omentin-1 overexpression cells constructed by lentivirus transfection. Rh-omentin could also inhibit H/R-induced apoptotic molecules, oxidative stress molecules, and GAS6/Axl signaling molecules which as evidence by increased omentin-1, GAS6, Axl, p-Axl, NQO1, HO-1, Nrf2, Bcl2 and decreased Bax expressions. However, GAS6 siRNA could reverse rh-omentin-induced neuroprotection and the levels of these molecules mentioned above. In conclusion, these findings suggest that omentin-1 treatment exerts neuroprotection against H/R injury partly via activating GAS6/Axl signaling at least. Therefore, these finding may favor omentin-1 a potential neuroprotective drug candidate to alleviate ischemia-reperfusion injury in clinic.

Activation of ITLN‐1 attenuates oxidative stress injury via activating SIRT1/PGC1‐α signaling in neuroblastoma cells

“…It is reported that low ITLN‐1 level indicates high risk of ischemic stroke (Kazimierczak‐Kabzińska et al, 2020; Lin et al, 2021; Xu et al, 2020). Also, our previous study further demonstrated that ITLN‐1 protects against cerebral hypoxia/reoxygenation injury in N2a cells (Niu et al, 2021). The above evidence denotes that ITLN‐1 has a powerful potential neuroprotection.…”

“…Passaging was performed once the cell confluence reached approximately 80%. The N2a cells were subjected to serum starvation before the experiment, as described in the previous literature (Niu et al, 2021). To induce oxidative stress injury, the cells were exposed to different concentrations of H 2 O 2 (0.5, 1, 2, and 4 mM) for 4 h. According to cell viability and cell morphology, the most appropriate concentration was selected for subsequent experiments.…”

The Potency of Serum Omentin-1 Quantification in Predicting Major Adverse Cardiac and Cerebrovascular Events Risk in Patients Receiving Hemodialysis

“…13 the occurrence of MACCE (Dong et al 2021;Lin et al 2021;Ma et al 2022;Niu et al 2021;Tan et al 2019;Wang et al 2020;Watanabe et al 2016). As a result, omentin-1 reflected reduced MACCE risk in patients receiving hemodialysis.…”

The Role of Adipokines in Inflammatory Mechanisms of Obesity

“…The concentration of omentin-1 is inversely related to the levels of pro-inflammatory cytokines such as IL-6 and TNF-α [ 106 ]. A positive effect of omentin on endothelial function through improvement of the production of nitric oxide [ 107 ], which reduces oxidative stress and apoptosis [ 108 ], has been demonstrated.…”