Akt / GSK3β / Nrf2 / HO-1 pathway activation by flurbiprofen protects the hippocampal neurons in a rat model of glutamate excitotoxicity

Farhat, Fatma; Nofal, Shahira; Raafat, Eman; Ahmed, Ashraf M.

doi:10.1016/j.neuropharm.2021.108654

Cited by 26 publications

(11 citation statements)

References 73 publications

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“…It has been reported that activation of the Nrf2/HO-1 signaling pathway protects against damage to hippocampal neurons in rats with glutamate excitotoxicity. 43 The results of this study found that PD administration significantly increased Nrf2 and downstream effector HO-1 protein expression in vitro and in vivo, suggesting that PD acts as an antioxidant to attenuate oxidative stress.…”

Section: Discussionmentioning

confidence: 60%

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway

Lu,

Xie,

et al. 2024

J. Agric. Food Chem.

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The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

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Section: Discussionmentioning

confidence: 60%

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway

Lu,

Xie,

et al. 2024

J. Agric. Food Chem.

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“…Secondary, GSK3β activation decreases the translocation of Nrf2 to the nuclear and downregulates genes transcription of the antioxidant response elements (Farhat et al, 2021). GSK3β regulates mitochondrial function via Nrf2/GPX4 mediated ferroptosis pathway.…”

Section: Discussionmentioning

confidence: 98%

“…GSK3β also directly phosphorylates Drp1 at Ser40 and Ser 44, activates Drp1 GTPase activity, leads mitochondrial fragment and enhances oxidative stress (Rippin & Eldar‐Finkelman, 2021). Secondary, GSK3β activation decreases the translocation of Nrf2 to the nuclear and downregulates genes transcription of the antioxidant response elements (Farhat et al, 2021). GSK3β regulates mitochondrial function via Nrf2/GPX4 mediated ferroptosis pathway.…”

Section: Discussionmentioning

confidence: 99%

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Zhang,

Sun,

et al. 2024

Cell Biology International

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Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK‐3β activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR‐treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4‐mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK‐3β through four covalent bonds and reduced GSK‐3β activity. In conclusion, our findings suggest that CUR treatment inhibits GSK‐3β activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA‐induced neuropathic pain.

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“…In human umbilical vein endothelial cells, atheroprotective laminar flow activates Nrf2 via the PI3K/AKT pathway [ 47 ]. In hippocampal neurons, flurbiprofen triggers the phosphorylation of AKT and GSK3β, which in turn decreases Nrf2 nuclear export and increases Nrf2 translocation [ 48 ]. In our previous study, AKT/GSK3β also mediates SDF-1/CXCR7 axis, activating Nrf2 activity [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism

Yan

Xia

et al. 2022

Cells

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The impairment in endothelial progenitor cell (EPC) functions results in dysregulation of vascular homeostasis and dysfunction of the endothelium under diabetic conditions. Improving EPC function has been considered as a promising strategy for ameliorating diabetic vascular complications. Liraglutide has been widely used as a therapeutic agent for diabetes. However, the effects and mechanisms of liraglutide on EPC dysfunction remain unclear. The capability of liraglutide in promoting blood perfusion and angiogenesis under diabetic conditions was evaluated in the hind limb ischemia model of diabetic mice. The effect of liraglutide on the angiogenic function of EPC was evaluated by cell scratch recovery assay, tube formation assay, and nitric oxide production. RNA sequencing was performed to assess the underlying mechanisms. Liraglutide enhanced blood perfusion and angiogenesis in the ischemic hindlimb of db/db mice and streptozotocin-induced type 1 diabetic mice. Additionally, liraglutide improved tube formation, cell migration, and nitric oxide production of high glucose (HG)-treated EPC. Assessment of liraglutide target pathways revealed a network of genes involved in antioxidant activity. Further mechanism study showed that liraglutide decreased the production of reactive oxygen species and increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 deficiency attenuated the beneficial effects of liraglutide on improving EPC function and promoting ischemic angiogenesis under diabetic conditions. Moreover, liraglutide activates Nrf2 through an AKT/GSK3β/Fyn pathway, and inhibiting this pathway abolished liraglutide-induced Nrf2 activation and EPC function improvement. Overall, these results suggest that Liraglutide represents therapeutic potential in promoting EPC function and ameliorating ischemic angiogenesis under diabetic conditions, and these beneficial effects relied on Nrf2 activation.

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Akt / GSK3β / Nrf2 / HO-1 pathway activation by flurbiprofen protects the hippocampal neurons in a rat model of glutamate excitotoxicity

Cited by 26 publications

References 73 publications

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism

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