Loss of PHLDA1 has a protective role in OGD/R-injured neurons via regulation of the GSK-3β/Nrf2 pathway

Abstract

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a multifunctional protein that plays a role in diverse pathological conditions. However, whether PHLDA1 participates in cerebral ischemia-reperfusion injury has not been reported. The goals of the present work were to assess the possible relationship between PHLDA1 and cerebral ischemia-reperfusion injury. Hippocampal neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate cerebral ischemia-reperfusion injury in vitro, which led to significant increases in the expression of PHLDA1. Cellular functional studies showed that the knockdown of PHLDA1 produced a protective role in OGD/R-injured neurons via the down-regulation of neuronal apoptosis, oxidative stress and proinflammatory cytokine release. On the contrary, the overexpression of PHLDA1 rendered neurons more vulnerable to OGD/R injury. In-depth research revealed that the inhibition of PHLDA1 resulted in the enhancement of nuclear factor erythroid 2 like 2 (Nrf2) signaling in OGD/R-injured neurons. The reactivation of glycogen synthase kinase 3β (GSK-3β) abolished the PHLDA1-inhibition-mediated activation of Nrf2 signaling. Moreover, the restraint of Nrf2 signaling diminished the PHLDA1-knockdown-induced neuroprotective effects in OGD/R-injured neurons. In summary, the data of our work show that the loss of PHLDA1 protects against OGD/R injury via potentiating Nrf2 signaling via the regulation of GSK-3β. This work underscores a potential role of PHLDA1 in cerebral ischemia-reperfusion injury and proposes PHLDA1 as an attractive target for the development of neuroprotective therapy.

Protective effect of basic helix-loop-helix family member e40 on cerebral ischemia/reperfusion injury: Inhibition of apoptosis via repressing the transcription of pleckstrin homology-like domain family A, member 1

“…29 In addition, other work has shown that PHLDA1 deficiency protects against OGD/R injury, which makes it one of the new targets for treating cerebral injury. 45 Consistently, in the study, the data showed that PHLDA1 was upregulated in the hippocampal neurons exposed to OGD/R, and PHLDA1 overexpression inhibited the cell viability and promoted the cell apoptosis caused 46 There is growing evidence for the protective role of neuropsychiatric disorders, 47,48 which provides theoretical and clinical implications. Moreover, many new applications for psychiatric and neurological disorders have been reported, including non-invasive stimulation techniques 49,50 and prognostic biomarkers.…”

TDAG51 deficiency attenuates dextran sulfate sodium-induced colitis in mice

“…Interestingly, it has been reported that TDAG51 expression is rapidly induced by the Toll-like receptor (TLR) 2/4-mediated signaling pathway 20,21,23,24 . Moreover, TDAG51 deficiency exerts a protective effect against acute-or chronic inflammation-associated disorders, such as atherosclerosis, obesity, neuroinflammation, ischemia/reperfusion injury and lung injury 13,18,20,[23][24][25][26] . Thus, we hypothesized that the functional role of TDAG51 is possibly linked to the regulation of the inflammatory response in intestinal tissues.…”

PHLDA1 knockdown inhibits inflammation and oxidative stress by regulating JNK/ERK pathway, and plays a protective role in sepsis-induced acute kidney injury

“…27 Fatty acid-binding protein 4 mediates inflammatory response and cell apoptosis in sepsis-induced AKI, and might act as a novel therapeutic target for sepsisinduced AKI. 28 PHLDA1 is reported to be involved in OGD/ R-mediated neurons, 14 ulcerative colitis and dysplasia, 15 ovarian cancer, 16 and hepatic ischemia/reperfusion injury. 17 However, participation of PHLDA1 in sepsis-induced AKI remains to be explored.…”

“…13 In addition, PHLDA1 is engaged in the oxygen glucose deprivation and reperfusion (OGD/R)-mediated neurons by modulating GSK-3β/Nrf2 pathway. 14 PHLDA1 is majorly expressed in ulcerative colitis, which could provide a novel biomarker for managing dysplasia. 15 PHLDA1 is involved in human ovarian cancer cells by modulating endoplasmic reticulum stress response as well as oxidative stress.…”