Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury

Yu, Shanshan; Jiang, Beibei; Tan, Li; Gao, Minna; Lei, Shipeng; Li, Peng; Zhao, Yong

doi:10.3389/fncel.2017.00099

Cited by 31 publications

(23 citation statements)

References 35 publications

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“…Consistent with these results, we found that viability of neurons co-cultured with astrocytes was greater than neurons cultured alone. We used neurobasal medium to support the greater nutritional requirements for the co-cultured neurons [ 28 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Transient middle cerebral artery occlusion (MCAO)-reperfusion was performed and cerebral blood flow (CBF) was monitored as described previously [ 26 – 28 ]. Briefly, adult male Sprague-Dawley rats (250–280 g) were anesthetized with 3.5% chloral hydrate (350 mg/kg), and then placed on a heating pad to maintain body temperature at 37 ± 0.5 °C.…”

Section: Methodsmentioning

confidence: 99%

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Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury

Zhao

et al. 2018

J Mol Med

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Astrocytes are involved in neuroprotection, and DJ-1 is an important antioxidant protein that is abundantly expressed in reactive astrocytes. However, the role of DJ-1 in astrocytes’ neuroprotection in cerebral ischemia/reperfusion injury and its potential mechanism is unclear. Thus, to explore effects and mechanisms of DJ-1 on the neuroprotection of astrocytes, we used primary co-cultures of neurons and astrocytes under oxygen and glucose deprivation/reoxygenation in vitro and transient middle cerebral artery occlusion/reperfusion in vivo to mimic ischemic reperfusion insult. Lentiviral was used to inhibit and upregulate DJ-1 expression in astrocytes, and DJ-1 siRNA blocked DJ-1 expression in rats. Inhibiting DJ-1 expression led to decreases in neuronal viability. DJ-1 knockdown also attenuated total and nuclear Nrf2 and glutathione (GSH) levels in vitro and vivo. Similarly, loss of DJ-1 decreased Nrf2/ARE-binding activity and expression of Nrf2/ARE pathway-driven genes. Overexpression of DJ-1 yielded opposite results. This suggests that the mechanism of action of DJ-1 in astrocyte-mediated neuroprotection may involve regulation of the Nrf2/ARE pathway to increase GSH after cerebral ischemia/reperfusion injury. Thus, DJ-1 may be a new therapeutic target for treating ischemia/reperfusion injury.Key Messages Astrocytes protect neurons in co-culture after OGD/RDJ-1 is upregulated in astrocytes and plays an important physiological roles in neuronal protection under ischemic conditionsDJ-1 protects neuron by the Nrf2/ARE pathway which upregulates GSH

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury

Zhao

et al. 2018

J Mol Med

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“…Moreover, Prdx6 signaling through TLR4 increases after an ischemic stroke, leading to NfκB-mediated inflammation and cell death [87,100,101]. Similarly, the pharmacological inhibition of aiPLA 2 with MJ33 reduces inflammation in an experimental stroke model, supporting the idea that aiPLA 2 has a pro-inflammatory role in the brain under such conditions [102].…”

Section: Prdx6 Signaling In Diseasementioning

confidence: 96%

The Role of Peroxiredoxin 6 in Cell Signaling

Arevalo

Vázquez‐Medina

2018

Antioxidants

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Peroxiredoxin 6 (Prdx6, 1-cys peroxiredoxin) is a unique member of the peroxiredoxin family that, in contrast to other mammalian peroxiredoxins, lacks a resolving cysteine and uses glutathione and π glutathione S-transferase to complete its catalytic cycle. Prdx6 is also the only peroxiredoxin capable of reducing phospholipid hydroperoxides through its glutathione peroxidase (Gpx) activity. In addition to its peroxidase activity, Prdx6 expresses acidic calcium-independent phospholipase A2 (aiPLA2) and lysophosphatidylcholine acyl transferase (LPCAT) activities in separate catalytic sites. Prdx6 plays crucial roles in lung phospholipid metabolism, lipid peroxidation repair, and inflammatory signaling. Here, we review how the distinct activities of Prdx6 are regulated during physiological and pathological conditions, in addition to the role of Prdx6 in cellular signaling and disease.

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“…Also, Prdx6 has been shown to inhibit neurogenesis through downregulation of WDFY 1 -mediated TLR4 signal [30]. Moreover, the pharmacological inhibition of aiPLA2 activity of Prdx6 reduces in ammation in an experimental stroke model [31]. This evidence makes the role of Prdx6 controversial in neurodegenerative diseases, which seems to be linked to the differential expression of Prdx6 and its activity in various neurodegenerative disease models.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Prdx6 by Nrf-2 is mediated through aiPLA2 in white matter reperfusion injury

Daverey

Agrawal

2020

Preprint

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Abstract BackgroundMechanisms involving upregulation of cytoprotective genes under the control of transcription factors, such as Prdx6 and Nrf2, exist to protect cells from permanent damage and dysfunction under hypoxic conditions. Hypoxia and reperfusion produces overproduction of ROS (reactive oxygen species), which may lead to mitochondrial dysfunction leading to cell death and apoptosis. Here, we explore the hypothesis that Prdx6 protects the spinal cord white matter from hypoxia-reperfusion injury and elucidate the possible mechanism by which Prdx6 elicits its protective effects.MethodsBriefly, rats were deeply anesthetized with 5% isoflurane and maintained at 1.5%-2.5% isoflurane. A 30 mm section of spinal cord was rapidly removed and placed in cold Ringer’s solution (2-4 °C), and then a dorsal column segment was micro-dissected from the spinal cord and adjacent gray matter after longitudinal sectioning. The dissected dorsal column was exposed to hypoxia by perfusing 95% N 2 /5% CO 2 for 1 h. For reperfusion experiments, the Ringer’s was reperfused with 95% O 2 and 5% CO 2 for 2 h and 4 h.ResultsOur results show that the expression of Prdx6 significantly upregulated in white matter after hypoxia compared to the sham group, whereas reperfusion caused a gradual decrease in Prdx6 expression after 2 h and 4 h of reperfusion injury. For the first time, our study revealed the novel expression and localized expression of Prdx6 in astrocytes after hypoxia, and possible communication of astrocytes and axons through Prdx6. Interestingly we observed a gradual increase in Nrf2 expression, which suggests a negative regulation of Prdx6 through Nrf2 signaling. Furthermore, inhibition of aiPLA2 activity of Prdx6 by MJ33 shows that the regulation of Prdx6 by Nrf2 is mediated through aiPLA2 activity.ConclusionThe present study uncovers a differential distribution of Prdx6 in axons and astrocytes under a hypoxic environment of white matter, and regulation of Prdx6 in hypoxia-reperfusion injury. Our data show that low levels of Prdx6 in reperfusion injury leads to increased inflammation and apoptosis in white matter, therefore the results of this study suggests that Prdx6 has a protective role in spinal hypoxia-reperfusion injury.

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Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury

Cited by 31 publications

References 35 publications

Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury

Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury

The Role of Peroxiredoxin 6 in Cell Signaling

Regulation of Prdx6 by Nrf-2 is mediated through aiPLA2 in white matter reperfusion injury

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