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NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neural cell survival.

Calandria JM, Asatryan A, Balaszczuk V, Knott EJ, Jun BK, Mukherjee PK, Belayev L, Bazan NG - Cell Death Differ. (2015)

Bottom Line: NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways.These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation.Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, School of Medicine, LSU Health Sciences Center, 2020 Gravier Street, New Orleans, LA 70112, USA.

ABSTRACT
Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

No MeSH data available.


Related in: MedlinePlus

BIRC3 mediates the pro-survival response induced by the DHA/NPD1 pathway in an ischemia-reperfusion stroke model. (a–c) Model for inducing ischemia-reperfusion by middle cerebral artery occlusion (MCAo) in rats. (a) Timeline showing surgery, treatment and tests performed. (b) Coronal brain diagram (bregma level –0.3 mm) showing locations of regions for western blot and immunohistochemistry for Figure 7, and lipidomic analysis (A: anterior; P: posterior). (c) Diagram of MCAo model obtained by introducing intraluminal filament (red). (d) Total neurological score (normal score =0, maximal deficit=12), tactile placing (proprioceptive, lateral, dorsal reactions; normal score=0, maximal deficit=2) in rats after MCAo. DHA treatment improved the total and placing deficits on days 1, 3 and 7 compared with the saline-treated group. (e) Content of NPD1 and a second product of the stabilized precursor, 17HDHA, in penumbra regions of rats subjected to MCAo and treated with DHA or vehicle as a control. Data are means±standard error of the mean; n=6 per group. *P<0.05 in repeated-measures, ANOVA followed by Bonferroni test. DHA treatment=teal bars
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fig6: BIRC3 mediates the pro-survival response induced by the DHA/NPD1 pathway in an ischemia-reperfusion stroke model. (a–c) Model for inducing ischemia-reperfusion by middle cerebral artery occlusion (MCAo) in rats. (a) Timeline showing surgery, treatment and tests performed. (b) Coronal brain diagram (bregma level –0.3 mm) showing locations of regions for western blot and immunohistochemistry for Figure 7, and lipidomic analysis (A: anterior; P: posterior). (c) Diagram of MCAo model obtained by introducing intraluminal filament (red). (d) Total neurological score (normal score =0, maximal deficit=12), tactile placing (proprioceptive, lateral, dorsal reactions; normal score=0, maximal deficit=2) in rats after MCAo. DHA treatment improved the total and placing deficits on days 1, 3 and 7 compared with the saline-treated group. (e) Content of NPD1 and a second product of the stabilized precursor, 17HDHA, in penumbra regions of rats subjected to MCAo and treated with DHA or vehicle as a control. Data are means±standard error of the mean; n=6 per group. *P<0.05 in repeated-measures, ANOVA followed by Bonferroni test. DHA treatment=teal bars

Mentions: To test the significance of NPD1 as a modulator of BIRC3 expression in vivo, we used experimental ischemic stroke by means of middle cerebral artery occlusion (MCAo) (Figures 6a–c). Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)-based mediator lipidomic analysis revealed that upon DHA treatment, 17-HDHA (the stable derivative of HpDHA, the precursor of NPD1) as well as NPD1 were increased greatly only 1 day after the ischemic event on the ipsilateral side (Figure 6e). Supplementary Figure S8 shows the mass spectrometry fragmentation pattern of these lipids isolated from the ipsilateral side of the brain. Rats treated with DHA consistently exhibited an improved composite neurologic score compared with the saline-treated group on days 1, 3 and 7 after stroke (Figure 6d). These rats displayed improved tactile placement (proprioceptive, lateral and dorsal), forelimb placement, and an overall increased neurological score (Figure 6d).


NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neural cell survival.

Calandria JM, Asatryan A, Balaszczuk V, Knott EJ, Jun BK, Mukherjee PK, Belayev L, Bazan NG - Cell Death Differ. (2015)

BIRC3 mediates the pro-survival response induced by the DHA/NPD1 pathway in an ischemia-reperfusion stroke model. (a–c) Model for inducing ischemia-reperfusion by middle cerebral artery occlusion (MCAo) in rats. (a) Timeline showing surgery, treatment and tests performed. (b) Coronal brain diagram (bregma level –0.3 mm) showing locations of regions for western blot and immunohistochemistry for Figure 7, and lipidomic analysis (A: anterior; P: posterior). (c) Diagram of MCAo model obtained by introducing intraluminal filament (red). (d) Total neurological score (normal score =0, maximal deficit=12), tactile placing (proprioceptive, lateral, dorsal reactions; normal score=0, maximal deficit=2) in rats after MCAo. DHA treatment improved the total and placing deficits on days 1, 3 and 7 compared with the saline-treated group. (e) Content of NPD1 and a second product of the stabilized precursor, 17HDHA, in penumbra regions of rats subjected to MCAo and treated with DHA or vehicle as a control. Data are means±standard error of the mean; n=6 per group. *P<0.05 in repeated-measures, ANOVA followed by Bonferroni test. DHA treatment=teal bars
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fig6: BIRC3 mediates the pro-survival response induced by the DHA/NPD1 pathway in an ischemia-reperfusion stroke model. (a–c) Model for inducing ischemia-reperfusion by middle cerebral artery occlusion (MCAo) in rats. (a) Timeline showing surgery, treatment and tests performed. (b) Coronal brain diagram (bregma level –0.3 mm) showing locations of regions for western blot and immunohistochemistry for Figure 7, and lipidomic analysis (A: anterior; P: posterior). (c) Diagram of MCAo model obtained by introducing intraluminal filament (red). (d) Total neurological score (normal score =0, maximal deficit=12), tactile placing (proprioceptive, lateral, dorsal reactions; normal score=0, maximal deficit=2) in rats after MCAo. DHA treatment improved the total and placing deficits on days 1, 3 and 7 compared with the saline-treated group. (e) Content of NPD1 and a second product of the stabilized precursor, 17HDHA, in penumbra regions of rats subjected to MCAo and treated with DHA or vehicle as a control. Data are means±standard error of the mean; n=6 per group. *P<0.05 in repeated-measures, ANOVA followed by Bonferroni test. DHA treatment=teal bars
Mentions: To test the significance of NPD1 as a modulator of BIRC3 expression in vivo, we used experimental ischemic stroke by means of middle cerebral artery occlusion (MCAo) (Figures 6a–c). Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)-based mediator lipidomic analysis revealed that upon DHA treatment, 17-HDHA (the stable derivative of HpDHA, the precursor of NPD1) as well as NPD1 were increased greatly only 1 day after the ischemic event on the ipsilateral side (Figure 6e). Supplementary Figure S8 shows the mass spectrometry fragmentation pattern of these lipids isolated from the ipsilateral side of the brain. Rats treated with DHA consistently exhibited an improved composite neurologic score compared with the saline-treated group on days 1, 3 and 7 after stroke (Figure 6d). These rats displayed improved tactile placement (proprioceptive, lateral and dorsal), forelimb placement, and an overall increased neurological score (Figure 6d).

Bottom Line: NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways.These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation.Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, School of Medicine, LSU Health Sciences Center, 2020 Gravier Street, New Orleans, LA 70112, USA.

ABSTRACT
Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

No MeSH data available.


Related in: MedlinePlus