Neuroglobin Regulates Hypoxic Response of Neuronal Cells through Hif-1<i>α</i>- and Nrf2-mediated Mechanism

Hota, Kalpana Barhwal; Hota, Sunil Kumar; Srivastava, Ravi B.; Singh, Shashi Bala

doi:10.1038/jcbfm.2012.21

Cited by 50 publications

(42 citation statements)

References 39 publications

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“…The underlying mechanisms responsible for this discrepancy are unclear. We assume that HIF-1α activated by SE stimulates different signaling pathways in the cellular nucleus and cytoplasm that regulate expression of PICs due to different HIF-1α-targeted genes [5,6].…”

Section: Discussionmentioning

confidence: 99%

“…Accumulated subunit HIF-1α in the cellular nucleus and cytoplasm modulates the expression of several target genes which are involved in neuroprotection, erythropoiesis, and apoptosis modulation [5,6]. Additionally, inadequate oxygen supply is likely to appear in the brain regions during SE, which is associated with seizure-evoked behavioral activities [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting HIF-1α Decreases Expression of TNF-α and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus

Yang

He²,

Meng³

et al. 2016

Cell Physiol Biochem

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Background/Aims: A recent study demonstrates that pro-inflammatory cytokines (PICs, i.e., IL-1β, IL-6 and TNF-α) in specific brain regions of rats play a role in regulating kainic acid (KA)-induced status epilepticus (SE) via a GABAergic mechanism. The purposes of this report were to examine contributions of hypoxia inducible factor subtype 1α (HIF-1α) to expression of PICs in these specific brain regions in epileptic rats. Particularly, we investigated the parietal cortex, hippocampus and amygdala. In addition, we further examined expression of Caspase-3 indicating cell apoptosis in those brain regions of epileptic rats after infusing 2-methoxyestradiol (2-MET, inhibitor of HIF-1α) and etanercept (TNF-α receptor antagonist). Methods: ELISA was used to determine the levels of HIF-1α and PICs and western blot analysis was used to examine Caspase-3 expression. Results: Our data show that HIF-1α was significantly increased in the parietal cortex, hippocampus and amygdala 1, 3 and 7 days after induction of SE (P<0.05 vs. control rats). Our results also show that inhibiting HIF-1α by central infusion of 2-MET significantly decreased the amplified TNF-α expression in these brain regions evoked by SE (P<0.05 vs. vehicle control), but did not modify IL-1β and IL-6. Our results demonstrate that 2-MET and etanercept attenuated an increase in Caspase-3 evoked by SE. Conclusion: Overall, we suggest that HIF-1α activated by SE is likely to contribute to epileptic activity via a TNF-α pathway, which has pharmacological implications to target specific HIF-1α and TNF-α pathways for neuronal dysfunction and vulnerability related to epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibiting HIF-1α Decreases Expression of TNF-α and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus

Yang

He²,

Meng³

et al. 2016

Cell Physiol Biochem

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“…Accumulated subunit HIF-1α in the cellular nucleus and cytoplasm modulates the expression of several target genes that involve in neuroprotection, erythropoiesis, and apoptosis modulation [11,12]. Additionally, inadequate oxygen supply appears in the brain regions during global ischemia, which is associated with ischemiaevoked pathophysiologic changes [13,14].…”

Section: Introductionmentioning

confidence: 99%

HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia

Xing

2016

Cell Physiol Biochem

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Background/Aims: This study was to examine the role played by hypoxia inducible factor-1 (HIF-1α) in regulating pro-inflammatory cytokines (PICs) pathway in the rat hippocampus after cardiac arrest (CA) induced-transient global ischemia followed by cardiopulmonary resuscitation (CPR). Those PICs include interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Methods: A rat model of CA induced by asphyxia was used in the current study. Following CPR, the hippocampus CA1 region was obtained for ELISA to determine the levels of HIF-1α and PICs; and Western Blot analysis to determine the protein levels of PIC receptors. Results: Our data show that IL-1β, IL-6 and TNF-α were significant elevated in the hippocampus after CPR as compared with control group. This was companied with increasing of HIF-1α and the time courses for HIF-1α and PICs were similar. In addition, PIC receptors, namely IL-1R, IL-6R and TNFR1 were upregulated in CA rats. Also, stimulation of HIF-1α by systemic administration of ML228, HIF-1α activator, significantly attenuated the amplified IL-6/IL-6R and TNF-α /TNFR1 pathway in the hippocampus of CA rats, but did not modify IL-1β and its receptor. Moreover, ML228 attenuated upregulated expression of Caspase-3 indicating cell apoptosis evoked by CA. Conclusion: Transient global ischemia induced by CA increases the levels of IL-1β, IL-6 and TNF-α and thereby leads to enhancement in their respective receptor in the rat hippocampus. Stabilization of HIF-1α plays a role in attenuating amplified expression IL-6R, TNFR1 and Caspase-3 in the processing of transient global ischemia. Results of our study suggest that PICs contribute to cerebral injuries evoked by transient global ischemia and in this pathophysiological process activation of HIF-1α improves tissues against ischemic injuries. Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that HIF-1α plays an important role in regulating PIC signal pathways and Caspase-3. The subsequent induction of HIF-1α and its target signals is likely a part of the intrinsic neuroprotective effects aimed at attenuating damage as a result of global cerebral ischemia. Thus, targeting one or more of these signaling molecules has clinical implications for treatment and improvement of CA-evoked global cerebral ischemia often observed in clinics.

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“…A recent study showed that Ngb regulates Hif1α and Nrf2 (Nfe2l2) expression and antioxidant levels in cells exposed to hypoxia (26). Therefore, the following genes were chosen for differential expression analysis using RT-qPCR in the dark-adapted retina: Hif1α, the Hif1α target gene Bnip3 (27), the glutathione system genes Gsr and Gstz1, the master regulator of oxidative stress responsive genes Nfe2l2 (28) and the unfolded protein response regulator Xbp1 (29).…”

Section: H 5 H ------------------------------------------------------mentioning

confidence: 99%

Effect of light on global gene expression in the neuroglobin-deficient mouse retina

et al. 2014

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Abstract. Several previous studies have raised controversy over the functional role of neuroglobin (Ngb) in the retina. Certain studies indicate a significant impact of Ngb on retinal physiology, whereas others are conflicting. The present is an observational study that tested the effect of Ngb deficiency on gene expression in dark-and light-adapted mouse retinas. Large-scale gene expression profiling was performed using GeneChip ® Mouse Exon 1.0 ST arrays and the results were compared to publicly available data sets. The lack of Ngb was found to have a minor effect on the light-induced retinal gene expression response. In addition, there was no increase in the expression of marker genes associated with hypoxia, endoplasmic reticulum-stress and oxidative stress in the Ngb-deficient retina. By contrast, several genes were identified that appeared to be differentially expressed between the genotypes when the effect of light was ignored. The present study indicates that Ngb deficiency does not lead to major alternations in light-dependent gene expression response, but leads to subtle systemic differences of a currently unknown functional significance.

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Neuroglobin Regulates Hypoxic Response of Neuronal Cells through Hif-1α- and Nrf2-mediated Mechanism

Cited by 50 publications

References 39 publications

Inhibiting HIF-1α Decreases Expression of TNF-α and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus

Inhibiting HIF-1α Decreases Expression of TNF-α and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus

HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia

Effect of light on global gene expression in the neuroglobin-deficient mouse retina

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