HIF-1α/Beclin1-Mediated Autophagy Is Involved in Neuroprotection Induced by Hypoxic Preconditioning

Lu, Na; Li, Xingxing; Tan, Ruolan; An, Jing; Cai, Zhenlu; Hu, Xiaoxuan; Wang, Feidi; Wang, Haoruo; Lu, Chengbiao; Lü, Haixia

doi:10.1007/s12031-018-1162-7

Cited by 93 publications

(67 citation statements)

References 60 publications

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“…Li et al 34 , reported that FG4592 induced autophagy in SH-SY5Y cells via LC3II/LC3I upregulation and p62 downregulation. The "clinical" PHD inhibitors significantly upregulated Beclin1 in the PC12 cells, which is line with the study by Lu et al 35 showed that HIF-1/ BNIP3/Beclin1 signalling pathway modulates autophagy and contributes to hypoxia preconditioning-induced protection against OGD/Reperfusion. Although rapamycin promoted autophagy (shown by LC3-II upregulation and p62 downregulation), it did not upregulate the expression of Beclin1.…”

Section: Discussionsupporting

confidence: 88%

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model

Singh

Wilson

Schofield

et al. 2020

Sci Rep

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This study compared effects of five hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) inhibitors on PC12 cells and primary rat neurons following oxygen-glucose deprivation (OGD). At 100 µM, the PHD inhibitors did not cause cytotoxicity and apoptosis. MTT activity was only significantly reduced by FG4592 or Bayer 85-3934 in PC12 cells. The PHD inhibitors at 100 µM significantly increased the LC3-II/LC3-I expression ratio and downregulated p62 in PC12 cells, so did FG4592 (30 µM) and DMOG (100 µM) in neurons. HIF-1α was stabilised in PC12 cells by all the PHD inhibitors at 100 µM except for DMOG, which stabilised HIF-1α at 1 and 2 mM. In primary neurons, HIF-1α was stabilised by FG4592 (30 µM) and DMOG (100 µM). Pretreatment with the PHD inhibitors 24 hours followed by 24 hour reoxygenation prior to 6 hours OGD (0.3% O 2) significantly reduced LDH release and increased MTT activity compared to vehicle (1% DMSO) pretreatment. In conclusion, the PHD inhibitors stabilise HIF-1α in normoxia, induce autophagy, and protect cells from a subsequent OGD insult. The new class of PHD inhibitors (FG4592, FG2216, GSK1278863, Bay85-3934) have the higher potency than DMOG. The interplay between autophagy, HIF stabilisation and neuroprotection in ischaemic stroke merits further investigation.

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Section: Discussionsupporting

confidence: 88%

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model

Singh

Wilson

Schofield

et al. 2020

Sci Rep

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“…Hypoxic preconditioned-MSCs exert superior protected role and has been confirmed to involve HIF1α and Bec-lin1 signaling pathway in several conditions [96][97][98]. Pretreatment of MSCs with different hypoxic oxygen concentrations have shown promising outcomes in the therapeutics of MCSs by critically influencing their inherent characteristics including reduced senescence.…”

Section: Reducing Premature Senescencementioning

confidence: 99%

Improved therapeutics of modified mesenchymal stem cells: an update

Pei²,

et al. 2020

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Background: Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. Body: In the quest to circumvent these challenges, several modification techniques have been applied to the naïve MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. Conclusion: The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.

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“…In recent years, many studies have shown that hypoxia preconditioning (HPC) could increase the resistance of brain to subsequent hypoxic insults [1][2][3]. Gidday et al [4] showed that after pre-exposure to 8% oxygen for 3 h for 1 day, the rat brain can be protected from hypoxic-ischemic injury induced 1 day after HPC.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat

Wang

et al. 2020

Neurosurg Rev

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Hypoxia preconditioning (HPC), a well-established preconditioning model, has been shown to protect the brain against severe hypoxia or ischemia caused by traumatic brain injury (TBI), but the mechanism has not been well elucidated. Anaerobic glycolysis is the major way for neurons to produce energy under cerebral ischemia and hypoxia after TBI, and it requires large amounts of glucose. We hypothesized that glucose transport, as a rate-limiting step of glucose metabolism, may play key roles in the neuroprotective effects of HPC on cerebral cortex tissue against TBI. The aim of this study was to investigate the effect of HPC on glucose transport activity of rat cerebral cortex tissue after TBI through examining the gene expression of two major glucose transporters (GLUT1 and GLUT3) and their upstream target gene hypoxia-inducible factor-1α (HIF-1α). Sprague-Dawley rats were treated with HPC (50.47 kPa, 3 h/d, 3d). Twenty-four hours after the last treatment, the rats were injured using the Feeney free falling model. Cortex tissues of injured rats were removed at 1 h, 4 h, 8 h, 12 h, 1 day, 3 days, 7 d, and 14 days post-injury for histological analysis. Compared with TBI alone, HPC before TBI resulted in the expression of HIF-1α, GLUT1, and GLUT3 to increase at 1 h; they were markedly increased at 4 h, 8 h, 12 h, 1 day, and 3 days and decreased thereafter (p < 0.05). HPC before TBI could improve neuronal survival in rats by examining NeuN staining and observing reduced apoptosis by examining TUNEL staining. The result showed that HPC before TBI could increase the expression of GLUT1 and GLUT3. And through double immunofluorescence staining for GLUT3 and NeuN, the results strongly suggest that HPC improved glucose transport activity of neurons in rats with TBI. In summary, our results further support that HPC can improve hypoxia tolerance and attenuate neuronal loss of cerebral cortex in rats after TBI. The mechanism is mainly related to the increase of glucose transport activity through inducing GLUT1 and GLUT3 expression through upregulating HIF-1α expression.

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HIF-1α/Beclin1-Mediated Autophagy Is Involved in Neuroprotection Induced by Hypoxic Preconditioning

Cited by 93 publications

References 60 publications

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model

Improved therapeutics of modified mesenchymal stem cells: an update

Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat

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