Hamartin: An Endogenous Neuroprotective Molecule Induced by Hypoxic Preconditioning

Li, Sijie; Ren, Chang­hong; Stone, Christopher; Chandra, Ankush; Xu, Jiali; Li, Ning; Han, Cong; Ding, Yuchuan; Ji, Xunming; Shao, Guo

doi:10.3389/fgene.2020.582368

Cited by 5 publications

(6 citation statements)

References 115 publications

(129 reference statements)

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“…The upregulation of TSC1 inhibits the mTOR pathway by reducing the energy demand of cells, thereby providing protection against hypoxic/ischemic injury. A commonality between the mechanisms that underlie the HPC and IPC is the metabolic depression of cerebral metabolism and activity to produce a hibernation-like state, the ability to regulate body temperature and thus metabolic rate lies at the center of metabolic depression [1]. We found that HPC can induce TSC1 expression in both mRNA and protein levels in CA1.…”

Section: Discussionmentioning

confidence: 70%

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Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning

Xie

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. It has been reported that ischemia and ischemic preconditioning (IPC) have different effects on the expression of tuberous sclerosis complex 1 (TSC1), which may contribute to the tolerance to ischemia/hypoxia with the increase of autophagy. The mechanisms of TSC1 differential expression are still unclear under ischemia/IPC conditions in hippocampal Cornu Ammon 1 (CA1) and Cornu Ammon 3 (CA3) area neuronal cells. While we have shown that 5-Aza-CdR, a DNA methyltransferase inhibitor, can upregulate TSC1 and increase hypoxic tolerance by autophagy in vivo and in vitro, in this study, we examined whether DNA methylation was involved in the differential expression of TSC1 in the CA1 and CA3 regions induced by hypoxic preconditioning (HPC). Methods. Level of rapamycin (mTOR) autophagy, a downstream molecular pathway of TSC1/TSC2 complex, was detected in HPC mouse hippocampal CA1 and CA3 areas as well as in the HPC model of mouse hippocampal HT22 cells. DNA methylation level of TSC1 promoter (-720 bp~ -360 bp) was determined in CA1 and CA3 areas by bisulfite-modified DNA sequencing (BMDS). At the same time, autophagy was detected in HT22 cells transfected with GFP-LC3 plasmid. The role of TSC1 in neuroprotection was measured by cell viability and apoptosis, and the role of TSC1 in metabolism was checked by ATP assay and ROS assay in HT22 cells that overexpressed/knocked down TSC1. Results. HPC upregulated the expression of TSC1, downregulated the level of P-mTOR (Ser2448) and P-p70S6K (Thr389), and enhanced the activity of autophagy in both in vivo and in vitro. The increased expression of TSC1 in HPC may depend on its DNA hypomethylation in the promoter region in vivo. HPC also could reduce energy consumption in HT22 cells. Overexpression and knockdown of TSC1 can affect cell viability, cell apoptosis, and metabolism in HT22 cells exposed to hypoxia. Conclusion. TSC1 expression induced by HPC may relate to the downregulation of its DNA methylation level with the increase of autophagy and the decrease of energy demand.

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Section: Discussionmentioning

confidence: 70%

“…The brain is the most sensitive to hypoxic/ischemic injury due to its high demand for oxygen and glucose [1,2]. The hippocampal CA1 area is sensitive to hypoxic/ischemic injury extremely, while its adjacent CA3 area is remarkably resistant to hypoxic/ischemic injury [3,4].…”

Section: Introductionmentioning

confidence: 99%

Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning

Xie

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…A possible endogenous neuroprotective mechanism of HPC is the downregulation of "bad genes" with damage effects and the upregulation of "good genes" with protection effects through regulation of the gene expression. 2,13 BDNF is a typical "good gene" that regulates many neurological functions and plays a critical role in the recovery of the brain from injury. 20 Our results showed that BDNF was significantly upregulated at the mRNA and protein levels in the hippocampus of HPC mice (Figure 1).…”

Section: ■ Discussionmentioning

confidence: 99%

“…The protective effect of HPC is endogenous and may be due to changes in gene expression when cells are under extreme conditions . The regulation of gene expression involves epigenetics.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice

Zhang

Jia

et al. 2023

ACS Chem. Neurosci.

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Hypoxic preconditioning (HPC) as an endogenous mechanism can resist hypoxia/ischemia injury and exhibit protective effects on neurological function including learning and memory. Although underlying molecular mechanisms remain unclear, HPC probably regulates the expression of protective molecules by modulating DNA methylation. Brain-derived neurotrophic factor (BDNF) activates its signaling upon binding to the tropomyosin-related kinase B (TrkB) receptor, which is involved in neuronal growth, differentiation, and synaptic plasticity. Therefore, this study focused on the mechanism by which HPC regulates BDNF and BDNF/TrkB signaling through DNA methylation to influence learning and memory. Initially, the HPC model was established by hypoxia stimulations on ICR mice. We found that HPC downregulated the expression of DNA methyltransferase (DNMT) 3A and DNMT3B. Then, the upregulation of BDNF expression in HPC mice was generated from a decrease in DNA methylation of the BDNF gene promoter detected by pyrophosphate sequencing. Subsequently, upregulation of BDNF activated BDNF/TrkB signaling and ultimately improved learning and spatial memory in HPC mice. Moreover, after mice were intracerebroventricularly injected with the DNMT inhibitor, the restraint of DNA methylation accompanied by an increase of BDNF and BDNF/TrkB signaling was also discovered. Finally, we observed that the inhibitor of BDNF/TrkB signaling prevented HPC from ameliorating learning and memory in mice. However, the DNMT inhibitor promoted spatial cognition in mice. Thus, we suggest that HPC may upregulate BDNF by inhibiting DNMTs and decreasing DNA methylation of the BDNF gene and then activate BDNF/TrkB signaling to improve learning and memory in mice. This may provide theoretical guidance for the clinical treatment of cognitive dysfunction caused by ischemia/hypoxia disease.

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“…Ischemic stroke is generally caused by arterial embolization or the thrombotic occlusion of the brain. The brain is susceptible to hypoxic and ischemic injury due to its high demand for oxygen and glucose [ 4 ]; therefore, there is an urgent need to explore the molecular mechanisms of hypoxic and ischemic injury to search for targeted therapeutics for neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

The Role of the lncRNA MALAT1 in Neuroprotection against Hypoxic/Ischemic Injury

Wang

Stone

et al. 2022

Biomolecules

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Hypoxic and ischemic brain injury can cause neurological disability and mortality, and has become a serious public health problem worldwide. Long-chain non-coding RNAs are involved in the regulation of many diseases. Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) is a type of long non-coding RNA (lncRNA), known as long intergenic non-coding RNA (lincRNA), and is highly abundant in the nervous system. The enrichment of MALAT1 in the brain indicates that it may be associated with important functions in pathophysiological processes. Accordingly, the role of MALAT1 in neuronal cell hypoxic/ischemic injury has been gradually discovered over recent years. In this article, we summarize recent research regarding the neuroprotective molecular mechanism of MALAT1 and its regulation of pathophysiological processes of brain hypoxic/ischemic injury. MALAT1 may function as a regulator through interaction with proteins or RNAs to perform its role, and may therefore serve as a therapeutic target in cerebral hypoxia/ischemia.

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Hamartin: An Endogenous Neuroprotective Molecule Induced by Hypoxic Preconditioning

Cited by 5 publications

References 115 publications

Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning

Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice

The Role of the lncRNA MALAT1 in Neuroprotection against Hypoxic/Ischemic Injury

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