Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia

Vetrovoy, O. V.; Sarieva, Kseniia; Lomert, Ekaterina; Nimiritsky, Peter; Eschenko, Natalia; Galkina, Olga; Lyanguzov, A. Yu.; Tyulkova, E. I.; Рыбникова, Е. А.

doi:10.1007/s12031-019-01469-8

Cited by 28 publications

(17 citation statements)

References 55 publications

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“…As mentioned above, HIF-mediated signaling modulates the expressions of multiple target genes, some of which can evoke pathological processes ( Sheldon et al, 2009 ; Barteczek et al, 2017 ). HIF-1 activation during the early acute phase of the hypoxic response triggers a cascade of adverse cerebral events that are associated with pentose phosphate pathway suppression ( Vetrovoy et al, 2019 ). Under oxygen-glucose deprivation, glucose oxidation via the pentose phosphate pathway terminates oxidative stress development through modulation of redox homeostasis and the antioxidant system of the cell ( Fernandez-Fernandez et al, 2012 ; Sun et al, 2017 ; Vetrovoy et al, 2019 ).…”

Section: Adverse Effects Of Hif-1α Signaling In Ischemiamentioning

confidence: 99%

“…HIF-1 activation during the early acute phase of the hypoxic response triggers a cascade of adverse cerebral events that are associated with pentose phosphate pathway suppression ( Vetrovoy et al, 2019 ). Under oxygen-glucose deprivation, glucose oxidation via the pentose phosphate pathway terminates oxidative stress development through modulation of redox homeostasis and the antioxidant system of the cell ( Fernandez-Fernandez et al, 2012 ; Sun et al, 2017 ; Vetrovoy et al, 2019 ). During hypoxia, HIF-1 also strongly upregulates expression of the gene encoding the Na + -dependent chloride transporter NKCC1 ( Yang et al, 2019 ).…”

Section: Adverse Effects Of Hif-1α Signaling In Ischemiamentioning

confidence: 99%

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Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

Митрошина

Savyuk

Ponimaskin

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia is one of the most common pathological conditions, which can be induced by multiple events, including ischemic injury, trauma, inflammation, tumors, etc. The body’s adaptation to hypoxia is a highly important phenomenon in both health and disease. Most cellular responses to hypoxia are associated with a family of transcription factors called hypoxia-inducible factors (HIFs), which induce the expression of a wide range of genes that help cells adapt to a hypoxic environment. Basic mechanisms of adaptation to hypoxia, and particularly HIF functions, have being extensively studied over recent decades, leading to the 2019 Nobel Prize in Physiology or Medicine. Based on their pivotal physiological importance, HIFs are attracting increasing attention as a new potential target for treating a large number of hypoxia-associated diseases. Most of the experimental work related to HIFs has focused on roles in the liver and kidney. However, increasing evidence clearly demonstrates that HIF-based responses represent an universal adaptation mechanism in all tissue types, including the central nervous system (CNS). In the CNS, HIFs are critically involved in the regulation of neurogenesis, nerve cell differentiation, and neuronal apoptosis. In this mini-review, we provide an overview of the complex role of HIF-1 in the adaptation of neurons and glia cells to hypoxia, with a focus on its potential involvement into various neuronal pathologies and on its possible role as a novel therapeutic target.

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Section: Adverse Effects Of Hif-1α Signaling In Ischemiamentioning

confidence: 99%

Section: Adverse Effects Of Hif-1α Signaling In Ischemiamentioning

confidence: 99%

Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

Митрошина

Savyuk

Ponimaskin

et al. 2021

Front. Cell Dev. Biol.

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“…Topotecan is reported to attenuate LPS-mediated acute lung injury via the NF-κB pathway [ 22 ]. Additionally, Oleg et al [ 23 ] demonstrated that targeted inhibition of HIF-1 might represent a novel neuroprotective strategy by preventing neuronal apoptosis in rat hippocampus caused by severe hypoxia. Compelling evidence indicates that topotecan administration inhibits HIF-1a expression and improves retinal ganglion cell survival leading to a functional protection against retinal ischemia–reperfusion [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible transcription factor-1α inhibition by topotecan protects against lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes

Zhang

Zhou

et al. 2021

BioMed Eng OnLine

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Background Myocarditis, an inflammatory disease of the myocardium, is a serious hazard to human life due to the expansion of inflammatory lesions in the myocardium. The aim of this study was to investigate the role of hypoxia-inducible transcription factor (HIF)-1α and its inhibitor topotecan in the pathogenesis of myocarditis. Methods H9c2 cardiomyoblasts was stimulated with lipopolysaccharide (LPS) to simulate myocarditis model in vitro. The levels of myocardial damage markers were determined using commercially available kits. Western blotting was used to evaluate HIF-1α expression after LPS challenge. Then, after HIF-1α silencing, the contents of inflammatory factors were determined with enzyme-linked immunosorbent assay (ELISA). Cell viability was tested by means of a cell counting kit-8 (CCK-8) assay. Cell apoptosis was assessed by flow cytometry, and the expression of apoptotic proteins was examined using western blot analysis. Subsequently, HIF-1α was overexpressed and topotecan was employed to treat H9c2 cells under LPS exposure condition. The biological functions were detected again. Results LPS significantly elevated the levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin-I (cTn-I) in supernatant of H9c2 cell lysates. Additionally, LPS led to the notably upregulated expression of HIF-1α. HIF-1α-knockdown markedly decreased the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 compared with the LPS-induced group. Moreover, the cell viability was conspicuously enhanced and cell apoptotic ratio was remarkably reduced, accompanied by downregulated expression of Bax, Bim, caspase 3 and caspase 9 after HIF-1α silencing. Consistently, HIF-1α gain-of-function significantly promoted the production of inflammatory cytokines and cell apoptosis, which was partially counteracted by topotecan administration. Conclusion To conclude, these findings demonstrated that HIF-1α inhibition by topotecan ameliorates LPS-induced myocarditis in vitro, providing a new approach in the treatment of myocarditis.

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“…In this study, mfat-1 transgenic mice had protective effects on HIBD-induced brain damage by signi cantly reduced infarct range, greatly improved neurobehavioral defects, relatively lower level of neuronal necrosis, apoptosis and in ammation. Although many studies have revealed its pathological mechanism [55,56], the molecular details of the subsequent events after HIBD and the underlying protective mechanism from mfat-1 mice still needed to be further elucidated. RNA-seq technology was used to identify the full gene expression pro les of WT and mfat-1 mice at 24 h after acute ischemia and hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of high n-3/n-6 PUFA ratio on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice and possible inflammation-related targets identified by transcriptome analysis

Geng¹,

Wang²,

Leng³

et al. 2020

Preprint

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BackgroundAcute hypoxic-ischemic brain damage (HIBD) occurs not only in newborns but also in adults. It is associated with series of cellular and biochemical pathways that lead to neuronal injury. N-3 polyunsaturated fatty acids (PUFAs) have been reported to improve neuron functions via G protein-coupled receptor 120 signal pathway in cells or with exogenous supplementation. Possible protective targets and underlying mechanisms of high proportion of n-3/n-6 PUFAs contained in the brains of mfat-1 transgenic mice on HIBD-induced adult brain damage needed to be further investigated.MethodsThe adult C57BL/6J (WT) and mfat-1 transgenic mice adopted HIBD model. A gas chromatograph was used to determine the composition of PUFAs. Neurological deficit scores test, TTC staining and Nissl staining were employed to evaluate the neuroprotective effects. Cleaved-caspase3 and TUNEL experiment were used to detect apoptosis after injury. Inflammatory factors were detected by ELISA assay. RNA-sequencing analysis was processed and the differential expressed genes were verified by real-time quantitative PCR. Key factors related to inflammation were detected by immunofluorescence and western blot.ResultsThe mfat-1 transgenic mice with high ratio of n-3/n-6 PUFAs in brain tissues were showed to have protective effects on HIBD-induced brain damage by reduced infarct range and greatly improved neurobehavioral defects. Further analysis revealed that the level of neuronal necrosis, apoptosis and inflammation induced by brain injury were relatively low. RNA-seq analysis showed multiple pathways and targets involved in this process. Significant activation of GPR120, reduction of phosphorylation of TAK1 and NF-κB P65 in the downstream of the pro-inflammatory pathway were found in the brains of mfat-1 mice on HIBD. ConclusionsThe study showed that mfat-1 transgenic mice had protective effects on HIBD-induced brain injury by multiple pathways. Activation of GPR120 and reduction of related pro-inflammatory pathway involved in this process, which may improve or prevent dangerous perioperative and postoperative complications, innovate clinical intervention strategy and potentially benefit more patients.

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Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia

Cited by 28 publications

References 55 publications

Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

Hypoxia-inducible transcription factor-1α inhibition by topotecan protects against lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes

Protective effect of high n-3/n-6 PUFA ratio on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice and possible inflammation-related targets identified by transcriptome analysis

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