High glucose and palmitic acid induces neuronal senescence by NRSF/REST elevation and the subsequent mTOR-related autophagy suppression

He, Cheng-Feng; Zhou, Renyuan; Xu, Xilong; Xiang, Lv-Xuan; Wang, Jiantao; Wang, Xinru; Zhou, Houguang; Guo, Jing-Chun

doi:10.1186/s13041-022-00947-2

Cited by 19 publications

(7 citation statements)

References 45 publications

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“…To investigate the effect of WH on T2DM-mediated dysfunctional endothelium, an in vitro model of TeloHAEC cells treated with combined HG and PA treatment was used [ 42 , 43 , 44 ]. The single effect of different concentrations of HG (10, 15, 20, and 30 mM) and PA (0.05, 0.1, 0.2, and 0.5 mM) on cell viability was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…TeloHAEC (CRL-4052) cultured in vascular cell basal media (PCS-100-030) supplemented with cell growth kit-VEGF (PCS-100-041) were all obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and properly maintained at 5% CO 2 in 37 °C incubator. The concomitant stimulation with high glucose (HG) and fatty acid (palmitic acid, PA) was used to mimic the in vivo T2DM-related hyperglycemia and hyperlipidemia condition on EC, as reported in different in vitro T2DM models [ 42 , 43 , 44 ]. EC were treated with PA (up to 0.5 mM) and HG (up to 30 mM) for a maximum time of 72 h. WH treatments were performed up to 72 h with different volumes (5–20% v / v ).…”

Section: Methodsmentioning

confidence: 99%

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Whey Improves In Vitro Endothelial Mitochondrial Function and Metabolic Redox Status in Diabetic State

et al. 2023

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Endothelial dysfunction plays a critical role in the progression of type 2 diabetes mellitus (T2DM), leading to cardiovascular complications. Current preventive antioxidant strategies to reduce oxidative stress and improve mitochondrial function in T2DM highlight dietary interventions as a promising approach, stimulating the deepening of knowledge of food sources rich in bioactive components. Whey (WH), a dairy by-product with a considerable content of bioactive compounds (betaines and acylcarnitines), modulates cancer cell metabolism by acting on mitochondrial energy metabolism. Here, we aimed at covering the lack of knowledge on the possible effect of WH on the mitochondrial function in T2DM. The results showed that WH improved human endothelial cell (TeloHAEC) function during the in vitro diabetic condition mimicked by treating cells with palmitic acid (PA) (0.1 mM) and high glucose (HG) (30 mM). Of note, WH protected endothelial cells from PA+HG-induced cytotoxicity (p < 0.01) and prevented cell cycle arrest, apoptotic cell death, redox imbalance, and metabolic alteration (p < 0.01). Moreover, WH counteracted mitochondrial injury and restored SIRT3 levels (p < 0.01). The SiRNA-mediated suppression of SIRT3 abolished the protective effects exerted by WH on the mitochondrial and metabolic impairment caused by PA+HG. These in vitro results reveal the efficacy of whey as a redox and metabolic modulator in the diabetic state and pave the way for future studies to consider whey as the source of dietary bioactive molecules with health benefits in preventive strategies against chronic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Whey Improves In Vitro Endothelial Mitochondrial Function and Metabolic Redox Status in Diabetic State

et al. 2023

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“…Reduction in mTORC1 activity under conditions of nutritional and other stressors is a major promoter of autophagy 68 – 70 . However, a report on diabetes-induced neuronal senescence found that REST elevation under these conditions was associated with a decline in mTOR-mediated autophagy 20 . HIF1α and autophagy are shown to contribute to resistance to chemotherapy and radiation in many cancers 34 , 49 .…”

Section: Discussionmentioning

confidence: 97%

“…Interestingly, REST function is important during aging and in the pathology of neurodegenerative disorders, and appears to involve dysregulation of autophagy 18 , 19 . However, REST upregulation which accompanies exposure of neurons to high glucose and palmitic acid, is also associated with a decrease in autophagy and an increase in senescence-like phenotypes 20 . Other studies have also shown that REST downregulation results in a failure of autophagy, loss of proteostasis, increased oxidative stress, senescence, and cell death in mouse neurons 21 .…”

Section: Introductionmentioning

confidence: 99%

REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma

Singh,

Cheng,

Swaminathan

et al. 2024

Sci Rep

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The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)—a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein – a component of an E3 ligase complex that ubiquitinates HIF1α. Human SHH-medulloblastoma tumors with higher REST expression exhibit nuclear localization of HIF1α, in contrast to its cytoplasmic localization in low-REST tumors. In vitro, REST knockdown promotes an increase in VHL levels and a decrease in cytoplasmic HIF1α protein levels, and autophagy flux. In contrast, REST elevation causes a decline in VHL levels, as well as its interaction with HIF1α, resulting in a reduction in HIF1α ubiquitination and an increase in autophagy flux. These data suggest that REST elevation promotes autophagy in SHH medulloblastoma cells by modulating HIF1α ubiquitination and stability in a VHL-dependent manner. Thus, our study is one of the first to connect VHL to REST-dependent control of autophagy in a subset of medulloblastomas.

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“…Primary cortical neurons were extracted from the cerebral cortex of 1–2 day(s) neonatal mice, as described previously 34 . In brief, mice were anesthetized by CO 2 inhalation.…”

Section: Methodsmentioning

confidence: 99%

Omarigliptin inhibits brain cell ferroptosis after intracerebral hemorrhage

Zhang,

Liu,

Yong

et al. 2023

Sci Rep

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Intracerebral hemorrhage (ICH) is a disastrous disease without effective treatment. An extensive body of evidence indicate that neuronal ferroptosis is a key contributor to neurological disfunctions after ICH. Omarigliptin, also known as MK3102, is an anti-diabetic drug that inhibits dipeptidyl peptidase (DPP4). Recently, MK3102 is reported to exhibit anti-ferroptosis and anti-oxidative effects in different pathological conditions. However, the anti-ferroptosis ability of MK3102 in ICH injury is unknown. Hemin was administrated to model ICH injury in cultured primary cortical neurons, and collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 was administered after ICH. Cell Counting Kit-8 (CCK-8) was applied to detect cell viability. Neurological functions were assessed through the Focal deficits neurological scores and corner test. HE and TUNEL staining was applied to evaluate brain damage areas and cell death, respectively. Ferroptosis was evaluated in cultured neurons by fluorescent probe DCFH-DA, FerroOrange, Liperfluo and immunofluorescence of GPX4, AIFM2 and FACL4. Perls staining was performed to visualize Fe3+ deposition. Ferroptosis-related proteins in mouse brain were measured by immunohistochemistry and western blotting. MK3102 reduced the neurotoxicity of hemin in cultured primary cortical neurons. It improved neurological functions associated with a decrease in the number of dead neurons and the area of brain damage after ICH in mice. Moreover, MK3102 prominently upregulated glucagon-like peptide-1 receptor (GLP-1R) levels after ICH. In addition, the elevation of iron content, lipid peroxidation and FACL4 after ICH; and reduction of GPX4 and AIFM2; were mitigated by MK3102 in vitro and in vivo. The neuroprotective effect of MK3102 may be related to anti-ferroptosis by regulating GLP-1R after ICH injury.

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High glucose and palmitic acid induces neuronal senescence by NRSF/REST elevation and the subsequent mTOR-related autophagy suppression

Cited by 19 publications

References 45 publications

Whey Improves In Vitro Endothelial Mitochondrial Function and Metabolic Redox Status in Diabetic State

Whey Improves In Vitro Endothelial Mitochondrial Function and Metabolic Redox Status in Diabetic State

REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma

Omarigliptin inhibits brain cell ferroptosis after intracerebral hemorrhage

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