MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells

Khan, Mehtab; Rutten, Bart P. F.; Kim, Myeong Ok

doi:10.3390/ijms20102504

Cited by 35 publications

(18 citation statements)

References 73 publications

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“…ROS assay was performed as previously described with slight modification [38,39]. The cells were cultured in 96-well plates in 200 μL DMEM containing 10% FBS and 1% penicillin/streptomycin in every well.…”

Section: Methodsmentioning

confidence: 99%

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Khan

Ullah

Rehman

et al. 2019

Cells

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Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17β-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17β-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress–mediated JNK/NF-ҡB overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17β-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17β-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17β-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17β-estradiol, in an ERα/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress–mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.

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Section: Methodsmentioning

confidence: 99%

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Khan

Ullah

Rehman

et al. 2019

Cells

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“…It has been demonstrated that consumption of a high-calorie diet intake enhanced oxidative stress in several tissues, including brain tissue [34,49]. Similarly, others also demonstrated that consumption of HFD significantly reduced the protein expression level of hemeoxygenase-1 (HO-1) and nuclear factor-2 erythroid-2 (Nrf-2) in HFD-fed mice brains [28].…”

Section: Hfd Induces Oxidative-stress-mediated Brain Insulin Resistanmentioning

confidence: 97%

Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer’s Like Pathology in Mice Brain

Hahm

Ullah

et al. 2020

Cells

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Oxidative stress and insulin resistance play major roles in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). A high-fat diet induces obesity-associated oxidative stress, neuronal insulin resistance, microglial activation, and neuroinflammation, which are considered important risk factors for neurodegeneration. Obesity-related metabolic dysfunction is a risk factor for cognitive decline. The present study aimed to elucidate whether chronic consumption of a high-fat diet (HFD; 24 weeks) can induce insulin resistance, neuroinflammation, and amyloid beta (Aβ) deposition in mouse brains. Male C57BL/6N mice were used for a high-fat diet (HFD)-induced pre-clinical model of obesity. The protein expression levels were examined via Western blot, immunofluorescence, and the behavior analysis was performed using the Morris water maze test. To obtain metabolic parameters, insulin sensitivity and glucose tolerance tests were performed. We found that metabolic perturbations from the chronic consumption of HFD elevated neuronal oxidative stress and insulin resistance through adiponectin receptor (AdipoR1) suppression in HFD-fed mice. Similarly, our in vitro results also indicated that knockdown of AdipoR1 in the embryonic mouse hippocampal cell line mHippoE-14 leads to increased oxidative stress in neurons. In addition, HFD markedly increased neuroinflammatory markers’ glial activation in the cortex and hippocampus regions of HFD mouse brains. More importantly, we observed that AdipoR1 suppression increased the amyloidogenic pathway both in vivo and in vitro. Furthermore, deregulated synaptic proteins and behavioral deficits were observed in the HFD mouse brains. Taken together, our findings suggest that excessive consumption of an HFD has a profound impact on brain function, which involves the acceleration of cognitive impairment due to increased obesity-associated oxidative stress, insulin resistance, and neuroinflammation, which ultimately may cause early onset of Alzheimer’s pathology via the suppression of AdipoR1 signaling in the brain.

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“…Activation of the MST1-JNK pathway has been described to promote cell death (72). We, thus, studied whether chronic GPER1 actions deactivate the MST1-JNK axis in H9c2 cardiomyoblasts treated with H 2 O 2 agent.…”

Section: Chronic Gper1 Activation Reduces Mst1-jnk Signalingmentioning

confidence: 99%

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

et al. 2020

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Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H 2 O 2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H 2 O 2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but Imam Aliagan et al. Chronic GPER1 Actions and Cell Death with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGFβ and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stressinduced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).

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MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells

Cited by 35 publications

References 73 publications

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer’s Like Pathology in Mice Brain

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

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