Palmitic acid methyl ester is a novel neuroprotective agent against cardiac arrest

Lee, Reggie Hui‐Chao; Possoit, Harlee E.; Lerner, F.; Chen, Po-Yi; Azizbayeva, Rinata; Citadin, Cristiane T.; Neumann, Jake T.; Lin, Hung Wen

doi:10.1016/j.plefa.2018.11.011

Cited by 28 publications

(24 citation statements)

References 52 publications

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“…1B). Since hypoperfusion is most prevalent 24 h after ACA (16,17), we measured cortical CBF at this time point (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…The heart and brain are the most sensitive to ischemic injury since both organs rely heavily upon electrical ionic fluctuations that uses copious amounts of energy. Therefore, most of these disabilities are products of immense neuronal death, particularly in brain regions responsible for learning/memory formation, i.e., CA1 region of the hippocampus (17). Numerous clinical trials have been conducted to treat cerebral ischemia, but beneficial outcomes are still challenging (except for hypothermia) (7), further highlighting the great need to develop novel pharmacological interventions.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Lee

Grames

Lien

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiopulmonary arrest (CA) is the leading cause of death and disability in the United States. CA-induced brain injury is influenced by multi-factorial processes, including reduced cerebral blood flow (hypoperfusion) and neuroinflammation, which can lead to neuronal cell death and functional deficits. We have identified serum and glucocorticoid-regulated kinase-1 (SGK1) as a new target in brain ischemia previously described in the heart, liver, and kidneys (i.e. diabetes and hypertension). Our data suggest brain SGK1 mRNA and protein expression (i.e. hippocampus), presented with hypoperfusion (low cerebral blood flow) and neuroinflammation leading to further studies of the potential role of SGK1 in CA-induced brain injury. We used a 6-mins asphyxia cardiac arrest (ACA) rat model to induce global cerebral ischemia. Modulation of SGK1 was implemented via GSK650394, a SGK1 specific inhibitor (1.2 μg/kg, intracerebroventricular injection). Treatment with GSK650394 attenuated cortical hypoperfusion and neuroinflammation (via Iba1 expression) after ACA, whereas neuronal survival was enhanced in the CA1 region of the hippocampus. Learning/memory deficits were observed 3 days after ACA but ameliorated with GSK650394. SGK1 is a major contributor to ACA-induced brain injury and neurological deficits, while inhibition of SGK1 with GSK650394 provided neuroprotection against CA-induced hypoperfusion, neuroinflammation, neuronal cell death, and learning/memory deficits. Our studies could lead to a novel, therapeutic target for alleviating brain injury following cerebral ischemia.

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“…1B). Since hypoperfusion is most prevalent 24 h after ACA (16,17), we measured cortical CBF at this time point (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Lee

Grames

Lien

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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“…In fact, co-expression of PRMT8 and sodium channel 1.2 enhanced sodium currents, which suggest that arginine-based methylation can modulate neuronal excitability (Baek et al, 2014), as PRMT8 is also a synaptic protein involved in hippocampal-dependent fear learning, dendritic spine maturation, and actin cytoskeleton modulation (Lo et al, 2020;Penney et al, 2017). We previously described that PRMT8 was enhanced in the presence of palmitic acid methyl ester, a known vasodilator and inflammatory regulator against brain ischemia (Lee et al, 2019;Lin & Perez-Pinzon, 2013;Lin et al, 2008;Wu et al, 2021). Therefore, in this study, we further investigated the functional role(s) of brain PRMT8 in response to cellular stress.…”

Section: Discussionmentioning

confidence: 98%

Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and neuroinflammation after hypoxic stress

Clemons

Acosta

Chen

et al. 2021

Journal of Neurochemistry

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Arginine methylation is a post-translational process that is involved in epigenetic regulation, mRNA splicing, cell signaling, protein ubiquitination, phosphorylation, and acetylation (Kandel, 2001).The protein arginine methyltransferase (PRMT) family of enzymes are responsible for the transfer of methyl groups onto target arginine residues (e.g., RGG/RG motifs) on proteins, to result in a variety of cellular and protein signaling responses (Blanc & Richard, 2017). Recent studies have been focused on understanding PRMT function in various pathologies; however, the exact role of PRMTs has not been well elucidated in neurological function

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“…Previous studies have shown that PAME can enhance cerebral blood flow (CBF), thereby alleviating neuronal cell death in the CA1 region of the hippocampus after cerebral ischemia. Furthermore, PAME also exerts other nonvasodilation-dependent neuroprotective effects (i.e., antiapoptosis) [40, 41]. In the present study, our data revealed that PAME did not cause apoptosis and necrosis in hBM-MSCs (Figures 2(e) and 2(f)) but did increase the expression of p21 (Figure 4(b)), which has been indicated to act as an inhibitor of apoptosis in a number of systems [42].…”

Section: Discussionmentioning

confidence: 99%

Palmitic Acid Methyl Ester Induces G₂/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway

Lin

Ting

Lee

et al. 2019

Stem Cells International

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Bone marrow-derived mesenchymal cells (BM-MSCs) are able to differentiate into adipocytes, which can secrete adipokines to affect BM-MSC proliferation and differentiation. Recent evidences indicated that adipocytes can secrete fatty acid metabolites, such as palmitic acid methyl ester (PAME), which is able to cause vasorelaxation and exerts anti-inflammatory effects. However, effects of PAME on BM-MSC proliferation remain unclear. The aim of this study was to investigate the effect of PAME on human BM-MSC (hBM-MSC) proliferation and its underlying molecular mechanisms. hBM-MSCs were treated with PAME for 48 h and then subjected to various analyses. The results from the present study show that PAME significantly reduced the levels of G2/M phase regulatory proteins, cyclin-dependent kinase 1 (Cdk1), and cyclin B1 and inhibited proliferation in hBM-MSCs. Moreover, the level of Mdm2 protein decreased, while the levels of p21 and p53 protein increased in the PAME-treated hBM-MSCs. However, PAME treatment did not significantly affect apoptosis/necrosis, ROS generation, and the level of Cdc25C protein. PAME also induced intracellular acidosis and increased intracellular Ca2+ levels. Cotreatment with PAME and Na+/H+ exchanger inhibitors together further reduced the intracellular pH but did not affect the PAME-induced decreases of cell proliferation and increases of the cell population at the G2/M phase. Cotreatment with PAME and a calcium chelator together inhibited the PAME-increased intracellular Ca2+ levels but did not affect the PAME-induced cell proliferation inhibition and G2/M cell cycle arrest. Moreover, the half-life of p53 protein was prolonged in the PAME-treated hBM-MSCs. Taken together, these results suggest that PAME induced p53 stabilization, which in turn increased the levels of p53/p21 proteins and decreased the levels of Cdk1/cyclin B1 proteins, thereby preventing the activation of Cdk1, and eventually caused cell cycle arrest at the G2/M phase. The findings from the present study might help get insight into the physiological roles of PAME in regulating hBM-MSC proliferation.

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Palmitic acid methyl ester is a novel neuroprotective agent against cardiac arrest

Cited by 28 publications

References 52 publications

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and neuroinflammation after hypoxic stress

Palmitic Acid Methyl Ester Induces G₂/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway

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Palmitic acid methyl ester is a novel neuroprotective agent against cardiac arrest

Cited by 28 publications

References 52 publications

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and neuroinflammation after hypoxic stress

Palmitic Acid Methyl Ester Induces G2/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway

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Palmitic Acid Methyl Ester Induces G₂/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway