• Korean Journal of Biological Psychiatry
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• v.23 no.1
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• pp.18-23
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• 2016

Depression is a complicated psychiatric illness with severe consequences. Despite recent advanced achievements of molecular neurobiology, pathophysiology of depression has not been well elucidated. Among new findings of pathophysiology of depression, the possible fast antidepressant effect by N-methyl-D-asparate receptor antagonist, such as ketamine, is regarded as a promising treatment target of depression. Ketamine stimulates the mammalian target of rapamycin (mTOR) signaling pathway and activation of mTOR signaling pathway may be a key mechanism of the antidepressant effect of ketamine. Thus, this review describes the role of mTOR signaling in the pathophysiology of depression and developing a new treatment target of depression.

• Clinical and Experimental Pediatrics
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• v.54 no.6
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• pp.241-245
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• 2011

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that results from mutations in the TSC1 or TSC2 genes, and is associated with hamartomas in several organs, including subependymal giant cell tumors. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. The TSC1- and TSC2-encoded proteins modulate cell function via the mammalian target of rapamycin (mTOR) signaling cascade, and are key factors in the regulation of cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. The mTOR pathway represents a logical candidate for drug targeting, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

• Asian-Australasian Journal of Animal Sciences
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• v.29 no.11
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• pp.1646-1652
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• 2016

Mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and metabolism and is sufficient to induce specific metabolic processes, including de novo lipid biosynthesis. Elongation of very-long-chain fatty acids 1 (ELOVL1) is a ubiquitously expressed gene and the product of which was thought to be associated with elongation of carbon (C) chain in fatty acids. In the present study, we examined the effects of rapamycin, a specific inhibitor of mTORC1, on ELOVL1 expression and docosahexaenoic acid (DHA, C22:6 n-3) synthesis in bovine mammary epithelial cells (BMECs). We found that rapamycin decreased the relative abundance of ELOVL1 mRNA, ELOVL1 expression and the level of DHA in a time-dependent manner. These data indicate that ELOVL1 expression and DHA synthesis are regulated by mTORC1 in BMECs.

• Asian-Australasian Journal of Animal Sciences
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• v.27 no.5
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• pp.635-647
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• 2014

Unfertilized oocytes age inevitably after ovulation, which limits their fertilizable life span and embryonic development. Rapamycin affects mammalian target of rapamycin (mTOR) expression and cytoskeleton reorganization during oocyte meiotic maturation. The goal of this study was to examine the effects of rapamycin treatment on aged porcine oocytes and their in vitro development. Rapamycin treatment of aged oocytes for 24 h (68 h in vitro maturation [IVM]; $44h+10{\mu}M$ rapamycin/24 h, $47.52{\pm}5.68$) or control oocytes (44 h IVM; $42.14{\pm}4.40$) significantly increased the development rate and total cell number compared with untreated aged oocytes (68 h IVM, $22.04{\pm}5.68$) (p<0.05). Rapamycin treatment of aged IVM oocytes for 24 h also rescued aberrant spindle organization and chromosomal misalignment, blocked the decrease in the level of phosphorylated-p44/42 mitogen-activated protein kinase (MAPK), and increased the mRNA expression of cytoplasmic maturation factor genes (MOS, BMP15, GDF9, and CCNB1) compared with untreated, 24 h-aged IVM oocytes (p<0.05). Furthermore, rapamycin treatment of aged oocytes decreased reactive oxygen species (ROS) activity and DNA fragmentation (p<0.05), and downregulated the mRNA expression of mTOR compared with control or untreated aged oocytes. By contrast, rapamycin treatment of aged oocytes increased mitochondrial localization (p<0.05) and upregulated the mRNA expression of autophagy (BECN1, ATG7, MAP1LC3B, ATG12, GABARAP, and GABARAPL1), anti-apoptosis (BCL2L1 and BIRC5; p<0.05), and development (NANOG and SOX2; p<0.05) genes, but it did not affect the mRNA expression of pro-apoptosis genes (FAS and CASP3) compared with the control. This study demonstrates that rapamycin treatment can rescue the poor developmental capacity of aged porcine oocytes.

• Asian-Australasian Journal of Animal Sciences
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• v.29 no.8
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• pp.1102-1110
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• 2016

The mammalian target of rapamycin (mTOR) regulates cellular processes such as cell growth, metabolism, transcription, translation, and autophagy. Rapamycin is a selective inhibitor of mTOR, and induces autophagy in various systems. Autophagy contributes to clearance and recycling of macromolecules and organelles in response to stress. We previously reported that vitrified-warmed mouse oocytes show acute increases in autophagy during warming, and suggested that it is a natural response to cold stress. In this follow-up study, we examined whether the modulation of autophagy influences survival, fertilization, and developmental rates of vitrified-warmed mouse oocytes. We used rapamycin to enhance autophagy in metaphase II (MII) oocytes before and after vitrification. The oocytes were then subjected to in vitro fertilization (IVF). The fertilization and developmental rates of vitrified-warmed oocytes after rapamycin treatment were significantly lower than those for control groups. Modulation of autophagy with rapamycin treatment shows that rapamycin-induced autophagy exerts a negative influence on fertilization and development of vitrified-warmed oocytes.

• Development and Reproduction
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• v.4 no.1
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• pp.29-35
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• 2000

A phosphatidylinositol 3-kinase (PI3K) is a upstream component of insulin signaling by which protein synthesis can be stimulated in many systems. To elucidate involvement of PI3K and its downstream mammalian target of rapamycin (mTOR) in the insulin signaling in pleimplantation mouse embryos, 8-cell embryos were cultured to blastocysts in the presence or absence of insulin and／or inhibitor drugs. The number of blastomeres per blastocyst, protein synthesis, and protein phosphorylation were examined. There was significant difference in embryonic development to blastocyst stage and hatching was potentiated by the insulin supplementation. The increase in the mean celt numbers per blastocyst was apparent in the insulin culture. Wortmannin, a PI3K inhibitor and rapamycin, an inhibitor of mTOR abolished the stimulatory effect of insulin on morphological development mitosis and protein synthesis. In autoradiography, phosphoproteins pp22 and pp30 which undergo phosphorylation in response to insulin were identified. Taken together, it can be suggested that PI3K and mTOR engaged in insulin signaling in the mouse embryo 8-cell onward and mediate embryotropic offset of insulin.

• BMB Reports
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• v.57 no.2
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• pp.92-97
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• 2024

Elevated blood glucose is associated with an increased risk of atherosclerosis. Data from the current study showed that glucosamine (GlcN), a normal glucose metabolite of the hexosamine biosynthetic pathway (HBP), promoted lipid accumulation in RAW264.7 macrophage cells. Oleic acid- and lipopolysaccharide (LPS)-induced lipid accumulation was further enhanced by GlcN in RAW264.7 cells, although there was no a significant change in the rate of fatty acid uptake. GlcN increased acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), scavenger receptor class A, liver X receptor, and sterol regulatory element-binding protein-1c (SREBP-1c) mRNA expression, and; conversely, suppressed ATP-binding cassette transporter A1 (ABCA-1) and ABCG-1 expression. Additionally, GlcN promoted O-GlcNAcylation of nuclear SREBP-1 but did not affect its DNA binding activity. GlcN stimulated phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase. Rapamycin, a mTOR-specific inhibitor, suppressed GlcN-induced lipid accumulation in RAW264.7 cells. The GlcN-mediated increase in ACC and FAS mRNA was suppressed, while the decrease in ABCA-1 and ABCG-1 by GlcN was not significantly altered by rapamycin. Together, our results highlight the importance of the mTOR signaling pathway in GlcN-induced macrophage lipid accumulation and further support a potential link between mTOR and HBP signaling in lipogenesis.

• Food Science and Biotechnology
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• v.17 no.5
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• pp.1047-1051
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• 2008

Overexpression of HER2 in breast cancer cells is considered to induce the expression of acetyl-CoA carboxylase $\alpha$ (ACACA) and fatty acid synthase (FASN) through activation of mammalian target of rapamycin (mTOR) signaling pathway. Resveratrol, a red wine polyphenol, has been shown to induce apoptosis in several cancers by interfering in several signaling pathways. Present study elucidated the mechanism by which resveratrol downregulates ACACA and FASN in breast cancer cells. Resveratrol activated AMP-activated protein kinase (AMPK) and downregulated mTOR in BT-474 cells. These effects of resveratrol were mimicked by AICAR, an AMPK activator, and exogenously expressed constitutively active AMPK, while they were abolished by a dominant-negative mutant of AMPK. The downregulation of mTOR was not accompanied with changes in Akt, the upstream regulator of mTOR. These findings indicate that the downregulation of ACACA and FASN by resveratrol is mediated by the downregulation of mTOR signaling pathway via activation of AMPK.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3725-3728
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• 2013

Background: The mammalian target of rapamycin (mTOR) /RPS6KB1 activation has recently been implicated in tumour development, but its role in lung cancer remains unclear. The aim of this study was to explore the role of mTOR/RPS6KB1 signaling pathway in non-small-cell lung cancer (NSCLC). Methods: Immunohistochemistry was performed to assess the expression of phosphorylated mammalian target of rapamycin (p-mTOR) and its downstream ribosomal phosphorylated RPS6KB1 (p-RPS6KB1) in NSCLC patients. We also analyzed p-mTOR/p-RPS6KB1 protein expression in 45 fresh NSCLC tissues using Western blotting. Results: The expression level of p-mTOR and p-RPS6KB1 was significantly higher in NSCLC tumor specimens than that in adjacent noncancerous normal lung tissues (P<0.01). p-mTOR expression correlated with p-RPS6KB1. Furthermore, high expression level of p-mTOR or p-RPS6KB1 in NSCLC was associated with a shorter overall survival (both P<0.01). Multivariate analysis indicated high level of p-mTOR expression was an independent prognostic factor (HR=2.642, 95%CI 1.157-4.904, p=0.002). Conclusions: p-mTOR and p-RPS6KB1 could be useful prognostic markers for NSCLC.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.4
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• pp.365-374
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• 2021

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 μl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.