• Animal Bioscience
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• v.35 no.9
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• pp.1444-1453
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• 2022

Objective: Acetate plays an important role in host lipid metabolism. However, the network of acetate-regulated lipid metabolism remains unclear. Previous studies show that mitogen-activated protein kinases (MAPKs) and mechanistic target of rapamycin (mTOR) play a crucial role in lipid metabolism. We hypothesize that acetate could affect MAPKs and/or mTOR signaling and then regulate lipid metabolism. The present study investigated whether any cross talk occurs among MAPKs, mTOR and acetate in regulating lipid metabolism. Methods: The ceramide C6 (an extracellular signaling-regulated kinases 1 and 2 [ERK1/2] activator) and MHY1485 (a mTOR activator) were used to treat rabbit adipose-derived stem cells (ADSCs) with or without acetate, respectively. Results: It indicated that acetate (9 mM) treatment for 48 h decreased the lipid deposition in rabbit ADSCs. Acetate treatment decreased significantly phosphorylated protein levels of ERK1/2 and mTOR but significantly increased mRNA level of hormone-sensitive lipase (HSL). Acetate treatment did not significantly alter the phosphorylated protein level of p38 MAPK and c-Jun aminoterminal kinase (JNK). Activation of ERK1/2 and mTOR by respective addition in media with ceramide C6 and MHY1485 significantly attenuated decreased lipid deposition and increased HSL expression caused by acetate. Conclusion: Our results suggest that ERK1/2 and mTOR signaling pathways are associated with acetate regulated HSL gene expression and lipid deposition.

• BMB Reports
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• v.50 no.9
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• pp.437-444
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• 2017

Different types of eukaryotic cells may adopt seemingly distinct modes of directional cell migration. However, several core aspects are regarded common whether the movement is either ameoboidal or mesenchymal. The region of cells facing the attractive signal is often termed leading edge where lamellipodial structures dominates and the other end of the cell called rear end is often mediating cytoskeletal F-actin contraction involving Myosin-II. Dynamic remodeling of cell-to-matrix adhesion involving integrin is also evident in many types of migrating cells. All these three aspects of cell migration are significantly affected by signaling networks of TorC2, TorC1, and PP2A/B56. Here we review the current views of the mechanistic understanding of these regulatory signaling networks and how these networks affect eukaryotic cell migration.

• BMB Reports
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• v.43 no.2
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• pp.140-145
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• 2010

The present study investigated whether the mammalian target of rapamycin (mTOR) signal pathway is involved in the regulation of high glucose-induced intramuscular adipogenesis in porcine muscle satellite cells. High glucose (25 mM) dramatically increased intracellular lipid accumulation in cells during the 10-day adipogenic differentiation period. The expressions of CCAAT/enhancer binding protein-$\alpha$ (C/EBP-$\alpha$) and fatty acid synthase (FAS) protein were gradually enhanced during the 10-day duration while mTOR phosphorylation and sterol-regulatory- element-binding protein (SREBP)-1c protein were induced on day 4. Moreover, inhibition of mTOR activity by rapamycin resulted in a reduction of SREBP-1c protein expression and adipogenesis in cells. Collectively, our findings suggest that the adipogenic differentiation of porcine muscle satellite cells and a succeeding extensive adipogenesis, which is triggered by high glucose, is initiated by the mTOR signal pathway through the activation of SREBP-1c protein. This process is previously uncharacterized and suggests a cellular mechanism may be involved in ectopic lipid deposition in skeletal muscle during type 2 diabetes.

• Molecules and Cells
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• v.37 no.2
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• pp.118-125
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• 2014

Osteosarcoma is the most common primary malignant bone tumor with a very poor prognosis. Treating osteosarcoma remains a challenge due to its high transitivity. Tenascin-C, with large molecular weight variants including different combinations of its alternative spliced FNIII repeats, is specifically over expressed in tumor tissues. This study examined the expression of Tenascin-C FNIIIA1 in osteosarcoma tissues, and estimated the effect of mechanical stimulation on A1 expression in MG-63 cells. Through immunohistochemical analysis, we found that the A1 protein was expressed at a higher level in osteosarcoma tissues than in adjacent normal tissues. By cell migration assay, we observed that there was a significant correlation between A1 expression and MG-63 cell migration. The relation is that Tenascin-C FNIIIA1 can promote MG-63 cell migration. According to our further study into the effect of mechanical stimulation on A1 expression in MG-63 cells, the mRNA and protein levels of A1 were significantly up-regulated under mechanical stress with the mTOR molecule proving indispensable. Meanwhile, 4E-BP1 and S6K1 (downstream molecule of mTOR) are necessary for A1 normal expression in MG-63 cells whether or not mechanical stress has been encountered. We found that Tenascin-C FNIIIA1 is over-expressed in osteosar-coma tissues and can promote MG-63 cell migration. Furthermore, mechanical stress can facilitate MG-63 cell migration though facilitating A1 overexpression with the necessary molecules (mTOR, 4E-BP1 and S6K1). In con-clusion, high expression of A1 may promote the meta-stasis of osteosarcoma by facilitating MG-63 cell migration. Tenascin-C FNIIIA1 could be used as an indicator in metastatic osteosarcoma patients.

• IMMUNE NETWORK
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• v.24 no.4
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• pp.24.1-24.8
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• 2024

Complement C5a receptor (C5aR) signaling in immune cells has various functions, inducing inflammatory or anti-inflammatory responses based on the type of ligand present. The Co1 peptide (SFHQLPARSRPLP) has been reported to activate C5aR signaling in dendritic cells. We investigated the effect of C5aR signaling via the Co1 peptide on macrophages. In peritoneal macrophages, the interaction between C5aR and the Co1 peptide activated the mTOR pathway, resulting in the production of pro-inflammatory cytokines. Considering the close associations of mTOR signaling with IL-6 and TNF-α in macrophage training, our findings indicate that the Co1 peptide amplifies β-glucan-induced trained immunity. Overall, this research highlights a previously underappreciated aspect of C5aR signaling in trained immunity, and posits that the Co1 peptide is a potentially effective immunomodulator for enhancing trained immunity.

• Oncology Letters
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• v.17 no.3
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• pp.3589-3598
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• 2019

Colorectal cancer (CRC) is a complex disease involving numerous genetic abnormalities. One of the major characteristics of CRC is enhanced Wnt signaling caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene. Previously, it has been demonstrated that the majority of malignant phenotypes following APC deletion in adult murine small intestines could be rescued when Myc, a downstream target of the Wnt pathway, was deleted. This indicated that Myc is a critical regulator of CRC development following APC loss. Previous studies reported that cyclic adenosine 3',5'-monophosphate (cAMP) can influence the AKT/mammalian target of rapamycin (mTOR) survival pathway in cancer and Myc is a critical downstream molecule of AKT/mTOR signaling. Phosphodiesterase 4D (PDE4D), a member of the cAMP-specific PDE4 family, has been associated with drug resistance in CRC. However, the association between PDE4D and Myc remains unclear. To investigate the potential role of PDE4D in Myc regulation in CRC, the present study evaluated the expression levels of PDE4 subtypes in DLD-1 CRC cells. Additionally, the effects of PDE4 inhibitors on Myc expression and oncogenic properties were analyzed by western blot analysis, reverse transcription-quantitative polymerase chain reaction, colony formation and soft agar assays. It was demonstrated that cAMP/PDE4D signals serve a critical role in regulating Myc expression in DLD-1 CRC cells. Furthermore, PDE4D was identified to be a main hydrolyzer of cAMP and suppression of PDE4D using selective inhibitors of PDE4 increased intracellular cAMP levels, which resulted in a marked decrease in the oncogenic properties of DLD-1 cells, including colony formation, cell proliferation and anchorage-independent growth. Notably, the current data imply that cAMP represses Myc expression via the downregulation of AKT/mTOR signaling, which was abolished by high PDE4D activities in DLD-1 cells. Additionally, a natural polyphenol resveratrol in combination with forskolin elevated the concentration of cAMP and enhanced the expression of Myc and the malignant phenotype of DLD-1 cells, reproducing the effect of known chemical inhibitors of PDE4. In conclusion, the present study identified that cAMP/PDE4D signaling is a critical regulator of Myc expression in DLD-1 and possibly other CRC cells.

• Journal of Microbiology and Biotechnology
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• v.23 no.11
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• pp.1569-1576
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• 2013

In mice, supplementation of t10,c12 conjugated linoleic acid (CLA) increases liver mass and hepatic steatosis via increasing uptake of fatty acids released from adipose tissues. However, the effects of t10,c12 CLA on hepatic lipid synthesis and the associated mechanisms are largely unknown. Thus, we tested the hypothesis that gut microbiota-producing t10,c12 CLA would induce de novo lipogenesis and triglyceride (TG) synthesis in HepG2 cells, promoting lipid accumulation. It was found that treatment with t10,c12 CLA ($100{\mu}M$) for 72 h increased neutral lipid accumulation via enhanced incorporation of acetate, palmitate, oleate, and 2-deoxyglucose into TG. Furthermore, treatment with t10,c12 CLA led to increased mRNA expression and protein levels of lipogenic genes including SREBP1, ACC1, FASN, ELOVL6, GPAT1, and DGAT1, presenting potential mechanisms by which CLA may increase lipid deposition. Most strikingly, t10,c12 CLA treatment for 3 h increased phosphorylation of mTOR, S6K, and S6. Taken together, gut microbiota-producing t10,c12 CLA activates hepatic de novo lipogenesis and TG synthesis through activation of the mTOR/SREBP1 pathway, with consequent lipid accumulation in HepG2 cells.

• 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.

• Journal of the Korean Mathematical Society
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• v.60 no.5
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• pp.1087-1107
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• 2023

Let E be an elliptic curve defined over ℚ of conductor N, c the Manin constant of E, and m the product of Tamagawa numbers of E at prime divisors of N. Let K be an imaginary quadratic field where all prime divisors of N split in K, P_K the Heegner point in E(K), and III(E/K) the Shafarevich-Tate group of E over K. Let 2u_K be the number of roots of unity contained in K. Gross and Zagier conjectured that if P_K has infinite order in E(K), then the integer c · m · u_K · |III(E/K)| $\frac{1}{2}$ is divisible by |E(ℚ)_tor|. In this paper, we prove that this conjecture is true if E(ℚ)_tor ≅ ℤ/2ℤ or ℤ/4ℤ except for two explicit families of curves. Further, we show these exceptions can be removed under Stein-Watkins conjecture.

• Natural Product Sciences
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• v.19 no.2
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• pp.155-159
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• 2013

Honokiol, a naturally occurring neolignan mainly found in Magnolia species, has exhibited a potential anti-proliferative activity in human cancer cells. However, the growth inhibitory activity against hepatocellular carcinoma cells and the underlying molecular mechanisms has been poorly determined. The present study was designed to examine the anti-proliferative effect of honokiol in SK-HEP-1 human hepatocellular cancer cells. Honokiol exerted anti-proliferative activity with cell-cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death. The cell-cycle arrest was well correlated with the down-regulation of checkpoint proteins including cyclin D1, cyclin A, cyclin E, CDK4, PCNA, retinoblastoma protein (Rb), and c-Myc. The increase of sub-G1 peak by the higher concentration of honokiol ($75{\mu}M$) was closely related to the induction of apoptosis, which was evidenced by decreased expression of Bcl-2, Bid, and caspase-9. Hohokiol was also found to attenuate the activation of signaling proteins in the Akt/mTOR and ERK pathways. These findings suggest that the anti-proliferative effect of honokiol was associated in part with the induction of cell-cycle arrest, apoptosis, and dow-nregulation of Akt/mTOR signaling pathways in human hepatocellular cancer cells.