• Asian-Australasian Journal of Animal Sciences
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• v.31 no.2
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• pp.218-224
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• 2018

Objective: This study evaluated the effects of different levels of protein concentrate supplementation on the growth performance of yak calves, and correlated the growth rate to changes occurring in the plasma- amino acids, -insulin profile, and signaling activity of mammalian target of rapamycin (mTOR) cascade to characterize the mechanism through which the protein synthesis can be improved in early weaned yaks. Methods: For this study, 48 early (3 months old) weaned yak calves were selected, and assigned into four dietary treatments according to randomized complete block design. The four blocks were balanced for body weight and sex. The yaks were either grazed on natural pasture (control diet) in a single herd or the grazing yaks was supplemented with one of the three protein rich supplements containing low (17%; LP), medium (19%; MP), or high (21%; HP) levels of crude proteins for a period of 30 days. Results: Results showed that the average daily gain of calves increased (0.14 vs 0.23-0.26 kg; p<0.05) with protein concentrates supplementation. The concentration of plasma methionine increased (p<0.05; 8.6 vs $10.1-12.4{\mu}mol/L$), while those of serine and tyrosine did not change (p>0.05) when the grazing calves were supplemented with protein concentrates. Compared to control diet, the insulin level of calves increased (p<0.05; 1.86 vs $2.16-2.54{\mu}IU/mL$) with supplementation of protein concentrates. Addition of protein concentrates up-regulated (p<0.05) expression of mTOR-raptor, mammalian vacuolar protein sorting 34 homolog, the translational regulators eukaryotic translation initiation factor 4E binding protein 1, and S6 kinase 1 genes in both Longissimus dorsi and semitendinosus. In contrast, the expression of sequestosome 1 was down-regulated in the concentrate supplemented calves. Conclusion: Our results show that protein supplementation improves the growth performance of early weaned yak calves, and that plasma methionine and insulin concentrations were the key mediator for gene expression and protein deposition in the muscles.

• Tuberculosis and Respiratory Diseases
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• v.75 no.1
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• pp.9-17
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• 2013

Background: In cancer cells, autophagy is generally induced as a pro-survival mechanism in response to treatment-associated genotoxic and metabolic stress. Thus, concurrent autophagy inhibition can be expected to have a synergistic effect with chemotherapy on cancer cell death. Monensin, a polyether antibiotic, is known as an autophagy inhibitor, which interferes with the fusion of autophagosome and lysosome. There have been a few reports of its effect in combination with anticancer drugs. We performed this study to investigate whether erlotinib, an epidermal growth factor receptor inhibitor, or rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, is effective in combination therapy with monensin in non-small cell lung cancer cells. Methods: NCI-H1299 cells were treated with rapamycin or erlotinib, with or without monensin pretreatment, and then subjected to growth inhibition assay, apoptosis analysis by flow cytometry, and cell cycle analysis on the basis of the DNA contents histogram. Finally, a Western blot analysis was done to examine the changes of proteins related to apoptosis and cell cycle control. Results: Monensin synergistically increases growth inhibition and apoptosis induced by rapamycin or erlotinib. The number of cells in the sub-$G_1$ phase increases noticeably after the combination treatment. Increase of proapoptotic proteins, including bax, cleaved caspase 3, and cleaved poly(ADP-ribose) polymerase, and decrease of anti-apoptotic proteins, bcl-2 and bcl-xL, are augmented by the combination treatment with monensin. The promoters of cell cycle progression, notch3 and skp2, decrease and p21, a cyclin-dependent kinase inhibitor, accumulates within the cell during this process. Conclusion: Our findings suggest that concurrent autophagy inhibition could have a role in lung cancer treatment.

• Journal of Applied Biological Chemistry
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• v.58 no.3
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• pp.219-226
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• 2015

The anticancer activity of a methanolic extract from lemon leaves (MLL) was assessed in MCF-7-SC human breast cancer stem cells. MLL induced apoptosis in MCF-7-SC, as evidenced by increased apoptotic body formation, sub-G1 cell population, annexin V-positive cells, Bax/Bcl-2 ratio, as well as proteolytic activation of caspase-9 and caspase-3, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Concomitantly, MLL induced the formation of acidic vesicular organelles, increased LC3-II accumulation, and reduced the activation of Akt, mTOR, and p70S6K, suggesting that MLL initiates an autophagic progression in MCF-7-SC via the Akt/mTOR pathway. Epithelial-mesenchymal transition (EMT), a critical step in the acquisition of the metastatic state, is an attractive target for therapeutic interventions directed against tumor metastasis. At low concentrations, MLL induced anti-metastatic effects on MCF-7-SC by inhibiting the EMT process. Exposure to MLL also led to an increase in the epithelial marker E-cadherin, but decreased protein levels of the mesenchymal markers Snail and Slug. Collectively, this study provides evidence that lemon leaves possess cytotoxicity and anti-metastatic properties. Therefore, MLL may prove to be beneficial as a medicinal plant for alternative novel anticancer drugs and nutraceutical products.

• Journal of Life Science
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• v.29 no.11
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• pp.1251-1257
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• 2019

Peptidoglycan (PG) is found in atheromatous lesions of arteries, where monocytes/macrophages express inflammatory cytokines, including tumor necrosis factor-alpha ($TNF-{\alpha}$). This study investigated the effects of PG on $TNF-{\alpha}$ expression and examined possible cellular factors involved in $TNF-{\alpha}$ upregulation. The overall aim was to identify the molecular mechanisms underlying inflammatory responses to bacterial pathogen-associated molecular patterns in the artery. Exposure of human THP-1 monocytic cells to PG enhanced the secretion of $TNF-{\alpha}$ and induced its gene transcription. Inhibition of TLR-2/4 with OxPAPC significantly inhibited $TNF-{\alpha}$ gene expression, whereas inhibition of LPS by polymyxin B did not. The PG-induced expression of $TNF-{\alpha}$ was also significantly suppressed by pharmacological inhibitors that modulate activities of cellular signaling molecules; for example, U0126 (an ERK inhibitor), SB202190 (a p38 MAPK inhibitor), and SP6001250 (a JNK inhibitor) significantly attenuated PG-induced transcription of $TNF-{\alpha}$ and secretion of its gene product. $TNF-{\alpha}$ expression was also inhibited by rapamycin (an mTOR inhibitor), LY294002 (a PI3K inhibitor), and Akt inhibitor IV (an Akt inhibitor). ROS-regulating compounds, like NAC and DPI, also significantly attenuated $TNF{\alpha}$ expression induced by PG. These results suggest that PG induces $TNF-{\alpha}$ expression in monocytes/macrophages by multiple molecules, including TLR-2, PI3K, Akt, mTOR, MAPKs, and ROS.

• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.599-610
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• 2023

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

• Journal of Ginseng Research
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• v.47 no.6
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• pp.726-734
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• 2023

Background: Skeletal muscles play a key role in physical activity and energy metabolism. The loss of skeletal muscle mass can cause problems related to metabolism and physical activity. Studies are being conducted to prevent such diseases by increasing the mass and regeneration capacity of muscles. Ginsenoside Rg5 has been reported to exhibit a broad range of pharmacological activities. However, studies on the effects of Rg5 on muscle differentiation and growth are scarce. Methods: To investigate the effects of Rg5 on myogenesis, C2C12 myoblasts were induced to differentiate with Rg5, followed by immunoblotting, immunostaining, and qRT-PCR for myogenic markers and promyogenic signaling (p38MAPK). Immunoprecipitation confirmed that Rg5 increased the interaction between MyoD and E2A via p38MAPK. To investigate the effects of Rg5 on prevention of muscle mass loss, C2C12 myotubes were treated with dexamethasone to induce muscle atrophy. Immunoblotting, immunostaining, and qRT-PCR were performed for myogenic markers, Akt/mTOR signaling for protein synthesis, and atrophy-related genes (Atrogin-1 and MuRF1). Results: Rg5 promoted C2C12 myoblast differentiation through phosphorylation of p38MAPK and MyoD/E2A heterodimerization. Furthermore, Rg5 stimulated C2C12 myotube hypertrophy via phosphorylation of Akt/mTOR. Phosphorylation of Akt induces FoxO3a phosphorylation, which reduces the expression of Atrogin-1 and MuRF1. Conclusion: This study provides an understanding of how Rg5 promotes myogenesis and hypertrophy and prevents dexamethasone-induced muscle atrophy. The study is the first, to the best of our knowledge, to show that Rg5 promotes muscle regeneration and to suggest that Rg5 can be used for therapeutic intervention of muscle weakness and atrophy, including cancer cachexia.

• Animal Bioscience
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• v.37 no.3
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• pp.509-521
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• 2024

Objective: It was shown that microRNAs (miRNAs) play an important role in milk protein synthesis. However, the post-transcriptional regulation of casein expression by exogenous miRNA (xeno-miRNAs) in ruminants remains unclear. This study explores the regulatory roles of alfalfa xeno-miR162 on casein synthesis in bovine mammary epithelial cells (bMECs). Methods: The effects of alfalfa xenomiR-162 and G protein subunit gamma 11 (GNG11) on proliferation and milk protein metabolism of bMECs were detected by 5-Ethynyl-2'-Deoxyuridine (EdU) staining, flow cytometry, cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Dual-luciferase reporter assay was used to verify the targeting relationship between GNG11 and xenomiR-162. Results: Results showed that over-expression of xenomiR-162 inhibited cell proliferation but promoted apoptosis, which also up-regulated the expression of several casein coding genes, including CSN1S1, CSN1S2, and CSN3, while decreasing the expression of CSN2. Furthermore, the targeting relationship between GNG11 and xenomiR-162 was determined, and it was confirmed that GNG11 silencing also inhibited cell proliferation but promoted apoptosis and reduced the expression of casein coding genes and genes related to the mammalian target of rapamycin (mTOR) pathway. Conclusion: Alfalfa xenomiR-162 appears to regulate bMECs proliferation and milk protein synthesis via GNG11 in the mTOR pathway, suggesting that this xeno-miRNA could be harnessed to modulate CSN3 expression in dairy cows, and increase κ-casein contents in milk.

• Korean Journal of Biological Psychiatry
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• v.20 no.2
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• pp.29-30
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• 2013

First-line therapy of depression is a pharmacological treatment. Many prescribed antidepressants modulate monoamine neurotransmitters including serotonin, norepinephrine and dopamine. Recently, Ketamine, an N-methyl-D-aspartate receptor antagonist, has received attention and has been investigated for clinical trials and neurobiological studies. Here, I introduce ketamine as a rapid-acting antidepressant.

• Proceedings of the Korean Operations and Management Science Society Conference
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• 2004.05a
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• pp.197-200
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• 2004

기존의 제어실 정보표시는 계통 및 기기정보를 바탕으로 하는 사건중심의 나열식 정보표시체계를 가지므로써 운전원이 표시되는 정보를 검색하고 판단하기까지는 많은 정신적 부담이 있었으며 이로 인한 운전오류가 많이 발생하였다. 이에 따라 본 논문은 일체형원자로(SMART:System-integrated Modular Advanced ReacTor) 제어실에서 운전원이 감독자 기능을 지원할 수 있도록 운전원이 쉽고 빠르게 필요한 운전정보를 검색하여 필요한 조치를 취할 수 있는 정보체계를 제안한다.

• Journal of the Korean Statistical Society
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• v.30 no.1
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• pp.21-30
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• 2001

Suppose we observe a set of data (X$_1$,Y$_1$(, …, (X$_{n}$,Y$_{n}$) and use the Nadaraya-Watson regression estimator to estimate m(x)=E(Y│X=x). in this article bandwidth selection problem for the Nadaraya-Watson regression estimator is investigated. In particular cross validation method based on average square error(ASE) is considered. Theoretical results here include a central limit theorem that quantifies convergence rates of the bandwidth selector.tor.