Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice

Yu, S.J.,Bae, S.,Kang, J.S.,Yoon, J.H.,Cho, E.J.,Lee, J.H.,Kim, Y.J.,Lee, W.J.,Kim, C.Y.,Lee, H.S. North-Holland ; Elsevier Science Ltd 2015 european journal of pharmacology Vol.762 No.-

<P>Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin Con bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA) induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh BAT cells were treated with bile acid, apoptosis was induced by endoplasmic retiiculum stress related JNK activation but vitamin C attenuated bile acid induced hepatocyte apoprosis in vitro. In our in vivo experiments. LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury. (C) 2015 Elsevier B.V. All rights reserved.</P>

한우 비육에 관한 연구 1 . Methylthiouracil 첨가 및 Estradiol 17β - Cypionate 주사가 약령 모우 비육에 미치는 효과

김창기 ( C K Kim ),이택원 ( T W Lee ),김종욱 ( J W Kim ),배대식 ( D S Bae ),오선균 ( S K Oh ),조지훈 ( C H Cho ),김법회 ( B H Kim ),김상렬 ( S Y Kim ),배신석 ( S S Bae ) 한국축산학회 1971 한국축산학회지 Vol.13 No.1

This study was performed to affirm any effects of methylthiouracil and estradiol 17β-cypionate administered to young bulls for short term fattening. Eighteen bulls of Korean native breed, approximately 1.5 to 2 years of age and 260㎏ to 360㎏ in weight, were used in this study. All bulls had received a basal ration of soiling corn and concentrate made up of 55% grains, 40% brans and 5% others, in a period of 40 days. Bulls were divided into six groups as follows: group C was not treated, group M-2 received 2g of methylthiouracil per day, group M-3 received 3g of methylthiouracil per day, group EM-0 was injected intramusculary with 25㎎ of estradiol 17β-cypionate in the neck region 10 days after the beginning of the fattening period, group EM-2 was injected with estradiol 17β-cypionate as above mentioned and simultaneously received 2g of methylthiouracil per day, and group EM-3 was injected with estradiol 17β-cypionate as above mentioned and simultaneously received 3g of methylthiouracil per day. The results obtained were summarized as follows. 1. The average daily gain was for group C: 0.83㎏, group M-2: 1.07㎏, group M-3: 1.40㎏, group EM-0, 0.93㎏, group EM-2: 0.95㎏, and group EM-3: 1.18㎏. The M-3 group gained significantly(P$lt;0.05) more weight than C and EM-0 group. There were no significant differences in the average daily gain between the groups injected with estradiol 17β-eypionate and the control group. 2. The average daily concentrate intake was as follows: group C: 5.47㎏, group M-2: 5.00㎏, group M-3: 4.52㎏, group EM-0: 5.21㎏, group EM-2: 4.35㎏, and group EM-3: 4.61㎏. The consumption of concentrate was decreased by 17% in the M-3 group compared with the C group. There was no significant difference in the soiling corn intake among these groups. 3. Feed consumed for 1㎏ gain were decreased by the supplementation of methylthiouracil. The consumption of DCP for 1㎏ gain was in group C: 0.82㎏, group M-2: 0.59㎏, group M-3: 0.41㎏, group EM-0: 0.70㎏, group EM-2: 0.59㎏, and group EM-3: 0.50㎏. The amounts of TDN required were; group C: 6.57㎏, group M-2: 4.76㎏, group M-3: 3.39㎏, group EM-0: 5.67㎏, group EM-Z: 4.87㎏, and group EM-3: 4.08㎏. The consumption of DCP and TDN for 1㎏ gain in the M-3 group was about a half of that in the C group. 4. There was not any significant difference in the increase in body measurements among the various groups. 5. The average margins in the fattening period of 40 days were for group C: 2,950won, group M-2: 5,327won, group M-3: 9,158won, group EM-0: 3,310won, group EM-2: 3,623won, and group EM-3: 5,575won. The margin of group M-3 was about three times higher than that of group C. In short, this experiment demonstrated that methylthiouracil when fed to young native Korean bulls at the proper level 40 days before slaughter would bring a noticeable effect on weight gain, feed efficiency and economic advantage. There were no advantages from the simultaneous injecting estradiol 17β-cypionate with methylthiouracil. The proper supplementation level of methylthiouracil would appear to be 3g per head per day in this experiment.

Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ^ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis

Dal Rhee, S.,Kim, C.H.,Seon Park, J.,Hoon Jung, W.,Bum Park, S.,Youn Kim, H.,Hwan Bae, G.,Jan Kim, T.,Young Kim, K. North-Holland ; Elsevier Science Ltd 2012 european journal of pharmacology Vol.691 No.1

Carbenoxolone is the 3-hemisuccinate of glycyrrhetinic acid, the active principal of licorice (Glycyrrhiza glabra). It was reported that carbenoxolone improved glucose tolerance with increased insulin sensitivity in mice with high fat diet-induced obesity. In the present study, we elucidated the protective effect of carbenoxolone in fatty liver animal models of C57BL/6-Lep<SUP>ob/ob</SUP> mice through inhibition of hepatic lipogenesis and apoptosis. In addition, the potential mechanisms by which carbenoxolone could exert such protection were elucidated. Carbenoxolone was daily administrated by gavage for 28 days in C57BL/6 and C57BL/6-Lep<SUP>ob/ob</SUP> mice. Carbenoxolone prevented the plasma triglyceride and free fatty acid accumulation associated with the reduction of the expression of sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase and acethyl-CoA carboxylase in the livers of C57BL/6-Lep<SUP>ob/ob</SUP> mice. Carbenoxolone also prevented hepatic injury through anti-apoptotic action in the livers of C57BL/6-Lep<SUP>ob/ob</SUP> mice, accompanied by increased Bcl-2 expression and suppressed Bax and cytochrome c expression. As a mechanism, increased inflammatory cytokine expressions were inhibited by carbenoxolone in the fatty livers of C57BL/6-Lep<SUP>ob/ob</SUP> mice. Furthermore, carbenoxolone inhibited free fatty acid (oleate/palmitate) induced reactive oxygen species formation and reversed free fatty acid induced mitochondrial membrane depolarization in HepG2 cells. Carbenoxolone prevents the development of fatty liver by inhibiting sterol regulatory element binding protein-1c expression and activity with an anti-apoptotic mechanism via the inhibition of inflammatory cytokine and reactive oxygen species formation in the livers of C57BL/6-Lep<SUP>ob/ob</SUP> mice. It is suggested that carbenoxolone prevents the development and progression of fatty liver disease in patients with insulin resistance.

산란계 사료내 CLA 함유 Oil (CLAzen 80) 첨가가 난황내 지방산 조성에 미치는 영향

황보종,장종수,정일병,이병석,김동운,조성백,김희도,배해득,손진혁,홍의철,최낙진,Hwangbo J.,Chang J. S.,Chung I. B.,Lee B. S.,Kim D. U.,Cho S. B.,Kim H. D.,Bae H. D.,Son J. H.,Hong U. C.,Choi N. J. 한국가금학회 2005 韓國家禽學會誌 Vol.32 No.1

본 연구는 oil 형태의 conjugated linoleic acid(CLAzen 80)를 산란계 사료에 수준별로 첨가 급여하였을 때 산란율과 난황내 지방산 조성의 변화를 조사하기 위하여 수행하였다. 59주령의 산란계 72수를 완전임의배치법으로 4개 처리구에 6주간 공시하였다. 처리구는 CLAzen 80를 첨가하지 않은 대조구와 각각 1, 2 및 $3\%$를 첨가구를 두었다. 연구 결과를 살펴보면 산란율은 처리구별 통계적 유의차가 없었지만, 난황내 지방산 조성은 CLAzen 80 첨가에 의하게 크게 영향을 받았다. 난황내 C16:0과 C18:0과 같은 포화 지방산 함량은 CLAzen 80 첨가에 의하여 증가하였으나, 일가불포화지방산인 C18:1 함량은 오히려 감소하였다. 한편, 난황내 C18:2와 C18:3와 같은 다가불포화지방산은 CLAzen 80 급여 2$\~$4주사이에는 모든처리구들에 있어서 그 함량이 일정하게 유지되었다. 그러나, 대조구와 비교하여 CLAzen 80 급여 6주 째에는 난황내 C18:2 함량이 감소하였다. 불포화지방산:포화지방산 비율과 n-6:n-3 불포화지방산 비율은 2$\~$4주 사이에는 처리구별간에 통계적 유의차가 없었고, 6주째 불포화지방산:포화지방산 비율이 CLAzen 80 첨가에 의하여 감소하였다. 한편, 난황내 CLA 함량은 CLAzen 80 첨가수준에 비례하여 증가하였다. 따라서, 산란계 사료 내 CLAzen 80 첨가는 난황내 CLA 함량을 증진시키는 것으로 요약할 수 있다. The objectives of the present study were to investigate the effects of varying levels of dietary oil containing conjugated linoleic acid (CLA) on the egg production and fatty acid composition of egg yolk. Seventy-two 59-wk-old ISA Brown laying hens were randomly allotted to four dietary treatments, each consisting of three replicates with six birds per replicate. There were four treatments that consist of diets containing 0, 1, 2, or $3\%$ commercial CLA-containing oil. Egg production was not significantly different among the dietary treatments at 0, 2, 4, and 6 week. The proportion of saturated fatty acids such as C16:0 and C18:0 in egg yolk were increased, but that of monounsaturated fatty acid C18:1 was decreased by feeding CLA-containing oil supplementation. However, the proportion of polyunsaturated fatty acids such as C18:2 and C18:3 in egg yolk were not different among dietary treatments at 2 and 4 wk of the experiment. At 6 week, the proportion of C18:2 in egg yolk was decreased by feeding CLA-containing oil compared with the control. Polyunsaturated fatty acid:saturated fatty acid (P:S) ratio and n-6:n-3 polyunsaturated fatty acid ratio were similar across the treatments between 2 and 4 week. The P:S ratio was decreased by dietary CLA-containing oil supplementation at 6 week. The proportion of CLA in egg yolk was linearly increased with increasing levels of CLA-containing oil supplementation. In conclusion, dietary supplementation of CLA-containing oil to laying hens increased beneficially increased CLA content in their egg yolk.

S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Yi, S.,Um, S.,Lee, J.,Yoo, J.,Bang, S.,Park, E.,Lee, M.,Nam, K.,Jeon, Y.,Park, J.,You, J.,Lee, S.J.,Bae, G.U.,Rhie, J.,Kozma, Sara C.,Thomas, G.,Han, J.W. Cell Press 2016 Molecular Cell Vol.62 No.3

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.

Probiotic Characterization of Acid- and Bile-tolerant Lactobacillus salivarius subsp. salivarius from Korean Faeces

Bae, H.C.,Nam, M.S.,Lee, J.Y. Asian Australasian Association of Animal Productio 2002 Animal Bioscience Vol.15 No.12

This study was conducted to investigate lactobacillus salivarius subsp. salivarius having probiotic properties to be used as the health adjuncts with fermented milk products. Acid- and bile-tolerant lactobacillus salivarius subsp. salivarius was isolated with lactobacilli MRS broth from faeces of 80 healthy persons (infants, children and adults). It was used as a probiotic strain in fermented milk products. The pH of fermented milk decreased from pH 6.7 to 5.0 and titratable acidity increased from 0.3% to 1.0% by L. salivarius subsp. salivarius (isolation strain 20, 35, and 37), when incubated for 36 h at 37$^{\circ}C$. The number of viable cell counts of fermented milk was maximized at this incubation condition. The SDS-PAGE evidenced no significant change of casein but distinct changes of whey protein were observed by isolated L. salivarius subsp. salivarius for titratable acidity being incubated by 0.9-1.0% at 37$^{\circ}C$. All of the strains produced 83.43 to 131.96 mM of lactic acid and 5.39 to 26.85 mM of isobutyric acid in fermented products. The in vitro culture experiment was performed to evaluate ability to reduce cholesterol levels and antimicrobial activity in the growth medium. The selected L. salivarius subsp. salivarius reduced 23-38% of cholesterol content in lactobacilli MRS broth during bacterial growth for 24 h at 37$^{\circ}C$. All of the isolated L. salivarius subsp. salivarius had an excellent antibacterial activity with 15-25 mm of inhibition zone to E. coli KCTC1039, S. enteritidis KCCM3313, S. typhimurium M-15, and S. typhimurium KCCM40253 when its pH had not been adjusted. Also, all of the isolated L. salivarius subsp. salivarius had partial inhibition zone to E. coli KCTC1039, E. coli KCTC0115 and S. enteritidis KCCM3313 when it had been adjusted to pH 5.7. The selected strains were determined to have resistances of twelve antibiotic. Strains 27 and 35 among the L. salivarius subsp. salivarius showed the highest resistance to the antibiotics. These results indicated that some of the L. salivarius subsp. salivarius (strain 27 and 35) are considered as effective probiotic strains with a potential for industrial applications, but the further study is needed to establish their use as probiotics in vivo.

韓國 低所得層의 小兒結核症에 對한 臨床 및 統計的 考察

金晟澤,裵鍾三,趙宗大,金大成,趙璋濟,金贊榮 金原出版 1969 小兒科 Vol.10 No.5

Phase I/II study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma

Park, S R,Kim, H K,Kim, C G,Choi, I J,Lee, J S,Lee, J H,Ryu, K W,Kim, Y-W,Bae, J-M,Kim, N K Cancer Research UK 2008 The British journal of cancer Vol.98 No.8

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1–14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30–45 mg m<SUP>−2</SUP> b.i.d.) and docetaxel (25–40 mg m<SUP>−2</SUP>); MTD was 45 mg m<SUP>−2</SUP> b.i.d. S-1/35 mg m<SUP>−2</SUP> docetaxel and RD was 40 mg m<SUP>−2</SUP> b.i.d. S-1/35 mg m<SUP>−2</SUP> docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8–79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9–8.1) and 13.7 months (95% CI: 9.9–17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.British Journal of Cancer (2008) 98, 1305–1311. doi:10.1038/sj.bjc.6604312 www.bjcancer.com Published online 25 March 2008

Suppression of c-Myc induces apoptosis via an AMPK/mTOR-dependent pathway by 4-O-methyl-ascochlorin in leukemia cells

Shin, J. M.,Jeong, Y. J.,Cho, H. J.,Magae, J.,Bae, Y. S.,Chang, Y. C. Springer Science + Business Media 2016 Apoptosis Vol.21 No.5

<P>4-O-Methyl-ascochlorin (MAC) is a methylated derivative of the prenyl-phenol antibiotic ascochlorin, which was isolated from an incomplete fungus, Ascochyta viciae. Although the effects of MAC on apoptosis have been reported, the underlying mechanisms remain unknown. Here, we show that MAC promoted apoptotic cell death and downregulated c-Myc expression in K562 human leukemia cells. The effect of MAC on apoptosis was similar to that of 10058-F4 (a c-Myc inhibitor) or c-Myc siRNA, suggesting that the downregulation of c-Myc expression plays a role in the apoptotic effect of MAC. Further investigation showed that MAC downregulated c-Myc by inhibiting protein synthesis. MAC promoted the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its target proteins, including p70S6 K and 4E-BP-1. Treatment of cells with AICAR (an AMPK activator), rapamycin (an mTOR inhibitor), or mTOR siRNA downregulated c-Myc expression and induced apoptosis to a similar extent to that of MAC. These results suggest that the effect of MAC on apoptosis induction in human leukemia cells is mediated by the suppression of c-Myc protein synthesis via an AMPK/mTOR-dependent mechanism.</P>

Far upstream element-binding protein-1, a novel caspase substrate, acts as a cross-talker between apoptosis and the c-myc oncogene

Jang, M,Park, B C,Kang, S,Chi, S-W,Cho, S,Chung, S J,Lee, S C,Bae, K-H,Park, S G Macmillan Publishers Limited 2009 Oncogene Vol.28 No.12

Far upstream element-binding protein-1 (FBP-1) binds to an upstream element of the c-myc promoter and regulates the c-myc mRNA level. Earlier, FBP-1 was identified as a candidate substrate of caspase-7. Here, we report that FBP-1 is cleaved by executor caspases, both in vitro and during apoptosis. Cleavage occurs at the caspase consensus site (DQPD<SUP>74</SUP>) located within the classical bipartite nuclear localization signal sequence. In cells subjected to apoptotic stimuli, the caspase-mediated cleavage of FBP-1 leads to its decreased presence in the nucleus, concomitant with the marked downregulation of c-Myc and its various target proteins. By contrast, cells transfected with a non-cleavable mutant of FBP-1 (D74A) maintain higher levels of c-Myc and are protected from apoptosis. On the basis of these results, we suggest that the oncogenic potential of c-Myc is ‘switched off’ after apoptosis induction as a consequence of the caspase-mediated cleavage of FBP-1.Oncogene (2009) 28, 1529–1536; doi:10.1038/onc.2009.11; published online 16 February 2009