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Age-Related Changes in Sulfur Amino Acid Metabolism in Male C57BL/6 Mice
전장수,오정자,곽희찬,윤휘열,김형진,김영미,오수진,김상겸 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.2
Alterations in sulfur amino acid metabolism are associated with an increased risk of a number of common late-life diseases, which raises the possibility that metabolism of sulfur amino acids may change with age. The present study was conducted to understand the age-related changes in hepatic metabolism of sulfur amino acids in 2-, 6-, 18- and 30-month-old male C57BL/6 mice. For this purpose, metabolite profiling of sulfur amino acids from methionine to taurine or glutathione (GSH) was performed. The levels of sulfur amino acids and their metabolites were not significantly different among 2-, 6- and 18-month-old mice, except for plasma GSH and hepatic homocysteine. Plasma total GSH and hepatic total homocysteine levels were significantly higher in 2-month-old mice than those in the other age groups. In contrast, 30-month-old mice exhibited increased hepatic methionine and cysteine, compared with all other groups, but decreased hepatic S-adenosylmethionine (SAM), S-adenosylhomocysteine and homocysteine, relative to 2-month-old mice. No differences in hepatic reduced GSH, GSH disulfide, or taurine were observed. The hepatic changes in homocysteine and cysteine may be attributed to upregulation of cystathionine β-synthase and down-regulation of γ-glutamylcysteine ligase in the aged mice. The elevation of hepatic cysteine levels may be involved in the maintenance of hepatic GSH levels. The opposite changes of methionine and SAM suggest that the regulatory role of SAM in hepatic sulfur amino acid metabolism may be impaired in 30-month-old mice.
전장수 이화여자대학교 세포신호전달연구센터 2003 고사리 세포신호전달 심포지움 Vol. No.5
Cartilage serves as a template in the development of most bones. In limb buds of the chick embryo, cartilage development is initiated by the differentiation of mesenchymal cells into chondrocytes, which is initiated when mesenchymal cells are closely packed. In normal mature cartilage, differentiated chondrocyte which is the only cell type found in cartilage synthesizes sufficient amounts of cartilage-specific extracellular matrix to maintain the integrity of the matrix. However, such a homeostasis is destroyed in a degenerative disease including osteoarthritis and rheumatoid arthritis. Arthritis is characterized by structural and biochemical changes in chondrocytes and cartilage including the degradation of cartilage matrix, insufficient synthesis of matrix molecules by the loss of chondrocyte phenotype(i.e., de-differentiation), and increased numbers of apoptotic chondrocytes. Although morphological characteristics of chondrocyte differentiation and alterations in chondrocyte phenotype are well documented, the molecular mechanism including signal transduction involved in these process are yet to be clearly elucidated. Our series of studies indicated that complex protein kinase signaling cascades involving various isoforms of protein kinase C and mitogen-activated protein kinase subtypes including extracellular signal regulated protein kinase and p38 kinase regulate dedifferentiation and apoptosis of articular chondrocytes.
간 마이크로좀과 마우스에서 Omecamtiv mecarbil의 대사 연구
전장수,류창선,김상겸,김봉희 대한약학회 2016 약학회지 Vol.60 No.6
Omecamtiv mecarbil is a cardiac-specific myosin activator for developing the treatment of heart failure. Thepurpose of this study was to determine the metabolic stability and cytochrome P450 (CYP) inhibitory potential of omecamtivmecarbil, using human liver microsomes (HLM) to characterize its metabolic properties. In addition, pharmacokinetic analysiswas performed in mice treated intravenously (1 mg/kg) or orally (2 mg/kg) with omecamtiv mecarbil for comparisonwith our in vitro results. The half-life of omecamtiv mecarbil in HLM incubated with NADPH plus UDPGA was 83.1 min. In pharmacokinetic study, omecamtiv mecarbil was low systemic clearance (0.6±0.1 L/hr/kg) and 51.1% of oral bioavailability. Among CYP isoforms, CYP2C8 activity was selectively inhibited by omecamtiv mecarbil with an IC50 value of5.98 μM, comparable for that of quercetin, a positive control inhibitor for CYP2C8. These results suggest that omecamtivmecarbil can be used as a selective CYP2C8 inhibitor.
Nitric oxide in apoptosis and differentiation of chondrocytes
전장수 한국생명과학회 2001 한국생명과학회 학술발표회 Vol.33 No.-
Nitric oxide (NO) is known to regulate cartilage destruction by causing de-differentiation and apoptosis of chondrocytes. We investigated as the role of mitogen-activated protein (MAP) kinase subtypes, extracellular signal-regulated protein kinase (ERK)-1/-2 Erk-1 and -land p38 kinase, in NO-induced apoptosis ofin the regulation of chondroc rabbit articular chondrocytes and its relationship with de-differentiation. Generation of NO with sodium nitroprusside (SNP) caused de-differentiation as indicated by stopping of type II collagen expression and proteoglycan synthesis. NO generation also caused apoptosis that is accompanied by p53 accumulation and caspase-3 activation. SNP treatment caused activation of ERK-1/-2 and p38 kinase. Inhibition of ERK-1/-2 with PD98059 rescued SNP-induced de-differentiation but enhanced apoptosis up to 2-fold, whereas inhibition of p38 kinase with SB203580 enhanced de-differentiation with complete blockade of apoptosis. The stimulatory effects of ERK inhibition on apoptosis accompanied increased p53 accumulation and caspase-3 activity, whereas the inhibitory effects of p38 kinase blockade accompanied reduced p53 accumulation and caspase-3 activity. Thus, the results indicated that NO-induced p38 kinase activity function as an induction signal for apoptosis and maintenance of chondrocytes phenotype, whereas ERK activity causes de-differentiation and function as anti-apoptotic signal. NO generation is much less pro-apoptotic in de-differentiated chondrocytes induced by a serial monolayer culture or phorbol ester treatment. Compared with differentiated chondrocytes, NO-induced p38 kinase activity is low in de-differentiated cells with less accumulation of p53 and activity of caspase- 3. Taken together, our results indicated that ERK-1/-2 and p38 kinase oppositely regulate NO-induced apoptosis of chondrocytes in association with p53 accumulation, caspase-3 activation, and differentiation status