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Increase in sphingolipid catabolic enzyme activity during aging
Sacket, Santosh J,Chung, Hae-young,Okajima, Fumikazu,Im, Dong-soon Springer Science and Business Media LLC 2009 Acta pharmacologica Sinica. Vol.30 No.10
<P>AIM: To understand the contribution of sphingolipid metabolism and its metabolites to development and aging. METHODS: A systemic analysis on the changes in activity of sphingolipid metabolic enzymes in kidney, liver and brain tissues during development and aging was conducted. The study was conducted using tissues from 1-day-old to 720-day-old rats. RESULTS: Catabolic enzyme activities as well as the level of sphingomyelinase (SMase) and ceramidase (CDase) were higher than that of anabolic enzyme activities, sphingomyelin synthase and ceramide synthase. This suggested an accumulation of ceramide and sphingosine during development and aging. The liver showed the highest neutral-SMase activity among the tested enzymes while the kidney and brain exhibited higher neutral-SMase and ceramidase activities, indicating a high production of ceramide in liver and ceramide/sphingosine in the kidney and brain. The activities of sphingolipid metabolic enzymes were significantly elevated in all tested tissues during development and aging, although the onset of significant increase in activity varied on the tissue and enzyme type. During aging, 18 out of 21 enzyme activities were further increased on day 720 compared to day 180. CONCLUSION: Differential increases in sphingolipid metabolic enzyme activities suggest that sphingolipids including ceramide and sphingosine might play important and dynamic roles in proliferation, differentiation and apoptosis during development and aging.</P>
Chang, Young-Ja,Kim, Hyo-Lim,Sacket, Santosh J.,Kim, Kye-Ok,Han, Mi-Jin,Jo, Ji-Yeong,Im, Dong-Soon The Korean Society of Applied Pharmacology 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol. No.
In the present study, we have tested the effect of dioleoyl phosphatidic acid (PA) on intracellular $Ca_{2+}$ concentration ($[Ca^{2+}]_{i}$) in two human colon cancer cell lines (HCT116 and HT29). PA and lysophosphatidic acid (LPA), a bioactive lysolipid, increased $[Ca^{2+}]_{i}$ in both HCT116 and HT29 cell lines. Increases of $[Ca^{2+}]_{i}$ by PA and LPA were more robust in HCT116 cells than in HT29 cells. A specific inhibitor of phospholipase C (U73122), however, was not inhibitory to the cell responses. Pertussis toxin, a specific inhibitor of $G_{i/o}$ type G proteins, however, had an inhibitory effect on the responses except for an LPA-induced one in HT29 cells. Ruthenium red, an inhibitor of the ryanodine receptor, was not inhibitory on the responses, however, 2-APB, a specific inhibitor of inositol 1,4,5-trisphosphate receptor, completely inhibited both lipid-induced $Ca^{2+}$ increases in both cell types. Furthermore, by using Ki16425 and VPC32183, two structurally dissimilar specific antagonists for $LPA_{1}/LPA_{3}$ receptors, an involvement of endogenous LPA receptors in the $Ca^{2+}$ responses was observed. Ki16425 completely inhibited the responses but the susceptibility to VPC32183 was different to PA and LPA in the two cell types. Expression levels of five LPA receptors in the HCT116 and HT29 cells were also assessed. Our data support the notion that PA could increase $[Ca^{2+}]_{i}$ in human colon cancer cells, probably via endogenous LPA receptors, G proteins and $IP_{3}$ receptors, thereby suggesting a role of PA as an intercellular lipid mediator.
N,N-Dimethyl-D-ribo-phytosphingosine Modulates Cellular Functions of 1321N1 Astrocytes
Lee, Yun-Kyung,Kim, Hyo-Lim,Kim, Kye-Ok,Sacket, Santosh J.,Han, Mi-Jin,Jo, Ji-Yeong,Lim, Sung-Mee,Im, Dong-Soon The Korean Society of Applied Pharmacology 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol. No.
N,N-Dimethyl-D-ribo-phytosphingosine (DMPH) is an N-methyl derivative of sphingosine. In the present paper, we studied effects of DMPH on intracellular Ca$^{2+}$ concentration, pH, glutamate uptake, and cell viability in human 1321N1 astrocytes. DMPH increased intracellular Ca$^{2+}$ concentration and cytosolic pH significantly in a dose-dependent manner. DMPH also inhibited glutamate uptake by 1321N1 astrocytes. Finally, treatment of cells with DMPH for 24 h reduced viability of cells largely and concentration-dependently. In summary, DMPH increased intracellular Ca$^{2+}$ concentration and pH, inhibited glutamate uptake and evoked cytotoxicity in 1321N1 astrocytes. Our observations with DMPH in the 1321N1 astrocytes would enhance understanding of DMPH actions in the brain.
Increase of Membrane Potential by Ginsenosides in Prostate Cancer and Glioma cells
Yun-Kyung Lee,Young-Jin Im,Yu-Lee Kim,Santosh J. Sacket,Sung-Mee Lim,Kyeok Kim,Hyo-Lim Kim,Sung-Ryong Ko,Dong-Soon Im 고려인삼학회 2006 Journal of Ginseng Research Vol.30 No.2
Ginseng has an anti-cancer effect in several cancer models. As a mechanism study of ginsenoside-induced growth inhibition in cancer cells, we measured change of membrane potential in prostate cancer and glioma cells by ginsenosides, active constituents of ginseng. Membrane potential was estimated by measuring fluorescence change of DiBAC-loaded cells. Among 11 ginsenosides tested, ginsenosides Rb₂, Rg₃, and Rh₂ increased significantly and robustly the membrane potential in a concentration-dependent manner in prostate cancer and glioma cells. Ginsenosides Rc, Ro, and Rb₁ slightly increased membrane potential. The ginsenoside-induced membrane potential increase was not affected by treatment with pertussis toxin or U73122. The ginsenoside-induced membrane potential increase was not diminished in Na?-free or HCO₃?-free media. Furthermore, the ginsenoside-induced increase of membrane potential was not changed by EIPA (5-(N-ethyl-N-isopropyl)-amiloride), SITS (4-acetoamido-4’-isothiocyanostilbene-2,2’-disulfonic acid), and omeprazole. In summary, ginsenosides Rb₂, Rg₃, and Rh₂ increased membrane potential in prostate cancer and glioma cells in a GPCR-independent and Na? independent manner.
Increase of Membrane Potential by Ginsenosides in Prostate Cancer and Glioma cells
Lee, Yun-Kyung,Im, Young-Jin,Kim, Yu-Lee,Sacket Santosh J.,Lim, Sung-Mee,Kim, Kye-Ok,Kim, Hyo-Lim,Ko, Sung-Ryong,Lm, Dong-Soon The Korean Society of Ginseng 2006 Journal of Ginseng Research Vol.30 No.2
Ginseng has an anti-cancer effect in several cancer models. As a mechanism study of ginsenoside-induced growth inhibition in cancer cells, we measured change of membrane potential in prostate cancer and glioma cells by ginsenosides, active constituents of ginseng. Membrane potential was estimated by measuring fluorescence change of DiBAC-Ioaded cells. Among 11 ginsenosides tested, ginsenosides $Rb_2$, $Rg_3$, and $Rh_2$ increased significantly and robustly the membrane potential in a concentration-dependent manner in prostate cancer and glioma cells. Ginsenosides Rc, Ro, and $Rb_1$ slightly increased membrane potential. The ginsenoside-induced membrane potential increase was not affected by treatment with pertussis toxin or U73122. The ginsenoside-induced membrane potential increase was not diminished in $Na^+$-free or $HCO_3^-$-free media. Furthermore, the ginsenoside-induced increase of membrane potential was not changed by EIPA (5-(N-ethyl-N-isopropyl)-amiloride), SITS (4-acetoamido-4'-isothiocyanostilbene-2,2'-disulfonic acid), and omeprazole. In summary, ginsenosides $Rb_2$, $Rg_3$, and $Rh_2$ increased membrane potential in prostate cancer and glioma cells in a GPCR-independent and $Na^+$ independent manner.
Kim, Kyeok,Kim, Hyo-Lim,Lee, Yun-Kyung,Han, Mi-Jin,Sacket, Santosh J.,Jo, Ji-Yeong,Kim, Yu-Lee,Im, Dong-Soon 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.3
Lysophosphatidylserine (LPS) can be generated following phosphatidylserine-specific phospholipase $A_2$ activation. The effects of LPS on cellular activities and the identities of its target molecules, however, have not been fully elucidated. In this study, we observed that LPS stimulated intracellular calcium increased in mouse bone marrow-derived mast cells (BMMC), and rat C6 glioma and human HCT116 colon cancer cells and compared the LPS-induced $Ca^{2+}$ increases with the response by lysophosphatidic acid (LPA), a structurally related bioactive lysolipid. In order to test involvement of signaling molecules in the LPS-induced $Ca^{2+}$ signaling, we used pertussis toxin (PTX), U73122, and 2-APB, which are specific inhibitors for G proteins, phospholipase C (PLC), and $IP_3$ receptors, respectively. The increases due to LPS and LPA were inhibited by PTX, U-73122 and 2-APB, suggesting that both lipids stimulate calcium signaling via G proteins ($G_{i/o}$ types), PLC activation, and subsequent $IP_3$ production, although the sensitivity to pharmacological inhibitors varied from complete inhibition to partial inhibition depending on cell type and lysolipid. Furthermore, we observed that Ki16425 completely inhibited an LPS-induced $Ca^{2+}$ response in three cell types, but that the effect of VPC32183 varied from complete inhibition in BMMC and C6 glioma cells to partial inhibition in HCT116 cells. Therefore, we conclude that LPS increases $[Ca^{2+}]_i$ through Ki16425/VPC32183-sensitive G protein-coupled receptors (GPCR), G protein, PLC, and $IP_3$ in mouse BMMC, rat C6, and human HCT116 cells.
Kyeok Kim,Hyo-Lim Kim,Yun-Kyung Lee,Mijin Han,Santosh J. Sacket,Ji-Yeong Jo,Yu-Lee Kim,임동순 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.3
Lysophosphatidylserine (LPS) can be generated following phosphatidylserine-specific phospholipase A2 activation. The effects of LPS on cellular activities and the identities of its target molecules, however, have not been fully elucidated. In this study, we observed that LPS stimulated intracellular calcium increased in mouse bone marrow-derived mast cells (BMMC), and rat C6 glioma and human HCT116 colon cancer cells and compared the LPS-induced Ca2+ increases with the response by lysophosphatidic acid (LPA), a structurally related bioactive lysolipid. In order to test involvement of signaling molecules in the LPS-induced Ca2+ signaling, we used pertussis toxin (PTX), U73122, and 2-APB, which are specific inhibitors for G proteins, phospholipase C (PLC), and IP3 receptors, respectively. The increases due to LPS and LPA were inhibited by PTX, U-73122 and 2-APB, suggesting that both lipids stimulate calcium signaling via G proteins (Gi/o types), PLC activation, and subsequent IP3 production, although the sensitivity to pharmacological inhibitors varied from complete inhibition to partial inhibition depending on cell type and lysolipid. Furthermore, we observed that Ki16425 completely inhibited an LPS-induced Ca2+ response in three cell types, but that the effect of VPC32183 varied from complete inhibition in BMMC and C6 glioma cells to partial inhibition in HCT116 cells. Therefore, we conclude that LPS increases [Ca2+]i through Ki16425/VPC32183-sensitive G protein-coupled receptors (GPCR), G protein, PLC, and IP3 in mouse BMMC, rat C6, and human HCT116 cells.