The Experts below are selected from a list of 1257 Experts worldwide ranked by ideXlab platform
Jing Zhao - One of the best experts on this subject based on the ideXlab platform.
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Sphingosylphosphorylcholine alleviates hypoxia caused apoptosis in cardiac myofibroblasts via cam p38 stat3 pathway
Apoptosis, 2020Co-Authors: Wan-cheng Yang, Tian-liang Zhang, Yu-juan Yao, Wei-hua Kong, Jing ZhaoAbstract:Blockade of hypoxia-caused nonmyocytes apoptosis helps improve survival and mitigate ventricular remodeling and dysfunction during the chronic stage of myocardial infarction. But tools affecting nonmyocyte apoptosis are very rare. Sphingosylphosphorylcholine (SPC), a naturally occurring bioactive sphingolipid in plasma, was proved to protect cardiomyocyte against apoptosis in an ischemic model in our previous study. Here, we showed that SPC also inhibited hypoxia-induced apoptosis in myofibroblasts, an important type of nonmyocytes in the heart. Calmodulin (CaM) is an identified receptor of SPC. We clarified that SPC inhibited myofibroblast apoptosis through CaM as evidenced by decreased cleaved caspase 3, PARP1 and condensed nucleus. Furthermore, the employment of inhibitor and agonist of p38 and STAT3 suggests that SPC inhibits myofibroblast apoptosis by regulating the phosphorylation of p38 and STAT3, and they act as downstream of CaM. The present work may provide new evidence on the regulation of myofibroblasts apoptosis by SPC and a novel target for heart remodeling after hypoxia.
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Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway.
Apoptosis : an international journal on programmed cell death, 2020Co-Authors: Wan-cheng Yang, Tian-liang Zhang, Yu-juan Yao, Wei-hua Kong, Jing ZhaoAbstract:Blockade of hypoxia-caused nonmyocytes apoptosis helps improve survival and mitigate ventricular remodeling and dysfunction during the chronic stage of myocardial infarction. But tools affecting nonmyocyte apoptosis are very rare. Sphingosylphosphorylcholine (SPC), a naturally occurring bioactive sphingolipid in plasma, was proved to protect cardiomyocyte against apoptosis in an ischemic model in our previous study. Here, we showed that SPC also inhibited hypoxia-induced apoptosis in myofibroblasts, an important type of nonmyocytes in the heart. Calmodulin (CaM) is an identified receptor of SPC. We clarified that SPC inhibited myofibroblast apoptosis through CaM as evidenced by decreased cleaved caspase 3, PARP1 and condensed nucleus. Furthermore, the employment of inhibitor and agonist of p38 and STAT3 suggests that SPC inhibits myofibroblast apoptosis by regulating the phosphorylation of p38 and STAT3, and they act as downstream of CaM. The present work may provide new evidence on the regulation of myofibroblasts apoptosis by SPC and a novel target for heart remodeling after hypoxia.
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Emerging roles of Sphingosylphosphorylcholine in modulating cardiovascular functions and diseases
Acta pharmacologica Sinica, 2018Co-Authors: Hong-wei Yue, Honghong Liu, Jing ZhaoAbstract:Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid in blood plasma that is metabolized from the hydrolysis of the membrane sphingolipid. SPC maintains low levels in the circulation under normal conditions, which makes studying its origin and action difficult. In recent years, however, it has been revealed that SPC may act as a first messenger through G protein-coupled receptors (S1P1-5, GPR12) or membrane lipid rafts, or as a second messenger mediating intracellular Ca2+ release in diverse human organ systems. SPC is a constituent of lipoproteins, and the activation of platelets promotes the release of SPC into blood, both implying a certain effect of SPC in modulating the pathological process of the heart and vessels. A line of evidence indeed confirms that SPC exerts a pronounced influence on the cardiovascular system through modulation of the functions of myocytes, vein endothelial cells, as well as vascular smooth muscle cells. In this review we summarize the current knowledge of the potential roles of SPC in the development of cardiovascular diseases and discuss the possible underlying mechanisms.
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Sphingosylphosphorylcholine protects cardiomyocytes against ischemic apoptosis via lipid raft pten akt1 mtor mediated autophagy
Biochimica et Biophysica Acta, 2015Co-Authors: Hong-wei Yue, Jun-ying Miao, Ping-ping Liu, Jing Liu, Fen Chang, Jing ZhaoAbstract:Autophagy, evoked by diverse stresses including myocardial ischemia/reperfusion (I/R), profoundly affects the development of heart failure. However, the specific molecular basis of autophagy remains to be elucidated. Here we report that Sphingosylphosphorylcholine (SPC), a bioactive sphingolipid, significantly suppressed apoptosis and induced autophagy in cardiomyocytes. Blocking this SPC evoked autophagy by 3-methyladenine (3MA)-sensitized cardiomyocytes to serum deprivation-induced apoptosis. Subsequent studies revealed that SPC downregulated the phosphorylation of p70S6K and 4EBP1 (two substrates of mTOR) but enhanced that of JNK when inducing autophagy. We identified SPC as a switch for the activity of Akt1, a supposed upstream modulator of both mTOR and JNK. Furthermore, β-cyclodextrin, which destroys membrane cholesterol, abolished the SPC-reduced phosphorylation of both Akt and PTEN, thus inhibiting SPC-induced autophagy. In conclusion, SPC is a novel molecule protecting cardiomyocytes against apoptosis by promoting autophagy. The lipid raft/PTEN/Akt1/mTOR signal pathway is the underlying mechanism and might provide novel targets for cardiac failure therapy.
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Sphingosylphosphorylcholine in cancer progress
International journal of clinical and experimental medicine, 2015Co-Authors: Hong-wei Yue, Qing-chuan Jing, Ping-ping Liu, Jing Liu, Jing ZhaoAbstract:Sphingosylphosphorylcholine (SPC) is a naturally occurring bioactive sphingolipid in blood plasma, metabolizing from the hydrolysis of the membrane sphingolipid. It has been shown to exert multifunctional role in cell physiological regulation either as an intracellular second messenger or as an extracellular agent through G protein coupled receptors (GPCRs). Because of elevated levels of SPC in malicious ascites of patients with cancer, the role of SPC in tumor progression has prompted wide interest. The factor was reported to affect the proliferation and/or migration of many cancer cells, including pancreatic cancer cells, epithelial ovarian carcinoma cells, rat C6 glioma cells, neuroblastoma cells, melanoma cells, and human leukemia cells. This review covers current knowledge of the role of SPC in tumor.
Kid Törnquist - One of the best experts on this subject based on the ideXlab platform.
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Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner.
Cellular signalling, 2016Co-Authors: Kati Kemppainen, Nina Wentus, Taru Lassila, Asta Laiho, Kid TörnquistAbstract:Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid which regulates many cancer-related processes, including cellular proliferation. The Hippo signaling pathway consists of a cascade of tumor suppressive kinases Mst1/2 and Lats1/2 and their downstream targets YAP and TAZ which are generally pro-proliferative transcriptional regulators. Direct phosphorylation by Lats1/2 causes inhibition or degradation of YAP/TAZ and down-regulation of their target genes. We found SPC treatment of MDA-MB-435S breast cancer cells to strongly inhibit their proliferation and to induce a sustained Lats2 protein expression (6-24h). Therefore, we hypothesized that Hippo signaling might mediate the anti-proliferative SPC response. We also saw a cell density-dependent increase in S127-phosphorylated YAP (pS127-YAP) and a decrease in mRNA levels of YAP target genes (CTGF, Cyr61) in response to long (9h) SPC treatment. Knockdown of S1P receptor 2 (S1P2) prevented the SPC-induced up-regulation of Lats2 and attenuated the anti-proliferative effect of SPC. However, while knockdown of Lats2 alone or in combination with Lats1 expectedly increased basal proliferation it did not attenuate the SPC-induced inhibition of proliferation. Exogenous expression of wild-type or kinase-dead Lats2 and knockdown of YAP/TAZ also had no effect on the anti-proliferative SPC response. It has been previously shown that activation of S1P2-G12/13 by sphingosine-1-phosphate (S1P) leads to rapid de-phosphorylation and up-regulation of YAP. Similarly, we saw a decrease in pS127-YAP and an increase in total YAP levels with short (1h) SPC treatment as well as a subsequent transient increase in YAP target gene expression. Inhibition of S1P2 prevented the SPC-induced YAP de-phosphorylation. The rapid YAP activation and subsequent up-regulation of Lats2 mRNA does not constitute a negative feedback loop as knockdown of YAP/TAZ did not inhibit SPC-induced Lats2 expression. In conclusion, in this study we show that SPC is able to regulate Hippo signaling in a dual and opposite manner, causing an initial activation of YAP followed by an inhibition. However, even the strong SPC-induced effects seen in Lats2 and YAP did not mediate the anti-proliferative SPC response.
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antiproliferative effect of Sphingosylphosphorylcholine in thyroid fro cancer cells mediated by cell cycle arrest in the g2 m phase
Molecular and Cellular Endocrinology, 2007Co-Authors: Emad Afrasiabi, Tomas Blom, Sonja Balthasar, Kid TörnquistAbstract:Abstract Among the group of bioactive sphingolipids, Sphingosylphosphorylcholine (SPC) has been known to induce both antiproliferative and proliferative effects depending on cell type. In the present investigation we show that SPC (1–10 μM) reduced the proliferation of FRO cells (an anaplastic thyroid carcinoma cell line) in a concentration dependent manner. The effect was pertussis toxin insensitive, and independent of phospholipase C, protein kinase C, p38 kinase, or jun kinase. In addition to inhibiting the migration of FRO cells, application of SPC induced a rapid (
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Antiproliferative effect of Sphingosylphosphorylcholine in thyroid FRO cancer cells mediated by cell cycle arrest in the G2/M phase.
Molecular and Cellular Endocrinology, 2007Co-Authors: Emad Afrasiabi, Tomas Blom, Sonja Balthasar, Kid TörnquistAbstract:Abstract Among the group of bioactive sphingolipids, Sphingosylphosphorylcholine (SPC) has been known to induce both antiproliferative and proliferative effects depending on cell type. In the present investigation we show that SPC (1–10 μM) reduced the proliferation of FRO cells (an anaplastic thyroid carcinoma cell line) in a concentration dependent manner. The effect was pertussis toxin insensitive, and independent of phospholipase C, protein kinase C, p38 kinase, or jun kinase. In addition to inhibiting the migration of FRO cells, application of SPC induced a rapid (
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Sphingosylphosphorylcholine activates gq gi 2 and gi 3 in thyroid frtl 5 cells implications for the activation of calcium fluxes and na h exchange
Biochemical and Biophysical Research Communications, 1999Co-Authors: Anne Nikmo, Kid Törnquist, Sonja Bjorklund, Minna Vainio, Elina EkokoskiAbstract:Abstract In the present investigation of rat thyroid FRTL-5 cells, we show using reverse-transcriptase PCR that these cells express both Edg-1 and Edg-5. We show using a [35S]GTPγS-binding assay that Sphingosylphosphorylcholine (SPC), which binds to both Edg-1 and EDG-5, activates Gq, Gi-2, and Gi-3proteins. SPC potently increases intracellular free calcium concentrations ([Ca2+]i). This effect is mediated through both Gqand Giproteins, as the mobilization of sequestered calcium was insensitive to pertussis toxin (i.e., mediated by Gq), while the SPC-evoked calcium entry was inhibited by pretreatment with pertussis toxin (i.e., mediated by Gi). Furthermore, SPC in a concentration-dependent manner increases intracellular pH in acidified cells via a Na+-H+exchange mechanism. The enhanced activation of Na+-H+exchange is independent of both an increase in [Ca2+]iand an activation of protein kinase C. The effect of SPC on Na+-H+exchange is insensitive to pertussis toxin, suggesting an effect mediated via Gq.
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Sphingosylphosphorylcholine Activates an Amiloride‐Nsensitive Na+‐H+‐Exchange Mechanism in GH4C1 Cells
European journal of biochemistry, 1997Co-Authors: Kid Törnquist, Michael Woodside, Sergio GrinstetnAbstract:The effect of Sphingosylphosphorylcholine (SphPCho) on the intracellular pH (pHi) in GH4C1 cells was investigated. SphPCho evoked a very slow increase in basal pHi. In cells acidified with nigericin, SphPCho induced a rapid alkalinization of the cells. The effect was inhibited in a Na+-free buffer solution, but was insensitive to ethylisopropyl amiloride, a potent inhibitor of Na+-H+ exchangers (NHE). Reverse transcription and PCR showed that the predominant isoform of the antiport expressed in GH4C1, cells is NHE-1. The rate of alkalinization after stimulation with propionate, and after addition of Na1 to cells acidified with NH4Cl, was enhanced in cells treated with SphPCho. The initial rate of alkalinization after addition of Na+ to acidified cells treated with SphPCho gave an apparent Km value of 15 ± 2 mM for Na+. The Vmax value was 9 ± 22 mM H+/min. The effect was insensitive to ouabain, staurosporine and bafilomycin A. However, the SphPCho-evoked alkalinization was abolished in cells treated with 2-deoxy-D-glucose. The effect was not due to the charge of the molecule, as stearylamine increased pHi in Na+-containing and Na+-free buffer. The results show that SphPCho may activate Na+-H+ exchange, and that this effect is mediated via an amiloride-insensitive exchange mechanism.
Dong-seok Kim - One of the best experts on this subject based on the ideXlab platform.
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PP2A and DUSP6 are involved in Sphingosylphosphorylcholine-induced hypopigmentation
Molecular and Cellular Biochemistry, 2012Co-Authors: Hyo-soon Jeong, Kyoung-chan Park, Dong-seok KimAbstract:Activation of extracellular signal-related kinase (ERK) is involved in decreased melanogenesis by Sphingosylphosphorylcholine (SPC). In the present study, we confirmed that SPC activated ERK and that a specific inhibitor of the ERK pathway (PD98059) recovered SPC-induced hypopigmentation. Moreover, we found that SPC significantly reduces protein phosphatase 2A (PP2A) activity in Mel-Ab cells, and that PP2A activator treatment abrogated SPC-induced hypopigmentation. We determined that α-melanocyte-stimulating hormone (α-MSH) increased the expression of dual-specificity phosphatase 6 (DUSP6), an ERK phosphatase, in a time-dependent manner. In contrast, SPC decreased the level of DUSP6 in Mel-Ab cells. Furthermore, inhibiting DUSP6 increased ERK activation and subsequently augmented the SPC-induced hypopigmenting effects. Taken together, our data suggest that SPC-induced phosphatase inhibition is also responsible for the hypopigmentary effects.
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Involvement of mTOR signaling in Sphingosylphosphorylcholine-induced hypopigmentation effects
Journal of biomedical science, 2011Co-Authors: Hyo-soon Jeong, Nyoun Soo Kwon, Kyoung-chan Park, Seung Hoon Lee, Hye-young Yun, Kwang Jin Baek, Dong-seok KimAbstract:Background Sphingosylphosphorylcholine (SPC) acts as a potent lipid mediator and signaling molecule in various cell types. In the present study, we investigated the effects of SPC on melanogenesis and SPC-modulated signaling pathways related to melanin synthesis.
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involvement of mtor signaling in Sphingosylphosphorylcholine induced hypopigmentation effects
Journal of Biomedical Science, 2011Co-Authors: Hyo-soon Jeong, Nyoun Soo Kwon, Kyoung-chan Park, Seung Hoon Lee, Hye-young Yun, Kwang Jin Baek, Dong-seok KimAbstract:Background: Sphingosylphosphorylcholine (SPC) acts as a potent lipid mediator and signaling molecule in various cell types. In the present study, we investigated the effects of SPC on melanogenesis and SPC-modulated signaling pathways related to melanin synthesis. Methods: Melanin production was measured in Mel-Ab cells. A luciferase assay was used to detect transcriptional activity of the MITF promoter. Western blot analysis was performed to examine SPC-induced signaling pathways. Results: SPC produced significant hypopigmentation effects in a dose-dependent manner. It was found that SPC induced not only activation of Akt but also stimulation of mTOR, a downstream mediator of the Akt signaling pathway. Moreover, SPC decreased the levels of LC3 II, which is known to be regulated by mTOR. Treatment with the mTOR inhibitor rapamycin eliminated decreases in melanin and LC3 II levels by SPC. Furthermore, we found that the Akt inhibitor LY294002 restored SPC-mediated downregulation of LC3 II and inhibited the activation of mTOR by SPC.
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Sphingosylphosphorylcholine inhibits melanin synthesis via pertussis toxin-sensitive MITF degradation
The Journal of pharmacy and pharmacology, 2010Co-Authors: Dong-seok Kim, Seo-hyoung Park, Sun-bang Kwon, Nyoun Soo Kwon, Kyoung-chan ParkAbstract:Objectives Sphingolipids act as structural components in cell membranes, and form lipid intermediates that have functional roles as signalling molecules in various cellular processes. Our previous findings have suggested that sphingolipid metabolites are deeply involved in the regulation of melanogenic processes. In this study we aimed to examine Sphingosylphosphorylcholine-mediated signalling pathways related to melanogenesis. Methods We determined the hypopigmenting effects and the related signalling pathways of Sphingosylphosphorylcholine in Mel-Ab cells. In particular, we analysed the involvement of the G-protein-coupled receptor in Sphingosylphosphorylcholine-induced MITF degradation. Key findings Western blotting revealed that Sphingosylphosphorylcholine induced the activation of extracellular signal-regulated kinase (ERK), as well as Akt. Moreover, the specific Akt pathway inhibitor LY294002 blocked the hypopigmenting effect of Sphingosylphosphorylcholine and abrogated the Sphingosylphosphorylcholine-mediated down-regulation of microphthalmia-associated transcription factor (MITF), showing that the Akt pathway is involved in Sphingosylphosphorylcholine-mediated melanin inhibition. Treatment with the proteasome inhibitor MG132 blocked the decrease in MITF by Sphingosylphosphorylcholine, but Sphingosylphosphorylcholine did not decrease the level of MITF mRNA, indicating that the reduction in the level of MITF results from MITF degradation. Furthermore, pre-incubation of Mel-Ab cells with pertussis toxin completely abolished the hypopigmenting effects and the activation of ERK and Akt by Sphingosylphosphorylcholine, suggesting that the effects of Sphingosylphosphorylcholine are mainly dependent on the G-protein-coupled receptor). Conclusions Together, these results suggest that Sphingosylphosphorylcholine reduces melanin synthesis via pertussis toxin-sensitive ERK and Akt activation, and subsequent MITF degradation.
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Sphingosylphosphorylcholine induced erk activation inhibits melanin synthesis in human melanocytes
Pigment Cell Research, 2006Co-Authors: Dong-seok Kim, Seo-hyoung Park, Sun-bang Kwon, Eun Sang Park, Chang Hun Huh, Sang Woong Youn, Kyoung-chan ParkAbstract:Sphingosylphosphorylcholine (SPC) is emerging as a potent signaling-lipid mediator. In this study, we investigated the effects of SPC on melanogenesis using cultured human melanocytes. Our results show that SPC significantly inhibits melanin synthesis in a concentration-dependent manner, and further that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. SPC treatment was also found to induce short-thick dendrites in human melanocytes, but not to reduce tyrosinase activity in a cell-free system, whereas kojic acid directly inhibited tyrosinase. These results suggest that SPC reduces pigmentation by indirectly regulating tyrosinase. In further experiments, SPC was found to downregulate microphthalmia-associated transcription factor (MITF) and tyrosinase, and Western blotting showed that SPC induces the activations of extracellular signal-regulated kinase (ERK) and 90 kDa ribosomal S6 kinase (RSK-1). Moreover, the specific ERK pathway inhibitor, PD98059, blocked the hypopigmentation effect of SPC, and abrogated the SPC-mediated downregulation of MITF. These results suggest that the ERK pathway is involved in the melanogenic signaling cascade, and that ERK activation by SPC reduces melanin synthesis via MITF downregulation.
Sei Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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Involvement of Fyn tyrosine kinase in actin stress fiber formation in fibroblasts.
FEBS letters, 2007Co-Authors: Hiroko Kishi, Hozumi Kawamichi, Katsuko Kajiya, Yuichi Takada, Sei KobayashiAbstract:Lysophosphatidic acid (LPA) and Sphingosylphosphorylcholine (SPC) activated Fyn tyrosine kinase and induced stress fiber formation, which was blocked by pharmacological inhibition of Fyn, gene silencing of Fyn, or dominant negative Fyn. Overexpressed constitutively active Fyn localized at both ends of F-actin bundles and triggered stress fiber formation, only the latter of which was abolished by Rho-kinase (ROCK) inhibition. SPC, but not LPA, induced filopodia-like protrusion formation, which was not mediated by Fyn and ROCK. Thus, Fyn appears to act downstream of LPA and SPC to specifically stimulate stress fiber formation mediated by ROCK in fibroblasts.
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Cell membrane-derived lysophosphatidylcholine activates cardiac ryanodine receptor channels
Pflügers Archiv - European Journal of Physiology, 2007Co-Authors: Yuki Nakamura, Sei Kobayashi, Midori Yasukochi, Issei Imanaga, Kiyoko Uehara, Akira Honda, Ryuji Inoue, Akira UeharaAbstract:Lysophosphatidylcholine (LPC) is metabolized from a membrane phospholipid and modulates a variety of channels in the plasma membrane (PM). We examined LPC modulation of cardiac ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR) using the planar lipid bilayer method to measure the single-channel currents. Micromolar concentrations of LPC increased the open probability of the reconstituted RyR channels irrespective of whether LPC was added to the cis or trans chamber. LPC also increased the membrane capacitance of the bilayer. The effects of LPC contrasted well with those of Sphingosylphosphorylcholine (SPC). Taken together, these results suggest that amphipathic lipid LPC does not bind directly to the RyR channel protein, but rather, is incorporated into the bilayer membrane and activates the channel. Thus, we consider cell membrane-derived LPC to be a putative endogenous mediator that activates not only plasma membrane channels but also RyR channels and induces arrhythmogenic Ca^2+ mobilization in cardiomyocytes.
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Cholesterol primes vascular smooth muscle to induce Ca2+ sensitization mediated by a Sphingosylphosphorylcholine-Rho-kinase pathway : Possible role for membrane raft
Circulation research, 2006Co-Authors: Noriyasu Morikage, Hiroko Kishi, Masafumi Sato, Fengling Guo, Satoshi Shirao, Takashi Yano, Masaaki Soma, Kimikazu Hamano, Kensuke Esato, Sei KobayashiAbstract:Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase–mediated Ca2+ sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified Sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase–mediated Ca2+ sensitization. Here we report the strong linkage between cholesterol and the Ca2+ sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by β-c...
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Ca2+ and voltage dependence of cardiac ryanodine receptor channel block by Sphingosylphosphorylcholine.
Pflugers Archiv : European journal of physiology, 2003Co-Authors: Midori Yasukochi, Sei Kobayashi, Akira Uehara, Joshua R. BerlinAbstract:The effect of Sphingosylphosphorylcholine (SPC) on the cytoplasmic Ca2+ and voltage dependence of channel gating by cardiac ryanodine receptors (RyR) was examined in lipid bilayer experiments. Micromolar concentrations of the lysosphingolipid SPC added to cis solutions rapidly and reversibly decreased the single-channel open probability (Po) of reconstituted RyR channels. The SPC-induced decrease in Po was marked by an increase in mean closed time and burst-like channel gating. Gating kinetics during intraburst periods were unchanged from those observed in the absence of the sphingolipid, although SPC induced a long-lived closed state that appeared to explain the observed decrease in channel Po. SPC effects were observed over a broad range of cis [Ca2+] but were not competitive with Ca2+. Interestingly, the sphingolipid-induced, long-lived closed state displayed voltage-dependent kinetics, even though other channel gating kinetics were not sensitive to voltage. Assuming SPC effects represent channel blockade, these results suggest that the blocking rate is independent of voltage whereas the unblocking rate is voltage dependent. Together, these results suggest that SPC binds directly to the cytoplasmic side of the RyR protein in a location in or near the membrane dielectric, but distinct from cytoplasmic Ca2+ binding sites on the protein.
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Sphingosylphosphorylcholine induces cytosolic Ca2+ elevation in endothelial cells in situ and causes endothelium-dependent relaxation through nitric oxide production in bovine coronary artery
FEBS letters, 1999Co-Authors: Kimiko Mogami, Yoichi Mizukami, Natsuko Todoroki-ikeda, Masato Ohmura, Kazuki Yoshida, Saori Miwa, Masunori Matsuzaki, Masako Matsuda, Sei KobayashiAbstract:Sphingosylphosphorylcholine (SPC) increased intracellular Ca(2+) concentration ([Ca(2+)]i) and nitric oxide (NO) production in endothelial cells in situ on bovine aortic valves, and induced endothelium-dependent relaxation of bovine coronary arteries precontracted with U-46619. The SPC-induced vasorelaxation was inhibited by N(omega)-monomethyl-L-arginine, an inhibitor of both constitutive and inducible NO synthase (NOS), but not by 1-(2-trifluoromethylphenyl) imidazole, an inhibitor of inducible NOS (iNOS). Immunoblotting revealed that endothelial constitutive NOS, but not iNOS, was present in endothelial cells in situ on the bovine aortic valves. We propose that SPC activates [Ca(2+)]i levels and NO production of endothelial cells in situ, thereby causing an endothelium-dependent vasorelaxation.
Chang Hoon Lee - One of the best experts on this subject based on the ideXlab platform.
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Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment.
Cancers, 2019Co-Authors: Mi Kyung Park, Chang Hoon LeeAbstract:Sphingosylphosphorylcholine (SPC) is a unique type of lysosphingolipid found in some diseases, and has been studied in cardiovascular, neurological, and inflammatory phenomena. In particular, SPC's studies on cancer have been conducted mainly in terms of effects on cancer cells, and relatively little consideration has been given to aspects of tumor microenvironment. This review summarizes the effects of SPC on cancer and tumor microenvironment, and presents the results and prospects of modulators that regulate the various actions of SPC.
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Sphingosylphosphorylcholine Induces Thrombospondin-1 Secretion in MCF10A Cells via ERK2.
Biomolecules & therapeutics, 2017Co-Authors: June Hee Kang, Mi Kyung Park, Hyun Ji Kim, Chang Hoon LeeAbstract:Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and Ca²⁺ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia. TSP-1 promotes aggressive phenotype via epithelial mesenchymal transition (EMT). The relationship between SPC and TSP-1 is unclear. We found SPC induced EMT leading to mesenchymal morphology, decrease of E-cadherin expression and increases of N-cadherin and vimentin. SPC induced secretion of thrombospondin-1 (TSP-1) during SPC-induced EMT of various breast cancer cells. Gene silencing of TSP-1 suppressed SPC-induced EMT as well as migration and invasion of MCF10A cells. An extracellular signal-regulated kinase inhibitor, PD98059, significantly suppressed the secretion of TSP-1, expressions of N-cadherin and vimentin, and decrease of E-cadherin in MCF10A cells. ERK2 siRNA suppressed TSP-1 secretion and EMT. From online PROGgene V2, relapse free survival is low in patients having high TSP-1 expressed breast cancer. Taken together, we found that SPC induced EMT and TSP-1 secretion via ERK2 signaling pathway. These results suggests that SPC-induced TSP-1 might be a new target for suppression of metastasis of breast cancer cells.
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Novel involvement of RhebL1 in Sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization: Binding to and activation of AKT1.
Oncotarget, 2017Co-Authors: Hyun Ji Kim, Hyun Jung Byun, Mi Kyung Park, Eun Ji Kim, Gyeoung Jin Kang, Chang Hoon LeeAbstract:// Hyun Ji Kim 1 , Hyun Jung Byun 1 , Mi Kyung Park 1 , Eun Ji Kim 1 , Gyeoung Jin Kang 1 , Chang Hoon Lee 1 1 College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea Correspondence to: Chang Hoon Lee, email: uatheone@dongguk.edu Keywords: Sphingosylphosphorylcholine, RhebL1, AKT1, keratin reorganization, migration Received: December 12, 2016 Accepted: February 06, 2017 Published: February 15, 2017 ABSTRACT Sphingosylphosphorylcholine induces keratin phosphorylation and reorganization, and increases viscoelasticity of metastatic cancer cells such as PANC-1 cells. However, the mechanism involved in Sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization is largely unknown. Sphingosylphosphorylcholine dose- and time-dependently induces the expression of RhebL1. The involvement of RhebL1 in Sphingosylphosphorylcholine-induced events including keratin 8 (K8) phosphorylation, reorganization, migration and invasion was examined. Gene silencing of RhebL1 suppressed the Sphingosylphosphorylcholine-induced events and overexpression of RhebL1 enhanced those events even without Sphingosylphosphorylcholine treatment. We examined whether the G protein function of RhebL1 induces K8 phosphorylation using constitutively active RhebL1Q64L and dominant negative RhebL1D60K. G protein activity of RhebL1 is involved in Sphingosylphosphorylcholine-induced K8 phosphorylation. We found that RhebL1 binds and activates AKT1. G protein activity of RhebL1 is involved in the binding and activation of AKT1. MK2206 (AKT inhibitor) and gene silencing of AKT1 inhibited the Sphingosylphosphorylcholine-induced events, whereas overexpression of activated-AKT1 induced K8 phosphorylation, reorganization, migration and invasion even without Sphingosylphosphorylcholine treatment. The collective results indicate that RhebL1 is involved in Sphingosylphosphorylcholine-induced events in A549 lung cancer cells via binding to AKT1 leading to activation of it. These results suggest that suppression of RhebL1 or inhibition of RhebL1’s binding to AKT1 might be a novel way that prevents changes in the physical properties of metastatic cancer cells.
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Isolation of Soil Microorganisms Having Antibacterial Activity and Antimigratory Effects on Sphingosylphosphorylcholine-induced Migration of PANC-1 Cells.
Toxicological research, 2011Co-Authors: Jun Hee Kang, Mi Kyung Park, Hyun Ji Kim, Yuri Kim, Chang Hoon LeeAbstract:To obtain soil microorganisms producing antimigratory activity which is important in controlling the metastasis of cancer cells, more than three hundreds of soil microbes were isolated from sixteen soil sources including Namsan mountain and designated as DGU1001-10338. At first, their antibiotic activities were examined by paper-disc method. More than 40 soil microbes produced compounds with antibiotic activity. Then, antimigratory activities of selected soil microorganisms were examined in a Sphingosylphosphorylcholine-induced migration assay in PANC-1 cells. Six of 42 soil microorganisms having antibacterial activity also had more than 45% inhibitory activity on migration of PANC-1 cells. These results suggested that selected soil microorganisms were a useful starting point to find compounds for controlling metastasis of cancer cells.
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Characterizations of Sphingosylphosphorylcholine-induced scratching responses in ICR mice using naltrexon, capsaicin, ketotifen and Y-27632
European journal of pharmacology, 2008Co-Authors: Hyoung June Kim, Hyuk Kim, Eun-sil Han, Sun Mi Park, Jae-young Koh, Kwang-mi Kim, Minsoo Noh, Jung-ju Kim, Chang Hoon LeeAbstract:Abstract Sphingosylphosphorylcholine (SPC) is upregulated in the stratum corneum of atopic dermatitis patients by sphingomyelin deacylase. We conducted an investigation, both to confirm that intradermal injection of SPC elicits scratching in mice, and to elucidate the detailed mechanism of the SPC-induced itch–scratch response. Intradermal administration of SPC increased the incidence of scratching behavior in a dose-dependent manner. SPC-induced scratching could be suppressed, significantly, by the μ-opoid receptor antagonist, naltrexon, the vaniloid receptor agonist, capsaicin, and the histamine H 1 receptor antagonist ketotifen. d - erythro SPC, one of the SPC stereotypes, could elicit the scratch response, but not l - threo SPC. Y-27632 (1 mg/kg, an inhibitor of Rho-associated protein kinase (ROCK)), was found to suppress SPC-induced scratching. Both the stereospecificity of SPC and the involvement of the Rho/ROCK pathway suggested that SPC-induced scratching is related to the receptor.
