Highly potent inhibitors of tnf-α production. Part II: metabolic stabilization of a newly found chemical lead and conformational analysis of an active diastereoisomer

Matsui, Takuya; Kondo, Takashi; Nishita, Yoshitaka; Itadani, Satoshi; Fujita, Setsuko; Omawari, Nagashige; Sakai, Masaru; Nakazawa, Shuichi; Ogata, Akihito; Mori, Hiromu; Kamoshima, Wataru; Terai, Kouichiro; Ohno, Hiroyuki; Obata, Takaaki; Nakai, Hisao; Toda, Masaaki

doi:10.1016/s0968-0896(02)00380-2

Cited by 28 publications

(27 citation statements)

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“…Moreover, since de-phosphorylation of PCERA-1 would give rise to a cellpermeable CERA-1, one can predict that if PCERA-1 crosses the cell membrane by the mechanism suggested above for C1P, then exogenous CERA-1 should be at least as active as A c c e p t e d M a n u s c r i p t 7 exogenous PCERA-1. However, CERA-1 was found to be essentially inactive, both in-vivo Matsui et al, 2002c;Matsui et al, 2002d), and in-vitro (Goldsmith et al, 2008), suggesting that PCERA-1 acts in an extra-cellular manner. It should be noted however that exogenous phospholipids may also enter the cell by alternative mechanisms such as endocytosis (Boudker and Futerman, 1993) or via the scavenger receptor (Adachi and Tsujimoto, 2006).…”

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 96%

“…Yet, the -methyl group of PCERA-1 (Fig. 1) protects the phosphate from being enzymatically removed as shown by in-vitro stability assays with tissue homogenates (Matsui et al, 2002c;Matsui et al, 2002d). Moreover, since de-phosphorylation of PCERA-1 would give rise to a cellpermeable CERA-1, one can predict that if PCERA-1 crosses the cell membrane by the mechanism suggested above for C1P, then exogenous CERA-1 should be at least as active as A c c e p t e d M a n u s c r i p t 7 exogenous PCERA-1.…”

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 99%

“…Following the discovery of a lead compound by in-vivo screening in rodents, this drug was rationally developed as a potent in-vivo suppressor of LPS-induced TNF- secretion (Matsui et al, 2002b;Matsui et al, 2002d;Matsui et al, 2002e;Matsui et al, 2003). A thorough structure-activity relationships study has demonstrated that both the phosphate (Matsui et al, 2002c;Matsui et al, 2002d) and the lipidic (Matsui et al, 2002c;Matsui et al, 2002d) portions of PCERA-1 are required for activity. Interestingly, we noticed that these moieties and the correct spacing in-between them, are present also in the natural C1P (Fig.…”

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 99%

“…The mechanistic study was enabled by the finding that macrophages, both cultured and primary, are a major cell target of PCERA-1 Goldsmith et al, 2008). The ability of a PCERA-1 derivative to A c c e p t e d M a n u s c r i p t 8 reduce mortality and increase survival in a mouse LPS-induced sepsis model was attributed solely to the reduced production of the pro-inflammatory cytokine TNF (Matsui et al, 2002c). However, we found that in addition, PCERA-1 inhibited production of the p40 subunit of the proinflammatory cytokines IL-12 and IL-23, and elevated production of the anti-inflammatory cytokine IL-10, in LPS-challenged mice and in LPS-stimulated macrophages Goldsmith et al, 2008).…”

Section: The Receptor-mediated Activities Of Pcera-1mentioning

confidence: 99%

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Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

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. Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1). Molecular and Cellular Endocrinology, Elsevier, 2009, 314 (2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 Ceramide-1-phosphate (C1P) is known as a second messenger regulating a multitude of processes including cell growth, apoptosis and inflammation. Exciting recent findings now suggest that C1P can stimulate macrophages migration in an extra-cellular manner via a G protein-coupled receptor (GPCR). Interestingly, a synthetic C1P analog, named phospho-ceramide analogue-1 (PCERA-1), was recently described as a potent in-vivo anti-inflammatory agent, and was suggested to act on macrophages in an extra-cellular manner via a GPCR. Here we summarize and compare the receptor-mediated as well as receptor-independent activities of natural C1P and its synthetic analog. We also provide experimental data in support of distinct C1P and PCERA-1 receptors.Page 3 of 20A c c e p t e d M a n u s c r i p t 3 IntroductionIt is well-established that sphingolipids are crucial metabolites for controlling cell and tissue homeostasis. In particular, ceramides induce cell cycle arrest and are potent inducers of apoptosis. Also, ceramides play crucial roles in the regulation of cell differentiation, and inflammation (Hannun et al., 1986;Hannun, 1994;Hannun and Obeid, 1995;Hannun, 1996;Hannun and Obeid, 2002;Kolesnick, 1994;Kolesnick, 1987;Kolesnick and Hemer, 1990;Kolesnick et al., 2000;Merrill and Jones, 1990;Merrill et al., 1997;Merrill, 2002;Spiegel and Merrill, 1996).Ceramides are generated either by de novo synthesis, or by the action of different sphingomyelinases (SMases), whose activities, enzymology, and compartmentalization have been thoroughly reviewed by others (Cremesti et al., 2002;Goni and Alonso, 2002;Kolesnick et al., 2000). A major metabolite of ceramide is ceramide-1-phosphate (C1P, Fig. 1), which is generated through direct phosphorylation of ceramide by ceramide kinase (CERK) (Bajjalieh et al., 1989;Kolesnick and Hemer, 1990). This enzyme was first shown to be confined to the microsomal fraction, but its location in the cytosol has also been reported (Mitsutake et al., 2004). Recently, Chalfant and co-workers demonstrated that CERK utilizes ceramide transported to the trans-Golgi apparatus by the ceramide transport protein (CERT). Of note, down-regulation of CERT by RNA interference resulted in strong inhibition of newly synthesized C1P, suggesting that CERT plays a critical role in C1P formation . However, this observation contrasts with that of Bornancin and...

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Section: Evidence For a Pcera-1 Receptormentioning

confidence: 96%

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 99%

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 99%

Section: The Receptor-mediated Activities Of Pcera-1mentioning

confidence: 99%

See 2 more Smart Citations

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

show abstract

“…A neutralizing monoclonal anti-mouse IL-10 antibody, rat IgG isotype control, recombinant mouse TNF␣ (rTNF␣) and ELISA reagents sets for TNF␣, IL-10, and IL-12p40 were purchased from R&D Systems (Minneapolis, MN). PCERA-1 and its non-phosphorylated analog, CERA-1, were synthesized according to published procedures [24,25]. PCERA-1 was dissolved in sterile PBS, while CERA-1 was initially dissolved in ethanol and then diluted in sterile PBS containing 4% fatty acid-free BSA.…”

Section: Reagents and Cell Culturementioning

confidence: 99%