Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes

Través, Paqui G.; Hortelano, Sonsoles; Zeini, Miriam; Chao, Ta-Hsiang; Lam, Thanh; Neuteboom, Saskia; Theodorakis, Emmanuel A.; Palladino, Michael A.; Castrillo, Antonio; Boscá, Lisardo

doi:10.1124/mol.106.031906

Cited by 38 publications

(22 citation statements)

References 41 publications

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“…[21][22][23][24][25][26][27][28][29][30][31][32][33] These findings clearly show the medicinal potential of 1. However, almost all of the biological activities described in the literature for 1 have been shown by the compound extracted from Acanthopanax koreanum, which resulted in the protection of the process for its extraction from this plant by an international patent, 21 and has attracted interest in its synthetic preparation and modification.…”

Section: Chemical Studiesmentioning

confidence: 75%

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Pinheiro

Xavier

Souza

et al. 2009

J. Braz. Chem. Soc.

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O presente trabalho descreve o isolamento, a partir do caule de Annona amazonica, do ácido acantóico, um diterpeno do tipo pimaradieno que possui várias e importantes atividades biológicas descritas na literatura. Neste estudo foi verificado que este composto apresenta significante atividade tripanocida contra as formas epimastigotas de Trypanosoma cruzi. Também foi constatado que este diterpeno é o constituinte majoritário da planta, encontrado em cerca de 65% do extrato hexânico, demonstrando que A. amazonica é uma nova fonte natural renovável desta substância. Além do ácido acantóico, a investigação química resultou no isolamento dos alcalóides liriodenina e cassiticina, entre outros compostos, tais como terpenos, esteróides e ácidos graxos. Adicionalmente, é descrita a completa e inequívoca atribuição dos deslocamentos químicos de RMN de 1 H e 13 C da cassiticina.The present work reports the isolation of acanthoic acid, a promising pimaradiene-type diterpene with several important biological activities described in the literature, from the stems of Annona amazonica. We found that acanthoic acid has significant trypanocidal activity against the epimastigote forms of Trypanosoma cruzi. This diterpene is the major constituent of the plant, comprising at least 65% of the hexane extract, demonstrating that A. amazonica is a new renewable natural source for this compound. The chemical investigation also resulted in the isolation of the alkaloids liriodenine and cassythicine, and other compounds including terpenes, sterols, and fatty acids. Additionally, the complete and unequivocal 1 H and 13 C NMR chemical shift assignments for cassythicine are provided. Keywords: Annona amazonica, Annonaceae, acanthoic acid, cassythicine, trypanocidal activity IntroductionThe family Annonaceae, comprised of tropical and subtropical species with about 135 genera and more than 2500 species and widely distributed in South and Central America, Africa, Asia, and Australia, 1 is known for its edible fruits and the medicinal properties of several species. 2 In Brazil, there are 26 genera with about 260 species, including the genus Annona, which contains approximately 120 species. 3 Chemical investigations of species of Annonaceae have revealed their high chemical diversity in terms of secondary metabolites, such as alkaloids, acetogenins, terpenoids and lactones. These compounds have shown important biological activities, including antiparasitic, in particular against Leishmania sp., Plasmodium falciparum, and Trypanosoma cruzi. [4][5][6][7][8][9][10][11][12] Annona amazonica R.E. Fries is a tropical tree that grows up to 20-25 m tall and 35-60 cm in diameter, and is found from Panama to South America. In Brazil this species commonly occurs in the Amazon, mainly in the states of Amazonas and Pará. 13 To the best of our knowledge, only one previous phytochemical study has described the isolation and identification of cyanogenic constituents from this species. 14 Here we describe the isolation and structural identification of the chemica...

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Section: Chemical Studiesmentioning

confidence: 75%

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Pinheiro

Xavier

Souza

et al. 2009

J. Braz. Chem. Soc.

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“…All animals received care according to methods approved under institutional guidelines for the care and use of laboratory animals in research. PMs and BMDMs were obtained as previously described [44], and cells were then stimulated with: LPS (Salmonella typhimurium, Sigma L726), IFN-b (PeproTech), IFN-g (PrepoTech), polyI:C (Invivogen), zymosan (Invivogen) or IL-10 (PeproTech). Wortmannin was purchased from Calbiochem, PD 0325901 was a gift from Prof. Philip Cohen, Dundee.…”

Section: Methodsmentioning

confidence: 99%

“…Wortmannin was purchased from Calbiochem, PD 0325901 was a gift from Prof. Philip Cohen, Dundee. The concentration of NO in cell supernatant was measured as previously described [44].…”

Section: Methodsmentioning

confidence: 99%

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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LPS stimulation activates IKK and different MAP kinase pathways, as well as the PI3K-AktmTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, a MAP3K responsible for the activation of the MKK1-Erk1/2, controls P-Ser473 Akt and P-Thr389 p70 S6k phosphorylation in LPS-stimulated macrophages. Analysis of the intracellular signalling in Cot/tpl2 KO macrophages versus WT macrophages reveals lower IjBa recovery and higher phosphorylation of JNK and p38a after 1 h of LPS stimulation. Moreover, Cot/tpl2 deficiency increases LPS-induced NO synthase 2 (NOS2) expression in macrophages. Inhibition of the PI3K pathway abolishes the differences in IjBa and NOS2 expression between Cot/tpl2 KO and WT macrophages following LPS administration. Furthermore, in zymosan-and polyI:C-stimulated macrophages, Cot/tpl2 mediates P-Ser473 Akt phosphorylation, increases IjBa levels and decreases NOS2 expression. In conclusion, these data reveal a novel role for the Cot/tpl2 pathway in mediating TLR activation of the Akt-mTOR-p70 S6k pathway, allowing Cot/tpl2 to fine-control the activation state of other signalling pathways.Key words: Akt . Cot/tpl2 . Macrophage . NO synthase 2 . p70 S6k . TLR See accompanying Commentary by Martinez Supporting Information available online IntroductionStimulation of TLRs by the different PAMPs triggers macrophage activation, starting a specific functional program that culminates in the production of inflammatory mediators. With the exception of TLR3, TLRs use MyD88 as a central intracellular adaptor, thereby activating multiple downstream intracellular pathways including IKK. TLR3 and TLR4 recruit the TRIF adaptor, which also activates IKK, but specifically activating TBK1 and the transcription factor IRF3 (reviewed in [1,2]). Translocation of IRF3 to the nucleus is necessary, although not sufficient, to induce IFN-b expression [3]. Most TLRs also activate the PI3K-Akt-mTOR-p70 S6k pathway, which is considered to be a negative regulator of TLR activation in macrophages and myeloid dendritic cells. Inhibition of this PI3K-Akt-mTOR-p70 S6k pathway in TLR-activated cells augments NO synthase 2 (NOS2) expression [4][5][6][7][8].Adequate TLR4 stimulation induces the formation of a TLR receptor complex that recruits proteins such as MyD88 and p85 PI3 K [9]. PI3K subsequently activates the Akt-mTOR-p70 S6k pathway. Moreover, TLR-bound MyD88 recruits IRAK4 and IRAK1. The phosphorylation of IRAK1 by IRAK4 facilitates TRAF6 [1,10]). Activated IKK-b phosphorylates p105 NF-kB at multiple residues [11][12][13], which targets the rapid degradation of p105 NF-kB to p50 NF-kB [11][12][13][14]. In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully...

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“…Western Blotting of Bone Marrow-derived Macrophage Extracts-Bone marrow derived macrophages (BMDM) were cultured as described previously (43), stimulated with zymosan (10 g/ml), and at the times indicated, the cell supernatants were frozen in liquid nitrogen, and the cells (5 ϫ 10 6 ) were utilized to prepare extracts for analysis in Western blots (37) using anti-COX2 (Santa Cruz Biotechnology) and anti-ERK2 (Santa Cruz Biotechnology) antibodies.…”

Section: Animals and Models Of Inflammation-c57bl/6jmentioning

confidence: 99%

Cot/tpl2 (MAP3K8) Mediates Myeloperoxidase Activity and Hypernociception following Peripheral Inflammation*

Soria-Castro

Krzyzanowska

Pelaéz

et al. 2010

Journal of Biological Chemistry

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Cot/tpl2 (also known as MAP3K8) has emerged as a new and potentially interesting therapeutic anti-inflammatory target. Here, we report the first study of Cot/tpl2 involvement in acute peripheral inflammation in vivo. Six hours after an intraplantar injection of zymosan, Cot/tpl2 ؊/؊ mice showed a 47% reduction in myeloperoxidase activity, concomitant with a 46% lower neutrophil recruitment and a 40% decreased luminol-mediated bioluminescence imaging in vivo. Accordingly, Cot/tpl2 deficiency provoked a 25-30% reduction in luminolmediated bioluminescence and neutrophil recruitment together with a 65% lower macrophage recruitment 4 h following zymosan-induced peritonitis. Significantly impaired levels of G-CSF and GM-CSF and of other cytokines such as TNF␣, IL-1␤, and IL-6, as well as some chemokines such as MCP-1, MIP-1␤, and keratinocyte-derived chemokine, were detected during the acute zymosan-induced intraplantar inflammatory response in Cot/ tpl2 ؊/؊ mice. Moreover, Cot/tpl2 deficiency dramatically decreased the production of the hypernociceptive ligand NGF at the inflammatory site during the course of inflammation. Most importantly, Cot/tpl2 deficiency significantly reduced zymosan-induced inflammatory hypernociception in mice, with a most pronounced effect of a 50% decrease compared with wild type (WT) at 24 h following intraplantar injection of zymosan. At this time, Cot/ tpl2 ؊/؊ mice showed significantly reduced NGF, TNF␣, and prostaglandin E 2 levels compared with WT littermates. In conclusion, our study demonstrates an important role of Cot/tpl2 in the NGF, G-CSF, and GM-CSF production and myeloperoxidase activity in the acute inflammatory response process and its implication in inflammatory hypernociception. 2). Cot/tpl2, also known as MAP3K8, is the sole MAP3K that activates the MKK1/ 2-ERK1/2 pathway in response to stimulation of the TLR/IL-1 receptor superfamily, as well as in response to the activation of some receptors of the TNF family (3-10). However, Cot/tpl2 does not participate in the activation of ERK1/2 by stimulation of the C-type lectin receptor dectin-1 (11). In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-B and ABIN2 (A20-binding inhibitor of NF-B2), among other proteins, to protect Cot/tpl-2 from degradation. Adequate TLR/IL-1 receptor stimulation induces the activation of the IKK complex; active IKK␤ kinase phosphorylates p105 NF-B, triggering its partial degradation to p50 NF-B (12-15). Cot/tpl2 is then dissociated from the complex and with an adequate phosphorylation state (16 -19) is capable of activating MKK1 and consequently ERK1/2 (6, 20 -22) prior to being rapidly degraded through the proteasome pathway (6,20,23). Cot/tpl2 is required to process pre-TNF␣ to its mature secreted form in LPS-stimulated macrophages (24). In addition, in different isolated cell types Cot/tpl2 controls the secretion of other cytokines and chemokines such as IL-8, MCP-1, MIP-1␤, KC,10,[24][25][26][27]. Moreover, Cot/tpl2 activation is necessary for the production of PGE 2 ...

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Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes

Cited by 38 publications

References 41 publications

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Cot/tpl2 (MAP3K8) Mediates Myeloperoxidase Activity and Hypernociception following Peripheral Inflammation*

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