Inhibition of NOS‐2 expression in macrophages through the inactivation of NF‐<i>κ</i>B by andalusol

Heras, Beatriz de las; Navarro, Arturo Anadón; Díaz-Guerra, María José; Bermejo, Paloma; Castrillo, Antonio; Boscá, Lisardo; Villar, A.

doi:10.1038/sj.bjp.0702844

Cited by 45 publications

(29 citation statements)

References 45 publications

(57 reference statements)

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“…[32][33][34] The diterpene lactone AHAL has been reported to suppress the capsaicininduced ear edema, a valid model to screen compounds for potential antiallergic and local anti-inflammatory activities. However, it showed no obvious effect on paw edema induced by Compound 48/80, histamine or serotonin but effectively decreased the vascular permeability increase induced by intraperitoneal acetic acid.…”

Section: Discussionmentioning

confidence: 99%

Topically Applied Diterpenoids from Egletes viscosa (Asteraceae) Attenuate the Dermal Inflammation in Mouse Ear Induced by Tetradecanoylphorbol 13-Acetate- and Oxazolone

Calou

Sousa

Andrade

et al. 2008

Biological & Pharmaceutical Bulletin

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Over the past three decades, the prevalence of atopic dermatitis and allergic or irritant contact dermatitis has been increasing significantly in the general population, causing considerable economic costs and decreased quality of life. [1][2][3] Topical corticosteroids have been the first-choice therapy for treatment of these inflammatory skin diseases such as eczema, atopic and seborrheic dermatitis, and psoriasis. While effective in many patients, this form of therapy carry the concern of local and systemic adverse effects and may induce skin atrophy, especially after long-term use. 4,5) In contrast to topical corticosteroids, the more recently introduced calcineurin inhibitors like tacrolimus and pimecrolimus do not induce skin atrophy, even after long-term use but may induce adverse effects such as burning, erythema and pruritus and are contraindicated in patients younger than two years or in those who are immunosuppressed.6,7) Thus, the available drugs, although have efficacy they are associated with adverse effects and therefore the development of new and safe anti-inflammatory topical agents for the treatment of dermatitis is needed.Studies reveal that a large percentage of patients use some form of complementary and alternative medicine for the treatment of atopic and contact dermatitis, which include herbal remedies. [8][9][10] In the recent past, several diterpene compounds of plant origin such as abietic acid from Pimenta racemosa var. grissea, hypoestoxide from Hypoestes rosea and marrubiin from Marrubium vulgare were shown to be effective in the mouse model of ear edema induced by several phlogestogens like histamine, bradykinin, capsaicin, prostaglandin E 2 , Croton oil, TPA (12-O-tetradecanoylphorbol 13-acetate) or oxazolone.11-13) Centipedic acid (CA) and 12-acetoxy-hawtriwaic acid lactone (AHAL, Tanabalin) are the naturally occurring diterpenes isolated from the aerial parts of Egletes viscosa L. (Asteraceae), a traditional medicinal plant.14) Previously we reported on the gastroprotective and antinociceptive properties of these diterpenes as well as an anti-edematogenic activity of tanabolin against ear edema induced by capsaicin. 15,16) However, the anti-inflammatory efficacy of these two diterpene compounds was not tested in the models of ear edema induced by either TPA or oxazolone, the most commonly used ones for analysing the agents effective against contact or atopic dermatitis.17,18) Thus as a part of our continuation study, we describe here for the first time the anti-dermatitis effects of these two natural diterpenes from Egletes viscosa using the experimental models of acute and chronic dermatitis induced by TPA and oxazolone, respectively, in the mouse ear. MATERIALS AND METHODS Plant Material and Isolation of DiterpenoidsThe aerial parts (2.5 kg) of Egletes viscosa LESS. (Asteraceae) were collected from the experimental plantation pertaining to the Department of Agronomy of this University, after its authentication and the voucher specimen (#16327) was retained in Prisco Bezerra He...

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Section: Discussionmentioning

confidence: 99%

Topically Applied Diterpenoids from Egletes viscosa (Asteraceae) Attenuate the Dermal Inflammation in Mouse Ear Induced by Tetradecanoylphorbol 13-Acetate- and Oxazolone

Calou

Sousa

Andrade

et al. 2008

Biological & Pharmaceutical Bulletin

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“…In this regard, among the natural products assayed, various terpenoids have been described as potent inhibitors of NF-B activation in response to proinflammatory stimulation. Andalusol, a labdane diterpene from Sideritis exerted anti-inflammatory effects in vivo and in vitro by inhibiting NF-B activation (8,9). Triterpenes also inhibited NOS-2 expression in RAW 264.7 cells (IC 50 , 0.2-0.3 M) and impaired NF-B activity (10).…”

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confidence: 99%

Inhibition of the Nuclear Factor κB (NF-κB) Pathway by Tetracyclic Kaurene Diterpenes in Macrophages

Castrillo

Heras

Hortelano

et al. 2001

Journal of Biological Chemistry

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109

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The anti-inflammatory action of most terpenes has been explained in terms of the inhibition of nuclear factor B (NF-B) activity. Ent-kaurene diterpenes are intermediates of the synthesis of gibberellins and inhibit the expression of NO synthase-2 and the release of tumor necrosis factor-␣ in J774 macrophages challenged with lipopolysaccharide. These diterpenes inhibit NF-B and IB kinase (IKK) activation in vivo but failed to affect in vitro the function of NF-B, the phosphorylation and targeting of IB␣, and the activity of IKK-2. Transient expression of NF-B-inducing kinase (NIK) activated the IKK complex and NF-B, a process that was inhibited by kaurenes, indicating that the inhibition of NIK was one of the targets of these diterpenes. These results show that kaurenes impair the inflammatory signaling by inhibiting NIK, a member of the MAPK kinase superfamily that interacts with tumor necrosis factor receptor-associated factors, and mediate the activation of NF-B by these receptors. Moreover, kaurenes delayed the phosphorylation of p38, ERK1, and ERK2 MAPKs, but not that of JNK, in response to lipopolysaccharide treatment of J774 cells. The absence of a coordinate activation of MAPK and IKK might contribute to a deficient activation of NF-B that is involved in the anti-inflammatory activity of these molecules.Activation of the transcription factor NF-B 1 has been shown to be a key component of innate immunity (1), promoting the expression by macrophages of a set of genes involved in host defense, such as pro-inflammatory cytokines (2, 3), NOS-2, cyclooxygenase 2, cell adhesion molecules, and various matrix metalloproteinases (4 -6). NF-B is present constitutively in the cytosol of the cells, where it is retained through the interaction with inhibitory IB proteins that mask the nuclear localization domain of the complex (2). NF-B-dependent gene transcription requires the phosphorylation of IB␣ by IKK2, which releases this inhibitory component from the dimer of Rel proteins (mainly p50, p65, and c-Rel), and is followed by degradation of the phospho-IB by the proteasome (3, 7).Biochemical, pharmacological, and genetic data indicate that the control of NF-B activation constitutes a relevant target for the treatment of inflammatory diseases (2). For this reason, the research on molecules endowed with the capacity to inhibit the consecutive steps leading to NF-B activation has been a subject of current interest (2, 3). In this regard, among the natural products assayed, various terpenoids have been described as potent inhibitors of NF-B activation in response to proinflammatory stimulation. Andalusol, a labdane diterpene from Sideritis exerted anti-inflammatory effects in vivo and in vitro by inhibiting NF-B activation (8, 9). Triterpenes also inhibited NOS-2 expression in RAW 264.7 cells (IC 50 , 0.2-0.3 M) and impaired NF-B activity (10). In the case of sesquiterpenes, it has been described that some of these compounds induce HSP72, which in turn prevents NF-B activation and NOS-2 expression (11, 12).More recently,...

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“…1,2) We have recently reported the anti-inflammatory properties of a lipid fraction obtained from Sideritis javalambrensis and those of the diterpenoid (ent-13(16),14-labdadiene-6a,8a,18triol-andalusol-) isolated from the acetone extract of Sideritis foetens, an endemic plant of Southern Spain. 3,4,5) Inflammation is normally a localized protective response which serves to destroy, dilute, or wall-off both the injurious agent and the injured tissue. The inflammatory response is coordinated by cells such as macrophages, lymphocytes, leukocytes and mast cells.…”

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confidence: 99%

Anti-Inflammatory and Immunomodulating Properties of a Sterol Fraction from Sideritis foetens Clem.

Navarro

Heras

Villar

2001

Biological & Pharmaceutical Bulletin

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125

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Interest in the phytochemical study of species of the Sideritis genus (Lamiaceae) has been stimulated by their pharmacological activity and their wide range of medicinal folk uses in Spain such as vulnerary, anti-infectious, anti-inflammatory, anti-rheumatic and anti-ulcerous applications. Various flavonoids and terpenoids have been isolated from this genus. 1,2) We have recently reported the anti-inflammatory properties of a lipid fraction obtained from Sideritis javalambrensis and those of the diterpenoid (ent-13(16),14-labdadiene-6a,8a,18triol-andalusol-) isolated from the acetone extract of Sideritis foetens, an endemic plant of Southern Spain. 3,4,5) Inflammation is normally a localized protective response which serves to destroy, dilute, or wall-off both the injurious agent and the injured tissue. The inflammatory response is coordinated by cells such as macrophages, lymphocytes, leukocytes and mast cells. A large number of mediators produced by these cells play a key role, for example, arachidonic acid metabolites such as prostaglandins and leukotrienes, reactive oxygen species, hydrolytic enzymes, histamine, nitric oxide, cytokines, etc. [6][7][8] Acute inflammation is associated with a rapid, early infiltration of polymorphonuclear leukocytes and increased vascular permeability at the site of injury.In this paper, we have evaluated the in vivo anti-inflammatory properties of a sterol fraction obtained from S. foetens on different inflammatory responses in mice. In addition, the interaction of this fraction with the functional properties of leukocytes and mast cells was analyzed in vitro. Immunomodulating activity through interaction with complement activation was also investigated. MATERIALS AND METHODS Plant MaterialThe aerial parts of Sideritis foetens were collected in Sierra de Gádor, Almería province (Spain). A voucher specimen has been deposited in the Department of Botany, Faculty of Pharmacy, Complutense University, Madrid (Spain). Extraction and IdentificationThe carrageenan-induced mouse paw oedema model was used for a bioassay guidedfractionation based on the anti-inflammatory activity.Dried aerial parts of Sideritis foetens (3 kg) were macerated with 99.5% acetone (12 l) at room temperature. The acetone extract was evaporated in vacuo to yield 84.8 g of residue. This extract (11.8 g) was fractionated by flash column chromatography over a silica gel (450 g, 230-400 mesh) column (6ϫ80 cm) using cyclohexane: acetone 70/30 to yield nine fractions. The most active fraction (subfraction B) (1.5 g) was chromatographed over a silica gel column (80 g, 230-400 mesh) using cyclohexane/ethyl acetate 70/30 as solvent, yielding the sterol fraction as white needles (800 mg).Sterol identification was performed by GC analysis [Perkin Elmer Sigma 3B equipped with a SE-30 Sobrechromosob WHP 3/100 column (lenght 2 m, i.d. 0.32 mm). Experimental conditions were: injector temp., 295°C; oven temp., 270°C (isotherm); detection temp., 285°C)]. The relative retention times were compared to standard samples. Campester...

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Inhibition of NOS‐2 expression in macrophages through the inactivation of NF‐κB by andalusol

Cited by 45 publications

References 45 publications

Topically Applied Diterpenoids from Egletes viscosa (Asteraceae) Attenuate the Dermal Inflammation in Mouse Ear Induced by Tetradecanoylphorbol 13-Acetate- and Oxazolone

Topically Applied Diterpenoids from Egletes viscosa (Asteraceae) Attenuate the Dermal Inflammation in Mouse Ear Induced by Tetradecanoylphorbol 13-Acetate- and Oxazolone

Inhibition of the Nuclear Factor κB (NF-κB) Pathway by Tetracyclic Kaurene Diterpenes in Macrophages

Anti-Inflammatory and Immunomodulating Properties of a Sterol Fraction from Sideritis foetens Clem.

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