Dataset Information

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

ABSTRACT: Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-? in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

SUBMITTER: Morsy MA

PROVIDER: S-EPMC6556784 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Morsy Mohamed A MA Patel Snehal S SS El-Sheikh Azza A K AAK Savjani Jignasa K JK Nair Anroop B AB Shah Jigar N JN Venugopala Katharigatta N KN

Mediators of inflammation 20190527

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both <i>in silico</i> using molecular docking against glucocorticoid receptor (GR) and <i>in viv ...[more]

PMID: 31263381

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Project description:BACKGROUND: The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity. METHODOLOGY/PRINCIPAL FINDINGS: Here, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GR-DNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation. CONCLUSIONS/SIGNIFICANCE: The data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential steps in the receptor activation pathway, results presented here contribute to understand how specific ligands influence GR behavior.

Project description:Knowledge on species' reproductive biology is a fundamental pre-requisite of every conservation effort, but is often lacking. Sex steroids can provide valuable information for the assessment of reproductive success, whereas glucocorticoids are used to assess adrenocortical activity and stress-related bodily adaption. However, due to their perilous condition, access to animals is often difficult, which makes hormone measurement in non-invasively collected hair samples an attractive option. We determined cortisol, cortisone, corticosterone, testosterone and progesterone in Iberian lynx hair using enzyme immunoassay (EIA). Cross-validation was performed with high-performance liquid chromatography (HPLC) and high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Finally, we statistically evaluated the variations of sex steroids and glucocorticoids according to age, sex, origin, behavior and management. All steroids except corticosterone were detectable in Iberian lynx hair. Hair progesterone measured by EIA was overestimated by cross-reaction with 5α-dihydroprogesterone, a biologically active gestagene, and was highly correlated with HPLC-MS/MS results. Progesterone was higher in adult females compared to all other age-sex groups. Cortisol measured by EIA was overestimated due to antibody cross-reactivity with cortisone and was correlated to the sum of HPLC-MS/MS measurements for cortisol and cortisone. Cortisol was higher in females than in males measured by HPLC-MS/MS, but the EIA results were confounded by the lack of specificity. When using cortisol-cortisone and cortisol-dihydroepiandrosterone ratios, differences were noted between wild-caught and captive-bred lynxes. Additionally, longitudinal EIA measurements of an Iberian lynx after a wildfire showed an inversion of the cortisol-cortisone ratio that later subsided. These results validate the use of hair progesterone measurement for Iberian lynx reproductive monitoring and add to the growing evidence supporting the need for a more comprehensive approach to hair steroid measurement that accounts for local interconversion and co-regulation mechanisms.

Dataset Information

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Publications

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

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