Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Miner, Jeffrey N.; Ardecky, Bob; Benbatoul, Khalid; Griffiths, Kimberly; Larson, Christopher J.; Mais, Dale E.; Marschke, Keith B.; Rosen, Jon; Vajda, Eric G.; Zhi, Lin; Negro‐Vilar, A.

doi:10.1073/pnas.0705517104

Cited by 69 publications

(50 citation statements)

References 44 publications

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“…Both models have been used to test the anti-inflammatory activities of many compounds (10,14,52,53). Our data clearly show an anti-inflammatory function of Rg1 in both the acute and chronic inflammatory models.…”

Section: Discussionmentioning

confidence: 56%

“…The data were analyzed by oneway ANOVA, followed by the Fisher least significant difference test. A p value ,0.05 was considered to be statistically significant (14).…”

Section: Collagen-induced Arthritis Mouse Modelmentioning

confidence: 99%

“…The hypothesis that the active and repressive functions of GR are responsible for negative side effects and anti-inflammatory effects, respectively, has led to the discovery of a number of interesting compounds (2,3,(8)(9)(10)(11)(12)(13)(14). However, accumulating evidence suggests that the transcriptional repression by GR alone does not fully account for the repression of inflammatory genes (15).…”

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confidence: 99%

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Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Cheng

Zhu

et al. 2011

The Journal of Immunology

102

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Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, they cause debilitating side effects, which limit the use of these compounds. In the past decade, many researchers have attempted to find so-called dissociated GCs that have separate distinct transactivation and transrepression activities. Anti-inflammation of GCs is a result of glucocorticoid receptor (GR)-mediated transactivation and transrepression in some tissues, similar to their side effects; therefore, the goal to discover a compound that has anti-inflammatory properties, but lacks the negative side effects seen with GCs, has yet to be achieved. In the present study, we introduce a plant-derived compound, ginsenoside Rg1, which possesses GC and estrogen-like activities. In this study, we show that Rg1 downmodulates LPS-induced proinflammatory cytokine release and inhibits NF-κB nuclear translocation and DNA binding activity. The negative effects on NF-κB activation are due to a decrease in IκB phosphorylation and protein stabilization. Furthermore, the inhibitory effect of Rg1 on NF-κB is GR-dependent, as small interfering RNA knockdown of GR abrogated this function. Rg1 also displayed profound inhibitory effects on LPS-induced MAPK activation. Importantly, Rg1 did not impair proliferation or differentiation of mouse osteoblasts. Finally, we show that Rg1 can effectively inhibit acute and chronic inflammation in vivo, but it does not cause hyperglycemia or osteoporosis as seen with dexamethasone. These results suggest that ginsenoside Rg1 may serve as a novel anti-inflammatory agent and may exhibit a potential profile for therapeutic intervention in inflammatory diseases.

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Section: Discussionmentioning

confidence: 56%

“…The data were analyzed by oneway ANOVA, followed by the Fisher least significant difference test. A p value ,0.05 was considered to be statistically significant (14).…”

Section: Collagen-induced Arthritis Mouse Modelmentioning

confidence: 99%

mentioning

confidence: 99%

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Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Cheng

Zhu

et al. 2011

The Journal of Immunology

102

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“…One of the problems with conventional corticosteroids is that the steroid backbone can also bind to other nuclear hormone receptors such as MR and PR which also cause side effects. The development of dissociated corticosteroids with a non-steroidal backbone such as AL-438 and ZK 216348 may further improve the therapeutic index of these drugs [205,208] and also extend their duration of action to a once-a-day therapy.…”

Section: Future Developments In Inhaled Corticosteroid Therapymentioning

confidence: 99%

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

123

106

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International audienceInhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV and the rate of exacerbations. A reduction in the rate of decline in FEV of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases

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“…Many of these side effects are so severe with sustained use that it prevents the full anti-inflammatory potential of these drugs from being attained. 5,6 Sometimes the off-target side effects are due to a lack of specificity of the compound for a particular steroid receptor, as it is common to have a particular compound interact with more than 1 steroid hormone receptor. For example, progestins are commonly used for women's health issues, and although they have many therapeutic uses in oral contraceptives and hormone therapy, they often have unwanted side effects because of their interaction with other steroid receptors.…”

Section: N Uclear Receptors (Nrs) Are a Superfamily Of Tran-mentioning

confidence: 99%

Compound Profiling Using a Panel of Steroid Hormone Receptor Cell-Based Assays

Wilkinson¹,

Hayes²,

Thompson³

et al. 2008

SLAS Discovery

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A major focus in the current discovery of drugs targeting nuclear receptors (NRs) is identifying drugs with reduced side effects by improving selectivity, not only from other receptors but also by selective modulation of the NR of interest. Cellular assays not only provide valuable information on functional activity, potency, and selectivity but also are ideally suited for differentiating partial agonists and antagonists. The ability to partially activate a receptor is believed to be closely tied to the ability to selectively modulate the NR, resulting in expression of a subset of the normally regulated genes. To this end, the authors have built a complete panel of cell-based steroid hormone receptor assays for the androgen receptor, estrogen receptor alpha, estrogen receptor beta, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor by stably engineering a Gal4 DNA-binding domain/nuclear receptor ligand-binding domain fusion protein into an upstream activation sequence beta-lactamase reporter cell line. Each assay was validated with known agonists and antagonists for correct pharmacology and high-throughput compatibility. To demonstrate the utility of these assays, the authors profiled 35 pharmacologically relevant compounds in a dose-response format against the panel in both agonist and antagonist modes. The results demonstrated that selective estrogen receptor modulators can be identified and differentiated, as well as mixed and partial agonists and antagonists easily detected in the appropriate assays. Importantly, a comparison of the chimeric assays with fulllength reporter gene assay data from the literature shows a good degree of correlation in terms of selectivity and pharmacology of important ligands. Taken together, these steroid hormone receptor assays provide good selectivity, sensitivity, and appropriate pharmacology for high-throughput screening and selectivity profiling of modulators of steroid hormone receptors. (Journal of Biomolecular Screening 2008:755-765)

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Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Cited by 69 publications

References 44 publications

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Compound Profiling Using a Panel of Steroid Hormone Receptor Cell-Based Assays

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