scholarly journals LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2080-2089 ◽  
Author(s):  
Francisco J. López ◽  
Robert J. Ardecky ◽  
Bruce Bebo ◽  
Khalid Benbatoul ◽  
Louise De Grandpre ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Therapeutic Window ◽  
Glucocorticoid Treatment ◽  
Receptor Ligand ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Conditions ◽  
Differential Gene Regulation ◽  
Antiinflammatory Effects

Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.

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

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Mohamed A. Morsy ◽  
Snehal S. Patel ◽  
Azza A. K. El-Sheikh ◽  
Jignasa K. Savjani ◽  
Anroop B. Nair ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Tumor Necrosis ◽  
Serum Levels ◽  
Withaferin A ◽  
Boswellic Acid ◽  
Cotton Pellet ◽  
Anti Inflammatory ◽  
Necrosis Factor

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-α 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.

scholarly journals A Novel Antiinflammatory Maintains Glucocorticoid Efficacy with Reduced Side Effects

2003 ◽  
Vol 17 (5) ◽  
pp. 860-869 ◽  
Author(s):  
Michael J. Coghlan ◽  
Peer B. Jacobson ◽  
Ben Lane ◽  
Masaki Nakane ◽  
Chun Wei Lin ◽  
...  
Keyword(s):  
Side Effects ◽  
Inflammatory Disease ◽  
Target Genes ◽  
Negative Effects ◽  
Interacting Protein ◽  
Altered Gene ◽  
Antiinflammatory Effects

Abstract Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor γ coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.

scholarly journals Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy

2017 ◽  
Vol 7 (3) ◽  
pp. 643-653 ◽  
Author(s):  
Nura A. Mohamed ◽  
Robert P. Davies ◽  
Paul D. Lickiss ◽  
Blerina Ahmetaj-Shala ◽  
Daniel M. Reed ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Side Effects ◽  
Arterial Hypertension ◽  
Therapeutic Window ◽  
Endothelin 1 ◽  
Wide Range ◽  
Metal Organic ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

scholarly journals Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

2018 ◽  
Vol 97 (11) ◽  
pp. 1252-1259 ◽  
Author(s):  
J.J. Varghese ◽  
I.L. Schmale ◽  
D. Mickelsen ◽  
M.E. Hansen ◽  
S.D. Newlands ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Side Effects ◽  
Cellular Level ◽  
Systemic Administration ◽  
Therapeutic Window ◽  
Saliva Secretion ◽  
Life Issues ◽  
Localized Delivery ◽  
Gland Function

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration–approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

scholarly journals Alternate glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model

2012 ◽  
Vol 156 (2) ◽  
pp. 121-129 ◽  
Author(s):  
Sumitra Sengupta ◽  
William H. Bisson ◽  
Lijoy K. Mathew ◽  
Siva K. Kolluri ◽  
Robert L. Tanguay
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Tissue Regeneration ◽  
Receptor Ligand

scholarly journals It Is Not Just Folklore: The Aqueous Extract of Mung Bean Coat Is Protective against Sepsis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Shu Zhu ◽  
Wei Li ◽  
Jianhua Li ◽  
Arvin Jundoria ◽  
Andrew E. Sama ◽  
...  
Keyword(s):  
Mung Bean ◽  
Therapeutic Potential ◽  
Survival Rates ◽  
Saline Group ◽  
Therapeutic Window ◽  
Hmgb1 Protein ◽  
Inflammatory Conditions ◽  
Lethal Sepsis

Mung bean (Vigna Radiata) has been traditionally used in China both as nutritional food and herbal medicine against a number of inflammatory conditions since the 1050s. A nucleosomal protein, HMGB1, has recently been established as a late mediator of lethal systemic inflammation with a relatively wider therapeutic window for pharmacological interventions. Here we explored the HMGB1-inhibiting capacity and therapeutic potential of mung bean coat (MBC) extractin vitroandin vivo. We found that MBC extract dose-dependently attenuated LPS-induced release of HMGB1 and several chemokines in macrophage cultures. Oral administration of MBC extract significantly increased animal survival rates from 29.4% (in saline group,N=17mice) to 70% (in experimental MBC extract group,N=17mice,P<0.05).In vitro, MBC extract stimulated HMGB1 protein aggregation and facilitated both the formation of microtubule-associatedprotein-1-light-chain-3-(LC3-)containing cytoplasmic vesicles, and the production of LC3-II in macrophage cultures. Consequently, MBC extract treatment led to reduction of cellular HMGB1 levels in macrophage cultures, which was impaired by coaddition of two autophagy inhibitors (bafilomycin A1 and 3-methyladenine).Conclusion. MBC extract is protective against lethal sepsis possibly by stimulating autophagic HMGB1 degradation.

scholarly journals Epididymal glucocorticoid receptors promote intergenerational transmission of paternal stress

2018 ◽  
Author(s):  
Jennifer C Chan ◽  
Bridget M Nugent ◽  
Kathleen E Morrison ◽  
Eldin Jašarević ◽  
Natarajan V Bhanu ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Intergenerational Transmission ◽  
Noncoding Rna ◽  
Glucocorticoid Receptors ◽  
Drugs Of Abuse ◽  
Disease Risk ◽  
Glucocorticoid Treatment ◽  
Paternal Stress

AbstractPaternal preconception exposures and insults, including stress, dietary challenge and drugs of abuse, can shape offspring health and disease risk outcomes, as evidenced from retrospective human studies and more recent animal models1–16. Mechanistic examination has implicated small noncoding RNA populations in sperm, including microRNA (miRs), as carriers of paternal environmental information that consequently influence offspring development15,17–21. However, the cellular mechanisms by which these paternal signals are relayed to sperm and how they may persist remain unknown. Here, using our previously established paternal stress mouse model we identify caput epididymal epithelial glucocorticoid receptors as crucial upstream mediators of long-lasting germ cell programming. We show that glucocorticoid treatment of caput epididymal epithelial cells results in increased glucocorticoid receptor levels and enduring changes to the miR content of secreted extracellular vesicles (EVs), or epididymosomes, known to interact with sperm and alter their RNA content22,23. Further, significant changes were detected in the caput epididymal histone code long after stress ended, both in vitro and in vivo, as a potential mechanism whereby stress programmed enduring changes to EV miRs. Genetic targeting to reduce caput epididymal epithelial-specific glucocorticoid receptors reversed stress-induced chromatin remodeling and promoted cellular resilience to paternal stress, ultimately rescuing transmission of a stress dysregulated offspring phenotype. Taken together, these studies identify glucocorticoid receptor regulation of EV miRs in the caput epididymis as a key contributor in the intergenerational transmission of paternal environmental stress experiences.

scholarly journals Expression and Subcellular Distribution of the β-Isoform of the Human Glucocorticoid Receptor*

Endocrinology ◽  
1997 ◽  
Vol 138 (11) ◽  
pp. 5028-5038 ◽  
Author(s):  
Robert H. Oakley ◽  
Jeffrey C. Webster ◽  
Madhabananda Sar ◽  
C. Richard Parker ◽  
John A. Cidlowski
Keyword(s):  
Glucocorticoid Receptor ◽  
Subcellular Distribution ◽  
Messenger Rna ◽  
Biological Significance ◽  
Dominant Negative ◽  
Protein Isoforms ◽  
Glucocorticoid Treatment ◽  
Western Blots ◽  
Amino Acid Peptide

Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two highly homologous protein isoforms, termed hGRα and hGRβ, that differ at their carboxy-termini. In contrast to the well characterized hGRα isoform, which modulates gene expression in a hormone-dependent fashion, the biological significance of hGRβ has only recently begun to emerge. We and others have shown that the hGRβ messenger RNA transcript is widely expressed in human tissues and that the hGRβ protein functions as a dominant negative inhibitor of hGRα in transfected cells. Unfortunately, these initial studies did not determine whether the hGRβ protein was made in vivo. Such analyses are hindered because available anti-hGR antibodies cannot discriminate between the similarly sized hGRα and hGRβ proteins. Therefore, to investigate the expression of the hGRβ protein, we have produced an antipeptide, hGRβ-specific antibody termed BShGR. This antibody was made against the unique 15-amino acid peptide at the carboxy-terminus of hGRβ and recognizes both the native and denatured conformations of hGRβ, but does not cross-react with hGRα. Using BShGR on Western blots and in immunoprecipitation experiments, we detected the hGRβ protein in a variety of human cell lines and tissues. Immunocytochemistry was then performed with BShGR on HeLa S3 and CEM-C7 cells and on tissue sections prepared from lung, thymus, and liver to assess the cellular and subcellular distribution of hGRβ. In all immunopositive cells, hGRβ was found in the nucleus independent of glucocorticoid treatment. Within tissues, the hGRβ protein was expressed most abundantly in the epithelial cells lining the terminal bronchiole of the lung, forming the outer layer of Hassall’s corpuscle in the thymus, and lining the bile duct in the liver. As a potential in vivo inhibitor of hGRα activity, expression of hGRβ may be an important factor regulating target cell responsiveness to glucocorticoids.

Clomipramine and Exposure for Compulsive Rituals: II. Plasma Levels, Side Effects and Outcome

1980 ◽  
Vol 136 (2) ◽  
pp. 161-166 ◽  
Author(s):  
R. S. Stern ◽  
I. M. Marks ◽  
D. Mawson ◽  
D. K. Luscombe
Keyword(s):  
Side Effects ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Therapeutic Window ◽  
Obsessive Compulsive ◽  
Behavioural Treatment ◽  
Primary Metabolite ◽  
Exposure In Vivo

SummaryForty obsessive-compulsive ritualizers received nightly placebo or clomipramine up to 225 mgs nocte for 8 months, and received behavioural treatment (exposure in vivo) from weeks 4 to 10. Plasma concentrations of clomipramine and its primary metabolite N-desmethylclomipramine steadily increased over the first 4 weeks of treatment after which they remained relatively steady. Plasma levels correlated significantly with dose and with outcome but not with side effects. Patients with plasma clomipramine levels in the range 100–250 ng/ml and N-desmethylclomipramine levels between 230–550 ng/ml were found to improve significantly more than patients outside these ranges, thus suggesting a therapeutic window for clomipramine and its primary metabolite.

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