Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Burke, Susan J.; May, Amanda L.; Noland, Robert C.; Lu, Danhong; Powers, Alvin C.; Sherrill, Elizabeth; Karlstad, Michael D.; Campagna, Shawn R.; Stephens, Jacqueline M.; Collier, J. Jason

doi:10.1074/jbc.m114.632190

Cited by 10 publications

(16 citation statements)

References 61 publications

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“…The establishment and characterization of diverse mouse models of glucocorticoid delivery provide unique opportunities in which to investigate the effects of novel glucocorticoid receptor agonist molecules. For example, the use of azaxanthene, 60 arylindazole, 61 mercaptosteroid, 62 or other molecules designed to target inflammation, could potentially be novel therapeutic interventions for autoimmune and autoinflammatory diseases, including T1D. Our observations showing that corticosterone has lasting effects on insulitis 4 weeks after withdrawal (Figure 7) are analogous to the reported effects of prednisone in human T1D studies.…”

Section: Discussionsupporting

confidence: 79%

Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice

Burke

Batdorf

Eder

et al. 2017

The American Journal of Pathology

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Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic. This phenotype was fully reversed during the washout phase and readily reproducible across institutions. Relative to the vehicle control group, mice receiving corticosterone had a significant enhancement in pancreatic insulin-positive area, but a marked decrease in CD3 cell infiltration. In addition, there were striking increases in both citrate synthase gene expression and enzymatic activity in skeletal muscle of mice in the corticosterone group relative to vehicle control. Moreover, glycogen synthase expression was greatly enhanced, consistent with elevations in muscle glycogen storage in mice receiving corticosterone. Corticosterone-induced hyperglycemia, insulin resistance, and changes in muscle gene expression were all reversed by the end of the washout phase, indicating that the metabolic alterations were not permanent. Thus, male nonobese diabetic mice allow for translational studies on the metabolic and immunological consequences of glucocorticoid-associated interventions in a mouse model with genetic susceptibility to autoimmune disease.

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Section: Discussionsupporting

confidence: 79%

Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice

Burke

Batdorf

Eder

et al. 2017

The American Journal of Pathology

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“…Current synthetic GCs suppress inflammation induced by IL-1β but also reduce insulin sensitivity and modulate insulin secretion in β-cells. − With the recently renewed interest in development of glucocorticoid receptor agonists, this study provides novel insights into nonsteroidal arylpyrazole-based glucocorticoid receptor agonists (APGRAs) by investigating known and new molecules with more in-depth biochemical assays. These compounds were subjected to in vitro assays evaluating both transactivation and transrepression, and candidates displaying the most potent and/or selective anti-inflammatory properties were further evaluated to determine how insulin secretion was affected in cultured β-cells.…”

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confidence: 99%

“…Cell lysis, luciferase assays, and normalization to total protein content were carried out as described previously . Briefly, transrepression is measured using a previously reported CCL2-promoter luciferase plasmid construct that is activated with a known pro-inflammatory signal, IL-1β, followed by GR agonism. , Ligand-activated transactivation is measured using a previously reported 3XGRE-promoter luciferase plasmid construct in which increases in luciferase activity are measured in response to GR agonists. , …”

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confidence: 99%

Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion

Kennedy

Lato

Fisch

et al. 2021

ACS Med. Chem. Lett.

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Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.

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“…With a growing cadre of selective GR agonists being developed in attempts to reduce or eliminate metabolic side effects while retaining the important anti-inflammatory properties of such drugs [ 34 , 35 , 36 , 37 , 38 ], the GR regulation by SIAH2 is a novel aspect to be considered. Future studies will focus on whether the introduction of selective GR modulating compounds dissociate GR from SIAH2 control.…”

Section: Discussionmentioning

confidence: 99%

The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance

et al. 2020

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Glucocorticoids are clinically essential drugs used routinely to control inflammation. However, a host of metabolic side effects manifests upon usage beyond a few days. In the present study, we tested the hypothesis that seven-in-absentia mammalian homolog-2 (SIAH2), a ubiquitin ligase that regulates adipogenesis, is important for controlling adipocyte size, inflammation, and the ability of adipose tissue to expand in response to a glucocorticoid challenge. Using mice with global deletion of SIAH2 exposed or not to corticosterone, we found that adipocytes are larger in response to glucocorticoids in the absence of SIAH2. In addition, SIAH2 regulates glucocorticoid receptor (GR) transcriptional activity and total GR protein abundance. Moreover, these studies reveal that there is an increased expression of genes involved in fibrosis and inflammatory signaling pathways found in white adipose tissue in response to glucocorticoids in the absence of SIAH2. In summary, this is the first study to identify a role for SIAH2 to regulate transcriptional activity and abundance of the GR, which leads to alterations in adipose tissue size and gene expression during in vivo exposure to glucocorticoids.

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Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Cited by 10 publications

References 61 publications

Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice

Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice

Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion

The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance

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