title: Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function.
abstract: Glucocorticoids signal through the glucocorticoid receptor (GR) and are administered clinically for a variety of situations, including inflammatory disorders, specific cancers, rheumatoid arthritis, and organ/tissue transplantation. However, glucocorticoid therapy is also associated with additional complications, including steroid-induced diabetes. We hypothesized that modification of the steroid backbone is one strategy to enhance the therapeutic potential of GR activation. Toward this goal, two commercially unavailable, thiobenzothiazole-containing derivatives of hydrocortisone (termed MS4 and MS6) were examined using 832/13 rat insulinoma cells as well as rodent and human islets. We found that MS4 had transrepression properties but lacked transactivation ability, whereas MS6 retained both transactivation and transrepression activities. In addition, MS4 and MS6 both displayed anti-inflammatory activity. Furthermore, MS4 displayed reduced impact on islet β-cell function in both rodent and human islets. Similar to dexamethasone, MS6 promoted adipocyte development in vitro, whereas MS4 did not. Moreover, neither MS4 nor MS6 activated the Pck1 (Pepck) gene in primary rat hepatocytes. We conclude that modification of the functional groups attached to the D-ring of the hydrocortisone steroid molecule produces compounds with altered structure-function GR agonist activity with decreased impact on insulin secretion and reduced adipogenic potential but with preservation of anti-inflammatory activity.
authors: From the Laboratory of Islet Biology and Inflammation, the Departments of Nutrition and.
authors: Susan J
authors: SJ
authors: Burke
authors: Chemistry, University of Tennessee, Knoxville, Tennessee 37996.
authors: Amanda L
authors: AL
authors: May
authors: the Skeletal Muscle Metabolism Laboratory, and.
authors: Robert C
authors: RC
authors: Noland
authors: the Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina 27701.
authors: Danhong
authors: D
authors: Lu
authors: the Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and.
authors: Marcela
authors: M
authors: Brissova
authors: the Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and the Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee 37212.
authors: Alvin C
authors: AC
authors: Powers
authors: the Departments of Nutrition and.
authors: Elizabeth M
authors: EM
authors: Sherrill
authors: the Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, and.
authors: Michael D
authors: MD
authors: Karlstad
authors: Chemistry, University of Tennessee, Knoxville, Tennessee 37996.
authors: Shawn R
authors: SR
authors: Campagna
authors: the Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808.
authors: Jacqueline M
authors: JM
authors: Stephens
authors: From the Laboratory of Islet Biology and Inflammation, the Departments of Nutrition and the Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, and Jason.collier@pbrc.edu.
authors: J Jason
authors: JJ
authors: Collier
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D052160:Benzothiazoles; D007328:Insulin; D012333:RNA, Messenger; D013844:Thiazoles; C000600816:mercaptosteroid 4; C000600817:mercaptosteroid 6; D003907:Dexamethasone; D006854:Hydrocortisone
keywords: adipogenesis; chemokine; glucocorticoid; inflammation; insulin secretion