Browsing by Subject "glucocorticoids"

Now showing 1 - 5 of 5
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    Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link
    (Sage, 2022) Srinivasan, Mythily; Walker, Chandler; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases. Brain specific or global deficiency of core circadian trans-activator brain and muscle ARNT (Arylhydrocarbon Receptor Nuclear Translocator)-like protein 1 (BMAL1) or that of the transrepressor REV-ERBα, impaired neural function and cognitive performance in rodents. Consistently, transcripts of inflammatory cytokines and host immune responses have been shown to exhibit diurnal variation, in parallel with the disruption of the circadian rhythm. Glucocorticoids that exhibit both a circadian rhythm similar to that of the core clock transactivator BMAL1 and tissue specific ultradian rhythm are critical in the control of neuroinflammation and re-establishment of homeostasis. It is widely accepted that the glucocorticoids suppress nuclear factor-kappa B (NF-κB) mediated transactivation and suppress inflammation. Recent mechanistic elucidations suggest that the core clock components also modulate NF-κB mediated transactivation in the brain and peripheral tissues. In this review we discuss evidence for interactions between the circadian clock components, glucocorticoids and NF-κB signaling responses in the brain and propose glucocorticoid induced leucine zipper (GILZ) encoded by Tsc22d3, as a molecular link that connect all three pathways in the maintenance of CNS homeostasis as well as in the pathogenesis of neuroinflammation-neurodegeneration.
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    Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling
    (Oxford, 2019-07) Sato, Amy Y.; Cregor, Meloney; McAndrews, Kevin; Li, Troy; Condon, Keith W.; Plotkin, Lilian I.; Bellido, Teresita; Anatomy and Cell Biology, IU School of Medicine
    Excess of glucocorticoids (GCs) is a leading cause of bone fragility, and therapeutic targets are sorely needed. We report that genetic deletion or pharmacological inhibition of proline-rich tyrosine kinase 2 (Pyk2) prevents GC-induced bone loss by overriding GC effects of detachment-induced bone cell apoptosis (anoikis). In wild-type or vehicle-treated mice, GCs either prevented osteoclast apoptosis or promoted osteoblast/osteocyte apoptosis. In contrast, mice lacking Pyk2 [knockout (KO)] or treated with Pyk2 kinase inhibitor PF-431396 (PF) were protected. KO or PF-treated mice were also protected from GC-induced bone resorption, microarchitecture deterioration, and weakening of biomechanical properties. In KO and PF-treated mice, GC increased osteoclasts in bone and circulating tartrate-resistant acid phosphatase form 5b, an index of osteoclast number. However, bone surfaces covered by osteoclasts and circulating C-terminal telopeptides of type I collagen, an index of osteoclast function, were not increased. The mismatch between osteoclast number vs function induced by Pyk2 deficiency/inhibition was due to osteoclast detachment and anoikis. Further, GC prolongation of osteoclast lifespan was absent in KO and PF-treated osteoclasts, demonstrating Pyk2 as an intrinsic osteoclast-survival regulator. Circumventing Pyk2 activation preserves skeletal integrity by preventing GC effects on bone cell survival (proapoptotic for osteoblasts/osteocytes, antiapoptotic for osteoclasts) and GC-induced bone resorption. Thus, Pyk2/anoikis signaling as a therapeutic target for GC-induced osteoporosis.
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    Glucocorticoid-Induced Leucine Zipper in Central Nervous System Health and Disease
    (Springer, 2016) Srinivasan, Mythily; Lahiri, Debomoy K.; Department of Oral Pathology, Medicine and Radiology, School of Dentistry
    The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests that glucocorticoids exert both neuroprotective and neurodegenerative effects on the CNS. Glucocorticoids act by binding two related receptors in the cytoplasm, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The glucocorticoid receptor complex mediates cellular responses by transactivating target genes and by protein: protein interactions. The paradoxical effects of glucocorticoids on neuronal survival and death have been attributed to the concentration and the ratio of mineralocorticoid to glucocorticoid receptor activation. Glucocorticoid-induced leucine zipper (GILZ) is a recently identified protein transcriptionally upregulated by glucocorticoids. Constitutively, expressed in many tissues including brain, GILZ mediates many of the actions of glucocorticoids. It mimics the anti-inflammatory and anti-proliferative effects of glucocorticoids but exerts differential effects on stem cell differentiation and lineage development. Recent experimental data on the effects of GILZ following induced stress or trauma suggest potential roles in CNS diseases. Here, we provide a short overview of the role of GILZ in CNS health and discuss three potential rationales for the role of GILZ in Alzheimer’s disease pathogenesis.
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    Role and mechanism of action of Sclerostin in bone
    (Elsevier, 2017-03) Delgado-Calle, Jesus; Sato, Amy Y.; Bellido, Teresita; Anatomy and Cell Biology, School of Medicine
    After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass as well as the damaging effects of some cancers in bone. Thus, sclerostin has quickly become a promising molecular target for the treatment of osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are observed in animal studies and clinical trials using neutralizing antibodies against sclerostin. However, the anabolic effect of blocking sclerostin decreases with time, bone mass accrual is also accompanied by anti-catabolic effects, and there is bone loss over time after therapy discontinuation. Further, the cellular source of sclerostin in the bone/bone marrow microenvironment under physiological and pathological conditions, the pathways that regulate sclerostin expression and the mechanisms by which sclerostin modulates the activity of osteocytes, osteoblasts, and osteoclasts remain unclear. In this review, we highlight the current knowledge on the regulation of Sost/sclerotin expression and its mechanism(s) of action, discuss novel observations regarding its role in signaling pathways activated by hormones and mechanical stimuli in bone, and propose future research needed to understand the full potential of therapeutic interventions that modulate Sost/sclerostin expression.
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    Role of estrogen and progesterone receptors in neonatal uterine cell proliferation in the mouse
    (2015-01) Cooke, P.S.; Nanjappa, M. K.; Medrano, T.I.; Lydon, J.P.; Bigsby, Robert M.; Department of Obstetrics and Gynecology, IU School of Medicine
    The major endocrine regulators of the female reproductive tract are 17β-estradiol (E2) and progesterone (P4). This review discusses our recent work related to the roles of E2 and P4 and their receptors, estrogen receptor 1 (ESR1) and progesterone receptor (PR), respectively, in the neonatal uterus. Neonatal uterine cells in mice are mitogenically responsive to estrogens, but neonatal ovariectomy does not inhibit pre-weaning uterine cell proliferation, indicating that this process does not require endogenous estrogens. Neonatal uterine cell proliferation could result from ligand-independent growth factor activation of ESR1, or be independent of ESR1 neonatally despite its obligatory role in adult uterine epithelial proliferation. To determine the role of ESR1 in uterine development, we analyzed cell proliferation and uterine gland development (adenogenesis) in wild-type (WT) and Esr1 knockout (Esr1KO) mice postnatally. Our results indicate that pre-weaning uterine cell proliferation and adenogenesis are independent of ESR1, but these processes become dependent on E2/ESR1 signaling for maintenance and further proliferation and uterine growth during puberty. How pre- weaning uterine cell proliferation and adenogenesis occur independently of E2/ESR1 signaling remains unknown, but ligand-independent activation of ESR1 is not involved in this process. The synthetic glucocorticoid dexamethasone (Dex) inhibits luminal epithelial (LE) proliferation in neonatal mouse uteri, but it has been unclear whether Dex effects were mediated by glucocorticoid receptor (GR) and/or PR. We have used PR knockout (PRKO) mice to test whether PR is required for Dex inhibition of LE proliferation. Our results indicate that maximal inhibitory Dex effects on uterine LE proliferation require PR, possibly reflecting Dex crosstalk with PR. Inhibitory effects of Dex and P4 on LE proliferation may also involve GR binding, as indicated by the small but significant inhibition of LE proliferation by both Dex and P4 in PRKO mice.