Narjes Nasiri-Ansari

Clock genes alterations and endocrine disorders

Various endocrine signals oscillate over the 24‐hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.

Vitamin D affects glucocorticoid action in target cells

It is known that administration of glucocorticoids is the first choice therapy in many autoimmune and inflammatory diseases. Glucocorticoid resistance is a major problem in the treatment of a variety of diseases since 30% of patients display it [1]. Observational studies have linked vitamin D deficiency with increased risk of various inflammatory and autoimmune maladies, while replenishing vitamin D appears to reduce the incidence of diseases and improve their course [2]. In this context glucocorticoids and vitamin D can be often co-administered in clinical practice albeit it remains unclear how administration of vitamin D could alter the response to glucocorticoids. A wide range of experimental designs have been constructed aiming at studying the effects of vitamin D on immune responses; however, these experiments usually do not reflect the physiological conditions (i.e. concentrations that are not biologically attainable, time courses that do not correspond to physiological states). We studied the effect of the long-term (11 days) repletion of vitamin D-the supplementation of which is often proposed for the prevention or even treatment of autoimmune / inflammatory diseases-on the sensitivity of peripheral blood mononuclear cells (PBMCs) to glucocorticoids [3]. We used the active metabolite of vitamin D, 1,25(OH) 2 D, at concentrations that are biologically achievable and co-incubated with dexamethasone for the last 48 hours at saturating dose regarding glucocorticoid-induced leucine zipper (GILZ) expression, a dexamethasone inducible gene that mediates mainly anti-inflammatory and immunosuppressive glucocorticoid actions in a variety of cell types. We found that long-term action of vitamin D downregulated GILZ expression thus inducing glucocorticoid resistance in PBMCs derived from healthy volunteers. Based on our results this effect can, at least in part, be attributed to: i) decrease of glucocorticoid receptor (GR) expression owing to a mechanism that engages histone deacetylase(s) (HDACs), and ii) inhibition of GR translocation to the nucleus via modulation of the phosphorylation state of GR; in fact, vitamin D decreased phosphorylation of GR at Ser211 whilst enhanced phosphorylation of GR at Ser203 [3]. The role of GR phosphorylations at Ser203 and Ser211 in the inhibitory effect of vitamin D remains to be definitively established, and the responsive mitogen-activated protein kinase (MAPK) signaling pathway (i.e. extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 cascades) should be identified. Furthermore, the class(es) and member(s) of HDAC implicated in the reduction of GR expression remain to be determined. Other mechanisms such as reduced glucocorticoid binding to GR due to nitrosylation …

Altered expression of circadian clock genes in polyglandular autoimmune syndrome type III

PurposeCircadian timing system is a highly conserved, ubiquitous molecular “clock” which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PAS type III).MethodsNineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence.ResultsThere were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (Rpm/am) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (Fpm/am) was positively correlated with GILZ mRNA circadian pattern (Rpm/am) in the patient group and with the GR-a mRNA (Rpm/am) in the control group.ConclucionsOur findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease.

The role of epithelial growth factors and insulin growth factors in the adrenal neoplasms

Human fetal and adult adrenal gland express both insulin growth factor-1 (IGF-1) and IGF-2, their receptors (IGF-Rs) and a variety of specific IGF binding proteins suggesting their potential role in the regulation of adrenal growth and function. IGF-2 overexpression is essential for the growth of monoclonal lesions, such as large benign adenomas (ACA) and adrenocortical carcinomas (ACC) and has been found to contribute to tumorigenesis in Beckwith-Wiedemann syndrome. IGF-2 is the most highly expressed gene observed in more than 85% of ACCs. However, no significant differences in clinical, biological and transcriptomic traits were found between tumors with high and low expression of IGF-2. On the contrary, the expression of IGF-1R, mediating the IGF-2 effects in vivo, was more discriminant between malignant (overexpression) and benign tumors. Data on the role of epithelial growth factor (EGF) and its receptor (EGF-R) in adrenocortical tumorigenesis are controversial. Several studies have shown EGF-R overexpression in ACCs but not in benign ACAs, suggesting that EGF-R could potentially be used as a marker for the differential diagnosis of ACAs and ACCs. Although, in vitro and animal studies provide promising results in the therapeutic role of IGF and EGF pathway inhibitors, the available data in humans are still not encouraging. Herein, we aim to present recent data on the role of IGF and EGF pathways in adrenal development and tumorigenesis and their potential implication in the treatment of the ACC, a rare malignancy with very poor prognosis.