Optimized glucocorticoid therapy: Teaching old drugs new tricks

Strehl, Cindy; Buttgereit, Frank

doi:10.1016/j.mce.2013.01.026

Cited by 100 publications

(54 citation statements)

References 129 publications

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“…In this regard, it has been suggested that gene transrepression accounts for the majority of therapeutic GC effects, while transactivation of metabolic target genes is mainly responsible for the side effects (Strehl & Buttgereit 2013). Using this concept, several GR agonists dissociating transrepression from transactivation were developed (Löw-enberg et al 2008).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Rafacho¹,

Ortsäter²,

Nadal³

et al. 2014

Journal of Endocrinology

177

114

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Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic b-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of b-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic b-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Rafacho¹,

Ortsäter²,

Nadal³

et al. 2014

Journal of Endocrinology

177

114

View full text Add to dashboard Cite

show abstract

“…In the case of Transactivation, GC-GR complex binds with their DNAbinding sites, GRE, which are located in the promoter region of target genes. 22 Thus, it activates the transcription of anti-inflammatory proteins, such as Annexin-1, IêB. Activation of Annexin-1 reduces the liberation of free arachidonic acids and also prostaglandins, from membrane phospholipids.…”

Section: Anti-inflammatory and Immunosuppressive Actionmentioning

confidence: 99%

“…In this process, the hormone receptor complex interacts with transcription factors such as NFêB (a nuclear transcription factor), which thus inhibits proinflammatory cytokine (for example, TNF-a, IL-1, IL-6) production. 22,24 NFêB is also responsible for transcription of cyclooxygenase-2, which is needed to produce prostaglandins. Thus, by inhibiting NFêB, glucocorticoids interfere with prostaglandin synthesis.…”

Section: Anti-inflammatory and Immunosuppressive Actionmentioning

confidence: 99%

Does Low Dose Steroids Confer Benefits in Sepsis and Septic Shock?

Nazim

2017

Birdem Med J

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Over the last 40 years, the use of corticosteroids in sepsis and septic shock has evolved from the initial use of high-dose, short-duration steroid therapy in the 1980s, to the recent recommendation of using low-dose longerduration steroid therapy in refractory septic shock patients. A recent, prospective, open-label, randomized, controlled pilot trial of patients in four adult intensive care units in London-teaching hospitals showed that hydrocortisone decreased vasopressin requirements, reduced the duration and reduced the required dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. The optimal dosing of hydrocortisone, about 300 mg/day, was agreed uniformly. As this dose also provides sufficient mineralocorticoid effects, the additional use of mineralocorticoid is not needed. Despite the fact that severely ill septic shock patients are given treatment, according to the current guidelines, the survival benefit is unproven. The benefits of steroids on less severely ill septic patients are still questionable. More research is highly recommended to successfully identify the benefits of steroids in septic shock.Birdem Med J 2017; 7(1): 48-59

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“…This pathway, also known as transactivation, is believed to be responsible for many of the side effects of glucocorticoids. 22 Alternatively, the transrepression arm of glucocorticoid signaling involves the direct or indirect interaction of the monomeric receptor complex with specific transcription factors to regulate negatively proinflammatory gene expression, finally resulting in anti-inflammatory and immunosuppressive effects. 22 In an attempt to improve the therapeutic index of these compounds, structural variants of glucocorticoids that selectively modulate the transrepression arm of glucocorticoid signaling are currently being developed.…”

mentioning

confidence: 99%

“…22 Alternatively, the transrepression arm of glucocorticoid signaling involves the direct or indirect interaction of the monomeric receptor complex with specific transcription factors to regulate negatively proinflammatory gene expression, finally resulting in anti-inflammatory and immunosuppressive effects. 22 In an attempt to improve the therapeutic index of these compounds, structural variants of glucocorticoids that selectively modulate the transrepression arm of glucocorticoid signaling are currently being developed. [23][24][25][26][27][28][29][30][31] In the present study, we describe a novel crosstalk between glucocorticoid signaling and the apoptotic arm of the UPR, highlighting the potential use of glucocorticoid therapy in several disease conditions.…”

mentioning

confidence: 99%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

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Optimized glucocorticoid therapy: Teaching old drugs new tricks

Cited by 100 publications

References 129 publications

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Does Low Dose Steroids Confer Benefits in Sepsis and Septic Shock?

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

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