Side Effects Of Glucocorticoid Therapy Research Articles

High content omega-3 fish oil co-treatment maintains proper bone physiology in glucocorticoid treated autoimmune mice

Despite the known side effects of glucocorticoid therapy, such as a higher risk of osteoporosis, fractures, and reduced bone density, it remains a frequently prescribed treatment for autoimmune disorders due to its strong anti-inflammatory and immunosuppressive properties. If strategies could be identified to reduce the side effects commonly associated with glucocorticoid use, it could lead to more frequent and safer use of this treatment option for autoimmune diseases. In this work, the combined effects of high content omega-3 fish oil (HCW3FO) and a synthetic glucocorticoid, methylprednisolone (MP) medication are investigated in relation to bone mineral density (BMD) reduction in arthritis prone female MRL-lpr/lpr mice. Two treatment groups were introduced to the mice when they were 4 months old: one group was given weekly injections of PBS, while the other group was given either 5 mg/kg MP or 20 mg/kg MP. Additionally, both groups were provided with the AIN93M diet, supplemented with either 4% corn oil or 4% HCW3FO daily, for a duration of 8 weeks. Prior to initiating the drug injections and dietary modifications, the mice underwent dual energy x-ray absorptiometry (DXA) scans to establish their baseline BMD values. To find out their ultimate BMD values, the mice underwent another DXA scan eight weeks later, right before being sacrificed. Over the course of eight weeks, the MP treatment did not lead to a significant reduction in BMD across various bone regions, except for the lumbar regions. Similarly, the HCW3FO treatment alone did not offer protection against BMD loss in MRL-lpr/lpr mice. However, when MP and HCW3FO were combined, it resulted in a remarkable preservation of BMD in different bone regions. This enhanced protection against BMD loss was associated with a reduced number of tartrate-resistant acid phosphatase (TRAP) positive areas and an increased number of alkaline phosphatase (ALP) positive areas in tibial sections as revealed by immunohistochemistry. Our findings provide compelling evidence that the combination of MP and HCW3FO maintains bone health in arthritis-prone MRL-lpr/lpr mice by promoting a balance between bone resorption and bone formation. Co-treatment with HCW3FO may hold promise as a potential strategy for preventing bone deterioration induced by long-term glucocorticoid therapy. Before moving on to clinical trials, more in vitro research into the mechanisms should be carried out alongside preclinical studies in mice with inflammatory diseases. QUCG-CAS-2122-2. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glucocorticoid induced adrenal insufficiency in children: Morning cortisol values to avoid LDSST.

Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency. We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST. Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency. Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children.

A plant-derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy.

Continuous efforts have been made to move towards maintaining the beneficial anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator-like properties of a plant-derived compound caesaldekarin e (CA-e). The therapeutic efficacy of CA-e was evaluated in several mouse models, including dextran sulfate sodium-induced colitis, ovalbumin-induced lung allergic inflammation, imiquimod-induced psoriasis-like skin inflammation and skin atrophy. The action of CA-e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA-protein pull-down assays and mass spectrometry. CA-e selectively inhibited positive GC response element ((+) GRE)-mediated direct transactivation while maintaining and even enhancing the anti-inflammatory effects of treatment with dexamethasone. CA-e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA-e inhibited the formation of dimers by binding to the dimerization interface located in the ligand-binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to (+) GRE, eventually leading to the repression of (+) GRE-regulated genes. In addition, CA-e repressed NF-κB-dependent genes by enhancing the interaction between GR and p65. Our results reveal that CA-e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.

Update on the Treatment of Glucocorticoid-Induced Osteoporosis

Osteoporosis and osteoporotic fracture are one of the most common side effects of glucocorticoid therapy. All patients who are taking any dose of glucocorticoids for over 3 months should have a bone health assessment. After consideration of their clinical risk factors, glucocorticoid dose, bone mineral density measurement, and the Fracture Risk Assessment Tool score, patients can be stratified into low-, moderate-, and high-risk groups. General measures include optimization of calcium and vitamin D intake, reducing glucocorticoid dosage and lifestyle modifications. In patients with moderate to high risk of fracture, pharmacological agents should be prescribed, of which bisphosphonates, denosumab, and teriparatide are the most widely used.

Adrenal suppression from exogenous glucocorticoids: Recognizing risk factors and preventing morbidity.

Adrenal suppression (AS), a potential side effect of glucocorticoid therapy (including inhaled corticosteroids), can be associated with significant morbidity and even death. In Canada, adrenal crisis secondary to AS continues to be reported in children. Being aware of symptoms associated with AS, understanding the risk factors for developing this condition, and familiarity with potential strategies to reduce risks associated with AS, are essential starting points for any clinician prescribing glucocorticoids.

Glucocorticoid Receptor Transactivation Is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma.

PurposeGlucocorticoid (GC)–induced ocular hypertension (GC-OHT) is a serious side effect of prolonged GC therapy that can lead to glaucoma and permanent vision loss. GCs cause a plethora of changes in the trabecular meshwork (TM), an ocular tissue that regulates intraocular pressure (IOP). GCs act through the glucocorticoid receptor (GR), and the GR regulates transcription both through transactivation and transrepression. Many of the anti-inflammatory properties of GCs are mediated by GR transrepression, while GR transactivation largely accounts for GC metabolic effects and side effects of GC therapy. There is no evidence showing which of the two mechanisms plays a role in GC-OHT.MethodsGRdim transgenic mice (which have active transrepression and impaired transactivation) and wild-type (WT) C57BL/6J mice received weekly periocular dexamethasone acetate (DEX-Ac) injections. IOP, outflow facilities, and biochemical changes to the TM were determined.ResultsGRdim mice did not develop GC-OHT after continued DEX treatment, while WT mice had significantly increased IOP and decreased outflow facilities. Both TM tissue in eyes of DEX-treated GRdim mice and cultured TM cells isolated from GRdim mice had reduced or no change in the expression of fibronectin, myocilin, collagen type I, and α-smooth muscle actin (α-SMA). GRdim mouse TM (MTM) cells also had a significant reduction in DEX-induced cytoskeletal changes, which was clearly seen in WT MTM cells.ConclusionsWe provide the first evidence for the role of GR transactivation in regulating GC-mediated gene expression in the TM and in the development of GC-OHT. This discovery suggests a novel therapeutic approach for treating ocular inflammation without causing GC-OHT and glaucoma.

Treatment of adrenal crisis in patients with primary hypoadrenalism can lead to hypertension.

.Hypertension is one of the most serious side effects of glucocorticoid therapy. We retrospectively investigated the frequency of hypertension during treatment of adrenal crisis and analyzed the factors associated with its development. Patients who were admitted for primary hypoadrenalism due to diagnosed or suspected adrenal crisis were included. In the analysis, the subjects were divided into two groups: the hypertensive group (group H) and non-hypertensive group (group Non-H). The primary endpoint was the difference in the hourly therapeutic hydrocortisone (HDC) dosage between the two groups. The hourly therapeutic HDC dose in the two groups was defined as the hourly HDC dose from the start of HDC infusion until the development of hypertension in group H or until the last blood pressure measurement in group Non-H. Nine of 19 crises led to hypertension. There was no significant difference in the therapeutic HDC dosage between the groups (p = 0.108). In conclusion, hypertension developed in some patients during treatment for adrenal crisis. There was no significant difference in the therapeutic HDC dosage between groups H and Non-H.

New concepts to reduce glucocorticoid toxicity

70 years after their first use, low-dose glucocorticoids are a common part of pharmacological rheumatoid arthritis treatment. This is due to their well-proven capacities in symptom severity and disease activity reduction, in particular when combined with a disease-modifying anti-rheumatic drug, such as methotrexate. Nevertheless, glucocorticoid administration, in long-term especially, is also seen critically because of its potential adverse conditions. In order to achieve a reduction in treatment-related adverse events, modern therapy regimes should take into consideration patients' risk factors and therefore be individual. The Glucocorticoid Toxicity Index is a method to measure side effects of glucocorticoid therapy objectively and will be central in future studies comparing different therapy regimes. Such a new therapy regime is modified-release prednisone, which - thanks to a different time of liberation - seems to capable of reducing morning stiffness much more effectively than conventional prednisone, whilst showing similar properties in disease activity reduction and safety. Still, confirmation of these first data in further trials will be necessary. Eventually, other innovative concepts are liposomal glucocorticoids, dissociated agonists of glucocorticoid receptors and intramuscular application of glucocorticoids. Though these approaches appear to be promising, additional research will be required.

Glucocorticoid Receptor Transactivation is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma: A Deleterious Effect of Chronic Glucocorticoid Therapy

Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side-effect of prolonged GC therapy that can lead to glaucoma and permanent vision loss. GCs cause a plethora of changes in the trabecular meshwork (TM), an ocular tissue that regulates intraocular pressure (IOP). GCs act through the glucocorticoid receptor (GR), and the GR regulates transcription both through transactivation and transrepression. Many of the anti-inflammatory properties of GCs are mediated by GR transrepression, while GR transactivation largely accounts for GC metabolic effects and side effects of GC therapy. There is no evidence showing which of the two mechanisms play role in GC- OHT. Methods: GRdim transgenic mice (which have active transrepression and impaired transactivation) and wild type (WT) C57BL/6J mice received weekly periocular DEX-Ac injections. IOP, outflow facilities, and biochemical changes to the TM were determined. Results: GRdim mice did not develop GC-OHT DEX treatment, while WT mice had significantly increased IOP and decreased outflow facilities. Both TM tissue in eyes of DEX-treated GRdim mice and cultured TM cells isolated from GRdim mice had reduced or no change in the expression of fibronectin, myocilin, collagen type I, and α-SMA. GRdim MTM cells also had a significant reduction in DEX-induced cytoskeletal changes, which was clearly seen in WT MTM cells. Conclusion: We provide the first evidence for the role of GR transactivation in regulating GC-mediated gene expression in the TM and in the development of GC- OHT. This discovery suggests a novel therapeutic approach for treating ocular inflammation that will not cause the serious side effect of GC-OHT and glaucoma. Funding: NIH/NEI EY016242. Declaration of Interest: AFC is a consultant for Goodmans LLP, LayerBio, Kala Pharmacuticals and has received research support from Unity Biotechnology and Lung Therapeutics. However, none of these are related to the study presented. The other authors declare that they have no competing interests. Ethical Approval: All experimental protocols were approved by University of North Texas Health Science Center Institutional Animal Care and Use Committee regulations.

Role of the Alternatively Spliced Glucocorticoid Receptor Isoform GRβ in Steroid Responsiveness and Glaucoma

Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side effect of GC therapy in susceptible individuals. This OHT is due to increased aqueous humor (AH) outflow resistance in the trabecular meshwork (TM) caused by GC-mediated changes in TM structure and function. GCs may also play a role in the development of primary open-angle glaucoma (POAG). Elevated cortisol levels in the AH or enhanced GC sensitivity may be one of the reasons for elevated intraocular pressure in POAG patients. The GC OHT responder population is at greater risk of developing POAG compared with non-responders. We recently have gained insight into the molecular mechanisms responsible for this differential GC responsiveness, which is attributed to differences in GC receptor isoform expression in the TM. This article summarizes current knowledge on alternative GC receptor splicing to generate GC receptor alpha (GRα) and GRβ and their roles in the regulation of GC responsiveness in normal and glaucoma TM.

Glucocorticoids can increase the survival rate of patients with severe viral hepatitis B

Severe viral hepatitis B is a disease associated with significant morbidity and mortality. Clinical controlled trials show that the efficacy of treatment of severe viral hepatitis B with glucocorticoids remains debatable. Therefore, we carried out this meta-analysis to evaluate the safety, efficacy, and side effects of glucocorticoid therapy for severe viral hepatitis B. We searched PubMed, Medline, Embase, Cochrane Library, and Google Scholar for randomized-controlled trials published before April 2012 in which glucocorticoid therapy was compared with routine treatment for severe viral hepatitis B. The primary outcome was the survival rate of the two groups. We selected eight controlled clinical trials, which included 597 patients. We recorded a benefit of glucocorticoid treatment on the survival rate of patients with severe viral hepatitis B (597 patients) [risk ratio (RR)=1.188, 95% confidence interval (CI) 1.030-1.369, P=0.018]. The benefit was most noticeable in patients at the stage of preliver failure (409 patients) (RR=1.275, 95% CI 1.077-1.510, P=0.005), whereas there was no efficacy for patients with liver failure (188 patients) (RR=1.008, 95% CI 0.774-1.312, P=0.955). Glucocorticoid treatment was not associated with the development of secondary infection and bleeding. Treatment with glucocorticoids can significantly increase the survival rate of patients with severe hepatitis B. The benefit was most noticeable in patients at the stage of preliver failure. However, the incidence of secondary infection and bleeding did not change significantly. This finding suggests that prompt and timely glucocorticoid treatment is crucial.

Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis

Glucocorticoids are commonly prescribed medications to treat multiple diseases across many medical specialties. One of the most common yet largely unappreciated side effect of glucocorticoid use is increased risk of fracture. Many different therapies are indicated to prevent and treat this condition; many guidelines exist that suggest appropriate use of both glucocorticoids and the medications approved to prevent this common side effect of glucocorticoid therapy. Nevertheless, 30%–50% of patients on long-term glucocorticoid therapy sustain a fracture. Teriparatide, recombinant human parathyroid hormone (1–34), is a daily self-injectable therapy for 24 months approved for use in patients taking long-term glucocorticoids. Teriparatide has been shown to increase bone mineral density and reduce vertebral fracture risk in glucocorticoid-treated patients. Glucocorticoids have many adverse effects on bone that teriparatide has been shown to prevent or negate. Given the fact that preventive therapy for glucocorticoid-induced osteoporosis is often not prescribed, one wonders whether a daily self-injectable therapy for this condition would be prescribed by physicians and accepted by patients. This article reviews the epidemiology, pathophysiology, treatment, guidelines, and persistence data (when available) for patients with glucocorticoid-induced osteoporosis treated with teriparatide.

New Insights into the Anti-inflammatory Mechanisms of Glucocorticoids: An Emerging Role for Glucocorticoid-Receptor-Mediated Transactivation

Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GR(dim/dim) mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents.

Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity

PurposeGlucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.Patients and methodsHere we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR) up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay.ResultsWe show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα) are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC50 and IC50 concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day.ConclusionIn all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.

Understanding the side effects of glucocorticoid therapy: shining a light on a drug everyone thinks they know

Glucocorticoids are one of the most frequently prescribed therapies in rheumatology, a reflection of their effectiveness as a powerful anti-inflammatory drug. Glucocorticoids are also, however, associated with a wide range...

Effects of Alendronate on Bone Metabolism in Glucocorticoid-Induced Osteoporosis Measured by18F-Fluoride PET: A Prospective Study

Osteoporosis represents a significant side effect of glucocorticoid therapy, and alendronate has been reported to prevent this glucocorticoid-induced osteoporosis. Functional imaging with (18)F-fluoride PET allows quantitative analysis of bone metabolism in specific skeletal regions. However, only a few studies have quantitatively determined bone turnover and metabolism in glucocorticoid-induced osteoporosis by radiologic imaging techniques including PET. The aim of this study was to examine changes in regional bone remodeling and turnover as measured by (18)F-fluoride PET, the relationship between these measured changes and conventional bone metabolism parameters, and the effect of alendronate treatment. The study group consisted of 24 postmenopausal women (mean age, 59.7 y) who had various diseases, excluding rheumatoid arthritis, and had been treated with 10 mg or more of oral glucocorticoids (prednisolone equivalent) per day for more than 6 mo. Treatment with 5 mg of alendronate per day began at the time of study entry and continued for 12 mo. (18)F-fluoride PET was performed at baseline, 3 mo, and 12 mo to determine localized bone turnover, and the results were compared with other bone metabolism parameters. Lumbar spine standardized uptake values (SUVs) were significantly lower (P < 0.05) in the osteoporotic group (T-score < or = -2.5) than in the group that was healthy or osteopenic (T-score > -2.5). Patients treated with alendronate for 12 mo exhibited significant decreases in serum bone-specific alkaline phosphate (P < 0.05), urinary N-telopeptide for type I collagen (P < 0.01), lumbar spine SUV (P < 0.01), and femoral neck SUV (P < 0.01) in association with a gradual increase in bone mineral density (BMD) of the lumbar spine relative to the baseline value (P < 0.05). Although there was a significant correlation between BMD and SUV in the lumbar spine at baseline (P < 0.05), there was no correlation between the 2 variables at 12 mo of treatment with alendronate. Alendronate treatment resulted in significant decreases in bone metabolism and turnover in the lumbar spine. It also led to an increase in BMD of the lumbar spine in patients with glucocorticoid-induced osteoporosis. Our findings suggest that antiresorptive therapy has a direct bone-metabolism effect on skeletal kinetics in glucocorticoid-induced osteoporosis at the clinically important site of the lumbar spine.

Glucocorticoid therapy: minimizing side effects

To describe the main undesirable side effects of glucocorticoid therapy, mechanisms of action and the necessary measures to minimize side effects. Author's experience, supplemented with papers published in MEDLINE. The principles for minimizing undesirable side effects of glucocorticoid therapy include: a) only use glucocorticoids if they are essential; b) avoid the use of long-acting glucocorticoids, using short- and intermediate-acting glucocorticoids instead; c) keep treatment as short as possible, since treatment lasting 5 to 7 days shows fewer side effects and quick recovery of the hypothalamic-pituitary axis; d) use glucocorticoids with local activity preferentially, such as inhaled glucocorticoids; e) use in association with other drugs, especially with other more specific anti-inflammatory or immune suppressive drugs, promoting a synergistic effect in order to avoid the use of glucocorticoids or to reduce dosage and duration of glucocorticoid therapy; f) indicate the minimum effective dose, respecting individual sensitivity to glucocorticoids. In order to choose the best glucocorticoid schedule it is essential to understand the pharmacological characteristics and the biological action of glucocorticoids, allowing the most adequate indication, glucocorticoid dose, mode of administration and the duration of glucocorticoid therapy.

Corticoterapia: minimizando efeitos colaterais

OBJETIVO: Ressaltar os principais efeitos indesejáveis durante a corticoterapia, o mecanismo de seu desencadeamento e as medidas necessárias para minimizar os efeitos colaterais. FONTES DOS DADOS: Experiência do autor, complementada com trabalhos publicados no MEDLINE. SÍNTESE DOS DADOS: Os princípios para que se minimizem os efeitos indesejáveis da corticoterapia incluem: a) indicação rígida em que o uso do glicocorticóide seja essencial; b) evitar o uso de glicocorticóides de ação prolongada, preferindo glicocorticóide de ação curta ou intermediária; c) reduzir ao mínimo necessário a duração do tratamento, visto que tratamentos com duração entre 5 e 7 dias apresentam poucos efeitos colaterais e rápida recuperação do eixo hipotalâmico-hipofisário; d) preferir glicocorticóides de ação local, como glicocorticóides inalatórios; e) associação com outros fármacos, em especial outros antiinflamatórios ou imunossupressores mais específicos, buscando efeitos sinérgicos que permitam evitar o uso de glicocorticóides ou reduzir a dose e o tempo da corticoterapia; f) oferecer a menor dose necessária para o efeito desejado, respeitando a sensibilidade de cada indivíduo aos glicocorticóides. CONCLUSÕES: o conhecimento das características farmacológicas e ações biológicas dos glicocorticóides permite a melhor opção terapêutica quanto à indicação, dose, via de administração e duração da corticoterapia.

Human Chitinases and Chitinase-Like Proteins as Indicators for Inflammation and Cancer

Human Glyco_18 domain-containing proteins constitute a family of chitinases and chitinase-like proteins. Chitotriosidase and AMCase are true enzymes which hydrolyse chitin and have a C-terminal chitin-binding domain. YKL-40, YKL-39, SI-CLP and murine YM1/2 proteins possess solely Glyco_18 domain and do not have the hydrolytic activity. The major sources of Glyco_18 containing proteins are macrophages, neutrophils, epithelial cells, chondrocytes, synovial cells, and cancer cells. Both macrophages and neutrophils use the regulated secretory mechanism for the release of Glyco_18 containing proteins. Glyco_18 containing proteins are established biomarkers for human diseases. Chitotriosidase is overproduced by lipid-laden macrophages and is a major marker for the inherited lysosomal storage Gaucher disease. AMCase and murine lectin YM1 are upregulated in Th2-environment, and enzymatic activity of AMCase contributes to asthma pathogenesis. YKL proteins act as soluble mediators for the cell proliferation and migration, and are also involved in rheumatoid arthritis, inflammatory bowel disease, hepatic fibrosis and cirrhosis. Chitotriosidase and YKL-40 reflect the macrophage activation in atherosclerotic plaques. Serum level of YKL-40 is a diagnostic and prognostic marker for numerous types of solid tumors. YKL-39 is a marker for the activation of chondrocytes and the progression of the osteoarthritis in human. Recently identified SI-CLP is upregulated by Th2 cytokine IL-4 as well as by glucocorticoids. This unique feature of SI-CLP makes it an attractive candidate for the examination of individual sensitivity of patients to glucocorticoid treatment and prediction of side effects of glucocorticoid therapy. Human chitinases and chitinase-like proteins are found in tissues and circulation, and can be detected by non-invasive technologies.

Glucocorticoids suppress vasopressin gene expression in human suprachiasmatic nucleus

Sleep impairment is one of the major side effects of glucocorticoid therapy. The mechanism responsible for this circadian disorder is unknown, but alterations in the suprachiasmatic nucleus (SCN), the biological clock of the human brain, are presumed to play a major role. In the present study, the amount of vasopressin mRNA (AVP mRNA) expression in the SCN was investigated in 10 glucocorticoid-exposed patients and 10 glucocorticoid free, age- and clock time of death-matched controls. The total amount of AVP mRNA, expressed as masked silver grains in the SCN, was two times lower in glucocorticoid-exposed patients ( n = 10; 5115 ± 1314 μm 2) than that in controls ( n = 10; 11,021 ± 1408 μm 2) ( P = 0.006). There was also a 53% decrease in the total number of profiles in the SCN that expressed AVP mRNA in glucocorticoid-exposed patients (16,759 ± 3110) compared with those in controls (31,490 ± 3816) ( P = 0.01). In conclusion, glucocorticoids have an inhibitory effect on AVP mRNA expression in the human SCN, which may be the biological basis of the circadian rhythm disturbances during glucocorticoid therapy.