Search Results (282)

The endocrine stress response is a valuable tool for evaluating how organisms cope with environmental challenges. However, selecting an appropriate matrix for measuring glucocorticoids (GCs) requires careful consideration of sample quality and accessibility. This study reveals that blood sampling affects plasma cortisol levels in the subterranean rodent Ctenomys talarum, with the effect being reversed shortly thereafter. To facilitate a non-invasive approach, an enzyme-linked immunosorbent assay (EIA) that had previously been validated for measuring plasma cortisol in C. talarum was evaluated to measure adrenocortical activity by analyzing fecal glucocorticoid metabolites (FGCs). Using this assay, we monitored the stress response during wild capture, transport to captivity, adrenocorticotropic hormone (ACTH) stimulation, and immobilization. This showed that FGC levels accurately reflect adrenal activation in these contexts. We also documented a relationship between reproductive seasonality and FGCs. Finally, we provide evidence for a relationship between adrenal activity and behavior. Our results suggest that when considering plasma GCs for the assessment of acute stress, it is crucial to understand the magnitude and timing of the effects of blood sampling on the stress state of organisms. The validation of FGC measurement in C. talarum provides a new option for advancing ecophysiological studies in both the wild and captivity. Full article

Objective: Idiopathic nephrotic syndrome (INS) is a rare, relapsing kidney disease. Trigger for relapses, among others, may be exposure to gluten in patients with INS and celiac disease (CD). CD is a gluten-sensitive disorder. The prevalence of CD ranges from 1% in the general population to 8% in patients with autoimmune diseases. The aim of the study was to assess the incidence of CD in patients with INS and the influence of a gluten-free diet on the course of INS. Material and Methods: A retrospective cohort study was conducted on 147 patients hospitalized between February 2020 and September 2024 in a single medical center. Patients were categorized into two groups: 98 patients with INS and 49 from the control group. The analysis included age, gender, total dose of glucocorticoids (GCs), duration of INS, serum levels of immunoglobulin class A (IgA) and G (IgG), the presence of antibodies against tissue transglutaminase (tTG) and endomysium (EMA), and urine analysis. A medical questionnaire regarding pathological symptoms during infancy and allergic diseases of patients and family members was conducted. Results: CD was diagnosed in 8% of patients with INS. A total of 66% of patients with INS and CD who followed a gluten-free diet had no or less frequent relapses. Conclusions: CD is more common in patients with INS than in the general population. A gluten-free diet in patients with INS and CD may decrease the frequency of nephrotic proteinuria relapses. CD may be oligosymptomatic, and it is important to search for it in all patients with INS. Owing to the small number of patients with CD among INS in the study, this issue requires further research. Full article

Idiopathic nephrotic syndrome (INS) is the most prevalent glomerular illness in children. Even while immunologic processes are well-established, oxidative stress is becoming more widely acknowledged as a significant factor in the etiopathogenesis of illness. Assessing its activity and treatment response may be made easier with the use of trustworthy, non-invasive indicators to track redox balance. We report on the oxidative stress levels of a 10.7-year-old boy with INS with five clinical time points in one year. The FRAS5 analyzer was used to calculate the oxidative stress index (OSI), plasma antioxidant capacity (PAT) and derivatives of reactive oxygen metabolites (d-ROMs) as biomarkers. A 4-tier oxidative state classification scheme based on d-ROM and PAT thresholds was used to interpret the values. The patient had low antioxidant defense, moderate oxidative and increased OSI at relapses, a positive transition to reduced oxidative burden and enhanced defense during remission. The order of events showed a dynamic redox response associated with glucocorticoid (GC) medication and disease activity. The potential value of d-ROM, PAT, and OSI as dynamic biomarkers for tracking disease activity, response to treatment and residual oxidative burden in pediatric INS is supported by this case. To confirm their function in more comprehensive clinical decision-making, more research is required. Full article

Background: Glucocorticoid-induced hyperglycemia (GCIH) is a common adverse effect of glucocorticoid (GC) therapy. Although evidence on oral antidiabetic medications (OADMs) for GCIH is emerging, direct comparisons with insulin therapy remain limited. This study aimed to compare the efficacy and safety of OADMs and sliding scale insulin (SSI) in patients with autoimmune diseases who developed GCIH. Methods: We retrospectively analyzed 97 patients who developed GCIH during GC therapy equivalent to ≥20 mg/day of prednisolone. Patients were classified into SSI-only (n = 41), OADM (n = 31), and basal–bolus/basal or bolus insulin (BBI/BI) (n = 25) groups. The primary endpoint was mean preprandial blood glucose (BG), adjusted for patient characteristics. Secondary outcomes included hospital stay, hypoglycemia, insulin use, and glycated hemoglobin. Results: In univariate analysis, the mean preprandial BG levels during the treatment period were significantly associated with the mean initial preprandial BG levels. Adjusted mean preprandial BG during treatment did not differ significantly between the OADM and SSI-only groups, whereas the BBI/BI group had higher pre-breakfast BG (p = 0.016). Among first-time GC users, those in the OADM group using cyclophosphamide had significantly lower fasting BG than non-users (p = 0.011). Conclusions: In patients with autoimmune diseases receiving ≥20 mg/day GC, OADM provided glycemic control comparable to SSI with similar hypoglycemia risk. Early preprandial BG levels during the first 3 days of GC therapy may help predict glycemic outcomes. Prospective studies with standardized regimens are needed to optimize GCIH management. Full article

Glucocorticoid drugs (GCs), while effective in systemic lupus erythematosus (SLE), cause severe systemic side effects due to lack of tissue-specificity. To overcome this bottleneck, we developed a CD74-directed antibody–drug conjugate (Bud-ADC) to deliver budesonide, a potent GC drug, selectively to target CD74-expressing immune cells (e.g., B cells, dendritic cells), which play an important role in SLE pathogenesis. Bud-ADC combines a cross-species anti-CD74 antibody with budesonide via a cleavable linker, enabling immunosuppression on targeted cells. In vitro, Bud-ADC selectively inhibited CD74-high immune cell activation and cytokine production. In two SLE mouse models, Bud-ADC significantly alleviated disease hallmarks—reducing autoantibodies, splenomegaly, and kidney damage—while showing superior efficacy to free budesonide at equivalent doses. The therapeutic effects involved both direct targeting of CD74-high immune cells and indirect modulation of T cell responses despite low CD74 expression. This study establishes CD74-targeted ADC as a novel strategy to enhance GC efficacy in SLE, aiming at minimizing off-target toxicity while maintaining broad immunosuppressive activity. The translatable design supports further preclinical and clinical development for autoimmune diseases. Full article

Glucocorticoids (GCs) represent effective anti-cancer drugs for the treatment of hematological malignancies, but their clinical use is limited due to their multiple adverse effects. Selective glucocorticoid receptor agonists/modulators (SEGRAMs) modify glucocorticoid receptor (GR) function, shifting it towards therapeutically important transrepression and, therefore, could be safer alternative to GCs. Here we report on the biological activity of four novel glucocorticoid receptor (GR) ligands, derivatives of synephrine, a natural-origin molecule. We demonstrated the affinity of synephrine derivatives in silico and in vitro by molecular dynamics simulation and radioligand binding assay, correspondingly. Further, we tested the induction of apoptosis in cultured cells and cytotoxic effects in primary lymphoblasts from patients with acute lymphoblastic leukemia. Therapeutically important GR transrepression was evaluated by luciferase reporter assay and Q-PCR of transrepression marker genes, while GR transactivation associated with side effects was evaluated by Q-PCR analysis and by the level of GR phosphorylation at Ser211. Anti-cancer effects of the leader compound, 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2), were studied using a murine transplantable lymphoma P388 model. The potential of 10S-E2 to prevent the development of atrophic complication was evaluated using a murine model of glucocorticoid-induced osteoporosis. All studied synephrine derivatives demonstrated high GR affinity, with the IC₅₀ value of the most active derivative 10S-E2 being 0.56 µM; the effects on GR function were cell-type-specific. The leader compound, 10S-E2, revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo, inhibiting tumor growth by more than 60%. Although the anti-cancer effect of 10S-E2 was less pronounced than that of the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies. Full article

Background/Objective: Glucocorticoids (GC) have anti-inflammatory effects, but long-term use can suppress bone formation and cause osteoporosis. The impact of inflammatory environments, such as periodontitis, on alveolar bone metabolism remains insufficiently understood. Methods: We used wild-type (C57BL/6J, n = 47) mice to compare glucocorticoid (GC) effects with and without sustained-release GC pellets. Mice were divided into GC-administered (2 weeks: n = 8; 4 weeks: n = 8; 8 weeks: n = 7) and non-GC-administered groups (2 weeks: n = 8; 4 weeks: n = 8; 8 weeks: n = 8). A ligature wire was placed around the left first molar of all mice to induce periodontal disease, while the right first molar served as a control. Femur and alveolar bone changes were assessed at 2, 4, and 8 weeks using μCT, HE staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemistry (TNF-α). Anonymized evaluators performed histological analyses, and statistical analyses. One-way ANOVA with the Tukey post hoc test and t tests. Results: GC administration significantly reduced femoral bone mass at 2, 4, and 8 weeks. In mice without ligature, GC administration did not significantly affect alveolar bone mass or osteoblast number at 2 or 4 weeks, but a reduction was noted at 8 weeks post-treatment. No significant differences in osteoclast numbers or TNF-α levels were observed after GC administration. In a periodontal disease mouse model, GC administration led to greater bone loss, fewer osteoblasts, and increased osteoclasts and TNF-α levels. Conclusions: GC use in periodontal disease risks abnormal bone metabolism and progressive alveolar bone resorption. Full article

Background/Objectives: Osteoporosis is considered a surgical indication in primary hyperparathyroidism (PHPT), regardless of menopausal status. This pilot study aimed to evaluate the impact of menopause and PHPT on bone mineral density (BMD) and to explore additional clinical factors that may influence bone health. Methods: We conducted an observational pilot study including 204 postmenopausal women with osteopenia or osteoporosis who underwent surgery for sporadic PHPT between 2009 and 2021 at Cruces University Hospital (Spain). Demographic data, anthropometric data, date of last menstrual period, years since menopause (YSM), and the clinical history of bone fragility were collected prior to parathyroidectomy. Biochemical parameters and months with hypercalcemia (MHCa)—as a surrogate for PHPT exposure—were analyzed. BMD results were expressed as a densitometric index, the T-Score. Results: Higher age (p = 0.043), greater body mass index (BMI) (p = 0.039), more YSM (p = 0.027), lower serum calcium levels (s-Ca) (p = 0.04), and glucocorticoid treatment antecedents (GcT) (p = 0.029) were all significantly associated with femoral osteoporosis. Similarly, higher weight (p = 0.004), greater MHCa (p = 0.01), lower height (p = 0.01) and s-Ca levels (p = 0.002) were significantly associated with spinal osteoporosis. Furthermore, logistic regression multivariate analysis determined that femur density was independently influenced by YSM (p < 0.001), s-Ca (p = 0.018), BMI (p = 0.002) and GcT (p = 0.006). Osteoporosis of the spine was also independently associated with YSM (p = 0.036), s-Ca (p = 0.031) and also with body weight (p = 0.003). Conclusions: The duration of menopause (YSM), rather than PHPT severity, is an independent predictor of osteoporosis in postmenopausal women. Full article

Objective: To determine whether oral vitamin D supplementation reduces the risk of glucocorticoid (GC)-associated severe adverse events (SAEs) in patients with giant cell arteritis (GCA) included in the Spanish ARTESER registry. Methods: The ARTESER registry collected data from patients diagnosed with GCA across 26 Spanish public hospitals between June 2013 and March 2019. SAEs were defined as fatal, life-threatening, or requiring hospitalization. Patients were categorized according to the use or non-use of oral vitamin D supplements. Incidence rates (IRs) of SAEs were expressed per person-year with 95% confidence intervals (CIs). Cox proportional hazards models assessed vitamin D supplementation and its interaction with cumulative glucocorticoid dose. Results: Of 1568 patients (mean age 76.9 ± 8.1 years; 70.1% women) receiving GC, 120 (7.6%) experienced SAEs (IR 0.039; 95% CI 0.033–0.047). Vitamin D supplementation was documented in 1186 (75.6%) compared with 382 (24.4%) non-supplemented patients. SAE incidence was similar in supplemented (n = 89; 7.5%; IR 0.038, 95% CI 0.030–0.046) and non-supplemented patients (n = 31; 8.1%; IR 0.045, 95% CI 0.031–0.064) (p = 0.387). Multivariable Cox regression showed a significant interaction between vitamin D supplementation and cumulative glucocorticoid dose (interaction term HR 0.90; p = 0.033), consistent with a dose-dependent protective effect. Conclusions: Vitamin D supplementation was not independently associated with a lower incidence of GC-related SAEs, likely due to residual confounding factors. However, the interaction with cumulative GC exposure suggests a modulatory effect. Prospective studies incorporating stratified baseline vitamin D assessments are warranted. Full article

Background: Monocytes can commit to different phenotypes associated with specific features required in inflammation and homeostasis. Classical and alternative activation are two extremes of monocyte polarization and are both influenced by glucocorticoids (GCs). Methods: Human monocytes were sorted from the blood of healthy individuals and activated with LPS or IL-4 and IL-13, either in the absence or presence of dexamethasone (Dex). Metabolic adjustments were analyzed using Seahorse stress tests, SCENITH, and RT-qPCR. Results: LPS enhanced glycolysis and also, to a lesser extent, oxidative phosphorylation (OXPHOS), whereas addition of Dex induced a metabolic switch in favor of the latter. In contrast, activation of monocytes with IL-4 and IL-13 exclusively stimulated OXPHOS, which was suppressed by concomitant Dex treatment. The glycolytic function of monocytes matched alterations in gene expression of glucose transporters and metabolic enzymes, which were upregulated by LPS and inhibited by Dex via interference with the mTORC1 pathway but remained unaltered in response to IL-4 and IL-13. Although the dependency of classically and alternatively activated monocytes on OXPHOS and glucose usage markedly differed, modulation by GCs was limited to the latter polarization state. Conclusions: Our findings unravel a highly selective regulation of human monocyte energy metabolism by different activating stimuli as well as by GCs. Full article

Glucocorticoids (GCs) remain the cornerstone of asthma treatment due to their potent anti-inflammatory and eosinophil-suppressive effects in the airways, including the induction of peripheral eosinophil apoptosis and downregulation of type 2 cytokine signaling. However, emerging evidence reveals a paradoxical role for GCs in the bone marrow, where they enhance eosinophil production (eosinopoiesis), especially under allergic, infectious, or surgical stress conditions. This duality reflects a complex immunoendocrine interplay involving GC-induced modulation of eosinophil progenitor survival, proliferation, and responsiveness to eosinopoietic cytokines such as interleukin-5 and granulocyte-macrophage colony-stimulating factor. Furthermore, GCs synergize with lipid mediators like cysteinyl-leukotrienes and prostaglandins, modulating both transcriptional and adhesion molecule profiles that prime eosinophil precursors for migration and differentiation. This review examines the molecular and cellular mechanisms underlying GC-induced eosinopoiesis, its functional link to airway inflammation, and its clinical implications for asthma management. We also explore potential therapeutic strategies aimed at selectively modulating bone marrow eosinophil output without compromising the peripheral anti-inflammatory benefits of GCs. Understanding this paradoxical duality holds significant translational potential for improving disease control and preventing asthma exacerbations. Full article

Background/Objectives: To investigate microRNA (miRNA) expression profiles in the anterior lens capsules of patients with glucocorticoid-induced cataracts (GIC) and to identify miRNAs potentially associated with glucocorticoid (GC) exposure and posterior subcapsular cataract (PSC) formation. Methods: A total of 33 participants were divided into four groups based on their GC usage history and cataract type: GIC (n = 10), age-related PSC (n = 6), GC-treated age-related cataract (ARC) (n = 7), and normal control (n = 10). Anterior lens capsule samples were obtained during cataract surgery and total RNA was extracted for quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of 12 selected miRNAs were quantified using a customized miScript miRNA PCR array. Results: Among the twelve miRNAs analyzed, seven (let-7a-5p, let-7d-5p, miR-15a-5p, miR-16-5p, miR-23b-3p, miR-26a-5p, and miR-125a-5p) were significantly differentially expressed among the groups (p < 0.05). In the GIC group, let-7a-5p, miR-23b-3p, miR-26a-5p, and miR-125a-5p were significantly upregulated, whereas let-7d-5p, miR-15a-5p and miR-16-5p were significantly downregulated compared to that in the normal control group. No significant differences in miRNA expression were observed between the GIC and age-related PSC groups or between the GIC and GC-treated ARC groups. Conclusions: This study demonstrates distinct miRNA expression patterns in the anterior lens capsules of patients with GIC. Altered expression of specific miRNAs may be linked to the pathogenesis of GC-induced PSC formation. These findings provide a molecular basis for further investigation into the regulatory roles of miRNAs in GC-associated cataracts. Full article

Background: Community-acquired pneumonia (CAP) is a leading cause of pediatric hospitalizations and a risk factor for chronic respiratory conditions. Glucocorticoids (GCs) are used as adjunctive therapy to reduce inflammation, but their efficacy in infants and toddlers remains unclear. Method: A retrospective study of 1116 infants and toddlers with severe CAP was conducted, using causal forest to estimate individual treatment effects (ITEs), with the duration of intensive care unit (ICU) stay as the outcome. Patients were stratified based on ITEs to investigate the heterogeneous treatment effect (HTE) and identify responders. Generalized linear models validated the HTE across subclasses, followed by comparative analyses to characterize responders. Variable importance was assessed using the causal model, and Shapley additive explanations (SHAP) quantified each variable’s contribution to the ITE. Analysis was also performed in mechanically ventilated patients (MV group). Results: GCs demonstrated significant HTE. Older patients and those with elevated inflammation markers showed better responses, whereas no such benefit was observed in respiratory syncytial virus-infected patients. These subgroups experienced shorter ICU stays both in the whole cohort (β = −0.16, p < 0.001) and MV group (β = −0.34, p < 0.001), and shorter ventilation duration was observed in the MV group (β = −0.35, p < 0.001). Age and the anion gap were key predictors of ITEs. SHAP analysis revealed a positive correlation between age and GC effectiveness. Conclusions: Significant heterogeneity in GC treatment effects exists among infants and toddlers with severe CAP, highlighting the need for optimization of GC use in this population. Full article

Background/Objectives: This study investigated the correlation of oxidative stress biomarkers with the activity of idiopathic nephrotic syndrome (INS) in Slovenian children. Methods: In this prospective study, sequential plasma and urine samples from 20 children with INS in different phases of disease activity were taken: at first disease presentation or relapse (before glucocorticoid (GC) treatment), at time of remission achievement, and after discontinuation of GC treatment. This study measured oxidative stress biomarkers, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL) adduct, dityrosine (DiY), and 15-isoprostane F2t, using competitive enzyme-linked immunosorbent assay (ELISA) and assessed oxidative status using the FRAS 5 analytical system, which enables rapid photometric measurement of both oxidative and antioxidant capacity from biological fluids. Two complementary tests were performed: the d-ROMs test (derivatives of reactive oxygen metabolites) and the PAT (plasma antioxidant test). The oxidative stress index (OSI) was calculated as the ratio between them. Results: Concentrations of isoprostanes in urine were statistically significantly lower in patients at first disease presentation or relapse compared to time of remission achievement. Values of PAT test in serum were significantly highest after GC treatment. Values of d-ROMs test in serum were significantly lower at time of remission achievement compared to first disease presentation or relapse. Values of 8-OHdG, HEL, DiY (in plasma and urine), isoprostanes, and OSI in plasma did not statistically significantly differ in various phases of disease activity. Conclusions: Isoprostanes in urine and PAT in serum could serve as potential biomarkers of oxidative stress and disease activity in children with INS. Full article

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article