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Intra-articular glucocorticoid injections are effective in controlling inflammation and pain in arthritides but restricted by short duration of action and risk of joint degeneration. Controlled drug release using biocompatible hydrogels offers a unique solution, but limitations of in situ gelation restrict their application. Gellan sheared hydrogels (GSHs) retain the advantages of hydrogels, however their unique microstructures lend themselves to intra-articular application - capable of shear thinning under force but restructuring at rest to enhance residence. This study examined GSHs for extended intra-articular glucocorticoid delivery of prednisolone (10 mg mL -1 ); demonstrating links between material mechanics, steroid release, and preclinical assessment of efficacy in synoviocyte culture and transgenic(TNF)197Gkl (TNFtg) murine model of arthritis. GSHs demonstrated sustained release, with typical Fickian profiles over 18 days. Moreover, systems showed good stability under extended culture, with inherent cell-compatibility and suppression of inflammatory synoviocyte activation. In TNFtg animals, GSHs suppressed synovitis (70.08%, p < 0.05), pannus formation (45.01%, p < 0.05), and increased articular cartilage (82.23%, p < 0.05) relative to vehicle controls. The extended profile of steroid release from injectable GSH formulations holds promise in the treatment and management of inflammatory arthritides such as rheumatoid and osteoarthritis, representing a step-change in intra-articular drug delivery to suppress long-term joint inflammation., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Topical application of the glucocorticoid betamethasone (BM) is a common treatment for inflammatory-related skin diseases, such as psoriasis. However, enhancing its bioavailability remains challenging due to poor skin permeability. Herein, we developed and evaluated hyaluronan-cholesterol (HACH) based nanohydrogel systems (NHs) and NHs-Carbopol formulation for dermal delivery of BM. Various parameters were investigated including particle size, surface charge, encapsulation efficiency, in vitro drug release kinetics and stability. The HACH-based NHs demonstrated high encapsulation efficiency, with apparent solubility improved up to 9-fold, small size (∼190 nm) and good stability at 4 ℃ and during long-term storage. Besides, the NHs-Carbopol formulation exhibited excellent rheological properties and an occlusive effect suitable for cutaneous application. Both in-vitro (using Strat-M® membrane) and ex-vivo (using pig ear skin) permeation studies revealed that these formulations significantly improved skin permeation and drug retention in the deeper layers of the epidermis and dermis, making it advantageous for the topical delivery of BM in psoriasis treatment. Moreover, the NHs system demonstrated potential anti-psoriatic activity by downregulating the proinflammatory cytokines in vitro in human keratinocytes (HaCaT cell line) and in an ex vivo 3D skin tissue model (EpiDerm-FT™)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Excessive infiltration of neutrophil and inflammatory cytokines accumulation as well as the inadequate delivery of drugs to the targeted site are key pathological cascades in multiple sclerosis (MS). Herein, inflammation-targeting biomimetic nano-decoys (TFMN) is developed that inhibit the infiltration of immune cells and effectively deliver glucocorticoids to lesions for enhanced MS treatment. Nano-decoys encapsulated with the glucocorticoid methylprednisolone (MPS) are prepared by coating neutrophil membrane (NM) on nanoparticles formed by the self-assembly of tannic acid and poloxamer188/pluronic68. Benefiting from the natural inflammation-targeting ability of activated neutrophil membranes, TFMN can target the lesion site and prevent neutrophils infiltration by adsorbing and neutralizing elevated neutrophil-related cytokines, subsequently modulating the inflammatory microenvironment in experimental autoimmune encephalomyelitis mice. TFMN exhibits a strong antioxidant capacity and scavenged excessive reactive oxygen species to enhance neuronal protection. Furthermore, at the inflammation site, perforin, discharged by cytotoxic T-lymphocytes, triggered the controlled release of MPS within the TFMN through perforin-formed pores in the NM. Simultaneously, this mechanism protected neurons from perforin-induced toxicity. The MPS liberated at the targeted site achieves optimal drug accumulation, thereby enhancing therapeutic efficacy. In conclusion, the innovative system shows potential for integrating various therapeutic agents, offering a novel strategy for CNS disorders., (© 2024 Wiley‐VCH GmbH.)

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with a complex pathogenesis involving epidermal barrier dysfunction and aberrant lipid composition, particularly ceramides and fatty acids (FA). Conventional management options, such as topical glucocorticoids (GC), often lead to adverse effects upon prolonged usage, prompting the exploration of alternative therapeutic strategies. The lipid extract from Black Soldier Fly larvae (BSFL) biomass, holding a rich blend of FA, holds substantial potential as a novel ingredient to tackle skin barrier impairment. This study aimed to achieve proof-of-concept validation of innovative nanotechnology-based formulations tailored to enhance the topical management of AD. Specifically, solid lipid nanoparticles (SLNs) with BSFL lipid extract were developed to perform both as a carrier for dexamethasone (DEX), a representative GC, and as skin barrier repair adjuvants. Through systematic optimization using Box-Behnken Design, BSFL lipid extract-based SLNs demonstrated favorable physicochemical properties for topical application and satisfactory stability over 2 months. Notably, these SLNs exhibited favorable drug release kinetics, delivering the total DEX payload within a therapeutically relevant timeframe. Furthermore, these nanocarriers showed the ability to permeate human keratinocytes without pronounced toxicity, suggesting their potential utility in enhancing drug delivery and cellular uptake. Overall, these findings suggest that BSFL lipid extract is a promising natural and sustainable ingredient for the development of nanotechnology-driven approaches to AD management, offering a potential avenue for addressing the unmet needs in this challenging dermatologic condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Immune-inflammatory diseases are a class of conditions with high prevalence that severely impact the quality of life. Current treatment strategies include immunosuppressants, glucocorticoids, and monoclonal antibodies. However, these approaches have certain limitations, such as poor membrane permeability, immunogenicity, and the requirement for injection in large molecule drugs. Small molecule compounds, on the other hand, suffer from issues like poor selectivity, inability to inhibit non-enzymatic functions, and biological compensation. These factors constrain the effectiveness of current therapeutic strategies in immune-inflammatory diseases. As a novel small molecule drug development technology, proteolysis-targeting chimeras (PROTACs) regulate protein levels by inducing interactions between target proteins and E3 ubiquitin ligases, leading to the selective degradation of target proteins. This technology has already shown promising therapeutic effects in the treatment of immune-inflammatory diseases. This review aims to comprehensively summarize the application of PROTAC technology in the field of immune inflammation and provide insights into its potential in treating immune-inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

For the assay of methylprednisolone (MP) in pharmaceutical formulation, a fluorescence-based spectroscopic approach is developed using the protein, human serum albumin (HSA). The structural alterations in human serum albumin (HSA) following its interaction with methylprednisolone (MP) (10-32 μg mL -1 ) were determined by spectroscopy, which included the use of fluorescence and synchronous fluorescence. The calibration curve was modeled using the fluorescence method. The devised approach has a limit of detection of 1.16 μg mL -1 and a limit of quantification of 3.535 μg mL -1 for MP estimation that is straightforward, sensitive, accurate, and selective. The reference approach and the suggested method were contrasted to show which was more appropriate for MP quality control in its dosage forms. The recovery data obtained from 99.63% to 100.0% for intra-day and 99.60-100.1%, for inter-day precision. The developed method showed remarkable sensitivity to dosage forms and real sample (urine), suggesting possible application, when applied to dose forms with a relative standard deviation of less than 2%., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Glucocorticoids (GCs) are hallmarks of anti-inflammatory activity. They are used as adjuvant therapy in oncology medications to alleviate some of the associated side effects. Although recent research has indicated that GCs have favorable anticancer potential, some scientific evidence suggests a pro-proliferation impact of GCs on cancer cells. This may create a scientific confusion on the utility of GCs and the choice of which GC enhances the anticancer potential and mitigates the negative effect. Accurate in-silico prediction and correct ranking of biological activity may be limited by the impact of the physicochemical interaction between small molecules and biological membranes. Chromatographic retention is inherently dependent on the physicochemical properties of the test molecule. It can scale the relative hydrophobicity and tentatively indicate the membrane permeability. In this study, the relationship between the in-silico binding affinity, the chromatographic retention and the in-vitro anticancer activity was investigated. Fifteen GCs were chromatographically separated on an Inertsil® C18 (4.6 * 250 mm; 5 μm) HPLC column. The binding affinity of the test GCs was determined on three receptors involved in cancer cell proliferation (topoisomerase II (TOPII), glucocorticoid receptor (GR) and ATP-binding cassette (ABCG2)). The antiproliferative potential of the test steroids was determined as per their IC 50 . The correlation between chromatographic retention and the binding affinity to the observed IC 50 was investigated by multiple linear regression (MLR). Results revealed that some GCs exhibited a remarkably favorable inhibitory potential against cancer cell lines over normal cell lines. Our data indicated a significant correlation between the retention times of different GCs and the determined binding affinity, especially to the GR (r 2  = 0.677; p = 0.011) and the estrone sulphate (ESS) binding site of the ABCG2 (r 2  = 0.643; p = 0.018). Concurrently, the retention times were well correlated to the observed IC 50 on the colorectal cancer cell lines (r 2  = 0.580; p = 0.038) and the hypopharyngeal cell lines (r 2  = 0.638; p = 0.019). Significant MLR models (n = 4) correlating the retention times of the tested steroids and the binding affinity to the observed IC 50 were created. The MLR model correlating the retention times and the ABCG2&#95;ESS binding affinity to the IC 50 on lung cancer was the most significant (p = 0.004). The accuracy of the model was 107.12 ± 29.18 % indicating good IC 50 prediction abilities. In conclusion, chromatographic retention can be employed as a low-cost and simple auxiliary tool for improving the in-silico prediction of the in-vitro activities of small molecules., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to identify the difference on pain intensity and disability between particulate and nonparticulate steroid injections in patients with lumbar radicular pain. Subgroup analysis by study design, type of particulate steroid, and follow-up duration were performed., Data Sources: We performed the literature search in the PubMed, Embase, and Cochrane Library up March, 2023., Study Selection: Studies, including randomized controlled trials (RCTs) and nonrandomized studies, that compared particulate steroid injection and nonparticulate steroid injection in patients with lumbar radicular pain were independently reviewed by 2 reviewers for eligibility for inclusion., Data Extraction: Outcomes of interest were pain intensity and disability. Two reviewers independently assessed the quality of included studies using the revised Cochrane Risk of Bias (RoB2.0) tool for RCTs and the Risk of Bias in Nonrandomized Studies of Interventions Tool (ROBINS-I) for nonrandomized studies. Effect sizes were estimated using mean difference (MD) and standardized mean difference (SMD)., Data Synthesis: A total of 10 studies were included in this meta-analysis. The results showed no significant difference in visual analog scale, disability score and the numbers of patients with 50% pain reduction between particulate and nonparticulate steroid injection groups (P>.05). Particulate steroid injections showed significant better effect in pain scale in RCTs (MD=0.62; 95% CI 0.08-1.16, P=.02). In subgroup analysis with steroid types, methylprednisolone showed better effect compared with dexamethasone, while dexamethasone showed better effect compared with betamethasone., Conclusions: This meta-analysis suggested no significant differences between the particulate and nonparticulate steroid groups in pain or disability score. Therefore, considering the safety profile of nonparticulate steroids, nonparticulate steroid injection may be helpful in patients with lumbar radicular pain., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Bioactive peptides play a crucial role in the field of regenerative medicine and tissue engineering. However, their application in vivo and clinic is hindered by their poor stability, short half-life, and low retention rate. Herein, we propose a novel strategy for encapsulating bioactive peptides using giant macrocycles. Platelet-derived growth factor (PDGF) bioactive mimicking peptide Nap-FFGVRKKP (P) was selected as the representative of a bioactive peptide. Quaterphen[4]arene (4) exhibited extensive host-guest complexation with P, and the binding constant was (1.16 ± 0.10) × 10 7  M -1 . In vitro cell experiments confirmed that P + 4 could promote the proliferation of BMSCs by 2.27 times. Even with the addition of the inhibitor dexamethasone (Dex), P + 4 was still able to save 76.94% of the cells in the control group. Compared to the Dex group, the bone mass of the mice with osteoporosis in the P + 4 group was significantly increased. The mean trabecular thickness (Tb.Th) increased by 17.03%, and the trabecular bone volume fraction (BV/TV) values increased by 40.55%. This supramolecular bioactive peptide delivery strategy provides a general approach for delivering bioactive peptides and opens up new opportunities for the development of peptide-based drugs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Over the past decades, the synthetic glucocorticoids (GCs) have been widely used in clinical practice and animal husbandry. Given the health hazard of these toxic residues in food, it is necessary to explore the detailed interaction mechanisms of typical GCs and their main target glucocorticoid receptor (GR). Hence, this work compared the GR binding and agonist activities of typical GCs. Fluorescence polarization assay showed that these GCs were potent ligands of GR. Their GR binding affinities were in the order of methylprednisolone>betamethasone≈prednisolone>dexamethasone, with IC 50 values of 1.67, 2.94, 2.95, and 5.58 nM. Additionally, the limits of detection of dexamethasone, betamethasone, prednisolone, and methylprednisolone were 0.32, 0.14, 0.19, and 0.09 μg/kg in fluorescence polarization assay. Reporter gene assay showed that these GCs induced GR transactivation in a dose-dependent manner, confirming their GR agonist activities. Among which, dexamethasone at the concentration of 100 nM produced a maximal induction of more than 11-fold over the blank control. Molecular docking and molecular dynamics simulations suggested that hydrogen-bonding and hydrophobic interactions played an important role in stabilizing the GC-GR-LBD complexes. In summary, this work might help to understand the GR-mediated endocrine disrupting effects of typical GCs., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Curcumin is a yellow pigment in turmeric (Curcuma longa) with various physiological effects in the body. To elucidate the molecular mechanisms by which bioactive compounds exert their function, identification of their molecular targets is crucial. In this study, we show that curcumin activates G protein-coupled receptor 97 (GPR97). Curcumin dose-dependently activated serum-response element-, but not serum-response factor-response element-, nuclear factor of activated T-cell-response element-, or cAMP-response element-, mediated transcription in cells overexpressed with GPR97. The structure-activity relationship indicated that (i) the double-bonds of the central 7-carbon chain were essential for activation; (ii) a methoxy group on the aromatic ring was required for maximal activity; (iii) the addition of glucuronic acid moiety or a methoxy group to the aromatic ring, but not the methylation of the aromatic p-hydroxy group, eliminated the activity; (iv) the stability of curcumin would be related to receptor activation. Both mutant GPR97(T250A) lacking the cleavage at GPCR proteolysis site and mutant GPR97(ΔN) lacking the N-terminal extracellular region were activated by curcumin and its related compounds similar to wild-type GPR97. In contrast, the synthetic glucocorticoid beclomethasone dipropionate and l-Phe activated wild-type GPR97 and GPR97(T250A), but not GPR97(ΔN). Moreover, curcumin exerted an additive effect on the activation of wild-type GPR97 with beclomethasone dipropionate, but not with l-Phe. Taken together, these results indicate that curcumin activates GPR97 coupled to Gi/Go subunit, and suggest that curcumin and glucocorticoid activate GPR97 in a different manner., Competing Interests: Declaration of competing interest Authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Optimising intranasal distribution and retention of topical therapy is essential for effectively managing patients with chronic rhinosinusitis, including those that have had functional endoscopic sinus surgery (FESS). This study presents a new technique for quantifying in vitro experiments of fluticasone propionate deposition within the sinuses of a 3D-printed model from a post-FESS patient., Methods: Circular filter papers were placed on the sinus surfaces of the model. Deposition of fluticasone on the filter paper was quantified using high-performance liquid chromatography (HPLC) assay-based techniques. The deposition patterns of two nasal drug delivery devices, an aqueous nasal spray (Flixonase) and metered dose inhaler (Flixotide), were compared. The effects of airflow (0 L/min vs. 12 L/min) and administration angle (30° vs. and 45°) were evaluated., Results: Inhaled airflow made little difference to sinus deposition for either device. A 45° administration angle improved frontal sinus deposition with the nasal spray and both ethmoidal and sphenoidal deposition with the inhaler. The inhaler provided significantly better deposition within the ethmoid sinuses (8.5x) and within the maxillary sinuses (3.9x) compared with the nasal spray under the same conditions., Conclusion: In the post-FESS model analysed, the inhaler produced better sinus deposition overall compared with the nasal spray. The techniques described can be used and adapted for in vitro performance testing of different drug formulations and intranasal devices under different experimental conditions. They can also help validate computational fluid dynamics modelling and in vivo studies., (© 2022. The Author(s).)

Background: Treatments for catastrophic antiphospholipid syndrome (CAPS) rose from recommendations and consensus of international experts based on case series or case reports. We aimed to evaluate the treatment scheme with the best cost-effectiveness ratio associated with lower mortality as a high-impact clinical benefit., Methods: The CAPS Registry was used as our source of structured data on the different therapeutic strategies, their frequency, and their effectiveness (survival). Starting from around 50 different schemes, we identified those with a mortality of less than 33% within the 18 most frequently utilized. After applying the efficiency frontier method, we included two schemes to conduct a cost-effectiveness analysis from the Colombian healthcare sector perspective. Scheme 1 (Glucocorticoids + Anticoagulation + Anti-aggregation + Intravenous IgG immunoglobulin) and scheme 2 (Glucocorticoids + Anticoagulation + Anti-aggregation + Plasma exchange) were compared in terms of costs and survival. Deterministic and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted to evaluate model robustness and uncertainty., Results: Our analysis uses the information corresponding to 427 cases from the CAPS registry, the majority being women (68.8%), with a mean age of 45.7 years and bearing general mortality of 38.17% (female: 38.4%, male: 37.5%). Scheme 2 was the cost-effective strategy over scheme 1. The results were robust on discrete sensitivity analysis and probability sensitivity analysis (Monte Carlo simulation)., Conclusion: To our knowledge, this is the first economic evaluation focused on the treatment of CAPS. For the Colombian health system, schemes 1 and 2 have similar behavior; nevertheless, scheme 2 represents the best cost-effectiveness ratio. This treatment approach is highly susceptible to the allocation of resources by the system and beneficial in terms of health outcomes.

Urbanization drives phenotypic variation in many animal species. This includes behavioral and physiological traits such as activity patterns, aggression, and hormone levels. A current challenge of urban evolutionary ecology is to understand the environmental drivers of phenotypic variation in cities. Moreover, do individuals develop tolerance to urban environmental factors, which underlie adaptative responses and contribute to the evolution of urban populations? Most available evidence comes from correlative studies and rare experiments where a single urban-related environmental factor has been manipulated in the field. Here we present the results of an experiment in which we tested for differences in the glucocorticoid (CORT) response of urban and rural blue tits nestlings (Cyanistes caeruleus) to artificial light at night (ALAN). ALAN has been suggested to alter CORT response in several animal species, but to date no study has investigated whether this effect of ALAN differs between urban and rural populations. Immediately after hatching, urban and forest broods were either exposed to 2 lux of ALAN (using an LED source mounted inside the nestbox) or received no treatment (dark control). The experiment lasted until the chicks fledged. When the chicks were 13 days old plasma samples were collected to measure baseline CORT concentrations, and feather samples to provide an integrative measure of CORT during growth. Forest birds had higher plasma CORT (pCORT) concentrations than their urban counterparts, irrespective of whether they were exposed to ALAN or not. Conversely, we found population-specific responses of feather CORT to ALAN. Specifically, urban birds that received ALAN had increased feather CORT compared with the urban dark controls, while the opposite was true for the forest birds. pCORT concentrations were negatively associated to fledging success, irrespective of population and treatment, while feather CORT was positively associated to fledging success in broods exposed to ALAN, but negatively in the dark control ones. Our results demonstrate that ALAN can play a role in determination of the glucocorticoid phenotype of wild animals, and may thus contribute to phenotypic differences between urban and rural animals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

The glucocorticoid receptor is a key regulator of essential physiological processes, which under the control of the Hsp90 chaperone machinery, binds to steroid hormones and steroid-like molecules and in a rather complicated and elusive response, regulates a set of glucocorticoid responsive genes. We here examine a human glucocorticoid receptor variant, harboring a point mutation in the last C-terminal residues, L773P, that was associated to Primary Generalized Glucocorticoid Resistance, a condition originating from decreased affinity to hormone, impairing one or multiple aspects of GR action. Using in vitro and in silico methods, we assign the conformational consequences of this mutation to particular GR elements and report on the altered receptor properties regarding its binding to dexamethasone, a NCOA-2 coactivator-derived peptide, DNA, and importantly, its interaction with the chaperone machinery of Hsp90.

The relationship between physiological and behavioral stress markers is documented in several rodent species. However, there is no information regarding the role of adrenocortical activity in behavior of the black rat (Rattus rattus). Therefore, we hypothesize that the adrenocortical activity of black rats varies between individuals and is related to some of the behaviors in a novel environment. To test this hypothesis, we (i) validated a method for quantifying glucocorticoid metabolites from feces (fGCMs) with an enzyme immunoassay (EIA); (ii) examined variation and diurnal rhythms of feces and GCM production; and (iii) examined the relationship between GCM levels and exploratory behavioral traits. We fulfilled the first aim (i) by successfully performing an ACTH challenge test to validate the use of a 5α-pregnane-3β,11β,21-triol-20-one EIA for measuring fGCMs. Second (ii) we detected considerable consistent interindividual variability in production of both feces and glucocorticoids. The peak production of feces occurred in the first hour of the dark cycle, the peak of fGCMs occurred approximately 3 h later. Lastly, (iii) there was no clear relationship between behavior in the hole board test and GCMs. Grooming, a typical behavioral stress marker, was negatively associated with stress reactivity, while head-dipping in the hole-board test (traditionally considered an exploratory behavior independent of stress) was not correlated with the GCMs. This study offers a first look at GCMs in the black rat, successfully validates a method for their measurement and opens possibilities for future research of the relationship between glucocorticoids and exploratory behavior in this species., (© 2021 Wiley Periodicals LLC.)

Polychlorinated dibenzo-p-dioxins (PCDDs) are hypothesized to exert their toxic effects in wildlife and humans via endocrine disruption. However, very scanty information is available on the underlying molecular interactions that trigger this disruption. In this study, molecular docking simulation was used to predict the susceptibility of 12 nuclear receptors to disruption via PCDD bindings. Findings revealed that androgen (AR and AR an), estrogen (ER α and ER β), glucocorticoid (GR) and thyroid hormone (TR α and TR β) receptors are the most probable protein targets that bind to PCDDs. Further molecular docking analyses showed that PCDD molecules mimic the modes of interaction observed for the co-crystallized ligands of the affected receptors, resulting in the formation of ligand-receptor complexes that were stabilized through electrostatic, van der Waals, pi-effect and hydrophobic interactions with 18, 17, 17, 16, 18, eight and four amino acid residues in the active sites of AR, AR an, ER α, ER β, GR, TR α and TR β respectively. The commonalities of these interacting amino acid residues with those utilized by dihydrotestosterone in AR, bicalutamide in AR an, 17β-estradiol in ER α, 17β-estradiol in ER β, cortisol in GR, thyromimetic GC-1 in TR α and thyromimetic GC-1 in TR β are 86%, 74%, 94%, 80%, 82%, 50% and 43% respectively. The results obtained in this study provide supporting evidence that PCDD molecules may interfere with the endocrine system via binding interactions with some vital amino acid residues in the binding pockets of AR, ERs, GRs and TRs., (© 2020 John Wiley & Sons, Ltd.)

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available 1-3 . Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97) 4-6 , a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G o complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W 6.53 , which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G o protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G o protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.

Heterogeneous solid catalysis by the commercially available perfluorosulfonic ionomer Aquivion-H allowed 1,2:5,6-diacetonide of d-mannitol (1), immediate precursor of important unichiral C3-synthons, to be efficiently obtained from d-mannitol and 2,2-dimethoxypropane in DMF at room temperature. The 1,2-monoacetonide, whose intermediate formation is the rate-limiting step, could be almost completely converted into 1 with limited concurrent transformation of 1 into triacetonides. In line with recent literature reports, these results indicate that heterogeneous catalysis by Aquivion-H surpasses the performances of homogeneous acidic catalysis assuring, presumably for its peculiar morphology, a higher product selectivity. Easy recovery at the end of the reaction and recyclability are additional advantages of this solid acid catalyst., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Asthma is one of the most frequent chronic diseases all over the world. Glucocorticoids (GCs), both inhaled (ICSs) and oral (OCSs), are the most effective treatment in asthma because they control symptoms and prevent exacerbations., Areas Covered: The present article reviews the new therapeutic indications of GCs for the treatment of asthma and focuses on new molecules and safety issues., Expert Opinion: Most patients with asthma benefit from corticosteroid-based treatments. Side effects are mainly due to prolonged use of oral GCs, while they are minor with inhaled GCs. Interesting insights come from the new ICSs, which are characterized by lower oral bioavailability and higher lipophilicity and are more effective with less side effects. Recent trials have shown the efficacy of early use of ICSs in mild asthma. Furthermore, the possibility to prescribe targeted therapies using specific biomarkers in steroid-sensitive asthma can reduce doses and duration of treatment, while biological agents should be reserved for non-responding patients. All this evidence confirm the need to continue on the path toward precision medicine, in which the treatments are based on clinical and molecular traits.

The photodegradation process of seven glucocorticoids (GCs), cortisone (CORT), hydrocortisone (HCORT), betamethasone (BETA), dexamethasone (DEXA), prednisone (PRED), prednisolone (PREDLO) and triamcinolone (TRIAM) was studied in tap and river water at a concentration close to the environmental ones. All drugs underwent sunlight degradation according to a pseudo-first-order decay. The kinetic constants ranged from 0.00082 min -1 for CORT to 0.024 min -1 for PRED and PREDLO. The photo-generated products were identified by high-pressure liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The main steps of the degradation pathways were the oxidative cleavage of the chain 17 for CORT, HCORT and the rearrangement of the cyclohexadiene moiety for the other GCs. The acute and chronic toxicity of GCs and of their photoproducts was assessed by the V. fischeri and P. subcapitata inhibition assays. The bioassays revealed no significant differences in toxicity between the parent compounds and their photoproducts, but the two organisms showed different responses. All samples produced a moderate acute toxic effect on V. fisheri and no one in the chronic tests. On the contrary, evident hormesis or eutrophic effect was produced on the algae, especially for long-term contact.

In this study, the ability of different beta-cyclodextrins to facilitate homogeneous dispersion of triamcinolone acetonide (TA) into chitosan membranes is assessed. Drug loading was assessed through atomic force microscopy (AFM), scanning electron microscopy (MEV-FEG), and X-ray diffraction analyses. Drug interactions with the co-polymer were investigated with Fourier transform infrared spectroscopy, thermal analyses. Swelling assay, and in vitro drug release experiment were used to assess TA release behavior. Undispersed particles of drug were observed to remain in the simple chitosan membranes. Hydroxypropyl-β-cyclodextrin enabled the dispersion of TA into chitosan membranes and subsequent sustained drug release. In addition, the membrane performance as a drug delivery device is improved by adding specified amounts of the co-solvent triethanolamine. The experimental data presented in this study confirm the utility of our novel and alternative approach for obtaining a promising device for slow and controlled release of glucocorticoids, such as triamcinolone acetonide, for topical ulcerations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The formyl peptide receptor 2 (ALX/FPR2), a G-protein-coupled receptor (GPCR), plays an important role in host defense and inflammation. This receptor can be driven as pro- or anti-inflammatory depending on its agonist, such as N -formyl-Met-Leu-Phe-Lys (fMLFK) and resolvin D1 (RvD1) or its aspirin-triggered 17 (R)-epimer, AT-RvD1, respectively. However, the activation mechanism of ALX/FPR2 by pro- and anti-inflammatory agonists remains unclear. In this work, on the basis of molecular dynamics simulations, we evaluated a model of the ALX/FPR2 receptor activation process using two agonists, fMLFK and AT-RvD1, with opposite effects. The simulations by both fMLFK and AT-RvD1 induced the ALX/FPR2 activation through a set of receptor-core residues, in particular, R205, Q258, and W254. In addition, the activation was dependent on the disruption of electrostatic interactions in the cytoplasmic region of the receptor. We also found that in the AT-RvD1 simulations, the position of the H8 helix was similar to that of the same helix in other class-A GPCRs coupled to arrestin. Thus our results shed light on the mechanism of activation of the ALX/FPR2 receptor by pro-inflammatory and pro-resolution agonists.

Conservation strategies for crocodilians often include captive breeding to create stable assurance populations. Evaluating adrenal and gonadal hormone patterns can provide animal managers with data to more effectively monitor animal welfare and reproductive status. This study evaluated the effects of season (breeding, nesting, or off), sex (male and female), and reproductive status of females (egg-laying/housed with a male or non-laying/housed solo) on concentrations of fecal glucocorticoid metabolite (FGM), fecal androgen metabolite (FAM), and fecal progestogen metabolite (FPM) in seven Cuban crocodiles, Crocodylus rhombifer, at the Smithsonian's National Zoological Park. Overall, seasonal changes in FGM and FPM concentrations were only observed in egg-laying females; FGM and FPM concentrations were both higher during the nesting season compared to the breeding and off seasons. Seasonal changes in FAM concentrations were only observed in males; males had higher FAM concentrations during the breeding and nesting seasons compared to the off season. Future studies investigating the use of fecal hormone metabolites in crocodilians are necessary to understand differences between individuals and species, to further elucidate the interactions between hormones and environmental factors, such as social housing, and to develop long-term datasets for the management of this species., (© 2020 Wiley Periodicals LLC.)

Sarcopenia is a common disease in older people due to aging, and it can also occur in midlife because of diseases including cancer. Sarcopenia, characterized by rapid loss of muscle mass and accelerated loss of function, can lead to adverse outcomes such as frailty, falls, and even mortality. The development of pharmacological and therapeutic approaches to treat sarcopenia remains challenging. The growth status and quantity of myoblasts are the key factors directly affecting muscle formation. Therefore, enhancing the function of myoblasts is crucial for the treatment of sarcopenia. In our study, we introduced an insulin-like growth factor-I (IGF-1) mimicking supramolecular nanofibers/hydrogel formed by Nap-FFGSSSR that effectively promoted proliferation and significantly reduced dexamethasone-induced apoptosis of myoblasts, assisted myoblasts to differentiate into myotubes, and prevented the fibrosis of muscle tissue and the deposition of collagen, ultimately achieving outstanding effects in the treatment of sarcopenia. The RNA-sequencing results revealed that our nanofibers possessed similar bioactivity to the growth factor IGF-1, which increased the phosphorylation of Akt by activating the insulin signaling pathway. We prepared novel supramolecular nanomaterials to reverse glucocorticoid-induced myoblast dysfunction, which was promising for the treatment of muscular atrophy. In addition, we envisioned the generation of biofunctional nanomaterials by molecular self-assembly for the treatment of chronic diseases in middle-aged and older people.

Glucocorticoids are widely used anti-inflammatory drugs in clinical settings. However, they can induce skeletal muscle atrophy by reducing fiber cross-sectional area and myofibrillar protein content. Studies have proven that antioxidants can improve glucocorticoid-induced skeletal muscle atrophy. Quercetin is a potent antioxidant flavonoid widely distributed in fruits and vegetables and has shown protective effects against dexamethasone-induced skeletal muscle atrophy. In this study, we demonstrated that dexamethasone significantly inhibited cell growth and induced cell apoptosis by stimulating hydroxyl free radical production in C2C12 skeletal muscle cells. Our results evidenced that quercetin increased C2C12 skeletal cell viability and exerted antiapoptotic effects on dexamethasone-treated C2C12 cells by regulating mitochondrial membrane potential (ΔΨm) and reducing oxidative species. Quercetin can protect against dexamethasone-induced muscle atrophy by regulating the Bax/Bcl-2 ratio at the protein level and abnormal ΔΨm, which leads to the suppression of apoptosis.

Endangered whooping cranes (Grus americana) have been produced in captivity for reintroduction programs since the 1980s, using techniques such as artificial insemination, multiple clutching, and captive-rearing to speed recovery efforts. Chicks are often hand-reared (HR) by caretakers in crane costumes, socialized into groups and released together, unlike parent-reared (PR) cranes that are raised individually by a male/female crane pair and released singly. HR cranes historically exhibit greater morbidity rates during development than PR cranes, involving musculoskeletal and respiratory system disease, among others. We hypothesized that HR crane chicks exhibit a higher baseline fecal glucocorticoid metabolite (FGM) concentrations during the development compared with PR chicks. Fecal samples were collected between 15 and 70 days of age from HR (n = 15) and PR (n = 8) chicks to test for differences in FGM concentrations using a radioimmunoassay technique following ethanol extraction for steroids. Linear mixed model analysis suggests increasing age of the chick was associated with an increase in FGM (p < .001). Analysis also supported the interaction between rearing strategy and sex of the crane chick (p < .01). Female PR chicks had greater FGM concentrations than all other groups (PR male, p < .01; HR female, p < .001; and HR male, p < .001). This result suggests that there may be an effect of rearing strategy on stress physiology of whooping crane chicks, especially among females. Further research is needed to investigate whether the FGM concentrations are reflective of true differences in stress physiology of young cranes and whether this may impact health and conservation success., (© 2020 Wiley Periodicals, Inc.)

Background: Epidural steroid injection (ESI) is a common practice for pain treatment since 1953. In 2014, the FDA issued a warning about ESI. Studies have focused on the effect of the particle size and their ability to generate harmful aggregates. Although steroid aggregates provide longer times for reabsorption, therefore a longer anti-inflammatory effect, they are potentially harmful to the central nervous system via embolic mechanisms.Previous studies have established that steroidal aggregates with asizes over 100 mu m are potentially able to occlude blood vessels. Studies by Tiso et al and Benzon et al addressed the role of steroids on CNS adverse events, with similar outcomes. The main difference was on the role of aggregates with a size over 100 mu m, which Benzon et al. attributed to the ability of certain steroid preparations to rapidly precipitate and form large aggregates., Objectives: Studying the effect of the time elapsed between mixing the steroid preparation and injection on the number and size of aggregates with sizes above 100 mu m., Study Design: Original study in basic science., Setting: Basic scienceMETHODS: Steroids evaluated are commonly used in Spain for ESI: betamethasone, triamcinolone, and dexamethasone. The size and number of the aggregates was determined for undiluted commercial steroid preparations in the usual amount for a single and double dosage used for ESI.Samples were examined with a Leica TCS-SP2 microscope at the first, the fifth and the 30th minute after shaking the preparations. Aggregates observed in the different preparations were manually counted and grouped in the following size range: 0-20, 20-50, 50-100, 100-300, 300-500 and > 500 mu m.Statistical analysis was carried out using the R software. Nonparametric techniques were used in the comparison of aggregate size. Global comparison of the groups using the Kruskal-Wallis test and post-hoc comparisons using the Wilcoxon test, adjusting P-values by the Holm method for multiple comparisonsRESULTS: Aggregates present in triamcinolone and betamethasone samples were statistically larger than in dexamethasone samples. Triamcinolone suspensions produced significantly larger aggregates than betamethasone five minutes after mixing. Triamcinolone preparations produced greater particle aggregates (> 500 mu m), which were not present in dexamethasone and betamethasone preparations., Limitations: Study how the human internal factors like blood elements and spinal fluid could interact with steroids and influence the size of the aggregates formed., Conclusions: This study demonstrates that the size of the particles injected depends on the type of steroid and the time allowed between mixing and injecting. The results demonstrate that waiting longer than 5 minutes between mixing and injecting can predispose the formation of potentially harmful aggregates in triamcinolone and betamethasone samples. The presence of greater particle aggregates (> 500 mu m) may occlude some important vessels and arteries with serious adverse results. Vigorous shaking of the injectable could prevent such events., Key Words: Epidural steroid injection, triamcinolone, betamethasone, dexamethasone, steroid aggregates.

Objective: Compounded oral solutions for respiratory illnesses such as the common cold and cough are commonly prepared and dispensed by licensed pharmacists in the United States and Puerto Rico (PR). Standard protocols for their preparation and quality assessment and for patient counseling are available for most of the prescribed compounded solutions. However, in PR there is a common prescription approach colloquially referred to as "mezclitas": mixtures of antitussives, expectorants, decongestants, and other active ingredients available in commercial solutions for which there are no science-driven compounding guidelines for local pharmacists., Methods: This study evaluated the physicochemical stability of a commonly dispensed compounded preparation (containing guaifenesin, dextromethorphan, and dexamethasone) that is used for the treatment of respiratory illnesses in PR. The stability indicators tested included clarity, odor, pH, and viscosity. Changes in stability indicators were evaluated for different storage conditions (ambient temperature and refrigerated) over a period of 6 months., Results: The samples exhibited small changes in color, odor, and viscosity. Although the observed changes were small, they may be indicative of chemical and/or physical transformations that occurred over time. A survey of local pharmacists also evidenced the absence of standardized protocols for the preparation and dispensation of the mezclitas in PR., Conclusion: In spite of the absence of protocols for compounding oral solutions for respiratory illnesses, our study suggests that the stability of such solutions is not heavily compromised. However further chemical and physical testing is needed and the findings of such testing used to develop standardized protocols for the compounding of oral solutions for respiratory illnesses.

Synthetic glucocorticoids are generally preferred over their natural counterparts as these compounds exhibit improved anti-inflammatory potency and glucocorticoid receptor selectivity. However, the biotechnological production of these molecules is often subject to limitations inferred by restricted enzyme stability, selectivity or inhibition thereof. The latter is particularly important during 6α-methylprednisolone production, as the essential C21-hydroxylation of its precursor medrane appears to be hampered by product inhibition of the steroid-21-hydroxylase (CYP21A2). To circumvent this bottleneck, we established a two-step reaction for controlled mixed-culture fermentation, using recombinant E. coli. This process comprises the previously reported C21-hydroxylation of medrane by CYP21A2, followed by an instant derivatization of the hydroxylated product premedrol by chloramphenicol acetyl transferase 1 (CAT1). The CAT1-mediated C21-acetylation prevents the product from regaining access to the enzyme's active site which effectively shifts the chemical equilibrium toward premedrol formation. The successful circumvention of product inhibition at optimized conditions resulted in the formation of more than 1.5 g of product per liter which corresponds to an increase by more than 100 %. Taken together, we demonstrate an efficient system to enhance cytochrome P450-mediated biotransformations, holding great ecologic and economic potential to be applied in industrial processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Many of new chemical discovered in pharmaceutical industry are hydrophobic compounds. Various techniques have been used to overcome solubility problems of hydrophobic drugs in aqueous media. In the meantime, dendrimers have been considered for sustainability, nanoscale size, high carry capacity, tunable terminal functional groups in terms of drug delivery and solubility. In this work, we have synthesized poly(propylene imine) (PPI) dendrimer up to fifth generation using reduction of nitrile groups after Michael addition and also, polyamidoamine (PAMAM) dendrimer up to fourth generation using Michael addition and amidation reactions. fourth and fifth generations of PPI dendrimer and fourth and third generations of PAMAM dendrimer in different concentrations were used to evaluate the solubility of two hydrophobic drugs (tetracycline and dexamethasone). Furthermore, cytotoxicity of dendrimers and dendrimers/drugs hybrids was studied. The results showed that with increasing concentrations and also the generation of dendrimers, the solubility of these two hydrophobic drugs was increased. Cytotoxicity study through MTT assay against Osteoblast-like cell line (MG-63 cells) showed that dendrimers were relatively cytotoxic where adding dexamethasone caused higher cytotoxicity. However, tetracycline showed no significant effect on cytotoxicity whereas prevented cell proliferation., (© 2019 Wiley Periodicals, Inc.)

Introduction: Topical corticosteroids, available in an array of vehicles are used to control a variety of inflammatory skin diseases. Patients preferences for different vehicles may affect their willingness to use treatment. We assess corticosteroid vehicle preference and potential impact of topical characteristics on adherence and quality of life in patients with psoriasis. Methods: Subjects with psoriasis were recruited from Wake Forest University Dermatology Clinic. Subjects sampled desoximetasone 0.25% spray, betamethasone valerate 0.1% cream, triamcinolone acetonide 0.1% ointment, fluocinonide 0.05% gel, betamethasone valerate 0.1% lotion, clobetasol propionate 0.05% foam, and fluocinonide 0.05% solution in a predetermined randomized order. Subjects completed a Vehicle Preference Measure, Determinants of Adherence Measure, and a Determinants of Quality of Life Measure. Results: Patients preferences for the various products were highly variable. Regarding Determinants of Adherence, patients perception of absorption of the medication was ranked as 'quite important/extremely important' by 85% of total subjects. A majority of patients rated medication side effects as 'quite important/extremely important' when asked to consider topical characteristics effect on quality of life. Discussion: There was wide variation in patient preference for topical medication vehicles used for treating psoriasis. Several vehicle characteristics were considered important to adherence. Given the marked variation in vehicle preference, topical treatment should be individualized according to patients preferences.

Recurrence of glomerulonephritis is the third-leading cause of allograft loss. Graft loss due to IgA nephropathy occurs in 10% at 10-year follow-up. The NEFIGAN trial demonstrated that Target Release Formulation (TRF) of budesonide is a specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation with favorable safety profile. We are reporting a case of successful treatment of a patient with posttransplant IgA nephropathy with TRF of budesonide.

Background: Nonmedicinal ingredients in topical corticosteroids might exacerbate pre-existing conditions in patients with contact allergies. In Canada, no database exists to help the clinician identify rapidly the ingredients in a topical product. Thus, prescribing topical corticosteroids to patients with contact allergies represents a challenge., Objectives: This study aimed to identify potential allergens contained in topical corticosteroids available in Canada., Methods: Ingredients from 140 topical corticosteroids available in Canada were compiled. Ingredients with stronger allergenic potential were identified., Results: The most frequent potential allergens found in topical corticosteroids were propylene glycol (42.9%) and parabens (27.9%). Chlorocresol was listed in 11.4% of topical corticosteroids, mostly in high potency products. Formaldehyde releasers were also found in 7.1% of topical products., Conclusions: This study confirms that ingredients in topical corticosteroids may be the cause of recalcitrant dermatitis in certain patients with contact allergies. Prescribing an adapted topical corticosteroid to patients with allergies is primordial in order to ensure optimal care.

The threat of predation can cause increased adrenal secretion of glucocorticoids that, if sustained, can result in chronic stress that might predispose animals to disease, reduced growth, or poor fertility. Fecal glucocorticoid metabolite (FGM) concentrations were measured between September 2011 and July 2012 in two Montana bison ( Bison bison ) herds, one herd living with and the other without wolves ( Canis lupus ) in their habitat. The relevance of FGM concentrations (as measured by the corticosterone enzyme immunoassay) and a confirmation of an acute adrenal response was demonstrated by transient increases ( P <0.001) in FGM concentrations in bison herded through a chute system and following a wolf encounter. The FGM concentrations were higher in the herd with wolves than the herd without wolves overall ( P =0.045), but the monthly differences between the herds were inconsistent (magnitude=0.3-3.5 µg/g; P =0.011 month×herd). The herd with wolves had higher FGM in April, June, July, September, and November, but the herd without wolves had higher FGM in January, February, and May. Seasonal changes in FGM concentrations ( P <0.001) were measured across the year in both herds (magnitude=10.8 and 6.9 µg/g, respectively), exceeding any differences between herds potentially attributable to wolf presence. Concentrations of FGM were highest in April-July and were lowest in January-February. Evidence of a chronic stress response was not found, and increased disease susceptibility in the bison living with wolves seems unlikely.

Budesonide (BUD) is a low water soluble (S 0  = 5.028·10 -5  M) corticosteroid used as preferred therapy for the treatment of Eosinophilic Esophagitis (EoE), a chronic allergic-immune condition with an increased incidence in the paediatric population. Currently there are no commercial medicines indicated for EoE, and, therefore, in the hospital pharmacy the BUD is extemporaneously formulated as viscous oral suspension at the initial dose of 1-2 mg per day for children, highlighting the need of a mucoadhesive drug delivery system (MDDS) that adheres to the site of action and prolongs the therapeutic activity of the administered drug. Considering the ability of hydroxypropyl-β-cyclodextrin (HP-β-CD, 100 mM) to increase the water solubility of BUD (S HP - β -CD  = 4.3·10 -3  M; K 1:1  = 861.11 M -1 ), a mucoadhesive thiolated HP-β-CD (HP-β-CD-SH) was synthesized and characterized by mass spectroscopy, 1 H- and 13 C NMR techniques. Phase-solubility studies demonstrated the capability of HP-β-CD-SH (100 mM) to form a reversible water soluble inclusion complex with BUD (S HP- β -CD-SH  = 10.9·10 -3  M; K 1:1  = 2013.52 M -1 ), which increases its permanence on the target site as proved by mucoadhesive studies on porcine oesophagus mucosa. HP-β-CD-SH might be a useful MDDS for the pharmacist to prepare BUD oral liquid formulations at the recommended doses, with pH values below 5, which guarantee the chemical stability of the new mucoadhesive excipient., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Non-invasive measures of stress are crucial for captive and conservation management programs. The adrenal hormone dehydroepiandrosterone-sulfate (DHEAS) has recently been adopted as a stress marker, but there is little investigation of its relationship to glucocorticoids (GC), well-known indicators of stress. This study examined the influence of age, reproductive state and environment on GC and DHEAS levels in orangutans, to test whether the GC/DHEAS ratio can provide an index of stress response in primates. We measured fecal GC (fGC) and fecal DHEAS (fDHEAS) concentrations in 7 captive orangutans from zoological parks in Japan and 22 wild orangutans from Danum Valley Conservation Area, Malaysia. We found that in a stressful condition (transportation), fDHEAS levels increased 2 days after the fGC response, which occurred 1 day after the stressor. One pregnant female had elevated levels of both hormones, and a higher fGC/fDHEAS ratio than baseline. Females in the first year of lactation had fGC levels and the fGC/fDHEAS ratio significantly higher than both baseline and females in the second and subsequent years of lactation. There was no effect of age on fGC levels, but the fGC/fDHEAS ratio was higher in infants than adults and adolescents. fDHEAS concentrations were lower in infants than juveniles, adolescents and adults, a phenomenon known as adrenarche, shared with humans and other great apes. We suggest that changes in DHEAS during orangutan life history are associated with changes in the dynamics of maintaining homeostasis that vary with age and reproductive state. The GC/DHEAS ratio index is useful to evaluate age-related abilities of responding to stressful challenges.

Background: Prednisolone displays significant pharmacokinetic variability and exposure-outcome relationships in renal transplant recipients, suggesting a role for drug monitoring in some scenarios. It is highly protein-bound, and the free form is pharmacologically active but cumbersome to measure. Saliva concentrations might reflect free plasma prednisolone and present an alternative measurement. The aim of this study was to examine the correlation between total and free plasma and saliva prednisolone in adult renal transplant recipients., Methods: Total and free plasma and saliva prednisolone concentrations were measured in 20 patients receiving oral prednisolone 1-2 months after transplant, between pre-dose and 12 hours post-dose. Prednisolone was determined using high-performance liquid chromatography mass spectrometric detection. The Pearson coefficient was used to assess the association between plasma and salivary prednisolone concentrations and area under the concentration-time curves (AUC0-12)., Results: When considering all time points, the total and free plasma prednisolone concentrations correlated well (r = 0.81), but there was poor correlation between saliva and free (r = 0.003) and total (r = 0.01) plasma concentrations. When concentrations before the maximum free prednisolone plasma value were excluded, the correlation between free plasma and saliva concentrations improved (r = 0.57). There was a moderate correlation between free and total plasma prednisolone AUC0-12 (r = 0.62) using all time points, but a poor correlation between free and total plasma prednisolone AUC0-12 and saliva AUC0-12 (r = 0.07; r = 0.17)., Conclusions: Total and free plasma prednisolone measurements correlated poorly with saliva measurements; however, correlation improved when concentrations early in the dosing interval were excluded.

There is evidence that encapsulating glucocorticoids into nucleic acid-containing nanoparticles reduces the inflammatory toxicities of the nanoparticles. Herein, using betamethasone acetate (BA), a glucocorticoid, and a solid lipid nanoparticle formulation of siRNA, we confirmed that coencapsulating BA into the siRNA solid lipid nanoparticles significantly reduced the proinflammatory activity of the siRNA nanoparticles in a mouse model. Using TNF-α siRNA, we then showed that the BA and TNF-α siRNA coencapsulated into the solid lipid nanoparticles acted as a dual anti-inflammatory and synergistically reduced TNF-α release by mouse macrophages in culture following stimulation with lipopolysaccharide, as compared to solid lipid nanoparticles encapsulated with TNF-α siRNA or BA alone. Importantly, upon studying the effect of the ratio of BA and TNF-α siRNA on the proinflammatory activity of the resultant nanoparticles, we identified that BA and TNF-α siRNA coencapsulated solid lipid nanoparticles prepared with a BA to TNF-α siRNA weight ratio of 2:1 induced the lowest proinflammatory cytokine production by macrophages in culture. This result was in comparison to nanoparticles prepared with BA to TNF-α siRNA ratios both higher and lower than 2:1 (i.e., 4:1, 1:1, and 0.5:1) and is likely due to differences in molecular interactions among the various components in the BA and TNF-α-siRNA coencapsulated solid lipid nanoparticles at these ratios. Encapsulating glucocorticoids into siRNA-nanoparticles represents a viable strategy to reduce the proinflammatory activity of the nanoparticles; however, the ratio of the glucocorticoid to siRNA in the nanoparticles requires optimization.

The glucocorticoid resistance hereditary condition may emerge from the occurrence of point mutations in the glucocorticoid receptor (GR), which could impair its functionality. Because the main feature of such pathology is the resistance of the hypothalamic-pituitary-adrenal axis to the hormone cortisol, we used the GR ligand binding domain three-dimensional structure to perform computational analysis for eight variants known to cause this clinical condition (I559 N, V571A, D641V, G679S, F737L, I747 M, L753F and L773P), aiming to understand, on the atom scale, how they cause glucocorticoid resistance. We observed that the mutations generated a reduced affinity to cortisol and they alter some loop conformations, which could be a consequence from changes in protein motion, which in turn could result from the reduced stability of mutant GR structures. Therefore, the analyzed mutations compromise the GR ligand binding domain structure and cortisol binding, which could characterize the glucocorticoid resistance phenotype., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Glucocorticoids influence a wide array of metabolic, anti-inflammatory, immunosuppressive, and cognitive signaling processes, playing an important role in homeostasis and preservation of normal organ function. Synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the primary glucocorticoid in humans. Synthetic glucocorticoids are important pharmacological agents that augment the anti-inflammatory and immunosuppressive properties of endogenous cortisol and are widely used for the treatment of asthma, Crohn's disease, and rheumatoid arthritis, amongst other chronic conditions. The homeostatic activity of cortisol is disrupted by the administration of synthetic glucocorticoids and so there is interest in developing treatment options that minimize HPA axis disturbance while maintaining the pharmacological effects. Studies suggest that optimizing drug administration time can achieve this goal. The present review provides an overview of endogenous glucocorticoid activity and recent advances in treatment options that have further improved patient safety and efficacy with an emphasis on chronopharmacology., (Copyright © 2019. Published by Elsevier B.V.)

Glucocorticoids (GCs) are secreted into the blood by the adrenal glands and are also locally-produced by organs such as the lymphoid organs (bone marrow, thymus, and spleen). Corticosterone is the primary circulating GC in many species, including mice, rats and birds. Within lymphoid organs, corticosterone can be locally produced from the inactive metabolite, 11-dehydrocorticosterone (DHC). However, very little is known about endogenous DHC levels, and no immunoassays are currently available to measure DHC. Here, we developed an easy-to-use and inexpensive immunoassay to measure DHC that is accurate, precise, sensitive, and specific. The DHC immunoassay was validated in multiple ways, including comparison with a mass spectrometry assay. After assay validations, we demonstrated the usefulness of this immunoassay by measuring DHC (and corticosterone) in mice, rats and song sparrows. Overall, corticosterone levels were higher than DHC levels across species. In Study 1, using mice, we measured steroids in whole blood and lymphoid organs at postnatal day (PND) 5, PND23, and PND90. Corticosterone and DHC showed distinct tissue-specific patterns across development. In Studies 2 and 3, we measured circulating corticosterone and DHC in adult rats and song sparrows, before and after restraint stress. In rats and song sparrows, restraint stress rapidly increased circulating levels of both steroids. This novel DHC immunoassay revealed major changes in DHC concentrations during development and in response to stress, which have important implications for understanding GC physiology, effects of stress on immune function, and regulation of local GC levels., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Development of topically administered drug delivery systems for the treatment of ocular diseases have majorly focused on enhancing bioavailability of drugs in the ocular tissues. However, control of spatial distribution of topically administered drugs so as to restrict/avoid drug bioavailability at sensitive ocular tissues that are prone to drug induced adverse effects has not been explored. In this study, we aimed to reduce the bioavailability of topically administered corticosteroid, triamcinolone acetonide (TA) in lens via controlled spatial distribution in order to minimize TA induced posterior subcapsular cataract (PSC). For this, a negatively charged polymeric core-shell nanoparticulate drug delivery system composed of polycaprolactone (PCL) core and pluronic® F-68 (PF68) shell was fabricated. For in vivo studies, coumarin-6 (COU) loaded nanoparticles (NPs) were fabricated and studied for their biodistribution after topical administration in mice eyes and compared with free COU biodistribution. The administered COU loaded NPs differentially distributed in mice eyes and showed lower bioavailability in lens compared to free COU. Further, in vivo efficacy of the delivery system for its ability to minimize the rate of PSC progression was evaluated in diabetic rats. The results demonstrated that TA loaded PCL-PF68 NPs decreased PSC progression compared to free TA when administered topically., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well as act as transcorneal absorption promoters. In this study, a well-known aliphatic polyester, poly(1,4-butylene succinate) (PBS), was used as starting material to produce hydrophobic microfibrillar scaffolds by means of electrospinning technique. Plasma-assisted chemical surface functionalization of the PBS scaffolds with appropriate biopolymers (inulin, α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide, heparin) was carried out to confer to the final ocular inserts ad hoc properties as wettability, mucoadhesion and cytocompatibility on human corneal epithelial cells, by improving surface hydrophilicity without modifying the bulk properties of the material. The lipophilic drug triamcinolone acetonide was loaded into the obtained ocular insert and release studies were carried out to demonstrate the ability of drug loaded inserts to release the active until 30 days., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A reduction in the thermogenic activity of brown adipose tissue (BAT) is presently discussed as a possible determinant for the development of obesity in humans. One group of endogenous factors that could potentially affect BAT activity is the glucocorticoids (e.g. cortisol). We analyse here studies examining the effects of alterations in glucocorticoid signaling on BAT recruitment and thermogenic capacity. We find that irrespective of which manipulation of glucocorticoid signaling is examined, a seemingly homogeneous picture of lowered thermogenic capacity due to glucocorticoid stimulation is apparently obtained: e.g. lowered uncoupling protein 1 (UCP1) protein levels per mg protein, and an increased lipid accumulation in BAT. However, further analyses generally indicate that these effects result from a dilution effect rather than a true decrease in total capacity; the tissue may thus be said to be in a state of pseudo-atrophy. However, under conditions of very low physiological stimulation of BAT, glucocorticoids may truly inhibit Ucp1 gene expression and consequently lower total UCP1 protein levels, but the metabolic effects of this reduction are probably minor. It is thus unlikely that glucocorticoids affect organismal metabolism and induce the development of obesity through alterations of BAT activity., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We characterized behavioral and adrenocortical activities of Tamandua tetradactyla under human care driven by the hypothesis that they vary between males and females. We also assessed the potential association between natural or abnormal behaviors and adrenocortical activity. We kept females and males T. tetradactyla in individual, contiguous enclosures at Córdoba Zoo (Argentina), under natural photoperiod and temperature. During 29 consecutive days we monitored the animals' behavior by recording their activity pattern every 5 min using infrared cameras (8352 records/individual). We collected all feces and measured fecal glucocorticoid metabolites (FGM) with an 11-oxoaetiocholanolone enzyme immunoassay. We found individual differences in all behavioral variables. We detected that females exhibited lower total activity than males (23.8 ± 0.2% and 32.3 ± 0.3%, respectively; p = .005). Females were more active at night and males during the day (p < .05) and exhibited less abnormal behaviors than males (p = .05). Although we did not find sex-related differences for average FGM, we detected individual differences (p < .0001). We found that daily FGM showed negative (-0.39) and positive (0.38) correlations with natural and abnormal behaviors, respectively (p < .0001). Thus, we consider that individual input and sex are factors to be considered in stress responses of the species in captivity. Natural and abnormal behaviors may demand different levels of adrenocortical activity. Our findings may prove useful as normative data for ex situ management of conservation programs., (© 2019 Wiley Periodicals, Inc.)

The aim of the present study was to assess the potential of biocompatible polymeric nanosheets as topical and transdermal drug-delivery devices. Nanosheets are two-dimensional nanostructures with a thickness in the nanometer order, and their extremely large aspect ratios result in unique properties, including high transparency, flexibility, and adhesiveness. Nanosheet formulations containing betamethasone valerate (BV) as a model drug and consisting of poly (L-lactic acid) or poly (lactic-co-glycolic) acid were fabricated through a spin-coating-assisted layer-by-layer method using a water-soluble sacrificial membrane. The fabricated formulations could incorporate and release higher amounts of BV compared with a commercial ointment, and the amounts could be controlled by the polymers used, the amount of BV added, and the use of controlled-release membranes. The presence of BV had a minimal effect on thickness, transparency, adhesiveness, and moisture permeability of nanosheets, permitting their application to any area of skin for a long period of time. Therefore, this biocompatible polymeric nanosheet formulation represents a novel and promising topical and transdermal drug delivery device, which has potential to deliver drugs regardless of the area of skin., (Copyright © 2019 Elsevier B.V. All rights reserved.)