Association of seasonal changes in circulating cortisol concentrations with the expression of cortisol biosynthetic enzymes and a glucocorticoid receptor in the blubber of common bottlenose dolphin.

Cortisol is secreted from the adrenal cortex in response to stress, and its circulating levels are used as robust physiological indicators of stress intensity in various animals. Cortisol is also produced locally in adipose tissue by the conversion of steroid hormones such as cortisone, which is related to fat accumulation. Circulating cortisol levels, probably induced by cold stress, increase in cetaceans under cold conditions. However, whether cortisol production in subcutaneous adipose tissue is enhanced when fat accumulation is renewed during the cold season remains unclear. Therefore, in this study, we examine the effect of environmental temperature on the expression of cortisol synthesis-related enzymes and a glucocorticoid receptor in the subcutaneous fat (blubber) and explore the association between these expressions and fluctuations in circulating cortisol levels in common bottlenose dolphins (Tursiops truncatus). Skin biopsies were obtained seasonally from eight female dolphins, and seasonal differences in the expression of target genes in the blubber were analyzed. Blood samples were collected throughout the year, and cortisol levels were measured. We found that the expressions of cytochrome P450 family 21 subfamily A member 2 (CYP21A2) and nuclear receptor subfamily 3 group C member 1 (NR3C1), a glucocorticoid receptor, were increased in the cold season, and 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) showed a similar trend. Blood cortisol levels increased when the water temperature decreased. These results suggest that the conversion of 17-hydroxyprogesterone to cortisol via 11-deoxycortisol and/or of cortisone to cortisol is enhanced under cold conditions, and the physiological effects of cortisol in subcutaneous adipose tissue may contribute to on-site lipid accumulation and increase the circulating cortisol concentrations. The results obtained in this study highlight the role of cortisol in the regulation of the blubber that has developed to adapt to aquatic life.

11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene expression in muscle is linked to reduced skeletal muscle index in sarcopenic patients.

BACKGROUND: Glucocorticoids play a significant role in metabolic processes and pathways that impact muscle size, mass, and function. The expression of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) has been previously described as a major regulator of skeletal muscle function in glucocorticoid-induced muscle atrophy and aging humans. Our study aimed to investigate glucocorticoid metabolism, including the expression of HSD11B1 in skeletal muscle, in patients with sarcopenia. METHODS: Muscle biopsies were taken from the vastus lateralis muscle of thirty-three patients over 60 years of age with hip fractures. Sarcopenia status was assessed according to the criteria of the European Working Group on Sarcopenia in Older People 2. Skeletal muscle mass was measured by bioelectrical impedance analysis. Cortisol and cortisone concentrations were measured in serum. Gene expression analysis of HSD11B1, NR3C1, FBXO32, and TRIM63 in muscle biopsies was performed. Serial cross sections of skeletal muscle were labeled with myosin heavy chain slow (fiber type-1) and fast (fiber type-2) antibodies. RESULTS: The study included 33 patients (21 women) with a mean age of 82.5 ± 6.3 years, 17 patients revealed sarcopenic (n = 16 non-sarcopenic). Serum cortisone concentrations were negatively correlated with muscle mass (ß = - 0.425; p = 0.034) and type-2 fiber diameter (ß = - 0.591; p = 0.003). Gene expression of HSD11B1 (ß = - 0.673; p = 0.008) showed a negative correlation with muscle mass in the sarcopenic group. A significant correlation was found for the non-sarcopenic group for NR3C1 (ß = 0.548; p = 0.028) and muscle mass. CONCLUSION: These findings suggest a pathogenetic role of HSD11B1 in sarcopenic muscle.

Chronic exposure to cortisone induces thyroid endocrine disruption and retinal dysfunction in adult female zebrafish (Danio rerio).

Cortisone has a large content in rivers because of its wide range of medical applications and elimination by organisms that naturally secrete it. As a steroid hormone, cortisone is recognized as a novel endocrine disruptor. Although ecotoxicological effects of the reproductive endocrine system have mainly been reported recently, thyroid endocrine in fish remains relatively less understood. Here, adult female zebrafish were exposed to cortisone at 0.0 (control), 3.2, 38.7, and 326.9 ng/L for 60 days. Evidence in this study came from fish behavior, hormone levels, gene expression, histological and morphological examinations. The results showed that THs (thyroid hormone) level disruption and pathohistological changes occurred in the thyroid gland, which may account for the gene expression changes in the hypothalamus-pituitary-thyroid gland axis. Specifically, more conversion of T4 (thyroxine) to T3 (triiodothyronine) led to an increased TSH (thyroid stimulating hormone) level in plasma. Severe thyroid tissue damage mainly occurred in the zebrafish exposed to 326.9 ng/L of cortisone. Meanwhile, consistent with the THs trend, the fish locomotion activity displayed more anxiety and excitement, the partial blockage of GABA (γ - aminobutyric acid) synthetic pathway genes might be the explanation of the underlying mechanism. Cortisone affected the gene expressions in the visual cycle and the circadian rhythm network also suggested interactions between thyroid endocrine disruption, retinal dysfunction, and abnormal behaviors of zebrafish. In summary, these findings suggest chronic exposure to cortisone induced various adverse effects in adult female zebrafish, which may help us better understand the risk of cortisone to fish in the wild.

First in human randomised trial of J2H-1702: A novel 11ß-hydroxysteroid dehydrogenase type 1 inhibitor for non-alcoholic steatohepatitis treatment.

BACKGROUND: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which is an enzyme that converts cortisone to cortisol, plays a role in the regulation of glucose metabolism and inflammation. J2H-1702 is a novel 11ß-HSD1 inhibitor, and the inhibition of 11ß-HSD1 has been shown to improve insulin sensitivity, reduce inflammation, and prevent the development of nonalcoholic steatohepatitis (NASH) in preclinical models. AIMS: We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of J2H-1702 after a single-dose oral administration. METHODS: A randomised, double-blinded, placebo-controlled, single-dose, dose-escalation study was conducted on 50 healthy volunteers. Blood and urine samples were collected to assess the PK and PD of J2H-1702. RESULTS: The peak plasma concentration of J2H-1702 was observed at 2-2.9 h after a single-dose oral administration. J2H-1702 reduced 11ß-HSD1 activity compared to the placebo at all dose levels. The drug reached its maximal inhibitory effect within 12-24 h post-dose administration, and the inhibitory effect was maintained till 1 day after administration of the study drug. The drug showed typical first-order elimination kinetics, with a mean elimination half-life of 9.8-14.7 h. Systemic exposure to J2H-1702 increased in a dose-dependent manner. J2H-1702 was well tolerated after a single oral administration of up to 300 mg. A total of 11 treatment-emergent adverse events (TEAEs) occurred in seven (14%) participants, all of which were mild and resolved spontaneously. The most common TEAE was diarrhoea (8%), followed by dizziness (4%). CONCLUSIONS: The results of this study suggest that J2H-1702 could be developed as an effective therapeutic option for NASH.

Identification of cortisol metabolites with LC-MS/MS in plasma, skin mucus, bile and faeces for stress evaluation of farmed Atlantic salmon.

As a stress hormone, cortisol and more recently its metabolites are analysed when assessing fish stress and welfare status, although the exact identity of these metabolites is not clearly defined for the Atlantic salmon. LC-MS/MS techniques, owing to their specificity, sensitivity and ability to simultaneously identify and measure several relevant compounds, can be useful tools for this purpose. Using the guidelines provided by the European Decision no. 657/2002/EC for validation, the LC-MS/MS method presented here, can reliably identify and quantify cortisol and five of its metabolites (5ß-THF, cortisone, 5ß-DHE, 5ß-THE and ß-cortolone) in bile and faeces, and cortisol and cortisone in skin mucus and blood plasma of farmed Atlantic salmon within 15 min. Identified as the most predominant compound in faeces and bile, 5ß-THE is proposed as a candidate stress biomarker when using these matrices. A decision limit (CCα) below 5 ng/mL, a detection capability (CCß) and a limit of detection (LOD) below 10 ng/mL and a limit of quantitation (LOQ) below 30 ng/mL were typically obtained for most of the compounds. The concentrations of these compounds measured in either non-stressed or stressed fish were all above the CCα, CCß, LOD and the LOQ of the method. The latter consequently demonstrated significant difference in cortisol metabolites concentrations between the two groups of fish. The present study further demonstrates that pooling of samples from several individuals could provide reliable results for farmed fish stress evaluation, when sample materials are insufficient in terms of quantity.

Dysregulation of steroid metabolome in follicular fluid links phthalate exposure to diminished ovarian reserve of childbearing-age women.

The widespread use of phthalates (PAEs) has drawn increasing attention due to their endocrine disruption and reproductive toxicity, while the steroid metabolome is essential for follicular development. However, the mechanism by which PAE exposure affects ovarian reserve through the steroid metabolome remains unclear. This study recruited 264 childbearing-age women in Tianjin (China) from April 2019 to August 2020 in a cross-sectional design. Target metabolome analysis of 16 steroids was performed in follicular fluid (FF) to compare diminished ovarian reserve (DOR) against normal ovarian reserve (NOR) women and differential steroids were identified using binary logistic analyses. Further analysis of eleven PAE metabolites (mPAEs) in FF was conducted, and the retrieved oocyte number (RON) representing ovarian reserve was counted. Multiple linear regression and quantile-based g-computation (qgcomp) models were used to associate individual mPAEs and mPAE mixture with the DOR-related differential steroids in FF. Mediation analysis was used to discuss the mediating effect of DOR-related steroids on the association between mPAEs and RON. Androstenedione (A4), corticosterone (CORT), cortisol (COR) and cortisone were significantly down-regulated in FF from women with DOR. Nine mPAEs with detection frequencies greater than 60% and median concentrations of 0.02-4.86 ng/mL were incorporated into statistical models. Negative associations with COR and CORT were found for mono-ethyl phthalate (mEP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and mono-2-ethylhexyl phthalate (mEHP). A positive association with cortisone was found for mEOHP, mEHP, monobutyl phthalate (mBP), and mono (2-isobutyl) phthalate (miBP). The qgcomp and mediation analyses revealed that mEP and mEOHP not only significantly contributed to the decline of COR and CORT in the mixed exposure but also indirectly reduced RON through the mediating effects of COR and CORT. In conclusion, PAE exposure may decrease ovarian reserve by downregulating COR and CORT.

iTRAQ-Based Quantitative Proteomic Analysis of Arthrobacter simplex in Response to Cortisone Acetate and Its Mutants with Improved Δ1-Dehydrogenation Efficiency.

Arthrobacter simplex is extensively used for cortisone acetate (CA) biotransformation in industry, but the Δ1-dehydrogenation molecular fundamental remains unclear. Herein, the comparative proteome revealed several proteins with the potential role in this reaction, which were mainly involved in lipid or amino acid transport and metabolism, energy production and conversion, steroid degradation, and transporter. The influences of six proteins were further confirmed, where pps, MceGA, yrbE4AA, yrbE4BA, and hyp2 showed positive impacts, while hyp1 exhibited a negative effect. Additionally, KsdD5 behaved as the best catalytic enzyme. By the combined manipulation in multiple genes under the control of a stronger promoter, an optimal strain with better catalytic enzyme activity, substrate transportation, and cell stress tolerance was created. After biotechnology optimization, the production peak and productivity were, respectively, boosted by 4.1- and 4.0-fold relative to the initial level. Our work broadens the understanding of the Δ1-dehydrogenation mechanism, also providing effective strategies for excellent steroid-transforming strains.

Changes in serum cortisol levels after 10 days of overfeeding and fasting.

Chronic caloric deprivation and obesity are complicated by hypercortisolemia. The effects of acute overfeeding and fasting on circulating free cortisol levels and conversion of cortisone to free cortisol are unknown. We hypothesized that serum-free cortisol and free cortisol-to-cortisone ratio would increase after both overfeeding and fasting. This is a prospective study of 22 healthy volunteers who completed a 10-day high-calorie protocol followed by a 10-day fast, separated by a 2-wk washout. Morning free and total cortisol and free cortisone levels (LC/MS) were measured at baseline and after 10 days of each intervention. Both high-calorie feeding and fasting increased total and free cortisol and the free cortisol-to-free cortisone ratio (P = 0.001 to P = 0.046). There were sex interactions, with significant effects in men (P < 0.001), but not in women (P = 0.898 and 1.000, respectively) in subset analyses examining the effects of fasting on free cortisol and the free-to-total cortisol ratio. Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. Further study is warranted to determine whether elevated cortisol levels contribute to complications of starvation and obesity, such as bone fragility.NEW & NOTEWORTHY Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. The effect of fasting on free cortisol levels is modified by sex. Further study is needed to determine the mechanisms driving the increases in cortisol.

Utero-placental expression and functional implications of HSD11B1 and HSD11B2 in canine pregnancy†.

Glucocorticoids modulate the feto-maternal interface during the induction of parturition. In the dog, the prepartum rise of cortisol in the maternal circulation appears to be erratic, and information about its contribution to the prepartum luteolytic cascade is scarce. However, the local placental upregulation of glucocorticoid receptor (GR/NR3C1) at term led to the hypothesis that species-specific regulatory mechanisms might apply to the involvement of cortisol in canine parturition. Therefore, here, we assessed the canine uterine/utero-placental spatio-temporal expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1; reduces cortisone to cortisol), and -2 (HSD11B2; oxidizes cortisol to the inactive cortisone). Both enzymes were detectable throughout pregnancy. Their transcriptional levels were elevated following implantation, with a strong increase in HSD11B2 post-implantation (days 18-25 of pregnancy), and in HSD11B1 at mid-gestation (days 35-40) (P < 0.05). Interestingly, when compared pairwise, HSD11B2 transcripts were higher during post-implantation, whereas HSD11B1 dominated during mid-gestation and luteolysis (P < 0.05). A custom-made species-specific antibody generated against HSD11B2 confirmed its decreased expression at prepartum luteolysis. Moreover, in mid-pregnant dogs treated with aglepristone, HSD11B1 was significantly higher than -2 (P < 0.05). HSD11B2 (protein and transcript) was localized mostly in the syncytiotrophoblast, whereas HSD11B1 mRNA was mainly localized in cytotrophoblast cells. Finally, in a functional approach using placental microsomes, a reduced conversion capacity to deactivate cortisol into cortisone was observed during prepartum luteolysis, fitting well with the diminished HSD11B2 levels. In particular, the latter findings support the presence of local increased cortisol availability at term in the dog, contrasting with an enhanced inactivation of cortisol during early pregnancy.

Effects of the therapy shift from cortisone acetate to modified-release hydrocortisone in a group of patients with adrenal insufficiency.

Objective: Patients with adrenal insufficiency (AI) may be exposed to supraphysiological glucocorticoids levels during standard treatment with cortisone acetate (CA) or immediate-release hydrocortisone (IR-HC). Recent studies, predominantly including patients in IR-HC treatment, suggested that modified-release hydrocortisone (MRH) provide a more physiological cortisol rhythm, improving metabolic control and quality of life. Our primary aim was to assess clinical and biochemical modifications in patients shifted from CA to MRH. Design/Methods: We designed a retrospective longitudinal study, enrolling 45 AI patients (22 primary and 23 secondary AI) treated exclusively with CA thrice daily, shifted to MRH once daily; 29/45 patients concluded at least 18-months follow-up (MRH-group). We recruited 35 AI patients continuing CA as a control group (CA-group). Biochemical and clinical data, including metabolic parameters, bone quality, and symptoms of under- or overtreatment were collected. In 24 patients, a daily salivary cortisol curve (SCC) performed before and one month after shifting to MRH was compared to healthy subjects (HS). Results: No significant changes in glycometabolic and bone parameters were observed both in MRH and CA-groups during a median follow-up of 35 months. A more frequent decrease in blood pressure values (23.1% vs 2.8%, p=0.04) and improvement of under- or overtreatment symptoms were observed in MRH vs CA-group. The SCC showed a significant steroid overexposure in both CA and MRH-groups compared to HS [AUC (area under the curve) = 74.4 ± 38.1 nmol×hr/L and 94.6 ± 62.5 nmol×hr/L respectively, vs 44.1 ± 8.4 nmol×hr/L, p<0.01 for both comparisons], although SCC profile was more similar to HS in MRH-group. Conclusions: In our experience, patients shifted from CA to equivalent doses of MRH do not show significant glycometabolic modifications but blood pressure control and symptoms of over-or undertreatment may improve. The lack of amelioration in glucose metabolism and total cortisol daily exposure could suggest the need for a dose reduction when shifting from CA to MRH, due to their different pharmacokinetics.

Chronic stress causes cortisol, cortisone and DHEA elevations in scales but not serum in rainbow trout.

Fish scales have been reported to incorporate cortisol over long periods of time and thus provide a promising means of assessing long-term stress in many species of teleost fish. However, the quantification of other stress related hormones has only been accomplished in our previous study conducted in goldfish (Carassius auratus). DHEA is a precursory androgen with anti-stress effects used alongside cortisol to diagnose chronic stress via the cortisol:DHEA ratio in mammals. Included in DHEA's anti-stress mechanisms are changes in the metabolism of cortisol to its inactive metabolite cortisone suggesting the relationships between cortisol, DHEA and cortisone may be additionally informative in the assessment of long-term stress. Therefore, to further explore these concepts in a native fish species and generate more comprehensive comparisons between scale and serum hormone concentrations than was possible in our previous study we implemented a 14-day stress protocol in adult rainbow trout (Oncorhynchus mykiss) and quantified resulting scale and serum cortisol, cortisone and DHEA concentrations. As predicted, elevations in scale concentrations of all hormones were observed in stressed trout compared to controls but were not reflected in serum samples. Significant differences in the cortisol:DHEA and cortisone:cortisol ratios were also found between control and stressed group scales but not serum. These results suggest not only that scales provide a superior medium for the assessment of long-term stress but also that the addition of scale cortisone and DHEA may provide additional relevant information for such assessments.

Alteration in glucocorticoids secretion and metabolism in patients affected by cystic fibrosis.

Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11ß-hydroxysteroid dehydrogenase type 2, 5α- and 5ß-reductases. In contrast, the activity of 11ß-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11ß-hydroxyandrosterone/11ß-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11ßHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.

Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

25-Hydroxyvitamin D Increases Insulin-Stimulated Glucose Uptake by Enhancing Adipocyte Differentiation.

Vitamin D and its receptor (vitamin D receptor; VDR) regulate calcium homeostasis in mammals. Recently, studies have shown that serum concentrations of 25-hydroxyvitamin D (25VD) are negatively associated with insulin resistance and the incidence of type 2 diabetes. In adipose tissues, glucose transporter 4 (GLUT4) contributes to insulin-stimulated glucose uptake; however, the effect of 25VD on glucose uptake in adipocytes remains unclear. We examined the role of 25VD in glucose uptake and the differentiation of adipose-derived stromal cells. Insulin-stimulated glucose uptake in adipocytes was increased by treatment with 25VD and decreased by VDR knockdown. The expression levels of GLUT4 were upregulated by 25VD treatment. 25VD exposure increased the expression of adipocyte differentiation-related genes including peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding proteins through VDR, thereby enhancing the formation of mature adipocytes. Moreover, 25VD increased the expression levels of 11ß-hydroxysteroid dehydrogenase 1 (HSD11B1), which catalyzes the conversion of cortisone to cortisol in a concentration-dependent manner. 25VD-stimulated adipocyte differentiation was suppressed by HSD11B1 knockdown. Cortisone together with 25VD enhanced adipocyte differentiation, whereas synthesized glucocorticoid dexamethasone-induced adipocyte differentiation is not promoted by 25VD. Overall, these results indicate that 25VD stimulates adipocyte differentiation through the induction of HSD11B1 expression, leading to increased insulin-induced glucose uptake in adipocytes.

Percutaneous absorption of steroids from finite doses: Predicting urinary excretion from in vitro skin permeation testing.

Pharmacokinetic (PK) models are widely used to describe drug permeation across the epidermal membrane barrier, the stratum corneum (SC). Here, we extend our previously reported diffusion and compartment-in-series models to describe plasma concentrations, urinary excretion-time profiles and exposure estimates after topically applied finite doses of solvent deposited solids. In vivo models were derived by convolution of a skin absorption input function for finite dosing with that for in vivo disposition PK. In vitro skin permeation test (IVPT) and in vivo urinary excretion data for cortisone, desoxycorticosterone, and testosterone were extracted from literature for model validation and establishment of in vitro - in vivo relationships (IVIVR). Both SC diffusion and SC 3-compartment-in-series PK models adequately described experimental in vitro and in vivo permeation data, with similar model parameter estimates for SC diffusion time and bioavailability. A satisfactory IVIVR was generated for cortisone, whereas testosterone and desoxycorticosterone showed higher bioavailability in vitro compared to in vivo. In recognising that future prospective studies need to both have an adequate sampling schedule and be harmonized for robust IVIVRs, we developed expressions for predicting extent of absorption and time for peak absorption for both in vitro and in vivo studies. Other study parameters, such as application site, applied dose, and application techniques, can also affect drug permeability through skin during dosage form metamorphosis after finite dose application, and a lack of correlation may result if these are poorly matched.

Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics, leading to cell death.

Stress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca alkaloid family, which dismantle the microtubule network, affects SG assembly and disassembly pathways and influences cell viability in cancer cells and human-derived organoids. Cortisone augmented SG formation when combined with vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, VRB and cortisone signaled through the integrated stress response mediated by eIF2α (also known as EIF2S1), yet induced different kinases, with cortisone activating the GCN2 kinase (also known as EIF2AK4). Cortisone increased VRB-induced cell death and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by the core SG proteins G3BP1 and G3BP2. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity.

The effects of music listening on somatic symptoms and stress markers in the everyday life of women with somatic complaints and depression.

Despite a growing body of literature documenting the health-beneficial effects of music, empirical research on the effects of music listening in individuals with psychosomatic disorders is scarce. Using an ambulatory assessment design, we tested whether music listening predicts changes in somatic symptoms, subjective, and biological stress levels, and examined potential mediating processes, in the everyday life of 58 women (M = 27.7 years) with somatic symptom disorder (SSD) and depressive disorders (DEP). Multilevel models revealed that music listening predicted lower subjective stress ratings (p ≤ 0.02) irrespective of mental health condition, which, in turn, predicted lower somatic symptoms (p ≤ 0.03). Moreover, specific music characteristics modulated somatic symptoms (p = 0.01) and autonomic activity (p = 0.03). These findings suggest that music listening might mitigate somatic symptoms predominantly via a reduction in subjective stress in women with SSD and DEP and further inform the development of targeted music interventions applicable in everyday life.

Altered Cortisol Metabolism Increases Nocturnal Cortisol Bioavailability in Prepubertal Children With Type 1 Diabetes Mellitus.

Objective: Disturbances in the activity of the hypothalamus-pituitary-adrenal axis could lead to functional alterations in the brain of diabetes patients. In a later perspective of investigating the link between the activity of the hypothalamus-pituitary-adrenal axis and the developing brain in children with diabetes, we assessed here nocturnal cortisol metabolism in prepubertal children with type 1 diabetes mellitus (T1DM). Methods: Prepubertal patients (aged 6-12 years) diagnosed with T1DM at least 1 year previously were recruited, along with matched controls. Nocturnal urine samples were collected, with saliva samples taken at awakening and 30 minutes after awakening. All samples were collected at home over 5 consecutive days with no detectable nocturnal hypoglycaemia. The State-Trait Anxiety Inventory (trait scale only) and Child Depression Inventory were also completed. Glucocorticoid metabolites in the urine, salivary cortisol (sF) and cortisone (sE) were measured by liquid chromatography-tandem mass spectrometry. Metabolic data were analysed by logistic regression, adjusting for sex, age, BMI and trait anxiety score. Results: Urine glucocorticoid metabolites were significantly lower in T1DM patients compared to controls. 11ß-hydroxysteroid dehydrogenase type 1 activity was significantly higher, while 11ß-hydroxysteroid dehydrogenase type 2, 5(α+ß)-reductase and 5α-reductase levels were all lower, in T1DM patients compared to controls. There was a significant group difference in delta sE level but not in delta sF level between the time of awakening and 30 minutes thereafter. Conclusions: Our findings suggest that altered nocturnal cortisol metabolism and morning HPA axis hyperactivity in children with T1DM leads to greater cortisol bioavailability and lower cortisol production as a compensatory effect. This altered nocturnal glucocorticoid metabolism when cortisol production is physiologically reduced and this HPA axis hyperactivity question their impact on brain functioning.

Perinatal determinants of neonatal hair glucocorticoid concentrations.

Adult hair glucocorticoid concentrations reflect months of hypothalamic-pituitary-adrenal axis activity. However, little is known about the determinants of neonatal hair glucocorticoids. We tested associations between perinatal exposures and neonatal hair glucocorticoids. Cortisol and cortisone were measured by LC-MS/MS in paired maternal and infant hair samples collected within 10 days of birth (n = 49 term, n = 47 preterm), with neonatal samples collected at 6-weeks in n = 54 preterm infants. We demonstrate cortisol accumulation in hair increases with fetal maturity, with hair cortisol being higher in term than preterm born infants after delivery (median 401 vs 106 pg/mg; p < 0.001). In term born infants, neonatal hair cortisol is positively associated with maternal hair cortisol concentration (ß = 0.240, p = 0.045) and negatively associated with birthweight z-score (ß = -0.340, p = 0.006). Additionally, being born without maternal labour is associated with lower hair cortisol concentrations (ß = -0.489, p < 0.001) and a lower ratio of cortisol to cortisone (ß = -0.484, p = 0.001). In preterm infants, histological chorioamnionitis is associated with a higher cortisol to cortisone ratio in hair (ß = 0.459, p = 0.001). In samples collected 6 weeks after preterm birth, hair cortisol concentration is associated with cortisol hair concentrations measured after birth (ß = 0.523, p < 0.001), chorioamnionitis (ß = 0.250, p = 0.049) and postnatal exposures including intravenous hydrocortisone therapy (ß = 0.343, p < 0.007) and neonatal sepsis (ß = 0.290, p = 0.017). In summary, neonatal hair cortisol is associated with birth gestation, maternal hair cortisol concentration and fetal growth. Additionally, exposures at delivery are important determinants of hair cortisol, and should be considered in the design of future research investigating how neonatal hair cortisol relates to prenatal exposures or fetal development.

Synergistic integration of dihydro-artemisinin with γ-aminobutyric acid results in a more potential anti-depressant.

Three hybrids of dihydro-artemisinin (DHA) with ß-aminopropionic acid, γ-aminobutyric acid, and histamine have been designed and synthesized. The conjugate of DHA with GABA labelled as 5b was confirmed the most active candidate against both Cort- and SNP-induced PC12 cell impairments with EC50 value of 8.04 ± 0.35, and 9.38 ± 0.56 µM, respectively. 5b was clearly highlighted as a good modulator on protein expression of Akt, Bcl-2, and Bax, indicating its functions against programmed cell apoptosis. 5b significantly reversed the Cort-induced excessive calcium influx and release from internal organelles. It was demonstrated the ability to express increased levels of ß-tubulin III and to up-regulate phosphorylation level of cAMP response element-binding protein (CREB), leading to cell differentiation. It can penetrate blood - brain barrier (BBB) with propriate stability. Altogether, these data strongly support that 5b is a potential anti-depressant.