Chitosan/Pomegranate Seed Oil Emulgel Composition as a New Strategy for Dermal Delivery of Hydrocortisone.

Multifunctional delivery systems capable of modulating drug release and exerting adjunctive pharmacological activity have attracted particular attention. Chitosan (CS) and pomegranate seed oil (PO) appear to be attractive bioactive components framing the strategy of complex therapy and multifunctional drug carriers. This research is aimed at evaluating the potential of CS in combination with PO in studies on topical emulgels containing hydrocortisone as a model anti-inflammatory agent. Its particular goal was to distinguish alterations in anti-inflammatory action followed with drug dissolution or penetrative behavior between the designed formulations that differ in CS/PO weight ratio. All formulations favored hydrocortisone release with up to a two-fold increase in the drug dissolution rate within first 5 h as compared to conventional topical preparations. The clear effect of CS/PO on the emulgel biological performance was observed, and CS was found to be prerequisite for the modulation of hydrocortisone absorption and accumulation. In turn, a greater amount of PO played the predominant role in the inhibition of hyaluronidase activity and enhanced the anti-inflammatory effect of preparation E-3. Emulgels showed a negligible reduction in mouse fibroblasts' L929 cell viability, confirming their non-irritancy with skin cells. Overall, the designed formulation with a CS/PO ratio of 6:4 appeared to be the most promising topical carrier for the effective treatment of inflammatory skin diseases among the tested subjects.

Oxidative Stress Induced by Cortisol in Human Platelets.

Hypercortisolism is known to affect platelet function. However, few studies have approached the effect of exogenous cortisol on human platelets, and the results obtained are conflicting and unconvincing. In this study, the effect of exogenous cortisol on several parameters indicative of oxidative status in human platelets has been analysed. We have found that cortisol stimulates ROS production, superoxide anion formation, and lipid peroxidation, with these parameters being in strict correlation. In addition, cortisol decreases GSH and membrane SH-group content, evidencing that the hormone potentiates oxidative stress, depleting platelet antioxidant defence. The involvement of src, syk, PI3K, and AKT enzymes in oxidative mechanisms induced by cortisol is shown. The main sources of ROS in cells can include uncontrolled increase of NADPH oxidase activity and uncoupled aerobic respiration during oxidative phosphorylation. Both mechanisms seem to be involved in ROS formation induced by cortisol, as the NADPH oxidase 1 inhibitor 2(trifluoromethyl)phenothiazine, and rotenone and antimycin A, complex I and III inhibitor, respectively, significantly reduce oxidative stress. On the contrary, the NADPH oxidase inhibitor gp91ds-tat, malate and NaCN, complex II and IV inhibitor, respectively, have a minor effect. It is likely that, in human platelets, oxidative stress induced by cortisol can be associated with venous and arterial thrombosis, greatly contributing to cardiovascular diseases.

Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish.

Introduction: Stress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response. Methods: In common carp (Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ - the head kidney. The potential involvement of CXC receptors and stress hormone receptors in stress-induced neutrophil redistribution was determined by an in vivo study with selective CXCR inhibitors and antagonists of the receptors involved in stress regulation: glucocorticoid/mineralocorticoid receptors (GRs/MRs), adrenergic receptors (ADRs) and the melanocortin 2 receptor (MC2R). Results: The stress-induced increase of blood neutrophils was accompanied by a neutrophil decrease in the hematopoietic organs. This increase was cortisol-induced and GR-dependent. Moreover, stress upregulated the expression of genes encoding CXCL12 and CXCL8 chemokines, their receptors, and the receptor for granulocytes colony-stimulation factor (GCSFR) and matrix metalloproteinase 9 (MMP9). Blocking of the CXCR4 and CXCR1 and 2 receptors with selective inhibitors inhibited the stress-induced neutrophil redistribution and affected the expression of genes encoding CXC chemokines and CXCRs as well as GCSFR and MMP9. Discussion: Our data demonstrate that acute stress leads to the mobilization of the immune system, characterized by neutrophilia. CXC chemokines and CXC receptors are involved in this stress-induced redistribution of neutrophils from the hematopoietic tissue into the peripheral blood. This phenomenon is directly regulated by interactions between cortisol and the GR/MR. Considering the pivotal importance of neutrophilic granulocytes in the first line of defense, this knowledge is important for aquaculture, but will also contribute to the mechanisms involved in the stress-induced perturbation in neutrophil redistribution as often observed in clinical practice.

JM-20 potently prevents the onset of caffeine-induced anxiogenic phenotypes in zebrafish (Danio rerio).

Anxiety is among the most prevalent mental disorders present in the general population. Benzodiazepines are the most commonly prescribed drugs for the treatment of anxiety. Using zebrafish as a model organism, we investigated the anxiolytic activity of JM-20, a novel hybrid molecule with a 1,5-benzodiazepine ring fused to a dihydropyridine moiety. Firstly, we carried out some assays to analyze the possible toxicity mediated by JM-20. For this, zebrafish were exposed to different JM-20 concentrations (0-5 µM) for 96 h. Then, using the novel tank test, we evaluated both locomotor and anxiety-like behavior of the animals. Furthermore, brain, liver and plasma were removed to assess toxicity parameters. JM-20 exposure did not cause changes on novel tank, and also did not alter brain viability, hepatic LDH and plasma ALT levels. Afterward, we investigated whether a pre-exposure to JM-20 would prevent the anxiogenic effect evoked by caffeine. In the novel tank test, caffeine significantly decreased the time spent at the top, as well as the number of transitions to the top area. Moreover, caffeine decreased both the total and average time spent in the lit area, as well as increased the number of risk episodes evaluated by the light-dark test. Whole-body cortisol levels were also increased by caffeine exposure. Interestingly, pre-treatment with JM-20 abolished all alterations induced by caffeine. The anxiolytic effect profile of JM-20 was similar to those found for diazepam (positive control). Our findings show, for the first time, the anxiolytic effect of JM-20 in zebrafish, and its relationship with cortisol regulation.

Hydrocortisone cardioprotection in ischaemia/reperfusion injury involves antioxidant mechanisms.

BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids. AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress. MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis. RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI. CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.

Effects of pre-winter cortisol exposure on condition, diet, and morphology of wild juvenile brown trout (Salmo trutta).

Winter is an energetically challenging period for many animals in temperate regions because of the relatively harsh environmental conditions and reduction in food availability during this season. Moreover, stressors experienced by individuals in the fall can affect their subsequent foraging strategy and energy stores after exposure has ended, referred to as carryover effects. We used exogenous cortisol manipulation of wild juvenile brown trout (Salmo trutta) in the fall to simulate a physiological stress response and then investigated short-term (2 weeks) and long-term (4 months) effects on condition metrics (hepatosomatic index and water muscle content), diet (stomach contents and stable isotopes), and morphology during growth in freshwater. We revealed some short-term impacts, likely due to handling stress, and long-term (seasonal) changes in diet, likely reflecting prey availability. Unfortunately, we had very few recaptures of cortisol-treated fish at long-term sampling, limiting detailed analysis about cortisol effects at that time point. Nonetheless, the fish that were sampled showed elevated stable isotopes, suggestive of a cortisol effect long after exposure. This is one of few studies to investigate whether cortisol influences foraging and morphology during juvenile growth, thus extending the knowledge of proximate mechanisms influencing ecologically-relevant phenotypes.

Cortisol enhances aerobic metabolism and locomotor performance during the transition to land in an amphibious fish.

Amphibious fishes on land encounter higher oxygen (O2) availability and novel energetic demands, which impacts metabolism. Previous work on the amphibious mangrove killifish (Kryptolebias marmoratus) has shown that cortisol becomes elevated in response to air exposure, suggesting a possible role in regulating metabolism as fish move into terrestrial environments. We tested the hypothesis that cortisol is the mechanism by which oxidative processes are upregulated during the transition to land in amphibious fishes. We used two groups of fish, treated fish (+metyrapone, a cortisol synthesis inhibitor) and control (-metyrapone), to determine the impact of cortisol during air exposure (0 and 1 h, 7 days) on O2 consumption, terrestrial locomotion, the phenotype of red skeletal muscle, and muscle lipid concentration. Metyrapone-treated fish had an attenuated elevation in O2 consumption rate during the water to air transition and an immediate reduction in terrestrial exercise performance relative to control fish. In contrast, we found no short- (0 h) or long-term (7 days) differences between treatments in the oxidative phenotype of red muscles, nor in muscle lipid concentrations. Our results suggest that cortisol stimulates the necessary increase in aerobic metabolism needed to fuel the physiological changes that amphibious fishes undergo during the acclimation to air, although further studies are required to determine specific mechanisms of cortisol regulation.

Cardioprotective Effect of 2-Ethyl-3-Hydroxy-6-Methylpyridinium 2-Nitroxysuccinate Against Adrenaline/Hydrocortisone-Induced Myocardial Ischemia in Mice: Modulation of Free-Radical Processes in Biomembranes and Monoamine Oxidase A Activity.

Oxidative stress (OS) plays a key role in the development of cardiovascular diseases (CVD) in three major ways: reactive oxygen species (ROS)-induced reduction of nitric oxide (NO) bioavailability, ROS-induced inflammation and ROS-induced mitochondrial dysfunction. Oxidation of lipid molecules under the action of ROS leads to damage to membrane structures, changes the functioning of membrane-bound enzymes, and impairs membrane permeability and stability. An increase in OS results in the occurrence of endothelial dysfunction and drug tolerance, side effects, requiring discontinuation of drugs. All of these are significant problems of cardiotherapy. Therefore, the search for new alternative NO donors continues. The present research was aimed at studying the protective effect of 2-ethyl-3-hydroxy-6-methylpyridinium 2-nitroxysuccinate (NS) on the cardiovascular system on mouse myocardial ischemia (MI) model. The NS hybrid molecule includes a synthetic vitamin B6 analog 2-ethyl-3-hydroxy-6-methylpyridine (an antioxidant) and 2-nitroxysuccinic acid (a source of nitric oxide). Using the electron paramagnetic resonance (EPR) method and biochemical methods, we showed that the pronounced ability of NS to release NO is favorably combines with the capacity to prevent OS due to mechanisms such as suppression of the lipid peroxidation (LPO) process, antiradical activity and inhibition of the mitochondrial membrane-bound monoamine oxidase A (MAO-A). Using histological methods, we established that the administration of NS (10 mg/kg, i.p.) reduces the number of ischemic fibers and protects cardiomyocytes against ischemia injury. Thus, the complex protective effect allows us to consider NS as an alternative NO donor and a candidate for the development of a new pharmaceutical agent for the treatment of CVD.

Effects of Cortisol Administration on Resting-State Functional Connectivity in Women with Depression.

Previous resting-state functional connectivity (rsFC) research has identified several brain networks impacted by depression and cortisol, including default mode (DMN), frontoparietal (FPN), and salience networks (SN). In the present study, we examined the effects of cortisol administration on rsFC of these networks in individuals varying in depression history and severity. We collected resting-state fMRI scans and self-reported depression symptom severity for 74 women with and without a history of depression after cortisol and placebo administration using a double-blind, crossover design. We conducted seed-based rsFC analyses for DMN, FPN, and SN seeds to examine rsFC changes after cortisol vs. placebo administration in relation to depression history group and severity. Results revealed a main effect of depression group, with lower left amygdala (SN)-middle temporal gyrus connectivity in women with a history of depression. Cortisol administration increased insula (SN)-inferior frontal gyrus and superior temporal gyrus connectivity. We also found that greater depression severity was associated with increased PCC (DMN)-cerebellum connectivity after cortisol. These results did not survive Bonferroni correction for seed ROIs and should be interpreted with caution. Our findings indicate that acute cortisol elevation may normalize aberrant connectivity of DMN and SN regions, which could help inform clinical treatments for depression.

Effects of menstrual cycle phase and ovulation on the salivary cortisol awakening response.

The cortisol awakening response (CAR) is influenced by several state and trait variables, one of which might be the menstrual cycle in women. Previous results suggested that the CAR is enhanced around ovulation, which is why it has been recommended to avoid sampling during the ovulatory phase. In two separate studies, we aimed to replicate previous findings that reported the CAR's modulation across the menstrual cycle, especially during ovulation. In Study 1, a group of 27 healthy naturally cycling women collected saliva at 0, 30, 45, and 60 min post-awakening on two days during their follicular, ovulatory, and luteal phases in a repeated measures design. In Study 2, CAR samples were collected from 30 healthy naturally cycling women on seven consecutive days around the expected ovulation. To increase reliability of CAR measurements, participants' compliance of saliva sampling times was monitored, ovarian steroids (estradiol and progesterone) were collected, and ovulation was confirmed with specific test kits. Contrary to our expectations, we detected no differences in the CAR over the menstrual cycle, and no significant association with variations in estradiol and progesterone. In addition, we excluded confounding effects such as compliance and validated the cycle phase. These results suggest that the CAR is largely robust against hormonal variations across the menstrual cycle, including the mid-cycle phase around ovulation. However, further research is needed to understand the potential ovarian steroid-induced modulation of HPA axis functioning and the menstrual cycle's effects on salivary cortisol levels in psychobiological studies.

Effect of oral melatonin treatment on insulin resistance and diurnal blood pressure variability in night shift workers. A double-blind, randomized, placebo-controlled study.

BACKGROUND: Night shift work is associated with sleep disturbances, obesity, and cardiometabolic diseases. Disruption of the circadian clock system has been suggested to be an independent cause of type 2 diabetes and cardiovascular disease in shift workers. We aimed to improve alignment of circadian timing with social and environmental factors with administration of melatonin. METHODS: In a randomized, placebo-controlled, prospective study, we analysed the effects of 2 mg of sustained-release melatonin versus placebo on glucose tolerance, insulin resistance indices, sleep quality, circadian profiles of plasma melatonin and cortisol, and diurnal blood pressure profiles in 24 rotating night shift workers during 12 weeks of treatment, followed by 12 weeks of wash-out. In a novel design, the time of melatonin administration (at night or in the morning) depended upon the shift schedule. We also compared the baseline profiles of the night shift (NS) workers with 12 healthy non-night shift (NNS)-working controls. RESULTS: We found significantly impaired indices of insulin resistance at baseline in NS versus NNS (p < 0.05), but no differences in oral glucose tolerance tests nor in the diurnal profiles of melatonin, cortisol, or blood pressure. Twelve weeks of melatonin treatment did not significantly improve insulin resistance, nor did it significantly affect diurnal blood pressure or melatonin and cortisol profiles. Melatonin administration, however, caused a significant improvement in sleep quality which was significantly impaired in NS versus NNS at baseline (p < 0.001). CONCLUSIONS: Rotating night shift work causes mild-to-moderate impairment of sleep quality and insulin resistance. Melatonin treatment at bedtime improves sleep quality, but does not significantly affect insulin resistance in rotating night shift workers after 12 weeks of administration.

Glucocorticoids with or without fludrocortisone in septic shock: a narrative review from a biochemical and molecular perspective.

Two randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies.

Cortisol Sensitizes Cochlear Hair Cells to Gentamicin Ototoxicity Via Endogenous Apoptotic Pathway.

BACKGROUND: The widespread use of aminoglycosides is a prevalent cause of sensorineural hearing loss. Patients receiving aminoglycosides usually have elevated levels of circulating stress hormones due to disease or physiological stress; however, whether the stress hormone cortisol impacts aminoglycoside-mediated injury of cochlear hair cells has not been fully investigated. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells with or without cortisol pretreatment were exposed to gentamicin, we investigated the effect of cortisol pretreatment on gentamicin ototoxicity by assessing cell viability. Molecular pathogenesis was explored by detecting apoptosis and oxidative stress. Meanwhile, by inhibiting glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), the potential roles of receptor types in cortisol-mediated sensitization were evaluated. RESULTS: Cortisol concentrations below 75 µmol/l did not affect cell viability. However, pretreatment with 50 µmol/l cortisol for 24 hours sensitized hair cells to gentamicin-induced apoptosis. Further mechanistic studies revealed that cortisol significantly increased hair cell apoptosis and oxidative stress, and altered apoptosis-related protein expressions induced by gentamicin. In addition, blockade of either GR or MR attenuated cortisol-induced hair cell sensitization to gentamicin toxicity. CONCLUSION: Cortisol pretreatment increased mammalian hair cell susceptibility to gentamicin toxicity. Sensitization was related to the activation of the intrinsic apoptotic pathway and excessive generation of reactive oxygen species. Cortisol may exacerbate aminoglycoside ototoxicity.

Clotrimazole ameliorates chronic mild stress-induced depressive-like behavior in rats; crosstalk between the HPA, NLRP3 inflammasome, and Wnt/ß-catenin pathways.

Depression is a major emotional disorder that has a detrimental effect on quality of life. The chronic mild stress (CMS)-depression model was adopted in rats to evaluate the neurotherapeutic effect of Clotrimazole (CLO) and investigate the possible mechanisms of its antidepressant action via its impact on the hypothalamic pituitary adrenal (HPA) axis and the stress hormone, cortisol. It was found that azole antifungals affect steroidogenesis and the HPA axis. Behavioral, histopathological, inflammatory, and apoptotic pathways were assessed. Serum cortisol, inflammasome biomarkers, hippocampal NLRP3, caspase-1, and IL-18, and the canonical Wnt/ß-catenin neurogenesis biomarkers, Wnt3a, and non-phosphorylated ß-catenin levels were also determined. Different stressors were applied for 28 days to produce depressive-like symptoms, and CLO was administered at a daily dose of 30 mg/kg body weight. Subsequently, behavioral and biochemical tests were carried out to assess the depressive-like phenotype in rats. Stressed rats showed increased immobility time in the forced swimming test (FST), decreased grooming time in the splash test (ST), increased serum cortisol levels, increased inflammasome biomarkers, and decreased neurogenesis. However, administration of CLO produced significant antidepressant-like effects in rats, which were accompanied by a significant decrease in immobility time in FST, an increase in grooming time in ST, a decrease in serum cortisol level, a decrease in inflammasome biomarkers, and an increase in neurogenesis biomarkers. The antidepressant mechanism of CLO involves the HPA axis and the anti-inflammatory effect, followed by neurogenesis pathway activation. Therefore, CLO may have the potential to be a novel antidepressant candidate.

Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells.

OBJECTIVES: Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. METHODS: BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. RESULTS: Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads. CONCLUSIONS: BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Characterizing Alterations in Cortisol Secretion During Cardiac Surgery.

Cortisol is a neuroendocrine hormone of the hypothalamus-pituitary-adrenal (HPA) axis secreted from adrenal glands in response to stimulation by adrenocorticotropic hormone (ACTH) from the anterior pituitary and corticotropin releasing hormone (CRH) from the hypothalamus. Cortisol has multiple functionalities in maintaining bodily homeostasis - including anti-inflammatory influences - through its diurnal secretion pattern (which has been studied extensively); its secretion is also increased in response to major traumatic events such as surgery. Due to the adverse health consequences of an abnormal immune response, it is crucial to understand the effect of cortisol in modulating inflammation. To address this physiological issue, we characterize the secretion of cortisol using a high temporal resolution dataset of ten patients undergoing coronary arterial bypass grafting (CABG) surgery, in comparison with a control group not undergoing surgery. We find that cortisol exhibits different pulsatile dynamics in those undergoing cardiac surgery compared to the control subjects. We also summarize the causality of cortisol's relationship with different cytokines (which are one type of inflammatory markers) by performing Granger causality analysis.Clinical relevance- This work documents time-varying patterns of the HPA axis hormone cortisol in the inflammatory response to cardiac surgery and may eventually help improve patients' prognosis post-surgery (or in other conditions) by enabling early detection of an abnormal cortisol or inflammatory response and enabling patient specific remedial interventions.

Identification of Potential miRNA Biomarkers to Detect Hydrocortisone Administration in Horses.

Circulating microRNAs (miRNAs) are stable in bodily fluids and are potential biomarkers of various diseases and physiological states. Although several studies have been conducted on humans to detect drug doping by miRNAs, research on drugs and miRNAs in horses is limited. In this study, circulating miRNAs in horses after hydrocortisone administration were profiled and variations in miRNAs affected by hydrocortisone administration during endogenous hydrocortisone elevation were examined. The miRNAs were extracted from thoroughbred horse plasma before and after hydrocortisone administration and subjected to small RNA sequencing and reverse transcription quantitative PCR (RT-qPCR). RT-qPCR validation was performed for the 20 miRNAs that were most affected by hydrocortisone administration. The effects of elevated endogenous hydrocortisone levels due to exercise and adrenocorticotropic hormone administration were also confirmed. The validation results showed that approximately half of the miRNAs showed the same significant differences as those obtained using small RNA sequencing. Among the twenty miRNAs, two novel miRNAs and miR-133a were found to vary differently between exogenous hydrocortisone administration and endogenous hydrocortisone elevation. This study provides basic knowledge regarding the circulating miRNA profile of horses after hydrocortisone administration and identifies three miRNAs that could potentially be used as biomarkers to detect hydrocortisone administration.

Cortisol decreases activation in extinction related brain areas resulting in an impaired recall of context-dependent extinction memory.

Conditioned responding gradually stops during successful extinction learning. The renewal effect is defined as the recovery of a extinguished conditioned response when the context of extinction is different from acquisition. The stress hormone cortisol is known to have an influence on extinction memory and associative learning. Different effects of cortisol on behaviour and brain activity have been observed with respect to stress timing, duration, and intensity. However, the influence of cortisol prior to the initial encoding of stimulus-outcome associations on extinction learning, renewal and its behavioural and neurobiological correlates is still largely unknown. In our study, 60 human participants received 20 mg cortisol or placebo and then learned, extinguished, and recalled the associations between food stimuli presented in distinct contexts and different outcomes in three subsequent task phases. Learning performance during acquisition and extinction phases was equally good for both treatment groups. In the cortisol group, significantly more participants showed renewal compared to placebo. In the subgroup of participants with renewal, cortisol treated participants showed significantly better extinction learning performance compared to placebo. Participants showing renewal had in general difficulties with recalling extinction memory, but in contrast to placebo, the cortisol group exhibited a context-dependent impairment of extinction memory recall. Imaging analyses revealed that cortisol decreased activation in the hippocampus during acquisition. The cortisol group also showed reduced dorsolateral prefrontal cortex activation when extinction learning took place in a different context, but enhanced activation in inferior frontal gyrus during extinction learning without context change. During recall, cortisol decreased ventromedial prefrontal cortex activation. Taken together, our findings illustrate cortisol as a potent modulator of extinction learning and recall of extinction memory which also promotes renewal.

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

Background: Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O). Methods: Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated. Results: Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events. Conclusion: Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.