Distinct anti-inflammatory properties of alpha1-antitrypsin and corticosteroids reveal unique underlying mechanisms of action.

Alpha1-antitrypsin (AAT) is a serum protease inhibitor that rises during inflammation and healthy pregnancies. Plasma-derived AAT, indicated for genetic AAT deficiency, is presently being explored for additional medical indications. Unlike corticosteroids, some anti-inflammatory activities of AAT involve NF-κB-dependent outcomes, e.g., induction of IL-1R antagonist. AAT activities were compared to dexamethasone (DEX), using various in-vitro cells assays, animal studies, and NF-κB-p65 localization and activity studies. Results demonstrate a cytokine shift towards resolution in AAT-treated cells, as opposed to pan-suppression in DEX-treated cells. AAT enhanced, while DEX suppressed LPS-induced IL-1Ra production and re-epithelialization. When drugs were combined, AAT allowed the immunosuppressive DEX activities, while DEX at medium to high levels antagonized beneficial AAT effects. Interestingly, lower levels of DEX maintained the immunosuppressive effect, while allowing upregulation of IL-1Ra. Therefore, AAT may represent a distinct endogenous anti-inflammatory, resolution-promoting agent that may improve tissue well-being while preventing undesired corticostroids side effects.

In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra.

The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.

Associations between adrenarcheal hormones, amygdala functional connectivity and anxiety symptoms in children.

OBJECTIVE: The transition from childhood to adolescence is a vulnerable period for the development of anxiety symptoms. There is some evidence that hormonal changes occurring during adrenarche, an early pubertal phase, might play a role in this increased vulnerability. Little is known about underlying brain mechanisms. Given the role of the amygdala-based fear circuit in anxiety, the current study aimed to investigate whether children's adrenarcheal hormone levels were associated with functional connectivity of the amygdala while processing fearful facial expressions, and how this in turn related to anxiety symptoms. METHOD: Participants were 83 children (M age 9.53 years) who completed two morning saliva collections to measure levels of dehydroepiandrosterone (DHEA), its sulphate (DHEAS), and testosterone. They also completed the Spence Children's Anxiety Scale (SCAS), and viewed fearful and calm facial expressions while undergoing a functional MRI scan. Psychophysiological interaction (PPI) analyses were performed to examine amygdala connectivity and significant clusters were fed into a bootstrapping mediation model. RESULTS: In boys, mediation analyses showed an indirect positive effect of testosterone on anxiety symptoms, which was mediated by amygdala-secondary visual cortex connectivity as well as amygdala-anterior cingulate connectivity. In girls, DHEAS showed a negative indirect association with anxiety symptoms mediated by amygdala connectivity to the fusiform face area and insula. CONCLUSION: The results indicate unique roles for adrenarcheal hormones in anxiety and suggest that amygdala connectivity may represent an important neural mechanism in these associations. Importantly, results reveal prominent sex differences in the biological mechanisms associated with anxiety in children undergoing adrenarche.

Corticosteroids and the brain.

The brain is continuously exposed to varying levels of adrenal corticosteroid hormones such as corticosterone in rodents and cortisol in humans. Natural fluctuations occur due to ultradian and circadian variations or are caused by exposure to stressful situations. Brain cells express two types of corticosteroid receptors, i.e. mineralocorticoid and glucocorticoid receptors, which differ in distribution and affinity. These receptors can mediate both rapid non-genomic and slow gene-mediated neuronal actions. As a consequence of these factors, natural (e.g. stress-induced) shifts in corticosteroid level are associated with a complex mosaic of time- and region-dependent changes in neuronal activity. A series of experiments in humans and rodents have revealed that these time- and region-dependent cellular characteristics are also reflected in distinct cognitive patterns after stress. Thus, directly after a peak of corticosteroids, attention and vigilance are increased, and areas involved in emotional responses and simple behavioral strategies show enhanced activity. In the aftermath of stress, areas involved in higher cognitive functions become activated allowing individuals to link stressful events to the specific context and to store information for future use. Both phases of the brain's response to stress are important to face a continuously changing environment, promoting adaptation at the short as well as long term. We argue that a balanced response during the two phases is essential for resilience. This balance may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation. This not only applies to psychiatric disorders but also to neurological diseases such as epilepsy.

The Role of the Sinonasal Epithelium in Allergic Rhinitis.

The sinonasal epithelial barrier is comprised of tight and adherens junction proteins. Disruption of epithelial barrier function has been hypothesized to contribute to allergic disease such as allergic rhinitis through increased passage of antigens and exposure of underlying tissue to these stimuli. Several mechanisms of sinonasal epithelial barrier disruption include antigen proteolytic activity, inflammatory cytokine-mediated tight junction breakdown, or exacerbation from environmental stimuli. Mechanisms of sinonasal epithelial barrier stabilization include corticosteroids and nuclear erythroid 2-related factor 2 (Nrf2) cytoprotective pathway activation. Additional studies will aid in determining the contribution of epithelial barrier function in allergic rhinitis pathophysiology and treatment.

Perinatal Depression, Adverse Life Events, and Hypothalamic-Adrenal-Pituitary Axis Response to Cold Pressor Stress in Latinas: An Exploratory Study.

BACKGROUND: Latinas are disproportionately affected by perinatal depression (PND) as well as by adverse life events (ALEs), an independent predictor of PND. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been seen both in women with PND and with a history of ALEs in non-Latinas. Although some evidence suggests that HPA axis dysregulation may mediate the link between ALEs and PND, this hypothesis has received little attention and there are no studies that have examined these pathways in Latinas. The primary aim of the present study was to explore, in a Latina sample, associations between ALEs, PND, and HPA axis stress reactivity to a physical stressor, the cold pressor test (CPT). The secondary aim was to explore whether HPA axis reactivity and PND were associated with pain sensitivity to the CPT. METHODS: Thirty-four Latinas were enrolled in their third trimester of pregnancy and interviewed at 4 and 8 weeks postpartum. Depression status was determined using the Edinburgh Postnatal Depression Scale (≥10). At 8 weeks postpartum, 27 women underwent laboratory-induced pain testing using the CPT. Plasma adrenocorticotropic hormone and cortisol were sampled before and after the CPT to generate a stress reactivity score (post-pre). Pain sensitivity and ALEs were also assessed. RESULTS: At enrollment, 26% of women were depressed, and 18% were depressed at 8 weeks postpartum. Fifty-two percent reported at least one childhood ALE. There was a significant and positive association between any childhood ALE and prenatal depression scores (p = .025). Infant-related ALEs were significantly associated with greater adrenocorticotropic hormone reactivity to the CPT (p = .030). Women with a history of any childhood ALE exhibited a blunted cortisol response to the CPT (p = .045). Women with a history of PND at 4 weeks had greater adrenocorticotropic hormone stress reactivity to the CPT (p = .027). No effects of PND were seen for pain sensitivity measures in response to the CPT, although there was a positive and significant correlation between pain tolerance and cortisol response to the CPT in the whole sample. CONCLUSIONS: Given the associations between ALEs and PND and their individual effect on HPA axis stress reactivity, future studies on PND should include a larger sample of Latinas to test the mediating effects of HPA axis reactivity on associations between ALEs and PND.

Anxiety and Epigenetics.

Anxiety disorders are highly prevalent psychiatric disorders often comorbid with depression and substance abuse. Twin studies have shown that anxiety disorders are moderately heritable. Yet, genome-wide association studies (GWASs) have failed to identify gene(s) significantly associated with diagnosis suggesting a strong role for environmental factors and the epigenome. A number of anxiety disorder subtypes are considered "stress related." A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal (HPA) axis and of stress-responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting epigenetic marks associated with anxiety may prove fruitful in developing treatments.

Acute Lymphoblastic Leukemia Presenting With Pancytopenia Followed by a 14-Month-Long Period of Transient Remission Possibly Supporting the Adrenal Hypothesis of Leukemogenesis.

A small group of children with acute lymphoblastic leukemia (ALL) have a preleukemic phase of pancytopenia followed by a period of spontaneous remission before the diagnosis (pre-ALL). A 6-year-old girl presented with pancytopenia, fever, and myelodysplasia. Following transient remission pre-B ALL was diagnosed 14 months later. Clonal B-lineage blasts at the period of pancytopenia were identified retrospectively. The interval between pre-ALL and ALL-diagnosis was longer than previously reported. The infection was clinically severe and might have induced a significant endogenous corticosteroids production resulting in the long-lasting remission. The case supports the adrenal and the Coley's toxin hypothesis in leukemogenesis.

Network of nuclear receptor ligands in multiple sclerosis: Common pathways and interactions of sex-steroids, corticosteroids and vitamin D3-derived molecules.

Sex-steroids, corticosteroids and vitamin D3-derived molecules have all been subject to experimental studies and clinical trials in a plethora of autoimmune diseases. These molecules are all derived from cholesterol metabolites and are ligands for nuclear receptors. Ligation of these receptors results in direct regulation of multiple gene transcription involved in general homeostatic and adaptation networks, including the immune system. Indeed, the distinct ligands affect the function of both myeloid and lymphoid cells, eventually resulting in a less pro-inflammatory immune response which is considered beneficial in autoimmune diseases. Next to the immune system, also the central nervous system is prone to regulation by these nuclear receptor ligands. Understanding of the intricate interactions between sex-steroids, corticosteroids and vitamin D3 metabolites, on the one hand, and the immune and central nervous system, on the other hand, may reveal novel approaches to utilize these nuclear receptor ligands to full extent as putative treatments in multiple sclerosis, the prototypic immune-driven disease of the central nervous system.

[The history of the Science of Stress: From Hans Selye to the discovery of anti-inflammatory medication]. / L'histoire de la science du stress : de Hans Selye à la découverte des anti-inflammatoires.

To make an important scientific discovery that will make history takes a lot of determination, creativity, perseverance and luck! The story behind the discovery of stress and its biological basis is a fascinating one that places Dr. Hans Selye in the forefront. Dr. Selye was a great scientist that taught at the Université de Montréal from 1945 to his death in 1982. Dr. Selye was curious and hard working. He was determined to understand how various disorders can lead to similar physical manifestations, and this interest led him to discover the role of the adrenal glands involved in the stress response and to better understand the effects of glucocorticoids on the body. Today, the science of stress is based on the foundations established by Dr. Selye. In celebration of the 50th anniversary of the Département de psychiatrie de l'Université de Montréal, and the special issue of the Revue Santé Mentale au Québec, this historical review summarizes the discoveries of this great scientist who worked in Quebec.

Propofol-induced electroencephalographic seizures in neonatal rats: the role of corticosteroids and γ-aminobutyric acid type A receptor-mediated excitation.

BACKGROUND: An imbalance between excitation and inhibition in the developing central nervous system may result in a pathophysiological outcome. We investigated the mechanistic roles of endocrine activity and γ-aminobutyric acid type A receptor (GABAAR)-mediated excitation in electroencephalographic seizures caused by the GABAAR-selective anesthetic propofol in neonatal rats. METHODS: Postnatal day 4-6 Sprague Dawley rats underwent a minor surgical procedure to implant electrodes to measure electroencephalographic activity for 1 hour before and 1 hour after intraperitoneal administration of propofol (40 mg·kg). Various treatments were administered 15 minutes before administration of propofol. RESULTS: Episodes of electroencephalographic seizures and persistent low-amplitude spikes occurred during propofol anesthesia. Multifold increases in serum levels of corticosterone (t(10) = -5.062; P = 0.0005) and aldosterone (t(10) = -5.069; P = 0.0005) were detected 1 hour after propofol administration in animals that underwent experimental manipulations identical to those used to study electroencephalographic activity. Pretreatment with bumetanide, the Na-K-2Cl cotransporter inhibitor, which diminishes GABAAR-mediated excitation, eliminated both seizure and spike electroencephalographic activities caused by propofol. Mineralocorticoid and glucocorticoid receptor antagonists, RU 28318 and RU486, depressed electroencephalographic seizures but did not affect the spike electroencephalographic effects of propofol. Etomidate, at a dose sufficient to induce loss of righting reflex, was weak at increasing serum corticosteroid levels and eliciting electroencephalographic seizures. Etomidate given to corticosterone-pretreated rat pups further increased the total duration of electroencephalographic seizures caused by administration of exogenous corticosterone (t(21) = -2.512, P = 0.0203). CONCLUSIONS: Propofol increases systemic corticosteroid levels in neonatal rats, which along with GABAAR-mediated excitation appear to be required for propofol-induced neonatal electroencephalographic seizures. Enhancement of GABAAR activity alone may not be sufficient to elicit neonatal electroencephalographic seizures.

Does stress predispose to periodontal disease?

UNLABELLED: The relationship of a sound mind to the maintenance of a healthy body has been recognized throughout most of recorded history. The term 'stress' is used to describe adverse emotions or reactions to unpleasant experiences. Individuals with high levels of stress and poor coping skills experience twice as much periodontal disease as compared to those with minimal stress and good coping skills. Although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains the essential aetiologic factor. This review presents a summary of stress, discussing how it can predispose an individual to periodontal disease. CLINICAL RELEVANCE: Stress, which is a universal phenomenon, is implicated to have various systemic effects besides being a risk factor for periodontal disease. This article elucidates the relationship between psycho-social stress and destructive periodontal disease.

Steroids and insulin resistance in pregnancy.

Metabolism of glucose during pregnancy reflects the equilibrium between lactogenic hormones stimulating insulin production and counterregulatory hormones inducing insulin resistance. In physiological pregnancies, insulin-mediated glucose uptake is substantially decreased and insulin secretion increased to maintain euglycemia. This common state of peripheral insulin resistance arises also due to steroid spectra changes. In this review article, we have focused on the role of steroid hormones (androgens, estrogens, gestagens, mineralocorticoids, glucocorticoids, as well as secosteroid vitamin D) in the impairment of glucose tolerance in pregnancy and in the pathogenesis of gestational diabetes mellitus. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

Steroid profiling in pregnancy: a focus on the human fetus.

In this review we focused on steroid metabolomics in human fetuses and newborns and its role in the physiology and pathophysiology of human pregnancy and subsequent stages of human life, and on the physiological relevance of steroids influencing the nervous systems with regards to their concentrations in the fetus. Steroid profiling provides valuable data for the diagnostics of diseases related to altered steroidogenesis in the fetal and maternal compartments and placenta. We outlined a potential use of steroid metabolomics for the prediction of reproductive disorders, misbalance of hypothalamic-pituitary-adrenal axis, and impaired insulin sensitivity in subsequent stages of human life. A possible role of steroids exhibiting a non-genomic effect in the development of gestational diabetes and in the neuroprotection via negative modulation of AMPA/kainate receptors was also indicated. Increasing progesterone synthesis and catabolism, declining production of tocolytic 5ß-pregnane steroids, and rising activities of steroid sulfotransferases with the approaching term may be of importance in sustaining pregnancy. An increasing trend was demonstrated with advancing gestation toward the production of ketones (and 3ß-hydroxyl groups in the case of 3α-hydroxy-steroids) was demonstrated in the fetus on the expense of 3α-hydroxy-, 17ß-hydroxy-, and 20α-hydroxy-groups weakening in the sequence C17, C3, and C20. There was higher production of active progestogen but lower production of active estrogen and GABAergic steroids with the approaching term. Rising activities of placental CYP19A1 and oxidative isoforms of HSD17B, and of fetal CYP3A7 with advancing gestation may protect the fetus from hyperestrogenization. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

New insights into the role of perinatal HPA-axis dysregulation in postpartum depression.

Postpartum depression affects 10-20% of women following birth and exerts persisting adverse consequences on both mother and child. An incomplete understanding of its etiology constitutes a barrier to early identification and treatment. It is likely that prenatal hormone trajectories represent both markers of risk and also causal factors in the development of postpartum depression. During pregnancy the maternal hypothalamic-pituitary-adrenal axis undergoes dramatic alterations, due in large part, to the introduction of the placenta, a transient endocrine organ of fetal origin. We suggest that prenatal placental and hypothalamic-pituitary-adrenal axis dysregulation is predictive of risk for postpartum depression. In this model the positive feedback loop involving the systems regulating the products of the HPA axis results in higher prenatal levels of cortisol and placental corticotropin-releasing hormone. Greater elevations in placental corticotropin-releasing hormone are related to a disturbance in the sensitivity of the anterior pituitary to cortisol and also perhaps to decreased central corticotropin-releasing hormone secretion. Secondary or tertiary adrenal insufficiencies of a more extreme nature, which emerge during the prenatal period, may be predictive of an extended or more pronounced postpartum hypothalamic-pituitary-adrenal refractory period, which in turn represents a risk factor for development of postpartum depression. In addition to reviewing the relevant existing literature, new data are presented in support of this model which link elevated placental corticotropin-releasing hormone with low levels of ACTH at 3-months postpartum. Future research will further elucidate the role of hypothalamic-pituitary-adrenal axis dysregulation in postpartum depression and also whether prenatal placental and hypothalamic-pituitary-adrenal profiles might prove useful in the early identification of mothers at risk for postpartum mood dysregulation.

Characterization and modulation of glucose uptake in a human blood-brain barrier model.

The blood-brain barrier (BBB) plays a key role in limiting and regulating glucose access to glial and neuronal cells. In this work glucose uptake on a human BBB cell model (the hCMEC/D3 cell line) was characterized. The influence of some hormones and diet components on glucose uptake was also studied. ³H-2-deoxy-D-glucose ([³H]-DG) uptake for hCMEC/D3 cells was evaluated in the presence or absence of tested compounds. [³H]-DG uptake was sodium- and energy-independent. [³H]-DG uptake was regulated by Ca²âº and calmodulin but not by MAPK kinase pathways. PKC, PKA and protein tyrosine kinase also seem to be involved in glucose uptake modulation. Progesterone and estrone were found to decrease ³H-DG uptake. Catechin and epicatechin did not have any effect, but their methylated metabolites increased [³H]-DG uptake. Quercetin and myricetin decreased [³H]-DG uptake, and glucuronic acid-conjugated quercetin did not have any effect. These cells expressed GLUT1, GLUT3 and SGLT1 mRNA.

Stress and excitatory synapses: from health to disease.

Individuals are exposed to stressful events in their daily life. The effects of stress on brain function ranges from highly adaptive to increasing the risk to develop psychopathology. For example, stressful experiences are remembered well which can be seen as a highly appropriate behavioral adaptation. On the other hand, stress is an important risk factor, in susceptible individuals, for depression and anxiety. An important question that remains to be addressed is how stress regulates brain function and what determines the threshold between adaptive and maladaptive responses. Excitatory synapses play a crucial role in synaptic transmission, synaptic plasticity and behavioral adaptation. In this review we discuss how brief and prolonged exposure to stress, in adulthood and early life, regulate the function of these synapses, and how these effects may contribute to behavioral adaptation and psychopathology.

Glucocorticoids and inflammation: a double-headed sword in depression? How do neuroendocrine and inflammatory pathways interact during stress to contribute to the pathogenesis of depression?

Both glucocorticoids and inflammation have been implicated in the pathogenesis of depression. There is a large body of literature indicating that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) dysfunction are present in a significant proportion of depressed patients. There is also evidence of increased inflammatory processes in depressed populations, with higher levels of cytokines being a prominent finding - including raised levels of IL-6, and IL-1. These findings appear difficult to reconcile given the well-recognised property of glucocorticoids as prominent anti-inflammatory molecules. There are three potential solutions posed to this dilemma. Firstly, it has been argued that the glucocorticoid system and the inflammatory system exist in balance with one another and chronic stress can disrupt this balance in favour of inflammatory processes at the expense of glucocorticoid signalling. It has also been suggested that glucocorticoids have more complex actions than typically thought, and, in low levels can actually be pro-inflammatory, rather than universally anti-inflammatory. Lastly, it is possible that inflammation and glucocorticoid signalling may act on the same processes and structures without direct interaction to give rise to cumulative damage. Improved understanding of this interaction will allow further progress in determining targets for treatment.

PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity.

Surgery can suppress in vivo levels of NK cell cytotoxicity (NKCC) through various mechanisms, including catecholamine-, glucocorticoid (CORT)-, and prostaglandin (PG)-mediated responses. However, PGs are synthesized locally following tissue damage, driving proinflammatory and CORT responses, while their systemic levels are often unaffected. Thus, we herein studied the role of adrenal factors in mediating in vivo effects of PGs on NKCC, using adrenalectomized and sham-operated F344 rats subjected to surgery or PGE(2) administration. In vivo and ex vivo approaches were employed, based on intravenous administration of the NK-sensitive MADB106 tumor line, and based on ex vivo assessment of YAC-1 and MADB106 target-line lysis. Additionally, in vitro studies assessed the kinetics of the impact of epinephrine, CORT, and PGE(2) on NKCC. The results indicated that suppression of NKCC by epinephrine and PGE(2) are short lasting, and cannot be evident when these compounds are removed from the in vitro assay milieu, or in the context of ex vivo assessment of NKCC. In contrast, the effects of CORT are long-lasting and are reflected in both conditions even after its removal. Marginating-pulmonary NKCC was less susceptible to suppression than circulating NKCC, when tested against the xenogeneic YAC-1 target line, but not against the syngeneic MADB106 line, which seems to involve different cytotoxicity mechanisms. Overall, these findings indicate that elevated systemic PG levels can directly suppress NKCC in vivo, but following laparotomy adrenal hormones mediate most of the effects of endogenously-released PGs. Additionally, the ex vivo approach seems limited in reflecting the short-lasting NK-suppressive effects of catecholamines and PGs.