Unique and interactive effects of threat and deprivation on latent trait cortisol among emerging adults.

Though considerable work supports the Dimensional Model of Adversity and Psychopathology, prior research has not tested whether the dimensions-threat (e.g., abuse) and deprivation (e.g., neglect)-are uniquely related to salivary trait indicators of hypothalamic pituitary adrenal (HPA) axis activity. We examined the unique and interactive effects of threat and deprivation on latent trait cortisol (LTC)-and whether these effects were modified by co-occurring adversities. Emerging adults (n = 90; Mage = 19.36 years; 99.88% cisgender women) provided salivary cortisol samples four times a day (waking, 30 min and 45 min postwaking, bedtime) over three 3-day measurement waves over 13 weeks. Contextual life stress interviews assessed early adversity. Though the effects varied according to the conceptualization of early adversity, overall, threat-but not deprivation, nor other co-occurring adversities-was uniquely associated with the across-wave LTC. Specifically, the incidence and frequency of threat were each negatively related to the across-wave LTC. Threat severity was also associated with the across-wave LTC, but only among those with no deprivation. Finally, the effects of threat were modified by other co-occurring adversities. Findings suggest that threat has unique implications for individual differences in HPA axis activity among emerging adults, and that co-occurring adversities modify such effects.

Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy.

The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE.

Unveiling stress markers: A systematic review investigating psychological stress biomarkers.

Psychological stress is a ubiquitous facet of modern life, impacting individuals across diverse contexts and demographics. Understanding its physiological manifestations through biomarkers has gained substantial attention within the scientific community. A comprehensive search was conducted across multiple databases for peer-reviewed articles published within the past decade. Preliminary findings reveal many biomarkers associated with psychological stress across different biological systems, including the hypothalamic-pituitary-adrenal axis, immune system, cardiovascular system, and central nervous system. This systematic review explores psychological, physiological, and biochemical biomarkers associated with stress. Analyzing recent literature, it synthesizes findings across these three categories, elucidating their respective roles in stress response mechanisms. Psychological markers involve subjective assessments like self-reported stress levels, perceived stress scales, or psychometric evaluations measuring anxiety, depression, or coping mechanisms. Physiological markers include heart rate variability, blood pressure, and immune system responses such as cytokine levels or inflammatory markers. Biochemical markers involve hormones or chemicals linked to stress. It includes cortisol, catecholamines, copeptin, salivary amylase, IL-6, and C-reactive protein.

Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

The mind-skin connection: A narrative review exploring the link between inflammatory skin diseases and psychological stress.

Inflammatory skin diseases are known to negatively impact patient psychology, with individuals experiencing higher rates of stress and subsequent diminished quality of life, as well as mental health issues including anxiety and depression. Moreover, increased psychological stress has been found to exacerbate existing inflammatory skin diseases. The association between inflammatory skin diseases and psychological stress is a timely topic, and a framework to better understand the relationship between the two that integrates available literature is needed. In this narrative review article, we discuss potential neurobiological mechanisms behind psychological stress due to inflammatory skin diseases, focusing mainly on proinflammatory cytokines in the circulating system (the brain-gut-skin communications) and the default mode network in the brain. We also discuss potential descending pathways from the brain that lead to aggravation of inflammatory skin diseases due to psychological stress, including the central and peripheral hypothalamic-pituitary-adrenal axes, peripheral nerves and the skin barrier function.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Hair-cortisol and hair-BDNF as biomarkers of tinnitus loudness and distress in chronic tinnitus.

The role of stress and its neuroendocrine mediators in tinnitus is unclear. In this study, we measure cortisol as an indicator of hypothalamus-pituitary-adrenal (HPA) axis alterations and brain-derived neurotrophic factor (BDNF) as a marker of adaptive neuroplasticity in hair of chronic tinnitus patients to investigate relationships with tinnitus-related and psychological factors. Cross-sectional data from chronic tinnitus inpatients were analyzed. Data collection included hair sampling, pure tone audiometry, tinnitus pitch and loudness matching, and psychometric questionnaires. Elastic net regressions with n-fold cross-validation were performed for cortisol (N = 91) and BDNF (N = 87). For hair-cortisol (R2 = 0.10), the strongest effects were sampling in autumn and body-mass index (BMI) (positive), followed by tinnitus loudness (positive) and smoking (negative). For hair-BDNF (R2 = 0.28), the strongest effects were hearing aid use, shift work (positive), and tinnitus loudness (negative), followed by smoking, tinnitus-related distress (Tinnitus Questionnaire), number of experienced traumatic events (negative), and physical health-related quality of life (Short Form-12 Health Survey) (positive). These findings suggest that in chronic tinnitus patients, higher perceived tinnitus loudness is associated with higher hair-cortisol and lower hair-BDNF, and higher tinnitus-related distress with lower hair-BDNF. Regarding hair-BDNF, traumatic experiences appear to have additional stress-related effects, whereas hearing aid use and high physical health-related quality of life appear beneficial. Implications include the potential use of hair-cortisol and hair-BDNF as biomarkers of tinnitus loudness or distress and the need for intensive future research into chronic stress-related HPA axis and neuroplasticity alterations in chronic tinnitus.

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Shared postulations between bipolar disorder and polycystic ovary syndrome pathologies.

INTRODUCTION: Women with bipolar disorder (BD) present a high prevalence of polycystic ovary syndrome (PCOS) and other reproductive disorders even before diagnosis or treatment of the disease. Postulations on the potential molecular mechanisms of comorbid PCOS in women with BD remain limited to influence of medications and need further extension. OBJECTIVES: This review focuses on evidence suggesting that common metabolic and immune disorders may play an important role in the development of BD and PCOS. RESULTS: The literature covered in this review suggests that metabolic and immune disorders, including the dysfunction of the hypothalamic-pituitary-adrenal axis, chronic inflammatory state, gut microbial alterations, adipokine alterations and circadian rhythm disturbance, are observed in patients with BD and PCOS. Such disorders may be responsible for the increased prevalence of PCOS in the BD population and indicate a susceptibility gene overlap between the two diseases. Current evidence supports postulations of common metabolic and immune disorders as endophenotype in BD as well as in PCOS. CONCLUSIONS: Metabolic and immune disorders may be responsible for the comorbid PCOS in the BD population. The identification of hallmark metabolic and immune features common to these two diseases will contribute to the clarification of the effect of BD on the reproductive endocrine function and development of symptomatic treatments targeting the biomarkers of the two diseases.

Stress system dysfunction revealed by integrating reactivity of stress pathways to psychological stress in lean and overweight/obese men.

Although the patterns of response within the sympathoadrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways. We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems, which is not evident when considering either system alone. Age-matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary α-amylase, systolic blood pressure, diastolic blood pressure, and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. Although analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Furthermore, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation in the other.

Adverse effects of antiepileptic drugs on hormones of the hypothalamic-pituitary-gonadal axis in males: A review.

The HPG axis is critical in the maintenance of spermatogenesis and sexual function in males. The GnRH-releasing neurons of the hypothalamus are the axis's main hierarchical element. These neurons make connections with different areas of the brain to regulate the release of GnRH. Neurotransmitters have a critical in the connections between these neurons. So, neurotransmitters can inhibit or stimulate the release of GnRH by affecting GnRH-releasing neurons. In neurological disorders, neurotransmitter's activities inevitably change; therefore, these changes can affect the HPG axis via affecting GnRH-releasing neurons, just like in epilepsy. Many investigations have attracted attention to be decreased fertility potential in males with epilepsy. It has been stated that changes in the HPG axis hormone levels have been found in these patients. Moreover, it has also been observed that sperm quality decreased in patients. It has been emphasized that a decrease in sperm quality may be related to both epilepsy and AEDs. It has been shown that AEDs caused decreased sperm quality by impairing the HPG axis, so they act like endocrine-disrupting chemicals. AEDs can affect fertility and cause additive adverse effects in terms of sperm quality together with epilepsy. Therefore, it is crucial to investigate the adverse reproductive effects of AEDs, which are frequently used during reproductive ages, and determine the role of the HPG axis on potential reproductive pathologies.

Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease.

The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aß)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BACKGROUND: Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. METHODS: Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. SUMMARY: Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. CONCLUSIONS: CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) accounts for 90-95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160-190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17ß-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.

Exploring the link between adolescent inhalant misuse and suicidal behaviour: a behavioural toxicology perspective.

Adolescent inhalant misuse has a known association with suicidal thoughts and behaviour. This association persists even after inhalant misuse has ceased. Previous studies have hypothesised that this association may derive from socioeconomic disadvantage or vulnerability, and potentially mediated by impulsivity. This association may also be due to the central nervous system depressant effects of inhalants. This review takes a behavioural toxicology perspective, focussed particularly on the serotonergic system and the Hypothalamic-Pituitary-Adrenal (HPA) axis, as potential links between adolescent inhalant misuse and suicidal behaviour. The challenges of bridging the pre-clinical and clinical literature in this area are discussed, along with promising avenues for future research; ultimately aimed at reducing suicide risk in a vulnerable adolescent population group.

Jie-Yu-He-Huan Capsule Ameliorates Anxiety-Like Behaviours in Rats Exposed to Chronic Restraint Stress via the cAMP/PKA/CREB/BDNF Signalling Pathway.

Chronic stress is a critical factor in the aetiology of anxiety disorders; however, in the clinic, enduring and preventive measures are not available, and therapeutic drugs are associated with inevitable side effects. Our study established an anxiety rat model using chronic restraint stress (CRS) and assessed these animals using the open-field test, elevated plus-maze test, and light-dark box test. Jie-Yu-He-Huan capsule (JYHH), a Chinese medicine formula, was used as a preventative drug. The HPA axis-mediated release of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone from the hypothalamus was tested. In the hippocampus and prefrontal cortex, concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid, as well as monoamine oxidase A, glucocorticoid receptor, and 5-HT1A receptor expression levels, were measured. Furthermore, we examined protein and mRNA expression of cAMP-PKA-CREB-BDNF pathway components. The results showed that JYHH had a significant preventative effect on the anxiety-like behaviour induced by CRS and prevented abnormal changes in the HPA axis and 5-HT system. Furthermore, CRS inhibited the cAMP-PKA-CREB-BDNF pathway, which returned to normal levels following JYHH treatment. This might be the underlying molecular mechanism of the antianxiety effect of JYHH, which could provide a new clinical target for preventative anxiolytic drugs for chronic stress.

Externalizing behavior in healthy young adults is associated with lower cortisol responses to acute stress and altered neural activation in the dorsal striatum.

The externalizing spectrum is characterized by disinhibition, impulsivity, antisocial-aggressive behavior as well as substance (mis)use. Studies in forensic samples and mentally impaired children suggested that higher rates of externalization are linked to lower cortisol stress responses and altered affect-related neural activation. In this fMRI-study, we investigated whether externalizing behavior in healthy participants is likewise associated with altered cortisol responses and neural activity to stress. Following a quasi-experimental approach, we tested healthy participants (N = 61, 31 males) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure. All participants were exposed to ScanSTRESS, a standardized psychosocial stress paradigm for scanner environments. In both groups, ScanSTRESS induced a significant rise in cortisol levels with the high externalization group showing significantly lower cortisol responses to stress than the low externalization group. This was mainly driven by males. Further, individual increases in cortisol predicted neural response differences between externalization groups, indicating more activation in the dorsal striatum in low externalization. This was primarily driven by females. In contrast, post-hoc analysis showed that hypothalamic-pituitary-adrenal axis hyporeactivity in males was associated with prefrontal and hippocampal activation. Our data substantiate that individuals from the general population high on externalization, show reduced cortisol stress responses. Furthermore, dorsal striatum activity as part of the mesolimbic system, known to be sensitive to environmental adversity, seems to play a role in externalization-specific cortisol stress responses. Beyond that, a modulating influence of gender was disclosed.

Diurnal pattern of salivary cortisol and progression of aortic stiffness: Longitudinal study.

BACKGROUND: The positive direct relation between stress and the development of cardiovascular disease has increasingly been recognized. However, the link between hypothalamic-pituitary-adrenal (HPA) dysregulation and subclinical cardiovascular disease has not been studied longitudinally. We investigated the relation of diurnal salivary cortisol, as a biological marker of stress levels, with progression of aortic stiffness over five years. METHODS: A total of 3281 people (mean age 65.5) in the Whitehall II prospective study provided six saliva samples on a single weekday. We assessed the diurnal salivary cortisol using the daytime slope and bedtime level. Aortic stiffness was measured by carotid-femoral pulse wave velocity (PWV) at baseline (2007-2009) and five years later (2012-2013). Linear mixed models were used to estimate the association of diurnal salivary cortisol with baseline PWV and five-year longitudinal changes. RESULTS: Diurnal salivary cortisol were not associated with PWV at baseline. Among women but not men, a 1-SD shallower salivary cortisol slope at baseline was associated with a five-year increase in PWV (ß = 0.199; 95% CI = 0.040, 0.358 m/s) and higher bedtime cortisol level (ß = 0.208, 95% CI = 0.062, 0.354 m/s). CONCLUSIONS: Dysregulation of the HPA axis measured using salivary cortisol (shallower slope, higher bedtime level) predicted the rate of progression of aortic stiffness among women.

Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis.

AIM: Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation. METHODS: After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue. RESULTS: Of note, MSZRD can shorten the sleep latency of insomnia mice (P < 0.05, 0.01), prolonged the sleep duration of mice (P < 0.05, 0.01), and improve the circadian rhythm disorder relative to placebo-treated animals. Furthermore, MSZRD effectively increased the content of 5-HT and 5-HTR1A protein in the hypothalamus of insomnia mice (P < 0.05, 0.01), while downregulated the content of DA and NE (P < 0.05, 0.01). Importantly, serum GABA concentration was increased by treatment with MSZRD (P < 0.05), as reflected by a decreased Glu/GABA ratio (P < 0.05). Moreover, MSZRD decreased the levels of CORT, ACTH, and CRH related hormones in HPA axis (P < 0.05, 0.01). At the same time, MSZRD significantly downregulated the serum Orexin-A content in insomnia mice (P < 0.05), as well as hypothalamic OX2R expression (P < 0.05). In addition, MSZRD also improved the histopathological changes in hypothalamus in insomnia mice. CONCLUSION: MSZRD has sleep-improvement effect in mice model of insomnia. The mechanism may be that regulating the expression of Orexin-A affects the homeostasis of HPA axis and the release of related neurotransmitters in mice with insomnia.