Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Corticotropin releasing hormone is present in the feline placenta and maternal serum.

Background: In women, placental corticotropin releasing hormone (CRH) can be detected in maternal blood throughout pregnancy and is important in the regulation of the timing of parturition. However, its role in other mammalian species is unclear. In fact, very little is known about the presence and localization of CRH in placentas other than human. In this study we report for the first time the presence of CRH in feline placenta and maternal serum. Methods: Presence of CRH mRNA and protein was assessed using RT-PCR and Western blot, respectively, in at term domestic cat placentas opportunistically obtained at a local animal shelter and spay clinic. In addition, CRH localization within the placenta was demonstrated via immunohistochemistry. Finally, presence of CRH in maternal blood from early (¾21 days) and mid (25-35 days) stages of pregnancy was investigated by ELISA. Results: CRH mRNA and protein were detected in feline placentas, and localized to larger decidual cells and fetal trophoblast cells, including the binucleate cells. CRH was detectable in maternal blood collected from early-stage pregnancies, and amounts significantly increased in mid-gestation samples. Conclusion: This is the first report on the presence and localization of CRH in the feline placenta, and its increase in maternal serum during the first half of pregnancy. These data lay the foundation for future studies to determine if CRH can be used as potential novel marker for early pregnancy diagnosis, determination, and monitoring in felids, and could greatly increase efficiency and success in zoo breeding programs utilizing artificial reproductive technologies for endangered feline species.

The addition of corticotropin-releasing hormone to 2-day low dose dexamethasone suppression test provides additional case detection.

ABSTARCT: PURPOSE: The diagnostic value of adding a Corticotropin-Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. METHODS: We identified 65 patients with Cushing disease (CD) and 42 patients in whom a diagnosis of Cushing disease could not be confirmed (NCD) after a minimum follow-up of 14 months who underwent the Dex-CRH test. RESULTS: The female sex ratio, median (range) age, and BMI were similar between the two groups. The follow-up for patients with CD and NCD was 74 (4-233) and 52 (14-146) months, respectively. Among 65 patients with CD, 5 (7.7%) had a cortisol level ≤1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of three patients, the LDDST was marginally normal (cortisol was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cutoff value of >1.4 µg/dL during the Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded (n = 74), the sensitivity did not change, but the specificity and accuracy of the Dex-CRH test increased to 97 and 99%, respectively. CONCLUSION: The Dex-CRH Test provided additional case detection in 5/65 (7.7%) patients with CD. It resulted in one false-positive case compared to LDDST. Measurement of dexamethasone improved diagnostic accuracy of the test.

Revisiting the placental clock: Early corticotrophin-releasing hormone rise in recurrent preterm birth.

OBJECTIVE: To determine if maternal plasma CRH and preterm birth history were associated with recurrent preterm birth risk in a high-risk cohort. STUDY DESIGN: Secondary analysis of pregnant women with a prior preterm birth ≤35 weeks receiving 17-alpha hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth. All women with a 24-week blood sample were included. Maternal plasma CRH level at 24- and 32-weeks' gestation was measured using both enzyme-linked immunosorbent assay (ELISA) and extracted radioimmunoassay (RIA) technologies. The primary outcome was spontaneous preterm birth <37 weeks. The association of CRH, prior preterm birth history, and the two combined was assessed in relation to recurrent preterm birth risk. RESULTS: Recurrent preterm birth in this cohort of 169 women was 24.9%. Comparing women who subsequently delivered <37 versus ≥37 weeks, mean levels of CRH measured by RIA were significantly different at 24 weeks (111.1±87.5 vs. 66.1±45.4 pg/mL, P = .002) and 32 weeks (440.9±275.6 vs. 280.2±214.5 pg/mL, P = .003). The area under the receiver operating curve (AUC) at 24 and 32 weeks for (1) CRH level was 0.68 (95% CI 0.59-0.78) and 0.70 (95% CI 0.59-0.81), (2) prior preterm birth history was 0.75 (95% CI 0.67-0.83) and 0.78 (95% CI 0.69-0.87), and (3) combined was 0.81 (95% CI 0.73-0.88, P = .001) and 0.81 (95% CI 0.72-0.90, P = .01) respectively for delivery <37 weeks. CRH measured by ELISA failed to correlate with gestational age or other clinical parameters. CONCLUSION: In women with a prior preterm birth, CRH levels were higher and had an earlier rise in women who experienced recurrent preterm birth. Second trimester CRH may be useful in identifying a sub-group of women with preterm birth due to early activation of the placenta-fetal adrenal axis. Assay methodology is a variable that contributes to difficulties in reproducibility of CRH levels in the obstetric literature.

Hypothalamic-Pituitary-Adrenal Activity in Adverse Events Reporting After Placebo Administration.

Participants of clinical trials who receive a placebo treatment often report a variety of adverse events, sometimes called nocebo effects. The reason why these adverse events occur is not clear, and understanding the underlying mechanisms represents a challenge that is likely to improve the interpretation of clinical trials as well as medical practice. Here, we studied 192 healthy subjects who received placebo oxygen through a mask after reading (READ) or not reading (NO-READ) a list of possible adverse events of oxygen breathing: headache, chest pain, abdominal pain, and cough. The whole hypothalamus-pituitary-adrenal axis was assessed just before and right after placebo breathing by measuring the hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol (COR). In addition, both state and trait anxiety were assessed. We found that 64.5% of the NO-READ group reported no adverse events, 30.2% had one, and only 5.2% had two adverse events. In contrast, only 20.8% of the READ group reported no adverse events, whereas 1, 2, 3, and 4 adverse events were reported with a frequency of 21.8%, 19.8%, 19.8%, and 17.7%, respectively. In addition, when the READ group reported three and four adverse events, CRH, ACTH, and COR were significantly increased compared to the NO-READ group, along with an increase in state anxiety scores. These data indicate that hypothalamic-pituitary-adrenal activity and state anxiety are increased in those subjects who report many adverse events after reading a list of adverse events, thus highlighting a possible neuroendocrine mechanism after placebo administration.

The Effects of Sampling Lateralization on Bilateral Inferior Petrosal Sinus Sampling for Pediatric Cushing's Disease-A Single Endocrinology Centre Experience and Review of the Literature.

Background: This study aims to analyze the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS), the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) in a group of pediatric patients with Cushing's disease (CD). Methods: This is a retrospective analysis which include 12 patients with hypercortisolemia and inconclusive pituitary MRI, who underwent bilateral inferior petrosal sinus sampling (BIPSS) and transsphenoidal surgery (TSS) from 2004 to 2020 in the Children's Memorial Health Institute (CMHI) Warsaw, Poland. Pituitary origin of ACTH secretion was considered if baseline central to peripheral (C/P) ACTH level ratio was ≥ 2 or C/P ratio was ≥ 3 after human corticotropin-releasing hormone (hCRH) stimulation. The diagnosis was histologically confirmed in almost all cases after TSS. Results: The diagnostic accuracy of BIPSS reached 75% at baseline and 83.3% after CRH stimulation. The compatibility of localization of a microadenoma by BIPSS with the surgical location was 66.7%. Conclusions: Owing to its high diagnostic effectiveness, BIPSS remains the best test to differentiate CD from EAS. The indications for the procedure should be carefully considered, because EAS in the pediatric population, unlike in adults, is extremely rare. Moreover BIPSS has only limited value for indicating tumor localization.

Differential Health Effects on Inflammatory, Immunological and Stress Parameters in Professional Soccer Players and Sedentary Individuals after Consuming a Synbiotic. A Triple-Blinded, Randomized, Placebo-Controlled Pilot Study.

The main objective of this research was to carry out an experimental study, triple-blind, on the possible immunophysiological effects of a nutritional supplement (synbiotic, Gasteel Plus®, Heel España S.A.U.), containing a mixture of probiotic strains, such as Bifidobacterium lactis CBP-001010, Lactobacillus rhamnosus CNCM I-4036, and Bifidobacterium longum ES1, as well as the prebiotic fructooligosaccharides, on both professional athletes and sedentary people. The effects on some inflammatory/immune (IL-1ß, IL-10, and immunoglobulin A) and stress (epinephrine, norepinephrine, dopamine, serotonin, corticotropin-releasing hormone (CRH), Adrenocorticotropic hormone (ACTH), and cortisol) biomarkers were evaluated, determined by flow cytometer and ELISA. The effects on metabolic profile and physical activity, as well as on various parameters that could affect physical and mental health, were also evaluated via the use of accelerometry and validated questionnaires. The participants were professional soccer players in the Second Division B of the Spanish League and sedentary students of the same sex and age range. Both study groups were randomly divided into two groups: a control group-administered with placebo, and an experimental group-administered with the synbiotic. Each participant was evaluated at baseline, as well as after the intervention, which lasted one month. Only in the athlete group did the synbiotic intervention clearly improve objective physical activity and sleep quality, as well as perceived general health, stress, and anxiety levels. Furthermore, the synbiotic induced an immunophysiological bioregulatory effect, depending on the basal situation of each experimental group, particularly in the systemic levels of IL-1ß (increased significantly only in the sedentary group), CRH (decreased significantly only in the sedentary group), and dopamine (increased significantly only in the athlete group). There were no significant differences between groups in the levels of immunoglobulin A or in the metabolic profile as a result of the intervention. It is concluded that synbiotic nutritional supplements can improve anxiety, stress, and sleep quality, particularly in sportspeople, which appears to be linked to an improved immuno-neuroendocrine response in which IL-1ß, CRH, and dopamine are clearly involved.

Water-Soluble Carbon Dots in Cigarette Mainstream Smoke: Their Properties and the Behavioural, Neuroendocrinological, and Neurotransmitter Changes They Induce in Mice.

BACKGROUND: It is well known that smoking is harmful to health; however, it can also ameliorate anxiety. To date, it is unclear whether any nanoparticles found in cigarette mainstream smoke (CS) contribute to this effect. AIM: The aim of this study was to assess the particle composition of CS to identify novel anti-anxiety components. METHODS: Carbon dots (CDs) from CS (CS-CDs) were characterised using high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-anxiety effects of CS-CDs in mouse models were evaluated and confirmed with the elevated plus maze and open-field tests. RESULTS: The quantum yield of CS-CDs was 13.74%, with a composition of C, O, and N. In addition, the surface groups contained O-H, C-H, C=O, C-N, N-H, C-O-C, and COO- bonds. Acute toxicity testing revealed that CS-CDs had low in vitro and in vivo toxicity within a certain concentration range. The results of the elevated plus maze and open-field tests showed that CS-CDs had a significant anti-anxiety effect and a certain sedative effect in mice. The mechanism of these effects may be related to the decrease in glutamate levels and promotion of norepinephrine production in the mouse brain, and the decrease in dopamine in mouse serum due to CS-CDs. CONCLUSION: CS-CDs may have anti-anxiety and certain sedative effects. This study provides a new perspective for a more comprehensive understanding of the components, properties, and functions of CS. Furthermore, it offers a novel target for the development of smoking cessation treatments, such as nicotine replacement therapy.

An in vivo explorative study to observe the protective effects of Puerariae flos extract on chronic ethanol exposure and withdrawal male mice.

Protective effects of Puerariae flos extract (PFE) on ethanol (EtOH) exposure have been previously verified. This study attempts to explore the protective effects of PEF on EtOH withdrawal models. Sixty male Kunming mice were involved which were randomly divided into five groups (intact control, EtOH group (35-day EtOH exposure), EtOH withdrawal group (28-day exposure + 7-day withdrawal), EtOH withdrawal group + positive control (Deanxit) group, and EtOH withdrawal group + PFE group). The changes of neuropsychological behaviors; hippocampal BDNF expression and CA1 neuronal density; and plasma corticotropin-releasing hormone (CRH), ACTH, and CORT levels were observed. It was found that depression-like behaviors reduced by EtOH exposure and increased by withdrawal under the 28-day EtOH exposure and 7-day withdrawal conditions. In addition, anxiety-like behaviors worsened by EtOH exposure and unchanged by withdrawal. Deanxit and PEF ameliorated such behaviors (vs. withdrawal group). Hippocampal BDNF expression was significantly downregulated by EtOH exposure and upregulated by withdrawal. Deanxit and PEF significantly upregulated the BDNF expression. The hippocampal CA1 neuronal density significantly decreased by EtOH exposure but unchanged by withdrawal and treatments. The plasma CRH, ACTH, and CORT levels show a significant enhancement by EtOH exposure and reduced by withdrawal. They were further reduced by Deanxit and PEF. The protective effects of PEF on EtOH chronic withdrawal mouse models were verified. The results of this study also indicated a complicated scenario of neuropsychological behaviors, hippocampal BDNF expression, and hypothalamic-pituitary-adrenal axis which are affected by the timing of EtOH exposure and withdrawal.

Cytokines in the colon, central nervous system and serum of irritable bowel syndrome rats.

OBJECTIVE: The aim of this study was to detect the expression of interleukin (IL)-1ß and transforming growth factor (TGF)-ß1 in the colonic tissue and serum of irritable bowel syndrome (IBS) rats, as well as the distribution and expression of corticotropin-releasing factor (CRF) in the spinal cord and brain of the visceral hypersensitivity rats, thus to ascertain the mechanism of visceral hypersensitivity signal conduction pathway. METHODS: The expression of IL-1ß and TGF-ß1 in the colonic tissue and serum of IBS rats was screened by the liquid chip technology and verified by RT-PCR technology. Then the quantitative analysis of CRF in the spinal cord and brain was achieved by the immunohistochemical method and computerized image system. RESULT: The rat model with visceral hypersensitivity was successfully established. Among the screened indicators of IL-1ß and TGF-ß1 in colon tissue and serum, only the expression of IL-1ß in the model group was up-regulated (P < 0.05). The immunohistochemical method showed that CRF was expressed in the spinal cord, hypothalamus, and the third ventricle. The positive index number of the model groups was higher than that of the control group (P < 0.01). CONCLUSION: From the research, it can be inferred that IL-1ß may participate in the pathogenesis mechanism of IBS via regulating the colon function. The increasing expression of CRF linked to stress in the spinal cord, hypothalamus and the third ventricle indicated that it might play an important role in the mechanisms of visceral hypersensitivity signal conduction pathway.

Comprehensive chemical analysis of Zhenshu Tiaozhi formula and its effect on ameliorating glucolipid metabolic disorders in diabetic rats.

The present study aims to reveal the compositions of Zhenshu TiaoZhi formula (FTZ) comprehensively, and investigate whether FTZ ameliorate glucolipid metabolism disorders in diabetic rats with the involvement of glucocorticoids in peripheral insulin-sensitive tissues. The fingerprint was established based on 11 batches of FTZ samples and chemical compostions of FTZ were identified by ultra performance liquid chromatography-time of flight/mass spectrometry (UPLC-TOF/MS). High-fat diet (HFD) and streptozotocin (STZ) induced diabetic rats were orally administrated with 3 and 6 g/kg body weight of FTZ for 8 weeks. Indices of glucolipid metabolism, including fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI) and blood lipids were evaluated after treatment of FTZ. The levels of HPA axis hormones were examined. Reverse transcription-polymerase chain reaction (RT-PCR) was adopted to investigate the relative mRNA expressions of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) and glucolipid metabolic indicators. A reference fingerprint was established and 93 compounds of FTZ were tentatively identified. In vivo, FTZ treatment exerted antidiabetic and antidyslipidemic effects while decreased the level of corticotropin releasing hormone (CRH). 11ß-HSD1 mRNA showed similar trajectory in both liver, adipose and skeletal muscle tissues, which was up-regulated in diabetic group and ameliorated in FTZ groups. Furthermore, the expressions of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK) and adipose triglyceride lipase (ATGL) were down-regulated in liver and skeletal muscle. These results elucidated the compositions of FTZ comprehensively and indicated its effect on ameliorating glucolipid metabolism of diabetic rats involved hypothalamus-pituitary-adrenal (HPA) axis homeostasis. Down-regulating 11ß-HSD1 in insulin-sensitive tissues might be a potential mechanism of FTZ in treating type 2 diabetes mellitus (T2DM).

Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: Insights from transcriptomics.

BACKGROUND: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PURPOSE: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). STUDY DESIGN AND METHODS: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. RESULTS: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 µg/ml. CONCLUSION: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

Ectopic ACTH- and/or CRH-Producing Pheochromocytomas.

CONTEXT: The characteristics of catecholamine-secreting pheochromocytomas have been well studied. However, less is known about the characteristics, management and outcome in patients with ectopic adrenocorticotropic hormone (ACTH) and/or corticotrophin-releasing hormone (CRH)-secreting pheochromocytomas. OBJECTIVE: To review the characteristics and outcomes of ACTH- and/or CRH-secreting pheochromocytomas. DATA SOURCE: A systematic search of PubMed/MEDLINE and Web of Science, identifying relevant reports published up to 10 February 2020. STUDY SELECTION: Original articles, including case reports and case series, reporting individual patient data from patients with ACTH- and/or CRH-secreting pheochromocytomas. DATA EXTRACTION: Information on sex, age, symptoms at presentation, comorbidities, biochemistry, imaging, histopathology, and outcomes was extracted. DATA SYNTHESIS: We identified 91 articles reporting on 99 cases of ACTH- and/or CRH-secreting pheochromocytomas (CRH-secreting n = 4). Median age at diagnosis was 49 years (interquartile range 38-59.5) with a 2:1 female to male ratio. Most patients presented with clinical Cushing syndrome (n = 79; 81%), hypertension (n = 87; 93%), and/or diabetes (n = 50; 54%). Blood pressure, glucose control, and biochemical parameters improved in the vast majority of patients postoperatively. Infections were the most common complication. Most cases (n = 70, 88%) with reported long-term outcome survived to publication (median follow-up 6 months). CONCLUSION: Ectopic ACTH- and/or CRH-secreting pheochromocytoma should be considered in patients presenting with ACTH-dependent Cushing syndrome and adrenal mass. Despite the challenge in diagnosis, patient outcomes appear favorable.

Investigating apoptotic, inflammatory, and growth markers in poor responders undergoing natural in vitro fertilization cycles: a pilot study.

This study investigates follicular fluid (FF) from patients with poor and normal ovarian response undergoing natural assisted reproductive technology cycles. We report about (1) cell-free DNA (cfDNA), which reflects apoptosis; (2) corticotropin-releasing hormone (CRH); (3) interleukin (IL)-15, which reflects inflammation; (4) granulocyte colony-stimulating factor (G-CSF); (5) vascular endothelial growth factor (VEGF); and (6) insulin-like growth factor I (IGF-I), which reflects follicular growth. Forty-four poor responders and 44 normal responders-according to the Bologna criteria-were recruited. FF samples were prepared for cfDNA quantification employing Q-PCR and for CRH, IL-15, G-CSF, VEGF, and IGF-I quantification employing ELISA. Statistically nonsignificant different levels of FF cfDNA, CRH, IL-15, VEGF, and IGF-I were observed. Interestingly, statistically significant higher G-CSF levels were observed in normal responders (302.48 ± 474.36 versus 200.10 ± 426.79 pg/mL, P = 0.003). Lower cfDNA integrity was observed in cycles resulting in clinical pregnancy for both groups (normal: 0.07 ± 0.04 versus 0.25 ± 0.17 ng/µL, P < 0.001; poor: 0.10 ± 0.06 versus 0.26 ± 0.12 ng/µL, P < 0.001). The results predominantly showcase similarities between normal and poor responders pertaining to inflammatory, apoptotic, and growth factors. This may be attributed to the employment of natural cycles in order to exclude controlled ovarian stimulation as a factor-indicating its detrimental effect. As G-CSF levels presented significantly higher in normal responders, its vital role in understanding a compromised ovarian response is highlighted.

Lilium davidii extract alleviates p­chlorophenylalanine­induced insomnia in rats through modification of the hypothalamic-related neurotransmitters, melatonin and homeostasis of the hypothalamic-pituitary-adrenal axis.

CONTEXT: Lilium davidii var. unicolour Cotton (Lilium genus, Liliaceae) is an edible plant and a herb used in China to alleviate insomnia. OBJECTIVE: To investigate the alleviating insomnia mechanism of L. davidii (LD). MATERIALS AND METHODS: Wistar rats were intraperitoneally injected with p-chlorophenylalanine (PCPA) to establish an insomnia model. Rats were divided into six groups (n = 8): Control, PCPA, Estazolam (0.5 mg/kg), LD extract in low, medium and high doses (185.22, 370.44, 740.88 mg/kg). Serum hormone levels of the HPA axis, levels of 5-HT, NE and MT, and the expression of GABAA and 5-HT1A receptors in hypothalamus were determined. Moreover, behavioural and pathological changes in the hypothalamus were evaluated. RESULTS: After LD administration, body weight and brain coefficient increased by 2.74% and 8.22%, respectively, and the adrenal coefficient decreased by 25%, compared with PCPA group. Elevation of the serum hypothalamic-pituitary-adrenal (HPA) axis hormone CRH (11.24 ± 3.16 ng/mL), ACTH (565.87 ± 103.44 pg/mL) and CORT (44.28 ± 8.73 ng/mL) in the PCPA group was reversed after LD treatment. Furthermore, abnormal excitatory behaviour [5 min movement distance (2096.34 ± 259.51 cm), central exercise time (5.28 ± 1.08 s)] of insomnia rats in the PCPA group was also relieved. LD extract increased 5-HT and MT levels, reduced NE level in the hypothalamus, and upregulated the expression of GABAA R and 5-HT1A. Moreover, LD extract may improve the pathology of neurons in the hypothalamus. CONCLUSIONS: LD can be considered to develop health-care food or novel drugs to cope with the increasing number of insomniacs.

Predictive value of serum CRH/5-HT ratio for postpartum depression.

OBJECTIVE: To analyze the changes in the serum levels of CRH and 5-HT in women with postpartum depression (PPD) and to study the value of the CRH/5-HT ratio for the prediction of PPD. METHODS: This prospective study recruited pregnant women from the Fourth Affiliated Hospital, China Medical University between January 2017 and October 2019. Women were considered for inclusion if they had no history, or no current evidence, of a psychiatric disorder. All women were assessed at postpartum day 10 with the Edinburgh Postnatal Depression Scale (EPDS). Blood samples were obtained at 20 weeks of pregnancy and the levels of CRH and 5-HT were determined by radioimmunoassay and ELISA. Associations between EPDS score, the demographic variables, and hormone levels were identified using bivariate logistic regression models. RESULTS: A total of 185 women were included. We found that the serum level of both CRH and 5-HT was significantly correlated with EPDS score; the AUC for CRH was 0.79, and 5-HT was 0.85, which indicated that both CRH and 5-HT are a reliable biomarker for PPD. The AUC, specificity, and sensitivity of CRH/5-HT were 0.92, 0.86, and 0.95, respectively, which were better than those of CRH or 5-HT individually. CONCLUSIONS: We believe that the serum CRH/5-HT ratio is an excellent biomarker for the prediction of PPD.

N-3 PUFA Have Antidepressant-like Effects Via Improvement of the HPA-Axis and Neurotransmission in Rats Exposed to Combined Stress.

Early life and adulthood stress increase vulnerability for mental illness, and eventually trigger depression. N-3 polyunsaturated fatty acids (PUFA) have antidepressant effects, but their effect on rats exposed to combined stress has been not investigated. This study aimed to investigate whether n-3 PUFA supplementation had antidepressant-like effects in rat models of depression induced by a combination of chronic mild stress (CMS) and maternal separation (MS) through the modulation of the hypothalamic-pituitary-adrenal (HPA) axis and neurotransmission. Rats were fed the n-3 PUFA diet during the pre-weaning or post-weaning period or for lifetime, and allocated to different groups based on the type of induced stress: non-stress (NS), CMS + MS, or CMS alone. N-3 PUFA improved the depressive behaviors of the CMS alone and CMS + MS groups and modulated the HPA-axis by reducing the circulating adrenocorticotropic hormone, corticosterone, and corticotropin-releasing factor expression, and increasing glucocorticoid receptor expression. N-3 PUFA also modulated brain phospholipid fatty acid concentration, thus reducing inflammatory cytokines; improved the serotonergic pathway, thus increasing the expression of the brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), serotonin-1A receptor, and serum levels of serotonin; but did not affect glutamatergic neurotransmission. Furthermore, n-3 PUFA decreased the hippocampal expression of microRNA-218 and -132, increased that of microRNA-155, and its lifetime supplementation was more beneficial than pre- or post-weaning supplementation. This study suggests that n-3 PUFA has an antidepressant effect in rats exposed to combined stress, through the improvement of the HPA-axis abnormalities, the BDNF-serotonergic pathway, and the modulation of microRNAs.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Vitamin D3 Supplementation in Diarrhea-Predominant Irritable Bowel Syndrome Patients: The Effects on Symptoms Improvement, Serum Corticotropin-Releasing Hormone, and Interleukin-6 - A Randomized Clinical Trial.

OBJECTIVES: This study aimed to evaluate whether vitamin D deficiency is associated with the severity of symptoms of irritable bowel syndrome (IBS) patients. Stress and gut inflammation can increase the serum level of corticotropin-releasing hormone (CRH) and interleukin-6 (IL-6), leading to a change in bowel movements. The aim of this study was to evaluate the anti-inflammatory and psychological effects of vitamin D3 supplementation on the symptom improvement of patients with a diarrhea-predominant form of IBS (IBS-D). METHODS: Eighty-eight IBS-D patients (age: 18-65 years) based on Rome IV criteria who suffered from vitamin D deficiency and/or insufficiency were enrolled in this randomized, placebo-controlled trial from February 2017 to May 2018 at Rasoul-e-Akram Hospital, Tehran, Iran. Participants were randomly divided into two groups. The intervention group received 50,000 IU vitamin D3 weekly and the control group received a placebo for 9 weeks. All patients received Mebeverine 135 mg twice a day besides supplementation. The IBS Severity Score System (IBS-SSS), serum 25(OH) vitamin D3, CRH, and IL-6 were measured before and after interventions. RESULTS: Seventy-four patients completed the study. The severity of IBS symptoms (p < 0.01) and IL-6 (p = 0.02) decreased significantly in the intervention group as compared to the control group, but there was no significant difference in the serum level of CRH. Also, in the treatment group, IBS-SSS and IL-6 were significantly reduced at the end of the study from baseline (p < 0.01 and p < 0.03, respectively). CONCLUSION: Our findings indicate that vitamin D3 supplementation can modulate the serum level of CRH and IL-6 and can improve symptoms in IBS-D patients. Vitamin D3 supplementation should be considered in IBS-D patients who suffer from vitamin D deficiency and/or insufficiency.