Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway / 中国中药杂志

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1β), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1β and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1β and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Corticotropin-releasing factor receptor signaling and modulation: implications for stress response and resilience

Abstract Introduction In addition to their role in regulation of the hypothalamic-pituitary-adrenal-axis, corticotropin-releasing factor (CRF) and its related peptides, the urocortins, are important mediators of physiological and pathophysiological processes of the central nervous, cardiovascular, gastrointestinal, immune, endocrine, reproductive, and skin systems. Altered regulation of CRF-mediated adaptive responses to various stressful stimuli disrupts healthy function and might confer vulnerability to several disorders, including depression and anxiety. Methodology This narrative review was conducted through search and analysis of studies retrieved from online databases using a snowball method. Results This review covers aspects beginning with the discovery of CRF, CRF binding protein and their actions via interaction with CRF receptors type 1 and type 2. These are surface plasma membrane receptors, activation of which is associated with conformational changes and interaction with a variety of G-proteins and signaling pathways. We also reviewed the pharmacology and mechanisms of the receptor signaling modulatory activity of these receptors. Conclusion This review compiles and presents knowledge regarding the CRFergic system, including CRF related peptides, CRF binding protein, and CRF receptors, as well as some evidence that is potentially indicative of the biological roles of these entities in several physiological and pathophysiological processes.

Determinación de valores de referencia de cortisol salival en lactantes sanos de 0 a 12 meses / Determination of reference values for salivary cortisol in healthy infants aged 0-12 months

Introducción. El cortisol salival es una herramienta útil como biomarcador de estrés en pediatría, ya que la obtención de muestras no es invasiva. Hay escasa información sobre su uso en niños, y no se reportaron valores de referencia en lactantes sanos en la Argentina. Es importante establecerlos en cada centro como base para realizar estudios posteriores en lactantes, en quienes parece ser la herramienta objetiva más relevante en la actualidad para evaluar estrés. Objetivo. Determinar los valores de referencia de cortisol salival en lactantes sanos de 0 a 12 meses de edad. Métodos. Estudio descriptivo, de corte transversal, que evaluó cortisol salival matutino de niños sanos de ambos sexos de 0 a 12 meses que concurrieron a control de salud en el Hospital Pirovano entre marzo de 2017 y marzo de 2018. Se tomaron muestras de saliva de 8 a 9 a. m. en ayunas y se procesaron con electroquimioluminiscencia. Los resultados se informaron como media y desvío estándar. Resultados. Se incluyeron 140 niños, y se obtuvieron 96 muestras. La media de cortisol salival matutino fue 5,46 nmol/l (intervalo de confianza del 95 %: 4,66-6,38), desvío estándar 2,15. No se observó correlación con la variable edad, por lo cual el intervalo de referencia no requirió el fraccionamiento por grupo etario. No se observaron diferencias significativas respecto a sexo, edad gestacional, peso al nacer, tipo de parto o tipo de alimentación. Conclusión. Se informó el intervalo de referencia de cortisol salival matutino en lactantes sanos de 0 a 12 meses.

Introduction. Salivary cortisol is a useful tool as a biomarker of stress in pediatrics because it allows for non-invasive sampling. There is little information about its use in children, and no reference values for healthy infants have been reported in Argentina. Reference values should be established at each site as the basis for subsequent tests in infants, for whom salivary cortisol appears to be the most relevant objective tool to assess stress at present. Objective. To determine reference values for salivary cortisol in healthy infants aged 0-12 months. Methods. Descriptive, cross-sectional study that assessed morning salivary cortisol levels in healthy male and female infants aged 0-12 months that attended Hospital Pirovano for a health checkup between March 2017 and March 2018. Fasting saliva samples were collected between 8 and 9 a.m. and were processed using electrochemiluminescence. Results were reported as mean and standard deviation. Results. A total of 140 infants were included, and 96 samples were collected. Mean morning salivary cortisol levels were 5.46 nmol/L (95 % confidence interval: 4.66-6.38), standard deviation: 2.15. No correlation to age was observed, so it was not necessary to divide the reference range into age groups. No significant differences were observed in terms of sex, gestational age, birth weight, type of delivery or type of feeding. Conclusion. The reference range of morning salivary cortisol levels in healthy infants aged 0-12 months was reported.

Sex-Related Effects of Prenatal Stress on Region-Specific Expression of Monoamine Oxidase A and β Adrenergic Receptors in Rat Hearts / Efeitos Sexo-Específicos de Estresse Pré-Natal na Expressão Região-Específica de Monoamina Oxidase A e Receptores Adrenérgicos Β no Coração de Ratos

Abstract Background: Prenatal stress may increase risk of developing cardiovascular disorders in adulthood. The cardiotoxic effects of catecholamines are mediated via prolonged adrenergic receptor stimulation and increased oxidative stress upon their degradation by monoamine oxidase A (MAO-A). Objectives: We investigated long-term effects of prenatal stress on β (1, 2, 3) adrenergic receptors and MAO-A gene expression in the hearts of adult rat offspring. Methods: Pregnant rats were exposed to unpredictable mild stress during the third week of gestation. RNA was isolated from left ventricular apex and base of adult offspring. Quantitative PCR was used to measure gene expression in collected ventricular tissue samples. The level of significance was set to p < 0.05. Results: β3 adrenergic receptor mRNA was undetectable in rat left ventricle. β1 adrenergic receptor was the predominantly expressed subtype at the apical and basal left ventricular myocardium in the control females. Male offspring from unstressed mothers displayed higher apical cardiac β1 than β2 adrenergic receptor mRNA levels. However, β1 and β2 adrenergic receptor mRNAs were similarly expressed at the ventricular basal myocardium in males. Unlike males, prenatally stressed females exhibited decreased β1 adrenergic receptor mRNA expression at the apical myocardium. Prenatal stress did not affect cardiac MAO-A gene expression. Conclusions: Collectively, our results show that prenatal stress may have exerted region- and sex-specific β1 and β2 adrenergic receptor expression patterns within the left ventricle.

Resumo Fundamento: Estresse pré-natal pode aumentar os riscos de desenvolver doenças cardiovasculares na idade adulta. Os efeitos cardiotóxicos de catecolaminas são mediados pela estimulação prolongada dos receptores adrenérgicos e pelo aumento do estresse oxidativo após sua degradação pela monoamina oxidase A (MAO-A). Objetivos: Investigamos os efeitos a longo prazo de estresse pré-natal nos receptores β (1, 2, 3) adrenérgicos e na expressão do gene MAO-A nos corações da prole adulta de ratos. Método: Ratas prenhes foram expostas a estresse crônico moderado imprevisível durante a terceira semana de gestação. O RNA foi isolado do ápice e da base do ventrículo esquerdo da prole adulta. Utilizou-se PCR quantitativa em tempo real para medir a expressão gênica nas amostras de tecido ventricular coletadas. O nível de significância foi estabelecido em p < 0,05. Resultados: Foi indetectável o mRNA do receptor adrenérgico β3 no ventrículo esquerdo dos ratos. O receptor adrenérgico β1 foi o subtipo mais expresso no miocárdio ventricular esquerdo apical e basal nas fêmeas controle. A prole masculina das mães não estressadas apresentou níveis cardíacos apicais de mRNA do receptor adrenérgico β1 mais altos do que os de β2. Porém, mRNAs dos receptores adrenérgicos β1 e β2 foram expressos de forma semelhante no miocárdio basal ventricular na prole masculina em geral. Ao contrário da prole masculina, a prole feminina exposta ao estresse pré-natal exibiu uma expressão diminuída do mRNA do receptor adrenérgico β1 no miocárdio apical. O estresse pré-natal não afetou a expressão gênica de MAO-A cardíaca. Conclusões: Coletivamente, nossos resultados mostram que estresse pré-natal pode ter exercido padrões de expressão região- e sexo-específica dos receptores adrenérgicos β1 e β2 no ventrículo esquerdo.

Effect of non-surgical periodontal therapy on the degree of gingival inflammation and stress markers related to pregnancy

Abstract Objectives The purpose of this study was to determine the impact of nonsurgical periodontal therapy considering the salivary stress-related hormone and cytokine levels in the gingival crevicular fluid (GCF) on pregnant and nonpregnant women. Material and Methods Thirty non-pregnant (control group) and 30 pregnant women (test group) that met the study inclusion criteria were chosen. Only participants with gingivitis were included. Clinical data and samples of GCF and saliva were collected at baseline and after periodontal therapy. The levels of interleukin-1 beta (Κ-1β) and IL-10, and concentration of salivary chromogranin A (CgA) hormone were analyzed by enzyme-linked immunosorbent assay (ELISA). The repeated measures analysis of variance was used for intragroup and intergroup analyses. Results A major decrease in the gingival inflammation was observed in both groups after periodontal therapy (p<0.05). Periodontal treatment decreased the level of IL-1β in GCF (p<0.05) in control group, but no statistical difference was determined for GCF IL-1β in the test group. However, after periodontal therapy, the CgA hormone concentration was reduced in both groups (p<0.05). However, there was no difference in salivary CgA concentration, GCF IL-10 levels, and perceived stress scale (PSS)-10 between the groups (p>0.05). Conclusions Within the limitations of this study, periodontal therapy significantly improved the periodontal status and stress level. In addition, the severity of the gingival inflammation during pregnancy was related to stress. However, further studies will be needed to substantiate these early findings.

Salivary cortisol and alpha-amylase: subclinical indicators of stress as cardiometabolic risk

Currently, the potential for cardiovascular (CV) stress-induced risk is primarily based on the theoretical (obvious) side effects of stress on the CV system. Salivary cortisol and α-amylase, produced respectively by the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary (SAM) system during stress response, are still not included in the routine evaluation of CV risk and require additional and definitive validation. Therefore, this article overviews studies published between 2010 and 2015, in which salivary cortisol and α-amylase were measured as stress biomarkers to examine their associations with CV/CMR (cardiometabolic risk) clinical and subclinical indicators. A comprehensive search of PubMed, Web of Science and Scopus electronic databases was performed, and 54 key articles related to the use of salivary cortisol and α-amylase as subclinical indicators of stress and CV/CMR factors, including studies that emphasized methodological biases that could influence the accuracy of study outcomes, were ultimately identified. Overall, the biological impact of stress measured by salivary cortisol and α-amylase was associated with CV/CMR factors. Results supported the use of salivary cortisol and α-amylase as potential diagnostic tools for detecting stress-induced cardiac diseases and especially to describe the mechanisms by which stress potentially contributes to the pathogenesis and outcomes of CV diseases.

Can reactivity to stress and family environment explain memory and executive function performance in early and middle childhood? / Reatividade ao estresse e ambiente familiar podem explicar o desempenho em memória e funções executivas na primeira infância e na idade escolar?

Abstract Introduction: According to the literature, children's overall reactivity to stress is associated with their socioeconomic status and family environment. In turn, it has been shown that reactivity to stress is associated with cognitive performance. However, few studies have systematically tested these three constructs together. Objective: To investigate the relationship between family environment, salivary cortisol measurements and children's memory and executive function performance. Method: Salivary cortisol levels of 70 children aged 9 or 10 years were measured before and after performing tasks designed to assess memory and executive functions. Questionnaires on socioeconomic issues, family environment and maternal psychopathologies were administered to participants' families during the children's early childhood and again when they reached school age. Results: Data were analyzed by calculating correlations between variables and conducting hierarchical regression. High cortisol levels were associated with poorer working memory and worse performance in tasks involving executive functions, and were also associated with high scores for maternal psychopathology (during early childhood and school age) and family dysfunction. Family environment variables and changes in cortisol levels explain around 20% of the variance in performance of cognitive tasks. Conclusion: Family functioning and maternal psychopathology in early and middle childhood and children's stress levels were associated with children's working memory and executive functioning.

Resumo Introdução: De acordo com a literatura, o nível socioeconômico e o ambiente familiar estão associados à reatividade ao estresse na criança. Essa reatividade ao estresse, por sua vez, tem sido associada com desempenho cognitivo. No entanto, poucos estudos testaram sistematicamente esses três construtos ao mesmo tempo. Objetivo: Investigar a relação entre ambiente familiar, medidas de cortisol salivar e desempenho em memória e funções executivas das crianças. Método: Os níveis de cortisol salivar de 70 crianças com idade entre 9 e 10 anos foram medidos antes e depois de tarefas de memória e funções executivas. As famílias dos participantes completaram questionários sobre questões socioeconômicas, ambiente familiar e psicopatologia materna durante a primeira infância e a idade escolar da criança. Resultados: Correlações e regressão hierárquica foram realizadas para análise de dados. Níveis de cortisol elevados, bem como alta psicopatologia materna (na primeira infância e em idade escolar) e disfunção familiar foram associados com baixo desempenho em tarefas de funções executivas e memória de trabalho. As variáveis ambiente familiar e alterações nos níveis de cortisol explicam cerca de 20% da variação no desempenho de tarefas cognitivas. Conclusão: O funcionamento familiar e a psicopatologia materna no início e meio da infância, bem como os níveis de estresse das crianças, foram associados com a memória de trabalho e o funcionamento executivo das crianças.

Anesthesia for EXIT procedure (ex utero intrapartum treatment) in congenital cervical malformation - a challenge to the anesthesiologist / Anestesia para procedimento EXIT (tratamento extraútero intraparto) em malformação congênita cervical - um desafio para o anestesiologista

The ex utero intrapartum treatment (EXIT) procedure consists of partial externalization of the fetus from the uterine cavity during delivery, allowing the maintenance of placental circulation. It is indicated in the presence of congenital malformation when difficulty in fetal airway access is anticipated, allowing it to be ensured by direct laryngoscopy, bronchoscopy, tracheostomy, or surgical intervention. Anesthesia for EXIT procedure has several special features, such as the appropriate uterine relaxation, maintenance of maternal blood pressure, fetal airway establishment, and maintenance of postpartum uterine contraction. The anesthesiologist should be prepared for the anesthetic particularities of this procedure in order to contribute to a favorable outcome for the mother and particularly the fetus.

O procedimento EXIT (tratamento extraútero intraparto) consiste na exteriorização parcial do feto da cavidade uterina durante o parto para permitir a manutenção da circulação fetoplacentária. Está indicado na presença de malformações congênitas em que se antecipa a dificuldade no acesso da via aérea fetal e permite que essa seja assegurada por laringoscopia direta, broncoscopia, traqueostomia ou intervenção cirúrgica. A anestesia para procedimento EXIT apresenta várias particularidades. O relaxamento uterino adequado, a manutenção da pressão arterial materna, o estabelecimento de via aérea fetal e a manutenção da contração uterina pós-parto são alguns exemplos. O anestesiologista deve estar preparado para as particularidades anestésicas desse procedimento, de modo a contribuir para um desfecho favorável para a mãe e particularmente para o feto.

Deleterious effects of prepubertal corticosterone treatment on rat prostate

PURPOSE: To investigate the structural and functional changes induced by corticosterone (CORT) in the ventral prostrate (VP) of rats in order to study chronic stress effects in the prepubertal phase. METHODS: Wistar rats received daily saline or CORT injections during the pubertal period from the 5th to 25th day of postnatal life. The animals were distributed into four groups: 1 - Control (n=5); 2 - Control 99mTc-P (n=5); 3 - Treated with CORT (n=14); 4 - Treated with CORT and 99mTc-P (n=10). All rats were sacrificed at two months of age. Technical tissue uptakes of 99mTc-P were used to evaluate the functional and stereological methods for morphological analysis. RESULTS: Acini distribution in the group treated with CORT differed significantly (p<0.0001) from the control. The control group's epithelial average height (10.01±0.24 microns) was statistically significant (p<0.0001) from rats treated with CORT (19.27±0.73microns). The collagen distribution was lower in the treated group (2.79%) when compared to control (3.97%). The radioactivity percentage in the groups marked with 99mTc-P (%Ati/g) did not demonstrate a statistically significant difference (p=0.285897). CONCLUSION: Chronic administration of corticosterone in prepubertal rats causes changes in their acinar structure and their ventral prostate stroma, indicating possible deleterious effects of this hormone. .

Social defeat protocol and relevant biomarkers, implications for stress response physiology, drug abuse, mood disorders and individual stress vulnerability: a systematic review of the last decade / Protocolo de derrota social e biomarcadores relevantes, implicações para a fisiologia de resposta ao estresse, abuso de drogas, transtornos do humor e vulnerabilidade individual ao estresse: revisão sistemática de estudos na última década

Introduction: Social defeat (SD) in rats, which results from male intraspecific confrontations, is ethologically relevant and useful to understand stress effects on physiology and behavior. Methods: A systematic review of studies about biomarkers induced by the SD protocol and published from 2002 to 2013 was carried out in the electronic databases PubMed, Web of Knowledge and ScienceDirect. The search terms were: social defeat, rat, neurotrophins, neuroinflammatory markers, and transcriptional factors. Results: Classical and recently discovered biomarkers were found to be relevant in stress-induced states. Findings were summarized in accordance to the length of exposure to stress: single, repeated, intermittent and continuous SD. This review found that the brain-derived neurotrophic factor (BDNF) is a distinct marker of stress adaptation. Along with glucocorticoids and catecholamines, BDNF seems to be important in understanding stress physiology. Conclusion: The SD model provides a relevant tool to study stress response features, development of addictive behaviors, clinic depression and anxiety, as well as individual differences in vulnerability and resilience to stress. .

Introdução: A derrota social (social defeat, SD) entre ratos, resultado da confrontação intraespecífica entre machos, é etologicamente relevante e útil para o entendimento dos efeitos do estresse na fisiologia e no comportamento. Métodos: Foi realizada uma revisão sistemática de estudos sobre biomarcadores induzidos pelo protocolo de SD publicados entre 2002 e 2013, usando as bases de dados PubMed, Web of Knowledge e ScienceDirect. Os termos usados na busca foram: derrota social, neurotrofinas, marcadores neuroinflamatórios e fatores de transcrição. Resultados: Biomarcadores clássicos ou recentemente descobertos mostraram-se relevantes nos estados induzidos pelo estresse. Os achados foram resumidos de acordo com o tempo de exposição ao estresse: SD única, repetida, intermitente ou contínua. O fator neurotrófico derivado do cérebro se mostrou um marcador específico de adaptação ao estresse. Assim como glicocorticóides e catecolaminas, o BDNF parece ser importante para o entendimento da fisiologia do estresse. Conclusão: O modelo de SD oferece uma ferramenta importante para estudar características da resposta ao estresse, desenvolvimento de comportamentos aditivos, depressão clínica e ansiedade, bem como diferenças individuais de vulnerabilidade e resiliência ao estresse. .

Changes in tau phosphorylation levels in the hippocampus and frontal cortex following chronic stress

Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.

Vitamina C restaura pressão arterial e a resposta vasodilatadora no antebraço em crianças obesas / Vitamin C restores blood pressure and vasodilator response during mental stress in obese children / Vitamina C restaura presión arterial y respuesta vasodilatadora en el antebrazo en niños obesos

FUNDAMENTO: A resposta vasodilatadora periférica tem um papel importante na fisiopatologia da obesidade e das doenças cardíacas. OBJETIVO: Avaliar o efeito crônico da suplementação de vitamina C (VitC) sobre a pressão arterial e na resposta vasodilatadora ao estresse mental. MÉTODOS: Neste estudo prospectivo, randomizado e duplo cego foram avaliadas crianças obesas, de ambos os gêneros e com idade entre 8 a 12 anos divididas em 2 grupos: 1) grupo de crianças suplementadas com 500 mg de vitamina C (n = 11) e, 2) substância placebo (n = 10) durante 45 dias. Oito crianças eutróficas, pareadas por idade também foram arroladas no estudo. Foi avaliada a pressão arterial média (PAM), frequência cardíaca (ECG) e fluxo sanguíneo no antebraço pela plestimografia de oclusão venosa. A condutância vascular no antebraço (CVA) foi obtida através da relação entre o fluxo sanguíneo no antebraço e a PAM (X100). RESULTADOS: Antes da intervenção, as crianças obesas apresentaram PAM maior e CVA menor quando comparadas às crianças eutróficas. Pós-intervenção, o Grupo VitC apresentou redução da PAM no repouso (81 ± 2 vs 75 ± 1 mmHg, p = 0,01), enquanto no Grupo Placebo não houve alteração da PAM (p = 0,58). Adicionalmente, VitC promoveu um aumento da CVA no repouso (3,40 ± 0,5 vs 5,09 ± 0,6 un, p = 0,04) e durante o estresse mental (3,92 ± 0,5 vs 6,68 ± 0,9 un, p = 0,03). Além disso, pós suplementação com VitC, os níveis da CVA foram estatisticamente semelhantes aos das crianças eutróficas no repouso (5,09 ± 0,6 vs 5,82 ± 0,4 un, p > 0,05) e durante o estresse mental (6,68 ± 0,9 vs 7,35 ± 0,5 un, p > 0,05). CONCLUSÃO: Suplementação com VitC reduziu a pressão arterial e restabeleceu a resposta vasodilatadora periférica em crianças obesas.

BACKGROUND: Peripheral vasodilation response plays an important role in the pathophysiology of obesity and heart disease. OBJECTIVE: To evaluate the chronic effect of vitamin C (VitC) supplementation on blood pressure and on vasodilation response to mental stress. METHODS: In a double-blind, randomized and prospective study we evaluated obese children with 8 to 12 years in 2 similar groups: 1) supplemented with 500 mg VitC (n = 11) and 2) placebo (n = 10) for 45 days. Eight age-matched lean control children were also studied. We evaluated: mean blood pressure (MBP), heart rate (HR) and forearm blood flow by venous occlusion plethismography. Forearm vascular conductance (FVC) was calculated by: (forearm blood flow/PAM) X100. RESULTS: On pre-intervention evaluations obese children showed higher MBP and lower FVC compared to lean control children. After intervention VitC diminished MBP at rest (81 ± 2 vs 75 ± 1 mmHg, p = 0.01), whereas placebo did not promote changes in MBP (p = 0.58). In addition, VitC promoted FVC increase at rest (3.40 ± 0.5 vs 5.09 ± 0.6 un, p = 0.04) and during the mental stress (3.92 ± 0.5 vs 6.68 ± 0.9 un, p = 0.03). Moreover, after VitC supplementation FVC levels were similar to the lean control children at rest (5.09 ± 0.6 vs 5.82 ± 0.4 un, p > 0.05) and during mental stress (6.68 ± 0.9 vs 7.35 ± 0.5 un, p > 0.05). CONCLUSION: VitC supplementation reduced the MBP and restored peripheral vasodilatation response during mental stress in obese children.

FUNDAMENTO: La respuesta vasodilatadora periférica tiene un papel importante en la fisiopatología de la obesidad y de las enfermedades cardíacas. OBJETIVO: Evaluar el efecto crónico de la suplementación de vitamina C (VitC) sobre la presión arterial y en la respuesta vasodilatadora al estrés mental. MÉTODOS: En este estudio prospectivo, randomizado y doble ciego fueron evaluados niños obesos, de ambos géneros, con edades entre 8 y 12 años divididos en 2 grupos: 1) grupo de niños suplementados con 500 mg de vitamina C (n = 11) y, 2) substancia placebo (n = 10) durante 45 días. Ocho niños eutróficos, pareados por edad también fueron incluidos en el estudio. Fueron evaluados la presión arterial media (PAM), la frecuencia cardíaca (ECG) y el flujo sanguíneo en el antebrazo por plestimografía de oclusión venosa. La conductancia vascular en el antebrazo (CVA) fue obtenida por medio de la relación entre el flujo sanguíneo en el antebrazo y la PAM (X100). RESULTADOS: Antes de la intervención, los niños obesos presentaron PAM mayor y CVA menor cuando fueron comparados con el Grupo C. Post intervención, el Grupo VitC presentó reducción de la PAM en reposo (81 ± 2 vs 75 ± 1 mmHg, p = 0,01), mientras en el Grupo Placebo no hubo alteración de la PAM (p = 0,58). Adicionalmente, VitC promovió un aumento de la CVA en reposo (3,40 ± 0,5 vs 5,09 ± 0,6 un, p = 0,04) y durante el estrés mental (3,92 ± 0,5 vs 6,68 ± 0,9 un, p = 0,03). Además de eso, post suplementación con VitC, los niveles de la CVA fueron estadísticamente semejantes a los del Grupo C en reposo (5,09 ± 0,6 vs 5,82 ± 0,4 un, p > 0,05) y durante el estrés mental (6,68 ± 0,9 vs 7,35 ± 0,5 un, p > 0,05). CONCLUSIÓN: Suplementación con VitC redujo la presión arterial y restableció la respuesta vasodilatadora periférica en niños obesos.

Neurobiología del estrés / Neurobiology of stress

Classically stress is defined as a threatening of homeostasis to which the organism, in order to survive, responds with a large number ofadaptative responses implicating the activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Acute stress response involves several brain regions (e.g. prefrontal cortex, amygdala, hippocampus, hypothalamus) where sex differences have been evidenced both in structure and function; limbic andforebrain regions are extremely sensitive to hormones released during stress, especially glucocorticoids. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes. Stress-induced structural/functional changes in brain regions may contribute to the development of psychiatric disorders such as depression and post-traumatic stress disorder. It is suggested that gonadal hormone influences provide complex contributions to sex differences in vulnerabilities to stress-related diseases.

Clásicamente el estrés se define como una amenaza a la homeostasis, frente a la cual el organismo, para sobrevivir, reacciona con un gran número de respuestas adaptativas que implican la activación del sistema nervioso simpático y el eje hipotalámico-pituitario-adrenal. La respuesta al estrés agudo incluye varias regiones cerebrales (ej. cortex prefrontal, amígdala, hipocampo, hipotálamo) donde se han evidenciado las diferencias sexuales, tanto en la estructura como en la función; las regiones límbicas y cerebrales anteriores son extremadamente sensibles a las hormonas liberadas durante el estrés, especialmente los glucocorticoides. Por otra parte, el estrés crónico causa plasticidad adaptativa en el cerebro, en el cual los neurotransmisores locales, como también las hormonas sistémicas, interactúan para producir cambios estructurales y funcionales. Los cambios estructurales/funcionales en las regiones cerebrales inducidos por el estrés pueden contribuir al desarrollo de desórdenes psiquiátricos, tales como depresión y trastorno por estrés postraumático. Se ha sugerido que las influencias de la hormona gonadal proporcionan complejas contribuciones a las diferencias sexuales en las vulnerabilidades a las enfermedades relacionadas con el estrés.

Salivary cortisol response to psychological stress in children with early childhood caries.

Aims and Objectives: Early Childhood Caries (ECC) is a multi-factorial disease and has numerous biological, psychological, and behavioral risk factors. In this study, we have attempted to study psychological stress as a risk factor for early childhood caries by investigating and comparing the response of event-related stress on salivary cortisol level in children with ECC and those without ECC and also compared the adaptability to various dental procedures in children with early childhood caries and without early childhood caries. Materials and Methods: One hundred children aged between four and five years were examined in the school and 16 pairs of children with caries and without caries were selected after cross-matching them on various risk factors for Early Childhood Caries. Oral prophylaxis and topical fluoride treatment procedures were used as stressors and salivary samples were collected at the time of arrival for the treatment, after Oral Prophylaxis and Fluoride treatment. The salivary samples were analyzed by radioimmunoassay for an unbound plasma cortisol level. Results: Statistical analysis was performed using a paired t-test, on the collected data, to compare the mean values of the salivary cortisol across the group and within the groups to evaluate the cortisol response to stress. No significant differences were found between the salivary cortisol levels prior to treatment, post oral prophylaxis, or post fluoride treatment at the first and second appointments of both groups. At the first appointment, the fluoride treatment caused a significant increase in the salivary cortisol level over the pretreatment level, in both the groups, but it was not evident in either of the two groups studied at the second appointment. Conclusion: We have concluded that the stress produced by different dental procedures was similar in children from the two groups studied, and the coping ability of the children was also similar in both the groups. Small sample size may be one of the reasons why no significant differences were found between the groups. Similar study needs to be repeated with a larger sample size.

Evaluation of salivary cortisol and psychological factors in patients with oral lichen planus.

Background and Objectives: Lichen planus is a relatively common chronic inflammatory disease of oral mucosa and skin. Cortisol, also called as "stress hormone", has been used as an indicator in various stress evaluation studies. Salivary cortisol measurement is an indicator of free cortisol or biologically active cortisol in human serum and provides noninvasive and easy technique. Recent studies have been conflicting, and hence, in the present study, evaluation of salivary cortisol levels and psychosocial factors in oral lichen planus (OLP) patients was done. Materials and Methods: A total of 30 patients with clinically and histopathologically proven cases of OLP, along with the age and sex-matched healthy controls were included in the study. Samples of stimulated saliva were collected, centrifuged and analyzed for the level of cortisol with cortisol enzyme linked immunosorbent assay. Psychosocial factors of study and control groups were measured by depression anxiety and stress scale. Student's t-test was used to compare the psychological factors and salivary cortisol levels between patients with the OLP and the control group. Results: Irrespective of sex, significantly higher depression (83.4 ± 15.4%), anxiety (80.5 ± 11.3%), and stress (94.2 ± 6.2%) scores were observed in OLP patients compared to controls. Increased cortisol levels were observed among 17 (56.6%) OLP patients in the study group. A positive correlation was found between psychological factors and salivary cortisol levels in the OLP patients. The values of Pearson's correlation coefficient "r", between depression, anxiety, and stress with salivary cortisol was: +0.42,S; +0.27,NS; and +0.65,HS, respectively among the study group.

Stress-induced neuroinflammation: mechanisms and new pharmacological targets

Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2), another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

Corticosteroid physiology and principles of therapy.

The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics. Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects, prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in patients receiving systemic high dose GC therapy must be borne in mind.

Ansiedade, pânico e o eixo hipotálamo-pituitária-adrenal / Anxiety, panic and the hypothalamic-pituitary-adrenal axis

OBJETIVO: Este artigo discute a ativação diferencial do eixo hipotálamo-pituitária-adrenal no transtorno de ansiedade generalizada e no transtorno de pânico. MÉTODO: Resultados de recentes revisões da literatura são resumidos e discutidos. RESULTADOS: Os resultados de estudos experimentais que dosaram o hormônio adrenocorticotrópico, o cortisol e a prolactina mostram que ataques de pânico naturais, bem como os provocados por agentes panicogênicos seletivos - como lactato de sódio e dióxido de carbono -, não ativam o eixo hipotálamo-pituitária-adrenal. Agonistas do receptor de colecistocinina do tipo B, como o peptídeo colecistocinina-4 e a pentagastrina, elevam os hormônios de estresse, independentemente da ocorrência de um ataque de pânico, parecendo ativar diretamente o eixo hipotálamo-pituitária-adrenal. O antagonista benzodiazepínico flumazenil não eleva o nível dos hormônios de estresse; porém, este agente farmacológico não induz ataques de pânico de modo consistente. Agentes farmacológicos que aumentam a ansiedade em pacientes de pânico (cafeína, ioimbina, agonistas serotonérgicos), assim como em pessoas saudáveis, elevam o nível dos hormônios de estresse. CONCLUSÕES: Além das diferenças na sintomatologia e na resposta farmacológica, o transtorno de ansiedade generalizada e o transtorno de pânico afetam os hormônios de estresse de modo distinto. Enquanto a ansiedade antecipatória e o transtorno de ansiedade generalizada ativam tanto o eixo hipotálamo-pituitária-adrenal como o simpático-adrenal, o ataque de pânico causa acentuada ativação simpática; porém, afeta pouco o eixo hipotálamo-pituitária-adrenal.

OBJECTIVE: This article focuses on the differential activation of the hypothalamic-pituitary-adrenal axis in generalized anxiety disorder and panic disorder. METHOD: The results of recently reported reviews of the literature are summarized and discussed. RESULTS: The results of experimental studies that assayed adrenocorticotropic hormone, cortisol and prolactin show that real-life panic attacks, as well as those induced by selective panicogenic agents such as lactate and carbon dioxide, do not activate the hypothalamic-pituitary-adrenal axis. Agonists of the cholecystokinin receptor B such as the cholecystokinin-4 peptide and pentagastrin increase stress hormones regardless of the occurrence of a panic attack and, thus, seem to activate the hypothalamic-pituitary-adrenal axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increase anxiety in both normal people and panic patients (caffeine, yohimbine, serotonergic agonists) raise stress hormone levels. CONCLUSIONS: In addition to the differences in symptomatology and pharmacological response, generalized anxiety disorder and panic disorder affect stress hormones in distinct ways. While anticipatory anxiety and generalized anxiety disorder activate both the hypothalamic-pituitary-adrenal and the sympathoadrenal axes, panic attack causes major sympathetic activation, but has little effect on the hypothalamic-pituitary-adrenal axis.

A study of melatonin levels and stress in female shift workers.

The aim of this study was to determine the relationship between saliva melatonin and stress levels in Thai female shift workers. Five older (38.4 +/- 1.82) and five younger (21.4 +/- 0.55) female workers voluntarily participated in this study. All participants worked both morning and night shifts at a glass manufacturing factory. Saliva was collected every three hours at the workplace and at the subjects' houses to examine melatonin profiles. The Mann-Whitney U test and the Wilcoxon signed ranks test were used. There was a significant (p < 0.05) difference between melatonin levels in younger and older subjects when measured during the night shift at 19:00. Differences between melatonin levels during the morning and night shifts in the older group were significant at 07:00 and at 19:00 in younger subjects (p < 0.05). Normal stress and mild stress were found. No significant differences in melatonin levels were found between workers with normal and mild stress levels. The onset time of increasing saliva melatonin was at 19:00, both in women working the morning shift and in those working the night shift. Peak melatonin production occurred at 22:00 for the night shift in both groups. During the morning shifts, the peak times were at 04:00 and 01:00 (in the younger and older groups, respectively), usually between 02:00 and 04:00. These findings show that melatonin levels in female shift workers adapted according to the shift worked, especially in the older group. Health surveillance programs should therefore be established to prevent further negative health effects for female shift workers.