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1.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34698826

RESUMO

PURPOSE: Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure. METHODS: In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC. RESULTS: During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH. CONCLUSIONS: Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.


Assuntos
Hormônio Liberador da Corticotropina/administração & dosagem , Hidrocortisona/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sepse/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Arginina Vasopressina/química , Corticosterona/sangue , Hipotálamo/metabolismo , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Hipófise/metabolismo , Adeno-Hipófise/metabolismo , Pró-Opiomelanocortina/química , Sepse/fisiopatologia , Transdução de Sinais
2.
Life Sci ; 285: 120016, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34614415

RESUMO

PURPOSE: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes. METHODS: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139-140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). RESULTS: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods. CONCLUSIONS: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health.


Assuntos
Corticosterona/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Retardo do Crescimento Fetal/enzimologia , Hidrocortisona/metabolismo , Fígado/enzimologia , Troca Materno-Fetal , Placenta/metabolismo , Animais , Transporte Biológico , Corticosterona/sangue , Feminino , Hidrocortisona/sangue , Gravidez , Ovinos
3.
Am J Physiol Heart Circ Physiol ; 321(5): H905-H919, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506227

RESUMO

Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades, the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized amyloid precursor protein (APP) overexpressing mouse model (hAPP23+/-), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 mo, hAPP23+/- mice had a lower survival, lower body weight, and increased corticosterone and VMA levels compared with C57BL/6 littermates. Systolic blood pressure was increased in hAPP23+/- animals compared with C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse-wave velocity (aPWV and cPWV) were increased in hAPP23+/- compared with C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of vascular function showed decreased adreno receptor dependent vasoconstriction of hAPP23+/- aortic segments, although the isobaric biomechanics of the aortic wall were similar to C57BL/6 aortic segments. In conclusion, hAPP23+/- mice exhibited high serum corticosterone levels, elevated systolic blood pressure, and increased arterial stiffness in vivo. However, ex vivo aortic stiffness of hAPP23+/- aortic segments was not changed and vascular reactivity to α1-adrenoceptor stimulation was attenuated. These findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of AD.NEW & NOTEWORTHY We showed that male amyloid precursor protein (APP) transgenic mice have higher circulating stress hormone levels. As a result, higher systolic blood pressure and pulse-wave velocity were measured in vivo in addition to a smaller α-adrenergic receptor-dependent contraction upon ex vivo stimulation with phenylephrine. Our findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of Alzheimer's disease.


Assuntos
Doença de Alzheimer/sangue , Precursor de Proteína beta-Amiloide/metabolismo , Aorta Torácica/metabolismo , Pressão Arterial , Corticosterona/sangue , Rigidez Vascular , Vasoconstrição , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Receptores Adrenérgicos alfa 1/metabolismo , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
4.
Nutrients ; 13(9)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34579131

RESUMO

In our previous study, intravenous (IV) injection of selenium alleviated breast cancer-related lymphedema (BCRL). This secondary analysis aimed to explore the metabolic effects of selenium on patients with BCRL. Serum samples of the selenium-treated (SE, n = 15) or the placebo-controlled (CTRL, n = 14) groups were analyzed by ultra-high-performance liquid chromatography with Q-Exactive Orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). The SE group showed a lower ratio of extracellular water to segmental water (ECW/SW) in the affected arm to ECW/SW in the unaffected arm (arm ECW/SW ratio) than the CTRL group. Metabolomics analysis showed a valid classification at 2-weeks and 107 differential metabolites were identified. Among them, the levels of corticosterone, LTB4-DMA, and PGE3-which are known anti-inflammatory compounds-were elevated in the SE group. Pathway analysis demonstrated that lipid metabolism (glycerophospholipid metabolism, steroid hormone biosynthesis, or arachidonic acid metabolism), nucleotide metabolism (pyrimidine or purine metabolism), and vitamin metabolism (pantothenate and CoA biosynthesis, vitamin B6 metabolism, ascorbate and aldarate metabolism) were altered in the SE group compared to the CTRL group. In addition, xanthurenic acid levels were negatively associated with whole blood selenium level (WBSe) and positively associated with the arm ECW/SW. In conclusion, selenium IV injection improved the arm ECW/SW ratio and altered the serum metabolic profiles in patients with BCRL, and improved the anti-inflammatory process in lipid, nucleotide and vitamin pathways, which might alleviate the symptoms of BCRL.


Assuntos
Neoplasias da Mama/complicações , Linfedema/sangue , Linfedema/tratamento farmacológico , Metabolômica/métodos , Selenito de Sódio/administração & dosagem , Alprostadil/análogos & derivados , Alprostadil/sangue , Cromatografia Líquida de Alta Pressão , Corticosterona/sangue , Feminino , Humanos , Injeções Intravenosas , Leucotrieno B4/sangue , Linfedema/etiologia , Placebos , Espectrometria de Massas em Tandem
5.
Front Immunol ; 12: 674532, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394074

RESUMO

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.


Assuntos
Experiências Adversas da Infância , Crescimento e Desenvolvimento/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Estresse Psicológico/imunologia , Imunidade Adaptativa/imunologia , Imunidade Adaptativa/fisiologia , Adulto , Animais , Corticosterona/sangue , Modelos Animais de Doenças , Feminino , Glucose , Crescimento e Desenvolvimento/fisiologia , Humanos , Masculino , Privação Materna , Ratos , Ratos Wistar
6.
Sci Rep ; 11(1): 17273, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446814

RESUMO

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.


Assuntos
Glicemia/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Resistência à Insulina , Som , Animais , Corticosterona/sangue , Transportador de Glucose Tipo 4/metabolismo , Imuno-Histoquímica/métodos , Insulina/sangue , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Músculo Esquelético/metabolismo , Ratos Wistar
7.
Dokl Biochem Biophys ; 499(1): 247-250, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34426921

RESUMO

The aim of the work was to study changes in the time range of heart rate variability (HRV) against the background of changes in the concentration of corticosterone in blood plasma in rats after surgical trauma to the nasal septum. Septoplasty was simulated in 30 mature male Wistar rats weighing 210-290 g. ECG was recorded with subsequent analysis of the time domain of HRV, as well as blood sampling to estimate changes in the concentration of corticosterone in the blood plasma was performed. As a result, SDNN significantly increased in comparison with the control on days 2 and 3 (p < 0.001) but decreased on days 4-5 (p < 0.001) and 6 (p < 0.01). rMSSD changed in waves with two irregular peaks on days 1 and 6. SDNN/rMSSD, in comparison with the 1st day of the postoperative period, increased on the 2nd day, continued to increase (p < 0.05), and then began to decrease on day 4 (p < 0.01). The total HRV power of was low throughout the postoperative period (p < 0.001), except for day 3, when it was equal to the control data. The increase in the total power index fell on day 3 after the operation (p <0.01), after which its decline was observed again. The concentration of corticosterone in the blood plasma in rats was significantly higher than before (p < 0.001). On postoperative day 2 to 4, its plateau was determined. Simulation of septoplasty leads to changes in the time range of HRV, an increase in the concentration of corticosterone in the blood plasma in rats with its maximum at the time of surgery and 24 h later, and the formation of a "plateau" on postoperative days 2 to 4, which coincides with the changes in HRV.


Assuntos
Corticosterona/sangue , Frequência Cardíaca , Septo Nasal/lesões , Septo Nasal/cirurgia , Animais , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
8.
Nature ; 595(7867): 409-414, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194038

RESUMO

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Microbioma Gastrointestinal/fisiologia , Neurônios/metabolismo , Comportamento Social , Estresse Psicológico , Animais , Corticosterona/sangue , Hormônio Liberador da Corticotropina/metabolismo , Enterococcus faecalis/metabolismo , Vida Livre de Germes , Glucocorticoides/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
9.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205191

RESUMO

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.


Assuntos
Encéfalo/metabolismo , Corticosterona/sangue , Angústia Psicológica , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Arginina Vasopressina/sangue , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Humanos , Metilprednisolona/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Glucocorticoides/sangue , Receptores de Mineralocorticoides/sangue , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/patologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Proteínas de Ligação a Tacrolimo/sangue
10.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206322

RESUMO

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/-) AD mouse model. Memory and spatial learning of male hAPP23+/- and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/- brains, amyloid-beta (Aß) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/- mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/- animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/- mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/- mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.


Assuntos
Doença de Alzheimer/sangue , Biomarcadores/sangue , Disfunção Cognitiva , Corticosterona/sangue , Resistência à Insulina , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Síndrome de Cushing/complicações , Modelos Animais de Doenças , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
11.
Sci Rep ; 11(1): 14231, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244555

RESUMO

Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.


Assuntos
Dor Facial/fisiopatologia , Locomoção/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Animais , Corticosterona/sangue , Eletroencefalografia , Dor Facial/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/sangue , Dor/fisiopatologia , Limiar da Dor , Reação em Cadeia da Polimerase em Tempo Real , Privação do Sono/sangue , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/sangue , Sono REM/fisiologia , Vigília/fisiologia
12.
J Endocrinol ; 250(2): 37-48, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34060474

RESUMO

Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signaling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signaling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (n = 5-8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment-induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signaling in female mice.


Assuntos
Corticosterona/administração & dosagem , Obesidade/etiologia , Receptores de Grelina/fisiologia , Transdução de Sinais/fisiologia , Adiposidade/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/sangue , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Grelina/sangue , Camundongos , Camundongos Knockout , Receptores de Grelina/deficiência , Receptores de Grelina/genética , Ganho de Peso/efeitos dos fármacos
13.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070933

RESUMO

Hippocampal damage after traumatic brain injury (TBI) is associated with late posttraumatic conditions, such as depression, cognitive decline and epilepsy. Mechanisms of selective hippocampal damage after TBI are not well understood. In this study, using rat TBI model (lateral fluid percussion cortical injury), we assessed potential association of immediate posttraumatic seizures and changes in corticosterone (CS) levels with neuroinflammation and neuronal cell loss in the hippocampus. Indices of distant hippocampal damage (neurodegeneration and neuroinflammation) were assessed using histological analysis (Nissl staining, Iba-1 immunohistochemical staining) and ELISA (IL-1ß and CS) 1, 3, 7 and 14 days after TBI or sham operation in male Wistar rats (n = 146). IL-1ß was elevated only in the ipsilateral hippocampus on day 1 after trauma. CS peak was detected on day 3 in blood, the ipsilateral and contralateral hippocampus. Neuronal cell loss in the hippocampus was demonstrated bilaterally; in the ipsilateral hippocampus it started earlier than in the contralateral. Microglial activation was evident in the hippocampus bilaterally on day 7 after TBI. The duration of immediate seizures correlated with CS elevation, levels of IL-1ß and neuronal loss in the hippocampus. The data suggest potential association of immediate post-traumatic seizures with CS-dependent neuroinflammation-mediated distant hippocampal damage.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Corticosterona/sangue , Hipocampo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Convulsões/metabolismo , Animais , Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Contagem de Células , Morte Celular , Modelos Animais de Doenças , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação , Interleucina-1beta/biossíntese , Masculino , Microglia/patologia , Neurônios/patologia , Ratos , Ratos Wistar , Convulsões/patologia , Convulsões/fisiopatologia , Fatores de Tempo
14.
Molecules ; 26(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063635

RESUMO

Tea is one of the most widely consumed beverages worldwide after water, and green tea accounts for 20% of the total tea consumption. The health benefits of green tea are attributed to its natural antioxidants, namely, catechins, which are phenolic compounds with diverse beneficial effects on human health. The beneficial effects of green tea and its major bioactive component, (-)-epigallocatechin-3-gallate (EGCG), on health include high antioxidative, osteoprotective, neuroprotective, anti-cancer, anti-hyperlipidemia and anti-diabetic effects. However, the review of green tea's benefits on female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis and dysmenorrhea, remains scarce. Thus, this review summarises current knowledge on the beneficial effects of green tea catechins on selected female reproductive disorders. Green tea or its derivative, EGCG, improves endometriosis mainly through anti-angiogenic, anti-fibrotic, anti-proliferative and proapoptotic mechanisms. Moreover, green tea enhances ovulation and reduces cyst formation in PCOS while improving generalised hyperalgesia, and reduces plasma corticosterone levels and uterine contractility in dysmenorrhea. However, information on clinical trials is inadequate for translating excellent findings on green tea benefits in animal endometriosis models. Thus, future clinical intervention studies are needed to provide clear evidence of the green tea benefits with regard to these diseases.


Assuntos
Catequina/farmacologia , Dismenorreia/tratamento farmacológico , Endometriose/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Chá/química , Inibidores da Angiogênese/farmacologia , Animais , Antioxidantes/uso terapêutico , Apoptose , Camellia sinensis , Catequina/análogos & derivados , Proliferação de Células , Corticosterona/sangue , Estudos Transversais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Extratos Vegetais/farmacologia , Útero/patologia
15.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063730

RESUMO

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.


Assuntos
Lesões Encefálicas Traumáticas/genética , Disfunção Cognitiva/genética , Deficiência do Fator XII/genética , Fator XII/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Corticosterona/sangue , Modelos Animais de Doenças , Deficiência do Fator XII/sangue , Deficiência do Fator XII/complicações , Deficiência do Fator XII/patologia , Humanos , Memória/fisiologia , Camundongos , Camundongos Knockout , Agregação Plaquetária/genética , Complexo Glicoproteico GPIb-IX de Plaquetas
16.
Nutrients ; 13(6)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064242

RESUMO

Evidence supports the role of exercise training and probiotics on reducing obesity. Considering the relationship between obesity and high-fat diet with anxiety indices, the aim of this study was to assess the effect of probiotic supplementation and high-intensity interval training (HIIT) on anxiety-like behaviors, corticosterone and obesity indices in high-fat diet (HFD)-induced obesity mice. Thirty male adult C57BL/6 mice were randomly divided into five groups: (1) Control with normal diet (CON), (2) High-fat diet (HFD), (3) HFD + exercise training (HT), (4) HFD + probiotics supplement (HP) and (5) HFD + exercise training +probiotics (HTP). Exercise training consisted of 8 weeks of high-intensity interval training (HIIT) programs. Probiotics supplement included 0.2 mL Lactobacillus rhamnosus GG. Anxiety-like behaviors were measured by open field (OF) and Elevated plus maze (EPM). OF and EPM tests, visceral fat mass (VFM) measurement, and blood sampling for corticosterone were performed after the intervention. Bodyweight was measured at different stages during the intervention. HFD regime in C57BL/6 mice increased bodyweight, VFM, and serum corticosterone levels and anxiety-like behaviors (p < 0.05). HIIT, probiotic and their combination, decreased bodyweight, VFM, and serum corticosterone levels and improved anxiety-like behavior in the HFD mice (p < 0.05). The effect of a combination of HIIT and probiotic on most of the anxiety indices was more than each one separately (p < 0.5). HIIT and probiotic supplements separately or above all in combination, may have beneficial effects in reducing obesity and anxiety indices.


Assuntos
Ansiedade/microbiologia , Corticosterona/sangue , Treinamento Intervalado de Alta Intensidade/psicologia , Obesidade/psicologia , Probióticos/farmacologia , Animais , Ansiedade/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/microbiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia
17.
Chem Biol Interact ; 345: 109564, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34161785

RESUMO

Suppressive effect of bis (3-amino-2-pyridine) diselenide (BAPD) on psychiatric disorders - atopic dermatitis (AD) comorbidity in mice was investigated. To sensitize the animals, 2,4-dinitrochlorobenzene (DNCB) was applied to their dorsal skin on days 1-3. Mice were challenged with DNCB on their ears and dorsal skin on days 14, 17, 20, 23, 26, and 29. BAPD and Dexamethasone were administered to the animals, from days 14-29, and skin severity scores and behavioral tests were determined. Oxidative stress and inflammatory parameters were evaluated on the dorsal skin of mice. Na+, K+-ATPase activity and corticosterone levels were determined in hippocampus/cerebral cortex and plasma of mice, respectively. BAPD improved cutaneous damage, scratching behavior, inflammatory and oxidative stress markers. BAPD showed anxiolytic- and antidepressant-like effects and restored Na+, K+-ATPase activity and corticosterone levels. The present study was performed using female mice due the susceptibility for this disease. But, the evaluation of AD model in male mice would help to verify whether the male gender has the same predisposition to present this pathology. Our data demonstrated the suppressive effect of BAPD on psychiatric disorders - AD comorbidity by regulating inflammatory and oxidative status in mice.


Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/epidemiologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Siloxanas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Comorbidade , Corticosterona/sangue , Corticosterona/metabolismo , Dermatite Atópica/complicações , Dermatite Atópica/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/complicações , Transtornos Mentais/complicações , Transtornos Mentais/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Siloxanas/uso terapêutico
18.
J Ethnopharmacol ; 276: 114218, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34029638

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. MATERIALS AND METHODS: Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. RESULTS: AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. CONCLUSIONS: These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Ocitocina/líquido cefalorraquidiano , Estresse Fisiológico/efeitos dos fármacos , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Defecação/efeitos dos fármacos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , Medicina Kampo/métodos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/ultraestrutura , Ratos Wistar , Restrição Física/efeitos adversos
19.
J Exp Zool A Ecol Integr Physiol ; 335(6): 541-551, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34018702

RESUMO

The inflammatory response is a complex process that relies on interactions among multiple endocrine and immune modulators. Studies incorporating time-related and integrative endocrine and immune responses to an immune challenge might shed light on the characterization of the phases of the inflammatory response in anurans. The present study investigated time-related changes (1, 3, 6, and 18 h post-challenge) in plasma corticosterone (CORT), melatonin (MEL) and testosterone (T) levels, phagocytosis percentage (PP), plasma bacterial killing ability (BKA), and neutrophil to lymphocyte ratio (NLR) following a lipopolysaccharide (LPS) immune challenge in Rhinella diptycha toads. Our results showed the response to LPS injection was characterized by increased CORT, PP, BKA, and NLR, with a concomitant decrease in plasma MEL and T. Increased CORT was more pronounced at 6 and 18 h, while increased NLR was observed only 18 h post-LPS injection. Meanwhile, plasma MEL and T decreased independently of the time post-LPS injection. Additionally, toads in better body condition showed higher BKA and PP in the LPS-treated group, regardless of the time postinjection. Our results show that toads (R. diptycha) were sensitive to the LPS challenge, mounting an inflammatory response, which started quickly (after 1 h) and developed over time and was influenced by body condition. These results demonstrate a time-related hormonal and immune variation as a consistent pattern of activation of the immune system, as well as of hypothalamic-pituitary-adrenal/interrenal and immune-pineal axes following an immune challenge more deeply studied in mammals, suggesting the evolutionary conservation of the regulatory mechanisms for tetrapod vertebrates.


Assuntos
Bufonidae/imunologia , Corticosterona/sangue , Imunomodulação/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Melatonina/sangue , Animais , Atividade Bactericida do Sangue , Inflamação/induzido quimicamente , Inflamação/imunologia , Linfócitos/fisiologia , Masculino , Neutrófilos/fisiologia , Fagocitose , Testosterona/sangue
20.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1081-G1092, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949202

RESUMO

Stress can trigger symptoms in patients with irritable bowel syndrome (IBS). Previously we demonstrated that chronic psychological stress induced microglial remodeling in the central nucleus of amygdala (CeA) and contributed to the development of visceral hypersensitivity via synaptic engulfment. However, the specific signaling mechanisms that microglia depend upon to recognize target neurons to facilitate visceral pain remain unknown. Here, we test the hypothesis that the microglia in the CeA contribute to chronic stress-induced visceral hypersensitivity via complement C1q/C3-CR3 signaling-mediated synaptic remodeling. In male and female Fischer-344 rats, micropellets of corticosterone (CORT) or cholesterol (control) were stereotaxically implanted bilaterally onto the CeA. After 7 days, microglial C1q, complement receptor 3 (CR3) expression, and microglia-mediated synaptic engulfment were assessed via RNAscope, quantitative PCR, and immunofluorescence. The microglial inhibitor minocycline, CR3 antagonist neutrophil inhibitory factor (NIF), or vehicle were daily infused into the CeA following CORT implantations. Visceral sensitivity was assessed via a visceromotor response (VMR) to graded pressures of isobaric colorectal distension (CRD). Our results suggest that chronic exposure to elevated CORT in the CeA induced visceral hypersensitivity and amygdala microglial morphological remodeling. CORT increased microglial C1q and CR3 expression and increased microglia-mediated synaptic engulfment. Both groups of animals with minocycline or NIF infusions reversed microglia-mediated synaptic remodeling and attenuated CORT-induced visceral hypersensitivity. Our findings demonstrate that C1q/C3-CR3 signaling is critical for microglia-mediated synaptic remodeling in the CeA and contributes to CORT-induced visceral hypersensitivity.NEW & NOTEWORTHY Patients with irritable bowel syndrome (IBS) show altered amygdala activity. We showed previously that stress induces visceral hypersensitivity partially through microglia-modulated synaptic plasticity in the central nucleus of the amygdala (CeA). Our current data suggest that the C1q/C3-CR3 cascade initiates microglia-mediated synaptic remodeling in the CeA. Blocking C3-CR3 interaction attenuates stress-induced visceral hypersensitivity. These findings uncover a role of microglia-synapse signaling in the brain-gut regulation and support a future therapeutic target to treat visceral pain.


Assuntos
Tonsila do Cerebelo/metabolismo , Complemento C1q/metabolismo , Complemento C3/metabolismo , Microglia/metabolismo , Plasticidade Neuronal/fisiologia , Dor Visceral/metabolismo , Animais , Colo/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Feminino , Síndrome do Intestino Irritável/metabolismo , Masculino , Percepção da Dor/fisiologia , Ratos , Ratos Endogâmicos F344
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