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1.
Circ Res ; 134(1): 9-29, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38047378

RESUMO

BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmnf/f/CD4Cre), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmnf/f/Foxp3YFP Cre), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.


Assuntos
Hipertensão , Fator 6 Associado a Receptor de TNF , Animais , Humanos , Camundongos , Acetatos/efeitos adversos , Acetatos/metabolismo , Angiotensina II/toxicidade , Angiotensina II/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Desoxicorticosterona/efeitos adversos , Desoxicorticosterona/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores , Fator 6 Associado a Receptor de TNF/metabolismo
2.
Molecules ; 28(22)2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38005332

RESUMO

Hypertension is a common disease that affects human health and can lead to damage to the heart, kidneys, and other important organs. In this study, we investigated the regulatory effects of bioactive peptides derived from Ruditapes philippinarum (RPP) on hypertension and organ protection in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We found that RPPs exhibited significant blood pressure-lowering properties. Furthermore, the results showed that RPPs positively influenced vascular remodeling and effectively maintained a balanced water-sodium equilibrium. Meanwhile, RPPs demonstrated anti-inflammatory potential by reducing the serum levels of inflammatory cytokines (TNF-α, IL-2, and IL-6). Moreover, we observed the strong antioxidant activity of RPPs, which played a critical role in reducing oxidative stress and alleviating hypertension-induced damage to the aorta, heart, and kidneys. Additionally, our study explored the regulatory effects of RPPs on the gut microbiota, suggesting a possible correlation between their antihypertensive effects and the modulation of gut microbiota. Our previous studies have demonstrated that RPPs can significantly reduce blood pressure in SHR rats. This suggests that RPPs can significantly improve both essential hypertension and DOAC-salt-induced secondary hypertension and can ameliorate cardiorenal damage caused by hypertension. These findings further support the possibility of RPPs as an active ingredient in functional anti-hypertensive foods.


Assuntos
Desoxicorticosterona , Hipertensão , Humanos , Ratos , Animais , Ratos Endogâmicos SHR , Desoxicorticosterona/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Peptídeos/farmacologia , Acetatos/farmacologia
4.
J Hypertens ; 41(10): 1554-1564, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37432904

RESUMO

OBJECTIVE: Endogenous ouabain (EO) increases in some patients with hypertension and in rats with volume-dependent hypertension. When ouabain binds to Na + K + -ATPase, cSrc is activated, which leads to multieffector signaling activation and high blood pressure (BP). In mesenteric resistance arteries (MRA) from deoxycorticosterone acetate (DOCA)-salt rats, we have demonstrated that the EO antagonist rostafuroxin blocks downstream cSrc activation, enhancing endothelial function and lowering oxidative stress and BP. Here, we examined the possibility that EO is involved in the structural and mechanical alterations that occur in MRA from DOCA-salt rats. METHODS: MRA were taken from control, vehicle-treated DOCA-salt or rostafuroxin (1 mg/kg per day, for 3 weeks)-treated DOCA-salt rats. Pressure myography and histology were used to evaluate the mechanics and structure of the MRA, and western blotting to assess protein expression. RESULTS: DOCA-salt MRA exhibited signs of inward hypertrophic remodeling and increased stiffness, with a higher wall:lumen ratio, which were reduced by rostafuroxin treatment. The enhanced type I collagen, TGFß1, pSmad2/3 Ser465/457 /Smad2/3 ratio, CTGF, p-Src Tyr418 , EGFR, c-Raf, ERK1/2 and p38MAPK protein expression in DOCA-salt MRA were all recovered by rostafuroxin. CONCLUSION: A process combining Na + K + -ATPase/cSrc/EGFR/Raf/ERK1/2/p38MAPK activation and a Na + K + -ATPase/cSrc/TGF-1/Smad2/3/CTGF-dependent mechanism explains how EO contributes to small artery inward hypertrophic remodeling and stiffening in DOCA-salt rats. This result supports the significance of EO as a key mediator for end-organ damage in volume-dependent hypertension and the efficacy of rostafuroxin in avoiding remodeling and stiffening of small arteries.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Ratos , Animais , Ouabaína/farmacologia , Pressão Sanguínea/fisiologia , Desoxicorticosterona , Hipertensão/metabolismo , Artérias Mesentéricas/metabolismo , Acetatos , Adenosina Trifosfatases , Receptores ErbB
5.
Wei Sheng Yan Jiu ; 52(3): 424-428, 2023 May.
Artigo em Chinês | MEDLINE | ID: mdl-37500522

RESUMO

OBJECTIVE: To investigate the difference of cortical hormones in cord artery and vein blood of newborns with different delivery modes. METHODS: A total of 65 pregnant women who delivered in the People's Hospital of Danyang City, Jiangsu Province from June to September 2021 were selected as the study subjects, including 26 cases of spontaneous delivery and 39 cases of cesarean section. The basic information of 65 pregnant women and newborns was collected by questionnaire survey. According to the mode of delivery, the levels of corticosteroids in umbilical vein and umbilical artery blood were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS), including corticosterone, 11-desoxycorticosterone, aldosterone, cortisol, 11-deoxycortisol and cortisone. The data were statistically analyzed using IBM SPSS Statistics 26.0 statistical software. RESULTS: The levels of cortisol, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in the umbilical vein blood of the spontaneous delivery group were(2.44±1.87), (0.64±0.29), (0.49±0.35), (54.95±40.80), (3.20±1.23) and(142.27±57.42)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in umbilical artery blood were(4.51±4.47), (0.57±0.28), (0.42±0.29), (60.79±45.53), (2.69±1.25) and(123.10±46.32)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisone, aldosterone, cortisol, 11-deoxycortisone and cortisone in umbilical vein blood of cesarean section group were(0.94±1.09), (0.47±0.14), (0.26±0.14), (22.63±19.82), (2.30±0.90) and(84.51±29.49)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in umbilical artery blood were(2.22±2.24), (0.43±0.17), (0.27±0.14), (30.09±25.93), (1.87±0.76) and(75.03±24.90)ng/mL, respectively. The levels of corticosterone, 11-desoxycorticosterone, aldosterone, cortisol, 11-deoxycortisol and cortisone in cord vein blood and cord artery blood in spontaneous labor group were significantly higher than those in cesarean section group(P<0.05). The levels of corticosterone and cortisol in cord vein blood were significantly lower in spontaneous labor group and cesarean section group than those in cord artery blood(P<0.05), the levels of 11-desoxycorticosterone, 11-deoxycortisol and cortisone in cord vein blood were significantly higher in spontaneous labor group and cesarean section group than those in cord artery blood(P<0.05). CONCLUSION: There are differences in the level of cortical hormones in cord artery and vein blood in different delivery modes.


Assuntos
Corticosterona , Cortisona , Feminino , Recém-Nascido , Gravidez , Humanos , Hidrocortisona , Aldosterona , Cortodoxona , Cesárea , Cromatografia Líquida , Espectrometria de Massas em Tandem , Desoxicorticosterona , Sangue Fetal , Artérias
6.
Hypertension ; 80(9): 1871-1880, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37470185

RESUMO

BACKGROUND: Mice prefer warmer environments than humans. For this reason, behavioral and physiological thermoregulatory responses are engaged by mice in response to a standard room temperature of 22 to 24 °C. Autonomic mechanisms mediating thermoregulatory responses overlap with mechanisms activated in hypertension, and, therefore, we hypothesized that housing at thermoneutral temperatures (TNs; 30 °C) would modify the cardiometabolic effects of deoxycorticosterone acetate (DOCA)-salt in mice. METHODS: The effects of DOCA-salt treatment upon ingestive behaviors, energy expenditure, blood pressure, heart rate (HR), and core temperature were assessed in C57BL/6J mice housed at room temperature or TN. RESULTS: Housing at TN reduced food intake, energy expenditure, blood pressure, and HR and attenuated HR responses to acute autonomic blockade by chlorisondamine. At room temperature, DOCA-salt caused expected increases in fluid intake, sodium retention in osmotically inactive pools, blood pressure, core temperature, and also caused expected decreases in fat-free mass, total body water, and HR. At TN, the effects of DOCA-salt upon fluid intake, fat gains, hydration, and core temperature were exaggerated, but effects on energy expenditure and HR were blunted. Effects of DOCA-salt upon blood pressure were similar for 3 weeks and exaggerated by TN housing in the fourth week. CONCLUSIONS: Ambient temperature robustly influences behavioral and physiological functions in mice, including metabolic and cardiovascular phenotype development in response to DOCA-salt treatment. Studying cardiometabolic responses of mice at optimal ambient temperatures promises to improve the translational relevance of rodent models.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Humanos , Camundongos , Animais , Acetato de Desoxicorticosterona/farmacologia , Temperatura , Camundongos Endogâmicos C57BL , Hipertensão/induzido quimicamente , Pressão Sanguínea/fisiologia , Desoxicorticosterona/farmacologia
7.
J Am Heart Assoc ; 12(13): e029179, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37382154

RESUMO

Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of identifying key immune cells for its treatment. This study aimed to determine the unknown effects of CD1d-dependent NKT cells on hypertension and vascular injury. Methods and Results Hypertension models were induced in male CD1d knockout (CD1dko), wild-type, and adoptive bone marrow transfer mice by angiotensin II (Ang II) or deoxycorticosterone acetate salt. Blood pressure was measured by the tail-cuff system and radiotelemetry. Vascular injury was assessed by histologic studies or aortic ring assay. Inflammation was detected by flow cytometry, quantitative real-time polymerase chain reaction, or ELISA. Results showed that Ang II infusion significantly reduced CD1d expression and NKT cell numbers in the aorta of mice. CD1dko mice exhibited worsened blood pressure elevation, vascular injury, and inflammatory response induced by Ang II or deoxycorticosterone acetate salt. However, these effects were markedly reversed in wild-type mice treated with NKT cell-specific activator. Adoptive transfer of CD1dko bone marrow cells to wild-type mice also significantly worsened Ang II-induced responses. Mechanistically, CD1dko increased Ang II-induced interleukin-6 production and activated signal transducer and activator of transcription 3 and orphan nuclear receptor γ, subsequently inducing interleukin-17A production. Neutralizing interleukin-17A partially reversed Ang II-induced hypertension and vascular injury in CD1dko mice. In addition, levels of NKT cells were lower in the blood of patients with hypertension (n=57) compared with normotensive individuals (n=87). Conclusions These findings reveal a previously unknown role for CD1d-dependent NKT cells in hypertension and vascular injury, indicating that NKT cell activation could be a promising therapeutic target for hypertension.


Assuntos
Hipertensão , Células T Matadoras Naturais , Lesões do Sistema Vascular , Animais , Masculino , Camundongos , Acetatos/efeitos adversos , Acetatos/metabolismo , Desoxicorticosterona/efeitos adversos , Desoxicorticosterona/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Lesões do Sistema Vascular/metabolismo
8.
Sci Rep ; 13(1): 7278, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37142643

RESUMO

Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of chronic stress on tissue levels of corticosterone (CORT), progesterone (PROG), 11-deoxycorticosterone (11DOC) and 11-dehydrocorticosterone (11DHC) and on gut microbiota, which may reshape the stress response. Male BALB/c mice, liquid chromatography-tandem mass spectrometry and 16S RNA gene sequencing were used to screen steroid levels and fecal microbiome, respectively. Stress induced greater increase of CORT in the brain, liver, and kidney than in the colon and lymphoid organs, whereas 11DHC was the highest in the colon, liver and kidney and much lower in the brain and lymphoid organs. The CORT/11DHC ratio in plasma was similar to the brain but much lower in other organs. Stress also altered tissue levels of PROG and 11DOC and the PROG/11DOC ratio was much higher in lymphoid organs that in plasma and other organs. Stress impacted the ß- but not the α-diversity of the gut microbiota and LEfSe analysis revealed several biomarkers associated with stress treatment. Our data indicate that social defeat stress modulates gut microbiota diversity and induces tissue-dependent changes in local levels of corticosteroids, which often do not reflect their systemic levels.


Assuntos
Corticosterona , Progesterona , Camundongos , Animais , Masculino , Desoxicorticosterona , Esteroides , Encéfalo , Cromatografia Líquida
9.
J Clin Endocrinol Metab ; 108(11): e1214-e1223, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37247379

RESUMO

CONTEXT: There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications. OBJECTIVE: We aimed to identify early, first-trimester prediction markers for GDM. METHODS: The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later. RESULTS: Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR). CONCLUSION: Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.


Assuntos
Cortisona , Diabetes Gestacional , Feminino , Humanos , Gravidez , Desoxicorticosterona , Diabetes Gestacional/diagnóstico , Frutosamina , Hidrocortisona , Primeiro Trimestre da Gravidez , Estudos de Casos e Controles
10.
Hypertens Res ; 46(8): 1934-1948, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37248323

RESUMO

Hypertension-induced renal injury is characterized by robust inflammation and tubulointerstitial fibrosis. Jumonji domain containing-3 (JMJD3) is closely linked with inflammatory response and fibrogenesis. Here we examined the effect of myeloid JMJD3 ablation on kidney inflammation and fibrosis in deoxycorticosterone acetate (DOCA)/salt hypertension. Our results showed that JMJD3 is notably induced in the kidneys with hypertensive injury. DOCA/salt stress causes an elevation in blood pressure that was no difference between myeloid specific JMJD3-deficient mice and wild-type control mice. Compared with wild-type control mice, myeloid JMJD3 ablation ameliorated kidney function and injury of mice in response to DOCA/salt challenge. Myeloid JMJD3 ablation attenuated collagen deposition, extracellular matrix proteins expression, and fibroblasts activation in injured kidneys following DOCA/salt treatment. Furthermore, myeloid JMJD3 ablation blunts inflammatory response in injured kidneys after DOCA/salt stress. Finally, myeloid JMJD3 ablation precluded myeloid myofibroblasts activation and protected against macrophages to myofibroblasts transition in injured kidneys. These beneficial effects were accompanied by reduced expression of interferon regulator factor 4. In summary, JMJD3 ablation in myeloid cells reduces kidney inflammation and fibrosis in DOCA salt-induced hypertension. Inhibition of myeloid JMJD3 may be a novel potential therapeutic target for hypertensive nephropathy. Myeloid JMJD3 deficiency reduces inflammatory response, myeloid fibroblasts activation, macrophages to myofibroblasts transition, and delays kidney fibrosis progression.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão Renal , Hipertensão , Animais , Camundongos , Acetato de Desoxicorticosterona/efeitos adversos , Rim , Pressão Sanguínea , Inflamação/metabolismo , Macrófagos/metabolismo , Fibrose , Desoxicorticosterona/efeitos adversos , Desoxicorticosterona/metabolismo , Camundongos Endogâmicos C57BL
11.
Theriogenology ; 202: 61-73, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36924697

RESUMO

To improve the quality of reproduction in Eurasian perch, Perca fluviatilis L., which is a promising candidate for Eurasian freshwater aquaculture that is currently cultivated in recirculating aquaculture systems (RAS), investigating the hormones that mediate and affect reproduction in this species is indispensable. The literature defines a group of four major corticosteroids (11-deoxycorticosterone, 11-deoxycortisol, corticosterone and cortisol) that might mediate critical stages of reproduction in female perch. Unfortunately, neither the basic roles nor the kinetics of these four corticosteroids throughout the reproductive cycle of female perch have been well defined to date. In this study, we therefore elucidated the plasma kinetics of these four corticosteroids during the reproductive cycle of domesticated female perch while monitoring the expression of the different receptors and enzymes that mediate their production and possible functions. Additionally, we performed an in vitro experiment during late vitellogenesis to investigate the possible direct roles of these steroids during that stage. Our results revealed that these four corticosteroids were detectable throughout the reproductive cycle, and the levels of most of them (11-deoxycorticosterone, 11-deoxycortisol, and cortisol) fluctuated significantly depending on the stage of reproduction. 11-Deoxycorticosterone and 11-deoxycortisol exhibited their highest levels, 1.8 ng/ml and 58 ng/ml, respectively, at the beginning of the reproductive cycle. By the end of the reproductive cycle, 11-deoxycortisol and cortisol plasma levels exhibited a surge, reaching 58 ng/ml and 150 ng/ml, respectively. During the perch reproductive cycle, the corticosteroid receptor complex is not regulated only at the hormone level, as the expression levels of all corticosteroid receptor genes showed a progressive and similar decline. In vitro exposure of vitellogenic oocytes to some of these corticosteroids (11-deoxycorticosterone and 11-deoxycortisol) induced an increase in yolk globule diameter and a decrease in the density of yolk globules, which indicates the involvement of both of these hormones in yolk globule coalescence. Taken together, these results implicate corticosteroids in the reproductive cycle, although the related cellular mechanisms remain to be investigated.


Assuntos
Percas , Receptores de Esteroides , Feminino , Animais , Percas/genética , Hidrocortisona , Vitelogênese , Cortodoxona/metabolismo , Expressão Gênica , Reprodução/genética , Desoxicorticosterona/metabolismo , Desoxicorticosterona/farmacologia , Receptores de Esteroides/metabolismo
12.
Epilepsia ; 64(6): 1684-1693, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36916834

RESUMO

OBJECTIVE: Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures. METHODS: Adult male GAERS (n = 38) and nonepileptic control (NEC) rats (n = 4) were used. First, rats were subjected to 30-min restraint stress to assess hypothalamic-pituitary-adrenal axis function. Next, we assessed the effects of 30-min noise stress, and cage tilt stress, on spike-wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone. RESULTS: GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p < .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p < .05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for >2 h. However, deoxycorticosterone, the precursor of corticosterone, increased seizures. SIGNIFICANCE: These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future antiseizure medication.


Assuntos
Epilepsia Tipo Ausência , Humanos , Ratos , Masculino , Animais , Epilepsia Tipo Ausência/genética , Metirapona/farmacologia , Corticosterona , Sistema Hipotálamo-Hipofisário , Alta do Paciente , Eletroencefalografia , Sistema Hipófise-Suprarrenal , Convulsões , Desoxicorticosterona , Modelos Animais de Doenças
13.
Clin Chim Acta ; 543: 117304, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36958425

RESUMO

BACKGROUND: A rapid and accurate measurement approach for 17α-hydroxyprogesterone (17-OHP) and related steroids in amount/volume-limited clinic samples is of importance for precise newborn diagnosis of congenital adrenal hyperplasia (CAH) and its subtypes in clinic. METHODS: Sixteen steroids (17-OHP, androstenedione, cortisol, tetrahydro-11-deoxycortisol, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 21-deoxycortisol, 11-deoxycortisol, dehydroepiandrosterone, testosterone, aldosterone, 17α-hydroxypregnenolone, dihydrotestosterone and 18-hydroxycorticosterone) were included in the panel of high-throughput microbore ultra-performance liquid chromatography-tandem mass spectrometry. Samples were collected from 126 normal subjects and 65 patients including different subtypes of CAH. RESULTS: The method was validated with satisfactory analytical performance in linearity, repeatability, recovery and limit of detection. Reference intervals for 16 steroids were established by quantifying the level of steroids detected in normal infants. The applicability of the method was tested by differentiating steroid metabolic characteristics between normal infants and infants with CAH, as well as between infants with different CAH subtypes. The relevance of 17-OHP, 21-deoxycortisol, and 17-OHP/11-deoxycortisol for 21-hydroxylase deficiency screening was demonstrated. The level of 11-deoxycorticosterone, 11-deoxycortisol, progesterone and androstenedione can be used for the diagnosis of different rare subtypes of CAH. CONCLUSION: This study provides a strategy for highly efficient steroid analysis of amount/volume-limited clinic samples and holds great potential for clinical diagnosis of CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Recém-Nascido , Lactente , Humanos , Hiperplasia Suprarrenal Congênita/diagnóstico , Cortodoxona/análise , Progesterona , Espectrometria de Massas em Tandem/métodos , Androstenodiona , Cromatografia Líquida , Esteroides , 17-alfa-Hidroxiprogesterona , Desoxicorticosterona
14.
J Hypertens ; 41(5): 794-810, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36883469

RESUMO

BACKGROUND: Inflammation and renal interstitial fibrosis are the main pathological features of hypertensive nephropathy. Interferon regulatory factor 4 (IRF-4) has an important role in the pathogenesis of inflammatory and fibrotic diseases. However, its role in hypertension-induced renal inflammation and fibrosis remains unexplored. METHOD AND RESULTS: We showed that deoxycorticosterone acetate (DOCA)-salt resulted in an elevation of blood pressure and that there was no difference between wild-type and IRF-4 knockout mice. IRF-4 -/- mice presented less severe renal dysfunction, albuminuria, and fibrotic response after DOCA-salt stress compared with wild-type mice. Loss of IRF-4 inhibited extracellular matrix protein deposition and suppressed fibroblasts activation in the kidneys of mice subjected to DOCA-salt treatment. IRF-4 disruption impaired bone marrow-derived fibroblasts activation and macrophages to myofibroblasts transition in the kidneys in response to DOCA-salt treatment. IRF-4 deletion impeded the infiltration of inflammatory cells and decreased the production of proinflammatory molecules in injured kidneys. IRF-4 deficiency activated phosphatase and tensin homolog and weakened phosphoinositide-3 kinase/AKT signaling pathway in vivo or in vitro . In cultured monocytes, TGFß1 also induced expression of fibronectin and α-smooth muscle actin and stimulated the transition of macrophages to myofibroblasts, which was blocked in the absence of IRF-4. Finally, macrophages depletion blunted macrophages to myofibroblasts transition, inhibited myofibroblasts accumulation, and ameliorated kidney injury and fibrosis. CONCLUSION: Collectively, IRF-4 plays a critical role in the pathogenesis of kidney inflammation and fibrosis in DOCA-salt hypertension.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão Renal , Hipertensão , Animais , Camundongos , Acetatos/efeitos adversos , Acetatos/metabolismo , Pressão Sanguínea , Desoxicorticosterona/efeitos adversos , Desoxicorticosterona/metabolismo , Acetato de Desoxicorticosterona/efeitos adversos , Fibrose , Hipertensão/etiologia , Hipertensão Renal/metabolismo , Inflamação/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Rim , Camundongos Knockout
15.
Genes (Basel) ; 14(2)2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36833439

RESUMO

In aquaculture, many stressors can negatively affect growth in teleosts. It is believed that cortisol performs glucocorticoid and mineralocorticoid functions because teleosts do not synthesize aldosterone. However, recent data suggest that 11-deoxycorticosterone (DOC) released during stress events may be relevant to modulate the compensatory response. To understand how DOC modifies the skeletal muscle molecular response, we carried out a transcriptomic analysis. Rainbow trout (Oncorhynchus mykiss) were intraperitoneally treated with physiological doses of DOC in individuals pretreated with mifepristone (glucocorticoid receptor antagonist) or eplerenone (mineralocorticoid receptor antagonist). RNA was extracted from the skeletal muscles, and cDNA libraries were constructed from vehicle, DOC, mifepristone, mifepristone plus DOC, eplerenone, and eplerenone plus DOC groups. The RNA-seq analysis revealed 131 differentially expressed transcripts (DETs) induced by DOC with respect to the vehicle group, mainly associated with muscle contraction, sarcomere organization, and cell adhesion. In addition, a DOC versus mifepristone plus DOC analysis revealed 122 DETs related to muscle contraction, sarcomere organization, and skeletal muscle cell differentiation. In a DOC versus eplerenone plus DOC analysis, 133 DETs were associated with autophagosome assembly, circadian regulation of gene expression, and regulation of transcription from RNA pol II promoter. These analyses indicate that DOC has a relevant function in the stress response of skeletal muscles, whose action is differentially modulated by GR and MR and is complementary to cortisol.


Assuntos
Oncorhynchus mykiss , Animais , Oncorhynchus mykiss/genética , Transcriptoma , Desoxicorticosterona/metabolismo , Desoxicorticosterona/farmacologia , Mifepristona/metabolismo , Mifepristona/farmacologia , Eplerenona/metabolismo , Eplerenona/farmacologia , Hidrocortisona/metabolismo , Músculo Esquelético/metabolismo
16.
J Vet Intern Med ; 37(2): 420-427, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36809682

RESUMO

BACKGROUND: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. OBJECTIVE: To describe cats with PH with a focus on long-term treatment. ANIMALS: Eleven cats with naturally occurring PH. METHODS: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months. RESULTS: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.


Assuntos
Doença de Addison , Insuficiência Adrenal , Doenças do Gato , Doenças do Cão , Gatos , Animais , Cães , Prednisolona/uso terapêutico , Doenças do Cão/tratamento farmacológico , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/veterinária , Desoxicorticosterona/uso terapêutico , Doença de Addison/tratamento farmacológico , Doença de Addison/veterinária , Doenças do Gato/diagnóstico por imagem , Doenças do Gato/tratamento farmacológico
17.
Crit Care ; 26(1): 343, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36345013

RESUMO

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .


Assuntos
Sepse , Choque Séptico , Adulto , Humanos , Hormônio Adrenocorticotrópico , Hidrocortisona/uso terapêutico , Mortalidade Hospitalar , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Mineralocorticoides/farmacologia , Mineralocorticoides/uso terapêutico , Corticosterona , Cortodoxona , Cromatografia Líquida , Espectrometria de Massas em Tandem , Sepse/tratamento farmacológico , Desoxicorticosterona/uso terapêutico
18.
Hypertension ; 79(11): 2480-2492, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36215165

RESUMO

BACKGROUND: GPCRs (G protein-coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by both canonical G protein signaling and noncanonical ß-arrestin mediated signaling, but the contributions of each remain largely unexplored. Here, we hypothesized that ß-arrestin contributes to fluid homeostasis and blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA) salt hypertension, a prototypical model of salt-sensitive hypertension. METHODS: Global ß-arrestin1 (Arrb1) and ß-arrestin2 (Arrb2) knockout mice were employed to evaluate drinking behavior, and BP was evaluated in Arrb2-knockout mice. Age- and sex-matched C57BL/6 mice served as controls. We measured intake of water and different sodium chloride solutions and BP employing a 2-bottle choice paradigm with and without DOCA. RESULTS: Without DOCA (baseline), Arrb2-knockout mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment, Arrb2-knockout mice exhibited a significant increase in both saline and water intake. Although Arrb2-knockout mice exhibited hypernatremia at baseline conditions, we did not find significant changes in total body sodium stores or sodium palatability. In a separate cohort, BP was measured via telemetry in Arrb2-knockout and C57BL/6 mice with and without DOCA. Arrb2-knockout did not exhibit significant differences in BP before DOCA treatment when provided water alone, or when provided a choice of water and saline. However, Arrb2-knockout exhibited an increased pressor response to DOCA-salt. CONCLUSIONS: These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1 (ß-arrestin 1), might counterbalance the canonical signaling of GPCRs.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Animais , Camundongos , Pressão Sanguínea/fisiologia , beta-Arrestina 2/genética , Camundongos Endogâmicos C57BL , Hipertensão/genética , Cloreto de Sódio na Dieta/farmacologia , Cloreto de Sódio/farmacologia , Sódio , beta-Arrestinas , Camundongos Knockout , Homeostase , Água , Desoxicorticosterona
19.
Nutrients ; 14(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35956350

RESUMO

Dietary intake of fermented soymilk is associated with hypotensive effects, but the mechanisms involved have not been fully elucidated. We investigated the anti-hypertensive effects of soymilk fermented by L. rhamnosus AC1 on DOCA-salt hypertension from the point of view of oxidative stress, inflammatory response and alteration of the gut microbiome. The antioxidant assays in vitro indicated the ethanol extract (EE) of L. rhamnosus AC1 fermented soymilk showed better antioxidative effects than the water extract (WE). Those extracts displayed a hypotensive effect using a tail-cuff approach to measuring blood pressure and improved nitric oxide (NO), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α) and interleukin factor-6 (IL-6) on DOCA-salt hypertensive rats. Furthermore, cardiac and renal fibrosis were attenuated by those extracts. The gut microbiota analysis revealed that they significantly reduced the abundance of phylum Proteobacteria, its family Enterobacteriaceae and genus Escherichia-Shigella. Moreover, metabolomic profiling revealed several potential gut microbiota-related metabolites which appeared to involve in the development and recovery of hypertension. In conclusion, fermented soymilk is a promising nutritional intervention strategy to improve hypertension via reducing inflammation and reverting dysbiotic microbiota.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Lacticaseibacillus rhamnosus , Acetatos/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Desoxicorticosterona , Acetato de Desoxicorticosterona/farmacologia , Ratos
20.
Int J Pharm ; 625: 122095, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35961420

RESUMO

Pharmacokinetic (PK) models are widely used to describe drug permeation across the epidermal membrane barrier, the stratum corneum (SC). Here, we extend our previously reported diffusion and compartment-in-series models to describe plasma concentrations, urinary excretion-time profiles and exposure estimates after topically applied finite doses of solvent deposited solids. In vivo models were derived by convolution of a skin absorption input function for finite dosing with that for in vivo disposition PK. In vitro skin permeation test (IVPT) and in vivo urinary excretion data for cortisone, desoxycorticosterone, and testosterone were extracted from literature for model validation and establishment of in vitro - in vivo relationships (IVIVR). Both SC diffusion and SC 3-compartment-in-series PK models adequately described experimental in vitro and in vivo permeation data, with similar model parameter estimates for SC diffusion time and bioavailability. A satisfactory IVIVR was generated for cortisone, whereas testosterone and desoxycorticosterone showed higher bioavailability in vitro compared to in vivo. In recognising that future prospective studies need to both have an adequate sampling schedule and be harmonized for robust IVIVRs, we developed expressions for predicting extent of absorption and time for peak absorption for both in vitro and in vivo studies. Other study parameters, such as application site, applied dose, and application techniques, can also affect drug permeability through skin during dosage form metamorphosis after finite dose application, and a lack of correlation may result if these are poorly matched.


Assuntos
Cortisona , Absorção Cutânea , Cortisona/metabolismo , Desoxicorticosterona/metabolismo , Permeabilidade , Estudos Prospectivos , Pele/metabolismo , Testosterona
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