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2.
Sci Rep ; 14(1): 8023, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580805

RESUMO

Toxic metals are vital risk factors affecting serum ion balance; however, the effect of their co-exposure on serum ions and the underlying mechanism remain unclear. We assessed the correlations of single metal and mixed metals with serum ion levels, and the mediating effects of mineralocorticoids by investigating toxic metal concentrations in the blood, as well as the levels of representative mineralocorticoids, such as deoxycorticosterone (DOC), and serum ions in 471 participants from the Dongdagou-Xinglong cohort. In the single-exposure model, sodium and chloride levels were positively correlated with arsenic, selenium, cadmium, and lead levels and negatively correlated with zinc levels, whereas potassium and iron levels and the anion gap were positively correlated with zinc levels and negatively correlated with selenium, cadmium and lead levels (all P < 0.05). Similar results were obtained in the mixed exposure models considering all metals, and the major contributions of cadmium, lead, arsenic, and selenium were highlighted. Significant dose-response relationships were detected between levels of serum DOC and toxic metals and serum ions. Mediation analysis showed that serum DOC partially mediated the relationship of metals (especially mixed metals) with serum iron and anion gap by 8.3% and 8.6%, respectively. These findings suggest that single and mixed metal exposure interferes with the homeostasis of serum mineralocorticoids, which is also related to altered serum ion levels. Furthermore, serum DOC may remarkably affect toxic metal-related serum ion disturbances, providing clues for further study of health risks associated with these toxic metals.


Assuntos
Arsênio , Metais Pesados , Selênio , Humanos , Chumbo/toxicidade , Arsênio/toxicidade , Cádmio/toxicidade , Análise de Mediação , Mineralocorticoides , Intoxicação por Metais Pesados , Zinco , Ferro , Íons , China , Metais Pesados/toxicidade
3.
Expert Opin Investig Drugs ; 33(4): 287-301, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38465470

RESUMO

INTRODUCTION: The evolution of treatment for diabetic nephropathy illustrates how basic biochemistry and physiology have led to new agents such as SGLT2 inhibitors and mineralocorticoid blockers. Conversely, clinical studies performed with these agents have suggested new concepts for investigational drug development. We reviewed currently available treatments for diabetic nephropathy and then analyzed early clinical trials of new agents to assess the potential for future treatment modalities. AREAS COVERED: We searched ClinicalTrials.gov for new agents under study for diabetic nephropathy in the past decade. Once we have identified investigation trials of new agents, we then used search engines and Pubmed.gov to find publications providing insight on these drugs. Current treatments have shown benefit in both cardiac and renal disease. In our review, we found 51 trials and 43 pharmaceuticals in a number of drug classes: mineralocorticoid blockers, anti-inflammatory, anti-fibrosis, nitric oxide stimulatory, and podocyte protection, and endothelin inhibitors. EXPERT OPINION: It is difficult to predict which early phase treatments will advance to confirmatory clinical trials. Current agents are thought to improve hemodynamic function. However, the coincident benefit of both myocardial function and the glomerulus argues for primary effects at the subcellular level, and we follow the evolution of agents which modify fundamental cellular processes.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Mineralocorticoides/farmacologia , Mineralocorticoides/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Ensaios Clínicos como Assunto
4.
Int Immunopharmacol ; 130: 111678, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38368773

RESUMO

Aldosterone is a key mineralocorticoid involved in regulating the concentration of blood electrolytes and physiological volume balance. Activation of mineralocorticoid receptor (MR) has been recently reported to participate in adaptive and innate immune responses under inflammation. Here, we evaluated the role of aldosterone and MR in inflammation bowel diseases (IBD). Aldosterone elevated in the colon of DSS-induced colitis mice. Aldosterone addition induced IL17 production and ROS/RNS level in group 3 innate lymphoid cells (ILC3s) and exacerbated intestinal injury. A selective mineralocorticoid receptor antagonism, eplerenone, inhibited IL17-producing ILC3s and its ROS/RNS production, protected mice from DSS-induced colitis. Mice lacking Nr3c2 (MR coding gene) in ILC3s exhibited decreased IL17 and ROS/RNS production, which alleviated colitis and colitis-associated colorectal cancer (CAC). Further experiments revealed that MR could directly bind to IL17A promoter and facilitate its transcription, which could be enhanced by aldosterone. Thus, our findings demonstrated the critical role of aldosterone-MR-IL17 signaling in ILC3s and gut homeostasis, indicating the therapeutic strategy of eplerenone in IBD clinical trial.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Aldosterona/metabolismo , Eplerenona , Mineralocorticoides/metabolismo , Imunidade Inata , Espécies Reativas de Oxigênio/metabolismo , Linfócitos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Inflamação/metabolismo
6.
Int J Mol Sci ; 25(2)2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38255942

RESUMO

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.


Assuntos
Nefropatias Diabéticas , MicroRNAs , Humanos , Aldosterona , Nefropatias Diabéticas/genética , Fibrose , Inflamação , MicroRNAs/genética , Mineralocorticoides , Receptores de Mineralocorticoides/genética
7.
Int J Mol Sci ; 25(2)2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38255827

RESUMO

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue.


Assuntos
Receptores de Mineralocorticoides , Neoplasias da Glândula Tireoide , Animais , Humanos , Ratos , Aldosterona/farmacologia , Técnicas de Cultura de Células , Mineralocorticoides , Receptores de Mineralocorticoides/genética , Câncer Papilífero da Tireoide
8.
Artigo em Inglês | MEDLINE | ID: mdl-38043634

RESUMO

The glucocorticoid cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis and crucial for the stress response in humans. Cortisol regulates numerous biological functions by binding to two different types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are found in the brain where they are crucially involved in various mental functions and in feedback inhibition of cortisol release. The precise role of both receptors in the human stress response is not completely understood. In this study, we examined the effects of pharmacological blockade of the MR or the GR on stress-induced cortisol release in a sample of 318 healthy young men (M = 25.42, SD = 5.01). Participants received the MR antagonist spironolactone (300 mg), the GR antagonist mifepristone (600 mg), or a placebo and were subjected 90 min later to a social-evaluative stressor (Trier Social Stress Test) or a non-stressful control condition. We found significantly higher stress-induced cortisol release in the spironolactone group, whereas participants after mifepristone administration did not differ from the control groups. These results suggest that MR blockade results in attenuated fast negative feedback processes and emphasize the important role of the MR during the early phase of the stress response.


Assuntos
Mifepristona , Espironolactona , Masculino , Humanos , Espironolactona/farmacologia , Espironolactona/metabolismo , Mifepristona/farmacologia , Mifepristona/metabolismo , Hidrocortisona/metabolismo , Mineralocorticoides/metabolismo , Mineralocorticoides/farmacologia , Receptores de Glucocorticoides/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico/tratamento farmacológico
9.
Diabetes Obes Metab ; 26(2): 417-430, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37885354

RESUMO

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is a major health challenge associated with a disproportionately high burden of end-stage renal disease, cardiovascular disease and death. This review summarizes the rationale, clinical evidence and practical implementation for non-steroidal mineralocorticoid receptor antagonists (nsMRAs), a drug class now approved and recommended for patients with T2D and CKD at risk of cardiorenal disease progression. Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Two large-scale, placebo-controlled, Phase 3 studies evaluated finerenone added to a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Over >2 years of treatment, finerenone was associated with a significant reduction in composite endpoints of renal and cardiovascular outcomes versus placebo. Esaxerenone or apararenone have both shown significant improvements in albuminuria versus placebo. In general, nsMRAs were well tolerated. Hyperkalaemia was the most notable treatment-related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Mineralocorticoides , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente
10.
J Clin Invest ; 134(1)2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37906287

RESUMO

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.


Assuntos
Hipertensão , Nefropatias , Ratos , Humanos , Animais , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Cromatina/genética , Amilorida/farmacologia , Mineralocorticoides/farmacologia , Rim , Nefropatias/genética , Perfilação da Expressão Gênica
11.
J Stroke Cerebrovasc Dis ; 33(1): 107449, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37995500

RESUMO

BACKGROUND: The usage rates of mineralocorticoids (fludrocortisone) to treat hyponatremia and isotonic crystalloids (saline and balanced crystalloids) to maintain intravascular volume in patients with aneurysmal subarachnoid hemorrhage (aSAH) patients across the United States are unknown. METHODS: We surveyed National Institute of Neurologic Disorders and Stroke (NINDS) StrokeNet sites in 2023, which are mostly large, tertiary, academic centers, and analyzed subarachnoid hemorrhage encounters from 2010 to 2020 in the Premier Healthcare Database that is representative of all types of hospitals and captures about 20 % of all acute inpatient care in the United States. RESULTS: Although mineralocorticoids are used by 70 % of the NINDS StrokeNet sites, it is used in less than 20 % of the aSAH encounters in the Premier Database. Although saline is ubiquitously used, balanced crystalloids are increasingly used for fluid therapy in aSAH patients. Its use in the NINDS StrokeNet sites and the Premier Healthcare Database is 41 and 45 %, respectively. CONCLUSIONS: The use of mineralocorticoids remains low, and balanced crystalloids are increasingly used as fluid therapy in aSAH patients. The effectiveness of mineralocorticoids and balanced crystalloids in improving outcomes for aSAH patients must be rigorously tested in randomized clinical trials.


Assuntos
Hiponatremia , Hemorragia Subaracnóidea , Humanos , Estados Unidos , Mineralocorticoides/uso terapêutico , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/tratamento farmacológico , Soluções Cristaloides/uso terapêutico , Hiponatremia/diagnóstico , Hiponatremia/terapia , Hidratação/efeitos adversos
12.
Br J Anaesth ; 132(1): 53-65, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38030548

RESUMO

Two randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies.


Assuntos
Glucocorticoides , Choque Séptico , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Fludrocortisona/farmacologia , Fludrocortisona/uso terapêutico , Hidrocortisona/farmacologia , Hidrocortisona/uso terapêutico , Choque Séptico/tratamento farmacológico , Mineralocorticoides/uso terapêutico , Receptores de Mineralocorticoides/uso terapêutico
13.
Diabetologia ; 67(2): 246-262, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38127122

RESUMO

The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.


Assuntos
Nefropatias Diabéticas , Insuficiência Cardíaca , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Mineralocorticoides/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Receptores de Mineralocorticoides/uso terapêutico
14.
Eur J Endocrinol ; 189(5): 537-545, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-38006230

RESUMO

OBJECTIVE: This study aims to identify susceptibility markers for adrenal crises (AC) in educated patients with chronic adrenal insufficiency (AI). DESIGN: A case-control study involving 66 patients with AI analyzing the impact of glucocorticoid and mineralocorticoid exposure, adrenomedullary function, inflammatory parameters, and educational status on AC frequency. Patients were categorized into low (n = 32) and high (n = 34) AC frequency groups based on AC occurrence (below or 2 times above the average of the reported AC frequency of 8.3 AC/100 patient-years in a previous prospective study). METHODS: Parameters, including cortisol plasma profile and urinary steroid excretion after administration of the morning glucocorticoid dose, 24-h urinary steroid profiling, salivary cortisol profiling, and hair cortisol, estimated cortisol exposure. Polymorphisms (single nucleotide polymorphism [SNP]) of the glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) associated with individual steroid sensitivity were assessed together with SNPs for 11ß-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11ß-hydroxysteroid dehydrogenase 2 (HSD11B2). Mineralocorticoid replacement was evaluated by serum and urinary electrolytes and osmolality, plasma-renin concentration, and ambulatory blood pressure levels. We additionally measured plasma and urinary catecholamines, serum levels of IL6 and hsCRP, and SNPs of IL6 and TNF-alpha. Patient knowledge of AC prevention was assessed by questionnaires. RESULTS: Frequent AC patients had higher daily glucocorticoid doses and hair cortisol levels, with no significant differences in other parameters investigated. AC frequency is inversely correlated with the frequency of self-reported adjustments of the glucocorticoid replacement. CONCLUSION: Higher glucocorticoid dosages in high-risk patients, despite unaffected cortisol metabolism, may be linked to decreased cortisol sensitivity or impaired glucocorticoid absorption. Proactive dose adjustments show a protective effect against AC, regardless of biological vulnerability.


Assuntos
Doença de Addison , Insuficiência Adrenal , Humanos , Hidrocortisona/metabolismo , Glucocorticoides/uso terapêutico , Mineralocorticoides , Estudos de Casos e Controles , Monitorização Ambulatorial da Pressão Arterial , Interleucina-6 , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/tratamento farmacológico , Doença de Addison/epidemiologia , Doença de Addison/genética , 11-beta-Hidroxiesteroide Desidrogenases/uso terapêutico , Causalidade
15.
Methods Enzymol ; 689: 167-200, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37802570

RESUMO

11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) converts active 11ß-hydroxyglucocorticoids to their inactive 11-keto forms, fine-tuning the activation of mineralocorticoid and glucocorticoid receptors. 11ß-HSD2 is expressed in mineralocorticoid target tissues such as renal distal tubules and cortical collecting ducts, and distal colon, but also in placenta where it acts as a barrier to reduce the amount of maternal glucocorticoids that reach the fetus. Disruption of 11ß-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypernatremia, hypokalemia and hypertension. Secondary hypertension due to 11ß-HSD2 inhibition has been observed upon consumption of excessive amounts of licorice and in patients treated with the azole fungicides posaconazole and itraconazole. Furthermore, inhibition of 11ß-HSD2 during pregnancy with elevated exposure of the fetus to cortisol can cause neurological complications with a lower intelligence quotient, higher odds of attention deficit and hyperactivity disorder as well as metabolic reprogramming with an increased risk of cardio-metabolic disease in adulthood. This chapter describes in vitro methods for the determination of 11ß-HSD2 activity that can be applied to identify inhibitors that may cause secondary hypertension and characterize the enzyme's activity in disease models. The included decision tree and the list of methods with their advantages and disadvantages aim to enable the reader to select and apply an in vitro method suitable for the scientific question and the equipment available in the respective laboratory.


Assuntos
Hipertensão , Síndrome de Excesso Aparente de Minerolocorticoides , Humanos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Mineralocorticoides/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Hidrocortisona
16.
Sci Rep ; 13(1): 14197, 2023 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-37648715

RESUMO

In this randomized, sham-controlled study, we explored the effects of acute transcutaneous vagus nerve stimulation (tVNS) on serum aldosterone in 20 younger (21-26 years) and 19 older (40-70 years) healthy participants. Blood samples were collected on two different days before and after a 20-min application of active tVNS at the inner tragus or sham stimulation of the earlobe. Irrespective of the stimulation mode, aldosterone levels decreased from pre- to post-stimulation in both the young (active: ß = - 1.610 (- 2.855, - 0.365), p = 0.022; sham: ß = - 0.857 (- 2.102, 0.388), p = 0.257) and the old cohort (active: ß = - 1.969 (- 3.234, - 0.703), p = 0.005; sham: ß = - 1.334 (- 2.600, - 0.069), p = 0.063). Although this decline was significant during active tVNS, the difference in estimated ß-coefficients between active and sham stimulation was not statistically significant in either cohort. Nevertheless, aldosterone concentrations showed a significant interaction effect between sex and age (p = 0.001). Among all study participants, younger women (23.3 ± 1.6 years) had the highest mineralocorticoid levels (pre active: 172.1 ± 102.0 pg/ml, pre sham: 214.3 ± 82.3 pg/ml), whereas the lowest were observed in older females (59.4 ± 9.4 years) (pre active: 104.9 ± 85.8 pg/ml, pre sham: 81.1 ± 53.8 pg/ml). This post hoc analysis did not suggest that active auricular tVNS reduces serum aldosterone levels compared to sham stimulation in healthy subjects. However, serum aldosterone levels differed among subjects depending on their age and sex, irrespective of tVNS.


Assuntos
Pavilhão Auricular , Estimulação do Nervo Vago , Idoso , Feminino , Humanos , Masculino , Aldosterona , Voluntários Saudáveis , Mineralocorticoides , Pessoa de Meia-Idade
17.
Sci Rep ; 13(1): 14111, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37644063

RESUMO

The exact link between systemic and ocular endogenous corticoids (steroidome) is unclear and whether the ocular steroidome is altered in CSCR eyes is unknown. The aims of this study were to analyze the human steroidome in the aqueous humor as a function of age, sex and time of the day, to correlate systemic and ocular steroidome and to analyze the ocular steroidome in long lasting complex inactive CSCR. Based on our results, we present two CSCR cases treated by the combination of oral mineralocorticoid antagonist and glucocorticoids drops. In a cross-sectional study, aqueous humor (AH) was collected between 8am and 6 pm from 50 unaffected individuals (25 men and 25 women) and from 14 patients with chronic CSCR, during cataract surgery. In addition, simultaneous serum and AH were collected from 27 individuals undergoing cataract surgery and, simultaneous AH and vitreous were collected from 9 patients undergoing cataract and vitrectomy to estimate corticoids levels in the different compartments. The steroidome was determined using a LC-MS/MS method that quantifies 13 endogenous corticoids from the gluco, mineralocorticoid and androgen pathways. In AH and vitreous, the highest corticoid level is reached by cortisol (F), that represents less than 10% of F serum level. The cortisol levels in the serum did not correlate with ocular cortisol levels. Serum and ocular cortisone (E) levels correlate, although less than 5% of circulating E reaches the eye. The only mineralocorticoids measured in the AH were corticosterone (B) and its inactive form, the 11-desoxycorticosterone (A). There was no influence of circadian rhythm on cortisol ocular levels and there was no correlation between the age or the sex and the level of F, E, A, and B. In eyes with chronic inactive CSCR, the levels of the active glucocorticoid form F was lower than in control eyes and the F/E ratio was reduced by 50% but the B/A ratio was higher indicating imbalance towards active mineralocorticoids. Base on this observation, we propose to combine an antagonist of the mineralocorticoid receptor together with topical glucocorticoids in two CSCR patients, resistant to all other treatments, with favorable outcome. Our results indicate that the ocular psteroidome is highly regulated suggesting a local metabolism of ocular corticoids. In eyes with long-lasting complex inactive CSCR, the steroidome analysis shows lower active glucocorticoids and higher active mineralocorticoids.


Assuntos
Catarata , Coriorretinopatia Serosa Central , Masculino , Humanos , Feminino , Coriorretinopatia Serosa Central/tratamento farmacológico , Glucocorticoides , Mineralocorticoides , Hidrocortisona , Cromatografia Líquida , Estudos Transversais , Espectrometria de Massas em Tandem
18.
Cells ; 12(13)2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37443819

RESUMO

The activation of the mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons seems to modify pain perception through both direct non-genomic and indirect genomic pathways. These distinct subpopulations of sensory neurons are not known for peripheral human nerves. Therefore, we examined MR and GR on subpopulations of sensory neurons in sectioned human and rat peripheral nerves. Real-time PCR (RT-PCR) and double immunofluorescence confocal analysis of MR and GR with the neuronal markers PGP9.5, neurofilament 200 (NF200), and the potential pain signaling molecules CGRP, Nav1.8, and TRPV1 were performed in human and rat nerve tissue. We evaluated mechanical hyperalgesia after intrathecal administration of GR and MR agonists. We isolated MR- and GR-specific mRNA from human peripheral nerves using RT-PCR. Our double immunofluorescence analysis showed that the majority of GR colocalized with NF200 positive, myelinated, mechanoreceptive A-fibers and, to a lesser extent, with peripheral peptidergic CGRP-immunoreactive sensory nerve fibers in humans and rats. However, the majority of MR colocalized with CGRP in rat as well as human nerve tissue. Importantly, there was an abundant colocalization of MR with the pain signaling molecules TRPV1, CGRP, and Nav1.8 in human as well as rat nerve tissue. The intrathecal application of the GR agonist reduced, and intrathecal administration of an MR agonist increased, mechanical hyperalgesia in rats. Altogether, these findings support a translational approach in mammals that aims to explain the modulation of sensory information through MR and GR activation. Our findings show a significant overlap between humans and rats in MR and GR expression in peripheral sensory neurons.


Assuntos
Hiperalgesia , Mineralocorticoides , Humanos , Ratos , Animais , Mineralocorticoides/metabolismo , Hiperalgesia/metabolismo , Receptores de Glucocorticoides/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Perna (Membro) , Dor/metabolismo , Células Receptoras Sensoriais/metabolismo , Biologia , Mamíferos/metabolismo
19.
Steroids ; 198: 109283, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37487816

RESUMO

Rapid non-genomic effects of corticosteroid hormones, affecting glutamatergic and GABAergic transmission, have been described for many limbic structures in the rodent brain. These rapid effects appear to be region specific. It is not always clear which (or even whether) corticosteroid receptor -the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR)- initiate these rapid effects. In the hippocampus and amygdala membrane-associated MR, but also membrane-associated GR (in amygdala), are involved. Other studies indicate that the rapid modulation may be induced by transactivation of kinases, or other receptors, like the G-protein coupled estrogen receptor (GPER) which was recently found to bind the mineralocorticoid aldosterone. In the current study we explored, in young adult male C57Bl6 mice, possible rapid effects of corticosterone on layer 2/3 infralimbic-prefrontal cortex (IL-PFC) neurons. We show that corticosterone, via non-genomic MR activation, reduces the mEPSC -but does not affect mIPSC- frequency; we observed no effect on mEPSC or mIPSC amplitude. As a result, overall spontaneous activity in the IL-PFC is suppressed. A potential role of GPER cannot be excluded, since G-15, an antagonist of GPER, also prevented the rapid effects of corticosterone.


Assuntos
Corticosterona , Receptores de Mineralocorticoides , Animais , Masculino , Camundongos , Corticosterona/farmacologia , Corticosterona/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Mineralocorticoides/metabolismo , Aldosterona/metabolismo , Mineralocorticoides , Receptores de Glucocorticoides/metabolismo , Córtex Pré-Frontal , Receptores Acoplados a Proteínas G/metabolismo
20.
Am J Vet Res ; 84(8)2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37279885

RESUMO

OBJECTIVE: To determine if urine electrolyte assessments can be used to monitor the adequacy of mineralocorticoid therapy in dogs with hypoadrenocorticism (HA). ANIMALS: 29 dogs with naturally occurring glucocorticoid- and mineralocorticoid-deficient HA. PROCEDURES: Urine sodium and potassium concentrations, sodium-to-potassium ratios, sodium-to-creatinine ratios, and potassium-to-creatinine (K:Cr) ratios were evaluated in dogs with newly diagnosed HA that were treated with desoxycorticosterone pivalate (DOCP). Dogs underwent measurements of urine and serum sodium, potassium, and creatinine concentrations and plasma renin activities twice monthly for up to 3 months. Regression analyses and calculation of coefficients of determination (R2) were performed to investigate potential associations between urine and serum variables. Urine variables also were compared between dogs considered to be undertreated or overtreated based on plasma renin activities. RESULTS: Urine K:Cr ratios were significantly associated with serum potassium concentrations 10 to 14 days (P = .002) and 30 days (P = .027) after the initial DOCP injection, but R2 values were only 0.35 and 0.17, respectively. Urine K:Cr ratios (median [IQR]) also were higher in dogs that were overtreated with DOCP (1.3 [0.7 to 2.3]) as compared to those dogs that were undertreated with DOCP (0.8 [0.5 to 0.9]) at 10 to 14 days after the initial DOCP injection (P = .039) but not at 30 days after the initial injection. Other urine variables were not significantly different between undertreated and overtreated dogs. CLINICAL RELEVANCE: Measures of urine electrolytes were not useful for assessing the adequacy of mineralocorticoid therapy in HA dogs that were treated with DOCP.


Assuntos
Insuficiência Adrenal , Doenças do Cão , Cães , Animais , Mineralocorticoides/uso terapêutico , Creatinina , Renina/uso terapêutico , Doenças do Cão/tratamento farmacológico , Insuficiência Adrenal/veterinária , Potássio/uso terapêutico , Eletrólitos , Sódio
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