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1.
Mol Psychiatry ; 28(7): 2872-2877, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37131073

RESUMO

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.


Assuntos
Remoção de Componentes Sanguíneos , COVID-19 , Humanos , Lipoproteínas LDL , Autoanticorpos , Síndrome de COVID-19 Pós-Aguda , Pandemias , Inflamação , Biomarcadores
2.
Mol Psychiatry ; 27(1): 34-37, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34140635

RESUMO

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.


Assuntos
Remoção de Componentes Sanguíneos , COVID-19 , Síndrome de Fadiga Crônica , COVID-19/complicações , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/tratamento farmacológico , Humanos , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda
3.
Horm Metab Res ; 54(8): 532-539, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35944524

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is currently one of the major health concerns worldwide accounting for many deaths and posing a great social and economic burden. Early activation of adrenal hormone secretion is pivotal to surviving systemic microbial infections. In addition, clinical studies demonstrated that glucocorticoids might also be beneficial in reducing disease progression and life deterioration in certain patients with COVID-19. Recent studies demonstrated that SARS-CoV-2 might target the adrenal glands, raising the possibility that at least some COVID-19 complications may be associated with adrenal dysfunction. Whether SARS-CoV-2 infection might cause adrenal dysfunction remains unknown. Histopathological examinations provided evidence that SARS-CoV-2 infection might indeed cause certain structural damage to the adrenal glands, especially concerning its vascular system. However, since no widespread cellular damage to cortical cells was observed, it is less likely that those changes could lead to an immediate adrenal crisis. This assumption is supported by the limited number of studies reporting rather adequate cortisol levels in patients with acute COVID-19. Those studies, however, could not exclude a potential late-onset or milder form of adrenal insufficiency. Although structural damage to adrenal glands is a rarely reported complication of COVID-19, some patients might develop a critical illness-related corticosteroid insufficiency (CIRCI), or iatrogenic adrenal insufficiency resulting from prolonged treatment with synthetic glucocorticoids. In this mini-review article, we aimed at describing and discussing factors involved in the adrenal gland function and possible dysfunction during COVID-19.


Assuntos
Insuficiência Adrenal , Tratamento Farmacológico da COVID-19 , COVID-19 , Glândulas Suprarrenais , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/etiologia , COVID-19/complicações , Glucocorticoides/uso terapêutico , Humanos , Pandemias , SARS-CoV-2
4.
Proc Natl Acad Sci U S A ; 116(44): 22269-22274, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611400

RESUMO

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Ferroptose/efeitos dos fármacos , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Insulina/metabolismo , Ferro/metabolismo , Ácido Linoleico/metabolismo , Camundongos , Mitotano/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transferrina/metabolismo
5.
Internist (Berl) ; 63(1): 4-11, 2022 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-34928398

RESUMO

Diseases of the adrenal cortex require particular attention during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Firstly, SARS-CoV­2 infections can give rise to extrapulmonary manifestations and cause endocrine disorders, particularly in the adrenal cortex. Furthermore, patients with pre-existing insufficiency of the adrenal cortex or hypercortisonism are particularly at risk from a severe infection such as SARS-CoV­2, to suffer from additional complications or a more severe course of a SARS-CoV­2 infection with a higher mortality. Especially in hemodynamically unstable patients with a SARS-CoV­2 infection, diseases of the adrenal glands should also be considered in the differential diagnostics and if necessary clarified, if this is not already known. Prolonged treatment of patients with a SARS-CoV­2 infection with regimens containing high doses of glucocorticoids can also result in a secondary adrenal insufficiency. In order to address these special aspects, some practical recommendations for the diagnostic and therapeutic management of functional disorders of the adrenal glands in patients with a SARS-CoV­2 infection are therefore presented.


Assuntos
Córtex Suprarrenal , Insuficiência Adrenal , COVID-19 , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/tratamento farmacológico , Humanos , Pandemias , SARS-CoV-2
6.
Crit Care Med ; 44(4): e190-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26491861

RESUMO

OBJECTIVES: Sepsis and septic shock are commonly present in the ICU and accompanied by significant morbidity, mortality, and cost. The frequency of secondary adrenal insufficiency in sepsis remains open to debate and a challenge to identify and treat appropriately. Animal models of sepsis using genetic or surgical initiation of adrenal insufficiency resulted in increased mortality, but the mechanisms are still unclear. The present study investigates the impact of adrenal inflammation in septic mice challenged with cecal ligation and puncture. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: C57BL/6N wild-type mice. INTERVENTIONS: Sepsis, induced by cecal ligation and puncture for 24 and 48 hours. MEASUREMENTS AND MAIN RESULTS: Both septic and control mice were carefully monitored (every 30 min) for up to 48 hours and divided into survivors and nonsurvivors. We observed a significant and massive increase of interleukin-6, interleukin-1ß, and tumor necrosis factor-α in adrenal protein extracts of nonsurvivors compared with sham animals and survivors. This pattern was partly reflected in liver and lung but not in plasma samples. Notably, a significant increase in nonsurvivors compared with survivors was only found for lung interleukin-6. In line with these findings, we detected a higher degree of leukocyte infiltration and hemorrhage in the adrenal glands of deceased mice. Evaluation of the hypothalamic-pituitary-adrenal axis response in these animals revealed an increase of adrenocorticotropic hormone, which was only partly reflected in the corticosterone level. Notably, using the adrenocorticotropic hormone stimulation test, we found an impaired adrenocorticotropic hormone response, particularly in nonsurvivors, which significantly correlated with the number of infiltrated leukocytes. CONCLUSIONS: Cecal ligation and puncture-induced murine sepsis induces a strong inflammatory response in the adrenal glands, which is accompanied by cell death and hemorrhage. Our data suggest that mortality and adrenal incapacitation are associated with the degree of adrenal inflammation, thereby underscoring the importance of adrenal function on survival.


Assuntos
Glândulas Suprarrenais/fisiopatologia , Inflamação/patologia , Choque Séptico/mortalidade , Glândulas Suprarrenais/patologia , Insuficiência Adrenal/fisiopatologia , Hormônio Adrenocorticotrópico/sangue , Animais , Ceco , Corticosterona/sangue , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal , Distribuição Aleatória , Choque Séptico/complicações , Choque Séptico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Proc Natl Acad Sci U S A ; 110(36): 14801-6, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23959899

RESUMO

Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.


Assuntos
Sistema Hipotálamo-Hipofisário/fisiologia , Inflamação/fisiopatologia , Fator 88 de Diferenciação Mieloide/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Córtex Suprarrenal/citologia , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Animais , Western Blotting , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Feminino , Expressão Gênica , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo
9.
Proc Natl Acad Sci U S A ; 110(6): 2288-93, 2013 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-23345449

RESUMO

Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local anti-inflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal ß-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status.


Assuntos
Hormônio Liberador de Gonadotropina/agonistas , Transplante das Ilhotas Pancreáticas/métodos , Condicionamento Pré-Transplante/métodos , Glândulas Suprarrenais/fisiologia , Glândulas Suprarrenais/cirurgia , Animais , Linhagem Celular , Técnicas de Cocultura , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/cirurgia , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética
10.
Hepatology ; 60(4): 1196-210, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24845056

RESUMO

UNLABELLED: The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibody-blockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. CONCLUSION: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesity-related metabolic dysregulation and, especially, NASH.


Assuntos
Antígenos B7/fisiologia , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/fisiopatologia , Animais , Antígenos B7/deficiência , Antígenos B7/genética , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Linfócitos T Reguladores/patologia
11.
Open Forum Infect Dis ; 11(1): ofad641, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38179103

RESUMO

Genetic defects in the interferon (IFN) system or neutralizing autoantibodies against type I IFNs contribute to severe COVID-19. Such autoantibodies were proposed to affect post-COVID-19 syndrome (PCS), possibly causing persistent fatigue for >12 weeks after confirmed SARS-CoV-2 infection. In the current study, we investigated 128 patients with PCS, 21 survivors of severe COVID-19, and 38 individuals who were asymptomatic. We checked for autoantibodies against IFN-α, IFN-ß, and IFN-ω. Few patients with PCS had autoantibodies against IFNs but with no neutralizing activity, indicating a limited role of type I IFNs in PCS pathogenesis. In a subset consisting of 28 patients with PCS, we evaluated IFN-stimulated gene activity and showed that it did not correlate with fatigue. In conclusion, impairment of the type I IFN system is unlikely responsible for adult PCS.

12.
Elife ; 122023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37449973

RESUMO

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1ß reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1ß-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.


Assuntos
Proteômica , Ácido Succínico , Camundongos , Animais , Glucocorticoides/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Inflamação/metabolismo
13.
Lancet Diabetes Endocrinol ; 11(9): 675-693, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37524103

RESUMO

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.


Assuntos
Doenças Metabólicas , Viroses , Humanos , Relevância Clínica , Viroses/complicações , Doenças Metabólicas/epidemiologia , Saúde Pública
14.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33491666

RESUMO

Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.


Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/fisiologia , Sistema Simpático-Suprarrenal/fisiologia , Simportadores/genética , Simportadores/fisiologia , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/fisiologia , Animais , Restrição Calórica , Catecolaminas/biossíntese , Linhagem Celular , Células Cromafins/fisiologia , Transportadores de Ácidos Dicarboxílicos/deficiência , Expressão Gênica , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Longevidade/genética , Longevidade/fisiologia , Malatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Atividade Motora/genética , Atividade Motora/fisiologia , Piridinas/farmacologia , Simportadores/deficiência
15.
Neuroimmunomodulation ; 17(3): 180-3, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20134197

RESUMO

Adrenal gland insufficiency - the clinical manifestation of deficient production or action of adrenal steroids - is a life-threatening disorder. Among many factors which can predispose to primary adrenal failure, an autoimmune adrenalitis and infectious agents play a major role. The initial host defense against bacterial infections is executed primarily by the pattern recognition receptors, e.g. Toll-like receptors (TLRs), expressed in cells from the innate immune system. Upon activation, TLRs have been found to regulate various levels of innate and adaptive immunity as well as control tissue inflammation. TLRs are implicated in adrenal cell turnover and steroidogenesis during inflammation. Therefore, TLRs play a crucial role in the activation of adrenal inflammation mediating adrenal gland dysfunction during septicemia.


Assuntos
Insuficiência Adrenal/imunologia , Inflamação/imunologia , Sepse/complicações , Sepse/imunologia , Receptores Toll-Like/metabolismo , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/fisiopatologia , Insuficiência Adrenal/microbiologia , Insuficiência Adrenal/fisiopatologia , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/fisiopatologia , Citocinas/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação/microbiologia , Inflamação/fisiopatologia
16.
Mol Cell Endocrinol ; 300(1-2): 57-65, 2009 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-19022344

RESUMO

During sepsis, an intact adrenal gland glucocorticoid stress response is critical for survival. Recently, we have shown that Toll-like receptors, particularly TLR2 and TLR4, are crucial in HPA axis regulation following inflammation, establishing a direct link between bacterial and viral ligands and the endocrine stress response. However, the exact role which TLRs play in adrenal homeostasis and malfunction is not yet sufficiently known. Using quantitative real-time PCR, confocal microscopy and the NF-kappaB reporter gene assay, we aimed to analyse both, expression and function of all relevant TLRs in the human adrenocortical cell line-NCI-H295R and adrenal cells in primary culture. Our results demonstrate a differential expression pattern of TLR1-9 in human adrenocortical cells as compared to immune cells and adrenocortical cancer cells. Consequently, activation of these cells by bacterial ligands leads to differential induction of cytokines including IL6, IL8 and TNF-alpha. Therefore, Toll-like receptors expression and function is a novel feature of the adrenal stress system contributing to adrenal tissue homeostasis, regeneration and tumorigenesis.


Assuntos
Córtex Suprarrenal , Regulação da Expressão Gênica , Isoformas de Proteínas/metabolismo , Receptores Toll-Like/metabolismo , Córtex Suprarrenal/citologia , Córtex Suprarrenal/metabolismo , Idoso , Células Cultivadas , Feminino , Homeostase , Humanos , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Isoformas de Proteínas/genética , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-32038494

RESUMO

Bacterial sepsis is a serious threat to the body homeostasis and is often associated with high mortality in non-coronary intensive stations. In order to survive sepsis, rapid activation of the hypothalamus-pituitary-adrenal gland axis and sympathomedullary system is necessary. In many patients with sepsis, the function of those two arms of the stress system is dysregulated with underlying mechanisms remaining unknown. In our previous experimental studies, we have demonstrated that LPS-induced systemic inflammation and CLP-induced peritonitis can result in adrenal gland damage. Histological and transcriptomic analysis revealed a potential involvement of the adrenal microvascular endothelium in this process. However, our knowledge about the function of adrenal microvascular cells during sepsis is scarce. In the present study, we have characterized transcriptomic alterations in isolated mouse adrenal microvascular endothelial cells induced by systemic administration of bacterial LPS. Our results revealed that LPS induced a distinct transcriptomic profile in the adrenal microvascular cells, including multiple genes regulating inflammation, activation of the coagulation cascade and vascular permeability. Activation of those genes may be potentially involved in the damage to the microvascular endothelium and altogether contribute to the sepsis-mediated adrenal dysregulation.

18.
J Steroid Biochem Mol Biol ; 191: 105360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028792

RESUMO

Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. In the present study, we have used RNA Sequencing (RNA-Seq) technology to analyze changes in adrenal transcriptome elucidated by bacterial LPS. We aimed to find particularly alterations in genes that were previously not reported to be involved in the adrenal gland dysregulation in contexts of sepsis. Our results demonstrate that systemic administration of LPS significantly altered expression of 8458 genes as compared to saline injected animals. The subsequent quality and functional analysis of these gene signatures revealed that LPS-induced highly homogenous transcriptional response in total upregulating 4312 and downregulating 4146 genes. Furthermore, functional annotation analysis together with gene enrichment set analysis (GSEA) clearly demonstrated that adrenal response to LPS involved alterations in multiple pathways related to the inflammatory response along with previously unexplored activation of the hypoxia pathway. In addition, LPS strongly downregulated genes involved in the adrenal homeostasis, development, and regeneration. Those alterations were subsequently verified in clinically relevant cecal ligation and puncture (CLP)-induced sepsis model. Collectively, our study demonstrates that RNA-seq is a very useful method that can be applied to search for new unexplored pathways potentially involved in adrenal gland dysregulation during sepsis.


Assuntos
Sepse/genética , Transcriptoma , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Regulação da Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/fisiopatologia , Análise de Sequência de RNA
19.
Exp Clin Endocrinol Diabetes ; 127(2-03): 165-175, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30562824

RESUMO

Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or mineralocorticoid deficiency due to failure of the adrenal cortex which may result in an adrenal crisis with potentially life-threatening consequences. Even though efficient and safe pharmaceutical preparations for the substitution of endogenous gluco- and mineralocorticoids are established in therapy, the mortality in patients with PAI is still increased and the health-related quality of life (HRQoL) is often reduced.PAI is a rare disease but recent data report an increasing prevalence. In addition to the common "classical" causes of PAI like autoimmune, infectious, neoplastic and genetic disorders, other iatrogenic conditions - mostly pharmacological side effects (e. g., adrenal haemorrhage associated with anticoagulants, drugs affecting glucocorticoid synthesis, action or metabolism and some of the novel anti-cancer checkpoint inhibitors) are contributing factors to this phenomenon.Due to the rarity of the disease and often non-specific symptoms at least in the early stages, PAI is frequently not considered resulting in a delayed diagnosis. Successful therapy is mainly based on adequate patient education as a cornerstone in the prevention and management of adrenal crisis. A focus of current research is in the development of pharmacokinetically optimized glucocorticoid preparations as well as regenerative therapies.


Assuntos
Doença de Addison/diagnóstico , Doença de Addison/tratamento farmacológico , Doença de Addison/etiologia , Doença de Addison/epidemiologia , Humanos
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