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1.
S Afr Med J ; 110(7): 678-685, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32880347

RESUMO

BACKGROUND: The outcome and response of idiopathic nephrotic syndrome (NS) to steroids have been linked to race. OBJECTIVES: To determine the age of presentation, sex, race, histopathology, kidney function and disease status at the last hospital visit and correlate these with steroid response in Indian and black African children with idiopathic NS. METHODS: This is a retrospective review of 231 children aged 1 - 14 years, who were seen at Inkosi Albert Luthuli Central Hospital, Durban, South Africa (SA) from 2003 to 2018. RESULTS: The mean (standard deviation (SD)) age of presentation was 6.2 (3.4) years, with the majority of children (n=107; 46.3%) presenting at an early age (1 - 3 years) with a mean (SD) follow-up of 3.0 (2.4) years. One-hundred and twenty-one (52.4%) were males and 110 (47.6%) were females, with a male/female ratio of 1.1:1. There were 166 (71.9%) black African and 65 (28.1%) Indian children. The latter presented at a younger age than black African children (p<0.001). Seventy-six (32.9%) children were steroid sensitive (SS) and 155 (67.1%) were steroid resistant (SR). Black African children were more likely to be SR (odds ratio (OR) 2.0; p=0.02; 95% confidence interval (CI) 1.1 - 3.7). A kidney biopsy was performed in 209 (90.5%) children. Minimal change disease (MCD) was observed in 32 (13.9%) children and 162 (70.1%) had focal segmental glomerulosclerosis (FSGS). Black African children were slightly more likely to have FSGS; this, however, did not reach statistical significance (122/166 (73.5%) v. 40/65 (61.5%); OR 1.73; p=0.08; 95% CI 0.94 - 3.18). On comparing disease status at last hospital visit by race, 49/65 (75.4%) Indian and 94/166 (56.6%) black African children were in remission. At last hospital visit, black African children were less likely to be in remission than Indian children (OR 0.47; p=0.02; 95% CI 0.2 - 0.9), while 15/65 (23.1%) Indian and 47/166 (28.3%) black African children had relapsed, with no significant difference between the two groups. One (1.5%) Indian child and 25 (15.1%) black African children had end-stage kidney disease (ESKD) (OR 9.27; p=0.03; 95% CI 1.2 - 70.4) ‒ the majority had FSGS. Sixteen (61.5%) received renal replacement therapy. CONCLUSIONS: Our study shows a rising incidence of FSGS, with the majority of patients having SRNS, particularly black African children. This highlights the need for alternative efficacious therapy in the management of this disease. Also, a higher percentage of black African children with both MCD and FSGS were SS on histopathological examination, which was in keeping with reports from other regions in SA. There are still major challenges for the inclusion of all children into a chronic dialysis and transplant programme.


Assuntos
Síndrome Nefrótica/epidemiologia , Adolescente , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Criança , Pré-Escolar , Resistência a Medicamentos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Glomerulosclerose Segmentar e Focal/epidemiologia , Glucocorticoides/farmacologia , Humanos , Lactente , Falência Renal Crônica/epidemiologia , Masculino , Nefrose Lipoide/epidemiologia , Terapia de Substituição Renal/estatística & dados numéricos , Estudos Retrospectivos , Distribuição por Sexo , África do Sul/epidemiologia
2.
Obstet Gynecol ; 136(4): 823-826, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32769659

RESUMO

Recent evidence supports the use of an early, short course of glucocorticoids in patients with COVID-19 who require mechanical ventilation or oxygen support. As the number of coronavirus disease 2019 (COVID-19) cases continues to increase, the number of pregnant women with the disease is very likely to increase as well. Because pregnant women are at increased risk for hospitalization, intensive care unit admission, and mechanical ventilation support, obstetricians will be facing the dilemma of initiating maternal corticosteroid therapy while weighing its potential adverse effects on the fetus (or neonate if the patient is postpartum and breastfeeding). Our objective is to summarize the current evidence supporting steroid therapy in the management of patients with acute respiratory distress syndrome and COVID-19 and to elaborate on key modifications for the pregnant patient.


Assuntos
Infecções por Coronavirus , Cuidados Críticos/métodos , Glucocorticoides , Conduta do Tratamento Medicamentoso/normas , Pandemias , Pneumonia Viral , Complicações Infecciosas na Gravidez , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Monitoramento de Medicamentos/métodos , Feminino , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Glucocorticoides/classificação , Glucocorticoides/farmacologia , Humanos , Recém-Nascido , Oxigenoterapia/métodos , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/terapia , Complicações Infecciosas na Gravidez/virologia , Respiração Artificial/métodos , Medição de Risco
3.
Respir Med ; 170: 106045, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32843175

RESUMO

The potential detrimental effects of steroids on the immune system to fight viral infections had always been a concern for patients on long term steroids in chronic conditions. A recent warning from WHO on systemic corticosteroid use amid COVID-19 raised suspicion among public and healthcare professionals regarding the safety of steroid use during the SARS-CoV-2 pandemic. The corticosteroids (inhaled and oral) are commonly prescribed in the management of asthma and COPD patients and any unsolicited changes in medications use may lead to potentially severe exacerbations and may risk patient lives. This article provides a critical review of clinical evidence and offers a detailed discussion on the safety and efficacy of corticosteroids in asthma and COPD patients, both with and without COVID-19.


Assuntos
Asma/tratamento farmacológico , Infecções por Coronavirus , Glucocorticoides/farmacologia , Pandemias , Pneumonia Viral , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Asma/epidemiologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Vias de Administração de Medicamentos , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Resultado do Tratamento
4.
PLoS One ; 15(8): e0236689, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785240

RESUMO

OBJECTIVE: To compare the effects of photobiomodulation therapy (PBMT) and pharmacological therapy (glucocorticoids and non-steroidal anti-inflammatory drugs) applied alone and in different combinations in mdx mice. METHODS: The animals were randomized and divided into seven experimental groups treated with placebo, PBMT, prednisone, non-steroidal anti-inflammatory drug (NSAIDs), PBMT plus prednisone and PBMT plus NSAID. Wild type animals were used as control. All treatments were performed during 14 consecutive weeks. Muscular morphology, protein expression of dystrophin and functional performance were assessed at the end of the last treatment. RESULTS: Both treatments with prednisone and PBMT applied alone or combined, were effective in preserving muscular morphology. In addition, the treatments with PBMT (p = 0.0005), PBMT plus prednisone (p = 0.0048) and PBMT plus NSAID (p = 0.0021) increased dystrophin gene expression compared to placebo-control group. However, in the functional performance the PBMT presented better results compared to glucocorticoids (p<0.0001). In contrast, the use of NSAIDs did not appear to add benefits to skeletal muscle tissue in mdx mice. CONCLUSION: We believe that the promising and optimistic results about the PBMT in skeletal muscle of mdx mice may in the future contribute to this therapy to be considered a safe alternative for patients with Duchenne Muscular Dystrophy (DMD) in a washout period (between treatment periods with glucocorticoids), allowing them to remain receiving effective and safe treatment in this period, avoiding at this way periods without administration of any treatment.


Assuntos
Distrofina/genética , Terapia com Luz de Baixa Intensidade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/efeitos da radiação , Distrofia Muscular de Duchenne/terapia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Terapia Combinada , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Glucocorticoides/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Prednisona/farmacologia
5.
Sci Rep ; 10(1): 13689, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792492

RESUMO

To describe the epidemiological and clinical characteristics of patients with Corona Virus Disease 2019 (COVID-19) in Beijing. To analyze the application of corticosteroids in patients with severe pneumonia. We collected information on demographic characteristics, exposure history, clinical characteristics, corticosteroids use, and outcomes of the 65 confirmed cases of COVID-19 at Fifth Medical Center of PLA General Hospital from Jan 20 to Feb 23, 2020. The final follow-up date observed was April 15th, 2020. The number of patients with mild, general, severe, and critical type were 10 (15.38%), 32 (49.23%), 8 (12.31%), and 15 (23.08%), respectively. The median incubation period was 6 days. Notable outliers were 1 patient at 16 days and 1 patient at 21 days. In lymphocyte subgroup analysis, decreases in total, T, CD4, and CD8 lymphocytes were more common as the disease worsened (All P < 0.05). Methylprednisolone (mPSL) was applied to 31 (47.69%) patients with pneumonia, including 10 (31.25%) general, 8 (100%) severe, and 13 (86.67%) critical patients, respectively. Corticosteroids inhibited Interleukin-6(IL-6) production (P = 0.0215) but did not affect T lymphocyte (P = 0.0796). There was no significant difference between patients using lower dose (≤ 2 mg/kg day) and higher dose (> 2 mg/kg day) mPSL in inhibiting IL-6 production (P = 0.5856). Thirty of 31 patients (96.77%) had stopped mPSL due to improvement of pneumonia. Virus RNA clearance time lengthened with disease progression (P = 0.0001). In general type, there was no significant difference in virus clearance time between patients with (15, 12-19 days) and without (14.5, 11-18 days) (P = 0.7372) mPSL use. Lymphocyte, especially T lymphocyte, in severe and critical patients showed a dramatic decrease. Application of lower dose corticosteroids (≤ 2 mg/kg day) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose. Proper use corticosteroids in general type patients did not delay virus clearance.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Pequim/epidemiologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Criança , Pré-Escolar , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Contagem de Linfócitos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , RNA Viral/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
6.
J Zhejiang Univ Sci B ; 21(8): 628-636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32748578

RESUMO

BACKGROUND: Currently, there are no drugs that have been proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because of its broad antiviral activity, interferon (IFN) should be evaluated as a potential therapeutic agent for treatment of coronavirus disease 2019 (COVID-19), especially while COVID-19-specific therapies are still under development. METHODS: Confirmed COVID-19 patients hospitalized in the First Affiliated Hospital, School of Medicine, Zhejiang University in Hangzhou, China, from January 19 to February 19, 2020 were enrolled in a retrospective study. The patients were separated into an IFN group and a control group according to whether they received initial IFN-α2b inhalation treatment after admission. Propensity-score matching was used to balance the confounding factors. RESULTS: A total of 104 confirmed COVID-19 patients, 68 in the IFN group and 36 in the control group, were enrolled. Less hypertension (27.9% vs. 55.6%, P=0.006), dyspnea (8.8% vs. 25.0%, P=0.025), or diarrhea (4.4% vs. 19.4%, P=0.030) was observed in the IFN group. Lower levels of albumin and C-reactive protein and higher level of sodium were observed in the IFN group. Glucocorticoid dosage was lower in the IFN group (median, 40 vs. 80 mg/d, P=0.025). Compared to the control group, fewer patients in the IFN group were ventilated (13.2% vs. 33.3%, P=0.015) and admitted to intensive care unit (ICU) (16.2% vs. 44.4%, P=0.002). There were also fewer critical patients in the IFN group (7.4% vs. 25.0%, P=0.017) upon admission. Although complications during admission process were comparable between groups, the discharge rate (85.3% vs. 66.7%, P=0.027) was higher and the hospitalization time (16 vs. 21 d, P=0.015) was shorter in the IFN group. When other confounding factors were not considered, virus shedding time (10 vs. 13 d, P=0.014) was also shorter in the IFN group. However, when the influence of other factors was eliminated using propensity score matching, virus shedding time was not significantly shorter than that of the control group (12 vs. 15 d, P=0.206). CONCLUSIONS: IFN-α2b spray inhalation did not shorten virus shedding time of SARS-CoV-2 in hospitalized patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Sprays Nasais , Pneumonia Viral/tratamento farmacológico , Eliminação de Partículas Virais/efeitos dos fármacos , Albuminas/análise , Antivirais/administração & dosagem , Betacoronavirus , Proteína C-Reativa/análise , Estudos de Casos e Controles , China , Glucocorticoides/farmacologia , Hospitalização , Humanos , Pandemias , Pontuação de Propensão , Estudos Retrospectivos , Sódio/sangue
7.
Nat Commun ; 11(1): 3737, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719355

RESUMO

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC = 0.92, p-value = 3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs' effects on clinical outcomes likely dependent on functional adaptive immune responses.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Artroplastia de Quadril/efeitos adversos , Glucocorticoides/farmacologia , Ferimentos e Lesões/etiologia , Ferimentos e Lesões/imunologia , Doença Aguda , Idoso , Estudos de Casos e Controles , Método Duplo-Cego , Fadiga/tratamento farmacológico , Feminino , Humanos , Masculino , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Inibidor de NF-kappaB alfa/metabolismo , Dor/tratamento farmacológico , Fenótipo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Resultado do Tratamento
8.
Life Sci ; 257: 118044, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622944

RESUMO

AIMS: High-dose glucocorticoid (GC) administration causes osteoporosis. Many previous studies from our group and other groups have shown that melatonin participates in the regulation of osteoblast proliferation and differentiation, especially low concentrations of melatonin, which enhance osteoblast osteogenesis. However, the role of melatonin in glucocorticoid-induced osteoblast differentiation remains unknown. MATERIALS AND METHODS: An examination of the expression of osteoblast differentiation markers (ALP, OCN, COLL-1), as well as alkaline phosphatase staining and alkaline phosphatase enzymatic activity assay to measure osteoblast differentiation and quantifying Alizarin red S staining to measure mineralization, were performed to determine the effects of dexamethasone (Dex) and melatonin on the differentiation of MC3T3-E1 cells. We used immunofluorescence staining to detect the expression of Runx2 in melatonin-treated MC3T3-E1 cells. The expression of mRNA was determined by qRT-PCR, and protein levels were measured by western blotting. KEY FINDINGS: In the present study, we found that 100 µM Dex significantly reduced osteoblast differentiation and mineralization in MC3T3-E1 cells and that 1 µM melatonin attenuated these inhibitory effects. We found that only inhibition of PI3K/AKT (MK2206) and BMP/Smad (LDN193189) signalling abolished melatonin-induced differentiation and mineralization. Meanwhile, MK2206 decreased the expression of P-AKT and P-Smad1/5/9 and LDN193189 decreased the expression of P-Smad1/5/9 but had no obvious effect on P-AKT expression in melatonin-treated and Dex-induced MC3T3-E1 cells. SIGNIFICANCE: These findings suggest that melatonin rescues Dex-induced inhibition of osteoblast differentiation in MC3T3-E1 cells via the PI3K/AKT and BMP/Smad signalling pathways and that PI3K/AKT signalling may be the upstream signal of BMP/Smad signalling.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Melatonina/metabolismo , Osteoblastos/metabolismo , Animais , Biomineralização/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Linhagem Celular , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Melatonina/farmacologia , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo
9.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619553

RESUMO

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Carga Tumoral/fisiologia
10.
Eur J Pharmacol ; 882: 173328, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32603692

RESUMO

The novel coronavirus, later identified as SARS-CoV-2, originating from Wuhan in China in November 2019, quickly spread around the world becoming a pandemic. Despite the knowledge of previous coronaviruses, such as those responsible for the SARS and MERS-CoV epidemic, there is no drug or prophylaxis treatment to this day. The rapid succession of scientific findings on SARS-CoV-2 provides a significant number of potential drug targets. Nevertheless, at the same time, the high quantity of clinical data, generated by a large number of rapidly infected people, require accurate tests regarding effective medical treatments. Several in vitro and in vivo studies were rapidly initiated after the outbreak of the pandemic COVID-19. Initial clinical studies revealed the promising potential of remdesivir that demonstrated a powerful and specific in vitro antiviral activity for COVID-19. Promising effects appear to be attributable to hydroxychloroquine. Remdesivir and hydroxychloroquine are being tested in ongoing randomized trials. In contrast, oseltamivir was not effective and corticosteroids are not currently recommended. However, few data from ongoing clinical trials are identifying low molecular weight heparins, innate immune system stimulating agents, and inflammatory modulating agents as potential effective agents. The authors assume that the current pandemic will determine the need for a systematic approach based on big data analysis for identifying effective drugs to defeat SARS-Cov-2. This work is aimed to be a general reference point and to provide an overview as comprehensive as possible regarding the main clinical trials in progress at the moment.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Mediadores da Inflamação/farmacologia , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Mediadores da Inflamação/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Resultado do Tratamento
11.
Clin Sci (Lond) ; 134(12): 1305-1318, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32478397

RESUMO

Podocyte injury and loss contribute to proteinuria, glomerulosclerosis and eventually kidney failure. Recent studies have demonstrated that the loss of Kruppel-like factor 15 (KLF15) in podocytes increases the susceptibility to injury; however, the mechanism underlying the protective effects on podocyte injury remains incompletely understood. Herein, we showed that KLF15 ameliorates podocyte injury through suppressing NFAT signaling and the salutary effects of the synthetic glucocorticoid dexamethasone in podocyte were partially mediated by the KLF15-NFATc1 axis. We found that KLF15 was significantly reduced in glomerular cells of proteinuric patients and in ADR-, LPS- or HG-treated podocyets in vitro. Overexpression of KLF15 attenuated podocyte apoptosis induced by ADR, LPS or HG and resulted in decreased expression of pro-apoptotic Bax and increased expression of anti-apoptotic Bcl-2. Conversely, the flow cytometry analysis and TUNEl assay demonstrated that loss of KLF15 accelerated podocyte apoptosis and we further found that 11R-VIVIT, a specific NFAT inhibitor, and NFATc1-siRNA rescued KLF15-deficient induced podocyte apoptosis. Meanwhile, Western blot and RT-qPCR showed that the expression of NFATc1 was up-regulated in KLF15 silenced podocytes and reduced in KLF15 overexpressed podocytes. Mechanistically, ChIP analysis showed that KLF15 bound to the NFATc1 promoter region -1984 to -1861base pairs upstream of the transcription start site and the binding amount was decreased after treatment with LPS. The dual-luciferase reporter assay indicated that NFATc1 was a direct target of KLF15. In addition, we found that in vitro treatment with dexamethasone induced a decrease of NFATc1 expression in podocytes and was abrogated by knockdown of KLF15. Hence, our results identify the critical role of the KLF15-NFATc1 axis in podocyte injury and loss, which may be involved in mediating the salutary effects of dexamethasone in podocytes.


Assuntos
Glucocorticoides/uso terapêutico , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição NFATC/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Técnicas de Silenciamento de Genes , Inativação Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Glucose/toxicidade , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Biológicos , Transdução de Sinais
12.
Eur J Endocrinol ; 183(3): 297-306, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32570209

RESUMO

Objective: Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC. Design: Prospective, observational study. Methods: Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice. Results: In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively). Conclusions: We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.


Assuntos
HDL-Colesterol/sangue , Colesterol/metabolismo , Glucocorticoides/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fosfolipídeos/metabolismo , Estudos Prospectivos , Esfingolipídeos/metabolismo
13.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593491
14.
PLoS Genet ; 16(5): e1008757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379754

RESUMO

In the last decades in vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occurs in vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway and vice versa, in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling, both glucocorticoid receptor (Gr) responsiveness and endogenous cortisol levels are repressed in 5 days post fertilisation larvae. In addition, despite HIF activity being low at normoxia, our data show that it already impedes both glucocorticoid activity and levels. Secondly, we further analysed the in vivo contribution of glucocorticoids to HIF activity. Interestingly, our results show that both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) play a key role in enhancing it. Finally, we found indications that glucocorticoids promote HIF signalling via multiple routes. Cumulatively, our findings allowed us to suggest a model for how this crosstalk occurs in vivo.


Assuntos
Glucocorticoides/farmacologia , Fator 1 Induzível por Hipóxia/fisiologia , Receptor Cross-Talk/fisiologia , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucocorticoides/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Larva/genética , Larva/metabolismo , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
15.
Life Sci ; 255: 117817, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32446845

RESUMO

Glucocorticoids can promote cardiomyocyte maturation. However, the mechanism underlying glucocorticoid-mediated cardiomyocyte maturation is still unclear. Mitophagy plays a key role in cardiomyocyte maturation. Based on current knowledge, our study evaluated the effects of the glucocorticoid dexamethasone (100 nM) on the maturation of mouse embryonic stem cell-derived cardiomyocytes and the role of mitophagy in this maturation. The results showed that dexamethasone can promote embryonic stem cell-derived cardiomyocyte maturation, inhibit cardiomyocyte proliferation, and promote myocardial fiber arrangement. However, dexamethasone did not affect mitochondrial morphology in cardiomyocytes. Glucocorticoid receptor inhibitors (RU486, 1 nM) can inhibit dexamethasone-mediated cardiomyocyte maturation. Additionally, dexamethasone can promote mitophagy in embryonic stem cell-derived cardiomyocytes and induce LC3 and lysosomal aggregation in mitochondria. The inhibition of mitophagy can inhibit the cardiomyocyte maturation effect of dexamethasone. Furthermore, our research found that dexamethasone may mediate the occurrence of mitophagy in cardiomyocytes through Parkin. The siRNA-mediated inhibition of Parkin expression can inhibit mitochondrial autophagy caused by dexamethasone, thus inhibiting cardiomyocyte maturation. Overall, our study found that dexamethasone can promote embryonic stem cell-derived cardiomyocyte maturation through Parkin-mediated mitophagy.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Mitofagia/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/citologia , RNA Interferente Pequeno/administração & dosagem , Receptores de Glucocorticoides/metabolismo
16.
Adv Clin Exp Med ; 29(3): 345-353, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32237286

RESUMO

BACKGROUND: The pathogenesis of glucocorticoid (GC)-induced osteonecrosis (ON) of the femoral head remains unclear. Recent research has suggested that it is closely associated with injured bone microvascular endothelial cells (BMECs). However, few studies have used BMECs to perform research pertaining ON of the femoral head. OBJECTIVES: The objective of this study was to investigate the functional changes of BMECs treated with a GC and to detect the changes in related genes using microarrays. MATERIAL AND METHODS: Cells were isolated using an enzymatic method and identified with EC markers, such as von Willebrand factor (vWF), CD31 and vascular endothelial cadherin (VE-cadherin). Bone microvascular endothelial cells were treated with 0.1 mg/mL and 0.3 mg/mL of hydrocortisone to establish a GC-damaged model of BMECs. The mRNA microarrays were used to detect the differential expression profiles between BMECs with and without GC damage. RESULTS: Primary cells appeared as having a cobblestone-like morphology. Immunofluorescence staining revealed that the cells were 100% positive for vWF and CD31, and near 100% positive for VE-cadherin. It also confirmed that the cells were BMECs. Bone microvascular endothelial cells treated with 0.1 mg/mL of hydrocortisone showed shrinkage, and those treated with 0.3 mg/mL of hydrocortisone mostly showed apoptosis. The mRNA microarray showed that genes associated with endothelial cells, such as endothelin 1 (ET-1) receptor, angiotensin II (AII) receptor, intercellular adhesion molecule 1 (ICAM-1), and plasminogen activator inhibitor 1 (PAI-1), were upregulated, and genes associated with endothelial nitric oxide synthase (eNOS), endothelin 1 (ET-1), prostaglandin I2 (PGI2) synthase, PGI2 receptor, vascular endothelial growth factor (VEGF), prostaglandin E (PGE) synthase, and PGE receptor were downregulated. The results of quantitative polymerase chain reaction (qPCR) validation were consistent with the findings of mRNA microarrays. CONCLUSIONS: Glucocorticoids promoted BMECs to express vasoconstrictors and procoagulant factors and related receptors, and decreased the expression of vasodilators and their receptors.


Assuntos
Células Endoteliais/efeitos dos fármacos , Cabeça do Fêmur/citologia , Glucocorticoides/farmacologia , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos
17.
Invest Ophthalmol Vis Sci ; 61(4): 24, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32305042

RESUMO

Purpose: To identify processes that contribute to corticosteroid-induced ocular hypertension and candidate target genes for treatment. Methods: A systematic search identified five human microarray datasets investigating the effect of dexamethasone versus a control medium on trabecular meshwork (TM) tissue. After thorough quality control, samples of low quality were removed, and the datasets were integrated. Additionally, a bovine RNA-sequencing dataset allowed to investigate differences in gene expression profiling between cows with and without corticosteroid-induced ocular hypertension (responders vs. nonresponders). The obtained datasets were used as input for parallel pathway analyses. Significantly changed pathways were clustered into functional categories and the results were further investigated. A network visualizing the differences between the responders and nonresponders was created. Results: Seven functional pathway clusters were found to be significantly changed in TM cells exposed to dexamethasone versus a control medium and in TM cells of responders versus nonresponders: collagen, extracellular matrix, adhesion, WNT-signaling, inflammation, adipogenesis, and glucose metabolism. In addition, cell cycle and senescence were only significantly changed in responders versus nonresponders. The network of the differential gene expression between responders and nonresponders shows many connections between the identified processes via shared genes. Conclusions: Nine functional pathway clusters synthesize the molecular response to dexamethasone exposure in TM cells and are likely to be involved in the pathogenesis of corticosteroid-induced ocular hypertension.


Assuntos
Proteínas de Ciclo Celular/genética , Dexametasona/farmacologia , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica/fisiologia , Glucocorticoides/farmacologia , Hipertensão Ocular/induzido quimicamente , Malha Trabecular/efeitos dos fármacos , Animais , Bovinos , Células Cultivadas , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Hipertensão Ocular/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Malha Trabecular/metabolismo
18.
Otolaryngol Head Neck Surg ; 163(2): 382-388, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32204660

RESUMO

OBJECTIVE: Tympanic membrane (TM) fibroblast cytotoxicity of quinolone ear drops is enhanced by dexamethasone and fluocinolone. Hydrocortisone has not been evaluated. We aimed to assess the effects of these 3 steroids on mouse and human TM fibroblast survival. STUDY DESIGN: In vitro. SETTING: Academic laboratory. SUBJECTS AND METHODS: Mouse and human TM fibroblasts were exposed to hydrocortisone, dexamethasone, or fluocinolone at concentrations in commercial ear drops (1%, 0.1%, or 0.025%, respectively) and at steroid potency equivalents (1%, 0.033%, or 0.0033%, respectively), or dilute ethanol (control), twice within 24 hours or 4 times within 48 hours for 2 hours each time. Cells were observed with phase-contrast microscopy until the cytotoxicity assay was performed. RESULTS: Mouse and human TM fibroblasts treated with any of the steroids had lower survival after 24 and 48 hours compared to control (all P < .0001). After 24 hours, viability of mouse fibroblasts treated with the steroids was not different (P > .05), while treatment with hydrocortisone decreased human TM fibroblast viability (P < .0001). After 48 hours, at concentrations found in ear drops and at equivalent steroid potency, dexamethasone and fluocinolone had similar survival in mouse and human fibroblasts (all P > .05), but hydrocortisone had lower survival in both mouse (P = .02 and P < .0001) and human (P < .0001) fibroblasts. Phase-contrast images mirrored the cytotoxicity findings. CONCLUSION: Steroids found in commercial ear drops reduce survival of mouse and human TM fibroblasts. Hydrocortisone appears to be more cytotoxic than the more potent steroids, dexamethasone and fluocinolone. These findings should be considered when assessing clinical outcomes of ototopical preparations.


Assuntos
Dexametasona/farmacologia , Fibroblastos/efeitos dos fármacos , Fluocinolona Acetonida/análogos & derivados , Glucocorticoides/farmacologia , Hidrocortisona/farmacologia , Membrana Timpânica/citologia , Animais , Sobrevivência Celular , Células Cultivadas , Fluocinolona Acetonida/farmacologia , Humanos , Camundongos
19.
PLoS One ; 15(3): e0230514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187237

RESUMO

Several pathological conditions predict the use of glucocorticoids for the management of the inflammatory response; however, chronic or high dose glucocorticoid treatment is associated with hyperglycemia, hyperlipidemia, and insulin resistance and can be considered a risk factor for cardiovascular disease. Therefore, we investigated the mechanisms involved in the vascular responsiveness and inflammatory profile of mesenteric arteries of rats treated with high doses of glucocorticoids. Wistar rats were divided into a control (CO) group and a dexamethasone (DEX) group, that received dexamethasone for 7 days (2mg/kg/day, i.p.). Blood samples were used to assess the lipid profile and insulin tolerance. Vascular reactivity to Phenylephrine (Phe) and insulin, and O2•-production were evaluated. The intracellular insulin signaling pathway PI3K/AKT/eNOS and MAPK/ET-1 were investigated. Regarding the vascular inflammatory profile, TNF-α, IL-6, IL-1ß and IL-18 were assessed. Dexamethasone-treated rats had decreased insulin tolerance test and endothelium-dependent vasodilation induced by insulin. eNOS inhibition caused vasoconstriction in the DEX group, which was abolished by the ET-A antagonist. Insulin-mediated relaxation in the DEX group was restored in the presence of the O2.- scavenger TIRON. Nevertheless, in the DEX group there was an increase in Phe-induced vasoconstriction. In addition, the intracellular insulin signaling pathway PI3K/AKT/eNOS was impaired, decreasing NO bioavailability. Regarding superoxide anion generation, there was an increase in the DEX group, and all measured proinflammatory cytokines were also augmented in the DEX group. In addition, the DEX-group presented an increase in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-c) levels. In summary, treatment with high doses of dexamethasone promoted changes in insulin-induced vasodilation, through the reduction of NO bioavailability and an increase in vasoconstriction via ET-1 associated with generation of O2•- and proinflammatory cytokines.


Assuntos
Glucocorticoides/farmacologia , Insulina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Insulina/administração & dosagem , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Óxidos de Nitrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Anaesthesia ; 75(5): 654-663, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017012

RESUMO

These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri-operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone-producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin-releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Many more patients other than those with adrenal and hypothalamic-pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10-15 mg.m-2 hydrocortisone equivalent or greater in children may result in hypothalamo-pituitary-adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra-articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal.


Assuntos
Insuficiência Adrenal/tratamento farmacológico , Glucocorticoides/uso terapêutico , Assistência Perioperatória/métodos , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/fisiopatologia , Adulto , Criança , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Guias como Assunto , Humanos , Prevalência , Resultado do Tratamento , Reino Unido
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