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1.
Eur J Endocrinol ; 181(4): C13-C15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505455

RESUMO

A study has examined the rates of adrenal crises in patients treated with pituitary or adrenal surgery. Rates were substantial (approximately 9 per 100 patient years), perhaps representing suppression of corticotrope ACTH secretion and deprivation of normal corticotrope number postoperatively. Hormone withdrawal syndrome may have contributed to the rates of apparent adrenal crises given the definition used. Higher rates were seen in patients given relatively high dose glucocorticoids postoperatively in one of the two centres where patients were treated - perhaps some of the patients in the high dose centre had longer periods of corticotrope suppression from exogenous glucocorticoids, increasing the risk period for adrenal crises. The question of optimal glucocorticoid dose and weaning rate after cure of Cushing's syndrome remains a balance between weaning at a rate sufficiently rapid to allow resumption of normal corticotrope function thereby preventing adrenal crises and providing sufficient glucocorticoid support to avoid hormone withdrawal syndrome or even precipitating an adrenal crisis, in the vulnerable 4-6 month period after successful surgery. There is likely to be considerable inter-individual variability in optimum glucocorticoid dose and weaning rate so that close clinical and biochemical monitoring is currently a practical approach.


Assuntos
Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/terapia , Glândulas Suprarrenais/efeitos dos fármacos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto/métodos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Resultado do Tratamento
2.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
3.
Vet Immunol Immunopathol ; 216: 109892, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446206

RESUMO

Cyclosporine and glucocorticoids are powerful immunosuppressive agents used to treat many inflammatory diseases in dogs. Cyclosporine inhibits calcineurin-dependent pathways of T cell activation and resultant T cell cytokine production, and glucocorticoids directly inhibit genes coding for cytokines. Little work has been done comparing the effects of these agents on T cell cytokine production in dogs. Our study measured T cell interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production using flow cytometry and T cell IL-2 and IFN-γ gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in activated canine T cells incubated with cyclosporine and dexamethasone in vitro. For flow cytometric assays, diluted whole blood was cultured for 7 h in the presence of cyclosporine (10, 100, 500, and 1000 ng/mL) or dexamethasone (10 ng/mL, 100 ng/mL, 1 µg/mL, and 10 µg/mL). For qRT-PCR, whole blood was cultured for 5 h with the same drugs at the same concentrations, and RNA was then extracted from leukocytes. Flow cytometry and qRT-PCR both demonstrated inhibition of IL-2 and IFN-γ that was concentration-dependent in response to cyclosporine, and was more variable for dexamethasone. Quantitative RT-PCR but not flow cytometry documented significant reduction of IL-2 expression after dexamethasone treatment, while both methods showed concentration-dependent suppression of IFN-γ. Quantitative RT-PCR also revealed additional cytokine suppression at higher cyclosporine concentrations, an effect not found using flow cytometry, and may therefore be the preferred method for cytokine determination in dogs. Suppression of IL-2 and IFN-γ in activated T cells may have potential as an indicator of the efficacy of cyclosporine and glucocorticoids in suppressing canine T cell function in vivo, and may therefore be of value for characterizing the immunosuppression induced by these drugs in clinical patients.


Assuntos
Ciclosporina/farmacologia , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Ciclosporina/administração & dosagem , Dexametasona/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Glucocorticoides/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Interferon gama/genética , Interleucina-2/genética
4.
Biomed Khim ; 65(3): 222-226, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31258145

RESUMO

Along with modern new drugs, many therapeutic schemes also include known effective drugs, particularly, glucocorticoids. One of the most distributed of them is prednisolone that has pronounced anti-inflammatory properties. Its disadvantage is short-term circulation, resulting in a number of side effects. For this reason the development of its more effective and safe formulations is carried out. We have obtained the formulation of prednisolone included in nanoparticles from soy phosphatidylcholine with an average diameter of 20 nm. With oral administration to rats and analysis by HPLC an increase in prednisolone maximal concentration in of plasma and the duration of circulation as compared with free drug administration were shown. The experiment with mice with conconavalin A induced inflammation was also carried out: conconavalin A was injected subplantary in an hour after oral administration of both prednisolone formulations in several doses. The index of the inflammatory reaction (determined by the edema degree) was suppressed more effectively in the case of prednisolone in nanoparticles. Maximal suppression (62.2% as compared with 49.6% for free prednisolone) was observed even at a minimal dose (2.5 mg/kg), at which the free drug did not act at all. The results indicate an increase in the efficiency of prednisolone included in phospholipid nanoparticles, that makes it possible to diminish its administered doses and thereby reduce the risk of side effects.


Assuntos
Anti-Inflamatórios/farmacologia , Portadores de Fármacos/química , Glucocorticoides/farmacologia , Inflamação/tratamento farmacológico , Prednisolona/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacocinética , Glucocorticoides/farmacocinética , Camundongos , Nanopartículas , Fosfolipídeos , Prednisolona/farmacocinética , Ratos
5.
Mol Immunol ; 112: 394-398, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31291610

RESUMO

ANCA associated vasculitis is a serious, very often recurrent disease that despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infections, vasculitis activity, and renal disease. During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. Detection of several components of this system in the circulation and urine reflects disease activity, and thus may be useful for clinical prognosis and to set up personalised treatments. In fact, some components of the complement system, such as C5a, might be potential targets for therapy. In this Review an update on clinical evidence for the role of complement activation in AAV is provided and subsequently we discuss potential therapeutic strategies that target complement components and open the way for clinical use of this target therapy in the near future.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas do Sistema Complemento/imunologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Ciclofosfamida/farmacologia , Glucocorticoides/farmacologia , Humanos , Rituximab/farmacologia
6.
Am J Vet Res ; 80(8): 743-755, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31339769

RESUMO

OBJECTIVE: To evaluate the clinicopathologic, hemodynamic, and echocardiographic effects of short-term administration of anti-inflammatory dosages of prednisolone to systemically normal cats. ANIMALS: 10 cats with allergic dermatitis and 10 healthy control cats. PROCEDURES: Cats with allergic dermatitis were randomly allocated to 2 groups and received 2 dosages of prednisolone (1 and 2 mg/kg/d, PO, for 7 days) in a crossover design followed by 9-day tapering and 14-day washout periods. Each prednisolone-treated cat was matched to a healthy control cat on the basis of sex, neuter status, age (± 1 year), and body weight (± 10%). Control cats received no treatment during the 35-day observation period. Clinicopathologic, echocardiographic, and hemodynamic variables were measured at baseline (day 0) and predetermined times during and after prednisolone administration and compared within and between the 2 treatment groups. RESULTS: Prednisolone-treated cats had expected clinicopathologic alterations (mild increases in neutrophil and monocyte counts and serum concentrations of albumin, cholesterol, and triglycerides) but systolic arterial blood pressure; blood glucose, serum potassium, and cardiac biomarker concentrations; urinary sodium excretion; and echocardiographic variables did not differ significantly from baseline at any time. Statistically significant, albeit clinically irrelevant, increases in blood glucose and N-terminal pro-B-type natriuretic peptide concentrations were observed between baseline and the prednisolone pharmacokinetic steady state (7 days after initiation) only when the 2-mg/kg dosage was administered. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated short-term oral administration of anti-inflammatory dosages of prednisolone did not cause relevant hemodynamic, echocardiographic, or diabetogenic effects in systemically normal cats with allergic dermatitis.


Assuntos
Anti-Inflamatórios/farmacologia , Gatos , Glucocorticoides/farmacologia , Prednisolona/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doenças do Gato/tratamento farmacológico , Dermatite/tratamento farmacológico , Dermatite/veterinária , Ecocardiografia/efeitos dos fármacos , Ecocardiografia/veterinária , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Hemodinâmica/efeitos dos fármacos , Masculino , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Estudos Prospectivos , Distribuição Aleatória
7.
Chem Biol Interact ; 310: 108726, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255635

RESUMO

Tetrandrine (TET) and cepharanthine (CEP) are two bisbenzylisoquinoline alkaloids isolated from the traditional herbs. Recent molecular investigations firmly supported that TET or CEP would be a potential candidate for cancer chemotherapy. Prognosis of patients with glucocorticoid resistant T cell acute lymphoblastic leukemia (T-ALL) remains poor; here we examined the anti-T-ALL effects of TET and CEP and the underlying mechanism by using the glucocorticoid resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As the important markers of apoptosis, p53 and Bax were both upregulated by the treatment of TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will be another possible mechanism. During the process of apoptosis in Jurkat T cells, treatment with TET or CEP also increased the phosphorylation of JNK and p38. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat T cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into the clinical application of TET or CEP for the treatment of patients with relapsed T-ALL.


Assuntos
Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Benzilisoquinolinas/uso terapêutico , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172971

RESUMO

Dexamethasone inhibits mucin secretion considering the primary option for treating acute asthma exacerbation. However, the mechanism underlying dexamethasone-induced decreased in mucosecretion is unclear. Recent studies have reported that dexamethasone exerts an inhibitory effect on mucosecretion in the lung by modulating the expression of calcium processing genes. However, the expression of the calcium processing genes in the trachea is not examined yet. Thus, the present study is the first to report the localization of calcium processing proteins such as transient receptor potential vanilloid-4 (Trpv4), transient receptor potential vanilloid-6 (Trpv6), calbindin-D9k (CaBP-9k) and plasma membrane Ca2+-ATPase 1 (Pmca1) in the mouse trachea and their glucocorticoid-induced response. In this study, mice were subcutaneously injected with dexamethasone for 5 days, and their tracheal samples were collected by dividing the trachea into the cervical, and thoracic sections based on its anatomical structure. The localization of TRPV4, TRPV6, CaBP-9k, and PMCA1 proteins was detected in the tracheal epithelium, submucosal glands, cartilages and muscles. Dexamethasone treatment downregulated the mRNA expression of the four calcium processing genes and mucin producing genes. The dexamethasone-induced decrease in the secretion of mucosubstances in the trachea was determined by performing Alcian blue-periodic acid-Schiff staining. Thus, the findings of the present study suggest that glucocorticoids simultaneously can regulate the expression of calcium processing genes and tracheal mucosecretion.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Mucosa Respiratória/metabolismo , Proteína G de Ligação ao Cálcio S100/genética , Proteína G de Ligação ao Cálcio S100/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
9.
Cornea ; 38(8): 1017-1022, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31090593

RESUMO

PURPOSE: To determine in-use stability and sterility of fortified cefazolin, ceftazidime, vancomycin, amphotericin B, and methylprednisolone eye drops in a simulated inpatient setting with and without a mobile refrigerated container (MR). METHODS: Each drug was prepared and divided into 4 groups: 1) simulated patient use with the MR group: stored at 4°C and kept in the MR during drug administration, 2) simulated patient use without the MR (NoMR) group: stored at 4°C and no MR, 3) refrigerated control group: stored at 4°C, and 4) room temperature control group: stored at room temperature. Stability and sterility data were evaluated at days 0, 4, 7, 14, 21, and 28. Linear mixed-effects model and survival analysis were performed. RESULTS: Median time to 10% loss of concentration for in-use medications (MR/NoMR groups) was >28/27.9, 22.2/22.2, 19.4/19.4, 10.18/<4, and >28/>28 days for cefazolin, ceftazidime, vancomycin, amphotericin B, and methylprednisolone, respectively. There was no significant difference in the predicted concentration loss per day among all groups for vancomycin and methylprednisolone (all P > 0.05). For the other study medications, all room temperature control groups, the cefazolin NoMR group, and the ceftazidime NoMR group had significantly greater predicted concentration loss per day compared with the refrigerated control groups (all P ≤ 0.02). Culture results were negative for all drugs throughout the study. CONCLUSIONS: The NoMR group showed that the drug significantly degraded rapidly for cefazolin, ceftazidime, and amphotericin B. Implementation of MR could decrease the predicted loss of concentration per day for cefazolin and ceftazidime. In vitro antimicrobial activity and sterility were retained for 28 days.


Assuntos
Antibacterianos/análise , Estabilidade de Medicamentos , Glucocorticoides/análise , Preparações Farmacêuticas/análise , Esterilização , Anfotericina B/análise , Anfotericina B/farmacologia , Antibacterianos/farmacologia , Cefazolina/análise , Cefazolina/farmacologia , Ceftazidima/análise , Ceftazidima/farmacologia , Armazenamento de Medicamentos , Glucocorticoides/farmacologia , Metilprednisolona/análise , Metilprednisolona/farmacologia , Soluções Oftálmicas , Conservantes Farmacêuticos , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/análise , Vancomicina/farmacologia
10.
J Coll Physicians Surg Pak ; 29(6): 537-540, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133152

RESUMO

OBJECTIVE: To determine the effect of dexamethasone on regulating the TGF-ß1/Smad3 signalling pathway in airway remodelling model of asthmatic rats. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Pathology, The First Hospital of Wuhan, Hubei Province, China, from February 2017 to April 2018. METHODOLOGY: Thirty male SPF Sprague-Dawley rats were randomly divided into the control group, the model group and the dexamethasone group, with 10 rats in each group. Rats were sensitised and excited by ovalbumin (OVA) to establish the model of bronchial asthma. The bronchial basement membrane perimeter (Pbm), the bronchial wall thickness (Wat), the smooth muscle thickness (Wam), collagenous fiber thickness (Wac) and other airway remodelling indices were measured and calculated by image analysis system. The expressions of TGF-ß1 and Smad3 mRNA and protein in lung tissue of each group of rats were detected by RT-PCR and Western blot. RESULTS: Wat/Pbm, Wai/Pbm and Wam/Pbm in the model group were higher compared with those in the control group (all p<0.001); Wat/Pbm, Wai/Pbm, and Wam/Pbm in the dexamethasone group were significantly lower than those in the model group (all p<0.001). Relative expression levels of TGF-ß1, Smad3 mRNA and protein in the model group were higher than those in the control group (all p<0.001); the relative expression levels of TGF-ß1, Smad3 mRNA and protein in the dexamethasone group were lower than those in the model group (all p<0.001). CONCLUSION: Dexamethasone may antagonize airway remodeling by regulating TGF-ß1/Smad3 signaling pathway, which likely to play a role in the treatment of bronchial asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Asma/metabolismo , Brônquios/patologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Smad/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética
12.
Mol Cell Biochem ; 459(1-2): 49-59, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31098783

RESUMO

Glucocorticoid (GC) resistance is associated with poor response to the following chemotherapy in lymphoid malignancies, such as lymphoma and leukemia. However, it remains unclear whether GCs interfere with the cytotoxic effects of anti-cancer drugs on GC-resistant cells. In this study, we examined whether GCs affected the sensitivities to vincristine (VCR)/doxorubicin (DOX) and the expression of drug transporters in GC-resistant cells. The dexamethasone (DEX)/prednisolone (PSL)-resistant lymphoid and non-lymphoid cell lines Raji and HL60 were cultured with DEX for 7 days and then treated with VCR or DOX for 3 days. Seven days of DEX treatment increased the IC50s of both VCR and DOX in Raji cells but not in HL60 cells. The mRNA and protein expression levels of organic cation/carnitine transporter (OCTN) 2, one of the drug uptake transporters expressed in both cell lines, were decreased only in Raji cells. When Raji cells were cultured with PSL, the IC50 of DOX but not VCR increased as the expression of OCTN2 decreased. No significant increases in efflux transporter expression were induced by DEX or PSL. When siRNA against OCTN2 was introduced into Raji cells, the IC50 of DOX but not VCR increased significantly. These data suggested that both DEX and PSL decreased the sensitivity of the DEX/PSL-resistant Raji cells to DOX, a change that was at least partially due to reductions in OCTN2. Thus, the continuous usage of GCs may interfere with the effects of chemotherapy on GC-resistant lymphoid cells.


Assuntos
Dexametasona/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucocorticoides/farmacologia , Linfócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Prednisolona/farmacologia , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Linfócitos/patologia , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia
13.
Vet Immunol Immunopathol ; 210: 1-5, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30947974

RESUMO

Glucocorticoids are important drugs in the treatment of many inflammatory, autoimmune and allergic diseases in humans and animals. We investigated the effects of hydrocortisone and dexamethasone on TNF-α, IL-1Ra and INF-γ release in stimulated whole blood cell culture from healthy horses. Whole blood cell cultures proved to be useful for the characterization of the anti-inflammatory properties of new drugs. Diluted equine whole blood was exposed to lipopolysaccharide (LPS) and PCPwL (a cocktail consisting of phythemagglutinin E, concanavalin A, pokeweed mitogen and lipopolysaccharide) in the presence or absence of hydrocortisone and dexamethasone (10-12 - 10-5 M). TNF-α and IL-1Ra (LPS) as well as IFN-γ (PCPwL) levels were measured in the supernatants using specific enzyme-linked immunosorbent assay (ELISA). The LPS-induced TNF-α and IL-1Ra as well as the PCPwL-induced IFN-γ levels were more potently suppressed by dexamethasone than by hydrocortisone in a concentration-dependent manner. Dexamethasone inhibited TNF-α, IL-1Ra and IFN-γ with the half maximal inhibition concentration (IC50) values of 0.09 µM, 0.453 µM and 0.001 µM, respectively, whereas hydrocortisone inhibited these cytokines with lower IC50 values of 1.45 µM, 2.96 µM and 0.09 µM, respectively. Our results suggest that the equine whole blood test system is useful and reliable to evaluate drug effects and immunological alterations and offers several advantages including simple and cheap performance in physiological and pathological conditions.


Assuntos
Glucocorticoides/farmacologia , Interferon gama/sangue , Receptores de Interleucina-1/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Sangue/efeitos dos fármacos , Células Cultivadas , Concanavalina A/farmacologia , Dexametasona/farmacologia , Cavalos , Hidrocortisona/farmacologia , Concentração Inibidora 50 , Interferon gama/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Receptores de Interleucina-1/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
World J Gastroenterol ; 25(13): 1603-1617, 2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30983820

RESUMO

BACKGROUND: Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a life-threatening medical condition requiring hospitalization and often colectomy. Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases (IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated. AIM: To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis. METHODS: We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects. RESULTS: In the majority of the 22 included patients (68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d (mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4% were discharged from the hospital under continued oral tacrolimus therapy. In 36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment (mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%, respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects. CONCLUSION: The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroid-refractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Glucocorticoides/farmacologia , Imunossupressores/farmacologia , Tacrolimo/farmacologia , Adulto , Idoso , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Resistência a Medicamentos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Índice de Gravidade de Doença , Tacrolimo/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Nutrients ; 11(4)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934871

RESUMO

BACKGROUND: When given in the long term, whey proteins alone do not appear to be an optimal nutritional strategy to prevent or slow down muscle wasting during aging or catabolic states. It has been hypothesized that the digestion of whey may be too rapid during a catabolic situation to sustain the anabolic postprandial amino acid requirement necessary to elicit an optimal anabolic response. Interestingly, it has been shown recently that the duration of the postprandial stimulation of muscle protein synthesis in healthy conditions can be prolonged by the supplementary ingestion of a desynchronized carbohydrate load after food intake. We verified this hypothesis in the present study in two different cases of muscle wasting associated with anabolic resistance, i.e., glucocorticoid treatment and aging. METHODS: Multi-catheterized minipigs were treated or not with glucocorticoids for 8 days. Muscle protein synthesis was measured sequentially over time after the infusion of a 13C phenylalanine tracer using the arterio-venous method before and after whey protein meal ingestion. The energy bolus was given 150 min after the meal. For the aging study, aged rats were fed the whey meal and muscle protein synthesis was measured sequentially over time with the flooding dose method using 13C Valine. The energy bolus was given 210 min after the meal. RESULTS: Glucocorticoid treatment resulted in a decrease in the duration of the stimulation of muscle protein synthesis. The energy bolus given after food intake was unable to prolong this stimulation despite a simultaneous increase of insulin and glucose following its absorption. In old rats, a similar observation was made with no effect of the energy bolus on the duration of the muscle anabolic response following whey protein meal intake. CONCLUSIONS: Despite very promising observations in healthy situations, the strategy aimed at increasing muscle protein synthesis stimulation by giving an energy bolus during the postprandial period remained inefficient in our two anabolic resistance models.


Assuntos
Ração Animal/análise , Dexametasona/farmacologia , Ingestão de Energia , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Suínos/fisiologia , Envelhecimento , Animais , Glicemia , Dexametasona/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Injeções Intravenosas , Insulina/sangue , Masculino , Ratos
16.
BMC Cancer ; 19(1): 356, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987626

RESUMO

BACKGROUND: Glucocorticoid receptor (GR) activation has been associated with breast cancer cell survival in vitro. Glucocorticoid (GC)-dependent protection against tumor necrosis factor (TNF)-induced cell death has been well characterized in MCF7 luminal A breast cancer cells. The GR activates a variety of protective mechanisms, such as inhibitors of apoptosis proteins (IAPs). However, the relative contribution of the GR-dependent expression of IAPs in the protection of cell death has not, to our knowledge, been evaluated. METHODS: MCF7 cells were used for all experiments. GR was activated with cortisol (CORT) or dexamethasone (DEX) and inhibited with mifepristone (RU486). Cell viability was determined in real-time with the xCELLigence™ RTCA System and at specific endpoints using crystal violet stain. The mRNA levels of the eight members of the IAP family were measured by qRT-PCR. The protein levels of GR, PR, ERα, HER2, PARP1, c-IAP1 and XIAP were evaluated by Western blot analysis. The knockdown of c-IAP1 and XIAP was accomplished via transient transfection with specific siRNAs. GR activation was verified by a gene reporter assay. Via the cBioportal interphase we queried the mRNA levels of GR and IAPs in breast cancer tumors. RESULTS: RU486 significantly inhibited the anti-cytotoxic effect of both GCs. PARP1 processing was diminished in the presence of both GCs. The combined treatments of GCs + TNF increased the relative mRNA levels of Survivin>c-IAP1 > NAIP>Apollon>XIAP>Ts-IAP > ML-IAP > c-IAP2. Additionally, GR mRNA content increased with the combined treatments of GCs + TNF. Sustained levels of the proteins c-IAP1 and XIAP were observed after 48 h of the combined treatments with GCs + TNF. With c-IAP1 and XIAP gene silencing, the GC-mediated protection was diminished. In the breast tumor samples, the GR mRNA was coexpressed with Apollon and XIAP with a Pearson coefficient greater than 0.3. CONCLUSIONS: The effect of GCs against TNF-mediated cytotoxicity involves increased mRNA expression and sustained protein levels of c-IAP1 and XIAP. The antagonist effects of RU486 and the qRT-PCR results also suggest the role of the GR in this process. This finding may have clinical implications because the GR and IAPs are expressed in breast tumor samples.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Proteínas Inibidoras de Apoptose/genética , Fator de Necrose Tumoral alfa/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Genes Reporter , Humanos , Células MCF-7 , RNA Mensageiro/genética
17.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018557

RESUMO

Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.


Assuntos
Proliferação de Células/efeitos dos fármacos , Clobetasol/farmacologia , Glucocorticoides/farmacologia , Proteínas Hedgehog/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo
18.
Invest Ophthalmol Vis Sci ; 60(5): 1571-1580, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995314

RESUMO

Purpose: To understand the role and further dissect pathways downstream of tissue plasminogen activator (tPA) and the fibrinolytic pathway in modulating outflow facility. Methods: Outflow facility of tissue plasminogen activator (Plat) knockout (KO) mice was determined and compared to that of wild-type (WT) littermates. Gene expression of urokinase plasminogen activator (Plau), plasminogen activator inhibitor (Pai-1), plasminogen (Plg), and matrix metalloproteinases (Mmp-2, -9, and -13) was measured in angle tissues. Expression of the same genes and outflow facility were measured in KO and WT mice treated with triamcinolone acetonide (TA). Amiloride was used to inhibit urokinase plasminogen activator (uPA) in Plat KO mice, and outflow facility was measured. Results: Plat deletion resulted in outflow facility reduction and decreased Mmp-9 expression in angle tissues. Plasminogen expression was undetectable in both KO and WT mice. TA led to further reduction in outflow facility and decreases in expression of Plau and Mmp-13 in plat KO mice. Amiloride inhibition of uPA activity prevented the TA-induced outflow facility reduction in Plat KO mice. Conclusions: tPA deficiency reduced outflow facility in mice and was associated with reduced MMP expression. The mechanism of action of tPA is unlikely to involve plasminogen activation. tPA is not the only mediator of TA-induced outflow facility change, as TA caused reduction in outflow facility of Plat KO mice. uPA did not substitute for tPA in outflow facility regulation but abrogated the effect of TA in the absence of tPA, suggesting a complex role of components of the fibrinolytic system in outflow regulation.


Assuntos
Fibrinólise/fisiologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Plasminogênio/fisiologia , Ativador de Plasminogênio Tecidual/fisiologia , Malha Trabecular/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Amilorida/farmacologia , Animais , Diuréticos/farmacologia , Regulação da Expressão Gênica/fisiologia , Glucocorticoides/farmacologia , Injeções Intraoculares , Pressão Intraocular/fisiologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Malha Trabecular/efeitos dos fármacos , Triancinolona Acetonida/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores
19.
Int J Mol Sci ; 20(5)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845709

RESUMO

Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.


Assuntos
Glucocorticoides/farmacologia , Linfócitos T Reguladores/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos
20.
Med Sci Monit ; 25: 1936-1944, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30870403

RESUMO

BACKGROUND Hyperbilirubinemia is a common event that occurs after liver transplantation. Hyperbilirubinemia is usually caused by early allograft dysfunction. Glucocorticoid is widely used for immunosuppression, but few studies have analyzed the effects of steroid therapy on posttransplantation hyperbilirubinemia. The aim of this study was to assess whether glucocorticoid was beneficial in treating hyperbilirubinemia caused by early allograft dysfunction. MATERIAL AND METHODS Patients with postoperative hyperbilirubinemia (those with conditions such as biliary complications and rejections were excluded) were randomly assigned, in a 2: 1 ratio, to the steroid and control groups. Patients in the steroid group were treated with glucocorticoid combined with ursodeoxycholic acid, whereas patients in the control group were only treated with ursodeoxycholic acid. The primary endpoint was decrease in bilirubin and the secondary endpoint was safety. RESULTS From 1st June 2016 to 30th April 2018, 40 patients were enrolled into the steroid group, and 20 were enrolled into the control group. Donor, recipient, and operative data were similar between the 2 groups. The decrease in bilirubin levels in the steroid group was significantly greater than that in the control group on the first day after the intervention was finished (9.25±1.30 mg/dL vs. 3.11±1.45 mg/dL, p=0.005), and after 2 weeks (15.01±1.20 mg/dL vs. 8.88±1.98 mg/dL, p=0.007). The steroid group did not have a higher complication rate but it did have a shorter postoperative hospital stay than in the control group. CONCLUSIONS Low-dose steroid therapy was effective and safe for treating hyperbilirubinemia caused by early graft dysfunction, and it improved liver function.


Assuntos
Aloenxertos/efeitos dos fármacos , Hiperbilirrubinemia/tratamento farmacológico , Esteroides/uso terapêutico , Adolescente , Adulto , Idoso , Criança , China , Feminino , Glucocorticoides/farmacologia , Humanos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Tolerância ao Transplante/fisiologia , Transplante Homólogo/métodos , Ácido Ursodesoxicólico/farmacologia
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