Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25.049
Filtrar
1.
Nat Commun ; 13(1): 5789, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36184661

RESUMO

Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.


Assuntos
Antineoplásicos , Amiloidose de Cadeia Leve de Imunoglobulina , Mieloma Múltiplo , Amiloide/uso terapêutico , Animais , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Humanos , Cadeias Leves de Imunoglobulina , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Inibidores de Proteassoma , Proteômica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas
2.
Biomed Res Int ; 2022: 2369650, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36193302

RESUMO

Conventional breeding of wild (Cucumis melo var. makuwa Makino (CM)) and cultivated (Cucumis melo var. reticulatus (CR)) melons is aimed at improving their biological traits. Here, we prepared a nontoxic, bioactive extract of vitalmelon (F1 hybrid) and evaluated its antiadipogenic and antiobesity effects in fully differentiated 3T3-L1 adipocytes and high-fat diet- (HFD-) induced obese C57BL/6 mice. In fully differentiated 3T3-L1 adipocytes, the vitalmelon extract reduced the DMI- (dexamethasone, 3-isobutyl-1-methylxanthine, and insulin-) induced increases in lipid droplet number and intracellular glucose and triglyceride levels. In addition, the extract inhibited 3T3-L1 preadipocyte differentiation by downregulating PPAR-γ and target genes LPL, CD36, HMGCR, and L-FABP. To investigate the inhibitory effects of the vitalmelon extract on lipid metabolism, we measured serum lipid, hormone, and cytokine concentrations; lipolytic activity; lipid accumulation; and adipogenesis in HFD-fed mice treated with the extract. The HFD+vitalmelon-fed mice showed lower blood cholesterol, free fatty acid, sugar, leptin, and insulin concentrations but higher blood adiponectin concentrations than the HFD-fed mice. Moreover, the HFD+vitalmelon-fed mice showed lower abdominal fat levels, smaller fat cells, lower weight, and fewer lipid droplets in the liver tissue than the HFD-fed mice. Therefore, in HFD-fed mice, vitalmelon regulated lipid metabolism through PPAR-γ, highlighting its potential as a promising antiobesity functional food.


Assuntos
Adipogenia , Fármacos Antiobesidade , 1-Metil-3-Isobutilxantina/farmacologia , Células 3T3-L1 , Adiponectina/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Colesterol , Citocinas/farmacologia , Dexametasona/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos não Esterificados , Frutas/metabolismo , Glucose/farmacologia , Insulina , Leptina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Açúcares , Triglicerídeos
3.
Int J Mol Sci ; 23(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36077132

RESUMO

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized by adding resistance exercise training (RET) to EAA, and diet-free EAA would improve endurance. To test hypotheses, mice were randomized into the following four groups: control, EAA, RET, and EAA+RET. All mice except the control were subjected to DEX treatment. We evaluated the cumulative rate of myofibrillar protein synthesis (MPS) using 2H2O labeling and mass spectrometry. Neuromuscular junction (NMJ) stability, mitochondrial contents, and molecular signaling were demonstrated in skeletal muscle. Insulin sensitivity and glucose metabolism using 13C6-glucose tracing during oral glucose tolerance tests were analyzed. We found that EAA and RET synergistically improve muscle mass and/or strength, and endurance capacity, as well as insulin sensitivity, and glucose metabolism in DEX-treated muscle. These improvements are accomplished, in part, through improvements in myofibrillar protein synthesis, NMJ, fiber type preservation, and/or mitochondrial biogenesis. In conclusion, free EAA supplementation, particularly when combined with RET, can serve as an effective means that counteracts the adverse effects on muscle of DEX that are found frequently in clinical settings.


Assuntos
Resistência à Insulina , Treinamento de Força , Aminoácidos Essenciais/metabolismo , Animais , Dexametasona/farmacologia , Glucose/metabolismo , Humanos , Camundongos , Força Muscular , Músculo Esquelético/metabolismo
4.
Molecules ; 27(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36080454

RESUMO

Central retinal vein occlusion (CRVO) is a visually disabling condition resulting from a thrombus in the major outflow vessel of the eye. The inflammatory response in CRVO is effectively treated with a dexamethasone (DEX) intravitreal implant. Uncovering the proteome changes following DEX implant intervention in CRVO may identify key proteins that mediate the beneficial effects of DEX. In six Göttingen minipigs, CRVO was induced in both eyes with an argon laser using a well-established experimental model. The right eyes were treated with a DEX intravitreal implant (Ozurdex, Allergan), while the left control eyes received a sham injection. Eight weeks after DEX intervention, retinal samples were collected and analyzed with tandem mass tag-based mass spectrometry. DEX implant intervention resulted in the upregulation of peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5) and ubiquilin-4. Immunohistochemistry showed expression of FKBP5 in the nuclei in all cellular layers of the retina. Cell adhesion molecule 3, tumor necrosis factor receptor superfamily member 16, and trans-1,2-dihydrobenzene-1,2-diol dehydrogenase were downregulated following DEX intervention. The upregulation of the corticosteroid-sensitive protein FKBP5 suggests that the implant remained active at the molecular level after eight weeks of treatment. Future studies may investigate if FKBP5 regulates the efficacy and duration of the DEX implant.


Assuntos
Oclusão da Veia Retiniana , Animais , Dexametasona/farmacologia , Implantes de Medicamento , Glucocorticoides/farmacologia , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/metabolismo , Suínos , Porco Miniatura , Tomografia de Coerência Óptica , Resultado do Tratamento , Acuidade Visual
5.
PLoS One ; 17(9): e0273843, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36054185

RESUMO

INTRODUCTION: Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue turnover waste macromolecules from blood. LSECs also participate in liver immune responses. A challenge when studying LSEC biology is the rapid loss of the in vivo phenotype in culture. In this study, we have examined biological processes and pathways affected during early-stage primary culture of rat LSECs and checked for cell responses to the pro-inflammatory cytokine interleukin (IL)-1ß and the anti-inflammatory drug dexamethasone. METHODS: LSECs from male Sprague Dawley rats were cultured on type I collagen in 5% oxygen atmosphere in DMEM with serum-free supplements for 2 and 24 h. Quantitative proteomics using tandem mass tag technology was used to examine proteins in cells and supernatants. Validation was done with qPCR, ELISA, multiplex immunoassay, and caspase 3/7 assay. Cell ultrastructure was examined by scanning electron microscopy, and scavenger function by quantitative endocytosis assays. RESULTS: LSECs cultured for 24 h showed a characteristic pro-inflammatory phenotype both in the presence and absence of IL-1ß, with upregulation of cellular responses to cytokines and interferon-γ, cell-cell adhesion, and glycolysis, increased expression of fatty acid binding proteins (FABP4, FABP5), and downregulation of several membrane receptors (STAB1, STAB2, LYVE1, CLEC4G) and proteins in pyruvate metabolism, citric acid cycle, fatty acid elongation, amino acid metabolism, and oxidation-reduction processes. Dexamethasone inhibited apoptosis and improved LSEC viability in culture, repressed inflammatory and immune regulatory pathways and secretion of IL-1ß and IL-6, and further upregulated FABP4 and FABP5 compared to time-matched controls. The LSEC porosity and endocytic activity were reduced at 24 h both with and without dexamethasone but the dexamethasone-treated cells showed a less stressed phenotype. CONCLUSION: Rat LSECs become activated towards a pro-inflammatory phenotype during early culture. Dexamethasone represses LSEC activation, inhibits apoptosis, and improves cell viability.


Assuntos
Células Endoteliais , Proteoma , Animais , Dexametasona/metabolismo , Dexametasona/farmacologia , Células Endoteliais/metabolismo , Fígado/metabolismo , Masculino , Proteoma/metabolismo , Ratos , Ratos Sprague-Dawley , Secretoma
6.
Front Immunol ; 13: 900963, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119039

RESUMO

Current evidence highlights the critical role of the gut-kidney axis in the pathogenesis of IgA nephropathy (IgAN). However, few attempts have been made to explore targeted intestinal immunity therapy. This research aims to develop an oral intestine targeting medication based on extracellular vesicles (EVs) and investigate its therapeutic efficacy in IgAN. EVs were isolated from orange juice and electroporated with dexamethasone sodium phosphate (DexP). After oral administration, EVs-DexP was picked up by lymphocytes in the submucosal area of ileocecum. EVs-DexP outperformed DexP not only in suppressing lymphocyte stimulation in vitro but also in alleviating renal pathological lesions in the IgAN mouse model. Clinical improvement was accompanied by a reducing IgA secreted by the intestine and a decreasing IgA + B220 + lymphocytes in Peyer's patches. The present study develops a cost-effective, biofriendly EVs-based glucocorticoid strategy for IgAN.


Assuntos
Citrus sinensis , Vesículas Extracelulares , Glomerulonefrite por IGA , Animais , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Vesículas Extracelulares/patologia , Glucocorticoides/uso terapêutico , Imunoglobulina A , Linfócitos/patologia , Camundongos , Proteinúria
7.
Eur J Endocrinol ; 187(5): 637-650, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36070424

RESUMO

Objective: Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-adrenocorticotrophic hormone (ACTH)-stimulated AVS results. Design: Retrospective cohort study at a tertiary referral center. Methods: We analyzed 278 PA patients who underwent non-ACTH-stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-h urinary free cortisol (UFC) measurements. Patients were studied from 2013 to 2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcomes according to the primary aldosteronism surgical outcome (PASO) criteria. Results: Among the patients, 18.9% had a pathological DST result (1.9-5 µg/dL: n = 44 (15.8%); >5 µg/dL: n = 8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤1.8 vs >1.8 µg/dL: P = 0.499; ≤1.8 vs 1.8 ≤ 5 vs >5 µg/dL: P = 0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤1.8 µg/dL: 11.11 (5.36; 26.76) vs 1.9-5 µg/dL: 11.76 (4.9; 31.88) vs >5 µg/dL: 2.58 (1.67; 3.3); P = 0.008). PASO outcome was not different according to cortisol cosecretion. Conclusions: Marked cortisol cosecretion has the potential to influence non-ACTH-stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hiperaldosteronismo , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico , Aldosterona , Dexametasona/farmacologia , Humanos , Hidrocortisona , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Antagonistas de Receptores de Mineralocorticoides , Estudos Retrospectivos
8.
J Vet Sci ; 23(5): e76, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36174980

RESUMO

BACKGROUND: Clinical dexamethasone (DEX) treatment or stress in bovines results in extensive physiological changes with prominent hyperglycemia and neutrophils dysfunction. OBJECTIVES: To elucidate the effects of DEX treatment in vivo on cellular energy status and the underlying mechanism in circulating neutrophils. METHODS: We selected eight-month-old male bovines and injected DEX for 3 consecutive days (1 time/d). The levels of glucose, total protein (TP), total cholesterol (TC), and the proinflammatory cytokines interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α in blood were examined, and we then detected glycogen and adenosine triphosphate (ATP) content, phosphofructosekinase-1 (PFK1) and glucose-6-phosphate dehydrogenase (G6PDH) activity, glucose transporter (GLUT)1, GLUT4, sodium/glucose cotransporter (SGLT)1 and citrate synthase (CS) protein expression and autophagy levels in circulating neutrophils. RESULTS: DEX injection markedly increased blood glucose, TP and TC levels, the Ca2+/P5+ ratio and the neutrophil/lymphocyte ratio and significantly decreased blood IL-1ß, IL-6 and TNF-α levels. Particularly in neutrophils, DEX injection inhibited p65-NFκB activation and elevated glycogen and ATP contents and SGLT1, GLUT1 and GR expression while inhibiting PFK1 activity, enhancing G6PDH activity and CS expression and lowering cell autophagy levels. CONCLUSIONS: DEX induced neutrophils glucose uptake by enhancing SGLT1 and GLUT1 expression and the transformation of energy metabolism from glycolysis to pentose phosphate pathway (PPP)-tricarboxylic acid (TCA) cycle. This finding gives us a new perspective on deeper understanding of clinical anti-inflammatory effects of DEX on bovine.


Assuntos
Trifosfato de Adenosina , Neutrófilos , Animais , Anti-Inflamatórios , Glicemia , Bovinos , Colesterol , Citrato (si)-Sintase , Dexametasona/farmacologia , Transportador de Glucose Tipo 1 , Glucosefosfato Desidrogenase , Glicogênio , Interleucina-6 , Masculino , Sódio , Ácidos Tricarboxílicos , Fator de Necrose Tumoral alfa
9.
Eur J Pharm Sci ; 178: 106291, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36058499

RESUMO

The safety and efficacy of intratympanic (IT) histamine (HIS) injection as an adjuvant to increase the inner ear penetration of dexamethasone (DEX) was investigated in this study. IT injections of DEX-only, 1% HIS+DEX and 4% HIS+DEX were performed in mice with noise-induced hearing loss. An inflammatory reaction in the middle ear was observed only in the 4% HIS+DEX group although no serious cytotoxic effects on the organ of Corti (OC) were observed at that concentration. Compared with the DEX-only group, the perilymphatic concentration of DEX was approximately two times higher in the 1% HIS+DEX group and approximately five times higher in the 4% HIS+DEX group. The expression of the DEX receptor in the cochlea was significantly increased in the 4%-HIS+DEX group. HIS appeared to induce transient damage the microstructure of the RWM with recovery observed within 3 weeks. The 1 and 4% HIS + DEX groups showed a significant recovery of the OC compared with the control group and they also achieved significantly better hearing restoration at 8 kHz in the DPOAE hearing test (P < .05) when compared to the DEX-only group. IT HIS temporarily disrupts the structure of the RWM and middle ear mucosa and significantly enhances the inner ear penetration of DEX. Therefore, IT HIS injection could be a simple and effective adjuvant therapy to increase perilymph concentration of DEX and achieve OC recovery after cochlear damage.


Assuntos
Dexametasona , Histamina , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Animais , Dexametasona/farmacologia , Modelos Animais de Doenças , Injeção Intratimpânica , Camundongos , Perilinfa
10.
Respir Res ; 23(1): 249, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115998

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease caused by the induction of inflammatory cytokines and chemokines in the lungs. There is a dearth of drug applications that can be used to prevent cytokine storms in ARDS treatment. This study was designed to investigate the effects of tocilizumab and dexamethasone on oxidative stress, antioxidant parameters, and cytokine storms in acute lung injury caused by oleic acid in rats. METHODS: Adult male rats were divided into five groups: the CN (healthy rats, n = 6), OA (oleic acid administration, n = 6), OA + TCZ-2 (oleic acid and tocilizumab at 2 mg/kg, n = 6), OA + TCZ-4 (oleic acid and tocilizumab at 4 mg/kg, n = 6), and OA + DEX-10 (oleic acid and dexamethasone at 10 mg/kg, n = 6) groups. All animals were euthanized after treatment for histopathological, immunohistochemical, biochemical, PCR, and SEM analyses. RESULTS: Expressions of TNF-α, IL-1ß, IL-6, and IL-8 cytokines in rats with acute lung injury induced by oleic acid were downregulated in the TCZ and DEX groups compared to the OA group (P < 0.05). The MDA level in lung tissues was statistically lower in the OA + TCZ-4 group compared to the OA group. It was further determined that SOD, GSH, and CAT levels were decreased in the OA group and increased in the TCZ and DEX groups (P < 0.05). Histopathological findings such as thickening of the alveoli, hyperemia, and peribronchial cell infiltration were found to be similar when lung tissues of the TCZ and DEX groups were compared to the control group. With SEM imaging of the lung tissues, it was found that the alveolar lining layer had become indistinct in the OA, OA + TCZ-2, and OA + TCZ-4 groups. CONCLUSIONS: In this model of acute lung injury caused by oleic acid, tocilizumab and dexamethasone were effective in preventing cytokine storms by downregulating the expression of proinflammatory cytokines including TNF-α, IL-1ß, IL-6, and IL-8. Against the downregulation of antioxidant parameters such as SOD and GSH in the lung tissues caused by oleic acid, tocilizumab and dexamethasone upregulated them and showed protective effects against cell damage.


Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Animais , Anticorpos Monoclonais Humanizados , Antioxidantes/efeitos adversos , Síndrome da Liberação de Citocina , Citocinas/farmacologia , Dexametasona/farmacologia , Regulação para Baixo , Interleucina-6 , Interleucina-8 , Pulmão , Masculino , Ácido Oleico/toxicidade , Ratos , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/tratamento farmacológico , Superóxido Dismutase , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
11.
Nat Commun ; 13(1): 5505, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127421

RESUMO

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.


Assuntos
Metilação de DNA , Glioma , Biomarcadores , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Glioma/tratamento farmacológico , Glioma/genética , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Maleimidas , Prednisona
12.
Biomed Pharmacother ; 153: 113459, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076574

RESUMO

Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.


Assuntos
COVID-19 , Quinases Associadas a Receptores de Interleucina-1 , Inibidores de Proteínas Quinases , Síndrome do Desconforto Respiratório , Animais , COVID-19/tratamento farmacológico , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Células Endoteliais , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Lactamas/farmacologia , Lactamas/uso terapêutico , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/prevenção & controle
13.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S427, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36164184

RESUMO

CONTEXT: Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends the half-life and allows for once-per-cycle dosing, requiring less frequent dosing than nonpegylated G-CSF. OBJECTIVE: The objective was to compare the efficacy and safety of pegfilgrastim in heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily filgrastim. PATIENTS: 57 patients (31 M and 26 F) were enrolled, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r. 56-90) treated with several lines of treatments (median 7, r. 2-12), refractory to all drugs previously received. They received pomalidomide-dexamethasone (P 4 mg for 21 days, D 40 mg days 1, 8, 15, 22, pegfilgrastim day +8) every 28 days, until progression. In the first course in domestic setting, patients' blood counts were drawn once weekly and they received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, filgrastim (5 µgr/kg/day for 3 days) was given if neutrophils count was <1500 × 109 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 × 109 cells/L (r.0.3 - 1.5), with maximum duration of 14 days. For the second course, all patients switched to prophylaxis with pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. RESULTS: During treatment with pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patient for at least three courses of therapy (r. 3-6) registered at day + 11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain (21.2%). CONCLUSIONS: In MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.


Assuntos
Mieloma Múltiplo , Neutropenia , Antibacterianos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Filgrastim/farmacologia , Filgrastim/uso terapêutico , Fator Estimulador de Colônias de Granulócitos , Humanos , Mieloma Múltiplo/terapia , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/prevenção & controle , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Talidomida/análogos & derivados
14.
Cells ; 11(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36139376

RESUMO

Plant-derived extracellular vesicles, (EVs), have recently gained attention as potential therapeutic candidates. However, the varying properties of plants that are dependent on their growth conditions, and the unsustainable production of plant-derived EVs hinder drug development. Herein, we analyzed the secondary metabolites of Aster yomena callus-derived EVs (AYC-EVs) obtained via plant tissue cultures and performed an immune functional assay to assess the potential therapeutic effects of AYC-EVs against inflammatory diseases. AYC-EVs, approximately 225 nm in size, were isolated using tangential flow filtration (TFF) and cushioned ultracentrifugation. Metabolomic analysis, using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS), revealed that AYC-EVs contained 17 major metabolites. AYC-EVs inhibited the phenotypic and functional maturation of LPS-treated dendritic cells (DCs). Furthermore, LPS-treated DCs exposed to AYC-EVs showed decreased immunostimulatory capacity during induction of CD4+ and CD8+ T-cell proliferation and activation. AYC-EVs inhibited T-cell reactions associated with the etiology of asthma in asthmatic mouse models and improved various symptoms of asthma. This regulatory effect of AYC-EVs resembled that of dexamethasone, which is currently used to treat inflammatory diseases. These results provide a foundation for the development of plant-derived therapeutic agents for the treatment of various inflammatory diseases, as well as providing an insight into the possible mechanisms of action of AYC-EVs.


Assuntos
Asma , Vesículas Extracelulares , Animais , Proliferação de Células , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Vesículas Extracelulares/fisiologia , Lipopolissacarídeos/farmacologia , Camundongos
15.
Pol J Vet Sci ; 25(3): 419-427, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36156107

RESUMO

This study aimed to determine the effects of dexamethasone and minocycline alone and combined treatment with N-acetylcysteine (NAC) and vitamin E on serum coenzyme Q10 (CoQ10) and matrix metalloproteinase-9 (MMP-9) levels in rats administered aflatoxin B1 (AFB1). The study was carried out on 66 male Wistar rats. Following the intraperitoneal (IP) administration of AFB1 at dose of 2 mg/kg, minocycline (45 and 90 mg/kg, IP) and dexamethasone (5 and 20 mg/kg, IP) were administered alone and combined with NAC (200 mg/kg, IP) and vitamin E (600 mg/kg, IP). CoQ10 and MMP-9 levels were analyzed using the HPLC-UV method and a commercial kit by ELISA, respectively. AFB1 increased MMP-9 level and decreased CoQ10 level compared to the control group. After dexamethasone and minocycline administration, there is no increase in CoQ10 level, which is caused by AFB1. However, dexamethasone and minocycline combined with NAC+vitamin E caused significant increases in CoQ10 levels. Dexamethasone and minocycline alone and combined with NAC+vitamin E decreased MMP-9 levels compared to the single AFB1 treated group. The use of MMPs inhibitors and oxidative stress-reducing agents is anticipated to be beneficial in the poisoning with AFB1.


Assuntos
Acetilcisteína , Aflatoxina B1 , Acetilcisteína/farmacologia , Aflatoxina B1/toxicidade , Animais , Dexametasona/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Minociclina/farmacologia , Ratos , Ratos Wistar , Substâncias Redutoras , Ubiquinona/análogos & derivados , Vitamina E/farmacologia
16.
Biomed Pharmacother ; 153: 113456, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076569

RESUMO

Dexamethasone acts as an immunosuppressive drug and has been used recently in the management of specific coronavirus disease 2019 (COVID-19) cases; however, various adverse effects could limit its use. In this work, we studied the mitigation effects of black pepper oil (BP oil) on glycemic parameters, dyslipidemia, oxidative and nitrosative stress and pancreatic fibrosis in dexamethasone-treated rats. Animals were divided into five groups that were treated with vehicle, dexamethasone (10 mg/kg, SC) or black pepper oil (BP oil, 0.5 mL, or 1 mL/kg) or metformin (50 mg/kg) plus dexamethasone for 4 consecutive days. Serum insulin, blood glucose, total cholesterol, triglycerides, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were higher in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic nitric oxide, inducible nitric oxide synthase and malondialdehyde levels were increased in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic endothelial nitric oxide synthase and reduced glutathione were declined in the dexamethasone group vs the control group. They were increased in BP oil and metformin groups relative to the dexamethasone group. Moreover, the pancreatic islets diameter and collagen deposition were assessed and found to be higher in the dexamethasone group vs the control group. BP oil and metformin groups showed to regress this effect. In conclusion, BP oil may alleviate hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia and pancreatic structural derangements and fibrosis by suppressing oxidative stress, increasing endogenous antioxidant levels, modulating nitric oxide signaling, preventing pancreatic stellate cells transition and collagen deposition.


Assuntos
Dexametasona , Metformina , Pâncreas , Piper nigrum , Óleos Vegetais , Animais , Glicemia , COVID-19/tratamento farmacológico , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Dislipidemias/tratamento farmacológico , Fibrose , Resistência à Insulina , Metformina/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Piper nigrum/química , Óleos Vegetais/farmacologia , Óleos Vegetais/uso terapêutico , Ratos , Ratos Wistar
17.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S245-S246, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36163830

RESUMO

CONTEXT: The precise frequency of central nervous system (CNS) involvement in blastic plasmacytoid dendritic cell neoplasm (BPDCN) is currently unknown. Recent data suggest it may be ~10% at baseline and 30% at first relapse. CNS is a 'sanctuary' for systemic treatment and can lead to disease recurrence even after the achievement of a complete response (CR) at the medullary and skin level. Ensuring complete meningeal disease clearance is essential, and combining intrathecal (IT) chemotherapy with systemic treatment is a promising approach. Tagraxofusp (TAG, SL-401) is a first-in-class therapy targeting CD123, a molecule that is overexpressed in BPDCN. TAG, available in the US and Europe, is the only approved drug for patients with BPDCN. OBJECTIVE: To determine whether CNS prophylaxis/treatment impacts the prognosis and efficacy of systemic TAG treatment in patients with BPDCN. DESIGN: Retrospective single-center chart review. PATIENTS: Patients with BPDCN, with (CNS+) or without (CNS-) CNS involvement. INTERVENTION(S): Patients received TAG intravenous infusions at 12 mcg/kg daily on days 1-5 of a 21-day cycle. Intrathecal (IT) chemotherapy (cytarabine and dexamethasone ± methotrexate) was administered in combination with TAG at each cycle as prophylaxis (CNS-) or primary-intention treatment (CNS+). MAIN OUTCOME MEASURE(S): Assessments included CNS response, tumor response, survival, and adverse event (AE) monitoring. RESULTS: Data were collected on 5 patients (n=3 CNS+, n=2 CNS-); all received TAG as first-line therapy. The median number of TAG cycles was 3 (range 1-4). All 3 patients with CNS+ disease achieved CNS complete response (CR), and none reported CNS relapse. In patients receiving CNS prophylaxis, 1 patient received TAG plus HSCT and is in CR after 29 months; another received high-dose chemotherapy, achieved a good partial remission after TAG, and remains alive after 4 months with HSCT shortly planned. No AEs associated with IT chemotherapy were reported. CONCLUSIONS: These preliminary results confirm the feasibility of IT chemotherapy in combination with systemic TAG therapy. Baseline CNS involvement did not appear to impact the efficacy or safety profile of TAG. IT chemotherapy and TAG effectively cleared and controlled CNS involvement. IT prophylaxis should be considered in patients with BPDCN who receive CD123-targeted therapies.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Doença Aguda , Sistema Nervoso Central/patologia , Citarabina/uso terapêutico , Células Dendríticas/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Neoplasias Hematológicas/terapia , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Leucemia Mieloide Aguda/patologia , Metotrexato , Transtornos Mieloproliferativos/patologia , Recidiva Local de Neoplasia/patologia , Proteínas Recombinantes de Fusão , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
18.
PLoS One ; 17(9): e0274675, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107918

RESUMO

Glucocorticoids, such as dexamethasone (Dex), are used to prevent common side effects induced by chemotherapy and are heavily prescribed for solid cancers such as breast cancer. There is substantial pre-clinical data to support that Dex activation of the glucocorticoid receptor overrides chemotherapy-induced apoptosis in breast cancer cell lines. These findings are compounded by a recent study demonstrating that increased glucocorticoid receptor activation by endogenous stress hormones increased breast cancer heterogeneity and metastasis. Our study is the first to use both in vitro and in vivo models to thoroughly compare the Dex response on the migration of multiple estrogen receptor negative (ER-) and ER+ cancer cell lines. ER+ and ER- breast cancer cell lines were studied to compare their endogenous glucocorticoid activity as well as their metastatic ability in response to Dex treatment. We show that in the ER- breast cancer lines, Dex increases cell numbers, invasiveness, and migration, while decreasing apoptotic ability. Furthermore, we show that following Dex treatment, ER- breast cancer lines migrate further in an in vivo zebrafish model in comparison to ER+ cell lines. The use of ROR1 antibody to block WNT signaling diminished the metastatic properties of ER- cells, however recombinant WNT5A alone was not sufficient to induce migration. Taken together, we demonstrate that Dex treatment exacerbates the metastatic potential of ER- but not ER+ cells. These findings add to the growing body of data stressing the potential adverse role of endogenous and synthetic glucocorticoids in breast cancer biology.


Assuntos
Antieméticos , Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Dexametasona/farmacologia , Glucocorticoides , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/metabolismo , Peixe-Zebra/metabolismo
19.
Thromb Res ; 218: 157-168, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36054980

RESUMO

INTRODUCTION: Dexamethasone (DXM) or immunoglobulin (IVIg) are first-line therapies for primary immune thrombocytopenia (ITP), with an effective rate of 80 %. Some patients with both severe bleeding symptoms and platelet counts of <30 × 109/L received a combination of DXM and IVIg. Autoimmune disorders, especially involving CD4+ T-cells, play a key role in the pathogenesis of ITP. We assumed that variations in the immune status of CD4+ T-cells will lead to different treatment responses. Until now, there have been few relevant clinical studies on CD4+ T-cells and the outcome of first-line therapies. METHODS: A prospective study enrolling 42 newly diagnosed ITP patients and 30 normal control volunteers was performed. The profiles of major CD4+ T-cells, including T helper (Th)1, Th2, Th17, and regulatory T (Treg) cells, and the related levels of interleukin (IL)-2, IL-17, and IL-23 were examined. The platelet number was recorded at the time point of day 0, day 14, and day 30. RESULTS: Greater concentrations of Th1 and Th17 cells and lower relative numbers of Treg cells were found in the ITP group. As for the treatment outcome on day 14, the profiles of Th2 and IL-2 were significantly greater in the NR group, while the expression of IL-17 was elevated in the CR group. As for the treatment outcome on day 30, higher levels of Th2 cells were observed in those patients who needed 2× pulses of HD DXM compared to those who needed only 1× pulse of HD DXM and IVIg, and receiver operating characteristic curve analysis showed that lower Treg cell may predict favorable values. Meanwhile, the higher IL-23 value may predict a poor early response. CONCLUSIONS: Our results indicate that Th1, Th17, and Treg cells and IL-2 and IL-23 participate in the onset of ITP. Higher profiles of Th2, IL-2 and IL-23 may predict poor treatment outcomes. Higher levels of IL-17 and lower profile of Treg may predict sensitivity to HD DXM and IVIg combination therapy.


Assuntos
Púrpura Trombocitopênica Idiopática , Linfócitos T CD4-Positivos/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Interleucina-17/uso terapêutico , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Interleucina-2/uso terapêutico , Interleucina-23/metabolismo , Interleucina-23/farmacologia , Interleucina-23/uso terapêutico , Estudos Prospectivos , Linfócitos T Reguladores
20.
Food Funct ; 13(19): 10158-10170, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36106930

RESUMO

Oat ß-glucan (OBG) and L-arabinose (LA) have exhibited positive effects on diabetes and its complications. However, it is unclear whether OBG and LA have a synergistic effect. We investigated the effect of variable compositions (OBG : LA = 1 : 1, 1 : 2, 1 : 4,1 : 6, 1 : 8, 1 : 10, 2 : 1, 4 : 1, 6 : 1, 8 : 1, 10 : 1) on glucose uptake in IR-HepG2 cells induced by dexamethasone (DEX) to find out the optimal composition showing synergistic effects. Furthermore, this study evaluated the anti-diabetic activity of the optimal composition in db/db mice. In vitro, the OBG : LA = 1 : 1 group showed the strongest synergistic effects among the varied compositions, outperforming OBG and LA alone. In vivo, there were more beneficial effects in the OBG : LA = 1 : 1 group compared with the OBG and LA single-dosing groups. OBG : LA = 1 : 1 supplementation markedly decreased the levels of fasting blood glucose (FBG) and insulin (INS) in serum, improved glucose tolerance and insulin sensitivity, lowered blood lipid levels, and reduced liver lipid accumulation. Moreover, the western blot results indicated that the OBG : LA = 1 : 1 group up-regulated the protein expression of glucose transporter-4 (GLUT4), phosphatidylinositol 3-kinase (PI3K), and phospho-protein kinase B (p-AKT), while down-regulating the protein expression of phospho-phosphorylated insulin receptor substrate-1 (p-IRS1) to enhance insulin transduction in liver tissues. These findings suggest that OBG : LA = 1 : 1 synergistically ameliorated glucose metabolism disorders and alleviated insulin resistance by promoting the PI3K/AKT pathway in the liver.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Arabinose/farmacologia , Glicemia/metabolismo , Dexametasona/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células Hep G2 , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta-Glucanas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...