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1.
Biomed Khim ; 67(4): 352-359, 2021 Jul.
Artigo em Russo | MEDLINE | ID: mdl-34414894

RESUMO

Chronic obstructive pulmonary disease (COPD) is characterized by reduced sensitivity of cells to the anti-inflammatory effects of glucocorticoids (GCs). Azithromycin and a low dose theophylline have a significant impact on molecular mechanisms leading to corticosteroid resistance. The aim of this study was to evaluate the ability of azithromycin and theophylline to enhance the anti-inflammatory effects of GCs on the production of cytokines by NK and NKT-like blood cells of COPD patients. Whole blood cells from COPD patients (n=21) were incubated in the presence of budesonide (10 nM), azithromycin (10 µg/mL), theophylline (1 µM), or their combinations and stimulated with phorbol myristate acetate (50 ng/mL). Intracellular production of proinflammatory cytokines in NK (CD3-CD56+) and NKT-like (CD3+CD56+) blood cells was analyzed by flow cytometry. Budesonide reduced synthesis of interleukin 4 (IL-4), CXCL8, tumor necrosis factor α (TNFα) by NK and NKT-like cells, as well as production of interferon γ (IFNγ) by NK cells. Azithromycin suppressed production of IL-4 and CXCL8 by NK and NKT-like cells, and theophylline inhibited IL-4 synthesis by these lymphocytes. The combination of azithromycin and budesonide had a more pronounced inhibitory effect on the production of IL-4 and CXCL8 by NK and NKT-like cells than the effect of these drugs alone. The combination of theophylline and budesonide suppressed synthesis of IL-4 and CXCL8 by NK and NKT-like cells, as well as the production of TNFα and IFNγ by NK cells stronger than budesonide alone. The obtained results demonstrate the benefits for the combined use of GCs with theophylline at a low dose or azithromycin to suppress the inflammatory process in patients with COPD.


Assuntos
Glucocorticoides , Doença Pulmonar Obstrutiva Crônica , Azitromicina/farmacologia , Citocinas , Humanos , Células Matadoras Naturais , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/farmacologia
2.
PLoS One ; 16(5): e0251348, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34029327

RESUMO

BACKGROUND: A synergism has been reported between theophylline and corticosteroids, wherein theophylline increases and restores the anti-inflammatory effect of inhaled corticosteroids (ICS) by enhancing histone deacetylase-2 (HDAC) activity. Several studies have explored the efficacy of low-dose theophylline plus ICS therapy on chronic obstructive pulmonary disease (COPD) but the results are discrepant. METHOD: We conducted searches in electronic database such as PubMed, Web Of Science, Cochrane Library, and Embase to find out original studies. Stata/SE 15.0 was used to perform all data analysis. RESULT: A total of 47,556 participants from 7 studies were included in our analysis and the sample size of each study varied from 24 to 10,816. Theophylline as an add-on therapy to ICS was not associated with the reduction of COPD exacerbations (HR: 1.08, 95% CI: 0.97 to 1.19, I2 = 95.2%). Instead, the theophylline group demonstrated a higher hospitalization rate (HR: 1.12, 95% CI: 1.10 to 1.15, I2 = 20.4%) and mortality (HR: 1.19, 95% CI: 1.14 to 1.25, I2 = 0%). Further, the anti-inflammatory effect of low-dose theophylline as an adjunct to ICS on COPD was controversial. Besides, the theophylline group showed significant improvement in lung function compared with the non-theophylline group. CONCLUSION: Based on current evidence, low-dose theophylline as add-on therapy to ICS did not reduce the exacerbation rate. Instead, the hospitalization rate and mortality increased with theophylline. Thus, we do not recommend adding low-dose theophylline to ICS therapy in COPD patients. TRIAL REGISTRATION: PROSPERO Registration CRD42021224952.


Assuntos
Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/farmacologia , Teofilina/uso terapêutico , Administração por Inalação , Animais , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Quimioterapia Combinada/métodos , Hospitalização , Humanos
3.
Acta Histochem ; 123(3): 151696, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33652374

RESUMO

Sensorineural hearing loss is a health problem with global prevalence. Aminoglycoside antibiotics, for instance gentamicin, may cause ototoxicity in mammals as a result of apoptosis and elevated oxidative stress in cochlear hair cells. Our study aimed to examine the potential effects of theophylline, an HDAC2 agonist, on gentamicin-induced cytotoxicity to sensory hair cells. Mouse cochlear explants and HEI-OC1 cells were in vitro cultured and challenged by gentamicin to induce ototoxicity, with or without theophylline. Cochlear hair cells were evaluated by fluorescent microscopy, and their mechanotransduction was assessed by electrophysiology. Expression levels of HDAC2 and apoptosis pathway factors were also evaluated following gentamicin and theophylline treatments. The functional role of HDAC2 in this setting was investigated by siRNA targeted silencing. Theophylline protected cochlear hair cells from ototoxicity induced by gentamicin, in terms of preserving cochlear structure and mechanotransduction ability, and preventing the activation of the intrinsic apoptosis pathway dose-dependently. HDAC2 expression was downregulated by gentamicin, which could be restored by theophylline. HDAC2 silencing in HEI-OC1 cells negated the beneficial effect of theophylline against gentamicin-induced growth defect and apoptosis activation. Theophylline protects sensory hair cells from gentamicin ototoxicity by maintaining HDAC2 expression. Our study thereby discovers a critical role of HDAC2 in gentamicin-induced ototoxicity, which could shine light on potential therapeutic options for treatment against sensorineural hearing loss.


Assuntos
Apoptose/efeitos dos fármacos , Gentamicinas/farmacologia , Histona Desacetilase 2/metabolismo , Teofilina/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Gentamicinas/metabolismo , Células Ciliadas Auditivas/efeitos dos fármacos , Histona Desacetilase 2/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Teofilina/metabolismo
4.
Sci Rep ; 11(1): 2462, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510250

RESUMO

Biological computation requires in vivo control of molecular behavior to progress development of autonomous devices. miRNA switches represent excellent, easily engineerable synthetic biology tools to achieve user-defined gene regulation. Here we present the construction of a synthetic network to implement detoxification functionality. We employed a modular design strategy by engineering toxin-induced control of an enzyme scavenger. Our miRNA switch results show moderate synthetic expression control over a biologically active detoxification enzyme molecule, using an established design protocol. However, following a new design approach, we demonstrated an evolutionarily designed miRNA switch to more effectively activate enzyme activity than synthetically designed versions, allowing markedly improved extrinsic user-defined control with a toxin as inducer. Our straightforward new design approach is simple to implement and uses easily accessible web-based databases and prediction tools. The ability to exert control of toxicity demonstrates potential for modular detoxification systems that provide a pathway to new therapeutic and biocomputing applications.


Assuntos
Enzimas/metabolismo , MicroRNAs/genética , Biossíntese de Proteínas/genética , Toxinas Biológicas/toxicidade , Sequência de Bases , Citocromo P-450 CYP1A2/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inativação Gênica , Células HEK293 , Humanos , MicroRNAs/química , MicroRNAs/metabolismo , Conformação de Ácido Nucleico , Teofilina/farmacologia , Fatores de Tempo
5.
Bioorg Med Chem Lett ; 36: 127826, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33513384

RESUMO

Theophylline is long known for its anti-ageing and anti-oxidative properties. Moreover, Tyrosinase is a crucial enzyme that regulates the melanin synthetic pathway, which is involved in various physiological metabolic processes including aging. The current paper describes the synthesis of various heterocyclic systems coupled with theophylline moiety along with their tyrosinase inhibition activity in view to identify the potent nucleus. Around 19 compounds were synthesized and screened for enzyme inhibition. Based on the current study, it is suggested that compound 18 having thiosemicarbazide has strong enzyme inhibition potential. The enzyme kinetics and docking studies provide important insights into how the compound interacts with the mushroom tyrosinase active site. The work will provide clue to developing new, potent tyrosinase inhibitors for drug development.


Assuntos
Complexos de Coordenação/farmacologia , Cobre/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Teofilina/farmacologia , Agaricales/enzimologia , Sítios de Ligação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Semicarbazidas/química , Relação Estrutura-Atividade , Teofilina/química
6.
Int J Biol Macromol ; 173: 277-284, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453259

RESUMO

Natural polymers have been widely studied as vehicles that have gained much interest in the encapsulation and delivery of drugs and bioactive molecules. In this study, we developed starch-modified alginate nanoparticles using a green facile technique for drug delivery application. The potential of the prepared nanoparticles for controlled drug delivery applications is demonstrated using theophylline and bovine serum albumin as model drugs. The nanoparticles possessed the encapsulation efficiency of 60 to 75%. The results of in vitro drug release studies showed the pH dependent characteristics of the prepared nanoparticles. In vitro cytotoxicity test revealed the biocompatibility of the developed nanoparticles against L929 fibroblast cell lines. The in vitro cellular uptake of nanoparticles was visualized in L929 fibroblast cells using fluorescent microscopy. The preliminary investigation suggests the developed nanoparticle is a promising candidate for drug delivery application.


Assuntos
Alginatos/química , Soroalbumina Bovina/química , Amido/química , Teofilina/química , Animais , Cápsulas , Bovinos , Linhagem Celular , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia de Fluorescência , Nanopartículas , Soroalbumina Bovina/farmacologia , Teofilina/farmacologia
7.
Drug Test Anal ; 13(1): 36-43, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33188564

RESUMO

A systematic review was undertaken to evaluate studies on the effects of theophylline and theobromine on exercise performance in normal (healthy) subjects. Theophylline was found to have been studied on eight occasions and theobromine on one, the number of subjects per study ranging from seven to 15. In two exercise investigations, theophylline was superior to placebo at a p < 0.05 level and no different in four including one that was conducted in artificial hypoxia. In a treadmill time trial over 3 km, theobromine was superior to placebo and equal to caffeine, at the <0.05 level. In strength studies, theophylline increased wrist strength in one and showed a slight but not statistically significant increase in limb strength in four of the seven subjects in the other. Theophylline caused adverse effects in six participants. There were no adverse effects in the theobromine investigation. Although the studies showed contradicting results and/or insufficient data to draw solid conclusions, it appears both drugs have potential to enhance performance and could be considered for inclusion on the WADA banned list.


Assuntos
Broncodilatadores/farmacologia , Exercício Físico , Substâncias para Melhoria do Desempenho/farmacologia , Teobromina/farmacologia , Teofilina/farmacologia , Humanos , Esportes
8.
Eur Respir J ; 57(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33334939

RESUMO

BACKGROUND: The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment. METHODS: In this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks. The primary end-point was annualised exacerbation rate. RESULTS: 1670 subjects were randomised and 1242 completed the study (1142 with acceptable data at week 48). Subjects (75.7% male) had a mean age of 64.4 years, with mean±sd baseline post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.1±0.4 L (42.2% predicted) and St George's Respiratory Questionnaire (SGRQ) score 45.8±20.1. There were negligible differences between annualised exacerbation rates across the three treatments: 0.89 (95% CI 0.78-1.02) on theophylline plus prednisone, 0.86 (95% CI 0.75-0.99) on theophylline plus placebo and 1.00 (95% CI 0.87-1.14) on placebo. The rate ratio for theophylline plus prednisone versus pooled theophylline plus placebo and placebo was 0.96 (95% CI 0.83-1.12), for theophylline plus placebo versus placebo was 0.87 (95% CI 0.73-1.03; p=0.101) and for theophylline plus prednisone versus placebo was 0.90 (95% CI 0.76-1.06; p=0.201). Secondary outcomes of hospitalisations, FEV1, SGRQ and COPD Assessment Test score showed no statistically significant difference between treatment arms. Serious adverse events other than exacerbations were <2% and did not differ between treatment arms. CONCLUSIONS: Low-dose theophylline alone or in combination with prednisone did not reduce exacerbation rates or clinically important secondary end-points compared with placebo.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Teofilina , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , China , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/farmacologia , Teofilina/uso terapêutico
9.
Int J Mol Sci ; 21(23)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33260941

RESUMO

Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer's disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines-caffeine, theophylline and theobromine-and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class.


Assuntos
Doença de Alzheimer/genética , Cafeína/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neuroblastoma/genética , Xantinas/farmacologia , Linhagem Celular Tumoral , Genes Essenciais , Humanos , Pentoxifilina/farmacologia , Análise de Componente Principal , Teobromina/farmacologia , Teofilina/farmacologia , Transcrição Genética/efeitos dos fármacos , Xantinas/química
10.
Saudi J Kidney Dis Transpl ; 31(5): 982-997, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33229761

RESUMO

Renal ischemia-reperfusion injury (IRI) is commonly encountered in clinical practice during renal transplantation. In a trial to find the drug that best safeguards the kidney against IRI, dexamethasone (Dex), N-acetyl cysteine (NAC), and theophylline (Theo) were tested in experimental rat models. This study included 105 adult male albino rats, which were randomly assigned to the following five groups: Group I - sham-operated, n = 5, Group II - IRI n = 25, Group III - IRI + Dex n = 25, Group IV - IRI + NAC n = 25, and Group V -IRI + Theo n = 25. IRI was induced for 40 min followed by reperfusion. Rats were sacrificed 1, 2, 4, 6, and 24 h after reperfusion. This was preceded by blood and urine sampling for biochemical study of serum Cystatin C (Cys C), serum creatinine, and urinary Cys C. Kidneys were processed for histopathological evaluation and immune-histochemical staining for Cys C. The expression of Cys C in the proximal tubular cells was significantly lower in the IRI group compared to that of the sham group. There was a significant rise in the levels of serum and urinary Cys C after 1 h in the IRI group, while the rise in creatinine occurred later. Dex was superior to NAC and Theo 24 h after the IR insult, and the serum levels of creatinine and Cys C were significantly lower in this group than the other two drug groups (P <0.001 in both cases). Our study revealed a clear benefit for the use of Dex to ameliorate IRI over NAC and Theo if used immediately following the insult. The effect is evident 24-h after its use. The role of serum Cys C as an early marker of acute kidney injury compared to serum creatinine is confirmed.


Assuntos
Acetilcisteína/farmacologia , Injúria Renal Aguda , Dexametasona/farmacologia , Traumatismo por Reperfusão , Teofilina/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Creatinina/sangue , Cistatina C/sangue , Cistatina C/urina , Modelos Animais de Doenças , Inflamação , Rim/química , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
11.
Commun Biol ; 3(1): 555, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033363

RESUMO

Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer's disease. Here we report Notum activity can be inhibited by caffeine (IC50 19 µM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC50 of 46 µM. The dissociation constant (Kd) between Notum and caffeine is 85 µM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors.


Assuntos
Cafeína/farmacologia , Esterases/antagonistas & inibidores , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esterases/química , Esterases/metabolismo , Células HEK293 , Humanos , Ligação Proteica , Estrutura Terciária de Proteína , Teofilina/farmacologia
12.
Pharmacol Biochem Behav ; 198: 173035, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32910928

RESUMO

Considerable evidence indicates that adenosine and dopamine systems interact in the regulation of basal ganglia function. Nonselective adenosine antagonists such as the methylxanthine caffeine as well as selective adenosine A2A antagonists have been shown to produce antiparkinsonian and antidepressant effects in animal models. The present studies were conducted to assess if another methylxantine, theophylline, can reverse motor and motivational impairments induced by dopamine antagonism in rats. RESULTS: Theophylline (3.75-30.0 mg/kg, IP) reversed tremulous jaw movements (TJMs), catalepsy, and locomotor suppression induced by the dopamine D2 antagonist pimozide. It also reversed TJMs induced by the muscarinic receptor agonist pilocarpine, which is a well-known tremorogenic agent. Parallel studies assessed the ability of theophylline (5.0-20.0 mg/kg, IP) to reverse the changes in effort-related choice behavior induced by the dopamine D1 antagonist ecopipam (0.2 mg/kg, IP) and the D2 antagonist haloperidol (0.1 mg/kg, IP). Rats were tested on two different operant choice tasks which assess the tendency to work for a preferred reinforcer by lever pressing (for palatable pellets or a high 5% sucrose solution) vs. approaching and consuming a less preferred reinforcer (freely available lab chow or a less concentrated 0.3% sucrose solution). Theophylline restored food and sucrose-reinforced lever pressing in animals treated with the D2 antagonist. However, it was unable to reverse the effects of the D1 antagonist. Overall, the effects of theophylline resembled those previously reported for adenosine A2A antagonists, and suggest that theophylline could be clinically useful for the treatment of motor and motivational symptoms in humans.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Teofilina/farmacologia , Tremor/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Catalepsia/tratamento farmacológico , Catalepsia/metabolismo , Condicionamento Operante/efeitos dos fármacos , Haloperidol/farmacologia , Humanos , Masculino , Motivação/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Pimozida/farmacologia , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologia , Tremor/tratamento farmacológico
13.
Sci Rep ; 10(1): 15398, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958839

RESUMO

The ability to express genes ectopically in bacteria is essential for diverse academic and industrial applications. Two major considerations when utilizing regulated promoter systems for ectopic gene expression are (1) the ability to titrate gene expression by addition of an exogenous inducer and (2) the leakiness of the promoter element in the absence of the inducer. Here, we describe a modular chromosomally integrated platform for ectopic gene expression in Vibrio cholerae. We compare the broadly used promoter elements Ptac and PBAD to versions that have an additional theophylline-responsive riboswitch (Ptac-riboswitch and PBAD-riboswitch). These constructs all exhibited unimodal titratable induction of gene expression, however, max induction varied with Ptac > PBAD > PBAD-riboswitch > Ptac-riboswitch. We also developed a sensitive reporter system to quantify promoter leakiness and show that leakiness for Ptac > Ptac-riboswitch > PBAD; while the newly developed PBAD-riboswitch exhibited no detectable leakiness. We demonstrate the utility of the tightly inducible PBAD-riboswitch construct using the dynamic activity of type IV competence pili in V. cholerae as a model system. The modular chromosomally integrated toolkit for ectopic gene expression described here should be valuable for the genetic study of V. cholerae and could be adapted for use in other species.


Assuntos
Expressão Ectópica do Gene/genética , Perfilação da Expressão Gênica/métodos , Regulação Bacteriana da Expressão Gênica/genética , Proteínas de Bactérias/genética , GMP Cíclico , Expressão Ectópica do Gene/efeitos dos fármacos , Expressão Gênica/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Riboswitch/efeitos dos fármacos , Riboswitch/genética , Teofilina/farmacologia , Vibrio cholerae/genética
14.
Bioorg Med Chem Lett ; 30(23): 127545, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931913

RESUMO

Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A (CNA) and calcineurin B (CNB) complexes, respectively. PB-WUT-01 acting as a calcineurin inhibitor in the C. albicans cells enhances the cells' susceptibility. Therefore it could be a suitable alternative treatment in patients with candidiasis.


Assuntos
Antifúngicos/farmacologia , Inibidores de Calcineurina/farmacologia , Calcineurina/metabolismo , Candida albicans/efeitos dos fármacos , Teofilina/análogos & derivados , Animais , Antifúngicos/síntese química , Antifúngicos/metabolismo , Apoptose/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , Biofilmes/efeitos dos fármacos , Inibidores de Calcineurina/síntese química , Inibidores de Calcineurina/metabolismo , Candida albicans/fisiologia , Chlorocebus aethiops , Proteínas Fúngicas/metabolismo , Larva/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mariposas , Ligação Proteica , Teofilina/metabolismo , Teofilina/farmacologia , Células Vero
15.
Int J Biol Macromol ; 165(Pt A): 445-459, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987078

RESUMO

Drug delivery to lungs via pulmonary administration offers potential for the development of new drug delivery systems. Here we fabricated the etofylline (ETO) encapsulated mannose-anchored N,N,N-trimethyl chitosan nanoparticles (Mn-TMC NPs). The prominent characteristics like biocompatibility, controlled release, targeted delivery, high penetrability, enhanced physical stability, and scalability mark Mn-TMC NPs as a viable alternative to various nanoplatform technologies for effective drug delivery. Mannosylation of TMC NPs leads to the evolution of new drug delivery vehicle with gratifying characteristics, and potential benefits in efficient drug therapy. It is widely accepted that following pulmonary administration, the introduction of mannose to the surface of drug nanocarriers provide selective macrophage targeting via receptor-mediated endocytosis. The fabricated Mn-TMC NPs exhibited particle size of 223.3 nm, PDI 0.490, and ζ-potential -19.1 mV, drug-loading capacity 76.26 ± 1.2%, and encapsulation efficiency of 91.75 ± 0.88%. Sustained drug release, biodegradation studies, stability, safety, and aerodynamic behavior revealed the effectiveness of prepared nanoformulation for pulmonary administration. In addition, the in vivo pharmacokinetic studies in Wistar rat model revealed a significant improvement in therapeutic efficacy of ETO, illustrating mannosylation a promising approach for efficient therapy of airway diseases following pulmonary administration.


Assuntos
Quitosana , Portadores de Fármacos , Pneumopatias/tratamento farmacológico , Manose , Nanopartículas , Teofilina/análogos & derivados , Animais , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , Manose/química , Manose/farmacocinética , Nanopartículas/química , Nanopartículas/uso terapêutico , Ratos , Ratos Wistar , Teofilina/química , Teofilina/farmacocinética , Teofilina/farmacologia
16.
Sci Rep ; 10(1): 14181, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843670

RESUMO

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Hiperalgesia/prevenção & controle , Inflamação/fisiopatologia , Neuroglia/enzimologia , Nociceptividade/fisiologia , Receptor A1 de Adenosina/fisiologia , Receptor Muscarínico M3/fisiologia , Animais , Benzilatos/farmacologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Adjuvante de Freund/toxicidade , Genes Sintéticos , Temperatura Alta , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agonistas Muscarínicos/farmacologia , Neuroglia/fisiologia , Nortropanos/farmacologia , Regiões Promotoras Genéticas , Agonistas do Receptor Purinérgico P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Receptor A1 de Adenosina/efeitos dos fármacos , Receptor Muscarínico M3/efeitos dos fármacos , Receptor Muscarínico M3/genética , Receptores Acoplados a Proteínas G , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Teofilina/análogos & derivados , Teofilina/farmacologia , Tato , Xantinas/farmacologia
17.
Int J Toxicol ; 39(6): 542-546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32787589

RESUMO

The objective of this study was to extract low frequency respiratory "artifacts" from a standard arterial blood pressure (ABP) waveform to simultaneously derive reliable breathing rates (BR). Arterial blood pressure derived BR values were characterized against respiratory rates simultaneously obtained from the Respiratory Inductive Plethysmography (RIP) system (EMKA). Reference compounds were introduced to evaluate responsiveness of the derived measures to respiratory depressants and stimulants. Male beagle dogs (n = 3) were instrumented with minimally invasive telemetry devices for measurements of ABP and heart rate. The RIP system was utilized simultaneously to collect respiratory rate, tidal volume, and minute volume of each animal following pharmacological challenges. Early results revealed the derived BR's from ABP waveforms did not correlate well with those measured from the RIP system. Post study X-ray visualization revealed suboptimal catheter positioning, causing poor concordance of BR tallied from the ABP waveforms. Follow-up evaluations were conducted using additional animals instrumented with the ABP catheter tip placement advanced proximal to the thoracic diaphragm. Preliminary data from this subset of animals significantly improved the correlation of BR derived from ABP and respiratory rates recorded by the RIP. This proof of concept investigation was intended to evaluate an algorithm designed to extract additional data from routine cardiac waveforms. We clearly demonstrated that with optimal blood pressure catheter placement and acquisition algorithm, a reliable breathing rate can also be extracted from safety studies without the need for additional studies/animals to capture those respiratory end points.


Assuntos
Pressão Sanguínea/fisiologia , Dexmedetomidina/farmacologia , Monitorização Fisiológica/métodos , Taxa Respiratória/fisiologia , Teofilina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Cães , Masculino , Antagonistas de Receptores Purinérgicos P1/farmacologia
18.
Nitric Oxide ; 104-105: 20-28, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32828841

RESUMO

The adenosine (Ado) system may participate in regulation of kidney function in diabetes mellitus (DM), therefore we explored its role and interrelation with NO in the control of renal circulation and excretion in normoglycemic (NG) and streptozotocin-diabetic (DM) rats. Effects of theophylline (Theo), a non-selective Ado receptor antagonist, were examined in anaesthetized NG or in streptozotocin induced diabetic (DM) rats, untreated or after blockade of NO synthesis with l-NAME. We measured arterial blood pressure (MABP), whole kidney blood flow and renal regional flows: cortical and outer- and inner-medullary (IMBF), determined as laser-Doppler fluxes. Renal excretion of water, total solutes and sodium and in situ renal tissue NO signal (selective electrodes) were also determined. Theo experiments disclosed minor baseline vasoconstrictor and vasodilator tone in the kidney of NG and DM rats, respectively. NO blockade increased baseline MABP and decreased renal haemodynamics, similarly in NG and DM rats, indicating comparable vasodilator influence of NO in the two groups. Unexpectedly, in all rats with intact NO synthesis, Ado receptor blockade increased kidney tissue NO. In NO-deficient NG and DM rats, Ado receptor blockade induced comparable renal vasodilatation, suggesting similar vasoconstrictor influence of the Ado system. However, DM rats showed an unexplained association of decreased MABP and IMBF and increased NO signal. Higher baseline renal excretion in DM rats indicated inhibition of renal tubular reabsorption due to the prevalence of natriuretic A2 over antinatriuretic A1 receptors. In conclusion, the experiments provided new insights in functional interrelation of adenosine and NO in normoglycaemia and streptozotocin-diabetes.


Assuntos
Adenosina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Óxido Nítrico/metabolismo , Circulação Renal/efeitos dos fármacos , Eliminação Renal/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Inibidores Enzimáticos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Antagonistas de Receptores Purinérgicos P1/farmacologia , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismo , Estreptozocina , Teofilina/farmacologia
19.
Nat Commun ; 11(1): 3420, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647127

RESUMO

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.


Assuntos
Fator 1 de Elongação de Peptídeos/metabolismo , Remielinização/genética , Ativação Transcricional/genética , Acetilação , Envelhecimento/metabolismo , Animais , Desdiferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Lisina Acetiltransferase 5/metabolismo , Camundongos , Modelos Biológicos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Fatores de Transcrição SOXE/metabolismo , Fator de Transcrição STAT3/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Teofilina/farmacologia , Transativadores/metabolismo , Ativação Transcricional/efeitos dos fármacos
20.
Molecules ; 25(12)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32549218

RESUMO

Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.


Assuntos
Sirtuínas/antagonistas & inibidores , Sirtuínas/metabolismo , Teofilina/química , Teofilina/farmacologia , Sítios de Ligação , Desenho de Fármacos , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Sirtuína 2/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores , Sirtuína 3/metabolismo , Relação Estrutura-Atividade
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