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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120287, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455386

RESUMO

Duvelisib (DUV) is a is a small-molecule with inhibitory action for phosphoinositide 3-kinase (PI3K). It has been recently approved for the effective treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Novel charge transfer complex (CTC) between DUV, as electron donor, with chloranilic acid (CLA), as π electron acceptor has been synthesized and characterized using different spectroscopic and thermogravimetric techniques. UV-visible spectroscopy ascertained the formation of the CTC in different solvents of varying polarity indexes and dielectric constants via formation of new broad absorption band with maximum absorption peak (λmax) in the range of 488-532 nm. The molar absorptivity of the CTC was dependent on the polarity index and dielectric constant of the solvent; the correlation coefficients were 0.9955 and 0.9749, respectively. The stoichiometric ratio of DUV:CLA was 1:1. Electronic spectral analysis was conducted for characterization of the complex in terms of its electronic constants. Computational calculation for atomic charges of energy minimized DUV was conducted and the site of interaction on DUV molecule was assigned. The solid-state CTC of DUV:CLA (1:1) was synthesized, and its structure was characterized by UV-visible, mass, FT-IR, and 1H NMR spectroscopic techniques. Both FT-IR and 1H NMR confirmed that both CT and hydrogen bonding contributed to the molecular composition of the complex. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for DUV. The assay limits of detection and quantitation were 0.57 and 1.72 µg/well, respectively. The assay was validated and all validation parameters were acceptable. The method was implemented successfully with great precision and accuracy to the analysis of the DUV in its bulk and capsules.


Assuntos
Hidrogênio , Fosfatidilinositol 3-Quinases , Benzoquinonas , Isoquinolinas , Purinas , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Chemosphere ; 286(Pt 2): 131747, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34358893

RESUMO

Pyrimidine and purine bases (adenine, cytosine, guanine and thymine) are important precursors of organic chloramines (OC) and disinfection by-products (DBPs) during chlor(am)ination. In this study, OC and DBP formation derived from pyrimidine and purine bases during chlor(am)ination, post-chlor(am)ination after pretreated by UV alone and UV/chlorination were systematically investigated with ultraviolet light-emitting diodes (UV-LEDs, 265 and 275 nm) and low pressure mercury lamp (LPUV, 254 nm). The results revealed that higher OC formation was observed during chlorination than that during chloramination of pyrimidine and purine bases. The degradation of pyrimidine and purine bases followed the pseudo-first-order kinetics. Both solution pH and UV wavelength played vital influence on the degradation of pyrimidine and purine bases. In terms of fluence-based rate constants (kobs), the degradation rates of pyrimidine and purine bases decreased in the order of 275 nm > 265 nm > 254 nm in alkaline conditions. The synergistic effects of kobs, chlorine,kobs, •OH and kobs, RCS contributed to the differences of pyrimidine and purine bases degradation at different pH values and UV wavelengths. A vital suppression of OC formation was observed during post-chlorination after pretreated by 275 nm UV-LED/chlorination. In addition, compared with LPUV (254 nm), less DBP formation was observed at UV-LED (275 nm), especially during the UV/chlorine process. The phenomena obtained in this study indicated that 275 nm UV-LED combined with chlorine could be a preferred method to promote pyrimidine and purine bases degradation and control OC and DBP formation in practical water treatment.


Assuntos
Desinfetantes , Poluentes Químicos da Água , Purificação da Água , Cloraminas , Cloro , Desinfecção , Halogenação , Purinas , Pirimidinas , Poluentes Químicos da Água/análise
3.
Trials ; 22(1): 689, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627340

RESUMO

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. METHODS: The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to <18 years with active JIA-uveitis or chronic ANA-positive uveitis without systemic features. At least 20 patients who have had an inadequate response or intolerance to methotrexate (MTX-IR), but not biologic disease-modifying antirheumatic drugs (bDMARDs), will be randomized (1:1) to open-label baricitinib or adalimumab. Approximately 20 additional patients who are MTX-IR or bDMARD inadequate responders will receive baricitinib treatment. Patients will be treated with once daily oral baricitinib at a fixed dose by age group (4 mg for patients aged ≥6 to <18 years and 2 mg for patients <6 years) or adalimumab (20 mg for patients weighing <30 kg and 40 mg for patients ≥30 kg) as a subcutaneous injection every 2 weeks. Treatment with stable background conventional synthetic DMARDs, low-dose corticosteroids, and/or nonsteroidal anti-inflammatory drugs is allowed. The primary endpoint is the proportion of patients with response at week 24. Patients may continue treatment for up to 5 years. DISCUSSION: This is the first pediatric clinical trial to assess the clinical effectiveness and safety of a JAK inhibitor in JIA-uveitis or chronic ANA-positive uveitis. A novel Bayesian design is used to assess the efficacy of baricitinib, including an adalimumab reference arm, in this small patient population with unmet medical need. TRIAL REGISTRATION: EudraCT 2019-000119-10 . Registered on January 4, 2019; NCT04088409 . Registered on September 12, 2019.


Assuntos
Artrite Juvenil , Uveíte , Adalimumab/efeitos adversos , Adolescente , Anticorpos Antinucleares , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Azetidinas , Teorema de Bayes , Criança , Ensaios Clínicos Fase III como Assunto , Humanos , Estudos Multicêntricos como Assunto , Purinas , Pirazóis , Sulfonamidas , Resultado do Tratamento , Uveíte/diagnóstico , Uveíte/tratamento farmacológico
4.
J Org Chem ; 86(19): 13265-13275, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34528791

RESUMO

6-Chloropurine and 2,6-dichloropurine were regioselectively glycosylated at position 7 to give the corresponding peracetylated N7-nucleosides, which can be suitable for other purine transformations. In this work, we study the distribution of N7/N9-isomers produced via the Vorbrüggen method under different conditions, using an N-trimethylsilylated purine derivative and SnCl4 or TiCl4 as a catalyst. The main effort is devoted to reversing the disadvantageous predominant selectivity of most glycosylation reactions at the N9 position and thus to determining conditions that maximize the regioselectivity of glycosylation toward the desired N7-isomer.


Assuntos
Purinas , Estanho , Glicosilação , Titânio
5.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502368

RESUMO

Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques' formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes' inflammasome may trigger early inflammatory pathways involving IL-1ß production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments.


Assuntos
Inflamassomos/metabolismo , Queratinócitos/metabolismo , Psoríase/patologia , Humanos , Inflamação/imunologia , Interleucina-17/metabolismo , Interleucina-1beta , Interleucina-23/farmacocinética , Psoríase/metabolismo , Purinas/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Transdução de Sinais , Pele/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Aging (Albany NY) ; 13(18): 21866-21902, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531332

RESUMO

BACKGROUND: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/uso terapêutico , COVID-19/mortalidade , Humanos , Mesilato de Imatinib/uso terapêutico , Metanálise em Rede , Oxazóis/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Tioidantoínas/uso terapêutico , Resultado do Tratamento
7.
Mol Cell ; 81(18): 3775-3785, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547238

RESUMO

With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.


Assuntos
Redes e Vias Metabólicas/fisiologia , Metabolismo/fisiologia , Metaboloma/fisiologia , Animais , Humanos , Complexos Multienzimáticos/metabolismo , Mapas de Interação de Proteínas/fisiologia , Purinas/metabolismo
8.
Nanomedicine (Lond) ; 16(23): 2095-2115, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34523353

RESUMO

Aim: To develop and characterize bozepinib-loaded lipid-core nanocapsules (BZP-LNC+) as a potential treatment for glioblastoma (GBM). Methods: Characterization of nanocapsules was performed by diameter, polydispersity index, Zeta potential, pH and encapsulation efficiency. GBM cell viability, cell cycle and Annexin/PI were evaluated after BZP-LNC+ treatment. Synergism between BZP-LNC+ and temozolomide (TMZ) was performed by CompuSyn software and confirmed in vitro and in vivo. Results: BZP-LNC+ showed adequate particle sizes, positive Zeta potential, narrow size distribution and high encapsulation efficiency. BZP-LNC+ reduces GBM growth by inducing apoptosis. BZP-LNC+ and TMZ showed synergistic effect in vitro and reduced the in vivo glioma growth by approximately 81%. Conclusion: The present study provides proof-of-principle insights for the combination of these drugs for GBM treatment.


Assuntos
Glioblastoma , Nanocápsulas , Encéfalo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Nanocápsulas/uso terapêutico , Oxazepinas , Purinas
9.
Mol Syst Biol ; 17(9): e10426, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34486798

RESUMO

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.


Assuntos
Antivirais/farmacologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Animais , Azetidinas/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 1/metabolismo , Lipopolissacarídeos/toxicidade , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/virologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Células RAW 264.7 , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Sulfonamidas/farmacologia
10.
PLoS One ; 16(9): e0257206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34506566

RESUMO

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Oximas/farmacologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Sequência de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Indóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Oximas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Estrutura Secundária de Proteína , Purinas/química , Quinazolinonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
11.
Breast Cancer Res Treat ; 189(3): 689-699, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34414532

RESUMO

PURPOSE: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. METHODS: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). RESULTS: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. CONCLUSION: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2- ABC. TRIAL REGISTRATION: linicalTrials.gov NCT02941926.


Assuntos
Neoplasias da Mama , Qualidade de Vida , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Letrozol/uso terapêutico , Purinas , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona
12.
Int Immunopharmacol ; 99: 108027, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34343937

RESUMO

OBJECTIVES: This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to investigate the clinical efficacy and safety of Janus kinase (JAK) inhibitors for COVID-19 patients. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to July 12, 2021. RCTs comparing the clinical efficacy and safety of JAK inhibitors with a placebo or standard care in treating COVID-19 patients were included. The primary outcome was all-cause mortality rate at day 28. RESULTS: Three RCTs were included in this meta-analysis. The all-cause mortality rate at day 28 was lower among the patients receiving JAK inhibitors than among the controls (4.1% [28/647] versus 7.0% [48/684], OR, 0.57; 95% CI, 0.36-0.92, I2 = 0). The clinical recovery rate was higher among the patients receiving JAK inhibitors than among the controls (85.1% (579/680) versus 80.0% [547/684], OR, 1.45; 95% CI, 1.09-1.93, I2 = 0). Additionally, the use of JAK inhibitors was associated with a shorter time to recovery than among the controls (MD, -2.84; 95% CI, -5.56 to -0.12; I2 = 50%). The rate of invasive mechanical ventilation (MV) was lower in the patients who used JAK inhibitors than among the controls. Finally, no significant difference was observed between the patients who used JAK inhibitors and the controls in the risk of any adverse events (OR, 0.92; 95% CI, 0.64-1.34; I2 = 33%) and serious adverse events (OR, 0.80; 95% CI, 0.45-1.44; I2 = 46%). CONCLUSIONS: JAK inhibitors can lead to a better clinical outcome of hospitalized COVID-19 patients, and they are a safe agent in the treatment of COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Azetidinas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Piperidinas , Purinas , Pirazóis , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Sulfonamidas , Resultado do Tratamento
13.
Int J Mol Sci ; 22(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34445441

RESUMO

Nearly 40-50% of infertility problems are estimated to be of female origin. Previous studies dedicated to the analysis of metabolites in follicular fluid (FF) produced contrasting results, although some valuable indexes capable to discriminate control groups (CTRL) from infertile females (IF) and correlate with outcome measures of assisted reproduction techniques were in some instances found. In this study, we analyzed in blind FF of 35 control subjects (CTRL = patients in which inability to obtain pregnancy was exclusively due to a male factor) and 145 IF (affected by: endometriosis, n = 19; polycystic ovary syndrome, n = 14; age-related reduced ovarian reserve, n = 58; reduced ovarian reserve, n = 29; unexplained infertility, n = 14; genetic infertility, n = 11) to determine concentrations of 55 water- and fat-soluble low molecular weight compounds (antioxidants, oxidative/nitrosative stress-related compounds, purines, pyrimidines, energy-related metabolites, and amino acids). Results evidenced that 27/55 of them had significantly different values in IF with respect to those measured in CTRL. The metabolic pattern of these potential biomarkers of infertility was cumulated (in both CTRL and IF) into a Biomarker Score index (incorporating the metabolic anomalies of FF), that fully discriminated CTRL (mean Biomarker Score value = 4.00 ± 2.30) from IF (mean Biomarker Score value = 14.88 ± 3.09, p < 0.001). The Biomarker Score values were significantly higher than those of CTRL in each of the six subgroups of IF. Posterior probability curves and ROC curve indicated that values of the Biomarker Score clustered CTRL and IF into two distinct groups, based on the individual FF metabolic profile. Furthermore, Biomarker Score values correlated with outcome measures of ovarian stimulation, in vitro fertilization, number and quality of blastocysts, clinical pregnancy, and healthy offspring. These results strongly suggest that the biochemical quality of FF deeply influences not only the effectiveness of IVF procedures but also the following embryonic development up to healthy newborns. The targeted metabolomic analysis of FF (using empowered Redox Energy Test) and the subsequent calculation of the Biomarker Score evidenced a set of 27 low molecular weight infertility biomarkers potentially useful in the laboratory managing of female infertility and to predict the success of assisted reproduction techniques.


Assuntos
Biomarcadores/análise , Fertilização In Vitro , Líquido Folicular/metabolismo , Infertilidade Feminina/metabolismo , Metaboloma , Estresse Oxidativo , Adulto , Aminoácidos/análise , Antioxidantes/análise , Feminino , Humanos , Infertilidade Feminina/terapia , Itália , Pessoa de Meia-Idade , Estresse Nitrosativo , Indução da Ovulação , Purinas/análise , Pirimidinas/análise , Resultado do Tratamento
14.
Eur J Radiol ; 143: 109877, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34412009

RESUMO

PURPOSE: To evaluate a novel quantitative methodology to assess inflammatory changes in magnetic resonance imaging (MRI) data from patients with rheumatoid arthritis (RA) and the impact of image quality on imaging outcomes compared to the RA Magnetic Resonance Imaging Score (RAMRIS). METHODS: Three-dimensional, T1-weighted, fat-suppressed MRI sequences of the hand/wrist before and after intravenous Gadolinium contrast from patients with RA in a placebo-controlled clinical trial (NCT01185353) were re-evaluated post hoc. The methodology was integrated into proprietary software (DYNAMIKA®) and assessed inflammation through pixelated measurements of the contrast-enhancing (inflammatory) volume. A semi-automatic approach outlined contrast-enhancing synovial tissue in the wrist and second to fifth metacarpophalangeal joints with a rough region of interest (ROI); quantitative imaging biomarkers were generated by means of quantitative total volume of inflammation and quantitative degree of inflammation relative to the signal in a 1 cm in diameter ROI in the center of the thenar or lumbrical muscle for internal reference. The time from Gadolinium injection to finalization of the post-contrast images was calculated from the images' Digital Imaging and Communications in Medicine header. An experienced reader graded image quality as poor, acceptable, or good. RESULTS: Results from this quantitative methodology, especially when excluding images with poor quality scores (14-32%), provided a more pronounced and monotonically increasing dose-response than the original RAMRIS results on synovitis and osteitis. CONCLUSIONS: This computer-aided quantitative scoring method provided continuous measures of inflammatory changes relative to muscle and may be more sensitive and interpretable concerning dose/response separation between RA treatment groups.


Assuntos
Artrite Reumatoide , Azetidinas , Artrite Reumatoide/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Purinas , Pirazóis , Sulfonamidas
15.
Biomolecules ; 11(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439832

RESUMO

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.


Assuntos
Cálcio/metabolismo , Gânglios Espinais/metabolismo , Prurido/genética , Células Receptoras Sensoriais/metabolismo , Canal de Cátion TRPA1/genética , Canais de Cátion TRPV/genética , Acetanilidas/farmacologia , Animais , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Expressão Gênica , Histamina/administração & dosagem , Masculino , Metilistaminas/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imagem Molecular , Cultura Primária de Células , Prurido/induzido quimicamente , Prurido/tratamento farmacológico , Prurido/metabolismo , Purinas/farmacologia , Rutênio Vermelho/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
16.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445078

RESUMO

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Purinas/farmacologia , Receptor Smoothened/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Proteínas Hedgehog/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Purinas/química , Purinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/metabolismo
17.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360766

RESUMO

Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A2A receptor (A2AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (A2AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4-32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16-32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of A2AR in development of age-related cochlear degeneration.


Assuntos
Envelhecimento , Limiar Auditivo/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Presbiacusia , Purinas/farmacologia , Animais , Masculino , Camundongos , Presbiacusia/tratamento farmacológico , Presbiacusia/patologia , Presbiacusia/fisiopatologia
18.
Respir Investig ; 59(6): 799-803, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34413006

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide and is also an important disease in Japan. Thus, the optimal treatment strategy for severe COVID-19 should be established urgently. The effects of combination treatment with baricitinib-a Janus kinase inhibitor, remdesivir, and dexamethasone (BRD) are unknown. METHODS: Patients who received combination therapy with BRD at the Japanese Red Cross Medical Center were enrolled in the study. All patients received baricitinib (≤14 d), remdesivir (≤10 d), and dexamethasone (≤10 d). The efficacy and adverse events were evaluated. RESULTS: In total, 44 patients with severe COVID-19 were enrolled in this study. The 28-d mortality rate was low at 2.3% (1/44 patients). The need for invasive mechanical ventilation was avoided in most patients (90%, 17/19 patients). Patients who received BRD therapy had a median hospitalization duration of 11 d, time to recovery of 9 d, duration of intensive care unit stay of 6 d, duration of invasive mechanical ventilation of 5 d, and duration of supplemental oxygen therapy of 5 d. Adverse events occurred in 15 patients (34%). Liver dysfunction, thrombosis, iliopsoas hematoma, renal dysfunction, ventilator-associated pneumonia, infective endocarditis, and herpes zoster occurred in 11%, 11%, 2%, 2%, 2%, 2%, and 2% of patients, respectively. CONCLUSIONS: Combination therapy with BRD was effective in treating severe COVID-19, and the incidence rate of adverse events was low. The results of the present study are encouraging; however, further randomized clinical studies are needed.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Azetidinas/uso terapêutico , Dexametasona/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/efeitos adversos , Alanina/uso terapêutico , Azetidinas/efeitos adversos , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , Dexametasona/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Respiração Artificial , SARS-CoV-2 , Sulfonamidas/efeitos adversos , Resultado do Tratamento
19.
J Agric Food Chem ; 69(32): 9461-9471, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34355907

RESUMO

Target identification is one of the most important bases for novel pesticide development; pyruvate kinase (PK) was discovered as a potent fungicide target in our previous studies. To continue the PK-based fungicide development, novel isothiazole-purine derivatives were rationally designed and synthesized. Bioassay results showed that compound 5ai displayed excellent in vitro activity against Rhizoctonia solani with an EC50 of 1.5 µg/mL, which was superior to those of positive controls diflumetorim with its EC50 of 19.8 µg/mL and PK-based lead YZK-C22 with its EC50 of 4.2 µg/mL. Compounds 3b (5.2 µg/mL) and 3c (4.5 µg/mL) displayed better activities against Gibberella zeae with their EC50s falling between 4.0 and 5.5 µg/mL, while YZK-C22 showed an EC50 of 6.4 µg/mL. In addition, 5ah exhibited promising in vivo activity against Erysiphe graminis and Puccinia sorghi Schw. with 100% efficacy at 10 µg/mL and 90% efficacy at 2 µg/mL against P. sorghi Schw. Compound 5ai showed good PK inhibitory activity with an IC50 of 38.8 µmol/L, and it was well docked into the active site of the target enzyme PK, which was slightly more active than YZK-C22 with its IC50 of 42.4 µmol/L. Our studies discovered that isothiazole-purines were PK-based fungicidal leads deserving of further study.


Assuntos
Fungicidas Industriais , Fungicidas Industriais/farmacologia , Fusarium , Chumbo , Purinas , Piruvato Quinase , Rhizoctonia , Relação Estrutura-Atividade
20.
Medicine (Baltimore) ; 100(30): e26739, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397713

RESUMO

ABSTRACT: Baricitinib is a Janus kinase (JAK) inhibitor that selectively blocks against JAK1 and JAK2 signaling. This study aimed to determine the effect of baricitinib on disease activity based on musculoskeletal ultrasound in patients with rheumatoid arthritis (RA).A total of 20 patients with RA receiving baricitinib for 24 weeks were assessed. Ultrasound scores of gray scale and power Doppler synovitis, joint effusion, and bone erosion in each patient were assessed between baseline and 24 weeks for 27 affected joints. Disease activity in RA was evaluated using the disease activity score for 28-joint count with erythrocyte sediment rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI).Treatment with baricitinib for 12 weeks and 24 weeks significantly decreased disease activity composites such as DAS28-ESR, SDAI, and CDAI (P < .001 for all). Treatment with baricitinib for 24 weeks improved ultrasound-detected gray-scale and power Doppler synovitis and joint effusion compared to baseline (P = .002, P = .030, and P = .002, respectively). Bone erosion scores were not different between baseline and 24 weeks (P = .317). There were no differences in ultrasound abnormalities for improvement based on DAS28-ESR. Changes in power Doppler score were significantly associated with changes in DAS28-ESR (ß = 0.590, P = .044), but not SDAI and CDAI.This study demonstrates that baricitinib treatment has a favorable effect on ultrasound-detected abnormalities including synovitis and bone erosion in patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Sinovite/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Azetidinas/farmacologia , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sinovite/diagnóstico por imagem , Ultrassonografia
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