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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120272, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34428636

RESUMO

Hydrazine, as a toxic substance, seriously endangers human health and the environment. Based on the excellent luminescent properties and low biological toxicity of pyrene derivatives, combing with chalcone derivatives easily attacked by nucleophilic group, a pyrene derivative PCA decorated by acryloyl terminal group as fluorescent probe for hydrazine was developed. The compound shows fluorescent peak red shift and intensity enhancement with increasing solvent polarity from hexane (459 nm) to methanol (561 nm). Based on strong fluorescence emission in methanol, methanol-HEPES mixed solution was used as the solvent in the spectral recognition experiments. The probe exhibits fluorescent change from yellow fluorescence (576 nm) to blue fluorescence (393 nm) with 800-fold ratiometric fluorescence enhancement (I393nm/I576nm) after the reaction with hydrazine. The probe can recognize hydrazine in fast response rate with kinetic constant calculated being 2.7 × 10-3 s-1 and 15 min as response time. The probe also can monitor hydrazine in real water samples and various soils.


Assuntos
Chalcona , Chalconas , Corantes Fluorescentes , Humanos , Hidrazinas , Pirenos , Espectrometria de Fluorescência
2.
J Colloid Interface Sci ; 606(Pt 2): 1239-1248, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492462

RESUMO

Cuprous oxide (Cu2O) is a p-type semiconductor with excellent catalytic activity and stability that has gained much attention because it is non-toxic, abundant, and inexpensive. Porous carbon materials have large specific surface areas, which offer abundant electroactive sites, enhance the electrical conductivity of materials, and prevent the aggregation of Cu2O nanocubes. In this study, a composite with high electrocatalytic activity was prepared based on Cu2O nanocubes anchored onto three-dimensional macroporous carbon (MPC) by a simple, eco-friendly, and cheap method for hydrazine detection. Due to the synergistic effect of MPC and Cu2O, the sensor exhibited high electrocatalytic activity, sensitivity, better selectivity, and low limit of detection. The resulting sensor could be a sensitive and effective platform for detecting hydrazine and promising practical applications.


Assuntos
Carbono , Cobre , Hidrazinas
3.
Nihon Yakurigaku Zasshi ; 156(6): 370-381, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34719572

RESUMO

Anamorelin hydrochloride (hereinafter referred to as anamorelin) is an orally active, small-molecule drug with a similar pharmacological action to ghrelin, an endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R1a). It was first approved in Japan for the treatment of cancer cachexia, characterized by weight loss and anorexia. Anamorelin stimulated the secretion of growth hormone (GH) from cultured rat pituitary cells and increased plasma GH levels by oral administration to rats, pigs and humans. When anamorelin was orally administered once daily for 6 days to rats, larger body weight gain associated with increased food consumption compared to the control group was observed from after the first dose. Anamorelin is a selective agonist for GHS-R1a and enhanced GHS-R1a-mediated pituitary GH secretion and increased food consumption, resulting in body weight gain. In the two Japanese phase II studies in patients with cancer cachexia associated with non-small cell lung cancer (NSCLC), improvement of lean body mass (LBM) and body weight losses and anorexia were demonstrated. The tumor types of target patients in the Japanese phase III study were colorectal, gastric, and pancreatic cancer. As a result, maintenance and increase of LBM and body weight as well as improvement of anorexia were observed, and the efficacy against cancer cachexia associated with colorectal, gastric, and pancreatic cancer was confirmed. There were no observed events considered to be significant safety risks. In conclusion, anamorelin is expected to provide a new therapeutic option for cancer cachexia for which no effective treatment has been available.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Caquexia/tratamento farmacológico , Grelina , Humanos , Hidrazinas , Japão , Oligopeptídeos , Ratos , Suínos , Comprimidos , Resultado do Tratamento
4.
Rinsho Ketsueki ; 62(10): 1499-1504, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34732623

RESUMO

A 67-year-old woman diagnosed with adult T-cell leukemia/lymphoma received an induction chemotherapy and showed a partial response. She then underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling donor. Although cyclosporine (CS) was stopped at 120 days after transplantation, chronic graft-versus-host disease (cGVHD) of the skin developed. She was treated with a topical steroid, without exacerbation of the GVHD. She was admitted to our hospital due to the sudden development of pancytopenia at 212 days after the transplantation. She had an EB virus-associated post-transplant lymphoproliferative disorder (PTLD) in the hilum of the lung. The cGVHD of the skin resolved after the administration of prednisolone and CS. However, pancytopenia and PTLD persisted. Treatment with four cycles of rituximab (4×375 mg/m2/week) led to the complete resolution of PTLD, but transfusion-dependent cytopenia did not improve. Secondary engraftment failure was diagnosed, and granulocyte colony-stimulating factor (G-CSF) and eltrombopag (100 mg/day) were administered, leading to gradual improvement of pancytopenia. It was observed that persistent pancytopenia was caused by secondary engraftment failure due to cGVHD in this case. This case suggested that the treatment with G-CSF and eltrombopag is effective for cGVHD-associated secondary engraftment failure.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Linfoma , Transplante de Células-Tronco de Sangue Periférico , Idoso , Benzoatos , Transplante de Medula Óssea , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hidrazinas , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Pirazóis , Transplante Homólogo
5.
Exp Appl Acarol ; 85(2-4): 161-172, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34693496

RESUMO

Several genetic variants of the cd1- and ef-helices of the Qo site of mitochondrial cytochrome b have been associated with bifenazate resistance in the spider mite Tetranychus urticae, an important crop pest around the world. Maternal inheritance of bifenazate resistance has provided strong evidence for the involvement of many of these mutations alone or in combination. A number of populations highly resistant to bifenazate were uncovered that carried the G126S substitution in combination with other target-site mutations. This G126S mutation has therefore been investigated in several studies in the context of resistance evolution and the development of diagnostic markers. However, experimental data that link bifenazate resistance with the presence of the G126S mutation without additional cd1- and ef-helices mutations, remain very limited. Here, we genotyped 38 T. urticae field populations for cytochrome b and uncovered nine field populations with a fixed or segregating G126S substitution without other target-site mutations in the conserved cd1- and ef-helices of the cytochrome b Qo pocket. Toxicity bioassays showed that all nine field populations were very susceptible to bifenazate, providing strong evidence that G126S alone does not confer bifenazate resistance. These findings also implicate that previous T. urticae populations with G126S found to be low to moderately resistant to bifenazate, evolved alternative mechanisms of resistance, and more importantly, that this mutation cannot be used as a molecular diagnostic for bifenazate resistance.


Assuntos
Tetranychidae , Animais , Carbamatos , Citocromos b/genética , Hidrazinas , Tetranychidae/genética
6.
Analyst ; 146(22): 6840-6845, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34608469

RESUMO

The direct analysis of glycans by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) presents limited sensitivity due to the lower ionization efficiency of glycans. Various chemical derivatization methods have been developed to improve the detection sensitivity of glycans, but most of them need tedious preparation and cleanup procedures. Herein, a reactive matrix, 4-hydrazinoquinazoline (4-HQ), was developed for the rapid and sensitive detection of both neutral and sialylated glycans by MALDI MS. With 4-HQ as the reactive matrix, the detection limits of maltoheptaose and A3 glycan decreased 100-fold and 20-fold, respectively, compared with the conventional matrix. Moreover, 4-HQ formed homogeneous crystals and therefore showed good shot-to-shot reproducibility. Finally, the reactive matrix was successfully applied for the analysis of glycans released from glycoproteins and human serum. Importantly, the application of 4-HQ is the same as that of a conventional matrix with the additional advantage of on-target reaction at room temperature. Thus, 4-HQ can be used for the routine analysis of glycans by MALDI MS due to its simple use, great reproducibility, and enhanced detection of both neutral and sialylated glycans.


Assuntos
Hidrazinas , Polissacarídeos , Humanos , Quinazolinonas , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
7.
Blood Adv ; 5(19): 3799-3806, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34605871

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and risk of hemorrhage. Treatment with eltrombopag increases and maintains hemostatic platelet counts; however, to date, long-term data are lacking on the outcome of children with ITP who are treated with eltrombopag. This prospective, observational, longitudinal cohort study evaluated the efficacy and safety of eltrombopag in pediatric patients with persistent or chronic ITP. For the 116 pediatric patients enrolled, duration of eltrombopag treatment was at least 3 months. Median effective dose was 25 mg/day, 50 mg/day, and 50 mg/day, respectively, for children age 5 years or younger, 6 to 11 years, or 12 years or older. In all, 89 patients (76.7%) achieved overall response, 53 (45.7%) achieved complete response, and 36 (31.0%) achieved response. Median platelet counts increased by week 1 and were sustained throughout the treatment period. During treatment with eltrombopag, the proportion of patients with grade 1 to 4 bleeding symptoms decreased from 83.61% at baseline to 9.88% at 6 months when only grade 1 was reported. Forty-three patients (37.1%) reported using concomitant medications at study entry, which was reduced to 1 patient (2.5%) who needed concomitant medications at 12 months. All adverse events were grade 1 or 2 according to Common Terminology Criteria for Adverse Events. No serious adverse events, cataracts, malignancies, or thromboses were reported during the study. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts and reducing bleeding in most pediatric patients with persistent or chronic ITP. Combined with future studies, these findings will help establish how eltrombopag should best be used in the management of pediatric patients with East Asian ancestry.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Benzoatos/efeitos adversos , Criança , Pré-Escolar , China , Humanos , Hidrazinas , Estudos Longitudinais , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Resultado do Tratamento
8.
Hematology ; 26(1): 697-708, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34547980

RESUMO

OBJECTIVE: To assess real-world treatment patterns in patients with immune thrombocytopenia (ITP) who received thrombopoietin receptor agonists (TPO-RAs) in Germany. METHODS: This was a longitudinal, retrospective study using anonymized patient-level data (IQVIA healthcare prescription database, covering 82% of German statutory prescriptions). Eligible patients (aged ≥18 years) had received ≥1 TPO-RA prescription (romiplostim/eltrombopag) from July 2016 to June 2019 (treatment duration ≥30 days). ITP medication use was assessed for 18 months prior to, during and for ≥6 months after TPO-RA treatment. RESULTS: A total of 3553 patients (median age 64 years) were included. Median persistence on TPO-RAs was 12 months (range 1-34). In the periods before, during and after TPO-RA treatment, oral corticosteroids were the most commonly used therapy (64.4%, 43.4% and 36.1% of patients, respectively); median cumulative doses across each period were 2521.9, 2000.0 and 2277.8 mg. The median total duration of corticosteroid use before, during and after TPO-RA therapy was 15, 18 and 32 weeks, respectively. The total median cumulative corticosteroid dose was 6799.7 mg. CONCLUSION: We identified a potential overuse of corticosteroids in patients with ITP in Germany. Earlier use of TPO-RA therapy after a short course of corticosteroids could avoid side effects associated with long-term use.


Assuntos
Benzoatos/administração & dosagem , Bases de Dados Factuais , Prescrições de Medicamentos , Hidrazinas/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/administração & dosagem , Receptores Fc/administração & dosagem , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/epidemiologia , Estudos Retrospectivos
9.
Anal Chim Acta ; 1178: 338807, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34482879

RESUMO

In this work, we have designed and synthesized a new fluorescent molecular probe, DPY comprising of pyrene-diacetylpyridine conjugate, which was found to be sensitive to hydrazine as well as protonation. DPY is characterised by a strong emission both in solution (λem = 530 nm) as well as in solid state (λem = 610 nm), attributed to intramolecular charge-transfer. The probe responds to hydrazine with a ratiometric fluorescence emission change from yellow to blue, due to chalcone cyclisation reaction of α, ß-unsaturated carbonyl group resulting in the pyrazoline compound, DPY-Hy, imparting a strong greenish-blue emission in solution. Further, the strong fluorescence emission of DPY in powder and thin film was quenched upon exposure to TFA, and revived upon exposure to TEA. For developing on-site detection protocol, when DPY was drop-casted on nonfluorescent silica plate a vivid naked-eye colour change from orange-red to dark blue was realized. Interestingly, in the aggregated state, DPY exhibited a broad range emission from green to orange in a mixed solvent system of THF:H2O. A plausible explanation of the photophysical events is substantiated with theoretical calculations.


Assuntos
Chalcona , Chalconas , Corantes Fluorescentes , Hidrazinas , Pirenos
10.
BMC Cancer ; 21(1): 993, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488662

RESUMO

BACKGROUND: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. METHODS: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. RESULTS: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. CONCLUSION: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Hidrazinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Triazóis/administração & dosagem
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(9): 944-950, 2021.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34535211

RESUMO

OBJECTIVES: To systematically assess the efficacy and safety of eltrombopag in the treatment of children with immune thrombocytopenia (ITP). METHODS: PubMed, Embase, Cochrane Library, Weipu Data, CNKI, and Wanfang Data were searched for studies on eltrombopag used for the treatment of children with ITP. RevMan 5.3 and R version 3.6 were used to perform a Meta analysis of included studies. RESULTS: A total of 11 studies were included, with 2 randomized controlled trials and 9 cohort studies. The Meta analysis of the 9 cohort studies showed that eltrombopag had a response rate of about 70% (95%CI: 65%-76%) in the treatment of children with ITP, with no serious adverse events. The Meta analysis of the randomized controlled trials showed that the eltrombopag group had a higher response rate than the placebo group (RR=2.64, 95%CI: 1.58-4.44, P<0.05), while there was no significant difference in the incidence rates of adverse events and serious adverse events between the two groups (P>0.05). CONCLUSIONS: Eltrombopag has good efficacy and safety as a second-line treatment regimen for children with ITP.


Assuntos
Púrpura Trombocitopênica Idiopática , Benzoatos , Criança , Humanos , Hidrazinas/efeitos adversos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Receptores Fc , Trombopoetina
12.
FASEB J ; 35(10): e21925, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569663

RESUMO

In mammalian testes, extensive remodeling of the microtubule (MT) and actin cytoskeletons takes place in Sertoli cells across the seminiferous epithelium to support spermatogenesis. However, the mechanism(s) involving regulatory and signaling proteins remains poorly understood. Herein, A-kinase anchoring protein 9 (AKAP9, a member of the AKAP multivalent scaffold protein family) was shown to be one of these crucial regulatory proteins in the rat testis. Earlier studies have shown that AKAP9 serves as a signaling platform by recruiting multiple signaling and regulatory proteins to create a large protein complex that binds to the Golgi and centrosome to facilitate the assembly of the MT-nucleating γ-tubulin ring complex to initiate MT polymerization. We further expanded our earlier studies based on a Sertoli cell-specific AKAP9 knockout mouse model to probe the function of AKAP9 by using the techniques of immunofluorescence analysis, RNA interference (RNAi), and biochemical assays on an in vitro primary Sertoli cell culture model, and an adjudin-based animal model. AKAP9 robustly expressed across the seminiferous epithelium in adult rat testes, colocalizing with MT-based tracks, and laid perpendicular across the seminiferous epithelium, and prominently expressed at the Sertoli-spermatid cell-cell anchoring junction (called apical ectoplasmic specialization [ES]) and at the Sertoli cell-cell interface (called basal ES, which together with tight junction [TJ] created the blood-testis barrier [BTB]) stage specifically. AKAP9 knockdown in Sertoli cells by RNAi was found to perturb the TJ-permeability barrier through disruptive changes in the distribution of BTB-associated proteins at the Sertoli cell cortical zone, mediated by a considerable loss of ability to induce both MT polymerization and actin filament bundling. A considerable decline in AKAP9 expression and a disruptive distribution of AKAP9 across the seminiferous tubules was also noted during adjudin-induced germ cell (GC) exfoliation in this animal model, illustrating AKAP9 is essential to maintain the homeostasis of cytoskeletons to maintain Sertoli and GC adhesion in the testis.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Citoesqueleto de Actina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Espermatogênese , Testículo/citologia , Testículo/metabolismo , Animais , Núcleo Celular/metabolismo , Hidrazinas/metabolismo , Indazóis/metabolismo , Masculino , Modelos Animais , Ratos , Células de Sertoli/citologia , Células de Sertoli/metabolismo , Testículo/química
13.
Adv Ther ; 38(11): 5501-5518, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34561812

RESUMO

INTRODUCTION: Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678). METHODS: At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH). RESULTS: Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001). CONCLUSION: Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.


Assuntos
Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Hidrazinas , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia , Padrão de Cuidado , Triazóis
14.
Biochemistry ; 60(38): 2851-2864, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34516102

RESUMO

N-hydroxylating monooxygenases (NMOs) are a subclass of flavin-dependent enzymes that hydroxylate nitrogen atoms. Recently, unique NMOs that perform multiple reactions on one substrate molecule have been identified. Fosfazinomycin M (FzmM) is one such NMO, forming nitrosuccinate from aspartate (Asp) in the fosfazinomycin biosynthetic pathway in some Streptomyces sp. This work details the biochemical and kinetic analysis of FzmM. Steady-state kinetic investigation shows that FzmM performs a coupled reaction with Asp (kcat, 3.0 ± 0.01 s-1) forming nitrosuccinate, which can be converted to fumarate and nitrite by the action of FzmL. FzmM displays a 70-fold higher kcat/KM value for NADPH compared to NADH and has a narrow optimal pH range (7.5-8.0). Contrary to other NMOs where the kred is rate-limiting, FzmM exhibits a very fast kred (50 ± 0.01 s-1 at 4 °C) with NADPH. NADPH binds at a KD value of ∼400 µM, and hydride transfer occurs with pro-R stereochemistry. Oxidation of FzmM in the absence of Asp exhibits a spectrum with a shoulder at ∼370 nm, consistent with the formation of a C(4a)-hydroperoxyflavin intermediate, which decays into oxidized flavin and hydrogen peroxide at a rate 100-fold slower than the kcat. This reaction is enhanced in the presence of Asp with a slightly faster kox than the kcat, suggesting that flavin dehydration or Asp oxidation is partially rate limiting. Multiple sequence analyses of FzmM to NMOs identified conserved residues involved in flavin binding but not for NADPH. Additional sequence analysis to related monooxygenases suggests that FzmM shares sequence motifs absent in other NMOs.


Assuntos
Hidrazinas/metabolismo , Compostos Organofosforados/metabolismo , Dinitrocresóis , Flavina-Adenina Dinucleotídeo/metabolismo , Flavinas/metabolismo , Hidroxilação/fisiologia , Cinética , Oxigenases de Função Mista/metabolismo , NADP/metabolismo , Oxirredução , Ácido Succínico/metabolismo
15.
BMJ Open ; 11(8): e044885, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452956

RESUMO

INTRODUCTION: Immune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP. METHODS AND ANALYSIS: Randomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×109/L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites. ETHICS AND DISSEMINATION: The study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023. TRIAL REGISTRATION NUMBER: NCT03939637.


Assuntos
Púrpura Trombocitopênica Idiopática , Benzoatos/uso terapêutico , Criança , Ensaios Clínicos Fase III como Assunto , Humanos , Hidrazinas/uso terapêutico , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
Biomater Sci ; 9(18): 6236-6250, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34365495

RESUMO

A series of modified polysaccharide microparticles have been fabricated and their potential application for scavenging reactive oxygen species (ROS) and their derivatives to achieve osteoarthritis (OA) treatment has been explored. These microparticles were cross-linked dextran (Sephadex) with different carbazate substitution ratios determined by the TNBS assay and elemental analysis. It has been demonstrated that they could effectively scavenge carbonylated proteins and ROS including hydroxyl radicals (˙OH), superoxide anions (˙O2-) and H2O2 and their derivatives with high efficiency, improve the viability of H2O2-treated chondrocytes by reducing their ROS levels, as well as lower their inflammatory factors. The above ability of antioxidation and inflammation resistance improved with the increase of carbazate substitution ratio. Significantly, this work provided the proof that modified Sephadex successfully alleviated the deterioration of cartilage and the progression of OA in vivo. The proposed microparticles showed a very promising capability for reducing ROS levels and further treating OA.


Assuntos
Dextranos , Osteoartrite , Condrócitos , Humanos , Hidrazinas , Peróxido de Hidrogênio , Osteoartrite/tratamento farmacológico , Espécies Reativas de Oxigênio
17.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445782

RESUMO

Spodoptera exigua is a worldwide pest afflicting edible vegetables and has developed varying levels of resistance to insecticides. Methoxyfenozide (MET), an ecdysteroid agonist, is effective against lepidopteran pests such as S. exigua. However, the mechanism of MET to S. exigua remains unclear. In this study, we analyzed the expression patterns of genes related to the ecdysone signaling pathway in transcriptome data treated with sublethal doses of MET and analyzed how expression levels of key genes affect the toxicity of MET on S. exigua. Our results demonstrated that 2639 genes were up-regulated and 2512 genes were down-regulated in S. exigua treated with LC30 of MET. Of these, 15 genes were involved in the ecdysone signaling pathway. qPCR results demonstrated that ecdysone receptor A (EcRA) expression levels significantly increased in S. exigua when treated with different doses of MET, and that the RNAi-mediated silencing of EcRA significantly increased mortality to 55.43% at 72 h when L3 S. exigua larvae were exposed to MET at the LC30 dose. Additionally, knocking down EcRA suppressed the most genes expressed in the ecdysone signaling pathway. The combination of MET and dsEcRA affected the expression of E74 and enhanced the expression of TREA. These results demonstrate that the adverse effects of sublethal MET disturb the ecdysone signaling pathway in S. exigua, and EcRA is closely related to MET toxic effect. This study increases our collective understanding of the mechanisms of MET in insect pests.


Assuntos
Ecdisona/genética , Hidrazinas/farmacologia , Hormônios Juvenis/farmacologia , Interferência de RNA/fisiologia , Transdução de Sinais/efeitos dos fármacos , Spodoptera/efeitos dos fármacos , Transcriptoma/genética , Animais , Perfilação da Expressão Gênica/métodos , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Receptores de Esteroides/genética , Spodoptera/genética
18.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445197

RESUMO

The term "cachexia" is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer.


Assuntos
Caquexia/etiologia , Neoplasias/complicações , Anilidas/uso terapêutico , Animais , Caquexia/diagnóstico , Caquexia/fisiopatologia , Caquexia/terapia , Suplementos Nutricionais , Gerenciamento Clínico , Humanos , Hidrazinas/uso terapêutico , Neoplasias/fisiopatologia , Oligopeptídeos/uso terapêutico
19.
J Enzyme Inhib Med Chem ; 36(1): 1810-1828, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338135

RESUMO

Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hidrazinas/química , Ibuprofeno/química , Indóis/química , Quinazolinonas/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Indóis/síntese química , Indóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodos
20.
J Agric Food Chem ; 69(33): 9557-9570, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382800

RESUMO

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 µg/mL, which were obviously superior to that of boscalid against R. solani (0.94 µg/mL), fluopyram against F. graminearum (9.37 µg/mL), and B. cinerea (1.94 µg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Botrytis , Fungicidas Industriais/farmacologia , Fusarium , Hidrazinas , Simulação de Acoplamento Molecular , Doenças das Plantas , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Rhizoctonia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
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