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1.
Clin Transl Med ; 13(1): e1152, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36588088

RESUMO

BACKGROUND: Gut-brain axis is widely implicated in the pathophysiology of Parkinson's disease (PD). We take an integrated approach to considering the gut as a target for disease-modifying intervention, using continuous measurements of disease facets irrespective of diagnostic divide. METHODS: We characterised 77 participants with diagnosed-PD, 113 without, by dietary/exogenous substance intake, faecal metabolome, intestinal inflammation, serum cytokines/chemokines, clinical phenotype including colonic transit time. Complete-linkage hierarchical cluster analysis of metabolites discriminant for PD-status was performed. RESULTS: Longer colonic transit was linked to deficits in faecal short-chain-fatty acids outside PD, to a 'tryptophan-containing metabolite cluster' overall. Phenotypic cluster analysis aggregated colonic transit with brady/hypokinesia, tremor, sleep disorder and dysosmia, each individually associated with tryptophan-cluster deficit. Overall, a faster pulse was associated with deficits in a metabolite cluster including benzoic acid and an imidazole-ring compound (anti-fungals) and vitamin B3 (anti-inflammatory) and with higher serum CCL20 (chemotactic for lymphocytes/dendritic cells towards mucosal epithelium). The faster pulse in PD was irrespective of postural hypotension. The benzoic acid-cluster deficit was linked to (well-recognised) lower caffeine and alcohol intakes, tryptophan-cluster deficit to higher maltose intake. Free-sugar intake was increased in PD, maltose intake being 63% higher (p = .001). Faecal calprotectin was 44% (95% CI 5%, 98%) greater in PD [p = .001, adjusted for proton-pump inhibitors (p = .001)], with 16% of PD-probands exceeding a cut-point for clinically significant inflammation compatible with inflammatory bowel disease. Higher maltose intake was associated with exceeding this calprotectin cut-point. CONCLUSIONS: Emerging picture is of (i) clinical phenotype being described by deficits in microbial metabolites essential to gut health; (ii) intestinal inflammation; (iii) a systemic inflammatory response syndrome.


Assuntos
Doença de Parkinson , Humanos , Triptofano , Maltose , Inflamação , Dieta , Complexo Antígeno L1 Leucocitário/análise , Benzoatos
2.
Am J Cardiovasc Drugs ; 23(1): 101-112, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36622539

RESUMO

BACKGROUND: Tecarfarin (ATI-5923), a structural analog of warfarin, was designed to provide more uniform and stable anticoagulation. OBJECTIVE: We aimed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tecarfarin when administered in multiple ascending doses (MADs) to healthy Chinese volunteers. METHODS: Forty healthy Chinese volunteers were enrolled into four sequential cohorts (10, 20, 30, and 40 mg), with 10 subjects in each cohort. Participants in the MAD study for each sequential cohort were dose-titrated to achieve the target international normalized ratio (INR 1.7-2.0) for 14 days. Safety and tolerability were assessed throughout the study. RESULTS: The pharmacokinetic and pharmacodynamic profile of tecarfarin was investigated in a healthy Chinese population. Dose titration of tecarfarin was necessary to keep the INR in the target range in all subjects in the 20, 30 and 40 mg cohorts and a few subjects (n = 3) in the 10 mg cohort. Tecarfarin was well tolerated without serious adverse events. Only one treatment-related adverse event (hematochezia) resulted in early withdrawal from the MAD 40 mg cohort. CONCLUSION: Tecarfarin was well-tolerated by Chinese volunteers. Dose titration was needed for tecarfarin doses larger than 20 mg to keep the INR in the target range. REGISTRATION: ClinicalTrials.gov identifier: NCT04627116.


Assuntos
Varfarina , Humanos , Varfarina/efeitos adversos , Benzoatos/efeitos adversos , Benzoatos/farmacocinética , Cumarínicos/efeitos adversos , Cumarínicos/farmacocinética , Voluntários Saudáveis , Método Duplo-Cego , Relação Dose-Resposta a Droga
3.
Nitric Oxide ; 131: 18-25, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36565741

RESUMO

Low basal nitric oxide (NO) production is associated with a dysfunctional endothelium and vascular diseases. We have shown that some angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs), a group of clinic-approved blood pressure (BP)-lowering medications, are also capable of activating endothelial function acutely and chronically, both ex vivo and in vivo, in pleiotropic, AngII-independent fashions, which suggested that endothelial function enhancement with ARBs may be independent of their well-documented BP lowering properties. Herein, we attempt to identify the most potent ARB at activating endothelial function when administered at sub-BP-lowering doses and determine its anti-aortic root remodeling properties in a model of Marfan syndrome (MFS). Amongst the 8 clinically available ARBs tested, only telmisartan and azilsartan induced significant (70% and 49%, respectively) NO-dependent inhibition of aortic contractility when administered for 4 weeks at sub-BP lowering, EC5 doses. Low-dose telmisartan (0.47 mg/kg) attenuated MFS-associated aortic root widening, medial thickening, and elastic fiber fragmentation to the same degree as high-dose telmisartan (10 mg/kg) despite wide differences in BP lowering between the two doses. Our study suggests that telmisartan is the most potent ARB at promoting increased endothelial function at low sub-BP doses and that it retained major aortic root widening inhibition activities. ARBs may enhance endothelial function independently from BP-lowering pathways, which could lead to new therapeutic approaches.


Assuntos
Hipertensão , Síndrome de Marfan , Humanos , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Pressão Sanguínea , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Endotélio , Benzoatos/farmacologia , Hipertensão/tratamento farmacológico
4.
Orphanet J Rare Dis ; 17(1): 423, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36471344

RESUMO

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.


Assuntos
Dieta Cetogênica , Hiperglicinemia não Cetótica , Lactente , Humanos , Hiperglicinemia não Cetótica/tratamento farmacológico , Hiperglicinemia não Cetótica/diagnóstico , Glicina/uso terapêutico , Glicina/metabolismo , Encéfalo/metabolismo , Benzoatos/metabolismo , Benzoatos/uso terapêutico
5.
Chin Med J (Engl) ; 135(19): 2344-2350, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36535011

RESUMO

BACKGROUND: Recombinant human thrombopoietin (rh-TPO) and eltrombopag are two distinct TPO receptor agonists (TPO-RAs) with different mechanisms. During the pandemic, when immunosuppressive medications are controversial, switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA. We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia (ITP) patients. METHODS: This prospective, open-label, observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People's Hospital in China. The study evaluated response rates and platelet counts at different time points after the switch, bleeding events, time to response, duration of response, and adverse events. RESULTS: At 6 weeks after switching, response was observed in 21/49 patients (43%) who switched for inefficacy and 34/47 patients (72%) who switched for non-efficacy-related issues. In the inefficacy group, 9/27 patients (33%) responded to eltrombopag, and 12/22 patients (55%) responded to rh-TPO. In the non-efficacy-related group, 21/26 (81%) and 13/21 (62%) patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching, respectively. Response at 6 months was achieved in 24/49 patients (49%) switching for inefficacy and 37/47 patients (79%) switching for non-efficacy issues. In the inefficacy group, 13/27 patients (48%) responded to eltrombopag, and 11/22 patients (50%) responded to rh-TPO. In the non-efficacy-related group, 22/26 patients (85%) and 15/21 patients (71%) in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching, respectively. Both eltrombopag and rh-TPO were well tolerated. CONCLUSIONS: Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA. When the switch was motivated by other reasons, including patient preference and platelet count fluctuations, the probability of response was high. REGISTRATION: ClinicalTrials.gov, NCT04214951.


Assuntos
Benzoatos , Substituição de Medicamentos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Humanos , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Estudos Prospectivos , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Proteínas Recombinantes/uso terapêutico
6.
Hematology Am Soc Hematol Educ Program ; 2022(1): 286-295, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36485134

RESUMO

Chemotherapy-induced thrombocytopenia (CIT) is common, resulting in increased bleeding risk and chemotherapy delays, dose reduction, and treatment discontinuation, which can negatively affect oncologic outcomes. The only agent approved by the US Food and Drug Administration to manage CIT (oprelvekin) was voluntarily withdrawn from the market by the manufacturer, leaving few options for patients. Therefore, patients experiencing CIT present a significant clinical challenge in daily practice. The availability of thrombopoietin receptor agonists has led to formal clinical trials describing efficacy in CIT as well as a rather extensive body of published observational data from off-label use in this setting but no formal regulatory indications for CIT to date. The accumulated data, however, have affected National Comprehensive Cancer Network guidelines, which now recommend consideration of TPO-RA clinical trials as well as off-label use of romiplostim. This review article details the evidence to date for the management of CIT with thrombopoietin receptor agonists (TPO-RAs), discussing the efficacy data, the specific circumstances when treatment is warranted (and when it is generally unnecessary), and safety considerations. Specific recommendations regarding patient selection, initiation, dosing, titration, and discontinuation for TPO-RA therapy in CIT are given, based on published data and expert opinion where evidence is lacking.


Assuntos
Antineoplásicos , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Receptores de Trombopoetina/agonistas , Trombopoetina/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Antineoplásicos/efeitos adversos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Hidrazinas/uso terapêutico , Benzoatos/uso terapêutico
7.
Molecules ; 27(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36500598

RESUMO

A series of phenylsilsesquioxane-benzoate heptacopper complexes 1-3 were synthesized and characterized by X-ray crystallography. Two parallel routes of toluene spontaneous oxidation (into benzyl alcohol and benzoate) assisted the formation of the cagelike structure 1. A unique multi-ligation of copper ions (from (i) silsesquioxane, (ii) benzoate, (iii) benzyl alcohol, (iv) pyridine, (v) dimethyl-formamide and (vi) water ligands) was found in 1. Directed self-assembly using benzoic acid as a reactant afforded complexes 2-3 with the same main structural features as for 1, namely heptanuclear core coordinated by (i) two distorted pentameric cyclic silsesquioxane and (ii) four benzoate ligands, but featuring other solvate surroundings. Complex 3 was evaluated as a catalyst for the oxidation of alkanes to alkyl hydroperoxides and alcohols to ketones with hydrogen peroxide and tert-butyl hydroperoxide, respectively, at 50 °C in acetonitrile. The maximum yield of cyclohexane oxidation products as high as 32% was attained. The oxidation reaction results in a mixture of cyclohexyl hydroperoxide, cyclohexanol, and cyclohexanone. Upon the addition of triphenylphosphine, the cyclohexyl hydroperoxide is completely converted to cyclohexanol. The specific regio- and chemoselectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicate the involvement of of hydroxyl radicals. Complex 3 exhibits a high activity in the oxidation of alcohols.


Assuntos
Benzoatos , Peróxido de Hidrogênio , Peróxido de Hidrogênio/química , Catálise , Cobre/química , Oxirredução , Ligantes , Cristalografia por Raios X , Álcoois Benzílicos
8.
J Int Med Res ; 50(12): 3000605221143290, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36562113

RESUMO

OBJECTIVES: To examine the efficacy of deferasirox (DFX) by comparison with deferoxamine (DFO) in managing iron overload in patients with sickle cell anaemia (SCA). METHODS: Online databases were systematically searched for studies published from January 2007 to July 2022 that had investigated the efficacy of DFX compared with DFO in managing iron overload in patients with SCA. RESULTS: Of the 316 articles identified, three randomized clinical trials met the inclusion criteria. Meta-analysis of liver tissue iron concentration (LIC) showed that iron overload was not significantly higher in the DFX group compared with DFO group (WMD, -1.61 mg Fe/g dw (95% CI -4.42 to 1.21). However, iron overload as measured by serum ferritin was significantly lower in DFO compared with DFX group (WMD, 278.13 µg/l (95% CI 36.69 to 519.57). Although meta-analysis was not performed on myocardial iron concentration due to incomplete data, the original report found no significant difference between DFX and DFO. CONCLUSION: While limited by the number of studies included in this meta-analysis, overall, the results tend to show that DFX was as effective as DFO in managing iron overload in patients with SCA.


Assuntos
Anemia Falciforme , Sobrecarga de Ferro , Humanos , Deferasirox/uso terapêutico , Desferroxamina/uso terapêutico , Quelantes de Ferro/uso terapêutico , Benzoatos/uso terapêutico , Triazóis/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Ferro , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico
9.
Molecules ; 27(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36364037

RESUMO

Based on the previously reported involvement of homophthalic acid monoesters in the Castagnoli-Cushman reaction-type cyclocondensation with imines, we tested a number of other o-methyl benzoic acids bearing various electron-withdrawing groups in the α-position. The majority of these substrates delivered the expected tetrahydroisoquinolone adducts on activation with CDI or acetic anhydride. Homophthalic acid mononitriles displayed the highest promise as substrates for the new reaction, both in terms of scope and product yields. Homophthalic acid monoamides either gave low yields or failed to react with imines. Sulfonyl-substituted substrates gave the desired (and hitherto unknown) type of tetrahydroisoquinolines. Despite the low yields, this approach to sulfonyl-substituted tetrahydroisoquinolines appears practical as alternative syntheses based on the traditional, carboxylic acid CCR adducts would presumably be cumbersome and multistep. The azido- and nitro-substituted o-methyl benzoic acids failed to react with imines.


Assuntos
Elétrons , Tetra-Hidroisoquinolinas , Benzoatos , Iminas
10.
Arch Microbiol ; 204(11): 686, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319767

RESUMO

The present study aims to screen the anti-bacterial activity and synergistic interaction of A. graecorum Boiss. ethanolic extract with two food preservatives against five strains of foodborne bacteria. Disk diffusion and minimum inhibitory concentration were used for anti-bacterial assay, checkerboard assay and time-kill curve were used for the combination studies. HPLC analysis and molecular docking study were performed to corroborate the in vitro results. The ethanolic extract showed anti-bacterial activity against all tested bacterial strains with inhibition zones from 7.5 to 9.3 mm and MIC values ranged between 1.2 and 1.8 mg mL-1. The combination of the ethanolic extract with Na-benzoate or Na-propionate resulted in synergistic and additive interactions against the tested bacteria with fractional inhibitory concentration index (FICI) ranges 0.31-0.63 and no antagonism was shown. Time-kill curve assay showed that the synergistic and additive combinations have inhibitory effects on the tested strains. The ethanolic extract combination with Na-benzoate or Na-propionate can be used for development new sources of food preservatives. Testing new different natural plant extracts with food preservatives will help develop new anti-bacterial agents.


Assuntos
Fabaceae , Conservantes de Alimentos , Conservantes de Alimentos/farmacologia , Propionatos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Etanol , Bactérias , Benzoatos/farmacologia
11.
Life Sci ; 311(Pt B): 121161, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36375571

RESUMO

We have previously reported the inhibition of thioredoxin reductase (TrxR) and invasion by tricyclohexylphosphine gold (I) n-mercaptobenzoate (n = 2, 3, 4) labeled as 1-3 towards MCF-7 cells, in vitro. Nevertheless, the mode of death and its apoptotic pathway has yet to be revealed. The main aim of this study is to investigate the anti-neoplastic activity of this phosphanegold (I) thiolates against breast adenocarcinoma cells, MCF-7. Herein, we explored the role of gold(I) series, 1-3 for their apoptosis-inducing ability against MCF-7 cells. They were scrutinized for their antiproliferative activities which exhibited their IC50 values of 8.14 µM ± 0.10, 7.26 µM ± 0.33, and 9.03 µM ± 0.69, respectively, and indicated better cytotoxicities than that of cisplatin (positive control). Further, the mechanisms of their actions were studied by analyzing the status of ROS generation (by DCFH-DA), cytochrome c release (by ELISA), and activation of caspases 3/7, 8, 9, and 10, annexin V staining and cell cycle analysis by flow cytometry, respectively. It was observed that the compounds, 1-3 can promote ROS generation, cytochrome c release, and activation of caspases 3/7, caspase 8, caspase 9, and caspase 10 on MCF-7 cells. In addition, the compounds are shown to induce MCF-7 cell arrest at S-phase. Gene analysis via PCR array further clarified their effects by modulating the related genes upon the compounds' treatment. Further investigation on other breast cancer cells as well as in vivo studies on these compounds will further increase their potential as anti-breast cancer agents.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias da Mama/patologia , Citocromos c/metabolismo , Ouro/farmacologia , Ouro/uso terapêutico , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/farmacologia , Benzoatos/farmacologia , Pontos de Checagem do Ciclo Celular , Fosfinas/farmacologia
12.
Sci Rep ; 12(1): 18655, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333403

RESUMO

N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), a widely used labeling agent to introduce the 4-[18F]fluorobenzoyl-prosthetic group, is normally obtained in three consecutive steps from [18F]fluoride ion. Here, we describe an efficient one-step labeling procedure of [18F]SFB starting from a tin precursor. This method circumvents volatile radioactive side-products and simplifies automatization. [18F]SFB was obtained after HPLC purification in a yield of 42 + 4% and a radiochemical purity (RCP) > 99% (n = 6). In addition, we investigate the automation of the coupling of [18F]SFB to a nanobody (cAbBcII10, targeting ß-lactamase enzyme) and purification by size exclusion chromatography (PD-10 desalting column) to remove unconjugated reagent. Production and use of [18F]SFB were implemented on a radiosynthesis unit (Neptis®). The fully automated radiosynthesis process including purification and formulation required 160 min of synthesis time. [18F]SFB-labeled nanobody was obtained in a yield of 21 + 2% (activity yield 12 + 1% non-decay corrected) and a radiochemical purity (RCP) of > 95% (n = 3). This approach simplifies [18F]SFB synthesis to one-step, enhances the yield in comparison to the previous report and enables the production of radiolabeled nanobody on the same synthesis module.


Assuntos
Radioisótopos de Flúor , Anticorpos de Domínio Único , Radioisótopos de Flúor/química , Halogenação , Marcação por Isótopo/métodos , Succinimidas/química , Fluoretos , Benzoatos/química , Compostos Radiofarmacêuticos/química , Tomografia por Emissão de Pósitrons/métodos
13.
Protein Sci ; 31(12): e4499, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36335585

RESUMO

As a key regulator for hormone activity, human aldo-keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone-dependent or independent malignancies. It is a promising target for treating castration-resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000-fold anti-AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end-point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely "Inward" and "Outward," of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an "Inward" to an "Outward" state. Further 3D-QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next-generation AKR1C3 inhibitors with enhanced efficacy and reduced "off-target" effect for CRPC therapy.


Assuntos
Hidroxiprostaglandina Desidrogenases , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Hidroxiprostaglandina Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Benzoatos/química , Simulação por Computador , Isoformas de Proteínas , Hormônios
14.
Nat Commun ; 13(1): 7378, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36450720

RESUMO

Real time monitoring of chirality transfer processes is necessary to better understand their kinetic properties. Herein, we monitor an ideal chirality transfer process from a statistically random distribution to a diastereomerically pure assembly in real time. The chirality transfer is based on discrete trimeric tubular assemblies of planar chiral pillar[5]arenes, achieving the construction of diastereomerically pure trimers of pillar[5]arenes through synergistic effect of ion pairing between a racemic rim-differentiated pillar[5]arene pentaacid bearing five benzoic acids on one rim and five alkyl chains on the other, and an optically resolved pillar[5]arene decaamine bearing ten amines. When the decaamine is mixed with the pentaacid, the decaamine is sandwiched by two pentaacids through ten ion pairs, initially producing a statistically random mixture of a homochiral trimer and two heterochiral trimers. The heterochiral trimers gradually dissociate and reassemble into the homochiral trimers after unit flipping of the pentaacid, leading to chirality transfer from the decaamine and producing diastereomerically pure trimers.


Assuntos
Gastrópodes , Nanotubos , Animais , Aminas , Benzoatos , Alimentos
15.
Molecules ; 27(22)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36431954

RESUMO

Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of ß-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer's disease.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Animais , Doença de Alzheimer/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Modelos Animais de Doenças , Placa Amiloide , Uracila/farmacologia , Uracila/uso terapêutico , Benzoatos
16.
Front Public Health ; 10: 1000833, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36249223

RESUMO

Psychological problems affect a sizable portion of the population, and they require special care. In the current study, we aimed to assess patient satisfaction with the healthcare system at one of the multispecialty hospitals in Riyadh, Saudi Arabia, as well as to identify potential factors that can have an impact on patient satisfaction. A validated pre-tested questionnaire including features to evaluate general hospital services (HS-6 items), nursing services (NS-3 items), pharmacy services (PS-7 items), and a standard patient satisfaction questionnaire (PSQ-18 item) was administered to patients who had been receiving therapy for their psychological disease for the past 3 months. Using binary and multiple regression analysis, the strengths of the associations between sociodemographic factors and patient satisfaction measures were evaluated. The results were expressed as adjusted odds ratios (AOR), which were deemed significant when the P value was < 0.05. Sixty-six percent of the 258 study participants were men, and sixty percent of them were between the ages of 18 and 35 years. The bulk of survey respondents (74%) were employed, married, and well-educated. Our research revealed that those who were employed (AOR, HS-2.5; NS-2.65, PS-2.32), have a higher education (AOR, HS-2.23, NS-2.63, PS-2.82), male gender (AOR, HS-1.12, NS-1.08, PS-1.86) and between the ages of 18 and 35 years (AOR, HS-1.48, NS-1.53, PS-1.67) were more likely to be satisfied with general hospital, nursing, and pharmacy services. Further, those who were married had 1.43 and 1.21 times more chance of satisfaction with the pharmacy and nursing services, respectively, compared to singles. Additionally, those with employment had odds of being satisfied that were 2.4 times higher, highly educated individuals had odds that were 2.1 times higher, participants between the ages of 18 and 35 had odds that were 1.51 times higher, and men had odds that were 1.41 times higher on the patient satisfaction questionnaire scale (PSQ-18). Overall, the study participants' satisfaction with general hospital, nursing, and pharmacy services was 70, 76.3, and 83.3%, respectively, compared to only 61.2% on the PSQ-18. Participants in the survey awarded the hospital amenities, pharmacy services, and nursing care high ratings. The medical care, however, fell short of expectations. The study's findings suggest that action needs to be taken to enhance healthcare system services, particularly in the psychological departments of the medical organization.


Assuntos
Satisfação do Paciente , Satisfação Pessoal , Adolescente , Adulto , Benzoatos , Estudos Transversais , Feminino , Humanos , Masculino , Arábia Saudita , Adulto Jovem
17.
Org Lett ; 24(43): 7978-7982, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36268999

RESUMO

We report a new anionic cascade for assembling 2,4-substituted benzoate esters in one pot from racemic ß-fluoro-substituted conjugated tert-butylsulfinyl imines and 3-substituted methyl 2-butenoates. Dienolate formation triggers a Mannich addition followed by an amino-Cope like rearrangement, which results in immediate elimination of fluoride by a lithiated enamine. The newly formed 1,4-diene intermediate contains a highly acidic proton which is spontaneously deprotonated, leading to a facile intramolecular cyclization followed by sulfinamide group elimination and aromatization.


Assuntos
Benzoatos , Ésteres , Estereoisomerismo , Ciclização , Iminas , Ânions
18.
PLoS One ; 17(10): e0275775, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251636

RESUMO

Hearing loss (HL) is a global health problem with a high prevalence and profound socioeconomic impact. Pyrethroids are one of the most commonly used insecticides. Although previous studies have reported the relationship between pyrethroids and neurotoxicity, little is known about the effect of pyrethroid exposure on the auditory system among the general population. This study is aimed to investigate the association of pyrethroid exposure with hearing threshold shifts of adults in the United States. A total of 726 adults, aged from 20 to 69 years from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) data were included in the study. Urinary 3-phenoxybenzoic acid (3-PBA), a general pyrethroid metabolite, was used as a biomarker for pyrethroid exposure. HL was defined as a pure-tone average (PTA) at 0.5, 1, 2, 4 kHz ≥ 20 dB in the better ear. Analyses by using multivariate linear regressions were conducted to explore the associations of urinary 3-PBA with PTA hearing threshold shifts. There were no statistically significant correlations between Ln-transformed 3-PBA and either low-frequency or high-frequency hearing thresholds after adjusting for age, gender, race/ethnicity, education level, firearm noise exposure, occupational noise exposure, recreational noise exposure, serum cotinine, BMI, hypertension, and diabetes. However, associations of 3-PBA with both low-frequency and high-frequency hearing thresholds depended on age (P interaction < 0.0396 and 0.0017, respectively). Positive associations between Ln-transformed 3-PBA and both low-frequency and high-frequency hearing thresholds were observed in participants aged 20-39 years after adjusting confounders (ß = 1.53, 95% CI: 0.04-3.01, and ß = 3.14, 95% CI: 0.99-5.29, respectively) with the highest tertile (≥ 0.884 µg/g creatinine) of 3-PBA compared with the lowest tertile (< 0.407 µg/g creatinine). The possibility of interaction between 3-PBA and age on the hearing threshold shifts indicated that pyrethroid insecticides were prone to be more toxic to auditory system in younger adults than in older ones. Further studies will be required to confirm these findings.


Assuntos
Perda Auditiva , Inseticidas , Piretrinas , Adulto , Idoso , Benzoatos , Cotinina , Creatinina , Estudos Transversais , Audição , Perda Auditiva/induzido quimicamente , Perda Auditiva/epidemiologia , Humanos , Inseticidas/toxicidade , Inquéritos Nutricionais , Piretrinas/toxicidade , Estados Unidos/epidemiologia
19.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232858

RESUMO

Several semisynthetic, low-cardiotoxicity doxorubicin (DOXO) conjugated have been extensively described, considering the risk of cytotoxicity loss against resistant tumor cells, which mainly present drug efflux capacity. Doxorubicin 14-[4-(4-phenyl-5-thioxo-5H-[1,2]dithiol-3-yl)]-benzoate (H2S-DOXO) was synthetized and tested for its ability to overcome drug resistance with good intracellular accumulation. In this paper, we present a formulation study aimed to develop naked and decorated H2S-DOXO-loaded lipid nanoparticles (NPs). NPs prepared by the "cold dilution of microemulsion" method were decorated with hyaluronic acid (HA) to obtain active targeting and characterized for their physicochemical properties, drug entrapment efficiency, long-term stability, and in vitro drug release. Best formulations were tested in vitro on human-sensitive (MCF7) and human/mouse DOXO-resistant (MDA-MDB -231 and JC) breast cancer cells, on human (U-2OS) osteosarcoma cells and DOXO-resistant human/mouse osteosarcoma cells (U-2OS/DX580/K7M2). HA-decoration by HA-cetyltrimethyl ammonium bromide electrostatic interaction on NPs surface was confirmed by Zeta potential and elemental analysis at TEM. NPs had mean diameters lower than 300 nm, 70% H2S-DOXO entrapment efficiency, and were stable for almost 28 days. HA-decorated NPs accumulated H2S-DOXO in Pgp-expressing cells reducing cell viability. HA-decorated NPs result in the best formulation to increase the inter-cellular H2S-DOXO delivery and kill resistant cells, and therefore, as a future perspective, they will be taken into account for further in vivo experiments on tumor animal model.


Assuntos
Neoplasias Ósseas , Nanopartículas , Osteossarcoma , Animais , Benzoatos , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Ácido Hialurônico/química , Lipossomos , Camundongos , Nanopartículas/química , Osteossarcoma/patologia
20.
Eur J Med Chem ; 244: 114818, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36223680

RESUMO

The epigenetic regulator lysine specific demethylase 1 (LSD1), a MYCN cofactor, cooperatively silences MYCN suppressor genes. Furthermore, LSD1 has been correlated with adverse effects in neuroblastic tumors by propagating an undifferentiated, malignant phenotype. We observed that high LSD1 mRNA expression in MYCN-expressing neuroblastoma (NB) correlated with poor prognosis, implicating LSD1 as an oncogenic accomplice in high-grade NB. Thus, LSD1 inhibition is a potential strategy for targeting treatment-resistant MYCN-expressing NB. Tranylcypromine-based covalent LSD1 inhibitors have demonstrated anti-tumor activity but are associated with undesirable off-target effects, such that only 2 non-covalent LSD1 inhibitors are in clinical trials. We now report 3 novel scaffolds for reversible LSD1 inhibition: 2-(arylsulfonamido)benzoic acid, N-(2-(1H-tetrazol-5-yl)phenyl)benzenesulfonamide and 2-(arylcarboxamido)benzoic acid analogues. The most active of these analogues, compound 48, exhibited potent and selective mixed reversible inhibition of LSD1 (IC50 = 0.58 µM) and significantly increased global H3K4me2 in NB cells. In addition, combination treatment with 48 and bortezomib in NB cells results in a synergistic effect.


Assuntos
Histona Desmetilases , Neuroblastoma , Humanos , Linhagem Celular Tumoral , Histona Desmetilases/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Benzoatos/farmacologia , Benzoatos/uso terapêutico
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