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2.
Analyst ; 146(20): 6139-6144, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34486602

RESUMO

Serum copper levels are biomarkers for copper-related diseases. Quantification of levels of free copper (not bound to proteins) in serum is important for diagnosing Wilson's disease, in which the free copper concentration is elevated. Bioluminescence is commonly used in point-of-care diagnostics, but these assays require genetically engineered luciferase. Here, we developed a luciferase-independent copper detection platform. A luminogenic caged coelenterazine analogue (TPA-H1) was designed and synthesized to detect copper ions in human serum. TPA-H1 was developed by introducing a tris[(2-pyridyl)-methyl]amine (TPA) ligand, which is a Cu+ cleavable caging group, to the carbonyl group at the C-3 position of the imidazopyrazinone scaffold. The luciferin, named HuLumino1, is the product of the cleavage reaction of TPA-H1 with a copper ion and displays "turn-on" bioluminescence signals specifically with human serum albumin, which can be used to quantitatively analyse copper ions. TPA-H1 exhibited a fast cleavage of the protective group, high specificity, and high sensitivity for copper over other metal ions. This novel caged coelenterazine derivative, TPA-H1, can detect free copper ions in serum in a simple "mix-and-read" manner.


Assuntos
Cobre , Imidazóis , Humanos , Luciferases , Pirazinas
3.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361765

RESUMO

In this study, the aroma profile of 10 single origin Arabica coffees originating from eight different growing locations, from Central America to Indonesia, was analyzed using Headspace SPME-GC-MS as the analytical method. Their roasting was performed under temperature-time conditions, customized for each sample to reach specific sensory brew characteristics in an attempt to underline the customization of roast profiles and implementation of separate roastings followed by subsequent blending as a means to tailor cup quality. A total of 138 volatile compounds were identified in all coffee samples, mainly furan (~24-41%) and pyrazine (~25-39%) derivatives, many of which are recognized as coffee key odorants, while the main formation mechanism was the Maillard reaction. Volatile compounds' composition data were also chemometrically processed using the HCA Heatmap, PCA and HCA aiming to explore if they meet the expected aroma quality attributes and if they can be an indicator of coffee origin. The desired brew characteristics of the samples were satisfactorily captured from the volatile compounds formed, contributing to the aroma potential of each sample. Furthermore, the volatile compounds presented a strong variation with the applied roasting conditions, meaning lighter roasted samples were efficiently differentiated from darker roasted samples, while roasting degree exceeded the geographical origin of the coffee. The coffee samples were distinguished into two groups, with the first two PCs accounting for 73.66% of the total variation, attributed mainly to the presence of higher quantities of furans and pyrazines, as well as to other chemical classes (e.g., dihydrofuranone and phenol derivatives), while HCA confirmed the above results rendering roasting conditions as the underlying criterion for differentiation.


Assuntos
Coffea/química , Café/química , Furanos/química , Odorantes/análise , Pirazinas/química , Compostos Orgânicos Voláteis/química , América Central , Coffea/metabolismo , Café/metabolismo , Etiópia , Furanos/classificação , Furanos/isolamento & purificação , Furanos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Temperatura Alta , Humanos , Indonésia , Reação de Maillard , Análise de Componente Principal , Pirazinas/classificação , Pirazinas/isolamento & purificação , Pirazinas/metabolismo , Sementes/química , Paladar/fisiologia , Compostos Orgânicos Voláteis/classificação , Compostos Orgânicos Voláteis/isolamento & purificação , Compostos Orgânicos Voláteis/metabolismo
4.
Int Immunopharmacol ; 99: 108043, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34426105

RESUMO

BACKGROUND: Regarding the COVID-19 pandemic, potential therapeutic agents are being evaluated almost every day. Ciclosporin, a calcineurin inhibitor, is characterized by beneficial antiviral and immunomodulatory effects. The present study aimed to evaluate the efficacy of ciclosporin in managing COVID-19. METHODS: This study was a prospective non-controlled clinical trial carried out on 20 patients. Confirmed COVID-19 patients received two doses of ciclosporin (10 mg/kg and 5 mg/kg injections) 24 h apart. Mortality rate and the lengths of intensive care unit (ICU) and hospital stays were assessed for all 20 patients. RESULTS: The mortality rate and the need for mechanical ventilation were calculated as 50%. The percentage of ICU admission was 70%. The lengths of ICU and hospital stays were 8.13 ± 6.81 and 14.25 ± 8.55 days, respectively. The levels of ferritin and white blood cells were significantly higher after injecting the second dose of ciclosporin. Seven patients (35%) had radiologically improved lungs after ciclosporin therapy. CONCLUSION: It seems that the protocol of two doses of ciclosporin in combination with favipiravir does not have favorable effects among COVID-19 patients that do not respond to dexamethasone. Controlled trials are needed to confirm the results.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ciclosporina/uso terapêutico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dexametasona/uso terapêutico , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Prospectivos , Respiração Artificial , SARS-CoV-2 , Resultado do Tratamento , Adulto Jovem
5.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443411

RESUMO

Several novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C-N Buchwald-Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure-activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI50 ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI50 values. The effects of the methoxylated compounds 2b (2-OMeC6H4), 2f and 2g (3,4- or 3,5-diOMeC6H3, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI50 = 7.8 µM) and selective compound (2g) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Pontos de Checagem do Ciclo Celular , Pirazinas/síntese química , Pirazinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pirazinas/química
6.
Viruses ; 13(7)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34372559

RESUMO

The human BK polyomavirus (BKPyV) is latent in the kidneys of most adults, but can be reactivated in immunosuppressed states, such as following renal transplantation. If left unchecked, BK polyomavirus nephropathy (PyVAN) and possible graft loss may result from viral destruction of tubular epithelial cells and interstitial fibrosis. When coupled with regular post-transplant screening, immunosuppression reduction has been effective in limiting BKPyV viremia and the development of PyVAN. Antiviral drugs that are safe and effective in combating BKPyV have not been identified but would be a benefit in complementing or replacing immunosuppression reduction. The present study explores inhibition of the host DNA damage response (DDR) as an antiviral strategy. Immunohistochemical and immunofluorescent analyses of PyVAN biopsies provide evidence for stimulation of a DDR in vivo. DDR pathways were also stimulated in vitro following BKPyV infection of low-passage human renal proximal tubule epithelial cells. The role of Chk1, a protein kinase known to be involved in the replication stress-induced DDR, was examined by inhibition with the small molecule LY2603618 and by siRNA-mediated knockdown. Inhibition of Chk1 resulted in decreased replication of BKPyV DNA and viral spread. Activation of mitotic pathways was associated with the reduction in BKPyV replication. Chk1 inhibitors that are found to be safe and effective in clinical trials for cancer should also be evaluated for antiviral activity against BKPyV.


Assuntos
Vírus BK/genética , Quinase 1 do Ponto de Checagem/metabolismo , Infecções por Polyomavirus/tratamento farmacológico , Vírus BK/patogenicidade , Células Cultivadas , Quinase 1 do Ponto de Checagem/fisiologia , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Humanos , Rim/patologia , Rim/virologia , Transplante de Rim , Compostos de Fenilureia/farmacologia , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/imunologia , Pirazinas/farmacologia , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/genética , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologia
7.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360605

RESUMO

Piezo1/2 are mechanosensitive calcium-permeable channels that can be activated by various modes of membrane deformation. The identification of the small molecule Yoda1, a synthetic Piezo1 agonist, revealed the possibility of chemical activation of the channel. Stimulating effects of Yoda1 on Piezo1 have been mainly documented using over-expressing cellular systems or channel proteins incorporated in artificial lipid bilayers. However, the activating effect of Yoda1 on native Piezo1 channels in the plasma membrane of living cells remains generally undefined, despite the increasing number of studies in which the agonist is utilized as a functional tool to reveal the contribution of Piezo1 to cellular reactions. In the current study, we used the human myeloid leukemia K562 cell line as a suitable model to examine chemically induced Piezo1 activity with the use of the patch-clamp technique in various specific modes. The functional expression of Piezo1 in leukemia cells was evidenced using a combinative approach, including single channel patch-clamp measurements. Utilizing our established single-current whole-cell assay on K562 cells, we have shown, for the first time, the selective real-time chemical activation of endogenously expressed Piezo1. Extracellular application of 0.5-1 µM Yoda1 effectively stimulated single Piezo1 currents in the cell membrane.


Assuntos
Membrana Celular/metabolismo , Canais Iônicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Mecanotransdução Celular , Pirazinas/farmacologia , Análise de Célula Única/métodos , Tiadiazóis/farmacologia , Membrana Celular/efeitos dos fármacos , Humanos , Canais Iônicos/agonistas , Canais Iônicos/metabolismo , Leucemia/metabolismo , Leucemia/patologia
8.
Mol Syst Biol ; 17(8): e10239, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34339582

RESUMO

Understanding the mechanism of SARS-CoV-2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID-19. These were deduced from the gene expression signature of SARS-CoV-2-infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral-host interactome. We also identified immuno-modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID-19 patients, based on the transcriptome of ACE2-overexpressing A549 cells. Experiments with Vero-E6 cells infected by SARS-CoV-2, as well as independent syncytia formation assays for probing ACE2/SARS-CoV-2 spike protein-mediated cell fusion using HEK293T and Calu-3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero-E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID-19.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , COVID-19/genética , COVID-19/virologia , Chlorocebus aethiops , Reposicionamento de Medicamentos , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imidazóis/farmacologia , Pirazinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Xinafoato de Salmeterol/farmacologia , Células Vero
9.
Talanta ; 234: 122629, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364438

RESUMO

Two reversed-phase HPLC methods for molecular analysis of dissolved free monosaccharides in seawater were investigated comparatively by optimizing chromatographic separations and pre-column derivatization reactions. Monosaccharides derivatized with 2-amino benzamide or 2-amino pyrazine, and reduced with 2-picoline borane or 2-dimethylamino borane. According to results of optimization, separation performance, and detection limits, 2-amino benzamide method gave better results than 2-amino pyrazine method. Among 12 monosaccharides tested, it was possible to quantify glucose + galactose, galacturonic acid, glucuronic acid, xylose + arabinose, ribose, mannose, and N-acetyl-d-glucosamine with detection limits between 1.2 and 11 nM with intra-day repeatability of 2-9% and inter-day repeatability of 3-9%. The optimized method has the same level of detection limit with a widely used anion exchange chromatography method. Besides the preliminary results reported in this study, it may be possible to achieve higher sensitivity and to detect more monosaccharides by the use of shorter and narrow-bore columns at different polarities in further studies.


Assuntos
Monossacarídeos , Pirazinas , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Água do Mar
11.
Biomolecules ; 11(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34439805

RESUMO

Three novel 2-aminopyrazine Schiff bases derived from salicylaldehyde derivatives and their uranyl complexes were synthesized and characterized by elemental analysis, UV-vis, FTIR, molar conductance, and thermal gravimetric analysis (TGA). The proposed structures were optimized using density functional theory (DFT/B3LYP) and 6-311G ∗(d,p) basis sets. All uranyl complexes are soluble in DMSO and have low molar conductance, which indicates that all the complexes are nonelectrolytes. The DNA binding of those Schiff bases and their uranyl complexes was studied using UV-vis spectroscopy, and screening of their ability to bind to calf thymus DNA (CT-DNA) showed that the complexes interact with CT-DNA through an intercalation mode, for which the Kb values ranged from 1 × 106 to 3.33 × 105 M-1. The anticancer activities of the Schiff base ligands and their uranyl complexes against two ovarian (Ovcar-3) and melanoma cell lines (M14) were investigated, and the results indicated that uranyl complexes exhibit better results than the Schiff base ligands. Molecular docking identified the distance, energy account, type, and position of links contributing to the interactions between these complexes and two different cancer proteins (3W2S and 2OPZ).


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Substâncias Intercalantes/síntese química , Bases de Schiff/síntese química , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/química , Aldeídos/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , DNA/química , DNA/metabolismo , Teoria da Densidade Funcional , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Pirazinas/química , Bases de Schiff/metabolismo , Bases de Schiff/farmacologia , Solubilidade , Compostos de Urânio/química , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
12.
J Infect Public Health ; 14(9): 1247-1253, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34464921

RESUMO

OBJECTIVE: To assess the efficacy of Favipiravir compared to the standard therapy in treating patients with severe COVID-19 infection. METHODS: This is a retrospective cohort of patients with COVID-19 pneumonia who were treated with favipiravir, versus comparison group that received the standard of care. RESULTS: A total of 226 patients were included; 110 patients received favipiravir and 116 patients received standard of care. Patients who received favipiravir had longer time to recovery (14.2 ± 8.8 versus 12.8 ± 5.2, p = 0.17). Favipiravir was associated with an improved early day 14 mortality (4 [3.6%] versus 11 [9.5%]), p = 0.008), but was associated with a higher day 28 mortality (26 [23.6%] versus 11 [9.5%], p = 0.02). The overall mortality was higher in the favipiravir versus the standard of care group but difference was not statistically significant (33 [30.0%] versus 24 [20.7%], p = 0.10). CONCLUSION: The addition of favipiravir to standard of care was not associated with any improvement in clinical outcomes or mortality. Larger randomized controlled clinical trials are needed to further assess the efficacy of favipiravir.


Assuntos
COVID-19 , Amidas , Antivirais/uso terapêutico , Humanos , Pirazinas , Estudos Retrospectivos , SARS-CoV-2 , Padrão de Cuidado , Resultado do Tratamento
13.
FEBS Lett ; 595(18): 2366-2382, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34409597

RESUMO

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%-98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Pirazinas/farmacologia , RNA Viral/genética , RNA Polimerase Dependente de RNA/genética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Farmacorresistência Viral/genética , Mutação/genética , Mutação Puntual/genética
14.
ACS Nano ; 15(9): 14522-14534, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34414762

RESUMO

M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.


Assuntos
Estresse do Retículo Endoplasmático , Imunoterapia , Humanos , Hipóxia , Imidazóis , Macrófagos , Naftalenos , Estresse Oxidativo , Pirazinas
15.
Molecules ; 26(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34443658

RESUMO

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.


Assuntos
Antibacterianos/metabolismo , Produtos Biológicos/metabolismo , Metaboloma/genética , Pirazinas/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Cristalografia por Raios X , Fungos/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Espectrometria de Massas , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/metabolismo , Estereoisomerismo
16.
Expert Opin Drug Metab Toxicol ; 17(9): 1023-1030, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34275396

RESUMO

INTRODUCTION: The first-in-class BTK inhibitor ibrutinib has substantially changed the therapeutic landscape of chronic lymphocytic leukemia (CLL). The next-generation BTK inhibitor acalabrutinib is more selective and may have less off-target toxicities as compared to ibrutinib. Acalabrutinib has demonstrated safety and efficacy in CLL and has been approved to treat CLL. AREAS COVERED: Current clinical trials investigated acalabrutinib monotherapy or acalabrutinib-based combination therapies in relapsed/refractory and treatment-naive CLL. Data on the efficacy and safety of acalabrutinib in clinical trials were summarized in this review. The pharmacokinetic and pharmacodynamic data of acalabrutinib were also discussed. EXPERT OPINION: Acalabrutinib selectively inhibits BTK by covalent binding and shows rapid absorption and elimination. Acalabrutinib does not inhibit EGFR, TEC, or ITK and shows fewer off-target toxicities. Completed phase 3 trials have demonstrated that acalabrutinib improves the outcomes of patients with relapsed/refractory CLL and patients with treatment-naive CLL. The phase 3 trial that evaluates acalabrutinib versus ibrutinib has met its primary endpoint. Early phase studies suggested the combinations of acalabrutinib with a CD20 antibody and venetoclax led to high rates of undetectable minimal residual disease in the bone marrow in CLL patients and might provide a fixed-duration therapeutic option for patients with CLL.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/efeitos adversos , Pirazinas/farmacocinética
17.
Food Chem ; 363: 130298, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34237557

RESUMO

Ferulic acid (FA) and tetramethyl pyrazine (TMP) are intrinsic bioactive compounds in baijiu, and kafirin is the major protein of sorghum, which is the raw material of baijiu. In this study, the interactions of kafirin-FA and kafirin-TMP were investigated by multiple spectroscopic and molecular modeling techniques. Fluorescence spectra showed that intrinsic fluorescence of kafirin drastically quenched because of the formations of kafirin-FA and kafirin-TMP complexes. The CD studies indicated that the combination with FA or TMP decreased the α-helix content of kafirin slightly. The shifts and intensity changes of UV-Vis, FTIR and fluorescence spectra confirmed the formations of complexes. Moreover, the molecular docking and molecular dynamics studies showed that hydrophobic interactions and hydrogen bonds played major roles in the formations of kafirin-FA and kafirin-TMP complexes, and the formations of complexes made kafirin structures more compact. This work is of great importance for further quality improvement in baijiu and alcoholic beverages.


Assuntos
Sorghum , Ácidos Cumáricos , Simulação de Acoplamento Molecular , Pirazinas
19.
Molecules ; 26(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299616

RESUMO

Ladybug taint (also known as ladybird taint) is a relatively recently recognized fault that has been identified in wines from a wide range of terroirs. Alkyl-methoxypyrazines-particularly 2-isopropyl-3-methoxypyrazine-have been determined as the causal compounds, and these are introduced into grape must during processing, when specific species of vineyard-dwelling Coccinellidae are incorporated into the harvested fruit. Coccinella septempunctata, and especially the invasive Harmonia axyridis, are the beetles implicated, and climate change is facilitating wider dispersal and survivability of H. axyridis in viticultural regions worldwide. Affected wines are typically characterized as possessing excessively green, bell pepper-, and peanut-like aroma and flavor. In this paper, we review a range of vineyard practices that seek to reduce Coccinellidae densities, as well as both "standard" and novel wine treatments aimed at reducing alkyl-methoxypyrazine load. We conclude that while prevention of ladybug taint is preferable, there are several winery interventions that can remediate the quality of wine affected by this taint, although they vary in their relative efficacy and specificity.


Assuntos
Besouros/química , Odorantes/análise , Pirazinas/análise , Vitis/química , Vinho/análise , Animais , Contaminação de Alimentos/análise , Frutas/química
20.
Genes (Basel) ; 12(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204447

RESUMO

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Morte Celular/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Raios X , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Células Cultivadas , Reparo do DNA/efeitos dos fármacos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Humanos , Isoxazóis/farmacologia , Pirazinas/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Triazóis/farmacologia
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