RESUMO
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , PiridonasRESUMO
Expanding target pesticide species and intelligent pesticide recognition were formidable challenges for existing cholinesterase inhibition methods. To improve this status, multi-active Mel-Cu nanozyme with mimetic Cu-N sites was prepared for the first time. It exhibited excellent laccase-like and peroxidase-like activities, and can respond to some pesticides beyond the detected range of enzyme inhibition methods, such as glyphosate, carbendazim, fumonisulfuron, etc., through coordination and hydrogen bonding. Inspired by the signal complementarity of Mel-Cu and cholinesterase, an integrated sensor array based on the Mel-Cu laccase-like activity, Mel-Cu peroxidase-like activity, acetylcholinesterase, and butyrylcholinesterase was creatively constructed. And it could successfully discriminate 12 pesticides at 0.5-50 µg/mL, which was significantly superior to traditional enzyme inhibition methods. Moreover, on the basis of above array, a unified stepwise prediction model was built using classification and regression algorithms in machine learning, which enabled concentration-independent qualitative identification as well as precise quantitative determination of multiple pesticide targets, simultaneously. The sensing accuracy was verified by blind sample analysis, in which the species was correctly identified and the concentration was predicted within 10% error, suggesting great intelligent recognition ability. Further, the proposed method also demonstrated significant immunity to interference and practical application feasibility, providing powerful means for pesticide residue analysis.
Assuntos
Acetilcolinesterase , Técnicas Biossensoriais , Butirilcolinesterase , Cobre , Aprendizado de Máquina , Praguicidas , Triazinas , Triazinas/química , Triazinas/análise , Praguicidas/análise , Técnicas Biossensoriais/métodos , Cobre/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Butirilcolinesterase/análise , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Limite de DetecçãoRESUMO
Objective: To investigate the efficacy and safety of avapritinib in the treatment of molecular biologically positive core binding factor-acute myeloid leukemia (CBF-AML) with KIT mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: We retrospectively analyzed the clinical data of six patients with molecular biologically positive CBF-AML with KIT mutation after allo-HSCT, who were treated with avapritinib at Henan Cancer Hospital from December 2021 to March 2023, and evaluated the efficacy and safety of avapritinib. Results: After 1 month of treatment with avapritinib, the transcription level of the fusion gene decreased in six patients, and the transcription level decreased by ≥1 log in five patients. In four patients who received avapritinib for ≥3 months, the fusion gene turned negative, and the median time to turn negative was 2.0 (range: 1.0-3.0) months. Up to the end of follow-up, four patients had no recurrence. The most common adverse reaction of avapritinib was myelosuppression, including neutropenia in two cases, thrombocytopenia in two cases, and anemia in one case. The non-hematological adverse reactions were nausea in two cases, edema in one case, and memory loss in one case, all of which were grades 1-2. Conclusion: Avapritinib was effective for molecular biologically positive CBF-AML patients with KIT mutation after allo-HSCT. The main adverse reaction was myelosuppression, which could generally be tolerated.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mutação , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Estudos Retrospectivos , Proteínas Proto-Oncogênicas c-kit/genética , Transplante Homólogo , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazóis , Pirróis , TriazinasRESUMO
Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)-the active ingredient of Xofluza, an increasingly popular anti-influenza drug-and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogKd values for the rates of sorption of BALM (0.5-1.6) and BAL (1.8-3.1) on river sediment were higher than those of conventional drugs (-0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90-99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments.
Assuntos
Antivirais , Monitoramento Ambiental , Rios , Triazinas , Poluentes Químicos da Água , Antivirais/análise , Japão , Poluentes Químicos da Água/análise , Rios/química , Triazinas/análise , Morfolinas/análise , Piridonas/análise , Piridinas/análise , Dibenzotiepinas , Oseltamivir/análise , Piranos/análise , Águas Residuárias/química , Pirazinas/análiseRESUMO
Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.
Assuntos
Antivirais , Dibenzotiepinas , Farmacorresistência Viral , Sinergismo Farmacológico , Inibidores Enzimáticos , Morfolinas , Neuraminidase , Piridonas , Triazinas , Dibenzotiepinas/farmacologia , Antivirais/farmacologia , Triazinas/farmacologia , Morfolinas/farmacologia , Piridonas/farmacologia , Neuraminidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza B/efeitos dos fármacos , Animais , Piridinas/farmacologia , Tiazóis/farmacologia , Guanidinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Cães , Células Madin Darby de Rim Canino , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ácidos Siálicos , Vírus da Influenza A/efeitos dos fármacos , Tiepinas/farmacologia , Triazóis/farmacologia , Benzimidazóis/farmacologia , PiranosRESUMO
The high speed enrichment of benzoylurea insecticides (BUs) in complex matrices is an essential and challenging step. The present study focuses on the synthesis of a hierarchical pore nitrogen-doped carbon material for magnetic solid phase extraction (MSPE) of BUs. This material was prepared through the carbonization of a composite material ZIF-67@MCA which assembly with hydrogen-bonded organic frameworks (melamine-cyanurate, MCA) and zeolitic imidazolate framework (ZIF-67) at room temperature. The optimal adsorption effect is achieved when the mass ratio of ZIF-67 to MCA is 1/3, and the carbonization was performed at 600 °C, the such obtained carbon material was denoted as 1/3ZIF-67@MCA-DCs-600. The material was characterized with various physical methods including X-ray diffractometry (XRD), Fourier transform infrared spectrometry (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), Brunauer-Emmett-Teller (BET), vibrating sample magnetometer (VSM), water contact angle measurement, Raman spectrometry. 1/3ZIF-67@MCA-DCs-600 exhibits a macro-mesoporous 3D structure with a high degree of nitrogen doping and relatively large specific surface area, making it suitable for magnetic solid phase extraction (MSPE). The adsorption of BUs with concentration of 100 ng mL-1 can reach equilibrium within 5 s. The interaction between BUs and the adsorbent, facilitated by π-π stacking, hydrophobic interactions, hydrogen bonding forces, as well as the material's porosity, enables efficient extraction recoveries ranging from 45 % to 92 %. The enrichment of BUs was achieved through the establishment of an MSPE method under optimized conditions, which was further coupled with high performance liquid chromatography (HPLC) for the determination of the four BUs. The linear range spans from 5 ng ml-1 to 1000 ng ml-1 with the correlation coefficient (R2) of ≥ 0.99, Meanwhile, the detection limit for these four BUs falls within the range of 0.01 to 0.10 ng ml-1. The material exhibits good reusability and can be reused for at least 5 cycles. Inter day and intra-day precision ranges from 2.1-7.9 % and 1.0-5.4 %, respectively. The method demonstrates a high level of reliability in practical applications for the determination of BUs.
Assuntos
Carbono , Ligação de Hidrogênio , Inseticidas , Nitrogênio , Extração em Fase Sólida , Inseticidas/análise , Inseticidas/química , Inseticidas/isolamento & purificação , Extração em Fase Sólida/métodos , Adsorção , Carbono/química , Nitrogênio/química , Estruturas Metalorgânicas/química , Porosidade , Triazinas/química , Triazinas/isolamento & purificação , Limite de Detecção , Ureia/química , Zeolitas/químicaRESUMO
Triazine pesticide (atrazine and its derivatives) detection sensors have been developed to thoroughly check for the presence of these chemicals and ultimately prevent their exposure to humans. Sensitive coatings were designed by utilizing molecular imprinting technology, which aims to create artificial receptors for the detection of chlorotriazine pesticides with gravimetric transducers. Initially, imprinted polymers were developed, using acrylate and methacrylate monomers containing hydrophilic and hydrophobic side chains, specifically for atrazine, which shares a basic heterocyclic triazine structure with its structural analogs. By adjusting the ratio of the acid to the cross-linker and introducing acrylate ester as a copolymer, optimal non-covalent interactions were achieved with the hydrophobic core of triazine molecules and their amino groups. A maximum sensor response of 546 Hz (frequency shift/layer height equal to 87.36) was observed for a sensitive coating composed of 46% methacrylic acid and 54% ethylene glycol dimethacrylate, with a demonstrated layer height of 250 nm (6.25 kHz). The molecularly imprinted copolymer demonstrated fully reversible sensor responses, not only for atrazine but also for its metabolites, like des-ethyl atrazine, and structural analogs, such as propazine and terbuthylazine. The efficiency of modified molecularly imprinted polymers for targeted analytes was tested by combining them with a universally applicable quartz crystal microbalance transducer. The stable selectivity pattern of the developed sensor provides an excellent basis for a pattern recognition procedure.
Assuntos
Atrazina , Polímeros Molecularmente Impressos , Praguicidas , Triazinas , Praguicidas/análise , Praguicidas/química , Triazinas/química , Triazinas/análise , Atrazina/análise , Atrazina/química , Polímeros Molecularmente Impressos/química , Impressão Molecular/métodos , Metacrilatos/química , Polímeros/química , Acrilatos/químicaRESUMO
Lamotrigine is a phenyltriazine anticonvulsant that is primarily metabolized by phase II UDP-glucuronosyltransferases (UGT) to a quaternary N2-glucuronide, which accounts for ~ 90% of the excreted dose in humans. While there is consensus that UGT1A4 plays a predominant role in the formation of the N2-glucuronide, there is compelling evidence in the literature to suggest that the metabolism of lamotrigine is catalyzed by another UGT isoform. However, the exact identity of the UGT isoform that contribute to the formation of this glucuronide remains uncertain. In this study, we harnessed a robust reaction phenotyping strategy to delineate the identities and its associated fraction metabolized (fm) of the UGTs involved in lamotrigine N2-glucuronidation. Foremost, human recombinant UGT mapping experiments revealed that the N2-glucuronide is catalyzed by multiple UGT isoforms. (i.e., UGT1A1, 1A3, 1A4, 1A9, 2B4, 2B7, and 2B10). Thereafter, scaling the apparent intrinsic clearances obtained from the enzyme kinetic experiments with our in-house liver-derived relative expression factors (REF) and relative activity factors (RAF) revealed that, in addition to UGT1A4, UGT2B10 was involved in the N2-glucuronidation of lamotrigine. This was further confirmed via chemical inhibition in human liver microsomes with the UGT1A4-selective inhibitor hecogenin and the UGT2B10-selective inhibitor desloratadine. By integrating various orthogonal approaches (i.e., REF- and RAF-scaling, and chemical inhibition), we quantitatively determined that the fm for UGT1A4 and UGT2B10 ranged from 0.42 - 0.64 and 0.32 - 0.57, respectively. Finally, we also provided nascent evidence that the pharmacokinetic interaction between lamotrigine and valproic acid likely arose from the in vivo inhibition of its UGT2B10-mediated pathway.
Assuntos
Anticonvulsivantes , Interações Medicamentosas , Glucuronosiltransferase , Lamotrigina , Microssomos Hepáticos , Ácido Valproico , Lamotrigina/metabolismo , Lamotrigina/farmacocinética , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacocinética , Microssomos Hepáticos/metabolismo , Ácido Valproico/metabolismo , Ácido Valproico/farmacocinética , Isoenzimas/metabolismo , Glucuronídeos/metabolismo , Triazinas/metabolismo , Triazinas/farmacocinéticaRESUMO
Using halloysite clay and vitamin B1 hydrochloride, a novel acidic halloysite-dendrimer catalytic composite has been developed for conversion of fructose to 5-hydroxymthylfurfural. To grow the dendritic moiety on halloysite, it was first functionalized and then reacted with melamine, epichlorohydrin and vitamin B1 hydrochloride respectively. Then, the resulting composite was treated with ZnCl2 to furnish Lewis acid sites. Use of vitamin B1 as the cationic moiety of ionic liquid obviated use of toxic chemicals and resulted in more environmentally friendly composite. Similarly, dendritic moiety of generation 2 was also grafted on halloysite and the activity of both catalysts for conversion of fructose to 5-hydroxymthylfurfural was investigated to disclose the role of dendrimer generation. For the best catalytic composite, the reaction variables were optimized via RSM and it was revealed that use of 0.035 g catalyst per 0.1 g fructose at 95 °C furnished HMF in 96% yield in 105 min. Turnover numbers (TONs) and frequencies (TOFs) were estimated to be 10,130 and 5788 h-1, respectively. Kinetic studies also underlined that Ea was 22.85 kJ/mol. The thermodynamic parameters of Δ H ≠ , Δ S ≠ and Δ G ≠ , were calculated to be 23 kJ/mol, - 129.2 J/mol and 72.14 kJ/mol, respectively. Notably, the catalyst exhibited good recyclability and hot filtration approved heterogeneous nature of catalysis.
Assuntos
Argila , Dendrímeros , Furaldeído , Tiamina , Catálise , Argila/química , Furaldeído/análogos & derivados , Furaldeído/química , Dendrímeros/química , Dendrímeros/síntese química , Tiamina/química , Tiamina/análogos & derivados , Frutose/química , Cinética , Silicatos de Alumínio/química , Triazinas/química , Cloretos/química , Compostos de Zinco/químicaRESUMO
PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.
Assuntos
Anticonvulsivantes , Carbamazepina , Epilepsia , Lamotrigina , Levetiracetam , Efeitos Tardios da Exposição Pré-Natal , Ácido Valproico , Humanos , Feminino , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Criança , Gravidez , Masculino , Levetiracetam/efeitos adversos , Ácido Valproico/efeitos adversos , Lamotrigina/efeitos adversos , Lamotrigina/uso terapêutico , Carbamazepina/efeitos adversos , Epilepsia/tratamento farmacológico , Testes Neuropsicológicos , Triazinas/efeitos adversos , Estudos de Coortes , Piracetam/análogos & derivados , Piracetam/efeitos adversos , Adulto , Cognição/efeitos dos fármacos , Estudos Prospectivos , Inteligência/efeitos dos fármacosRESUMO
Reactive oxygen species (ROS) have been extensively suggested to stimulate ethylene production. However, the molecular mechanism by which ROS stimulate ethylene production remains largely unclear. Here, transcriptome profiling was used to verify if ROS could stimulate ethylene production via direct formation of ethylene from ROS. Trichloroisocyanuric acid (TCICA) can stimulate seed germination in rice. When transcriptome profiling was performed to determine the molecular responsiveness of rice seeds to TCICA, TCICA was initially proven to be a ROS-generating reagent. A total of 300 genes potentially responsive to TCICA treatment were significantly annotated to cysteine, and the expression of these genes was significantly upregulated. Nonetheless, the levels of cystine did not exhibit significant changes upon TCICA exposure. Cystine was then proven to be a substrate that reacted with TCICA to form ethylene under FeSO4 conditions. Moreover, 7 of 22 genes responsive to TCICA were common with the hydrogen peroxide (H2O2)-responsive genes. Ethylene was then proven to be produced from cysteine or cystine by reacting with H2O2 under FeSO4 condition, and the hydroxyl radical (OH-) was proposed to be the free radical species responsible for ethylene formation under FeSO4 condition. These results provide the first line of evidence that ethylene can be produced from ROS in a non-enzymatic manner, thereby unveiling one new molecular mechanism by which ROS stimulate ethylene production and offering novel insights into the crosstalk between ethylene and ROS.
Assuntos
Etilenos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Oryza , Espécies Reativas de Oxigênio , Sementes , Espécies Reativas de Oxigênio/metabolismo , Oryza/genética , Oryza/metabolismo , Oryza/efeitos dos fármacos , Sementes/efeitos dos fármacos , Sementes/genética , Sementes/metabolismo , Etilenos/metabolismo , Etilenos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Germinação/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Triazinas/farmacologiaRESUMO
Aim: The feasibility of using Tasso devices (Tasso-SST® and Tasso+) collecting capillary blood samples for measuring abrocitinib and its metabolites were evaluated, and assay concordance established between capillary and venous blood samplings.Methods: Capillary serum and venous plasma concentrations were measured using their respective qualified and validated assays. Concentration and exposure comparisons were conducted for abrocitinib and its metabolites (M1, M2 and M4) to establish assay concordance.Results: The correlation coefficient between capillary serum and venous plasma concentrations were >0.98 for all four analytes from three separate assays, and PK parameters (AUClast and Cmax) were compared and met bioequivalence criteria.Conclusion: These results demonstrate the feasibility of patient-centric microsampling device, such as Tasso, in future abrocitinib pediatric study.
[Box: see text].
Assuntos
Coleta de Amostras Sanguíneas , Humanos , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/instrumentação , Pirimidinas/sangue , Pirimidinas/farmacocinética , Masculino , Pirazinas , TriazinasRESUMO
eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione scaffold of our hits I4 and C1, structure-activity relationship analysis led to the discovery of several more active derivatives (e.g., 19, 34, and 36) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.
Assuntos
Antineoplásicos , Proliferação de Células , Quinase do Fator 2 de Elongação , Triazinas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Relação Estrutura-Atividade , Animais , Quinase do Fator 2 de Elongação/metabolismo , Quinase do Fator 2 de Elongação/antagonistas & inibidores , Triazinas/farmacologia , Triazinas/química , Triazinas/síntese química , Triazinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Feminino , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sobrevivência Celular/efeitos dos fármacosRESUMO
Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts.
Assuntos
Adenocarcinoma de Pulmão , Resistencia a Medicamentos Antineoplásicos , Éxons , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Feminino , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Benzamidas , Acrilamidas/uso terapêutico , Triazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Imidazóis , PirazinasRESUMO
Macroporous three-dimensional (3D) framework structured melamine foam-based Enzyme-Linked Immunosorbent Assay (f-ELISA) biosensors were developed for rapid, reliable, sensitive, and on-site detection of trace amount of biomolecules and chemicals. Various ligands can be chemically immobilized onto the melamine foam, which brings in the possibility of working with antibodies, nanobodies, and peptides, respectively, as affinity probes for f-ELISA biosensors with improved stability. Different chemical reagents can be used to modify the foam materials, resulting in varied reactivities with antibodies, nanobodies, and peptides. As a result, the f-ELISA sensors produced from these modified foams exhibit varying levels of sensitivity and performance. This study demonstrated that the chemical reagents used for immobilizing antibodies, nanobodies, and peptides could affect the sensitivities of the f-ELISA sensors, and their storage stabilities under different temperatures varied depending on the sensing probes used, with f-ELISA sensors employing nanobodies as probes exhibiting the highest stability. This study not only showcases the versatility of the f-ELISA system but also opens new avenues for developing cost-effective, portable, and user-friendly diagnostic tools with optimized sensitivity and stability.
Assuntos
Técnicas Biossensoriais , Ensaio de Imunoadsorção Enzimática , Anticorpos de Domínio Único , Triazinas , Triazinas/análise , Triazinas/química , Ensaio de Imunoadsorção Enzimática/métodos , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/química , Técnicas Biossensoriais/métodos , Peptídeos/química , Anticorpos/imunologia , Anticorpos/química , Anticorpos Imobilizados/imunologia , Anticorpos Imobilizados/química , Limite de DetecçãoRESUMO
The extensively applied triazine herbicides are easily transported by ocean currents over long distances. This study analyzed ten triazine herbicides in the Antarctic marginal seas and the Southern Indian Ocean during the austral summer for the first time, addressing their largely unexplored behavior in remote marine environments. The total triazine herbicides showed great spatial heterogeneity, with a range of 20-790 pg/L and an average of 31 ± 66 pg/L. The waterborne transport of triazine herbicides in the Antarctic was affected by hydrological processes, especially the blocking and accumulation effect of the polar front. Variations in sea ice extent and temperature were also important influencing factors, resulting in elevated triazine herbicides in surface seawater of East Antarctica, but reduced levels in West Antarctica. Furthermore, the source apportionment results indicated that approximately 55 % of the herbicides originated from sugarcane cultivation, 28 % from algaecide use, and 16 % from corn and sorghum farming.
Assuntos
Monitoramento Ambiental , Herbicidas , Triazinas , Poluentes Químicos da Água , Herbicidas/análise , Triazinas/análise , Poluentes Químicos da Água/análise , Regiões Antárticas , Água do Mar/química , Oceanos e MaresRESUMO
The flattened bamboo board (FB) represents a promising innovation in the bamboo industry. To address the challenges of flammability and hygroscopicity, composite coatings consisting of melamine (MEL), phytic acid (PA), cerium ions (Ce3+), and sodium laurate (La) are assembled on the FB surface through an in-situ impregnation strategy. The resulting MEL/PA-Ce3+@La FB exhibits exceptional flame retardancy. It achieves a V-0 rating in the vertical burning test (UL-94) and boasts a high limiting oxygen index (LOI) value of 38.5 %. The coated FB exhibits superhydrophobicity, evidenced by a water contact angle of 156.5°, which can be attributed to the in-situ growth of PA-Ce3+ complexes (for constructing micro/nanoscale coarse structures) and the modification with La (for reducing surface energy).This superhydrophobic surface imparts both self-cleaning and anti-mold properties to the coated FB. Moreover, the coated FB exhibits excellent mechanical stability, withstanding 36 cycles of sandpaper abrasion and tape peeling without losing its hydrophobicity. In summary, this work provides an innovative strategy for the bamboo processing industry to produce flattened bamboo boards with combined flame retardancy, superhydrophobic and anti-mold properties. Such versatility holds significant potential to facilitate the utilization of flattened bamboo boards in the construction and decorative materials industries.
Assuntos
Retardadores de Chama , Interações Hidrofóbicas e Hidrofílicas , Retardadores de Chama/análise , Triazinas/química , Propriedades de Superfície , Ácido Fítico/química , Água/química , Cério/química , MolhabilidadeRESUMO
Rapid and precise detection of harmful substances in food products is essential for ensuring public health and safety. This study introduces a novel surface-enhanced Raman spectroscopy (SERS) substrate, composed of a molybdenum disulfidesilver nanocomposite, applied to flexible, water-resistant filter paper for detecting melamine and bisphenol A (BPA) in milk. Optimized molybdenum disulfide (NMS) nanoflowers (NFs) were synthesized through hydrothermal methods and high-temperature annealing, then modified with silver (Ag) nanoparticles to form the NMS-Ag nanocomposite (NMSA6). This substrate greatly enhances the Raman signal, achieving an enhancement factor of approximately 1.49 × 107 and a detection limit as low as 10-11 M for simultaneous multi-component analysis. Finite-difference time-domain (FDTD) simulations confirm the enhancement mechanism. The NMSA6 substrate demonstrates remarkably low detection limits for BPA and melamine, facilitating the analysis of various hazardous substances. These findings highlight the substrate's potential for highly sensitive, label-free detection, presenting a viable tool for food safety monitoring.
Assuntos
Compostos Benzidrílicos , Contaminação de Alimentos , Limite de Detecção , Leite , Papel , Fenóis , Prata , Análise Espectral Raman , Triazinas , Leite/química , Contaminação de Alimentos/análise , Prata/química , Animais , Fenóis/análise , Fenóis/química , Análise Espectral Raman/métodos , Compostos Benzidrílicos/análise , Compostos Benzidrílicos/química , Triazinas/análise , Molibdênio/química , Nanocompostos/química , Dissulfetos/química , Nanopartículas Metálicas/químicaRESUMO
Sunitinib, N-desmethyl imatinib, dasatinib, imatinib, and bosutinib are tyrosine kinase inhibitors (TKIs) that are commonly employed in the treatment of a multitude of cancers. However, the inappropriate concentrations of TKIs can result in ineffective treatment or the emergence of multiple adverse effects. Consequently, the development of a rapid and sensitive analytical method for TKIs is of paramount importance for the safe administration of drugs. In this work, solid-phase microextraction (SPME) probe combined with an electrospray ionization mass spectrometry (ESI-MS) coupling platform was constructed for rapid and sensitive determination of TKIs. The covalent organic frameworks (COFs) coated SPME probe was made of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and 2,5-dibutoxyterephthalaldehyde (DBTA) by in-situ layer-by-layer chemical bonding synthesis strategy. The TAPT-DBTA-SPME probe exhibited several advantageous properties which rendered it suitable for the enrichment of TKIs. Under the optimal conditions, the developed analytical method demonstrated a broad linear range (0.05-500.00 µg/L), a low limit of detection (0.02 µg/L) and a high enrichment factor (51-203) for TKIs. The developed analytical method was successfully applied to a pharmacokinetic study of TKIs in mouse plasma and tissue matrix, demonstrating that the proposed analytical method has promise for clinical applications and metabolic monitoring.
Assuntos
Limite de Detecção , Inibidores de Proteínas Quinases , Microextração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray , Microextração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Camundongos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/sangue , Estruturas Metalorgânicas/química , Aço Inoxidável/química , Triazinas/análise , Triazinas/química , Triazinas/sangue , Reprodutibilidade dos TestesRESUMO
PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21â days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P â <â 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1 and 1.7â ±â 0.5â µg/ml per mg/kg) than those with the TT genotype (1.4â ±â 1.1â µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1â µg/ml per mg/kg) than those with the CC genotype (1.3â ±â 1.3â µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P â <â 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.