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1.
Environ Sci Technol ; 58(15): 6814-6824, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38581381

RESUMO

Identifying persistent, mobile, and toxic (PMT) substances from synthetic chemicals is critical for chemical management and ecological risk assessment. Inspired by the triazine analogues (e.g., atrazine and melamine) in the original European Union's list of PMT substances, the occurrence and compositions of alkylamine triazines (AATs) in the estuarine sediments of main rivers along the eastern coast of China were comprehensively explored by an integrated strategy of target, suspect, and nontarget screening analysis. A total of 44 AATs were identified, of which 23 were confirmed by comparison with authentic standards. Among the remaining tentatively identified analogues, 18 were emerging pollutants not previously reported in the environment. Tri- and di-AATs were the dominant analogues, and varied geographic distributions of AATs were apparent in the investigated regions. Toxic unit calculations indicated that there were acute and chronic risks to algae from AATs on a large geographical scale, with the antifouling biocide cybutryne as a key driver. The assessment of physicochemical properties further revealed that more than half of the AATs could be categorized as potential PMT and very persistent and very mobile substances at the screening level. These results highlight that AATs are a class of PMT substances posing high ecological impacts on the aquatic environment and therefore require more attention.


Assuntos
Atrazina , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Rios/química , Triazinas/análise , Atrazina/análise , China , Monitoramento Ambiental
2.
Int J Mol Sci ; 25(7)2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38612435

RESUMO

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.


Assuntos
Chalconas , Isocianatos , Mycobacterium tuberculosis , Chalconas/farmacologia , Antifúngicos/farmacologia , Staphylococcus aureus , Antibacterianos/farmacologia , Azepinas/farmacologia , Fluoruracila , Neisseria gonorrhoeae , Triazinas/farmacologia
3.
Environ Monit Assess ; 196(5): 423, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38570374

RESUMO

Mobile herbicides have a high potential for groundwater contamination. An alternative to decrease the mobility of herbicides is to apply materials with high sorbent capacity to the soil, such as biochars. The objective of this research was to evaluate the effect of eucalyptus, rice hull, and native bamboo biochar amendments on sorption and desorption of hexazinone, metribuzin, and quinclorac in a tropical soil. The sorption-desorption was evaluated using the batch equilibrium method at five concentrations of hexazinone, metribuzin, and quinclorac. Soil was amended with eucalyptus, rice hull, and native bamboo biochar at a rate of 0 (control-unamended) and 1% (w w-1), corresponding to 0 and 12 t ha-1, respectively. The amount of sorbed herbicides in the unamended soil followed the decreasing order: quinclorac (65.9%) > metribuzin (21.4%) > hexazinone (16.0%). Native bamboo biochar provided the highest sorption compared to rice hull and eucalyptus biochar-amended soils for the three herbicides. The amount of desorbed herbicides in the unamended soil followed the decreasing order: metribuzin (18.35%) > hexazinone (15.9%) > quinclorac (15.1%). Addition of native bamboo biochar provided the lowest desorption among the biochar amendments for the three herbicides. In conclusion, the biochars differently affect the sorption and desorption of hexazinone, metribuzin, and quinclorac mobile herbicides in a tropical soil. The addition of eucalyptus, rice hull, and native bamboo biochars is a good alternative to increase the sorption of hexazinone, metribuzin, and quinclorac, thus, reducing mobility and availability of these herbicides to nontarget organisms in soil.


Assuntos
Eucalyptus , Herbicidas , Oryza , Quinolinas , Sasa , Poluentes do Solo , Triazinas , Carvão Vegetal , Solo , Adsorção , Monitoramento Ambiental , Herbicidas/análise , Poluentes do Solo/análise
4.
J Exp Clin Cancer Res ; 43(1): 103, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570866

RESUMO

BACKGROUND: Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS: The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS: MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS: Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.


Assuntos
Benzamidas , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Imidazóis , Neoplasias Pulmonares , Triazinas , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mesotelina , Neoplasias Pulmonares/patologia , Proteínas Ligadas por GPI/metabolismo , Crizotinibe , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia
5.
Cardiovasc Diabetol ; 23(1): 105, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504316

RESUMO

BACKGROUND: Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic ß-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). METHODS: ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. RESULTS: Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. CONCLUSIONS: Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Triazinas , Camundongos , Animais , Estreptozocina/uso terapêutico , Camundongos Knockout , Aterosclerose/induzido quimicamente , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Apolipoproteínas E/genética , Camundongos Endogâmicos C57BL
6.
J Sep Sci ; 47(5): e2300746, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38471966

RESUMO

In this work, monodisperse and nano-porous poly(bismaleimide-co-divinylbenzene) microspheres with large specific surface area (427.6 m2 /g) and rich pore structure were prepared by one-pot self-stable precipitation polymerization of 2,2'-bis[4-(4-maleimidophenoxy) phenyl] propane and divinylbenzene. The prepared poly(bismaleimide-co-divinylbenzene) microspheres were employed as dispersive solid-phase extraction (DSPE) adsorbent for the extraction of triazine herbicides. Under optimized conditions, good linearities were obtained between the peak area and the concentration of triazine herbicides in the range of 1-400 µg/L (R2 ≥ 0.9987) with the limits of detection of 0.12-0.31 µg/L. Triazine herbicides were detected using the described approach in vegetable samples (i.e., cucumber, tomato, and maize) with recoveries of 93.6%-117.3% and relative standard deviations of 0.4%-3.5%. In addition, the recoveries of triazine herbicides remained above 80.7% after being used for nine DSPE cycles, showing excellent reusability of poly(bismaleimide-co-divinylbenzene) microspheres. The adsorption of poly(bismaleimide-co-divinylbenzene) microspheres toward triazine herbicides was a monolayer and chemical adsorption. The adsorption mechanism between triazine herbicides and adsorbents might be a combination of hydrogen bonding, electrostatic interaction, and π-π conjugation. The results confirmed the potential use of the poly(bismaleimide-co-divinylbenzene) microspheres-based DSPE coupled to the high-performance liquid chromatography method for the detection of triazine herbicide residues in vegetable samples.


Assuntos
Herbicidas , Verduras , Compostos de Vinila , Verduras/química , Cromatografia Líquida de Alta Pressão/métodos , Microesferas , Porosidade , Triazinas/análise , Extração em Fase Sólida/métodos , Herbicidas/análise , Limite de Detecção
7.
Parasit Vectors ; 17(1): 119, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459570

RESUMO

BACKGROUND: Models that provide high-quality veterinary care for more affordable prices are emerging, but not well documented outside of wellness and preventative care. Effective treatment guidelines for heartworm disease have been developed by the American Heartworm Society; however, not all owners are able to access treatment due to the high costs associated with sick and emergency care services. METHODS: To increase access to high-quality adulticidal treatment of canine heartworm disease, we developed and implemented a technician-leveraged heartworm treatment protocol for high-volume, outpatient community clinic settings based on the American Heartworm Society guidelines. Modifications were few and included limited pre-treatment blood work, pre-injection sedation, post-injection pain medication, and a reduced exercise restriction period. We monitored retention rates for 556 dogs throughout treatment, evaluated treatment success (defined as no antigen detection 9 months post treatment) for patients that returned for post-treatment antigen testing, and reported on adverse reactions and therapy adherence throughout treatment. RESULTS: Of the patients that began adulticide therapy, 539/556 (97%) successfully completed the three-injection series. No microfilariae were detected in 99% (428/433) of those who returned for post-injection microfilaria testing. Among those that returned for or reported the results of post-injection antigen testing, no antigen was detected for 99% (245/248) and no microfilariae were detected for 99.5% (200/201). During the course of treatment, 483/539 (90%) of patients experienced at least one adverse reaction, with the most frequently reported types being behavioral and injection site reactions. 25/539 (4.6%) of owners sought additional medical care for adverse reactions at some point during the treatment course. The overall mortality rate was 1.3% (7/556). CONCLUSIONS: This study represents the first evaluation of a heartworm treatment protocol optimized for implementation in a high-volume, outpatient community clinic setting. Our findings align with those previously reported in private practice or tertiary referral centers, illustrating that through the inclusion of pre-treatment blood work, employing short-acting or reversible sedatives, ensuring proper analgesia, minimizing the use of ancillary diagnostics, reducing the duration of in-clinic monitoring while focusing on outpatient care, and maximizing technician involvement, we can deliver effective and safe melarsomine therapy at a more affordable cost to pet owners.


Assuntos
Arsenicais , Dirofilaria immitis , Dirofilariose , Doenças do Cão , Filaricidas , Triazinas , Cães , Humanos , Animais , Dirofilariose/diagnóstico , Pacientes Ambulatoriais , Doenças do Cão/tratamento farmacológico
8.
EBioMedicine ; 102: 105090, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38547578

RESUMO

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).


Assuntos
Aminopiridinas , Neoplasias Ósseas , Condrossarcoma , Sarcoma , Triazinas , Humanos , Animais , Camundongos , Medicina de Precisão , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Ósseas/genética
9.
Lancet Oncol ; 25(4): 474-487, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38547892

RESUMO

BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. FUNDING: Pfizer and Celcuity.


Assuntos
Neoplasias da Mama , Morfolinas , Piperazinas , Piridinas , Triazinas , Feminino , Humanos , Adolescente , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Intervalo Livre de Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Serina-Treonina Quinases TOR
10.
Food Chem ; 446: 138879, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38430773

RESUMO

In this paper, a novel magnetic hyper-crosslinked polymer with amino and triazine bifunctional groups (M-NH2-THCP) was developed. M-NH2-THCP has strong nitroimidazoles (NDZs) enrichment effect, and therefore it was used as an adsorbent to extract five NDZs from lake water, catfish and shrimp meat prior to HPLC. Polar interaction, π-π stacking interaction, hydrogen bond and Lewis acid-base interaction were attested to be the major adsorption mechanism. The method has a good linearity in the range of 0.1-100 ng mL-1 for lake water, 10-400 ng g-1 for catfish and shrimp muscle with R2 > 0.9964. The limits of detection of NDZs were 0.03-0.04 ng mL-1 for lake water, 1.0-2.0 ng g-1 for catfish and 2.0-2.5 ng g-1 for shrimp, which is superior to most reported method. The method recoveries were 87.6-119 %, and relative standard deviations were less than 8.7 %. M-NH2-THCP holds great application potential in pollutants enrichment, separation and removal.


Assuntos
Nitroimidazóis , Polímeros , Polímeros/química , Nitroimidazóis/análise , Adsorção , Porosidade , Triazinas/química , Fenômenos Magnéticos , Água , Extração em Fase Sólida/métodos , Cromatografia Líquida de Alta Pressão , Limite de Detecção
11.
Sci Rep ; 14(1): 6178, 2024 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485716

RESUMO

Mitochondrial dysfunction in pancreatic ß-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment's effects on mQC in diabetic ß-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic ß-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db ß-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db ß-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced ß-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving ß-cell function and effective glycemic control in T2D.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Triazinas , Camundongos , Animais , Secreção de Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Glucose/metabolismo , Camundongos Endogâmicos , Mitocôndrias/metabolismo , Apoptose
12.
Antiviral Res ; 224: 105852, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428748

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 (COVID-19) and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated with various doses of ensitrelvir 24 h prior to a lethal SARS-CoV-2 challenge infection. Mouse body weight changes, survival rates, and viral titers in the lungs were evaluated, and plasma concentrations of ensitrelvir were determined. A single subcutaneous administration of ensitrelvir at 64 mg/kg or greater 24 h prior to SARS-CoV-2 challenge infection significantly protected aged mice against lethality and inhibited body weight loss. Pharmacokinetic analysis of ensitrelvir in the aged mice suggested that plasma concentrations ≥2.99 µg/mL resulted in a significant prophylactic effect against SARS-CoV-2 infection. In the aged mouse prophylaxis model, SARS-CoV-2 titers were suppressed in the lungs of mice treated with ensitrelvir 24 h prior to challenge infection, suggesting that the prophylactic administration of ensitrelvir exerted its prophylactic effect by suppressing viral proliferation. These findings suggest that ensitrelvir is a candidate drug for pre-exposure prophylactic treatment of individuals at high risk of COVID-19.


Assuntos
COVID-19 , Indazóis , SARS-CoV-2 , Triazinas , Triazóis , Animais , Camundongos , COVID-19/prevenção & controle , Antivirais/uso terapêutico , Antivirais/farmacologia , Pulmão
13.
Antiviral Res ; 224: 105853, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430970

RESUMO

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.


Assuntos
Dibenzotiepinas , Influenza Humana , Morfolinas , Triazinas , Humanos , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Oseltamivir/farmacologia , Neuraminidase/genética , Neuraminidase/uso terapêutico , Vírus da Influenza A Subtipo H3N2/genética , Pacientes Ambulatoriais , Estações do Ano , Estudos Prospectivos , Antivirais/uso terapêutico , Antivirais/farmacologia , Piridonas/uso terapêutico , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Febre/tratamento farmacológico
14.
Environ Monit Assess ; 196(4): 344, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438568

RESUMO

In this study, the photocatalytic removal of Reactive Red 120 (RR120) dye was examined using zeolite 13X incorporated with Zn-Ce under UV irradiation. The synthesis of Zn-Ce nanoparticles incorporated with zeolite 13X was conducted through the co-precipitation method, and the features of the prepared nanocatalyst were analyzed using various techniques. The SEM and BET analyses indicated successful incorporation of ZnO-Ce oxides on the surface of zeolite 13X and a specific surface area of 359.39 m2/gm, respectively. Further, the average size of crystal grains was 28 nm. The response surface methodology (RSM) approach was employed to optimize operating parameters. The quadratic model suggested by the RSM approach, characterized by a high regression coefficient (R2 = 0.9632), indicates a high level of reliability. Moreover, under optimal conditions (catalyst loading of 4 mg, pH of 3, H2O2 amount of 0.2 mL, UV power of 25 W, and reaction time of 60 min), the highest RR120 dye removal percentage was 99.97%. Kinetic data indicated an increase in the reaction rate constant from 0.0631 to 0.1796 min-1. The zeolite 13X incorporated with Zn-Ce photocatalyst exhibited excellent stability over 5 cycles, with only a 5.50% decrease in RR120 dye removal yield. This study demonstrates the promising potential of zeolite 13X incorporated with Zn-Ce nanoparticles for the removal of RR120 dye from aqueous suspension.


Assuntos
Óxidos , Triazinas , Zeolitas , Peróxido de Hidrogênio , Reprodutibilidade dos Testes , Monitoramento Ambiental , Zinco
15.
Sci Rep ; 14(1): 4008, 2024 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369538

RESUMO

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.


Assuntos
Pirimidinonas , Triazinas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Dano ao DNA
16.
J Chromatogr A ; 1717: 464707, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38310703

RESUMO

Detecting trace endocrine disruptors in water is crucial for evaluating the water quality. In this work, a innovative modified polyacrylonitrile@cyanuric chloride-triphenylphosphine nanofiber membrane (PAN@CC-TPS) was prepared by in situ growing triazine porous organic polymers on the polyacrylonitrile (PAN) nanofibers, and used in the dispersive solid phase extraction (DSPE) to enrich trace nitrobenzene phenols (NPs) in water. The resluted PAN@CC-TPS nanofiber membrane consisted of numerous PAN nanofibers cover with CC-TPS solid spheres (∼2.50 µm) and owned abundant functional groups, excellent enrichment performance and good stability. In addition, the method based on PAN@CC-TPS displayed outstanding capacity in detecting the trace nitrobenzene phenols, with 0.50-1.00 µg/L of the quantification, 0.10-0.80 µg/L of the detection limit, 85.35-113.55 % of the recovery efficiency, and 98.08-103.02 of the enrichment factor, which was comparable to most materials. Meanwhile, when PAN@CC-TPS was adopted in the real water samples (sea water and river water), the high enrichment factors and recovery percentages strongly confirmed the feasibility of PAN@CC-TPS for enriching and detecting the trace NPs. Besides, the related mechanism of extracting NPs on PAN@CC-TPS mainly involved the synergistic effect of hydrogen bonding, π-π stacking and hydrophobic effect.


Assuntos
Nanofibras , Nitrofenóis , Compostos Organofosforados , Nanofibras/química , Porosidade , Polímeros , Extração em Fase Sólida/métodos , Fenóis/análise , Antifúngicos , Triazinas/química , Nitrobenzenos , Limite de Detecção , Cromatografia Líquida de Alta Pressão/métodos
17.
Vet Parasitol Reg Stud Reports ; 48: 100971, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38316499

RESUMO

Canine coccidiosis caused by Cystoisospora canis and Cystoisospora ohioensis-complex is common in kennels. While often underestimated, coccidiosis may cause severe clinical signs in puppies and sometimes even lead to death, so preventative measures are important. This study examines Cystoisospora spp. infection at a Labrador retriever breeding facility in Madrid, Spain. To identify environmental factors associated with infection, dams were examined throughout a reproductive cycle (from oestrus to 60 days postpartum) and their puppies during their first 60 days of life. Also assessed was the efficacy of combined treatment with emodepside (0.9 mg/ml) and toltrazuril (18 mg/ml) at a dose of 0.5 ml/kg of weight, equivalent to 0.45 mg/kg and 9 mg/kg, respectively, in puppies on day 35 of life. Oocyst shedding was detected in 4.6-18.6% of 45 dams examined and in 2.2-9.1% of their litters (315 puppies). In both cases, peak opg elimination was recorded on day 30 postpartum/of life. The species of Cystoisospora detected were C. canis (91.3%) and C. ohioensis-complex (8.7%). While in both dams and puppies opg counts were higher in autumn when rainfall was at its highest, correlation between opg and rainfall emerged as significant only in puppies (p = 0.031). The treatment of 35 day-old puppies with toltrazuril was 100% effective in controlling this infection in the kennel. Our findings therefore suggest the need for a strict hygiene regime and the use of toltrazuril as blanket treatment to reduce Cystoisospora transmission in dog breeding facilities.


Assuntos
Coccidiose , Doenças do Cão , Isospora , Sarcocystidae , Feminino , Cães , Animais , Coccidiose/tratamento farmacológico , Coccidiose/prevenção & controle , Coccidiose/veterinária , Triazinas/uso terapêutico , Triazinas/farmacologia , Doenças do Cão/tratamento farmacológico , Doenças do Cão/prevenção & controle
18.
Chemosphere ; 346: 140533, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38303396

RESUMO

This paper proposes the preparation of a new sorbent material based on melamine sponges (MS) with superhydrophobic, superoleophilic, and magnetic properties. This study involved impregnating the surface of commercially available MS with eco-friendly deep eutectic solvents (DES) and Fe3O4 nanoparticles. The DES selection was based on the screening of 105 eutectic mixtures using COSMO-RS modeling. Other parameters affecting the efficiency and selectivity of oil removal from water were optimized using the Box-Bhenken model. Menthol:Thymol (1:1)@Fe3O4-MS exhibited the highest sorption capacity for real crude oils (101.7-127.3 g/g). This new sponge demonstrated paramagnetic behavior (31.06 emu/g), superhydrophobicity (151°), superoleophobicity (0°), low density (15.6 mg/cm3), high porosity (99 %), and excellent mechanical stability. Furthermore, it allows multiple regeneration processes without losing its sorption capacity. Based on these benefits, Menthol:Thymol (1:1)@Fe3O4-MS shows promise as an efficient, cost-effective, and eco-friendly substitute for the existing sorbents.


Assuntos
Petróleo , Triazinas , Água/química , Mentol , Timol , Interações Hidrofóbicas e Hidrofílicas , Fenômenos Magnéticos
19.
Drug Dev Res ; 85(1): e22154, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349259

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significantly impacted the HIV-1 wild-type due to their high specificity and superior potency. As well as different combinations of NNRTIs have been used on clinically approved combining highly active antiretroviral therapy (HAART) to resist the growth of HIV-1 and decrease the mortality rate of HIV/AIDS. Although the feeble strength against the drug-resistant mutant strains and the long-term damaging effects have been reducing the effectiveness of HAART, it could be a crucial challenge to develop novel Anti-HIV leads with a vital mode of action and the least side effects. The extensive chemical reactivity and the diverse chemotherapeutic applications of the 1,3,5-triazine have provided a wide scope of research in medicinal chemistry via a structural modification. In this review, we focused on the Anti-HIV profile of the tri-substituted s-triazine derivatives with structure-based features and also discussed the active mode of action to evaluate the significant findings. The tri-substituted 1,3,5-triazine derivatives have been found more promising to inhibit the growth of the drug-sensitive and drug-resistant variants of HIV-1, especially HIV-1 wild-type, HIV-1 K103N/Y181C, and HIV-1 Tyr181Cys. It has been observed that these derivatives have interacted with the enzyme protein residues via a significant π $\pi $ - π $\pi $ interaction and hydrogen bonding to resist the proliferation of the viral genomes. Further, the SAR and the active binding modes are critically described and highlight the role of structural variations with functional groups along with the binding affinity of targeted enzymes, which may be beneficial for rational drug discovery to develop highly dynamic Anti-HIV agents.


Assuntos
HIV-1 , Triazinas , Triazinas/farmacologia , Triazinas/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Química Farmacêutica , Descoberta de Drogas
20.
Rapid Commun Mass Spectrom ; 38(5): e9696, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38355880

RESUMO

RATIONALE: Enasidenib (EDB) is an orally active selective mutant isocitrate dehydrogenase-2 enzyme inhibitor approved by the U.S. Food and Drug Administration to treat acute myeloid leukemia. It lacks a reported forced degradation study and a stability-indicating assay method (SIAM). This study addresses this gap by establishing a degradation profile in accordance with the International Council for Harmonisation Q1A and Q1B (R2) guidelines and developing a validated SIAM for EDB. METHODS: EDB was exposed to forced degradation under various conditions (hydrolytic, photolytic, oxidative, and thermal stress). Degradation samples were analyzed using high-performance liquid chromatography on an Agilent ZORBAX Eclipse Plus C18 column with a mobile phase consisting of 0.1% formic acid in Milli-Q water and acetonitrile at a flow rate of 1 mL/min and detection at 270 nm. Liquid chromatography-quadrupole time-of-flight-high-resolution mass spectrometry (LC/Q-TOF HRMS) was used for the identification and characterization of degradation products. Nitrosamine risk assessment was conducted using a modified nitrosation assay procedure (NAP) test due to the presence of a secondary amine group in the drug, which is liable to forming nitrosamine drug substance-related impurities (NDSRI). RESULTS: The drug exhibited significant degradation under acidic, basic, photolytic, and oxidative conditions in the solution state. A total of nine degradation products (DP) were formed (DP-I, DP-III, and DP-IV: acidic conditions; DP-I and DP-III: basic conditions; DP-II, DP-V, DP-VI, and DP-VII: oxidative stress; and DP-VII, DP-VIII, and DP-IX: photolytic conditions), which were separated and identified using reversed-phase high-performance liquid chromatography and characterized using liquid chromatography-tandem mass spectrometry. The mechanism behind the formation of EDB degradation products has been discussed, and this study was the first to develop a degradation pathway for EDB. In addition, the possibilities of NDSRI formation for EDB were studied using a modified NAP test, which can contribute to the risk assessment of the drug. CONCLUSIONS: Forced degradation studies were conducted by establishing a SIAM for EDB. All the degradation products were characterized by mass spectral data obtained using LC/Q-TOF-HRMS.


Assuntos
Aminopiridinas , Nitrosaminas , Espectrometria de Massas por Ionização por Electrospray , Triazinas , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise
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