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1.
PLoS One ; 19(5): e0303027, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728353

RESUMO

Insecticide resistance in mosquitoes is spreading worldwide and represents a growing threat to vector control. Insecticide resistance is caused by different mechanisms including higher metabolic detoxication, target-site modification, reduced penetration and behavioral changes that are not easily detectable with simple diagnostic methods. Indeed, most molecular resistance diagnostic tools are costly and labor intensive and then difficult to use for routine monitoring of insecticide resistance. The present study aims to determine whether mosquito susceptibility status against the pyrethroid insecticides (mostly used for mosquito control) could be established by the protein signatures of legs and/or thoraxes submitted to MALDI-TOF Mass Spectrometry (MS). The quality of MS spectra for both body parts was controlled to avoid any bias due to unconformity protein profiling. The comparison of MS profiles from three inbreeds Ae. aegypti lines from French Guiana (IRF, IR03, IR13), with distinct deltamethrin resistance genotype / phenotype and the susceptible reference laboratory line BORA (French Polynesia), showed different protein signatures. On both body parts, the analysis of whole protein profiles revealed a singularity of BORA line compared to the three inbreeding lines from French Guiana origin, suggesting that the first criteria of differentiation is the geographical origin and/or the breeding history rather than the insecticide susceptibility profile. However, a deeper analysis of the protein profiles allowed to identify 10 and 11 discriminating peaks from leg and thorax spectra, respectively. Among them, a specific peak around 4870 Da was detected in legs and thoraxes of pyrethroid resistant lines compared to the susceptible counterparts hence suggesting that MS profiling may be promising to rapidly distinguish resistant and susceptible phenotypes. Further work is needed to confirm the nature of this peak as a deltamethrin resistant marker and to validate the routine use of MS profiling to track insecticide resistance in Ae. aegypti field populations.


Assuntos
Aedes , Resistência a Inseticidas , Inseticidas , Nitrilas , Piretrinas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Piretrinas/farmacologia , Aedes/efeitos dos fármacos , Aedes/genética , Aedes/metabolismo , Resistência a Inseticidas/genética , Nitrilas/farmacologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Inseticidas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Dengue/virologia , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Feminino
2.
Parasit Vectors ; 17(1): 222, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38745242

RESUMO

BACKGROUND: Culex pipiens pallens is a well-known mosquito vector for several diseases. Deltamethrin, a commonly used pyrethroid insecticide, has been frequently applied to manage adult Cx. pipiens pallens. However, mosquitoes can develop resistance to these insecticides as a result of insecticide misuse and, therefore, it is crucial to identify novel methods to control insecticide resistance. The relationship between commensal bacteria and vector resistance has been recently recognized. Bacteriophages (= phages) are effective tools by which to control insect commensal bacteria, but there have as yet been no studies using phages on adult mosquitoes. In this study, we isolated an Aeromonas phage vB AhM-LH that specifically targets resistance-associated symbiotic bacteria in mosquitoes. We investigated the impact of Aeromonas phage vB AhM-LH in an abundance of Aeromonas hydrophila in the gut of Cx. pipiens pallens and its effect on the status of deltamethrin resistance. METHODS: Phages were isolated on double-layer agar plates and their biological properties analyzed. Phage morphology was observed by transmission electron microscopy (TEM) after negative staining. The phage was then introduced into the mosquito intestines via oral feeding. The inhibitory effect of Aeromonas phage vB AhM-LH on Aeromonas hydrophila in mosquito intestines was assessed through quantitative real-time PCR analysis. Deltamethrin resistance of mosquitoes was assessed using WHO bottle bioassays. RESULTS: An Aeromonas phage vB AhM-LH was isolated from sewage and identified as belonging to the Myoviridae family in the order Caudovirales using TEM. Based on biological characteristics analysis and in vitro antibacterial experiments, Aeromonas phage vB AhM-LH was observed to exhibit excellent stability and effective bactericidal activity. Sequencing revealed that the Aeromonas phage vB AhM-LH genome comprises 43,663 bp (51.6% CG content) with 81 predicted open reading frames. No integrase-related gene was detected in the vB AH-LH genome, which marked it as a potential biological antibacterial. Finally, we found that Aeromonas phage vB AhM-LH could significantly reduce deltamethrin resistance in Cx. pipiens pallens, in both the laboratory and field settings, by decreasing the abundance of Aeromonas hydrophila in their midgut. CONCLUSIONS: Our findings demonstrate that Aeromonas phage vB AhM-LH could effectively modulate commensal bacteria Aeromonas hydrophila in adult mosquitoes, thus representing a promising strategy to mitigate mosquito vector resistance.


Assuntos
Aeromonas hydrophila , Bacteriófagos , Culex , Resistência a Inseticidas , Nitrilas , Piretrinas , Animais , Aeromonas hydrophila/virologia , Aeromonas hydrophila/efeitos dos fármacos , Culex/virologia , Culex/microbiologia , Bacteriófagos/fisiologia , Bacteriófagos/isolamento & purificação , Bacteriófagos/genética , Piretrinas/farmacologia , Nitrilas/farmacologia , Inseticidas/farmacologia , Mosquitos Vetores/virologia , Mosquitos Vetores/microbiologia , Feminino
3.
Braz Oral Res ; 38: e037, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38747824

RESUMO

Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) can differentiate into osteoblasts, indicating that both are potential candidates for bone tissue engineering. Osteogenesis is influenced by many environmental factors, one of which is lipopolysaccharide (LPS). LPS-induced NF-κB activity affects the osteogenic potencies of different types of MSCs differently. This study evaluated the effect of LPS-induced NF-κB activity and its inhibition in DPSCs and PDLSCs. DPSCs and PDLSCs were cultured in an osteogenic medium, pretreated with/without NF-κB inhibitor Bay 11-7082, and treated with/without LPS. Alizarin red staining was performed to assess bone nodule formation, which was observed under an inverted light microscope. NF-κB and alkaline phosphatase (ALP) activities were measured to examine the effect of Bay 11-7082 pretreatment and LPS supplementation on osteogenic differentiation of DPSCs and PDLSCs. LPS significantly induced NF-κB activity (p = 0.000) and reduced ALP activity (p = 0.000), which inhibited bone nodule formation in DPSCs and PDLSCs. Bay 11-7082 inhibited LPS-induced NF-κB activity, and partially maintained ALP activity and osteogenic potency of LPS-supplemented DPSCs and PDLSCs. Thus, inhibition of LPS-induced NF-κB activity can maintain the osteogenic potency of DPSCs and PDLSCs.


Assuntos
Fosfatase Alcalina , Diferenciação Celular , Polpa Dentária , Lipopolissacarídeos , NF-kappa B , Nitrilas , Osteogênese , Ligamento Periodontal , Células-Tronco , Humanos , Lipopolissacarídeos/farmacologia , Ligamento Periodontal/citologia , Ligamento Periodontal/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatase Alcalina/análise , Diferenciação Celular/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Células Cultivadas , Nitrilas/farmacologia , Sulfonas/farmacologia , Reprodutibilidade dos Testes , Fatores de Tempo , Adulto Jovem , Adolescente
4.
J Am Chem Soc ; 146(19): 13317-13325, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700457

RESUMO

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Nitrilas , Pirazóis , Pirimidinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Apoptose/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/síntese química , Rutênio/química , Rutênio/farmacologia , Luz , Estrutura Molecular , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo
5.
Biotechnol J ; 19(5): e2300672, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38719621

RESUMO

The production of recombinant adeno-associated virus (rAAV) for gene therapy applications relies on the use of various host cell lines, with suspension-grown HEK293 cells being the preferred expression system due to their satisfactory rAAV yields in transient transfections. As the field of gene therapy continues to expand, there is a growing demand for efficient rAAV production, which has prompted efforts to optimize HEK293 cell line productivity through engineering. In contrast to other cell lines like CHO cells, the transcriptome of HEK293 cells during rAAV production has remained largely unexplored in terms of identifying molecular components that can enhance yields. In our previous research, we analyzed global regulatory pathways and mRNA expression patterns associated with increased rAAV production in HEK293 cells. Our data revealed substantial variations in the expression patterns between cell lines with low (LP) and high-production (HP) rates. Moving to a deeper layer for a more detailed analysis of inflammation-related transcriptome data, we detected an increased expression of interferon-related genes in low-producing cell lines. Following upon these results, we investigated the use of Ruxolitinib, an interferon pathway inhibitor, during the transient production of rAAV in HEK293 cells as potential media additive to boost rAAV titers. Indeed, we find a two-fold increase in rAAV titers compared to the control when the interferon pathways were inhibited. In essence, this work offers a rational design approach for optimization of HEK293 cell line productivity and potential engineering targets, ultimately paving the way for more cost-efficient and readily available gene therapies for patients.


Assuntos
Dependovirus , Interferons , Transdução de Sinais , Humanos , Células HEK293 , Dependovirus/genética , Interferons/metabolismo , Interferons/genética , Nitrilas/farmacologia , Pirimidinas/farmacologia , Transfecção , Pirazóis/farmacologia
6.
J Drugs Dermatol ; 23(5): 378-379, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38709705

RESUMO

Alopecia areata (AA) is a common autoimmune disorder. Although its pathogenesis is not fully understood, AA involves CD8 T cell-mediated destruction of the hair follicle. Several treatment options exist; however, there is minimal evidence in the pediatric population. Currently, there are no curative treatments for AA. The literature suggests that Janus kinase (JAK) inhibitors may be an effective treat-ment for AA, but evidence in pediatric patients is limited. Here, we report a case of severe pediatric AA treated with topical ruxolitinib, a JAK inhibitor. J Drugs Dermatol. 2024;23(5):378-379. doi:10.36849/JDD.7782.


Assuntos
Alopecia em Áreas , Inibidores de Janus Quinases , Nitrilas , Pirazóis , Pirimidinas , Humanos , Alopecia em Áreas/tratamento farmacológico , Nitrilas/administração & dosagem , Pirimidinas/administração & dosagem , Pirazóis/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/uso terapêutico , Criança , Creme para a Pele/administração & dosagem , Resultado do Tratamento , Masculino , Administração Cutânea , Feminino
7.
Luminescence ; 39(5): e4758, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38712530

RESUMO

The ability of heterogeneous photocatalysis to effectively remove organic pollutants from wastewater has shown great promise as a tool for environmental remediation. Pure zinc ferrites (ZnFe2O4) and magnesium-doped zinc ferrites (Mg@ZnFe2O4) with variable percentages of Mg (0.5, 1, 3, 5, 7, and 9 mol%) were synthesized via hydrothermal route and their photocatalytic activity was checked against methylene blue (MB) taken as a model dye. FTIR, XPS, BET, PL, XRD, TEM, and UV-Vis spectroscopy were used for the identification and morphological characterization of the prepared nanoparticles (NPs) and nanocomposites (NCs). The 7% Mg@ZnFe2O4 NPs demonstrated excellent degradation against MB under sunlight. The 7% Mg@ZnFe2O4 NPs were integrated with diverse contents (10, 50, 30, and 70 wt.%) of S@g-C3N4 to develop NCs with better activity. When the NCs were tested to degrade MB dye, it was revealed that the 7%Mg@ZnFe2O4/S@g-C3N4 NCs were more effective at utilizing solar energy than the other NPs and NCs. The synergistic effect of the interface formed between Mg@ZnFe2O4 and S@g-C3N4 was primarily responsible for the boosted photocatalytic capability of the NCs. The fabricated NCs may function as an effective new photocatalyst to remove organic dyes from wastewater.


Assuntos
Compostos Férricos , Azul de Metileno , Compostos de Nitrogênio , Energia Solar , Poluentes Químicos da Água , Zinco , Catálise , Poluentes Químicos da Água/química , Compostos Férricos/química , Azul de Metileno/química , Zinco/química , Magnésio/química , Fotólise , Processos Fotoquímicos , Corantes/química , Nanocompostos/química , Grafite/química , Águas Residuárias/química , Nitrilas/química
8.
Mol Biol Rep ; 51(1): 572, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722394

RESUMO

BACKGROUND: Alzheimer's disease is a leading neurological disorder that gradually impairs memory and cognitive abilities, ultimately leading to the inability to perform even basic daily tasks. Teriflunomide is known to preserve neuronal activity and protect mitochondria in the brain slices exposed to oxidative stress. The current research was undertaken to investigate the teriflunomide's cognitive rescuing abilities against scopolamine-induced comorbid cognitive impairment and its influence on phosphatidylinositol-3-kinase (PI3K) inhibition-mediated behavior alteration in mice. METHODS: Swiss albino mice were divided into 7 groups; vehicle control, scopolamine, donepezil + scopolamine, teriflunomide (10 mg/kg) + scopolamine; teriflunomide (20 mg/kg) + scopolamine, LY294002 and LY294002 + teriflunomide (20 mg/kg). Mice underwent a nine-day protocol, receiving scopolamine injections (2 mg/kg) for the final three days to induce cognitive impairment. Donepezil, teriflunomide, and LY294002 treatments were given continuously for 9 days. MWM, Y-maze, OFT and rota-rod tests were conducted on days 7 and 9. On the last day, blood samples were collected for serum TNF-α analysis, after which the mice were sacrificed, and brain samples were harvested for oxidative stress analysis. RESULTS: Scopolamine administration for three consecutive days increased the time required to reach the platform in the MWM test, whereas, reduced the percentage of spontaneous alternations in the Y-maze, number of square crossing in OFT and retention time in the rota-rod test. In biochemical analysis, scopolamine downregulated the brain GSH level, whereas it upregulated the brain TBARS and serum TNF-α levels. Teriflunomide treatment effectively mitigated all the behavioral and biochemical alterations induced by scopolamine. Furthermore, LY294002 administration reduced the memory function and GSH level, whereas, uplifted the serum TNF-α levels. Teriflunomide abrogated the memory-impairing, GSH-lowering, and TNF-α-increasing effects of LY294002. CONCLUSION: Our results delineate that the improvement in memory, locomotion, and motor coordination might be attributed to the oxidative and inflammatory stress inhibitory potential of teriflunomide. Moreover, PI3K inhibition-induced memory impairment might be attributed to reduced GSH levels and increased TNF-α levels.


Assuntos
Disfunção Cognitiva , Crotonatos , Hidroxibutiratos , Nitrilas , Estresse Oxidativo , Toluidinas , Animais , Nitrilas/farmacologia , Camundongos , Hidroxibutiratos/farmacologia , Crotonatos/farmacologia , Toluidinas/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Escopolamina/farmacologia , Cromonas/farmacologia , Memória/efeitos dos fármacos , Cognição/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Morfolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Donepezila/farmacologia
9.
PLoS One ; 19(5): e0303238, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38709762

RESUMO

The Colorado potato beetle (CPB; Leptinotarsa decemlineata) is an important potato pest with known resistance to pyrethroids and organophosphates in Czechia. Decreased efficacy of neonicotinoids has been observed in last decade. After the restriction of using chlorpyrifos, thiacloprid and thiamethoxam by EU regulation, growers seek for information about the resistance of CPB to used insecticides and recommended antiresistant strategies. The development of CPB resistance to selected insecticides was evaluated in bioassays in 69 local populations from Czechia in 2017-2022 and in 2007-2022 in small plot experiments in Zabcice in South Moravia. The mortality in each subpopulation in the bioassays was evaluated at the field-recommended rates of insecticides to estimate the 50% and 90% lethal concentrations (LC50 and LC90, respectively). High levels of CPB resistance to lambda-cyhalothrin and chlorpyrifos were demonstrated throughout Czechia, without significant changes between years and regions. The average mortality after application of the field-recommended rate of lambda-cyhalothrin was influenced by temperature before larvae were sampled for bioassays and decreased with increasing temperature in June. Downwards trends in the LC90 values of chlorpyrifos and the average mortality after application of the field-recommended rate of acetamiprid in the bioassay were recorded over a 6-year period. The baseline LC50 value (with 95% confidence limit) of 0.04 mg/L of chlorantraniliprole was established for Czech populations of CPBs for the purpose of resistance monitoring in the next years. Widespread resistance to pyrethroids, organophosphates and neonicotinoids was demonstrated, and changes in anti-resistant strategies to control CPBs were discussed.


Assuntos
Clorpirifos , Besouros , Resistência a Inseticidas , Inseticidas , Neonicotinoides , Tiazinas , Animais , Besouros/efeitos dos fármacos , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Clorpirifos/farmacologia , Piretrinas/farmacologia , Nitrilas/farmacologia , Larva/efeitos dos fármacos , República Tcheca , Tiametoxam , Solanum tuberosum/parasitologia
10.
Anal Chem ; 96(19): 7772-7779, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38698542

RESUMO

There is growing attention focused toward the problems of ecological sustainability and food safety raised from the abuse of herbicides, which underscores the need for the development of a portable and reliable sensor for simple, rapid, and user-friendly on-site analysis of herbicide residues. Herein, a novel multifunctional hydrogel composite is explored to serve as a portable and flexible sensor for the facile and efficient analysis of atrazine (ATZ) residues. The hydrogel electrode is fabricated by doping graphite-phase carbon nitride (g-C3N4) into the aramid nanofiber reinforced poly(vinyl alcohol) hydrogel via a simple solution-casting procedure. Benefiting from the excellent electroactivity and large specific surface area of the solid nanoscale component, the prepared hydrogel sensor is capable of simple, rapid, and sensitive detection of ATZ with a detection limit down to 0.002 ng/mL and per test time less than 1 min. After combination with a smartphone-controlled portable electrochemical analyzer, the flexible sensor exhibited satisfactory analytical performance for the ATZ assay. We further demonstrated the applications of the sensor in the evaluation of the ATZ residues in real water and soil samples as well as the user-friendly on-site point-of-need detection of ATZ residues on various agricultural products. We envision that this flexible and portable sensor will open a new avenue on the development of next-generation analytical tools for herbicide monitoring in the environment and agricultural products.


Assuntos
Atrazina , Técnicas Eletroquímicas , Herbicidas , Hidrogéis , Atrazina/análise , Herbicidas/análise , Hidrogéis/química , Técnicas Eletroquímicas/instrumentação , Grafite/química , Eletrodos , Limite de Detecção , Nitrilas/química , Nitrilas/análise , Nanofibras/química , Poluentes Químicos da Água/análise
11.
Int J Mol Sci ; 25(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38732166

RESUMO

This current study assessed the impacts of morphology adjustment of perovskite BiFeO3 (BFO) on the construction and photocatalytic activity of P-infused g-C3N4/U-BiFeO3 (U-BFO/PCN) heterostructured composite photocatalysts. Favorable formation of U-BFO/PCN composites was attained via urea-aided morphology-controlled hydrothermal synthesis of BFO followed by solvosonication-mediated fusion with already synthesized P-g-C3N4 to form U-BFO/PCN composites. The prepared bare and composite photocatalysts' morphological, textural, structural, optical, and photocatalytic performance were meticulously examined through various analytical characterization techniques and photodegradation of aqueous rhodamine B (RhB). Ellipsoids and flakes morphological structures were obtained for U-BFO and BFO, and their effects on the successful fabrication of the heterojunctions were also established. The U-BFO/PCN composite exhibits 99.2% efficiency within 20 min of visible-light irradiation, surpassing BFO/PCN (88.5%), PCN (66.8%), and U-BFO (26.1%). The pseudo-first-order kinetics of U-BFO/PCN composites is 2.41 × 10-1 min-1, equivalent to 2.2 times, 57 times, and 4.3 times of BFO/PCN (1.08 × 10-1 min-1), U-BFO, (4.20 × 10-3 min-1), and PCN, (5.60 × 10-2 min-1), respectively. The recyclability test demonstrates an outstanding photostability for U-BFO/PCN after four cyclic runs. This improved photocatalytic activity exhibited by the composites can be attributed to enhanced visible-light utilization and additional accessible active sites due to surface and electronic band modification of CN via P-doping and effective charge separation achieved via successful composites formation.


Assuntos
Bismuto , Fotólise , Rodaminas , Catálise , Bismuto/química , Rodaminas/química , Luz , Compostos Férricos/química , Compostos de Nitrogênio/química , Titânio/química , Processos Fotoquímicos , Nitrilas/química , Cinética , Grafite , Óxidos , Compostos de Cálcio
12.
Prostate ; 84(9): 814-822, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38558458

RESUMO

BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.


Assuntos
Antagonistas de Androgênios , Benzamidas , Transportadores de Ácidos Monocarboxílicos , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Simportadores , Masculino , Humanos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/genética , Linhagem Celular Tumoral , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Nitrilas/farmacologia , Simportadores/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/genética , Benzamidas/farmacologia
13.
Chemosphere ; 357: 142027, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38621487

RESUMO

Myclobutanil (MYC), a typical broad-spectrum triazole fungicide, is often detected in surface water. This study aimed to explore the neurotoxicity of MYC and the underlying mechanisms in zebrafish and in PC12 cells. In this study, zebrafish embryos were exposed to 0, 0.5 and 1 mg/L of MYC from 4 to 96 h post fertilization (hpf) and neurobehavior was evaluated. Our data showed that MYC decreased the survival rate, hatching rate and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal neurobehaviors characterized by decreased swimming distance and movement time. MYC impaired cerebral histopathological morphology and inhibited neurogenesis in HuC:egfp transgenic zebrafish. MYC also reduced the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and downregulated neurodevelopment related genes (gfap, syn2a, gap43 and mbp) in zebrafish and PC12 cells. Besides, MYC activated autophagy through enhanced expression of the LC3-II protein and suppressed expression of the p62 protein and autophagosome formation, subsequently triggering apoptosis by upregulating apoptotic genes (p53, bax, bcl-2 and caspase 3) and the cleaved caspase-3 protein in zebrafish and PC12 cells. These processes were restored by the autophagy inhibitor 3-methyladenine (3-MA) both in vivo and in vitro, indicating that MYC induces neurotoxicity by activating autophagy and apoptosis. Overall, this study revealed the potential autophagy and apoptosis mechanisms of MYC-induced neurotoxicity and provided novel strategies to counteract its toxicity.


Assuntos
Apoptose , Autofagia , Larva , Triazóis , Peixe-Zebra , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células PC12 , Triazóis/toxicidade , Larva/efeitos dos fármacos , Nitrilas/toxicidade , Fungicidas Industriais/toxicidade , Poluentes Químicos da Água/toxicidade , Embrião não Mamífero/efeitos dos fármacos
14.
Ecotoxicol Environ Saf ; 276: 116296, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38593498

RESUMO

Microplastics (MPs), which are prevalent and increasingly accumulating in aquatic environments. Other pollutants coexist with MPs in the water, such as pesticides, and may be carried or transferred to aquatic organisms, posing unpredictable ecological risks. This study sought to assess the adsorption of lambda-cyhalothrin (LCT) by virgin and aged polyethylene MPs (VPE and APE, respectively), and to examine their influence on LCT's toxicity in zebrafish, specifically regarding acute toxicity, oxidative stress, gut microbiota and immunity. The adsorption results showed that VPE and APE could adsorb LCT, with adsorption capacities of 34.4 mg∙g-1 and 39.0 mg∙g-1, respectively. Compared with LCT exposure alone, VPE and APE increased the acute toxicity of LCT to zebrafish. Additionally, exposure to LCT and PE-MPs alone can induce oxidative stress in the zebrafish gut, while combined exposure can exacerbate the oxidative stress response and intensify intestinal lipid peroxidation. Moreover, exposure to LCT or PE-MPs alone promotes inflammation, and combined exposure leads to downregulation of the myd88-nf-κb related gene expression, thus impacting intestinal immunity. Furthermore, exposure to APE increased LCT toxicity to zebrafish more than VPE. Meanwhile, exposure to PE-MPs and LCT alone or in combination has the potential to affect gut microbiota function and alter the abundance and diversity of the zebrafish gut flora. Collectively, the presence of PE-MPs may affect the toxicity of pesticides in zebrafish. The findings emphasize the importance of studying the interaction between MPs and pesticides in the aquatic environment.


Assuntos
Microbioma Gastrointestinal , Microplásticos , Nitrilas , Estresse Oxidativo , Polietileno , Piretrinas , Poluentes Químicos da Água , Peixe-Zebra , Animais , Piretrinas/toxicidade , Nitrilas/toxicidade , Microplásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Polietileno/toxicidade , Adsorção
15.
Biosens Bioelectron ; 256: 116276, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38599073

RESUMO

Fat mass and obesity-associated protein (FTO) has gained attention as the first RNA N6-methyladenosine (m6A) modification eraser due to its overexpression being associated with various cancers. In this study, an electrochemiluminescence (ECL) biosensor for the detection of demethylase FTO was developed based on DNAzyme-mediated CRISPR/Cas12a signal cascade amplification system and carboxylated carbon nitride nanosheets/phosphorus-doped nitrogen-vacancy modified carbon nitride nanosheets (C-CN/PCNV) heterojunction as the emitter. The biosensor was constructed by modifying the C-CN/PCNV heterojunction and a ferrocene-tagged probe (ssDNA-Fc) on a glassy carbon electrode. The presence of FTO removes the m6A modification on the catalytic core of DNAzyme, restoring its cleavage activity and generating activator DNA. This activator DNA further activates the trans-cleavage ability of Cas12a, leading to the cleavage of the ssDNA-Fc and the recovery of the ECL signal. The C-CN/PCNV heterojunction prevents electrode passivation and improves the electron-hole recombination, resulting in significantly enhanced ECL signal. The biosensor demonstrates high sensitivity with a low detection limit of 0.63 pM in the range from 1.0 pM to 100 nM. Furthermore, the biosensor was successfully applied to detect FTO in cancer cell lysate and screen FTO inhibitors, showing great potential in early clinical diagnosis and drug discovery.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Técnicas Biossensoriais , Sistemas CRISPR-Cas , DNA Catalítico , Técnicas Eletroquímicas , Limite de Detecção , Medições Luminescentes , Metalocenos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Humanos , DNA Catalítico/química , Técnicas Eletroquímicas/métodos , Nitrilas/química , Endodesoxirribonucleases/química , Endodesoxirribonucleases/metabolismo , Proteínas Associadas a CRISPR/química , Adenosina/análogos & derivados , Adenosina/análise , Adenosina/química , Nanoestruturas/química , Compostos Ferrosos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética
16.
Sci Total Environ ; 927: 172099, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38580115

RESUMO

Until now, bacteria able to degrade, 3,3'-iminodipropionitrile (IDPN), a neurotoxin that destroys vestibular hair cells, causing ototoxicity, culminating in irreversible movement disorders, had never been isolated. The aim of this study was to isolate a novel IDPN-biodegrading microorganism and characterize its metabolic pathway. Enrichment was performed by inoculating activated sludge from a wastewater treatment bioreactor that treated IDPN-contaminated wastewater in M9 salt medium, with IDPN as the sole carbon source. A bacterial strain with a spherical morphology that could grow at high concentrations was isolated on a solid medium. Growth of the isolated strain followed the Monod kinetic model. Based on the 16S rRNA gene, the isolate was Paracoccus communis. Whole-genome sequencing revealed that the isolated P. communis possessed the expected full metabolic pathway for IDPN biodegradation. Transcriptome analyses confirmed the overexpression of the gene encoding hydantoinase/oxoprolinase during the exponential growth phase under IDPN-fed conditions, suggesting that the enzyme involved in cleaving the imine bond of IDPN may promote IDPN biodegradation. Additionally, the newly discovered P. communis isolate seems to metabolize IDPN through cleavage of the imine bond in IDPN via nitrilase, nitrile hydratase, and amidase reactions. Overall, this study lays the foundation for the application of IDPN-metabolizing bacteria in the remediation of IDPN-contaminated environments.


Assuntos
Biodegradação Ambiental , Reatores Biológicos , Nitrilas , Paracoccus , Eliminação de Resíduos Líquidos , Águas Residuárias , Nitrilas/metabolismo , Paracoccus/metabolismo , Paracoccus/genética , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/metabolismo , RNA Ribossômico 16S
17.
Chemosphere ; 356: 141780, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38604516

RESUMO

The degradation of three anti-cancer drugs (ADs), Capecitabine (CAP), Bicalutamide (BIC) and Irinotecan (IRI), in ultrapure water by ozonation and UV-irradiation was tested in a bench-scale reactor and AD concentrations were measured through ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). A low-pressure mercury UV (LP-UV) lamp was used and degradation by UV (λ = 254 nm) followed pseudo-first order kinetics. Incident radiation in the reactor was measured via chemical actinometry using uridine. The quantum yields (φ) for the degradation of CAP, BIC and IRI were 0.012, 0.0020 and 0.0045 mol Einstein-1, respectively. Ozone experiments with CAP and IRI were conducted by adding ozone stock solution to the reactor either with or without addition of tert-butanol (t-BuOH) as radical quencher. Using this experimental arrangement, no degradation of BIC was observed, so a semi-batch setup was employed for the ozone degradation experiments of BIC. Without t-BuOH, apparent second order reaction rate constants for the reaction of the ADs with molecular ozone were determined to be 3.5 ± 0.8 ∙ 103 L mol-1 s-1 (CAP), 7.9 ± 2.1 ∙ 10-1 L mol-1 s-1 (BIC) and 1.0 ± 0.3 ∙ 103 L mol-1 s-1 (IRI). When OH-radicals (∙OH) were quenched, rate constants were virtually the same for CAP and IRI. For BIC, a significantly lower constant of 1.0 ± 0.5 ∙ 10-1 L mol-1 s-1 was determined. Of the tested substances, BIC was the most recalcitrant, with the slowest degradation during both ozonation and UV-irradiation. The extent of mineralization was also determined for both processes. UV irradiation was able to fully degrade up to 80% of DOC, ozonation up to 30%. Toxicity tests with Daphnia magna (D. magna) did not find toxicity for fully degraded solutions of the three ADs at environmentally relevant concentrations.


Assuntos
Anilidas , Antineoplásicos , Capecitabina , Irinotecano , Nitrilas , Ozônio , Compostos de Tosil , Raios Ultravioleta , Poluentes Químicos da Água , Ozônio/química , Nitrilas/química , Poluentes Químicos da Água/química , Irinotecano/química , Anilidas/química , Capecitabina/química , Compostos de Tosil/química , Antineoplásicos/química , Cinética , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão
18.
Int J Biol Macromol ; 267(Pt 2): 131533, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608988

RESUMO

As a renewable aromatic compound with enormous production potential, lignin has various potential high-value utilization pathways, but the success achieved in the field of photocatalysis is limited. Herein, this work prepares a new type of photocatalyst by modifying Graphitic Carbon Nitride Nanotubes (CNT) with self-assembled lignin nanospheres for the photocatalytic production of H2O2 and the degradation of azo dyes. Under light conditions, lignin enhances the production of H2O2 through oxygen reduction and collaborates with carbon nitride tubes to generate O2- and 1O2. Furthermore, carbon nitride tubes form electron-rich regions with lignin, promoting the transfer of electrons from adsorbed aromatic pollutants to this region, thereby facilitating their degradation. The experimental results indicate that the addition of 5 % lignin significantly enhances the photocatalytic degradation efficiency of azo dyes, with a degradation rate 1.87 times higher than that of the original carbon nitride tubes. Furthermore, CNL also have excellent degradation ability to pollutants in actual wastewater. This study provides new insights and prospects for the high-value utilization of lignin, enabling it to be used as a photocatalytic co-catalyst to participate in the photocatalytic degradation of environmental pollutants.


Assuntos
Grafite , Peróxido de Hidrogênio , Lignina , Lignina/química , Grafite/química , Catálise , Peróxido de Hidrogênio/química , Nanotubos/química , Nitrilas/química , Compostos Azo/química , Compostos de Boro/química , Poluentes Químicos da Água/química , Processos Fotoquímicos , Nanotubos de Carbono/química , Compostos de Nitrogênio
19.
ACS Infect Dis ; 10(5): 1725-1738, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38602352

RESUMO

Host-acting compounds are emerging as potential alternatives to combating antibiotic resistance. Here, we show that bosutinib, an FDA-approved chemotherapeutic for treating chronic myelogenous leukemia, does not possess any antibiotic activity but enhances macrophage responses to bacterial infection. In vitro, bosutinib stimulates murine and human macrophages to kill bacteria more effectively. In a murine wound infection with vancomycin-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion. Mechanistically, bosutinib stimulates macrophage phagocytosis of bacteria by upregulating surface expression of bacterial uptake markers Dectin-1 and CD14 and promoting actin remodeling. Bosutinib also stimulates bacterial killing by elevating the intracellular levels of reactive oxygen species. Moreover, bosutinib drives NF-κB activation, which protects infected macrophages from dying. Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.


Assuntos
Compostos de Anilina , Macrófagos , Nitrilas , Fagocitose , Quinolinas , Nitrilas/farmacologia , Fagocitose/efeitos dos fármacos , Animais , Quinolinas/farmacologia , Macrófagos/efeitos dos fármacos , Compostos de Anilina/farmacologia , Camundongos , Humanos , Enterococcus faecalis/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Antibacterianos/farmacologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico
20.
Ann Hematol ; 103(6): 1941-1945, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38634915

RESUMO

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.


Assuntos
Dasatinibe , Derrame Pleural , Inibidores de Proteínas Quinases , Humanos , Dasatinibe/efeitos adversos , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Derrame Pleural/induzido quimicamente , Derrame Pleural/epidemiologia , Adulto , Incidência , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Idoso de 80 Anos ou mais , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Substituição de Medicamentos , Compostos de Anilina/efeitos adversos , Compostos de Anilina/uso terapêutico , Compostos de Anilina/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/uso terapêutico , Adulto Jovem , Estudos Retrospectivos , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico
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