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1.
Cancer Lett ; 594: 216980, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38797229

RESUMEN

Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment.


Asunto(s)
Diferenciación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Quinolinas , Proteína 1 Compañera de Translocación de RUNX1 , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Quinolinas/farmacología , Diferenciación Celular/efectos de los fármacos , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Precursores del ARN/metabolismo , Precursores del ARN/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Translocación Genética/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Empalme Alternativo/efectos de los fármacos , Línea Celular Tumoral , Animales , Ratones
2.
Food Chem X ; 22: 101360, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38699589

RESUMEN

This study evaluated the structural characteristics, processing properties, and antioxidant properties of hydrolysates prepared from donkey milk (DM) whey protein using different proteases (Alcalase, Neutrase, papain, and Flavourzyme). The results showed that enzymatic hydrolysis significantly increased hydrolysate solubility and reduced average particle size compared to those of DM whey protein. Neutrase and Flavourzyme hydrolysates exhibited higher degrees of hydrolysis (DH), along with elevated emulsification properties and surface hydrophobicity. The choice of protease influenced secondary and tertiary protein structures and amino acid composition. Enzymatic hydrolysis led to decreased molecular weight of DM whey proteins. Moreover, all hydrolysates exhibited higher fluorescence intensity at λmax compared to DM whey protein, implying distinct properties due to the varied impacts of the four proteases on DM whey protein structure. The preparation of hydrolysates from DM whey proteins using proteases contributes to the development of integrated-value DM products.

3.
Eur J Med Chem ; 271: 116395, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38626523

RESUMEN

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.


Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Humanos , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Animales , Estructura Molecular , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ratones , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/metabolismo
4.
Chem Commun (Camb) ; 60(37): 4938-4941, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38629231

RESUMEN

In this work, phosphate-rich cellulose beads (CBPs) were first used for cesium extraction from aqueous solutions. These green, abundant, cheap, and renewable CBPs demonstrated a high adsorption capacity and fast absorption rate. Besides, the CBPs also exhibited excellent stability and recycling performance, as well as good selectivity. This study presents the promising application potential of cellulose for efficient cesium extraction from aqueous media.

5.
Artículo en Inglés | MEDLINE | ID: mdl-38666586

RESUMEN

Stimuli-responsive micro/nanoscale photonic barcodes show great capacity for encryption and anticounterfeiting technologies due to multiple authentications, yet their application is commonly restricted by invasive stimuli. Herein, we report noninvasive light-stimulated high-security photonic barcodes based on spatially assembled photoresponsive two-dimensional (2D) 1,3,5-benzenetribenzoate (BTB)@Ln-MOF host-guest heterostructures. The photoluminescence (PL) spectra information on BTB@Ln-MOF heterostructures could be precisely controlled by the different wavelengths of ultraviolet (UV) light trigger. By using the PL properties and 2D heterostructures as cryptographic primitives, spatially resolved smart photonic barcodes based on both spectral and graphical coding are realized in BTB@Ln-MOF host-guest materials. These results will pave an avenue for the development of smart stimuli-responsive photonic barcodes for anticounterfeiting applications.

6.
Angew Chem Int Ed Engl ; 63(17): e202318568, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38433368

RESUMEN

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/uso terapéutico , Línea Celular Tumoral , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteolisis , Proteína p53 Supresora de Tumor/metabolismo
7.
Sci Total Environ ; 916: 170246, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38246385

RESUMEN

Atmospheric bioaerosols are influenced by multiple factors, including physical, chemical, and biotic interactions, and pose a significant threat to the public health and the environment. The nonnegligible truth however is that the primary driver of the changes in bioaerosol community diversity remains unknown. In this study, putative biological association (PBA) was obtained by constructing an ecological network. The relationship between meteorological conditions, atmospheric pollutants, water-soluble inorganic ions, PBA and bioaerosol community diversity was analyzed using random forest regression (RFR)-An ensemble learning algorithm based on a decision tree that performs regression tasks by constructing multiple decision trees and integrating the predicted results, and the contribution of different rich species to PBA was predicted. The species richness, evenness and diversity varied significantly in different seasons, with the highest in summer, followed by autumn and spring, and was lowest in winter. The RFR suggested that the explanation rate of alpha diversity increased significantly from 73.74 % to 85.21 % after accounting for the response of the PBA to diversity. The PBA, temperature, air pollution, and marine source air masses were the most crucial factors driving community diversity. PBA, particularly putative positive association (PPA), had the highest significance in diversity. We found that under changing external conditions, abundant taxa tend to cooperate to resist external pressure, thereby promoting PPA. In contrast, rare taxa were more responsive to the putative negative association because of their sensitivity to environmental changes. The results of this research provided scientific advance in the understanding of the dynamic and temporal changes in bioaerosols, as well as support for the prevention and control of microbial contamination of the atmosphere.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Monitoreo del Ambiente , Contaminación del Aire/análisis , Contaminantes Atmosféricos/análisis , Atmósfera , Estaciones del Año , Aerosoles/análisis
8.
Plant Reprod ; 37(1): 47-56, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-37758937

RESUMEN

KEY MESSAGE: Unreduced megagametophytes via second-division restitution were confirmed through heterozygosity analysis, and four candidate physical centromeres of rubber were located for the first time. The evaluation of maternal heterozygosity restitution (MHR) is vital in identifying the mechanism of 2n gametogenesis and assessing the utilization value of 2n gametes. In this study, three full-sib triploid populations were employed to evaluate the MHR of 2n female gametes of rubber tree clone GT1 and to confirm their genetic derivation. The 2n female gametes of GT1 were derived from second-division restitution (SDR) and transmitted more than half of the parental heterozygosity. In addition, low recombination frequency markers were developed, and four candidate physical centromeres of rubber tree were located for the first time. The confirmation that 2n female gametes of rubber tree clone GT1 are derived from SDR provides insights into the molecular mechanisms of 2n gametogenesis. In addition, the identified centromere location will aid in the development of centromeric markers for the rapid identification of the 2n gametogenesis mechanism.


Asunto(s)
Hevea , Triploidía , Hevea/genética , Diploidia , Células Germinativas , Centrómero/genética
9.
Cell Death Discov ; 9(1): 296, 2023 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-37580343

RESUMEN

Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.

10.
Bioorg Med Chem ; 91: 117404, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37429211

RESUMEN

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Neoplasias/tratamiento farmacológico , Fosforilación , Inhibidores de Proteínas Quinasas/química , Proliferación Celular , Antineoplásicos/química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular
11.
Eur J Med Chem ; 249: 115140, 2023 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-36736154

RESUMEN

Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.


Asunto(s)
Histona Desacetilasas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Pronóstico , Quinasas Ciclina-Dependientes , Células Madre Neoplásicas
12.
Gynecol Oncol ; 171: 39-48, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36804620

RESUMEN

OBJECTIVE: Sirtuin-7 (SIRT7) is a class III histone deacetylase that plays an important role in cancer development and frequently overexpressed in carcinomas. In this study, the tumor-supporting role and underlying mechanisms of SIRT7 were characterized in ovarian cancer (OC) aggressiveness. METHODS: SIRT7 expression was examined in OC tissues and cells. Interactions among SIRT7, GATA4, Wnt signaling pathway were explored by bioinformatics tools and experimental validations. The effect of SIRT7 and GATA4 on malignant phenotypes of OC cells were examined with gain- and loss-of-function experiments. A nude mouse model of OC was developed to verify the in vitro findings. RESULTS: It was noted that SIRT7 was highly expressed in OC tissues and cells. Cell lines with higher SIRT7 expression (OVCAR-3 and OVCAR-8) were used for subsequent in vitro experiments. The experimental data indicated that silencing of SIRT7 suppressed the OC cell proliferation, colony formation, migration, and invasion, and promoted cell senescence, which could be abolished by GATA4 knockdown. Mechanistically, SIRT7 promoted deacetylation of GATA4 and consequently inhibited the transcriptional activity of GATA4. In addition, GATA4 induced OC cell senescence by inhibiting Wnt signaling pathway. Further in vivo experiments substantiated that SIRT7 knockdown or overexpressed GATA4 could effectively inhibit tumor growth of nude mice. CONCLUSION: Taken together, our findings indicated that SIRT7 enhanced development of OC by suppressing GATA4 and activating Wnt signaling pathway, suggesting the potential of SIRT7/GATA4/Wnt axis as a therapeutic target for OC.


Asunto(s)
Neoplasias Ováricas , Sirtuinas , Animales , Ratones , Humanos , Femenino , Vía de Señalización Wnt , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Línea Celular Tumoral , Apoptosis/genética , Ratones Desnudos , Sirtuinas/genética , Sirtuinas/metabolismo , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción GATA4/genética , Factor de Transcripción GATA4/metabolismo
13.
Bioorg Med Chem ; 81: 117202, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36804726

RESUMEN

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutagénesis Insercional , Receptores ErbB , Inhibidores de Proteínas Quinasas/química , Mutación , Exones
14.
Plants (Basel) ; 11(19)2022 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-36235328

RESUMEN

Anoectochilus roxburghii (Wall.) Lindl has been used in Chinese herbal medicine for treating various ailments. However, its wild resources are endangered, and artificial cultivation of the plant is limited by the low regeneration rate of conventional propagation methods. The lack of A. roxburghii resources is detrimental to the commercial production of the plant and kinsenoside, which is unique to Anoectochilus species. To develop highly efficient methods for A. roxburghii micropropagation and find alternative resources for kinsenoside production, we created an induction, proliferation, and regeneration of PLBs (IPR-PLB) protocol for A. roxburghii. We also analyzed the kinsenoside and flavonoid contents during the induction and proliferation of PLBs. The best media of IPR-PLB for PLB induction and proliferation (secondary PLB induction and proliferation), shoot formation, and rooting medium were Murashige and Skoog (MS) + 3 mg/L 6-benzylaminopurine (6-BA) + 0.5 mg/L naphthaleneacetic acid (NAA) + 0.8 mg/L zeatin (ZT) + 0.2 mg/L 2,4-dichlorophenoxyacetic acid (2, 4-D), MS + 3 mg/L 6-BA + 0.5 mg/L NAA, and MS + 0.5 mg/L NAA, respectively. On these optimized media, the PLB induction rate was 89 ± 2.08%, secondary PLB induction rate was 120 ± 5%, secondary PLB proliferation rate was 400 ± 10% and 350 ± 10 % in terms of the quantity and biomass at approximately 1 month, shoot induction rate was 10.5 shoots/PLB mass, and root induction rate was 98%. All plantlets survived after acclimation. Darkness or weak light were essential for PLB proliferation, and light was crucial for PLB differentiation on these optimized media. The kinsenoside contents of PLBs and secondary PLBs were 10.38 ± 0.08 and 12.30 ± 0.08 mg/g fresh weight (FW), respectively. Moreover, the peak kinsenoside content during the proliferation of secondary PLBs was 34.27 ± 0.79 mg/g FW, which was slightly lower than that of the whole plant (38.68 ± 3.12 mg/g FW). Two flavonoids exhibited tissue- or temporal-specific accumulation patterns, and astragalin accumulated exclusively during the first 2 weeks of cultivation. The IPR-PLB protocol for A. roxburghii may facilitate the efficient micropropagation of A. roxburghii plants. Furthermore, the PLBs are a good alternative resource for kinsenoside production.

15.
Front Plant Sci ; 13: 862486, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35665153

RESUMEN

Cucumber (Cucumis sativus L.) is an important economic vegetable crop worldwide that is susceptible to various common pathogens, including powdery mildew (PM), downy mildew (DM), and Fusarium wilt (FM). In cucumber breeding programs, identifying disease resistance and related molecular markers is generally a top priority. PM, DM, and FW are the major diseases of cucumber in China that cause severe yield losses and the genetic-based cucumber resistance against these diseases has been developed over the last decade. Still, the molecular mechanisms of cucumber disease resistance remain unclear. In this review, we summarize recent findings on the inheritance, molecular markers, and quantitative trait locus mapping of cucumber PM, DM, and FM resistance. In addition, several candidate genes, such as PM, DM, and FM resistance genes, with or without functional verification are reviewed. The data help to reveal the molecular mechanisms of cucumber disease resistance and provide exciting new opportunities for further resistance breeding.

16.
Environ Res ; 208: 112652, 2022 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-34999034

RESUMEN

The metal-organic framework materials have an important application as sensors. In this work, a microporous three-dimensional (3D) Eu(III)-organic framework (Eu-MOF), [Eu2(3,5-bct)(phen)2(ox)2(H2O)]·H2O, was constructed from 3,5-bis(3'-carboxyphenyl)-1,2,4-triazole (3,5-H2bct), oxalate (ox) and 1,10-phenanthroline (phen) as a luminescent sensor. The free volume was found to be 15.7% per unit volume ignoring the free water molecules. The Eu-MOF showed bright red light due to the emission at 622 nm (5D0 → 7F2 transition) of the Eu(III) with high quantum yield (QY, 52.51%). The Eu-MOF exerted high luminescence stability in common organic solvents as well as aqueous solutions within a wide pH range from 4 to 11. Based on the luminescent Eu-MOF, the sensing behavior for colchicine in the aqueous environment was studied. Highly selective and sensitive detection (LOD = 2.43 × 10-5 mol L-1) of colchicine was observed by the Eu-MOF even in the presence of potential interfering components. The sensing mechanism for colchicine was investigated by experimental and theoretical results. It is worth noting that a film (Film@Eu-MOF) prepared by loading Eu-MOF showed intense characteristic red light emission under UV light. The luminescence color changed immediately from red to colorless when the Film@Eu-MOF came in contact with colchicine. Highly sensitive and rapid detection of colchicine in wastewater was achieved using this Film@Eu-MOF, which could be identified by the naked eye. The experimental results suggest that the synthesized Eu-MOF has potential application as a luminescent sensing material for pollutants in the environmental system.


Asunto(s)
Luminiscencia , Estructuras Metalorgánicas , Colchicina , Europio/química , Agua/química
17.
BMC Cancer ; 21(1): 1218, 2021 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-34774019

RESUMEN

BACKGROUND: MicroRNAs (miRNAs) have been reported to play significant roles in non-small-cell lung cancer (NSCLC). However, the roles of microRNA (miR)-1915-3p in NSCLC remain unclear. In this study, we aimed to explore the biological functions of miR-1915-3p in NSCLC. METHODS: The expression of miR-1915-3p and SET nuclear proto-oncogene (SET) in NSCLC tissues were examined by quantitative real-time PCR (qRT-PCR). Migratory and invasive abilities of lung cancer were tested by wound healing and transwell invasion assay. The direct target genes of miR-1915-3p were measured by dual-luciferase reporter assay and western blot. Finally, the regulation between METTL3/YTHDF2/KLF4 axis and miR-1915-3p were evaluated by qRT-PCR, promoter reporter assay and chromatin immunoprecipitation (CHIP). RESULTS: miR-1915-3p was downregulated in NSCLC tissues and cell lines, and inversely associated with clinical TNM stage and overall survival. Functional assays showed that miR-1915-3p significantly suppressed migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC cells. Furthermore, miR-1915-3p directly bound to the 3'untranslated region (3'UTR) of SET and modulated the expression of SET. SET inhibition could recapitulate the inhibitory effects on cell migration, invasion and EMT of miR-1915-3p, and restoration of SET expression could abrogate these effects induced by miR-1915-3p through JNK/Jun and NF-κB signaling pathways. What's more, miR-1915-3p expression was regulated by METTL3/YTHDF2 m6A axis through transcription factor KLF4. CONCLUSIONS: These findings demonstrate that miR-1915-3p function as a tumor suppressor by targeting SET and may have an anti-metastatic therapeutic potential for lung cancer treatment.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas de Unión al ADN/genética , Expresión Génica , Chaperonas de Histonas/genética , Neoplasias Pulmonares/genética , MicroARNs/fisiología , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/genética , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Transición Epitelial-Mesenquimal/genética , Femenino , Genes Reporteros , Genes Supresores de Tumor/fisiología , Chaperonas de Histonas/antagonistas & inhibidores , Chaperonas de Histonas/metabolismo , Humanos , Factor 4 Similar a Kruppel/genética , Factor 4 Similar a Kruppel/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Metiltransferasas/genética , Metiltransferasas/metabolismo , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
18.
J Med Chem ; 64(22): 16497-16511, 2021 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-34694800

RESUMEN

Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD+ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin-proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD+ AML.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Leucemia Mieloide Aguda/metabolismo , Quinolonas/química , Quinolonas/farmacología , Tirosina Quinasa 3 Similar a fms/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Mutación , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Ubiquitina/metabolismo , Tirosina Quinasa 3 Similar a fms/genética
19.
J Med Chem ; 64(21): 15825-15845, 2021 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-34704758

RESUMEN

Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.


Asunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Diterpenos/farmacología , Melanoma/patología , Necroptosis/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Compuestos Policíclicos/farmacología , Animales , Antibacterianos/farmacología , Antineoplásicos/farmacocinética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Humanos , Melanoma/metabolismo , Ratones , Ratones Desnudos , Pruebas de Sensibilidad Microbiana , Compuestos Policíclicos/química , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Pleuromutilinas
20.
Anal Bioanal Chem ; 413(26): 6627-6637, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34476525

RESUMEN

As a new low-cost photothermal nanoprobe, Prussian blue nanoparticles (PB NPs) have been demonstrated to have more potential in photothermometric-based point-of-care testing (POCT) application. However, most of the existing PB NP-based photothermometric sensors were constructed mainly relying on in situ generation of PB NPs or their combination with antigens and antibodies, therefore usually suffering from the inherent defects like complicated preparation and cumbersome surface process as well as high-cost modification. To break this limitation of PB NP-based photothermometric POCT, we proposed an ingenious redox reaction-controlled nanoprobe conversion strategy and successfully applied to photothermometric detection of ascorbate oxidase (AAO). In this design, the heat of PB NP photothermal system under 808-nm laser irradiation dramatically decreased with the addition of AA, due to a unique AA-induced Prussian blue to Prussian white (PB-to-PW) conversion. Upon AAO addition, the heat of reaction system increased because of the enzymatic catalytic reaction between AAO and AA, which led to a significant reduction of AA and resultantly inhibited PB-to-PW conversion. Such target-mediated nanoprobe conversion resulted in an obvious temperature change that could be easily detected by a common thermometer and exhibited good linear ranges from 0.25 to 14 mU/mL with a detection limit as low as 0.21 mU/mL for POCT analysis of AAO. This facile, convenient, and portable photothermometric sensing platform provides an innovative route for the design of PB NP nanoprobe-based photothermometric detection methods. A sensitive photothermometric AAO sensor based on a redox reaction-controlled nanoprobe conversion strategy from Prussian blue to Prussian white.


Asunto(s)
Ascorbato Oxidasa/análisis , Técnicas Biosensibles/métodos , Colorantes/química , Ferrocianuros/química , Animales , Pruebas de Enzimas/métodos , Humanos , Nanopartículas/química , Oxidación-Reducción
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