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BACKGROUND: Largemouth bass (Micropterus salmoides) has significant economic value as a high-yielding fish species in China's freshwater aquaculture industry. Determining the major genes related to growth traits and identifying molecular markers associated with these traits serve as the foundation for breeding strategies involving gene pyramiding. In this study, we screened restriction-site associated DNA sequencing (RAD-seq) data to identify single nucleotide polymorphism (SNP) loci potentially associated with extreme growth differences between fast-growth and slow-growth groups in the F1 generation of a largemouth bass population. RESULTS: We subsequently identified associations between these loci and specific candidate genes related to four key growth traits (body weight, body length, body height, and body thickness) based on SNP genotyping. In total, 4,196,486 high-quality SNPs were distributed across 23 chromosomes. Using a population-specific genotype frequency threshold of 0.7, we identified 30 potential SNPs associated with growth traits. Among the 30 SNPs, SNP19140160, SNP9639603, SNP9639605, and SNP23355498 showed significant associations; three of them (SNP9639603, SNP9639605, and SNP23355498) were significantly associated with one trait, body length, in the F1 generation, and one (SNP19140160) was significantly linked with four traits (body weight, height, length, and thickness) in the F1 generation. The markers SNP19140160 and SNP23355498 were located near two growth candidate genes, fam174b and ppip5k1b, respectively, and these candidate genes were closely linked with growth, development, and feeding. The average body weight of the group with four dominant genotypes at these SNP loci in the F1 generation population (703.86 g) was 19.63% higher than that of the group without dominant genotypes at these loci (588.36 g). CONCLUSIONS: Thus, these four markers could be used to construct a population with dominant genotypes at loci related to fast growth. These findings demonstrate how markers can be used to identify genes related to fast growth, and will be useful for molecular marker-assisted selection in the breeding of high-quality largemouth bass.
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Lubina , Polimorfismo de Nucleótido Simple , Animales , Lubina/genética , Frecuencia de los Genes , Genotipo , Peso Corporal/genéticaRESUMEN
The VIM (belonged to E3 ubiquitin ligase) gene family is crucial for plant growth, development, and stress responses, yet their role in salt stress remains unclear. We analyzed phylogenetic relationships, chromosomal localization, conserved motifs, gene structure, cis-acting elements, and gene expression patterns of the VIM gene family in four cotton varieties. Our findings reveal 29, 29, 17, and 14 members in Gossypium hirsutum (G.hirsutum), Gossypium barbadense (G.barbadense), Gossypium arboreum (G.arboreum), and Gossypium raimondii (G. raimondii), respectively, indicating the maturity and evolution of this gene family. motifs among GhVIMs genes were observed, along with the presence of stress-responsive, hormone-responsive, and growth-related elements in their promoter regions. Gene expression analysis showed varying patterns and tissue specificity of GhVIMs genes under abiotic stress. Silencing GhVIM28 via virus-induced gene silencing revealed its role as a salt-tolerant negative regulator. This work reveals a mechanism by which the VIM gene family in response to salt stress in cotton, identifying a potential negative regulator, GhVIM28, which could be targeted for enhancing salt tolerance in cotton. The objective of this study was to explore the evolutionary relationship of the VIM gene family and its potential function in salt stress tolerance, and provide important genetic resources for salt tolerance breeding of cotton.
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Regulación de la Expresión Génica de las Plantas , Gossypium , Familia de Multigenes , Filogenia , Proteínas de Plantas , Estrés Salino , Gossypium/genética , Gossypium/fisiología , Estrés Salino/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Genes de Plantas , Tolerancia a la Sal/genéticaRESUMEN
With the increasing incidence of chronic kidney disease (CKD), the development of safe and effective anti-renal fibrosis drugs is particularly urgent. Recently, Baicalin has been considered to have a renal protective effect, but its bioavailability is too low. Therefore, we synthesized baicalin-2-ethoxyethyl ester (BAE) by esterification of baicalin. We hope that this experiment will demonstrate the anti-renal fibrosis effect of BAE and explain its molecular mechanism. In this study, the chronic kidney injury model of SD rats was established by 5/6 nephrectomy, and BAE was given for 28 days. The results showed that after BAE treatment, the serum creatinine and urea nitrogen levels decreased significantly, and the pathological changes in kidneys were improved. In addition, RNA-seq analysis showed that the mechanism of BAE in relieving renal fibrosis was related to the ECM receptor, PI3K/AKT signaling pathway, and inflammatory reaction. The western blotting analysis confirmed that BAE could inhibit the expression of α-SMA, TGF-ß1, p-PI3K, p-AKT, p-IκBα, and NF-κB p65. We found that BAE can inhibit the inflammatory reaction and promote the degradation of the extracellular matrix by inhibiting the activation of the PI3K/AKT/NF-κB pathway, thus alleviating the symptoms of renal fibrosis in 5/6Nx rats, which revealed BAE was a potential compound to relieve renal fibrosis effect.
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Flavonoides , FN-kappa B , Insuficiencia Renal Crónica , Ratas , Animales , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ésteres/farmacología , Ratas Sprague-Dawley , Transducción de Señal , Fibrosis , InflamaciónRESUMEN
Many cancer cells exhibit enhanced glycolysis, which is seen as one of the hallmark metabolic alterations, known as Warburg effect. Substantial evidence shows that upregulated glycolytic enzymes are often linked to malignant growth. Using glycolytic inhibitors for anticancer treatment has become appealing in recent years for therapeutic intervention in cancers with highly glycolytic characteristic, including non-small cell lung cancer (NSCLC). In this work, we studied the anticancer effects and the underlying mechanisms of combination of benzerazide hydrocholoride (Benz), a hexokinase 2 (HK2) inhibitor and 64, a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor, in several NSCLC cell lines. We found that combination of Benz and 64 exhibited strong synergistic anticancer effects in NCI-H1975, HCC827, NCI-H1299 and SK-LU-1 cell lines. With this combination treatment, we observed changes of certain mechanistic determinants associated with metabolic stress caused by glycolysis restriction, such as mitochondrial membrane potential depolarization, overproduction of reactive oxygen species [1], activation of AMPK and down-regulation of mTOR, which contributed to enhanced apoptosis. Moreover, Benz and 64 together significantly suppressed the tumor growth in HCC827 cell mouse xenograft model. Taken together, our study may suggest that combined inhibition of HK2 and PDK1 using Benz and 64 could be a viable anticancer strategy for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Hexoquinasa , Neoplasias Pulmonares , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Glucólisis , Hexoquinasa/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Transducción de SeñalRESUMEN
Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.
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Antineoplásicos , Apoptosis , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Homeostasis , Ácidos Hidroxámicos , Hierro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Hierro/metabolismo , Hierro/química , Proliferación Celular/efectos de los fármacos , Homeostasis/efectos de los fármacos , Relación Estructura-Actividad , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/síntesis química , Estructura Molecular , Apoptosis/efectos de los fármacos , Aniones/química , Aniones/farmacología , Relación Dosis-Respuesta a Droga , Animales , Línea Celular Tumoral , Ratones , Quinina/análogos & derivadosRESUMEN
The elevator door system plays a crucial role in ensuring elevator safety. Fault prediction is an invaluable tool for accident prevention. By analyzing the sound signals generated during operation, such as component wear and tear, the fault of the system can be accurately determined. This study proposes a GNN-LSTM-BDANN deep learning model to account for variations in elevator operating environments and sound signal acquisition methods. The proposed model utilizes the historical sound data from other elevators to predict the remaining useful life (RUL) of the target elevator door system. Firstly, the opening and closing sounds of other elevators is collected, followed by the extraction of relevant sound signal characteristics including A-weighted sound pressure level, loudness, sharpness, and roughness. These features are then transformed into graph data with geometric structure representation. Subsequently, the Graph Neural Networks (GNN) and long short-term memory networks (LSTM) are employed to extract deeper features from the data. Finally, transfer learning based on the improved Bhattacharyya Distance domain adversarial neural network (BDANN) is utilized to transfer knowledge learned from historical sound data of other elevators to predict RUL for the target elevator door system effectively. Experimental results demonstrate that the proposed method can successfully predict potential failure timeframes for different elevator door systems.
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The polysaccharides from Stemona tuberosa Lour, a kind of plant used in Chinese herbal medicine, have various pharmacological activities, such as anti-inflammatory and antioxidant properties. However, the effects of the extraction methods and the activity of polysaccharides from different parts are still unknown. Therefore, this study aimed to evaluate the effects of different extraction methods on the yields, chemical compositions, and bioactivity of polysaccharides extracted from different parts of Stemona tuberosa Lour. Six polysaccharides were extracted from the leaves, roots, and stems of Stemona tuberosa Lour through the use of hot water (i.e., SPS-L1, SPS-R1, and SPS-S1) and an ultrasound-assisted method (i.e., SPS-L2, SPS-R2, and SPS-S2). The results showed that the physicochemical properties, structural properties, and biological activity of the polysaccharides varied with the extraction methods and parts. SPS-R1 and SPS-R2 had higher extraction yields and total sugar contents than those of the other SPSs (SPS-L1, SPS-L2, SPS-S1, and SPS-S2). SPS-L1 had favorable antioxidant activity and the ability to downregulate MUC5AC expression. An investigation of the anti-inflammatory properties showed that SPS-R1 and SPS-R2 had greater anti-inflammatory activities, while SPS-R2 demonstrated the strongest anti-inflammatory potential. The results of this study indicated that SPS-L1 and SPS-L2, which were extracted from non-medicinal parts, may serve as potent natural antioxidants, but further study is necessary to explore their potential applications in the treatment of diseases. The positive anti-inflammatory effects of SPS-R1 and SPS-R2 in the roots may be further exploited in drugs for the treatment of inflammation.
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Stemonaceae , Stemonaceae/química , Stemonaceae/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Polisacáridos/farmacología , Polisacáridos/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismoRESUMEN
The programmable nuclease TnpB is significantly smaller than Cas9, can edit genes in medicinal plants, including Artemisia annua, Salvia miltiorrhiza, Scutellaria baicalensis, Isatis indigotica, and Codonopsis pilosula, and has potential uses in molecular breeding to enhance crop yield and quality.
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BACKGROUND: Inositol monophosphates (IMP) are key enzymes in the ascorbic acid (AsA) synthesis pathways, which play vital roles in regulating plant growth and development and stresses tolerance. To date, no comprehensive analysis of the expression profile of IMP genes and their functions under abiotic stress in cotton has been reported. RESULTS: In this study, the genetic characteristics, phylogenetic evolution, cis-acting elements and expression patterns of IMP gene family in cotton were systematically analyzed. A total of 28, 27, 13 and 13 IMP genes were identified in Gossypium hirsutum (G. hirsutum), Gossypium barbadense (G. barbadense), Gossypium arboreum (G. arboreum), and Gossypium raimondii (G. raimondii), respectively. Phylogenetic analysis showed that IMP family genes could cluster into 3 clades. Structure analysis of genes showed that GhIMP genes from the same subgroup had similar genetic structure and exon number. And most GhIMP family members contained hormone-related elements (abscisic acid response element, MeJA response element, gibberellin response element) and stress-related elements (low temperature response element, defense and stress response element, wound response element). After exogenous application of abscisic acid (ABA), some GhIMP genes containing ABA response elements positively responded to alkaline stress, indicating that ABA response elements played an important role in response to alkaline stress. qRT-PCR showed that most of GhIMP genes responded positively to alkaline stress, and GhIMP10D significantly upregulated under alkaline stress, with the highest up-regulated expression level. Virus-induced gene silencing (VIGS) experiment showed that compared with 156 plants, MDA content of pYL156:GhIMP10D plants increased significantly, while POD, SOD, chlorophyII and AsA content decreased significantly. CONCLUSIONS: This study provides a thorough overview of the IMP gene family and presents a new perspective on the evolution of this gene family. In particular, some IMP genes may be involved in alkaline stress tolerance regulation, and GhIMP10D showed high expression levels in leaves, stems and roots under alkaline stress, and preliminary functional verification of GhIMP10D gene suggested that it may regulate tolerance to alkaline stress by regulating the activity of antioxidant enzymes and the content of AsA. This study contributes to the subsequent broader discussion of the structure and alkaline resistance of IMP genes in cotton.
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Antioxidantes , Ácido Ascórbico , Gossypium/genética , Ácido Abscísico , Filogenia , InositolRESUMEN
As an important cancer-associated fibroblast-specific biomarker, fibroblast activation protein (FAP) has become an attractive target for tumor diagnosis and treatment. However, most FAP-based radiotracers showed inadequate uptake and short retention in tumors. In this study, we designed and synthesized a novel FAP ligand (DOTA-GPFAPI-04) through assembling three functional moieties: a quinoline-based FAP inhibitor for specifically targeting FAP, a FAP substrate Gly-Pro as a linker for increasing the FAP protein interaction, and a 2,2',2â³,2â´-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator for radiolabeling with different radionuclides. The FAP targeting ability of DOTA-GPFAPI-04 was investigated by molecular docking studies. DOTA-GPFAPI-04 was then radiolabeled with 68Ga to give [68Ga]Ga-DOTA-GPFAPI-04 for positron emission tomography (PET) imaging of glioblastoma. [68Ga]Ga-DOTA-GPFAPI-04 exhibited a purity of >98% and high stability analyzed by radio-HPLC in saline and mouse serum. Cell uptake studies demonstrated the targeting specificity of the probe. Further in vivo pharmacokinetic studies in normal mice demonstrated the quick clearance of the probe. Moreover, compared with the widely studied [68Ga]Ga-FAPI-04, [68Ga]Ga-DOTA-GPFAPI-04 showed much higher U87MG tumor uptake values (4.467 ± 0.379 for [68Ga]Ga-DOTA-GPFAPI-04 and 1.267 ± 0.208% ID/g for [68Ga]Ga-FAPI-04 at 0.5 h post-injection, respectively). The area under the curve based on time-activity curve (TAC) analysis for tumor radioactivity in small animal models was 422.5 for [68Ga]Ga-DOTA-GPFAPI-04 and 98.14 for [68Ga]Ga-FAPI-04, respectively, demonstrating that the former had longer tumor retention time. The tumor-to-muscle (T/M) ratio for [68Ga]Ga-DOTA-GPFAPI-04 reached 9.15 in a U87MG xenograft animal model. PET imaging and blocking assays showed that [68Ga]Ga-DOTA-GPFAPI-04 had specific tumor uptake. In summary, this study demonstrates the successful synthesis and evaluation of a novel FAPI targeting probe, [68Ga]Ga-DOTA-GPFAPI-04, with a Gly-Pro sequence. It shows favorable in vivo glioblastoma imaging properties and relatively long tumor retention, highlighting DOTA-GPFAPI-04 as a promising molecular scaffold for developing FAP targeting tumor theranostic agents.
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Glioblastoma , Humanos , Ratones , Animales , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Radioisótopos de Galio , Simulación del Acoplamiento Molecular , Tomografía de Emisión de Positrones/métodos , Fibroblastos/metabolismo , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
In this paper, we describe the synthesis and properties of a Golgi-targeting fluorescent probe for the selective detection of chloride anions. Specifically, we have synthesized one quaternized quinoline derivative bearing a sulfanilamido group and found that this compound is able to primarily target the Golgi apparatus and detect the changes in the concentration of cellular chloride anions.
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Indole-3-carbinol, bisindolylmethanes (BIMs) and indole-3-methanamines exhibit diverse therapeutic activities. Fluorinated molecules are widely used in pharmaceuticals. Herein we report a facile and straightforward method for the successful synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines by a Friedel-Crafts reaction. The reaction involves the in situ generation of difluoroacetaldehyde from difluoroacetaldehyde ethyl hemiacetal in the presence of a base or an acid. This protocol is distinguished by its good to excellent yields, broad substrate compatibility, good functional group tolerance and scalability.
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INTRODUCTION: The pathogenesis of epigastric pain in functional dyspepsia (FD) is complex. The study aims to explore the effect of sleep improvement on this symptom. METHODS: In total, 120 patients with FD-associated epigastric pain and insomnia were randomly divided into experimental and control groups using the envelope method. After applying the exclusion criteria, 107 patients were enrolled in the experimental (56 patients) and control (51 patients) groups. Insomnia was graded according to the Pittsburgh Sleep Quality Index (PSQI). In the experimental group, eszopiclone 3 mg, eszopiclone 3 mg + estazolam 1 mg, and eszopiclone 3 mg + estazolam 2 mg were given to patients with mild, moderate, and severe insomnia, respectively. In the control group, patients were given 1, 2, or 3 tablets of vitamin B complex. Patient sleep quality was monitored with Sleepthing. Epigastric pain was evaluated with a Numeric Rating Scale. The serum levels of IL-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Pain scores, sleep parameters, and serum levels of inflammatory mediators were compared before and after treatment. RESULTS: After treatment, the pain scores, sleep parameters, and TNF-α and IL-6 levels in the experimental group were significantly lower than those in the control group (p < 0.05). PSQI insomnia scores were significantly associated with pain scores, IL-6, and TNF-α (p < 0.05) but not in IL-8 and IL-1ß levels (p > 0.05) among the three groups. CONCLUSIONS: Improving sleep with eszopiclone and/or estazolam alleviates FD-associated epigastric pain, possibly by inhibiting related downstream transmission pathways and reducing the release of inflammatory mediators.
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Dispepsia , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Dispepsia/complicaciones , Dispepsia/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Eszopiclona , Estazolam , Factor de Necrosis Tumoral alfa , Interleucina-6 , Mediadores de Inflamación , Interleucina-8 , Sueño , Dolor Abdominal/tratamiento farmacológico , Dolor Abdominal/etiología , Resultado del TratamientoRESUMEN
Cysteine, an early sulfur-containing compound in plants, is of significant importance in sulfur metabolism. CYS encodes cysteine synthetase that further catalyzes cysteine synthesis. In this investigation, CYS genes, identified from genome-wide analysis of Gossypium hirsutum bioinformatically, led to the discovery of GhCYS2 as the pivotal gene responsible for Cd2+ response. The silencing of GhCYS2 through virus-induced gene silencing (VIGS) rendered plants highly susceptible to Cd2+ stress. Silencing GhCYS2 in plants resulted in diminished levels of cysteine and glutathione while leading to the accumulation of MDA and ROS within cells, thereby impeding the regular process of photosynthesis. Consequently, the stomatal aperture of leaves decreased, epidermal cells underwent distortion and deformation, intercellular connections are dramatically disrupted, and fissures manifested between cells. Ultimately, these detrimental effected culminating in plant wilting and a substantial reduction in biomass. The association established between Cd2+ and cysteine in this investigation offered a valuable reference point for further inquiry into the functional and regulatory mechanisms of cysteine synthesis genes.
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Cadmio , Gossypium , Gossypium/genética , Cadmio/toxicidad , Supervivencia Celular , Cisteína , Fotosíntesis/genética , Compuestos de Azufre , AzufreRESUMEN
Upon prolonged use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC), acquired drug resistance inevitably occurs. This study investigates the combined use of EGFR-TKIs (gefitinib or osimertinib) with epigallocatechin gallate (EGCG) to overcome acquired drug resistance in NSCLC models. The in vitro antiproliferative effects of EGFR-TKIs and EGCG combination in EGFR-mutant parental and resistant cell lines were evaluated. The in vivo efficacy of the combination was assessed in xenograft mouse models derived from EGFR-TKI-resistant NSCLC cells. We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. The in vivo results obtained from mouse tumor xenograft model confirmed that EGCG effectively overcame osimertinib resistance. This study revealed that EGCG suppressed cancer bypass survival signaling and altered cancer metabolic profiles, which is a promising anticancer adjuvant of EGFR-TKIs to overcome acquired drug resistance in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Activadas por AMP , Neoplasias Pulmonares/patología , Proliferación Celular , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos , Receptores ErbB , Glucosa/farmacología , Línea Celular Tumoral , MutaciónRESUMEN
Cellular mesenchymal-epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives by means of selenium-based bioisosteric modifications and evaluated their antiproliferative activity. Most of these selenium-containing hybrids exhibited potent dual inhibitory activity toward c-Met and TrxR. Among them, compound 8b was the most active, with an IC50 value of 10 nM against MHCC97H cells. Studies on the mechanism of action revealed that compound 8b triggered cell cycle arrest at the G1 phase and caused ROS accumulations by targeting TrxR, and these effects eventually led to cell apoptosis. These findings strongly suggest that compound 8b serves as a dual inhibitor of c-Met and TrxR, warranting further exploitation for cancer therapy.
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Antineoplásicos , Selenio , Antineoplásicos/farmacología , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Selenio/farmacología , Piperidinas/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
DNA encoded library (DEL) technology allows for rapid identification of novel small-molecule ligands and thus enables early-stage drug discovery. DEL technology is well-established, numerous cases of discovered hit molecules have been published, and the technology is widely employed throughout the pharmaceutical industry. Nonetheless, DEL selection results can be difficult to interpret, as library member enrichment may derive from not only desired products, but also DNA-conjugated byproducts and starting materials. Note that DELs are generally produced using split-and-pool combinatorial chemistry, and DNA-conjugated byproducts and starting materials cannot be removed from the library mixture. Herein, we describe a method for high-throughput parallel resynthesis of DNA-conjugated molecules such that byproducts, starting materials, and desired products are produced in a single pot, using the same chemical reactions and reagents as during library production. The low-complexity mixtures of DNA-conjugate are then assessed for protein binding by affinity selection mass spectrometry and the molecular weights of the binding ligands ascertained. This workflow is demonstrated to be a practical tool to triage and validate potential hits from DEL selection data.
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ADN/química , Biblioteca de Genes , Espectrometría de Masas , Técnicas Químicas CombinatoriasRESUMEN
PURPOSE: To investigate the safety and effectiveness of primary conservative therapy for patients with symptomatic isolated mesenteric artery dissection (IMAD) with a severely compressed true lumen and/or a large dissecting aneurysm. MATERIALS AND METHODS: A total of 35 consecutive patients (all men; median age, 53 y) with symptomatic IMAD with a severely compressed true lumen and/or a large dissecting aneurysm but without intestinal necrosis or arterial rupture who were treated with primary conservative therapy between November 2018 and February 2020 were assessed. A severely compressed true lumen was defined as luminal stenosis > 70%. A large dissecting aneurysm was defined as dissecting aneurysm diameter ≥ 1.5 times larger than the normal mesenteric artery diameter. RESULTS: There was a strong positive relationship among abdominal pain, degree of luminal stenosis, and length of dissection (R = 0.811; P < .001). Conservative treatment was successful in all patients. Abdominal pain was eliminated within 4.7 d ± 4.8 (range, 2-31 d) in all patients, within 3.6 d ± 1.2 (range, 2-6) in the 31 patients with minor or moderate abdominal pain, and within 13.3 d ± 11.9 (range, 6-31 d) in the 4 patients with severe abdominal pain. Complete or partial remodeling of the mesenteric artery was achieved in 6 (17.1%) and 29 (82.9%) patients, respectively, during 8.6 mo ± 4.3 of follow-up. CONCLUSIONS: Primary conservative therapy can be used safely and effectively in patients with symptomatic IMAD with a severely compressed true lumen and/or a large dissecting aneurysm but without intestinal necrosis or arterial rupture.
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Dolor Abdominal/prevención & control , Disección Aórtica/terapia , Tratamiento Conservador , Arteria Mesentérica Inferior , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/terapia , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Adulto , Anciano , Disección Aórtica/complicaciones , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/fisiopatología , China , Tratamiento Conservador/efectos adversos , Humanos , Masculino , Arteria Mesentérica Inferior/diagnóstico por imagen , Arteria Mesentérica Inferior/fisiopatología , Arteria Mesentérica Superior/diagnóstico por imagen , Arteria Mesentérica Superior/fisiopatología , Oclusión Vascular Mesentérica/complicaciones , Oclusión Vascular Mesentérica/diagnóstico por imagen , Oclusión Vascular Mesentérica/fisiopatología , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción VascularRESUMEN
Two lysosome-targeting fluorescent anion transporters derived from coumarins, trifluoromethylated arylsquaramides and morpholines were synthesized, and their specificity and efficiency to target and alkalize lysosomes were investigated. They are able to target lysosomes specifically. Compared with the previous analogue without trifluoromethyl substituents, these two conjugates, in particular the one having a 3,5-bis(trifluoromethyl) substituent, exhibit significantly higher ability to facilitate the transport of chloride anions, alkalize lysosomes and reduce the activity of lysosomal Cathepsin B enzyme. The present finding suggests that improving the anionophoric activity of lysosome-targeting fluorescent anion transporters is favorable to the efficiency to alkalize lysosomes and deactivate lysosomal Cathepsin B enzyme.
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Catepsina B/antagonistas & inhibidores , Cumarinas/farmacología , Ciclobutanos/farmacología , Transporte Iónico/efectos de los fármacos , Lisosomas/efectos de los fármacos , Cloruros/metabolismo , Cumarinas/síntesis química , Ciclobutanos/síntesis química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Morfolinas/síntesis química , Morfolinas/farmacologíaRESUMEN
To minimize waste production and reduce reliance on fossil fuels, agricultural waste such as rice straw has been actively used in biochemical production. In Taiwan, cellulosic waste has been used in anaerobic digestion for bioethanol production. This process produces a large amount of biomass-associated sludge that may become a serious environmental issue. Therefore, in this study, the anaerobic digestion sludge was recycled for the production of activated carbon via pyrolysis and activation by KOH. Surface characterization showed increased surface area and development of microporous structure upon activation. The FTIR image showed that high temperature activation eliminated most functional groups in the activated carbon, except for CO and C-O groups. The results showed that the activated carbon could be used for pollutant adsorbents such as molecular dyes (methylene blue: 217 mg g-1) and metal ions (copper: 169 mg g-1) from aqueous solution. In addition, the as-synthesized activated carbon can be used for CO2 capture and capacitor. Instead of focusing on one single application, we proposed that centralized production of activated carbon could be used in various applications, while further modification could be adopted depending on the need of its specific application.