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Extensive exploration of the molecular subtypes of triple-negative breast cancer (TNBC) is critical for advancing precision medicine. Notably, the luminal androgen receptor (LAR) subtype has attracted attention for targeted treatment combining androgen receptor antagonists and CDK4/6 inhibitors. Unfortunately, this strategy has proven to be of limited efficacy, highlighting the need for further optimization. Using our center's comprehensive multiomics dataset (n = 465), we identified novel therapeutic targets and evaluated their efficacy through multiple models, including in vitro LAR cell lines, in vivo cell-derived allograft models and ex vivo patient-derived organoids. Moreover, we conducted flow cytometry and RNA-seq analysis to unveil potential mechanisms underlying the regulation of tumor progression by these therapeutic strategies. LAR breast cancer cells exhibited sensitivity to chidamide and enzalutamide individually, with a drug combination assay revealing their synergistic effect. Crucially, this synergistic effect was verified through in vivo allograft models and patient-derived organoids. Furthermore, transcriptomic analysis demonstrated that the combination therapeutic strategy could inhibit tumor progression by regulating metabolism and autophagy. This study confirmed that the combination of histone deacetylase (HDAC) inhibitors and androgen receptor (AR) antagonists possessed greater therapeutic efficacy than monotherapy in LAR TNBC. This finding significantly bolsters the theoretical basis for the clinical translation of this combination therapy and provides an innovative strategy for the targeted treatment of LAR TNBC.
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The Hamiltonian, which determines the evolution of a quantum system, is fundamental in quantum physics. Therefore, it is crucial to implement high-precision generation and measurement of the Hamiltonian in a practical quantum system. Here, we experimentally demonstrate ultrahigh-precision Hamiltonian parameter estimation with a significant quantum advantage in a superconducting circuit via sequential control. We first observe the commutation relation for noncommuting operations determined by the system Hamiltonian, both with and without adding quantum control, verifying the commuting property of controlled noncommuting operations. Based on this control-induced commuting property, we further demonstrate Hamiltonian parameter estimation for polar and azimuth angles in superconducting circuits, achieving ultrahigh metrological gains in measurement precision exceeding the standard quantum limit by up to 16.0 and 16.1 dB at N=100, respectively.
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The microtubule system plays an important role in the mitosis and growth of eukaryotic cells, and it is considered as an appealing and highly successful molecular target for cancer treatment. In fact, microtubule targeting agents, such as paclitaxel and vinblastine, have been approved by FDA for tumor therapy, which have achieved significant therapeutic effects and sales performance. At present, microtubule targeting agents mainly include microtubule-destabilizing agents, microtubule-stabilizing agents, and a few tubulin degradation agents. Although there are few reports about tubulin degradation agents at present, tubulin degradation agents show great potential in overcoming multidrug resistance and reducing neurotoxicity. In addition, some natural drugs could specifically degrade tubulin in tumor cells, but have no effect in normal cells, thus showing a good biosafety profile. Therefore, tubulin degradation agents might exhibit a better application. Currently, some small molecules have been designed to promote tubulin degradation with potent antiproliferative activities, showing the potential for cancer treatment. In this work, we reviewed the reports on tubulin degradation, and focused on the degradation mechanism and important functional groups of chemically synthesized compounds, hoping to provide help for the degradation design of tubulin.
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Antineoplásicos , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Microtúbulos , Antineoplásicos/química , Vinblastina/metabolismo , Vinblastina/farmacología , Paclitaxel/metabolismo , Moduladores de Tubulina/químicaRESUMEN
[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1-H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50 values of 9.47, 9.58 and 13.1 µM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents.
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Antineoplásicos , Neoplasias Gástricas , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/farmacología , Sistema de Señalización de MAP Quinasas , Estructura Molecular , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Proteins are a main organic nitrogen source for microorganisms. Many heterotrophic microorganisms secrete extracellular proteases (ex-proteases) to efficiently decompose proteins into oligopeptides and amino acids when exterior proteins are required for growth. These ex-proteases not only play important roles in microbial nutrient acquisition or host infection but also contribute greatly to the global recycling of carbon and nitrogen. Moreover, may microbial ex-proteases have important applications in industrial, medical, and biotechnological areas. Therefore, uncovering the mechanisms by which microorganisms initiate the expression of ex-protease genes in response to exterior proteins is of great significance. In this review, the progress made in understanding the induction mechanisms of microbial ex-proteases in response to exterior proteins is summarized, with a focus on the inducer molecules, membrane sensors, and downstream pathways. Problems to be solved for better understanding of the induction mechanisms of microbial ex-proteases are also discussed.
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Proteínas Bacterianas/metabolismo , Biotecnología/métodos , Carbono/metabolismo , Nitrógeno/metabolismo , Péptido Hidrolasas/metabolismo , Biodegradación AmbientalRESUMEN
Trichoderma spp. are main producers of peptide antibiotics known as peptaibols. While peptaibols have been shown to possess a range of biological activities, molecular understanding of the regulation of their production is largely unclear, which hampers the production improvement through genetic engineering. Here, we demonstrated that the orthologue of glucose sensors in the outstanding biocontrol fungus Trichoderma longibrachiatum SMF2, TlSTP1, participates in the regulation of peptaibols production. Deletion of Tlstp1 markedly impaired hyphal growth and conidiation, but significantly increased peptaibols yield by 5-fold for Trichokonins A and 2.6-fold for Trichokonins B. Quantitative real-time polymerase chain reaction analyses showed that the increased peptaibols production occurs at the transcriptional levels of the two nonribosomal peptide synthetase encoding genes, tlx1 and tlx2. Transcriptome analyses of the wild type and the Tlstp1 mutant strains indicated that TlSTP1 exerts a regulatory effect on a set of genes that are involved in a number of metabolic and cellular processes, including synthesis of several other secondary metabolites. These results suggest an important role of TlSTP1 in the regulation of vegetative growth and peptaibols production in T. longibrachiatum SMF2 and provide insights into construction of peptaibol-hyperproducing strains through genetic engineering.
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Proteínas Fúngicas , Peptaiboles/biosíntesis , Péptido Sintasas , Trichoderma , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Glucosa/metabolismo , Peptaiboles/genética , Péptido Sintasas/genética , Péptido Sintasas/metabolismo , Trichoderma/genética , Trichoderma/metabolismoRESUMEN
BACKGROUND: Structurally stable α-galactosidases are of great interest for various biotechnological applications. More thermophilic α-galactosidases with high activity and structural stability have therefore to be mined and characterized. On the other hand, few studies have been performed to prominently enhance the AOX1 promoter activity in the commonly used Pichia pastoris system, in which production of some heterologous proteins are insufficient for further study. RESULTS: ReGal2 encoding a thermoactive α-galactosidase was identified from the thermophilic (hemi)cellulolytic fungus Rasamsonia emersonii. Significantly increased production of ReGal2 was achieved when ReGal2 was expressed in an engineered Pastoris pichia expression system with a modified AOX1 promoter and simultaneous fortified expression of Mxr1 that is involved in transcriptionally activating AOX1. Purified ReGal2 exists as an oligomer and has remarkable thermo-activity and thermo-tolerance, exhibiting maximum activity of 935 U/mg towards pNPGal at 80 °C and retaining full activity after incubation at 70 °C for 60 h. ReGal2 is insensitive to treatments by many metal ions and exhibits superior tolerance to protein denaturants. Moreover, ReGal2 efficiently hydrolyzed stachyose and raffinose in soybeans at 70 °C in 3 h and 24 h, respectively. CONCLUSION: A modified P. pichia expression system with significantly enhanced AOX1 promoter activity has been established, in which ReGal2 production is markedly elevated to facilitate downstream purification and characterization. Purified ReGal2 exhibited prominent features in thermostability, catalytic activity, and resistance to protein denaturants. ReGal2 thus holds great potential in relevant biotechnological applications.
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Eurotiales/enzimología , Pichia , Proteínas Recombinantes , alfa-Galactosidasa , Clonación Molecular , Proteínas Fúngicas/genética , Expresión Génica , Cinética , Pichia/genética , Pichia/metabolismo , Regiones Promotoras Genéticas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , alfa-Galactosidasa/química , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismoRESUMEN
Habronematid nematodes were collected from the stomachs of donkeys, Equus asinus L., in the Tarim Basin, Xinjiang, China. After examination by light and scanning electron microscopy, Habronema muscae (Carter, 1861) and H. majus (Creplin, 1849) were identified. The morphology of our specimens representing H. muscae (Carter, 1861) agreed well with previous redescriptions in the shape of the lateral lips, origin of the lateral alae, ratio of left and right spicules, and number and arrangement of caudal papillae. However, H. majus (Creplin, 1849) differs from H. microstoma (Schneider, 1866) in the arrangement of the caudal papillae in the male. Moreover, molecular analysis also showed interspecific differences of 26.2-28.2% in ITS2 and 8.6-8.9% in cox1 between H. majus and H. microstoma, a divergence much higher than the known intraspecific variation of Habronema spp. (6.6-8.7% in ITS2; 0.2-2.2% in cox1). The results indicate that both H. microstoma (Schneider, 1866) and H. majus (Creplin, 1849) are valid species.
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Equidae/parasitología , Spiruroidea/clasificación , Animales , China , ADN Espaciador Ribosómico/genética , Complejo IV de Transporte de Electrones/genética , Femenino , Variación Genética , Masculino , Especificidad de la Especie , Spiruroidea/anatomía & histología , Spiruroidea/genéticaRESUMEN
UNLABELLED: Peptide uptake is important for nutrition supply for marine bacteria. It is also an important step in marine nitrogen cycling. However, how marine bacteria absorb peptides is still not fully understood. DppA is the periplasmic dipeptide binding protein of dipeptide permease (Dpp; an important peptide transporter in bacteria) and exclusively controls the substrate specificity of Dpp. Here, the substrate binding specificity of deep-sea Pseudoalteromonas sp. strain SM9913 DppA (PsDppA) was analyzed for 25 different dipeptides with various properties by using isothermal titration calorimetry measurements. PsDppA showed binding affinities for 8 dipeptides. To explain the multispecific substrate recognition mechanism of PsDppA, we solved the crystal structures of unliganded PsDppA and of PsDppA in complex with 4 different types of dipeptides (Ala-Phe, Met-Leu, Gly-Glu, and Val-Thr). PsDppA alternates between an "open" and a "closed" form during substrate binding. Structural analyses of the 4 PsDppA-substrate complexes combined with mutational assays indicate that PsDppA binds to different substrates through a precise mechanism: dipeptides are bound mainly by the interactions between their backbones and PsDppA, in particular by anchoring their N and C termini through ion-pair interactions; hydrophobic interactions are important in binding hydrophobic dipeptides; and Lys457 is necessary for the binding of dipeptides with a C-terminal glutamic acid or glutamine. Additionally, sequence alignment suggests that the substrate recognition mechanism of PsDppA may be common in Gram-negative bacteria. All together, our results provide structural insights into the multispecific substrate recognition mechanism of marine Gram-negative bacterial DppA, which provides a better understanding of the mechanisms of marine bacterial peptide uptake. IMPORTANCE: Peptide uptake plays a significant role in nutrition supply for marine bacteria. It is also an important step in marine nitrogen cycling. However, how marine bacteria recognize and absorb peptides is still unclear. This study analyzed the substrate binding specificity of deep-sea Pseudoalteromonas sp. strain SM9913 DppA (PsDppA; the dipeptide-binding protein of dipeptide permease) and solved the crystal structures of unliganded PsDppA and PsDppA in complex with 4 different types of dipeptides. The multispecific recognition mechanism of PsDppA for dipeptides is explained based on structural and mutational analyses. We also find that the substrate-binding mechanism of PsDppA may be common in Gram-negative bacteria. This study sheds light on marine Gram-negative bacterial peptide uptake and marine nitrogen cycling.
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Dipéptidos/metabolismo , Regulación Bacteriana de la Expresión Génica/fisiología , Pseudoalteromonas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Clonación Molecular , Dipéptidos/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Mutagénesis Sitio-Dirigida , Océanos y Mares , Conformación Proteica , Especificidad por SustratoRESUMEN
MRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-intermediate S. pneumoniae (PISP), and vancomycin-resistant enterococci (VRE). In this study, the in vivo efficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.
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Antibacterianos/uso terapéutico , Oxazolidinonas/uso terapéutico , Penicilinas/uso terapéutico , Animales , Antibacterianos/farmacología , Femenino , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Oxazolidinonas/farmacología , Penicilinas/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
As regulators of the surface land processes, soil fauna communities are the vital foundations for healthy terrestrial ecosystems. Soil fauna have been studied in China for more than 70 years. Great progresses have been achieved in exploring soil fauna species composition and geographical distribution patterns. Soil fauna eco-geography, as a bridge between soil fauna geographic patterns and ecosystem services, has a new development opportunity with the deep recognition of soil fauna ecological functions. Soil fauna eco-geography research could be partitioned into four dimensions including the spatio-temporal patterns of: 1) the apparent characteristics of soil fauna community, such as species composition, richness and abundance; 2) the intrinsic characteristics of soil fauna community, such as dietary and habits; 3) soil fauna-related biotic and abiotic interactions especially those indicating drivers of soil fauna community structure or shaping the roles of soil fauna in ecosystems; and 4) soil fauna-related or -regulated key ecological processes. Current studies focus solely on soil fauna themselves and their geographical distributions. To link soil fauna geography more closely with ecosystem services, we suggested that: 1) converting the pure biogeography studies to those of revealing the spatio-temporal patterns of the soil fauna-related or regulated key relationships and ecological processes;2) expanding the temporal and spatial scales in soil fauna geographical research;3) exploring the integrated analysis approach for soil fauna-related data with multi-scales, multi-factors, and multi-processes;and 4) establishing standard reference systems for soil fauna eco-geographical researches. Hence, the change patterns of ecological niche of soil fauna communities could be illustrated, and precision mani-pulations of soil fauna communities and their ecological functions would become implementable, which finally contributes to ecosystem health and human well-being.
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Biodiversidad , Ecosistema , Suelo , China , Suelo/química , Animales , Invertebrados/clasificación , Invertebrados/crecimiento & desarrollo , GeografíaRESUMEN
In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC50 = 0.034 µM), HCT-116 (IC50 = 0.081 µM) and KYSE30 cells (IC50 = 0.19 µM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of ß-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of ß-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents.
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Antineoplásicos , Neoplasias Gástricas , Humanos , Colchicina/farmacología , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Simulación del Acoplamiento Molecular , Neoplasias Gástricas/tratamiento farmacológico , Polimerizacion , Proliferación Celular , Sitios de Unión , Cumarinas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
The Internet Data Center (IDC) is one of the most important infrastructures in the field of information technology. The cooling system for heat dissipation of IDC is indispensable due to it generates a large amount of heat during its calculation process, which may potentially harm its normal operation. Electronic fluorinated fluids have been widely used in cooling systems of IDC with stable physical and chemical properties. However, the biological toxicity of electronic fluorinated fluids has not been fully evaluated and there is a lack of unified safety standards, which may pose potential risks to the environment and human health. Here, hexafluoropropylene terpolymer (HFPT) as an example has been systematically studied, fully considering the application scenarios of data centers. Also, the emergency effects of fluorinated coolants in mammalian models from the perspectives of inhalation, skin contact, accidental entry into eyes, accidental ingestion, and chronic toxicity, are evaluated. Multiple in vivo experiments have proven that HFPT not only has stable physical and chemical properties, that can maintain the safe operation of IDC, but also has low physiological toxicity to mammals and can provide health benefits to data center staff and the assurance of surrounding environment. This study proves the good biological safety of electronic fluorinated fluids and provides a reference for environmental assessment and risk management of liquid cooling technology in IDC. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00234-3.
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Several lines of evidence show that the nephrotoxic effect of melamine (MEL) in animals is consistent with combined ingestion of MEL and cyanuric acid (CYA). The aim of the present study was to compare the toxicokinetics of MEL in the presence and absence of CYA, and to elucidate the correlation between toxicity and kinetic properties of MEL. Sprague-Dawley rats were administered a single oral dose of MEL (100 mg kg(-1) ) with or without CYA (100 mg kg(-1) ). Plasma and tissue samples were analyzed by liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay. Significant changes in toxicokinetic parameters of MEL such as lower maximum concentration (7.4 ± 3.5 vs 78.0 ± 11.0 µg ml(-1) ) and area under curve (94.9 ± 53.5 vs 295.1 ± 93.7 µg h ml(-1) ), higher plasma elimination half-life (7.0 ± 3.3 vs 2.5 ± 0.3 h) and volume of distribution (11 505.5 ± 5030.3 vs 1312.7 ± 337.7 ml kg(-1) ), as well as significantly higher concentration of MEL in rat kidney (2.96-274.15 vs < 1 µg g(-1) ) were detected in the CYA co-administration group when compared with MEL alone group (P < 0.05). The differences in kinetic parameters between the two groups meant that CYA co-administration could lower absorption, slow excretion and induce tissue accumulation of MEL, which correlated well with the generation and development of renal toxicity. In conclusion, co-administration with CYA leads to the alteration of the kinetic characteristics of MEL, which provides an additional explanation for renal toxicity.
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Triazinas/toxicidad , Animales , Área Bajo la Curva , Disponibilidad Biológica , Nitrógeno de la Urea Sanguínea , Calibración , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Espectrometría de Masas , Farmacocinética , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Caracteres Sexuales , Triazinas/sangre , Triazinas/farmacocinéticaRESUMEN
Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase (GH) family 8. The recombinant XynB comprises an N-terminal domain (NTD) with unknown function and a catalytic domain, which is structurally novel among the characterized xylanases of GH family 8. XynB has the highest identity (38%) to rXyn8 among the characterized xylanases. The recombinant XynB showed maximal activity at pH 6-7 and 35 °C. It is thermolabile and salt-tolerant. XynB is an endo-xylanase that demands at least five sugar moieties for effective cleavage and to hydrolyze xylohexaose and xylopentaose into xylotetraose, xylotriose and xylobiose. NTD was expressed in Escherichia coli to analyze its function. The recombinant NTD exhibited a high binding ability to insoluble xylan and avicel and little binding ability to chitosan and chitin. Since the NTD shows no obvious homology to any known carbohydrate-binding module (CBM) sequence in public databases, XynB may contain a new type of CBM.
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Alteromonadaceae/enzimología , Clonación Molecular , Endo-1,4-beta Xilanasas/metabolismo , Escherichia coli/enzimología , beta-Glucosidasa/metabolismo , Alteromonadaceae/genética , Endo-1,4-beta Xilanasas/genética , Endo-1,4-beta Xilanasas/aislamiento & purificación , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Concentración de Iones de Hidrógeno , Tolerancia a la Sal , Temperatura , beta-Glucosidasa/genética , beta-Glucosidasa/aislamiento & purificaciónRESUMEN
INTRODUCTION: Post-operative nausea and/or vomiting (PONV) is a common post-operative adverse reaction and has been associated with post-operative sufentanil injection. The assessment of the relationship between intraoperative opioid consumption and PONV has been understudied. This study examined the relationship between intraoperative sufentanil administration and PONV. METHODS: This was a single-center retrospective observational study. Patients who underwent video-assisted thoracoscopic surgery under general anesthesia with the preoperative thoracic paravertebral block between January 2017 and June 2020 at the Peking University People's Hospital were recruited for this study. Patients were grouped into two groups according to whether or not PONV occurred on postoperative day 1 (POD1). The factors associated with PONV were analyzed using logistic regression. RESULTS: A total of 2733 patients, 1510 males and 1223 females, were included in this study. Among them, 143 patients developed PONV, a 5.2% (143/2733) PONV incidence. Logistic regression analysis showed that female, nonsmoking, sufentanil patient-controlled intravenous analgesia (PCIA), POD1 opioids consumption, and a time-weighted average of intraoperative sufentanil (twSuf) were associated with PONV. All patients were further divided into four subgroups based on intraoperative twSuf. Logistic regression analysis revealed that twSuf higher than 0.21 µg kg-1 h-1 was an independent risk factor for PONV. CONCLUSIONS: Intraoperative sufentanil injection with a twSuf higher than 0.21 µg kg-1 h-1 increased the risk of PONV in patients undergoing thoracoscopic surgery under general anesthesia after a preoperative thoracic paravertebral block.
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Background: Information seeking, as an important part of the prevention and control of infectious diseases, can lead to positive outcomes by reducing uncertainty and alleviating panic. However, most previous studies have limited their analysis to individual-level psychosocial factors, and little is known about how social-level factors influence individuals' information-seeking intentions. Methods: The cross-sectional survey was conducted from July 30, 2020 to August 15, 2020 in China. We used a convenience sampling strategy to recruit participants from among the Internet users. The structural equation model was used to identify the incentives associated with coronavirus disease 2019 (COVID-19) risk information-seeking intention. Results: In this study, the responses of 871 Internet users who reflected a response rate of 85% were analyzed. Information-seeking intention was found to be directed by informational subjective norms (ISNs), perceived information need, risk knowledge, the sense of community (SOC), and negative affective responses, and ISNs were found to be the strongest driving factor. Individuals with a stronger SOC, which was associated with greater pressure and expectations, show negative affective responses. COVID-19 risk knowledge can affect the information-seeking intention of Internet users not only directly but also indirectly through their perceived information need. In addition, more risk knowledge was associated with a lower perceived risk likelihood. Conclusion: When formulating risk communication strategies, governments and health institutions should take targeted measures to improve the public's SOC and knowledge. This will provide an opportunity to explore the role of individual cognition and environmental risk information in public health.
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Histone deacetylases, as a new class of anticancer targets, could maintain homeostasis by catalyzing histone deacetylation and play important roles in regulating the expression of target genes. Due to the fact that simultaneous intervention with dual tumor related targets could improve treatment effects, researches on innovative design of dual-target drugs are underway. HDAC is known as a "sensitizer" for the synergistic effects with other anticancer-target drugs because of its flexible structure design. The synergistic effects of HDAC inhibitor and other target inhibitors usually show enhanced inhibitory effects on tumor cells, and also provide new strategies to overcome multidrug resistance. Many research groups have reported that simultaneously inhibiting HDAC and other targets, such as tubulin, EGFR, could enhance the therapeutic effects. The o-aminobenzamide group is often used as a ZBG group in the design of HDAC inhibitors with potent antitumor effects. Given the prolonged inhibitory effects and reduced toxic side effects of HDAC inhibitors using o-aminobenzamide as the ZBG group, the o-aminobenzamide group is expected to become a more promising alternative to hydroxamic acid. In fact, o-aminobenzamide-based dual inhibitors of HDAC with different chemical structures have been extensively prepared and reported with synergistic and enhanced anti-tumor effects. In this work, we first time reviewed the rational design, molecular docking, inhibitory activities and potential application of o-aminobenzamide-based HDAC inhibitors with dual targeting capabilities in cancer therapy, which might provide a reference for developing new and more effective anticancer drugs.
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Antineoplásicos , Neoplasias , Inhibidores de Histona Desacetilasas/química , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Antineoplásicos/química , Tubulina (Proteína) , Proliferación Celular , Neoplasias/tratamiento farmacológicoRESUMEN
As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 µM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.
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Antineoplásicos , Neoplasias Gástricas , Humanos , Tranilcipromina/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Antineoplásicos/farmacología , Histona Demetilasas/metabolismo , Relación Estructura-Actividad , Proliferación CelularRESUMEN
Background: Neuroblastoma (NB) is a cancer that arises from neural-crest-derived sympathoadrenal lineage. Less is known about the pathogenesis and molecular characteristics of MYCN non-amplified (MYCN-NA) NB. Methods: We constructed a signature model targeting mucin family according to RNA sequencing data from GSE49710 dataset, and validated the prognostic performance. We also analyzed the gene expression matrix using DESeq2 R packages to screen the most differential mucin in high-risk NB samples. We further assessed its prognostic value, particularly in MYCN-NA NB samples. Moreover, we performed functional experiments to evaluate the impact of MUC15 overexpression on the migration of MYCN-NA NB cell lines. Results: The 8-mucin signature model showed good prognostic performance in the GSE49710 dataset. Among the mucin genes, MUC15 was significantly upregulated in the high-risk NB cohort and was associated with poor prognosis, especially in MYCN-NA NB samples. Furthermore, MUC15 overexpression and exogenous MUC15 protein enhanced the migration of MYCN-NA NB cell lines. Mechanistically, MUC15 promoted the phosphorylation of focal adhesion kinase (FAK) by inhibiting the expression of MYCT1, a target of c-Myc. Conclusions: Our findings suggested a potential network in controlling NB cell metastasis. Targeting MUC15 in MYCN-NA NB patients could be a promising therapeutic strategy.