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BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor with a very poor prognosis. Pyroptosis is an inflammatory form of cell death and plays an important role in cancer development. The prognostic value of pyroptosis-related genes (PRGs) in HCC has not been studied extensively. METHODS: Unsupervised consensus clustering analysis was performed to identify two subtypes based on the expression profiles of prognostic PRGs in the The Cancer Genome Atlas (TCGA) database, and the differences between the two subtypes were compared. A prognostic model based on four PRGs was established by further least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox regression analysis. RESULTS: Two subtypes (clusters 1 and 2) were identified by consensus clustering based on prognostic PRGs in HCC. Survival outcomes, biological function, genomic alterations, immune cell infiltration, and immune checkpoint genes were compared between the subtypes. Cluster 2 had a worse survival outcome than cluster 1. Cluster 2 was enriched for hallmarks of cancer progression, TP53 mutation, tumor-promoting immune cells, and immune checkpoint genes, which may contribute to the poor prognosis. A prognostic risk signature that predicted the overall survival (OS) of patients was constructed and validated. Consequently, a risk score was calculated for each patient. Combined with the clinical characteristics, the risk score was found to be an independent prognostic factor for survival of HCC patients. Further analysis revealed that the risk score was closely associated with the levels of immune cell infiltration and the expression profiles of immune checkpoint genes. CONCLUSIONS: Collectively, our study established a prognostic risk signature for HCC and revealed a significant correlation between pyroptosis and the HCC immune microenvironment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Prognóstico , Piroptose/genética , Microambiente Tumoral/genéticaRESUMO
The security issue of wireless communication is a common concern because of its broadcast nature, especially when the relay becomes an eavesdropper. In the orthogonal frequency division multiplexing (OFDM) relay system, when the relay is untrusted, the security of the system faces serious threats. Although there exist some resource allocation schemes in a single-carrier system with untrusted relaying, it is difficult to apply them to the multi-carrier system. Hence, a resource allocation scheme for the multi-carrier system is needed. Compared to the one-way relay system, a two-way relay system can improve the data transmission efficiency. In this paper, we consider joint secure resource allocation for a two-way cooperative OFDM system with an untrusted relay. The joint resource allocation problem of power allocation and subcarrier pairing is formulated to maximize the sum secrecy rate of the system under individual power constraints. To solve the non-convex problem efficiently, we propose an algorithm based on the alternative optimization method. The proposed algorithm is evaluated by simulation results and compared with the benchmarks in the literature. According to the numerical results, in a high signal-to-noise ratio (SNR) scenario, the proposed algorithm improves the achievable sum secrecy rate of the system by more than 15% over conventional algorithms.
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The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment.
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Antivirais/farmacologia , Ciclofilina A/antagonistas & inibidores , Diamida/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Terapia de Alvo Molecular , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Ciclofilina A/genética , Ciclofilina A/metabolismo , Diamida/síntese química , Diamida/química , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hepatite C Crônica/metabolismo , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ressonância de Plasmônio de SuperfícieRESUMO
Kentucky bluegrass (KB, Poa pratensis) is one of the most widely used cool-season turfgrass species, but it is sensitive to drought stress. Molecular studies in KB are hindered by its large and complex genome structure. In this study, a comparative transcriptomic study was conducted between a short and long period of water deficiency. Three transcriptome libraries were constructed and then sequenced by using leaf RNA samples of plants at 0, 2, and 16 h after PEG6000 treatment. A total of 199,083 differentially expressed genes (DEGs) were found. The Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation revealed that DEGs were enriched in "Plant hormone signal transduction" and "MAPK signaling pathway-Plant". Some key up-regulated genes, including PYL, JAZ, and BSK, were involved in hormone signaling transduction of abscisic acid, jasmonic acid, and brassinosteroid and possibly these genes play important roles in coping with drought stress in KB. Furthermore, our results showed that the concentrations of ABA, JA and BR increased significantly with the extension of the drought period. The specific DEGs encoding functional proteins, kinase and transcription factors, could be valuable information for genetic manipulation to promote drought tolerance of KB in the future.
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Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Poa/crescimento & desenvolvimento , Estresse Fisiológico , Ácido Abscísico/biossíntese , Brassinosteroides/biossíntese , Ciclopentanos/metabolismo , Secas , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Kentucky , Anotação de Sequência Molecular , Oxilipinas/metabolismo , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Poa/genética , Poa/metabolismo , Análise de Sequência de RNARESUMO
The Q8 compound is a unique derivative of berberine. The present study investigated the functional role of Q8 to evaluate its potential for use in bone regeneration, especially in osteoblast differentiation. The safe concentration of Q8 increased BMP4-induced alkaline phosphatase (ALP) activity, and induced RNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OC). The activities of ALP-, BSP- and OC-luciferase reporters were also increased by Q8. During osteoblast differentiation, Q8 stabilized the Runx2 and Osterix protein abundance by blocking the ubiquitin-proteasome pathway, which in turn promoted Runx2 and Osterix induced transcriptional activity and subsequently increased the osteoblast differentiation. Meanwhile, depletion of Runx2 and Osterix markedly abolished the bone anabolic effect of Q8 on osteoblast differentiation. To evaluate the signal transduction pathway involved in the Q8-mediated regulation of Runx2 and Osterix, we examined the reporter assay using various kinase inhibitors. Treatment with a protein kinase A (PKA) inhibitor, H89 inhibited the Q8-mediated regulation of Runx2 and Osterix. Based on these findings, this study demonstrates that Q8 promotes the osteoblast differentiation by stabilization of Runx2/Osterix through the increased activation of PKA signaling. The enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis.
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Berberina/análogos & derivados , Berberina/farmacologia , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células HEK293 , Humanos , Camundongos , Osteoblastos/metabolismo , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Fator de Transcrição Sp7 , Fatores de Transcrição/metabolismoRESUMO
Yogurt products fermented with probiotic bacteria are a consumer trend and a challenge for functional food development. So far, limited research has focused on the behavior of the various probiotic strains used in milk fermentation. In the present study, we characterized folic acid production and the sensory and textural characteristics of yogurt products fermented with probiotic bacteria. Yogurt fermented with Lactobacillus plantarum had improved nutrient content and sensory and textural characteristics, but the presence of L. plantarum significantly impaired the growth and survival of Lactobacillus delbrueckii ssp. bulgaricus during refrigerated storage. Overall, L. plantarum was a good candidate for probiotic yogurt fermentation; further studies are needed to understand the major metabolite path of lactic acid bacteria in complex fermentation.
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Fermentação , Ácido Fólico/administração & dosagem , Lactobacillus plantarum/fisiologia , Leite/química , Leite/microbiologia , Probióticos , Complexo Vitamínico B/administração & dosagem , Iogurte/microbiologia , Animais , Alimento Funcional , Lactobacillus delbrueckii/crescimento & desenvolvimentoRESUMO
Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50=0.35µM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications.
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Antagonistas de Receptores de Andrógenos/síntese química , Antineoplásicos/síntese química , Desenho de Fármacos , Próstata/efeitos dos fármacos , Receptores Androgênicos/química , Motivos de Aminoácidos , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Expressão Gênica , Genes Reporter , Luciferases/genética , Luciferases/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Niacinamida/química , Próstata/metabolismo , Estrutura Secundária de Proteína , Pirazinamida/química , Pirimidinas/química , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50=6.9µM) and 7h (IC50=12.2µM) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure- and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases.
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Aminopiridinas/química , Aminopiridinas/farmacologia , Desenho Assistido por Computador , Descoberta de Drogas , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células HT29 , Humanos , Concentração Inibidora 50RESUMO
Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia-reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.
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Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.
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Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.
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Due to its decade-long progression, colorectal cancer (CRC) is most suitable for population screening to achieve a significant reduction in its incidence and mortality. DNA methylation has emerged as a potential marker for the early detection of CRC. However, the current mainstream methylation detection method represented by bisulfite conversion has issues such as tedious operation, DNA damage, and unsatisfactory sensitivity. Herein, a new high-performance CRC screening tool based on the promising specific terminal-mediated polymerase chain reaction (STEM-PCR) strategy is developed. CRC-related methylation-specific candidate CpG sites are first prescreened through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using self-developed bioinformatics. Next, 9 homebrew colorectal cancer DNA methylated STEMâPCR assays (ColoC-mSTEM) with high sensitivity (0.1%) and high specificity are established to identify candidate sites. The clinical diagnostic performance of these selected methylation sites is confirmed and validated by a case-control study. The optimized diagnostic model has an overall sensitivity of 94.8% and a specificity of 95.0% for detecting early-stage CRC. Taken together, ColoC-mSTEM, based on a single methylation-specific site, is a promising diagnostic approach for the early detection of CRC which is perfectly suitable for the screening needs of CRC in primary healthcare institutions.
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Background: Both long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) are widely used in the treatment of chronic obstructive pulmonary disease (COPD). A novel LAMA/LABA combination of umeclidinium/vilanterol (UMEC/VI; 62.5 µg/25 µg) is approved for chronic obstructive pulmonary disease (COPD) treatment. Objective: This study aimed to assess the efficacy and cost-effectiveness of UMEC/VI versus tiotropium (TIO) 18 µg in symptomatic patients with COPD from the perspective of the Chinese National Healthcare System. Methods: A simple analysis included three studies in the meta-analysis that compared UMEC/VI with TIO. A Markov model was developed to estimate the cost-effectiveness of UMEC/VI compared with TIO treatment in symptomatic patients with COPD. First, utilities, clinical efficacy, and adverse events obtained from the literature were utilized as model inputs. Costs were from Chinese average data, including local data. Costs were expressed in dollars based on 2020 prices. Then, the model outputs including drug costs, other medical costs, and total costs, and quality-adjusted life years (QALYs) were estimated. Costs and outcomes were discounted at a 5% annual rate. Furthermore, incremental cost-effective ratios (ICERs) were analyzed. Finally, the influences of changing parameters on the uncertainty of the results were assessed by means of one-way and probabilistic sensitivity analyses. Results: This study revealed that UMEC/VI treatment had a higher rate of clinical efficacy in comparison with TIO, and the differences in the rate of adverse events between the two treatments were not significant. The results indicated that UMEC/VI was superior to TIO, which provided an increase in QALYs (0.002) and a total cost savings of $765.67 per patient over 3 years. In the base case, the ICER of UMEC/VI is -$397468.04/QALY compared with TIO, suggesting that UMEC/VI may be considered a dominant option over TIO. According to the Chinese medical system, the probability of UMEC/VI being cost-effective was 61.6% at a willingness-to-pay (WTP) of $31554/QALY. Sensitivity analyses confirmed that the results were robust. Conclusion: UMEC/VI could be considered a cost-effective treatment compared with TIO in symptomatic COPD patients from the Chinese National Healthcare System perspective. These results may help decision-makers in China when making judgements on which treatments to administer.
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Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Álcoois Benzílicos , Broncodilatadores/uso terapêutico , Clorobenzenos , Análise Custo-Benefício , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Quinuclidinas , Brometo de Tiotrópio/uso terapêutico , Resultado do TratamentoRESUMO
DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m6A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m6A modification in PDAC cells. The m6A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m6A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m6A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC.
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Adenosina/análogos & derivados , Dano ao DNA/genética , Reparo do DNA/genética , Flavonóis/genética , Proteínas de Homeodomínio/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Proteínas de Ligação a RNA/genética , Adenosina/genética , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Humanos , Rad51 Recombinase/genética , Reparo de DNA por Recombinação/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Neoplasias PancreáticasRESUMO
BACKGROUND: It remains controversial as to which pathological classification is most valuable in predicting the overall survival (OS) of patients with gastric cancer (GC). AIM: To assess the prognostic performances of three pathological classifications in GC and develop a novel prognostic nomogram for individually predicting OS. METHODS: Patients were identified from the Surveillance, Epidemiology, and End Results program. Univariate and multivariate analyses were performed to identify the independent prognostic factors. Model discrimination and model fitting were evaluated by receiver operating characteristic curves and Akaike information criteria. Decision curve analysis was performed to assess clinical usefulness. The independent prognostic factors identified by multivariate analysis were further applied to develop a novel prognostic nomogram. RESULTS: A total of 2718 eligible GC patients were identified. The modified Lauren classification was identified as one of the independent prognostic factors for OS. It showed superior model discriminative ability and model-fitting performance over the other pathological classifications, and similar results were obtained in various patient settings. In addition, it showed superior net benefits over the Lauren classification and tumor differentiation grade in predicting 3- and 5-year OS. A novel prognostic nomogram incorporating the modified Lauren classification showed superior model discriminative ability, model-fitting performance, and net benefits over the American Joint Committee on Cancer 8th edition tumor-node-metastasis classification. CONCLUSION: The modified Lauren classification shows superior net benefits over the Lauren classification and tumor differentiation grade in predicting OS. A novel prognostic nomogram incorporating the modified Lauren classification shows good model discriminative ability, model-fitting performance, and net benefits.
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OBJECTIVE: Studying the diagnostic value of CT imaging in non-small cell lung cancer (NSCLC), and establishing a prognosis model combined with clinical characteristics is the objective, so as to provide a reference for the survival prediction of NSCLC patients. METHOD: CT scan data of NSCLC 200 patients were taken as the research object. Through image segmentation, the radiology features of CT images were extracted. The reliability and performance of the prognosis model based on the optimal feature number of specific algorithm and the prognosis model based on the global optimal feature number were compared. RESULTS: 30-RELF-NB (30 optimal features, RELF feature selection algorithm and NB classifier) has the highest accuracy and AUC (area under the subject characteristic curve) in the prognosis model based on the optimal features of specific algorithm. Among the prognosis models based on global optimal features, 25-NB (25 global optimal features, naive Bayes classification algorithm classifier) has the highest accuracy and AUC. Compared with the prediction model based on feature training of specific feature selection algorithm, the overall performance and stability of the prediction model based on global optimal feature are higher. CONCLUSION: The prognosis model based on the global optimal feature established in this paper has good reliability and performance, and can be applied to the CT radiology of NSCLC.
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Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 µM, but no cytotoxicity at 100 µM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 µM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.
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Amidas/farmacologia , Antivirais/farmacologia , Ciclofilina A/antagonistas & inibidores , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Amidas/síntese química , Amidas/química , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Ciclofilina A/metabolismo , Relação Dose-Resposta a Droga , Hepacivirus/metabolismo , Hepatite C/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Células Tumorais CultivadasRESUMO
Phytoremediation is an effective approach to control soil heavy metal pollution. This study isolated a fungus strain from soils contaminated by cadmium (Cd) and lead (Pb) in Zhalong Wetland (China), which was identified as Simplicillium chinense QD10 via both genotypic and phenotypic analysis. The performance and mechanism of S. chinense QD10 in Cd and Pb adsorption was unraveled by morphological analysis and biosorption test, and its roles in ameliorating phytoremediation by Phragmites communis were tested in pot-experiments. Cd biosorption was attributed to the formation of Cd-chelate, whereas Pb was predominantly adsorbed by extracellular polymeric substances. Metal biosorption followed Langmuir isotherm, and the maximum biosorption capacity was 88.5 and 57.8â¯g/kg for Cd and Pb, respectively. Colonized in soils, such biosorption behavior of S. chinense QD10 can generate gradients of available Cr or Pb and drive their enrichment. Accordingly, S. chinense QD10 amendment significantly enhanced the phytoextraction of Cd and Pb by P. communis, possibly attributing to rhizospheric enrichment of Cd or Pb and defending effects on plants, explained by the significant removal of acid-extractable and reducible metals in soils and the increase of Cd and Pb content in P. communis tissues. The present study explored the mechanisms of S. chinense QD10 in Cd and Pb biosorption and proved its potential in ameliorating the phytoremediation performance at metal contaminated sites.
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Biodegradação Ambiental , Metais Pesados/metabolismo , Poluentes do Solo/metabolismo , Cádmio/metabolismo , China , Fungos/metabolismo , Chumbo/metabolismo , Metais Pesados/análise , Microbiologia do Solo , Poluentes do Solo/análiseRESUMO
With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 µM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.
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Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Isoquinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Biocatálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Tubulina (Proteína)/metabolismoRESUMO
The success rate of pre-hospital endotracheal intubation (ETI) by paramedics is lower than physicians. We aimed to establish a remote robot-assisted intubation system (RRAIS) and expected it to improve success rate of pre-hospital ETI. To test the robot's feasibility, 20 pigs were intubated by direct laryngoscope or the robot system. Intubation time, success rate, airway complications were recorded during the experiment. The animal experiment showed that participants achieved a higher success rate in absolute numbers by the robot system. In summary, we have successfully developed a remote robot-assisted intubation system. It is promising for RRAIS to improve the success rate of pre-hospital ETI and change the current rescue model.