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In this Letter, we describe quantitative magnetic imaging of superconducting vortices in RbEuFe_{4}As_{4} in order to investigate the unique interplay between the magnetic and superconducting sublattices. Our scanning Hall microscopy data reveal a pronounced suppression of the superfluid density near the magnetic ordering temperature in good qualitative agreement with a recently developed model describing the suppression of superconductivity by correlated magnetic fluctuations. These results indicate a pronounced exchange interaction between the superconducting and magnetic subsystems in RbEuFe_{4}As_{4}, with important implications for future investigations of physical phenomena arising from the interplay between them.
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The interactions between electrons and antiferromagnetic magnons (AFMMs) are important for a large class of correlated materials. For example, they are the most plausible pairing glues in high-temperature superconductors, such as cuprates and iron-based superconductors. However, unlike electron-phonon interactions (EPIs), clear-cut observations regarding how electron-AFMM interactions (EAIs) affect the band structure are still lacking. Consequently, critical information on the EAIs, such as its strength and doping dependence, remains elusive. Here we directly observe that EAIs induce a kink structure in the band dispersion of Ba1-xKxMn2As2, and subsequently unveil several key characteristics of EAIs. We found that the coupling constant of EAIs can be as large as 5.4, and it shows strong doping dependence and temperature dependence, all in stark contrast to the behaviors of EPIs. The colossal renormalization of electron bands by EAIs enhances the density of states at Fermi energy, which is likely driving the emergent ferromagnetic state in Ba1-xKxMn2As2 through a Stoner-like mechanism with mixed itinerant-local character. Our results expand the current knowledge of EAIs, which may facilitate the further understanding of many correlated materials where EAIs play a critical role.
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OBJECTIVES: Cancer cells differ from normal body cells in their ability to divide indefinitely and to evade programmed cell death. Crosstalk between apoptosis and cell cycle processes promotes balance between proliferation and death, and limits population growth and survival of cells. However, intricate relationships between them and how they are able to manipulate the fate of cancer cells still remain to be clarified. Identification of key factors involved in both apoptosis and cell cycle regulation may help to address this problem. MATERIALS AND METHODS: Identification of such key proteins was carried out, using a series of bioinformatics methods, such as network construction and key protein identification. RESULTS: In this study, we computationally constructed human apoptotic/cell cycle-related protein-protein interactions (PPIs) networks from five experimentally supported protein interaction databases, and further integrated these high-throughput data sets into a Naïve Bayesian model to predict protein functional connections. On the basis of modified apoptotic/cell cycle related PPI networks, we calculated and ranked all protein members involved in apoptosis and cell cycle regulation. Our results not only identified some already known key proteins such as p53, Rb, Myc and Src but also found that the proteasome, Cullin family members, kinases and transcriptional repressors play important roles in regulating apoptosis and the cell cycle. Furthermore, we found that the top 100 proteins ranked by PeC were enriched in some pathways such as those of cancer, the proteasome, the cell cycle and Wnt signalling. CONCLUSIONS: We constructed the global human apoptotic/cell cycle related PPI network based on five online databases, and a Naïve Bayesian model. In addition, we systematically identified apoptotic/cell cycle related key proteins in cancer cells. These findings may uncover intricate relationships between apoptosis and cell cycle processes and thus provide further new clues towards future anticancer drug discovery.
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Apoptosis , Ciclo Celular , Mapas de Interacción de Proteínas , Proteínas/metabolismo , Teorema de Bayes , Biología Computacional , Humanos , Neoplasias/metabolismoRESUMEN
OBJECTIVES: Protein kinases orchestrate activation of signalling cascades in response to extra- and intracellular stimuli for regulation of cell proliferation. They are directly involved in a variety of diseases, particularly cancers. Systems biology approaches have become increasingly important in understanding regulatory frameworks in cancer, and thus may facilitate future anti-cancer discoveries. Moreover, it has been suggested and confirmed that high-throughput virtual screening provides a novel, effective way to reveal small molecule protein kinase inhibitors. Accordingly, we aimed to identify kinase targets and novel kinase inhibitors. MATERIALS AND METHODS: A series of bioinformatics methods, such as network construction, molecular docking and microarray analyses were performed. RESULTS: In this study, we computationally constructed the appropriate global human protein-protein interaction network with data from online databases, and then modified it into a kinase-related apoptotic protein-protein interaction network. Subsequently, we identified several kinases as potential drug targets according to their differential expression observed by microarray analyses. Then, we predicted relevant microRNAs, which could target the above-mentioned kinases. Ultimately, we virtually screened a number of small molecule natural products from Traditional Chinese Medicine (TCM)@Taiwan database and identified a number of compounds that are able to target polo-like kinase 1, cyclin-dependent kinase 1 and cyclin-dependent kinase 2 in HeLa cervical carcinoma cells. CONCLUSIONS: Taken together, all these findings might hopefully facilitate discovery of new kinase inhibitors that could be promising candidates for anti-cancer drug development.
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Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Bases de Datos de Proteínas , Células HeLa , Humanos , MicroARNs/metabolismo , Simulación del Acoplamiento Molecular , Mapas de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Quinasa Tipo Polo 1RESUMEN
OBJECTIVES: The aim of this study was to explore sodium taurocholate co-transporting polypeptide (NTCP) exerting its function with hepatitis B virus (HBV) and its targeted candidate compounds, in HBV therapy. MATERIALS AND METHODS: Identification of NTCP as a novel HBV target for screening candidate small molecules, was used by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro virological examination, q-PCR, western blotting and cytotoxicity studies were used for validating efficacy of the candidate compound. RESULTS: We used the phylogenetic analysis of NTCP and constructed its protein-protein network. Also, we screened compounds from Drugbank and ZINC, among which five were validated for their authentication in HepG 2.2.15 cells. Then, we selected compound N4 (azelastine hydrochloride) as the most potent of them. This showed good inhibitory activity against HBsAg (IC50 = 7.5 µm) and HBeAg (IC50 = 3.7 µm), as well as high SI value (SI = 4.68). Further MD simulation results supported good interaction between compound N4 and NTCP. CONCLUSIONS: In silico analysis and experimental validation together demonstrated that compound N4 can target NTCP in HepG2.2.15 cells, which may shed light on exploring it as a potential anti-HBV drug.
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Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológico , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Ftalazinas/farmacología , Simportadores/metabolismo , Animales , Antivirales/química , Simulación por Computador , Diseño de Fármacos , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Ftalazinas/química , Filogenia , Simportadores/genéticaRESUMEN
OBJECTIVES: The legume lectin family, one of the most extensively studied plant lectin families, has received increasing attention for the remarkable anti-tumor activities of its members for binding specific cancer cell surface glycoconjugates. MicroRNAs, a class of small, non-coding RNAs, control translation and stability of mRNAs at post-transcriptional and translational levels. To date, accumulating evidence has revealed that microRNAs are involved in progression of a number of human diseases, especially cancers. However, the molecular manners of microRNA-modulated apoptosis in legume lectin-treated cancer cells are still under investigation. MATERIALS AND METHODS: We performed in silico analyses to study the interactions between three typical legume lectins (ConA, SFL and SAL) and some specific sugar-containing receptors (for example, EGFR, TNFR1, HSP70 and HSP90). Additionally, we predicted some relevant microRNAs which could significantly regulate these aforementioned targetreceptors and thus inhibiting down-stream cancer-related signaling pathways. RESULTS: The results showed that these three legume lectins could competitively bind sugar-containing receptors such as EGFR, TNFR1, HSP70 and HSP90 in two ways, via anti-apoptotic or survival pathways. On the one hand, the legume lectins could induce cancer cell death through triggering receptor-mediated signaling pathways, which resulted from indirect binding between legume lectins and mannoses resided in receptors. On the other hand, direct binding between legume lectins and receptors could lead to steric hindrance, which would disturb efficient interactions between them, and thus, the legume lectins would induce cancer cell death by triggering receptor-mediated signaling pathways. In addition, we identified several relevant microRNAs that regulated these targeted receptors, thereby ultimately causing cancer cell apoptosis. CONCLUSIONS: These findings provide new perspectives for exploring microRNA-modulated cell death in legume lectin-treated cancer cells, which could be utilized in combination therapy for future cancer drug development.
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Apoptosis/efectos de los fármacos , Lectinas/farmacología , Sitios de Unión , Concanavalina A/química , Concanavalina A/farmacología , Receptores ErbB/química , Receptores ErbB/metabolismo , Fabaceae/metabolismo , Proteínas HSP70 de Choque Térmico/química , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/metabolismo , Células HeLa , Humanos , Lectinas/química , MicroARNs/metabolismo , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Receptores Tipo I de Factores de Necrosis Tumoral/química , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Sophora/metabolismoRESUMEN
OBJECTIVES: Caspases, a family of cysteine proteases with unique substrate specificities, contribute to apoptosis, whereas autophagy-related genes (ATGs) regulate cytoprotective autophagy or autophagic cell death in cancer. Accumulating evidence has recently revealed underlying mechanisms of apoptosis and autophagy; however, their intricate relationships still remain to be clarified. Identification of caspase/ATG switches between apoptosis and autophagy may address this problem. MATERIALS AND METHODS: Identification of caspase/ATG switches was carried out using a series of elegant systems biology & bioinformatics approaches, such as network construction, hub protein identification, microarray analyses, targeted microRNA prediction and molecular docking. RESULTS: We computationally constructed the global human network from several online databases and further modified it into the basic caspase/ATG network. On the basis of apoptotic or autophagic gene differential expressions, we identified three molecular switches [including androgen receptor, serine/threonine-protein kinase PAK-1 (PAK-1) and mitogen-activated protein kinase-3 (MAPK-3)] between certain caspases and ATGs in human breast carcinoma MCF-7 cells. Subsequently, we identified microRNAs (miRNAs) able to target androgen receptor, PAK-1 and MAPK-3, respectively. Ultimately, we screened a range of small molecule compounds from DrugBank, able to target the three above-mentioned molecular switches in breast cancer cells. CONCLUSIONS: We have systematically identified novel caspase/ATG switches involved in miRNA regulation, and predicted targeted anti-cancer drugs. These findings may uncover intricate relationships between apoptosis and autophagy and thus provide further new clues towards possible cancer drug discovery.
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Autofagia/genética , Neoplasias de la Mama/enzimología , Caspasas/metabolismo , Autofagia/efectos de los fármacos , Sitios de Unión , Neoplasias de la Mama/patología , Caspasas/genética , Bases de Datos Genéticas , Femenino , Genes de Cambio/genética , Humanos , Células MCF-7 , MicroARNs/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Simulación del Acoplamiento Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Profármacos/química , Profármacos/farmacología , Estructura Terciaria de Proteína , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
OBJECTIVES: Lycoris is aurea agglutinin (LAA) has attracted rising attention due to its remarkable bioactivities. Here, we aimed at investigating its anti-tumor activities. MATERIAL AND METHODS: In vitro methods including MTT, cellular morphology observation, FCM and immunoblotting were performed. In vivo methods like detection of tumor volume, body weight and survival ratio, as well as TUNEL staining were performed. RESULTS AND CONCLUSION: LAA triggers G2 /M phase cell cycle arrest via up-regulating p21expression as well as down-regulating cdk-1cyclinA singling pathway, and induces apoptotic cell death through inhibiting PI3K-Akt survival pathway in human lung adenocarcinoma A549 cells. While LAA has no significant cytotoxic effect toward normal human embryonic lung fibroblast HELF cells, and moreover, LAA could amplify the antineoplastic effects of cisplatin toward A549 cells. Lastly LAA also bears anti-cancer and apoptosis-inducing effects in vivo, and it could decrease the volume and weight of subcutaneous tumor mass obviously as well as expand lifespan of mice. These findings may provide a new perspective for elucidating the complicated molecular mechanisms of LAA-induced cancer cell growth-inhibition and death, providing a new opportunity of LAA as a potential candidate anti-neoplastic drug for future cancer therapeutics.
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Adenocarcinoma/metabolismo , Apoptosis/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Lycoris/metabolismo , Adenocarcinoma del Pulmón , Aglutininas/farmacología , Antineoplásicos/farmacología , Proteína Quinasa CDC2/biosíntesis , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Ciclina A/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3 , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidoresRESUMEN
Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment.
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Muerte Celular , Neoplasias/metabolismo , Transducción de Señal , Animales , Muerte Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVES: Plant lectins, carbohydrate-binding proteins of non-immune origin, have recently been reported to induce programmed cell death (including apoptosis and autophagy) in many types of cancer cells. MicroRNAs (miRNAs), small, non-coding endogenous RNAs, ~22 nucleotides (nt) in length, have been well characterized to play essential roles in regulation of the autophagy process in cancer; however, how these miRNAs regulate autophagic pathways in plant lectin-induced cancer cells, still remains an enigma. MATERIALS AND METHODS: Identification of microRNA-regulated autophagic pathways was carried out using a series of elegant systems - biology and bioinformatics approaches, such as network construction, hub protein identification, targeted microRNA prediction, microarray analyses and molecular docking. RESULTS: We computationally constructed the human autophagic protein-protein interaction (PPI) network, and further modified this network into a plant lectin-induced network. Subsequently, we identified 9 autophagic hub proteins and 13 relevant oncogenic and tumour suppressive miRNAs, that could regulate these aforementioned targeted autophagic hub proteins, in human breast carcinoma MCF-7 cells. In addition, we confirmed that plant lectins could block the sugar-containing receptor EGFR-mediated survival pathways, involved in autophagic hub proteins and relevant miRNAs, thereby ultimately culminating in autophagic cell death. CONCLUSIONS: These results demonstrate that network-based identification of microRNAs modulate autophagic pathways in plant lectin-treated cancer cells, which may shed new light on the discovery of plant lectins as potent autophagic inducers, for cancer drug discovery.