RESUMEN
Kainoid synthases are key enzymes in the biosynthesis of kainoids. Kainoids, as represented by DA and KA, are a class of naturally occurring non-protein amino acids with strong neurotransmitter activity in the mammalian central nervous system. Marine algae kainoid synthases include PnDabC from diatoms, which synthesizes domoic acid (DA), and DsKabC and GfKabC from red algae, which synthesize kainic acid (KA). Elucidation of the catalytic mechanism of kainoid synthases is of great significance for the rational design of better biocatalysts to promote the industrial production of kainoids for use in new drugs. Through modeling, molecular docking, and molecular dynamics simulations, we investigated the conformational dynamics of kainoid synthases. We found that the kainoid synthase complexes showed different stability in the simulation, and the binding and catalytic processes showed significant conformational transformations of kainoid synthase. The residues involved in specific interactions with the substrate contributed to the binding energy throughout the simulation process. Binding energy, the relaxed active pocket, electrostatic potential energy of the active pocket, the number and rotation of aromatic residues interacting with substrates during catalysis, and the number and frequency of hydrogen bonds between the individual functional groups revealed the structure-activity relationships and affected the degree of promiscuity of kainoid synthases. Our research enriches the understanding of the conformational dynamics of kainoid synthases and has potential guiding significance for their rational design.
Asunto(s)
Diatomeas , Ácido Kaínico , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Ácido Kaínico/análogos & derivados , Diatomeas/enzimología , Rhodophyta/enzimología , Oxo-Ácido-Liasas/química , Oxo-Ácido-Liasas/metabolismo , Enlace de HidrógenoRESUMEN
Radiation-induced intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal, or retroperitoneal tumours. Recently, in the model of DSS (Dextran Sulfate Sodium Salt) -induced intestinal inflammatory injury, it has been found in the study that transgenic mice expressing hVDR in IEC (Intestinal Epithelial Cell) manifest highly anti-injury properties in colitis, suggesting that activated VDR in the epithelial cells of intestine may inhibit colitis by protecting the mucosal epithelial barrier. In this study, we investigated the effect of the expression and regulation of VDR on the protection of RIII, and the radiosensitivity in vitro experiments, and explored the initial mechanism of VDR in regulating radiosensitivity of IEC. As a result, we found that the expression of VDR in intestinal tissues and cells in mice can be induced by ionizing radiation. VDR agonists are able to prolong the average survival time of mice after radiation and reduce the radiation-induced intestinal injury. For lack of vitamin D, the radiosensitivity of intestinal epithelial cells in mice increased, which can be reduced by VDR activation. Ensuing VDR activation, the radiation-induced intestinal stem cells damage is decreased, and the regeneration and differentiation of intestinal stem cells is promoted as well. Finally, on the basis of sequencing analysis, we validated and found that VDR may target the HIF/PDK1 pathway to mitigate RIII. We concluded that agonism or upregulation of VDR expression attenuates radiation-induced intestinal damage in mice and promotes the repair of epithelial damage in intestinal stem cells.
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Colitis , Receptores de Calcitriol , Animales , Ratones , Colitis/patología , Sulfato de Dextran/efectos adversos , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Traumatismos Experimentales por RadiaciónRESUMEN
BACKGROUND: As one of the leading cause of cancer-related deaths in the worldwide, lung cancer needs to be understood better. Nowadays, increasing point mutations of specific oncogenes are biomarkers used to predict the therapeutic effect of targeted therapy and lung cancer has entered the age of individual treatment. At present, many relevant researchers have suggested that EGFR is a biomarker used to predict the therapeutic effect of targeted therapy. A large number of evidence indicates that EGFR/Akt pathway plays important role in cancer growth and metastasis. AIM OF THE STUDY: In this paper, we found EGFR was a target of miR-646. RESULTS: Overexpression of miR-646 not only downregulated EGFR/Akt pathway, but also inhibited lung cancer cell proliferation and metastasis. At the same time, miR-646 was a prognosis factor for overall survival. CONCLUSION: Our finding could provide new insights into the molecular therapeutic of lung cancer.
Asunto(s)
Antagomirs/uso terapéutico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Células A549 , Adulto , Anciano , Animales , Antagomirs/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , Persona de Mediana Edad , Terapia Molecular Dirigida , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución AleatoriaRESUMEN
ABSTRACT: With rapid technical advances, ionizing radiation has been put into wider application in ordinary living, with the worst cytological effect on the human body being cell death. Moreover, according to the Nomenclature Committee on Cell Death, the method of radiation-induced cell death, usually classified as interphase and proliferative death, undergoes more detailed classifications oriented by its molecular mechanism. Elaborating its mode and molecular mechanism is crucial for the protection and treatment of radiation injury, as well as the radiotherapy and recovery of tumors. Varying with the changes of the radiation dose and the environment, the diverse targets and pathways of ionizing radiation result in various cell deaths. This review focuses on classifications of radiation-induced cell death and its molecular mechanism. We also examine the main characteristics of ionizing radiation-induced cell death. The modes of radiation-induced cell death can be classified as apoptosis, necrosis, autophagy-dependent cell death, pyroptosis, ferroptosis, immunogenic cell death, and non-lethal processes. Once the dose is high enough, radiation effects mostly appear as destructiveness ("destructiveness" is used to describe a situation in which cells do not have the opportunity to undergo a routine death process, in which case high-dose radiation works like a physical attack). This breaks up or even shatters cells, making it difficult to find responses of the cell itself. Due to diversities concerning cell phenotypes, phases of cell cycle, radiation dose, and even cellular subregions, various methods of cell death occur, which are difficult to identify and classify. Additionally, the existence of common initial activation and signaling molecules among all kinds of cell deaths, as well as sophisticated crossways in cellular molecules, makes it more laborious to distinguish and classify various cell deaths.
Asunto(s)
Apoptosis , Neoplasias , Apoptosis/efectos de la radiación , Muerte Celular/efectos de la radiación , Humanos , Neoplasias/radioterapia , Radiación Ionizante , Transducción de Señal/efectos de la radiaciónRESUMEN
Polyvinyl pyrrolidone (PVP), playing roles as a templating agent, can be applied to prepare blue-emitting copper nanoclusters (Cu NCs@PVP) on the basis of a rapid chemical reduction synthesis method. The Cu NCs@PVP displayed a blue emission wavelength at 430 nm and the corresponding quantum yield (QY) could reach 10.4%. Subsequently, the as-synthesized Cu NCs@PVP were used for the trace analysis of furaltadone based on the inner filter effect (IFE) between Cu NCs@PVP and furaltadone, which caused the fluorescence to be effectively quenched. Additionally, this proposed determination platform based on the Cu NCs@PVP for furaltadone sensing possessed an excellent linear range from 0.5 to 100 µM with a lower detection limit of 0.045 µM (S/N = 3). Meanwhile, the Cu NCs@PVP also could be applied for the sensing of temperature. Furthermore, the practicability of the sensing platform has been successfully verified by measuring furaltadone in real samples, affirming its potential to increase fields for the determination of furaltadone.
Asunto(s)
Nitrofuranos , Oxazolidinonas , Cobre , Colorantes Fluorescentes , Espectrometría de Fluorescencia/métodos , TemperaturaRESUMEN
The incidence of lung cancer in China increases annually, and effective targets for the diagnosis and treatment of lung cancer are urgently needed. miRNAs are currently considered to be involved in the regulation of tumor development and growth. miR24 has been found to contribute to the development of several tumors. Menin is a key tumor suppressor gene, and its expression is generally low in lung cancer. The effects of miR24 on the biological behavior of lung cancer cells were detected by MTT and Transwell assays. In the present study, miR24 was found to be associated with menin, affecting the activity of the SMAD3 pathway in lung cancer by inhibiting menin expression. miR24 may promote the growth and metastasis and inhibit the apoptosis of lung cancer cells by targeting menin. Therefore, the aim of the present study was to provide a new theoretical basis for the targeted therapy of lung cancer.
Asunto(s)
Regulación hacia Abajo , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas/genética , Regiones no Traducidas 3' , Células A549 , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis de la Neoplasia , Pronóstico , Transducción de Señal , Proteínas Smad/genéticaRESUMEN
A reduction of Fe3O4 nanowires in nanoscopic reactors of amorphous C:H nanotubes (a-CNTs) was taken to understand features of the chemical reaction mechanism in nanoscale reactors. Fe3O4 nanowires encapsulated in a-CNTs were reduced into iron at a relatively low temperature of 570 degrees C, producing iron nanoparticles encapsulated in CNTs accompanied by the crystallization of the a-CNT shell. It was found that carbon in the a-CNT shell rather than hydrogen (5.5 wt % in it) reduced Fe3O4, showing features different from those in a macroscopic system. The possible mechanisms behind this phenomenon are discussed.
RESUMEN
The synthesis of novel carbon nanotubes (CNTs) with polygonal cross sections by heating a powder mixture of ferrocene, oxalic acid, and the alkali metal potassium at mediate temperatures (480-500 degrees C) is reported. This kind of special polygonized CNTs has two distinctive characters: first, ribbonlike polygonized CNTs have diameters between 60 and 200 nm, and the lengths as long as several microns; second, the edge of polygonized CNTs is well-graphitized, the wall of which is amorphous. On the basis of evidence that the formation of polygonized CNTs appears to be strongly determined by inhomogeneous catalytic activity of nonspherical Fe(3)O(4) nanoparticles, we propose the possible growth model.
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Surfactant solutions typically feature tunable nanoscale, internal structures. Although rarely utilized, they can be a powerful platform for probing thermal transport in nanoscale domains and across interfaces with nanometer-size radius. Here, we examine the structure and thermal transport in solution of AOT (Dioctyl sodium sulfosuccinate) in n-octane liquids using small-angle neutron scattering, thermal conductivity measurements, and molecular dynamics simulations. We report the first experimental observation of a minimum thermal conductivity occurring at the critical micelle concentration (CMC): the thermal conductivity of the surfactant solution decreases as AOT is added till the onset of micellization but increases as more AOT is added. The decrease of thermal conductivity with AOT loading in solutions in which AOT molecules are dispersed as monomers suggests that even the interfaces between individual oleophobic headgroup of AOT molecules and their surrounding non-polar octane molecules can hinder heat transfer. The increase of thermal conductivity with AOT loading after the onset of micellization indicates that the thermal transport in the core of AOT micelles and across the surfactant-oil interfaces, both of which span only a few nanometers, are efficient.
RESUMEN
In this work, we report a dielectric nanocomposite paper with layered boron nitride (BN) nanosheets wired by one-dimensional (1D) nanofibrillated cellulose (NFC) that has superior thermal and mechanical properties. These nanocomposite papers are fabricated from a filtration of BN and NFC suspensions, in which NFC is used as a stabilizer to stabilize BN nanosheets. In these nanocomposite papers, two-dimensional (2D) nanosheets form a thermally conductive network, while 1D NFC provides mechanical strength. A high thermal conductivity has been achieved along the BN paper surface (up to 145.7 W/m K for 50 wt % of BN), which is an order of magnitude higher than that in randomly distributed BN nanosheet composites and is even comparable to the thermal conductivity of aluminum alloys. Such a high thermal conductivity is mainly attributed to the structural alignment within the BN nanosheet papers; the effects of the interfacial thermal contact resistance are minimized by the fact that the heat transfer is in the direction parallel to the interface between BN nanosheets and that a large contact area occurs between BN nanosheets.