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1.
Mol Cell ; 83(19): 3485-3501.e11, 2023 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-37802024

RESUMEN

p62 is a well-characterized autophagy receptor that recognizes and sequesters specific cargoes into autophagosomes for degradation. p62 promotes the assembly and removal of ubiquitinated proteins by forming p62-liquid droplets. However, it remains unclear how autophagosomes efficiently sequester p62 droplets. Herein, we report that p62 undergoes reversible S-acylation in multiple human-, rat-, and mouse-derived cell lines, catalyzed by zinc-finger Asp-His-His-Cys S-acyltransferase 19 (ZDHHC19) and deacylated by acyl protein thioesterase 1 (APT1). S-acylation of p62 enhances the affinity of p62 for microtubule-associated protein 1 light chain 3 (LC3)-positive membranes and promotes autophagic membrane localization of p62 droplets, thereby leading to the production of small LC3-positive p62 droplets and efficient autophagic degradation of p62-cargo complexes. Specifically, increasing p62 acylation by upregulating ZDHHC19 or by genetic knockout of APT1 accelerates p62 degradation and p62-mediated autophagic clearance of ubiquitinated proteins. Thus, the protein S-acylation-deacylation cycle regulates p62 droplet recruitment to the autophagic membrane and selective autophagic flux, thereby contributing to the control of selective autophagic clearance of ubiquitinated proteins.


Asunto(s)
Autofagosomas , Proteínas Ubiquitinadas , Ratones , Ratas , Humanos , Animales , Autofagosomas/metabolismo , Proteínas Ubiquitinadas/metabolismo , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Autofagia/genética , Acilación , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mamíferos/metabolismo
2.
Neurol Sci ; 45(7): 3495-3501, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38714597

RESUMEN

BACKGROUND: Shunt obstruction is a type of ventriculoperitoneal shunt (VPS) failure. Whether changes in cerebrospinal fluid (CSF) parameters can influence shunt outcomes or not is debatable. METHODS: In this study, we retrospectively included adult hydrocephalus patients who received VPS from 6 general hospitals in different provinces of China from November 2013 to September 2021. The inclusion criteria: Patients with hydrocephalus of all etiologies underwent shunt surgery from 6 general hospitals in different provinces of China were included in the study. The exclusion criteria: 1.Patients under the age of 18; 2.Patients who had previous shunt surgery; 3. Shunt failure from other factors; 4.Patients died from other causes; 5. Patients with incomplete data. The CSF of shunt patients had been analyzed at the time of shunt insertion. The CSF samples were collected and analyzed when the shunt was implanted. The relationship between CSF parameters and the incidence rate of shunt obstruction in one year was analyzed. RESULTS: A total of 717 eligible patients from 6 hospitals were included, of whom 59(8.23%) experienced obstruction. Multivariate logistic regression analysis identified that protein level(odds ratio [OR] 1.161, 95% CI 1.005 ~ 1.341, p = 0.043), decreased glucose level(< 2.5 mmol/L)(odds ratio 3.784, 95% confidence interval 1.872 ~ 7.652, p = 0.001) and protein level increase(> 0.45 g/L) (odds ratio 3.653, 95% confidence interval 1.931 ~ 6.910, p = 0.001)were independent risk factors of shunt obstruction. CONCLUSION: This study suggested that increased protein level (> 0.45 g/L) and decreased glucose level (< 2.5 mmol/L) in CSF indicated an increased risk of shunt obstruction in a patient with hydrocephalus. Thus, shunt surgery should be more carefully considered when the CSF glucose and protein were abnormal.


Asunto(s)
Hidrocefalia , Derivación Ventriculoperitoneal , Humanos , Derivación Ventriculoperitoneal/efectos adversos , Femenino , Masculino , Hidrocefalia/cirugía , Hidrocefalia/líquido cefalorraquídeo , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , China/epidemiología , Adulto , Falla de Equipo
3.
EMBO Rep ; 22(9): e52252, 2021 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-34288348

RESUMEN

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb-susceptible mice and TB patients have relatively low miR-342-3p expression, while mice with miR-342-3p overexpression are more resistant to Mtb. We demonstrate that the miR-342-3p/SOCS6 axis regulates anti-Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR-342-3p/SOCS6 axis participates in the switching between Mtb-induced apoptosis and necrosis through A20-mediated K48-linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA-mRNA network and pave the way for host-directed therapies targeting these pathways.


Asunto(s)
MicroARNs , Mycobacterium tuberculosis , Tuberculosis , Animales , Muerte Celular , Humanos , Inflamación/genética , Ratones , MicroARNs/genética , Mycobacterium tuberculosis/genética , Proteínas Supresoras de la Señalización de Citocinas , Tuberculosis/genética
4.
Nanotechnology ; 34(27)2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37011606

RESUMEN

Perovskite nanocrystals (NCs) feature adjustable bandgap, wide absorption range, and great color purity for robust perovskite optoelectronic applications. Nevertheless, the absence of lasting stability under continues energization, is still a major hurdle to the widespread use of NCs in commercial applications. In particular, the reactivity of red-emitting perovskites to environmental surroundings is more sensitive than that of their green counterparts. Here, we present a simple synthesis of ultrathin ZrO2coated, Sr2+doped CsPbBrI2NCs. Introducing divalent Sr2+may significantly eliminate Pb° surface traps, whereas ZrO2encapsulation greatly improves environmental stability. The photoluminescence quantum yield of the Sr2+-doped CsPbBrI2/ZrO2NCs was increased from 50.2% to 87.2% as a direct consequence of the efficient elimination of Pb° surface defects. Moreover, the thickness of the ZrO2thin coating gives remarkable heat resistance and improved water stability. Combining CsPbSr0.3BrI2/ZrO2NCs in a white light emitting diode (LED) with an excellent optical efficiency (100.08 lm W-1), high and a broad gamut 141% (NTSC) standard. This work offers a potential method to suppress Pb° traps by doping with Sr2+and improves the performance of perovskite NCs by ultrathin coating structured ZrO2, consequently enabling their applicability in commercial optical displays.

5.
Phys Chem Chem Phys ; 25(3): 2366-2376, 2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36598003

RESUMEN

Monolayer XP3 (X = Ge, In) is a theoretically predicted two-dimensional (2D) material with fascinating adsorption efficiency, foreshadowing its potential applications in the photovoltaic and optoelectronic communities. To achieve a comprehensive understanding of its optical properties and to further boost quickly identifying its specific applications, in this paper we systematically investigated the polarization-resolved and helicity-resolved Raman spectra excited by two commonly used laser lines (532 nm and 633 nm) through density functional theory. The dynamical stability of monolayer XP3 is demonstrated by phonon dispersion. Monolayer GeP3 and InP3 are found to exhibit significantly different point group symmetries and thereby Raman properties due to the big difference in atomic size and electronic configurations between the Ge atom and In atom. Raman anisotropy of monolayer XP3 has been found when the wave vector of linear polarized incident light is parallel to the monolayer, and all the anisotropic Raman active phonons are categorized in terms of the locations of two (four) maxima in polarization angle dependent Raman intensities of the parallel (perpendicular) configuration. The polarization direction averaged Raman spectra have been further discussed according to the characteristics of light absorbance. The calculations of helicity-resolved Raman spectra indicate a stronger helicity selection rule under helical excitation with the wave vector normal to the monolayer. The present work paves the way for the suitable design, characterization and exploitation of the proposed 2D material with controllable surface properties for applications in electronics and optoelectronics.

6.
Bioorg Med Chem Lett ; 77: 129036, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36280150

RESUMEN

Mitomycin C (MMC) is a class of alkylating anticancer drug, which non-specifically interacts with nuclear DNA and cross-links guanine and cytosine of DNA, thereby affecting DNA replication and synthesis. However, toxic effects largely impeded MMC's clinical applications. In this study, triphenylphosphine groups (TPP+) were attached to MMC via the active aziridine amine with the aim to reduce its toxicity. MTT assay suggested that 5 possessed a good anticancer activity (IC50 = 1.09 µM, A549) with negligible effects on human normal cells (IC50 > 20 µM, L02 and HUVEC), while MMC exhibited IC50 values of less than 2.5 µM on the tested human normal cells. Dose range-finding experiments suggested that 5 had little effect on the body weight and tissues in mouse at a dose of 20 mg/kg, indicating significantly reduced toxicity as compared to MMC (LD50 < 2.5 mg/kg). Collectively, these data suggested that TPP+ group could be an effective vector to reduce toxicity of MMC.


Asunto(s)
ADN , Mitomicina , Ratones , Humanos , Animales , Mitomicina/farmacología
7.
Anal Chem ; 93(8): 4042-4050, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33586959

RESUMEN

As one of the most promising biomarkers for numerous malignant tumors, accurate and reliable reporting of Cathepsin B (CTSB) activity is of great significance to achieve efficient diagnosis of cancers at an early stage and predicting metastasis. Here, we report a vigorous ratiometric fluorescent method integrating a cancer-targeting recognition moiety with a remarkably large emission wavelength shift into a single matrix to report CTSB activity sensitively and specifically. As a proof of concept, we synthesized amine-rich carbon quantum dots (CQDs) with a blue fluorescence, which offered an efficient scaffolding to covalently assemble the nucleolin-targeting recognition nucleic acid aptamer AS1411 and a CTSB-cleavable peptide substrate Gly-Arg-Arg-Gly-Lys-Gly-Gly-Cys-COOH that tethered with a near-infrared (NIR) fluorophore chlorin e6 (Ce6-GRRGKGGC, Ce6-Pep), enabling a cancer-targeting and CTSB stimulus-responsive ratiometric nanoprobe AS1411-Ce6-CQDs. Owing to the efficient fluorescence resonance energy transfer (FRET) process from the CQDs to Ce6 inside the assembly of nanoprobe, the blue fluorescence of CQDs at ∼450 nm was remarkably quenched, along with an obvious NIR fluorescence enhancement of Ce6 at ∼650 nm. After selective entry into cancer cells via nucleolin-mediated endocytosis, the overexpressed CTSB in lysosome could cleave Ce6-Pep and trigger the Ce6 moiety dissociation from AS1411-Ce6-CQDs, thus leading to the termination of FRET process, achieving the efficient ratiometric fluorescence response toward endogenous CTSB with a remarkably large emission wavelength shift of ∼200 nm from NIR to blue emission region. Notably, the nanoprobe AS1411-Ce6-CQDs exhibited an excellent specificity for ratiometric fluorescent sensing of CTSB activity with an ultralow detection limit of 0.096 ng/mL, demonstrating its promising use for early precise cancer diagnosis in the near future.


Asunto(s)
Neoplasias , Puntos Cuánticos , Carbono , Catepsina B , Transferencia Resonante de Energía de Fluorescencia , Neoplasias/diagnóstico por imagen , Fosfoproteínas , Proteínas de Unión al ARN , Nucleolina
8.
Phys Chem Chem Phys ; 23(35): 19884-19891, 2021 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-34525144

RESUMEN

The structural, vibrational and Raman spectra properties of monolayer and bilayer Ti2C excited by two commonly used laser lines (532 nm and 633 nm) are investigated by first principles calculations to establish a correlation among layer stacks and optical features for two-dimensional MXenes. The stability of the monolayer and the energetically preferable stacking configuration are demonstrated by phonon dispersion. The monolayer and bilayer Ti2C systems are found to exhibit different point group symmetries and thereby the Raman properties due to the symmetry breaking of the bilayer structure caused by interlayer van der Waals interactions. We listed all Raman-active modes for monolayer (bilayer) Ti2C, i.e., one (five) out-of-plane A1g (A1) and one (five) pair (pairs) of degenerate in-plane Eg (E) vibration modes. Polarization angle dependent Raman intensity has been discussed in terms of the locations of two (four) maxima in the parallel (perpendicular) configuration, which might be applied in experimentally identifying monolayer and bilayer Ti2C. The difference in the polarization direction averaged Raman spectra between monolayer and bilayer Ti2C can be explained by the characteristics of light absorbance.

9.
Pestic Biochem Physiol ; 175: 104849, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33993967

RESUMEN

Staphylococcus aureus resistance poses nonnegligible threats to the livestock industry. In light of this, carbazole-oxadiazoles were designed and synthesized for treating S. aureus infection. Bioassay discovered that 3,6-dibromocarbazole derivative 13a had effective inhibitory activities to several Gram-positive bacteria, in particular to S. aureus, S. aureus ATCC 29213, MRSA and S. aureus ATCC 25923 (MICs = 0.6-4.6 nmol/mL), which was more active than norfloxacin (MICs = 6-40 nmol/mL). Subsequent studies showed that 3,6-dibromocarbazole derivative 13a acted rapidly on S. aureus ATCC 29213 and possessed no obvious tendency to induce bacterial resistance. Further evaluations indicated that 3,6-dibromocarbazole derivative 13a showed strong abilities to disrupt bacterial biofilm and interfere with DNA, which might be the power sources of antibacterial performances. Moreover, 3,6-dibromocarbazole derivative 13a also exhibited slight cell lethality toward Hek 293 T and LO2 cells and low hemolytic toxicity to red blood cells. The above results implied that the active molecule 13a could be studied in the future development of agricultural available antibiotics.


Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus , Antibacterianos/farmacología , Carbazoles/farmacología , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Oxadiazoles
10.
Anal Chem ; 92(19): 13396-13404, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-32867467

RESUMEN

Rapid, accurate, reliable, and risk-free tracking of pathogenic microorganisms at the single-cell level is critical to achieve efficient source control and prevent outbreaks of microbial infectious diseases. For the first time, we report a promising approach for integrating the concepts of a remarkably large Stokes shift and dual-recognition into a single matrix to develop a pathogenic microorganism stimuli-responsive ratiometric fluorescent nanoprobe with speed, cost efficiency, stability, ultrahigh specificity, and sensitivity. As a proof-of-concept, we selected the Gram-positive bacterium Staphylococcus aureus (S. aureus) as the target analyte model, which easily bound to its recognition aptamer and the broad-spectrum glycopeptide antibiotic vancomycin (Van). To improve the specificity and short sample-to-answer time, we employed classic noncovalent π-π stacking interactions as a driving force to trigger the binding of Van and aptamer dual-functionalized near-infrared (NIR) fluorescent Apt-Van-QDs to the surface of an unreported blue fluorescent π-rich electronic carbon nanoparticles (CNPs), achieving S. aureus stimuli-responsive ratiometric nanoprobe Apt-Van-QDs@CNPs. In the assembly of Apt-Van-QDs@CNPs, the blue CNPs (energy donor) and NIR Apt-Van-QDs (energy acceptor) became close to allow the fluorescence resonance energy transfer (FRET) process, leading to a remarkable blue fluorescence quenching for the CNPs at ∼465 nm and a clear NIR fluorescence enhancement for Apt-Van-QDs at ∼725 nm. In the presence of S. aureus, the FRET process from CNPs to Apt-Van-QDs was disrupted, causing the nanoprobe Apt-Van-QDs@CNPs to display a ratiometric fluorescent response to S. aureus, which exhibited a large Stokes shift of ∼260 nm and rapid sample-to-answer detection time (∼30.0 min). As expected, the nanoprobe Apt-Van-QDs@CNPs showed an ultrahigh specificity for ratiometric fluorescence detection of S. aureus with a good detection limit of 1.0 CFU/mL, allowing the assay at single-cell level. Moreover, we also carried out the precise analysis of S. aureus in actual samples with acceptable results. We believe that this work offers new insight into the rational design of efficient ratiometric nanoprobes for rapid on-site accurate screening of pathogenic microorganisms at the single-cell level in the early stages, especially during the worldwide spread of COVID-19 today.


Asunto(s)
Bacterias/química , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Técnicas Biosensibles/métodos , Colorantes Fluorescentes/síntesis química , Nanotecnología/métodos , Antibacterianos/farmacología , Aptámeros de Nucleótidos , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/microbiología , Fluorescencia , Transferencia Resonante de Energía de Fluorescencia , Microbiología de Alimentos/métodos , Humanos , Nanopartículas , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/microbiología , Sensibilidad y Especificidad , Espectroscopía Infrarroja Corta , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/química , Vancomicina/farmacología
11.
Angew Chem Int Ed Engl ; 58(1): 216-220, 2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30421847

RESUMEN

An organocatalytic one-step desymmetrizing dearomatization reaction of indoles with in situ formed vinylidene ortho-quinone methides is reported. A set of [6-6-5] and/or [5-6-5] fused indoline heterocycles were obtained in excellent yields with excellent diastereoselectivities (>20:1 d.r.) and enantioselectivities (up to 99 % ee). Moreover, some of the obtained products were screened against a panel of cancer cell lines, and one was identified to inhibit the proliferation of all the tested cancer cells, but showed marginal effects against non-cancerous cells. The methodology provides a platform for the synthesis of new leading compounds with antitumor activity.


Asunto(s)
Indoles/síntesis química , Catálisis , Estructura Molecular , Estereoisomerismo
12.
Bioorg Med Chem Lett ; 28(21): 3441-3445, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30266541

RESUMEN

Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors.


Asunto(s)
Acetofenonas/farmacología , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Acetofenonas/síntesis química , Acetofenonas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mitocondrias/efectos de los fármacos , Estructura Molecular , Fosforilación Oxidativa/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Relación Estructura-Actividad
13.
Neurol Neurochir Pol ; 52(3): 390-393, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29709301

RESUMEN

BACKGROUND: Intracranial involvement is an uncommon manifestation of Rosai-Dorfman disease (RDD) and had been rarely reported. In this study, we explore clinical characteristics, imageology manifestations and pathological features of primary intracranial RDD so as to improve the understanding for this disease. METHODS: One case (16-years-old boy) with primary intracranial RDD was analyzed and studied retrospectively by MRI features, histopathological observation and immunohistochemical staining, and the related literatures were reviewed. RESULTS: The case was single lesion and involved the dura of the left middle cranial fossa base, which was iso-hypo signal intensity on T1WI and hypointense on T2WI and FLAIR image. The lesion was a homogeneous contrast enhancement mass with dural tail sign and had peritumoral brain edema. Pathological analysis showed the lesion consisted of variable numbers of mature lymphocytes, plasma cells and neutrophils. The characteristic histiocytes were emperipolesis and positively expressed for S-100 and CD-68 and negatively expressed for CD-1a by immunohistochemical analysis. Based on clinical presentations and histological findings after surgical excision, a final diagnosis of primary intracranial RDD was made. CONCLUSION: Primary intracranial RDD, especially located in the cranial base, is exceptionally rare, which hard to be distinguished with meningoma by imageology and clinical manifestations, but could be diagnosed by pathological and immunohistochemical examinations. Surgery is of the most importance treatment and prognosis is optimistic for this disease.


Asunto(s)
Histiocitosis Sinusal , Adolescente , Duramadre , Histiocitos , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos
14.
Opt Lett ; 40(7): 1362-5, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25831333

RESUMEN

Silicon core optical fiber expanded silicon photonics to specialty fiber platform. Although great challenges still exist for the fiber fabrication, the presence of semiconductor material has already given optical fiber new features and enormous possibilities for fiber-based devices and sensors. In this Letter, an all fiber silicon cavity Fabry-Perot interferometer was made by splicing silicon core silica cladding fiber with conventional single-mode silica fiber. The cavity shows high temperature sensitivity around 82 pm/°C due to the larger thermo-optical coefficient of silicon material compared with that of silica material.

15.
Chemistry ; 21(18): 6700-3, 2015 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-25810003

RESUMEN

An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which ß-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product.


Asunto(s)
Alquenos/química , Clorofluorocarburos de Metano/química , Cobre/química , Éteres Cíclicos/síntesis química , Compuestos Heterocíclicos/síntesis química , Propanoles/química , Catálisis , Éteres Cíclicos/química , Compuestos Heterocíclicos/química , Metilación , Estructura Molecular , Estereoisomerismo
16.
Bioorg Med Chem Lett ; 24(21): 4963-8, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25301772

RESUMEN

Binding affinities of fluconazole and its analogue 2-(2,4-dichlorophenyl)-1,3-di(1H-1,2,4-triazol-yl)-2-propanol (DTP) to human serum albumin (HSA) were investigated under approximately human physiological conditions. The obtained result indicated that HSA could generate fluorescent quenching by fluconazole and DTP because of the formation of non-fluorescent ground-state complexes. Binding parameters calculated from the Stern-Volmer and the Scatchard equations showed that fluconazole and DTP bind to HSA with binding affinities of the order 10(4)L/mol. The thermodynamic parameters revealed that the binding was characterized by negative enthalpy and positive entropy changes, suggesting that the binding reaction was exothermic. Hydrogen bonds and hydrophobic interaction were found to be the predominant intermolecular forces stabilizing the drug-protein. The effect of metal ions on the binding constants of fluconazole-HSA complex suggested that the presence of Mg(2+) and Zn(2+) ions could decrease the free drug level and extend the half-life in the systematic circulation. Docking experiments revealed that fluconazole and DTP binds in HSA mainly by hydrophobic interaction with the possibility of hydrogen bonds formation between the drugs and the residues Arg 222, Lys 199 and Lys 195 in HSA.


Asunto(s)
Antifúngicos/metabolismo , Fluconazol/metabolismo , Albúmina Sérica/metabolismo , Triazoles/metabolismo , Sitios de Unión , Dicroismo Circular , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Unión Proteica , Conformación Proteica , Espectrometría de Fluorescencia , Termodinámica
17.
Eur J Med Chem ; 268: 116219, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38368710

RESUMEN

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.0066 mmol/L than norfloxacin. It was also revealed that imidazolyl ACE 6c not only possessed inconspicuous hemolytic rate and cytotoxicity, low drug resistance and no risk of penetrating the blood-brain barrier, but also exhibited obvious biofilm inhibition and eradication activities. The preliminary mechanism research suggested that imidazolyl ACE 6c could induce metabolic dysfunction by deactivating lactate dehydrogenase and promote the accumulation of reactive oxygen species to decrease the reduced glutathione and ultimately cause oxidative damage in bacteria. Furthermore, ACE 6c was also found that could insert into DNA to form the supramolecular complex of 6c-DNA and trigger cell death. The multidimensional effect might promote bacterial cell rupture, leading to the leakage of intracellular content. These findings manifested that novel imidazolyl ACE 6c as a potential multitargeting antibacterial agent with potent antibiofilm activity could provide new possibility for the treatment of refractory biofilm-intensified bacterial infections.


Asunto(s)
Antibacterianos , Norfloxacino , Humanos , Antibacterianos/farmacología , Norfloxacino/farmacología , Bacterias Gramnegativas , Bacterias , Biopelículas , ADN/farmacología , Pruebas de Sensibilidad Microbiana
18.
Eur J Med Chem ; 264: 116008, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38056298

RESUMEN

Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis. We successfully identified 6 compounds from a small molecule library through a structure-based virtual screening campaign and evaluated their enzymatic inhibitory potencies for PDK1-4. Our results indicated that compound 1 exhibited submicromolar inhibitory activities against PDK1-3 (IC50 = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC50 = 8.67 µM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC50 value of 10.7 µM. In addition, compound 1 induced cell apoptosis, arrested the cell cycle at the S phase, and reduced cell invasion and migration, while showing low in vivo toxicity at a high dose. Based on these observations, it can be concluded that compound 1 is a promising anti-PDK1-3 lead that merits further investigation.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Complejo Piruvato Deshidrogenasa , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismo , Fosforilación Oxidativa , División Celular
19.
Eur J Med Chem ; 275: 116610, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38896992

RESUMEN

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 µM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.

20.
Front Neurorobot ; 18: 1401075, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774519

RESUMEN

Introduction: In recent years, the perceptual capabilities of robots have been significantly enhanced. However, the task execution of the robots still lacks adaptive capabilities in unstructured and dynamic environments. Methods: In this paper, we propose an ontology based autonomous robot task processing framework (ARTProF), to improve the robot's adaptability within unstructured and dynamic environments. ARTProF unifies ontological knowledge representation, reasoning, and autonomous task planning and execution into a single framework. The interface between the knowledge base and neural network-based object detection is first introduced in ARTProF to improve the robot's perception capabilities. A knowledge-driven manipulation operator based on Robot Operating System (ROS) is then designed to facilitate the interaction between the knowledge base and the robot's primitive actions. Additionally, an operation similarity model is proposed to endow the robot with the ability to generalize to novel objects. Finally, a dynamic task planning algorithm, leveraging ontological knowledge, equips the robot with adaptability to execute tasks in unstructured and dynamic environments. Results: Experimental results on real-world scenarios and simulations demonstrate the effectiveness and efficiency of the proposed ARTProF framework. Discussion: In future work, we will focus on refining the ARTProF framework by integrating neurosymbolic inference.

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