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61.
Improved Controlled Release and Brain Penetration of the Small Molecule S14 Using PLGA Nanoparticles
Vanesa Nozal Elisa Rojas-Prats Ins Maestro Carmen Gil Daniel I. Perez Ana Martinez 《International journal of molecular sciences》2021,22(6)
Phosphodiesterase 7 (PDE7) is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), an important cellular messenger. PDE7’s role in neurotransmission, expression profile in the brain and the druggability of other phosphodiesterases have motivated the search for potent inhibitors to treat neurodegenerative and inflammatory diseases. Different heterocyclic compounds have been described over the years; among them, phenyl-2-thioxo-(1H)-quinazolin-4-one, called S14, has shown very promising results in different in vitro and in vivo studies. Recently, polymeric nanoparticles have been used as new formulations to target specific organs and produce controlled release of certain drugs. In this work, we describe poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles loaded with S14. Their preparation, optimization, characterization and in vivo drug release profile are here presented as an effort to improve pharmacokinetic properties of this interesting PDE7 inhibitor. 相似文献
62.
Jos L. Neira Ana Cmara-Artigas Jos Gins Hernndez-Cifre María Grazia Ortore 《International journal of molecular sciences》2021,22(6)
The histidine phosphocarrier protein (HPr) kinase/phosphorylase (HPrK/P) modulates the phosphorylation state of the HPr protein, and it is involved in the use of carbon sources by Gram-positive bacteria. Its X-ray structure, as concluded from crystals of proteins from several species, is a hexamer; however, there are no studies about its conformational stability, and how its structure is modified by the pH. We have embarked on the conformational characterization of HPrK/P of Bacillus subtilis (bsHPrK/P) in solution by using several spectroscopic (namely, fluorescence and circular dichroism (CD)) and biophysical techniques (namely, small-angle X-ray-scattering (SAXS) and dynamic light-scattering (DLS)). bsHPrK/P was mainly a hexamer in solution at pH 7.0, in the presence of phosphate. The protein had a high conformational stability, with an apparent thermal denaturation midpoint of ~70 °C, at pH 7.0, as monitored by fluorescence and CD. The protein was very pH-sensitive, precipitated between pH 3.5 and 6.5; below pH 3.5, it had a molten-globule-like conformation; and it acquired a native-like structure in a narrow pH range (between pH 7.0 and 8.0). Guanidinium hydrochloride (GdmCl) denaturation occurred through an oligomeric intermediate. On the other hand, urea denaturation occurred as a single transition, in the range of concentrations between 1.8 and 18 µM, as detected by far-UV CD and fluorescence. 相似文献
63.
Maria Buuales Maria Cristina Ballesteros-Briones Manuela Gonzalez-Aparicio Sandra Hervas-Stubbs Eva Martisova Uxua Mancheo Ana Ricobaraza Sara Lumbreras Cristian Smerdou Ruben Hernandez-Alcoceba 《International journal of molecular sciences》2021,22(8)
Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer. 相似文献
64.
Ivn Benito Ignacio J. Encío Fermín I. Milagro María Alfaro Ana Martínez-Peuela Miguel Barajas Florencio Marzo 《International journal of molecular sciences》2021,22(9)
Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (ApcMin/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 107 CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in ApcMin/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/β-catenin signaling pathway in the colon of ApcMin/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in ApcMin/+ mice. 相似文献
65.
Alfredo Jurez-Saldivar Elizabeth Barbosa-Cabrera Edgar E. Lara-Ramírez Alma D. Paz-Gonzlez Ana V. Martínez-Vzquez Virgilio Bocanegra-García Isidro Palos Nuria E. Campillo Gildardo Rivera 《International journal of molecular sciences》2021,22(11)
Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05–4.935 μg/mL), while folic acid showed activity against E. histolytica (0.186 μg/mL) and G. lamblia (5.342 μg/mL). 相似文献
66.
Pablo Bonilla Joaquim Hernandez Esther Giraldo Miguel A. Gonzlez-Prez Ana Alastrue-Agudo Hoda Elkhenany María J. Vicent Xavier Navarro Michael Edel Victoria Moreno-Manzano 《International journal of molecular sciences》2021,22(11)
We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments. 相似文献
67.
Roser Cervellera Xavier Ramis Josep Maria Salla Ana Mantecn Angels Serra 《应用聚合物科学杂志》2006,102(3):2086-2093
Diglycidyl ether of bisphenol A or 3,4‐epoxycyclohexylmethyl 3,4‐epoxycyclohexane carboxylate were mixed with different proportions of 4‐methyl‐1,3‐dioxolan‐2‐one and cured using lanthanide triflates as initiators. In order to compare the materials obtained, conventional initiators such as boron trifluoride complexes and N,N‐dimethylaminopyridine were also tested. The curing process was followed by differential scanning calorimetry (DSC) and Fourier transform IR in attenuated total reflectance mode. This technique proved that the carbonate accelerates the curing process because it helps to form the active initiating species, although it was not chemically incorporated into the network and remained entrapped in the material. The DSC kinetic study was also reported. © 2006 Wiley Periodicals Inc. J Appl Polym Sci 102: 2086–2093, 2006 相似文献
68.
Tracy Q. Gardner Ana I. Flores Richard D. Noble John L. Falconer 《American Institute of Chemical Engineers》2002,48(6):1155-1167
A transient permeation method presented here not only determines the adsorption and diffusion properties of the pores that are the transport pathways through zeolite membranes, but nondestructively estimates the effective thickness of the membrane. Transient responses of the permeate concentration to step changes in the feed were measured on two H-ZSM-5 tubular membranes and modeled assuming Maxwell-Stefan diffusion and Langmuir adsorption. The adsorption isotherms determined from these transient measurements at 298 K of N2 and CO2 were nearly identical to those measured by calorimetry on H-ZSM-5 powders. The CH4 isotherm at 298 K was similar to isotherms measured by calorimetry and gravimetric techniques on Na-ZSM-5 and silicalite powders. The similarity of the isotherms indicates that transport of these light gases occurs mainly through zeolite pores. The Maxwell-Stefan diffusion coefficients DMS depended on concentration and were higher for higher feed partial pressures. Average DMS values for the two membranes were 7.5, 5 and 1.5×10−10 m2/s for N2, CH4, and CO2, respectively; these are in the same range and order as diffusion coefficients measured in zeolite crystals. 相似文献
69.
Benchmarking Fluvial Dynamics for Process‐Based River Restoration: the Upper Rhine River (1816–2014) 下载免费PDF全文
Multi‐temporal analysis of river‐floodplain processes is a key tool for the identification of reference conditions or benchmarks and for the evaluation of deviations or deficits as a basis for process‐based river restoration in large modified rivers. This study developed a methodology for benchmarking fluvial processes at river segment level, focusing on those interrelations between morphodynamics (aggradation, erosion, channel shift) and vegetation succession (initial, colonization, transition) that condition habitat structure. Habitat maps of the free‐flowing Upper Rhine River downstream from Iffezheim dam (France–Germany border) were intersected with a geographic information system‐based approach. Patches showing trajectories of anthropization, changeless, progression and regression allowed for the identification of natural and human‐induced processes over almost 200 years. Before channelization, the riverine system was characterized by a shifting habitat mosaic with natural heterogeneity, high degree of surface water connectivity and equilibrium between progression and regression processes. On the other hand, the following 175 years of human interventions led to severe biogeomorphologic deficits evidenced by loss of natural processes and habitat heterogeneity, hydrological disconnection between the river and its floodplain and imbalance of progression versus regression dynamics. The main driving forces of change are found in hydromorphological impacts (channelization, regulation and hydropower plant construction). Regression processes are now almost absent and have to be the objective of process‐based river restoration measures for the studied river‐floodplain system. A sustainable view on water management and river restoration should aim at a more resilient riverine system by balancing the recovery of natural processes with societal needs. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
70.
For heterogeneous distributed computing systems, important design issues are scalability and system optimization. Given such systems, it is crucial to develop low computational complexity algorithms to schedule tasks in a manner that exploits the heterogeneity of the resources and applications. In this paper, we report and evaluate three scalable, and fast scheduling heuristics for highly heterogeneous distributed computing systems. We conduct a comprehensive performance evaluation study using simulation. The benchmarking outlines the performance of the schedulers, representing scalability, makespan, flowtime, computational complexity, and memory utilization. The set of experimental results shows that our heuristics perform as good as the traditional approaches, for makespan and flowtime, while featuring lower complexity, lower running time, and lower used memory. The experimental results also detail the various scenarios under which certain algorithms excel and fail. 相似文献