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961.
Alessia Carocci Alessia Catalano Maria Stefania Sinicropi Giuseppe Genchi 《Biometals》2018,31(5):715-735
Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (·OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies. 相似文献
962.
Wenxiu Wei Shida Li Hongmei Xu Feilong Zhou Yi Wen Zhimei Song Sijia Feng Runliang Feng 《AAPS PharmSciTech》2018,19(5):2041-2047
Macrolide antibiotics are lipophilic drugs with some limitations including low solubility, limited cellular permeation, patients discomfort, etc. With amphiphilic methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-PCL) copolymer and azithromycin (AZT) as drug carrier and model drug, AZT-loaded micelles were prepared via thin-membrane hydration method in order to overcome these limitations. Encapsulation efficiency of AZT-loaded micelles was 94.40% with good storage stability for 28 days, and AZT’s water solubility was enhanced to 944 μg/mL. Fourier transform infrared spectrum and x-ray diffraction analysis indicated that AZT was enveloped into the micelles in amorphous form due to its interaction with the copolymer. AZT’s in vitro release from the AZT-loaded micelles demonstrated a slow and continuous behavior when compared with raw AZT. The release dynamics was accorded with Weibull equation, meaning that release amount of AZT lowered with time and was proportional to remaining amount of drug in the AZT-loaded micelles. Korsmeyer-Peppas fitting result suggested that drug release process was a classical Fickian diffusion-controlled manner. With Staphylococcus aureus as bacterial strain, antibacterial activity of the AZT-loaded micelles displayed was comparable with raw AZT. In conclusion, MPEG-PCL should be a promising carrier for macrolide antibiotic delivery in treatment of bacterial infections. 相似文献
963.
The release of a potent bone-resorption inhibitor such as zoledronate from a versatile drug delivery system such as SBA 15
has been modeled. The initial and boundary conditions have been defined, together with the system parameters, including the
determination of equilibrium and transport parameters. Additionally, the experimental model of the same system has been observed
to validate the prediction here developed. This approach represents a powerful tool for the designing of mesoporous implantable
drug delivery systems because their release kinetics can be predicted in advance, and this leads to a considerable time and
resources saving. 相似文献
964.
Xiao F Gao W Wang X Chen T 《Apoptosis : an international journal on programmed cell death》2012,17(6):600-611
Although caspases have been demonstrated to be involved in artemisinin (ARTE)-induced apoptosis, their exact functions are
not well understood. The aim of this report is to explore the roles of caspase-8, -9 and -3 during ARTE-induced apoptosis
in human lung adenocarcinoma (ASTC-a-1) cells. ARTE treatment induces a rapid generation of reactive oxygen species (ROS),
and ROS-dependent apoptosis as well as the activation of caspase-8, -9 and -3 via time- and dose-dependent fashion. Of upmost
importance, inhibition of caspase-8 or -9, but not caspase-3, almost completely blocks the ARTE-induced not only activation
of the caspase-8, -9 and -3 but also apoptosis. In addition, the apoptotic process triggered by ARTE does not involve the
Bid cleavage, tBid translocation, significant loss of mitochondrial membrane potential and cytochrome c release from mitochondria.
Moreover, silencing Bax/Bak does not prevent the ATRE-induced cell death as well as the activation of caspase-8, -9 and -3.
Collectively, our data firstly demonstrate that ARTE triggers a ROS-mediated positive feedback amplification activation loop
between caspase-8 and -9 independent of mitochondria, which dominantly mediated the ARTE-induced apoptosis via a caspase-3-independent
apoptotic pathway in ASTC-a-1 cells. Our findings imply a potential to develop new derivatives from artemisinin to effectively
initiate the amplification activation loop of caspases. 相似文献
965.
966.
Zahra Fazeli Mir Davood Omrani Sayyed Mohammad Hossein Ghaderian 《Journal of cell communication and signaling》2016,10(4):273-282
Different signaling pathways are implicated in proliferation and differentiation of stem cells. Bone Morphogenesis Pathway (BMP) signaling was known to display an important function in osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs). In the present study, the authors investigated whether blocking BMP signaling was associated with down regulation of Nestin expression as neural stem cell marker in peripheral blood derived mesenchymal stem cells (PB-MSCs). At first, MSCs were isolated from peripheral blood by plastic adherent ability and flow cytometry analysis. After reaching the confluence, the cells were treated with medium containing Noggin as antagonist of BMP signaling upon 8 days. Real time PCR analysis indicated that the expression of Nestin was diminished in PB-MSCs by attenuating BMP signaling. The obtained results suggested that BMP signaling might have a regulatory function on the Nestin expression in mesenchymal stem cells. 相似文献
967.
The x-ray structure of the PTX:NADPH:L22F human mutant DHFR ternary complex was used as a structural template to generate structural models for the following wild type DHFR complexes: PTX:DHFR:NADPH, TMP:DHFR:NADPH, EPM:DHFR:NADPH, and TMQ:DHFR:NADPH. Each of these complexes were subsequently modeled in a 60 Å cube of explicit water and minimized to a rms gradient of from 1.0-3.0·10-5 kcal·Å-1. For each complex, interaction energies were calculated for the antifolate interaction with each of the following: the DHFR binding site residues, the entire DHFR protein, the solvated complex (containing DHFR, NADPH, and solvent water), water alone, and NADPH. Additionally, each antifolate was subdivided into distinct substructural regions and interaction energy calculations were performed in order to evaluate their contributions to overall antifolate interaction. Each antifolate showed its most stable interaction with the solvated complex. Substructural regions which consisted of a nitrogen containing aromatic ring system contributed most to the stability of the antifolate interactions, while the hydrocarbon aromatic rings, methoxy, and ethoxy groups showed much less stable interaction energies. Since the different substructural regions of nonclassical antifolates differ in their contributions to overall antifolate binding, those substructural regions which exhibit relatively unfavorable interaction energies may constitute important targets in the design of improved DHFR inhibitors. 相似文献
968.
Verkman AS Matthay MA Song Y 《American journal of physiology. Lung cellular and molecular physiology》2000,278(5):L867-L879
Fluid transport across epithelial and endothelial barriers occurs in the neonatal and adult lungs. Biophysical measurements in the intact lung and cell isolates have indicated that osmotic water permeability is exceptionally high across alveolar epithelia and endothelia and moderately high across airway epithelia. This review is focused on the role of membrane water-transporting proteins, the aquaporins (AQPs), in high lung water permeability and lung physiology. The lung expresses several AQPs: AQP1 in microvascular endothelia, AQP3 in large airways, AQP4 in large- and small-airway epithelia, and AQP5 in type I alveolar epithelial cells. Lung phenotype analysis of transgenic mice lacking each of these AQPs has been informative. Osmotically driven water permeability between the air space and capillary compartments is reduced approximately 10-fold by deletion of AQP1 or AQP5 and reduced even more by deletion of AQP1 and AQP4 or AQP1 and AQP5 together. AQP1 deletion greatly reduces osmotically driven water transport across alveolar capillaries but has only a minor effect on hydrostatic lung filtration, which primarily involves paracellular water movement. However, despite the major role of AQPs in lung osmotic water permeabilities, AQP deletion has little or no effect on physiologically important lung functions, such as alveolar fluid clearance in adult and neonatal lung, and edema accumulation after lung injury. Although AQPs play a major role in renal and central nervous system physiology, the data to date on AQP knockout mice do not support an important role of high lung water permeabilities or AQPs in lung physiology. However, there remain unresolved questions about possible non-water-transporting roles of AQPs and about the role of AQPs in airway physiology, pleural fluid dynamics, and edema after lung infection. 相似文献
969.
970.