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1.
Carbohydr Polym ; 235: 115935, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122478

RESUMO

A facile method for the activation of γ-cyclodextrin metal-organic framework (CD-MOF) without channel blockage and framework collapse was first developed using supercritical carbon dioxide (scCO2), which enabled higher surface area and larger pore volume. The scCO2-assisted impregnation method was also applied to introduce the insoluble drug, honokiol (HNK), into the pores of CD-MOF with higher cargo loading compared to the conventional liquid phase incorporation in ethanol. Notably, the resulting HNK-loaded CD-MOF (HNK@CD-MOF) had improved apparent solubility and enhanced dissolution rate. The intestinal cellular uptake and transport experiments demonstrated that CD-MOF could enhance cellular uptake and increase drug transport across the intestinal epithelial cells compared to the cyclodextrin inclusion complex. Moreover, the in vivo pharmacokinetic studies further confirmed that CD-MOF could significantly improve the oral absorption and bioavailability of HNK. Overall, the scCO2 activation and scCO2-assisted impregnation approaches were demonstrated as promising strategies to maximize the potential capability of CD-MOF.

2.
Inflammation ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103436

RESUMO

Chronic inflammatory diseases affect bone and teeth health tremendously. Characterized by osteolytic lesion and hyperactive osteoclastogenesis, inflammatory bone diseases are short of effective therapeutics and therefore highlight the importance of understanding pathogenesis and developing ideal medications. Reactive oxygen species (ROS) play a prominent role in the innate immune response of activated macrophages, as well as in the physiological signaling of osteoclasts (OCs) differentiation. N-acetylcysteine (NAC) is a potent ROS scavenger and a potential option for treating diseases characterized by excessive ROS generation. However, whether NAC can protect physiological bone remodeling from in vivo inflammatory conditions is largely undefined. We applied NAC treatment on lipopolysaccharide (LPS)-induced inflammatory osteolysis mice model and found that NAC could attenuate bone erosion and protect mice against LPS-induced osteolysis, due to the suppressive effect on osteoclastogenesis and stimulated effect on osteogenesis. Moreover, in vitro study demonstrated that, in OC precursors (pre-OCs), LPS-stimulated expressions of OC marker genes, such as tartrate-resistant acid phosphatase type 5 (Acp5), cathepsin K (Ctsk), OC stimulatory transmembrane protein (Oc-stamp), dendritic cell-specific transmembrane protein (Dc-stamp), and nuclear factor of activated T cells 1 (NFATc1), were all reduced because of the NAC pretreatment, thereby adversely affecting OC function including F-actin ring formation and bone resorption. Further mechanism study showed that NAC blocked LPS-induced ROS formation in both macrophages and pre-OCs, cutting off the LPS-stimulated autocrine/paracrine mechanism during inflammatory osteolysis. Our findings reveal that NAC attenuates inflammatory osteolysis via the elimination of ROS formation during LPS-stimulated osteoclastogenesis, and provide a potential therapeutic approach to treat inflammatory bone disease.

3.
Fish Shellfish Immunol ; 96: 245-253, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830564

RESUMO

RNA polymerase (RNAP) II (DNA-directed) (POLR2) genes are essential for cell viability under environmental stress and for the transfer of biological information from DNA to RNA. However, the function and characteristics of POLR2 genes in crustaceans are still unknown. In the present study, a POLR2H cDNA was isolated from Pacific white shrimp (Litopenaeus vannamei) and designated as Lv-POLR2H. The full-length Lv-POLR2H cDNA is 772 bp in length and contains a 32-bp 5'- untranslated region (UTR), a 284-bp 3'- UTR with a poly (A) sequence, and an open reading frame (ORF) of 456 bp encoding an Lv-POLR2H protein of 151 amino acids with a deduced molecular weight of 17.21 kDa. The Lv-POLR2H protein only contains one functional domain, harbors no transmembrane domains and mainly locates in the nucleus. The expression of the Lv-POLR2H mRNA was ubiquitously detected in all selected tissues, with the highest level in the gills. In situ hybridization (ISH) analysis showed that Lv-POLR2H was mainly located in the secondary gill filaments, the transcript levels of Lv-POLR2H in the gills were found to be significantly affected after challenge by pH, low salinity and high concentrations of NO2- and NH4+, indicating that Lv-POLR2H in gill tissues might play roles under various physical stresses. Specifically, under high-pH stress, knockdown of Lv-POLR2H via siRNA significantly decreased the survival rate of the shrimp, indicating its key roles in the response to high-pH stress. Our study may provide the first evidence of the role of POLR2H in shrimp responding to high-pH stress and provides new insight into molecular regulation in response to high pH in crustaceans.

4.
Adv Sci (Weinh) ; 6(20): 1901432, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31637170

RESUMO

Ionic evolution-induced phase transformation can lead to wide ranges of novel material functionalities with promising applications. Here, using the gating voltage during ionic liquid gating as a tuning knob, the brownmillerite SrCoO2.5 is transformed into a series of protonated H x SrCoO2.5 phases with distinct hydrogen contents. The unexpected electron to charge-neutral doping crossover along with the increase of proton concentration from x = 1 to 2 suggests the formation of exotic charge neutral H-H dimers for higher proton concentration, which is directly visualized at the vacant tetrahedron by scanning transmission electron microscopy and then further supported by first principles calculations. Although the H-H dimers cause no change of the valency of Co2+ ions, they result in clear enhancement of electronic bandgap and suppression of magnetization through lattice expansion. These results not only reveal a hydrogen chemical state beyond anion and cation within the complex oxides, but also suggest an effective pathway to design functional materials through tunable ionic evolution.

5.
Nat Commun ; 10(1): 4469, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578337

RESUMO

Magnetic topological insulators (MTIs) offer a combination of topologically nontrivial characteristics and magnetic order and show promise in terms of potentially interesting physical phenomena such as the quantum anomalous Hall (QAH) effect and topological axion insulating states. However, the understanding of their properties and potential applications have been limited due to a lack of suitable candidates for MTIs. Here, we grow two-dimensional single crystals of Mn(SbxBi(1-x))2Te4 bulk and exfoliate them into thin flakes in order to search for intrinsic MTIs. We perform angle-resolved photoemission spectroscopy, low-temperature transport measurements, and first-principles calculations to investigate the band structure, transport properties, and magnetism of this family of materials, as well as the evolution of their topological properties. We find that there exists an optimized MTI zone in the Mn(SbxBi(1-x))2Te4 phase diagram, which could possibly host a high-temperature QAH phase, offering a promising avenue for new device applications.

6.
Ecotoxicol Environ Saf ; 171: 579-586, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30654292

RESUMO

Norgestrel (NGT) is a synthetic progestin used in human and veterinary medicine. Adult female mosquitofish were exposed to NGT for 42 d at 377 ng L-1. The fin morphology and the liver transcriptome were assessed. NGT exposure increased ray 4:6 length ratio. As compared to the control, NGT treatment affected the expression of 11,772 annotated transcripts in female mosquitofish. Specifically, we found 5780 were repressed while 5992 were significantly induced. Gene ontology (GO) analysis showed that 53 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and 158 GO terms were significantly over expressed. Genes showing the largest magnitude of expression changes were related to fin development, androgen biosynthesis, and lipid and fatty acid metabolisms, suggesting the involvement of these biological processes in response to NGT exposure in G. affinis. This first comprehensive study on the transcriptomic alterations by NGT in G. affinis not only provides valuable information on the development of molecular markers but also opens new avenues for studies on the molecular mechanisms of effects of NGT in particular and possibly other progestins in G. affinis.


Assuntos
Ciprinodontiformes/genética , Fígado/efeitos dos fármacos , Norgestrel/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Ciprinodontiformes/metabolismo , Relação Dose-Resposta a Droga , Feminino , Fígado/metabolismo
7.
Eur J Med Chem ; 161: 118-130, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347326

RESUMO

Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ginsenosídeos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Toxicol Lett ; 300: 59-66, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30394303

RESUMO

To study the role of pirfenidone in rats exposed to silica dust, we established the rat silicosis model with 50 mg/ml silica by intratracheal instillation. From the first day after silica instillation, rats were given pirfenidone (50, 100 mg/kg/day) and rats were sacrificed at 14 days and 28 days to observe the histopathology of lungs, to analyze the level of TNF-α, IL-1ß, IL-6 in lung tissues and to measure the expression of TGF-ß1, Smad2/3, vimentin, and E-cadherin in lung tissues. Results showed that pirfenidone (50, 100 mg/kg/day) reduced the silica-induced alveolar inflammation, the damage of alveolar structure and the blue areas of collagen fibers in the lungs of rats. At the same time, pirfenidone also reduced the level of TNF-α, IL-1ß, IL-6 in lung tissues and the protein expression of collagen I. After pirfenidone intervention for 14 days and 28 days, the protein expression of vimentin was down-regulated and the protein expression of E-cadherin was up-regulated in lung tissues. In addition, the TGF-ß1/smad2/3 pathway was activated at 14 days and 28 days after silica instillation, and pirfenidone reduced the expression of TGF-ß1 and smad2/3 in the lungs. These results indicated that pirfenidone intervention inhibited the epithelial-mesenchymal transition and pulmonary fibrosis in rat silicosis model, which effects may be related to the TGF-ß1/smad pathway.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Piridonas/uso terapêutico , Dióxido de Silício/toxicidade , Silicose/tratamento farmacológico , Silicose/etiologia , Animais , Masculino , Modelos Animais , Ratos
9.
Exp Ther Med ; 15(1): 691-698, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29399073

RESUMO

The present study aimed to investigate the role of relaxin (RLX) on high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis, as well as the possible molecular mechanism. H9c2 cells were exposed to 33 mmol/l HG with or without RLX (100 nmol/ml). Cell viability, apoptosis, oxidative stress, cell hypertrophy and the levels of Notch1, hairy and enhancer of split 1 (hes1), atrial natriuretic polypeptide (ANP), brain natriuretic peptide (BNP), manganese superoxide dismutase (MnSOD), cytochrome C and caspase-3 were assessed in cardiomyocytes. Compared with the HG group, the viability of H9c2 cells was increased by RLX in a time- and dose-dependent manner, and was accompanied with a significant reduction in apoptosis. Furthermore, RLX significantly suppressed the formation of reactive oxygen species and malondialdehyde, and enhanced the activity of SOD. In addition, the levels of ANP, BNP, cytochrome C and caspase-3 were increased and Notch1, hes1 and MnSOD were inhibited in the HG group compared with those in the normal group. However, the Notch inhibitor DAPT almost abolished the protective effects of RLX. These results suggested that RLX protected cardiomyocytes from HG-induced hypertrophy and apoptosis partly through a Notch1-dependent pathway, which may be associated with reducing oxidative stress.

10.
Exp Cell Res ; 362(2): 436-443, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233682

RESUMO

Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-ß1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-ß1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-ß1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-ß1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-ß1/Smad pathway in patients with AF.


Assuntos
Fibrilação Atrial/genética , Fibrose/genética , Proteínas Musculares/genética , Miocárdio/metabolismo , Fator de Crescimento Transformador beta1/genética , Proteínas de Transporte Vesicular/genética , Adenoviridae/genética , Animais , Fibrilação Atrial/patologia , Diferenciação Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Modelos Animais de Doenças , Fibrose/patologia , Regulação da Expressão Gênica , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , Miocárdio/patologia , RNA Interferente Pequeno/genética , Ratos , Proteínas Smad/genética
11.
Adv Mater ; 29(46)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29057574

RESUMO

Field-effect transistors with ionic-liquid gating (ILG) have been widely employed and have led to numerous intriguing phenomena in the last decade, due to the associated excellent carrier-density tunability. However, the role of the electrochemical effect during ILG has become a heavily debated topic recently. Herein, using ILG, a field-induced insulator-to-metal transition is achieved in WO3 thin films with the emergence of structural transformations of the whole films. The subsequent secondary-ion mass spectrometry study provides solid evidence that electrochemically driven hydrogen evolution dominates the discovered electrical and structural transformation through surface absorption and bulk intercalation.

12.
Biomaterials ; 145: 106-127, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28865290

RESUMO

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated ß-amyloid proteins (Aß) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE2) and PGD2, PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Apoptose , Celecoxib/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Membrana Eritrocítica/metabolismo , Neurogênese , Presenilina-1/metabolismo , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Celecoxib/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Dinoprostona/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Células HEK293 , Humanos , Lipossomos/ultraestrutura , Camundongos Transgênicos , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosfolipídeos/química , Prostaglandina D2/farmacologia , Ratos Wistar , Superóxido Dismutase/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , beta-Arrestina 1/metabolismo
13.
Nature ; 546(7656): 124-128, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569818

RESUMO

Materials can be transformed from one crystalline phase to another by using an electric field to control ion transfer, in a process that can be harnessed in applications such as batteries, smart windows and fuel cells. Increasing the number of transferrable ion species and of accessible crystalline phases could in principle greatly enrich material functionality. However, studies have so far focused mainly on the evolution and control of single ionic species (for example, oxygen, hydrogen or lithium ions). Here we describe the reversible and non-volatile electric-field control of dual-ion (oxygen and hydrogen) phase transformations, with associated electrochromic and magnetoelectric effects. We show that controlling the insertion and extraction of oxygen and hydrogen ions independently of each other can direct reversible phase transformations among three different material phases: the perovskite SrCoO3-δ (ref. 12), the brownmillerite SrCoO2.5 (ref. 13), and a hitherto-unexplored phase, HSrCoO2.5. By analysing the distinct optical absorption properties of these phases, we demonstrate selective manipulation of spectral transparency in the visible-light and infrared regions, revealing a dual-band electrochromic effect that could see application in smart windows. Moreover, the starkly different magnetic and electric properties of the three phases-HSrCoO2.5 is a weakly ferromagnetic insulator, SrCoO3-δ is a ferromagnetic metal, and SrCoO2.5 is an antiferromagnetic insulator-enable an unusual form of magnetoelectric coupling, allowing electric-field control of three different magnetic ground states. These findings open up opportunities for the electric-field control of multistate phase transformations with rich functionalities.

14.
Cell Mol Immunol ; 14(5): 451-464, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-26549801

RESUMO

Alzheimer's disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1ß (IL-1ß) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1ß expression during Mg2+ dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1ß reduction using a recently developed compound, magnesium-L-threonate (MgT). Using human glioblastoma A172 and mouse brain D1A glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1ß in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways by phosphorylation, which resulted in IL-1ß suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPARγ induced IL-1ß upregulation in MgT-stimulated glial cells. In accordance with our in vitro data, the intracerebroventricular (i.c.v) injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Aß precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1ß. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg2+ influx into the ventricles of the mice blocked the effects of IL-1ß or amyloid ß-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1ß expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation.


Assuntos
Precursor de Proteína beta-Amiloide/fisiologia , Encéfalo/imunologia , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Magnésio/farmacologia , Presenilina-1/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Aging Cell ; 15(5): 861-71, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27240539

RESUMO

Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I2 , in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1α and pharynx-defective-1ß induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1α/1ß expression. As PGI2 is an important metabolic by-product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1α/1ß in neuronal cells and APP/PS1 mice. More importantly, ß-amyloid protein (Aß) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1α/1ß, which was blocked by NS398 incubation. Finally, the induction of APH-1α/1ß was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2 -induced AD progression but also are instrumental for improving clinical therapies to combat AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Endopeptidases/genética , Epoprostenol/farmacologia , Presenilina-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Administração Intranasal , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Animais , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Endopeptidases/metabolismo , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Nitrobenzenos/administração & dosagem , Nitrobenzenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
16.
Nanotechnology ; 27(13): 135102, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26901756

RESUMO

In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/administração & dosagem , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/síntese química , Nanopartículas/administração & dosagem , Verapamil/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Nanopartículas/química , Porosidade , Verapamil/química , Verapamil/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Biomed Nanotechnol ; 11(12): 2231-42, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26510316

RESUMO

A family of nanogel drug carriers has been designed to enhance the oral absorption of paclitaxel (PTX). The PAHy-based nanogels were prepared by the interpenetration of poly-α,ß-polyasparthydrazide (PAHy) chains and dicarboxyl-poly (ethylene glycol) (CPEG), forming a smart chain network. The PAHy-based nanogels were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DLS), X-ray diffraction (XRD) and high performance liquid chromatography (HPLC). The adhesion and retention properties of fluorescein isothiocyanate (FITC)-nanogels in vivo were investigated using an in vivo imaging system and confocal laser scanning microscopy (CLSM). The smart nanogels had a particle size of -200 nm, increased the degree and rate of release, and spent over 12 h in the gastrointestinal tract. They also produced excellent adhesion, permeability and retention (APR) effects and increased oral absorption, confirming their use as potential sustained-release carriers for the oral delivery of the hydrophobic anticancer agent PTX.


Assuntos
Portadores de Fármacos/química , Hidrazinas/química , Nanoestruturas/química , Nylons/química , Paclitaxel/administração & dosagem , Paclitaxel/química , Administração Oral , Animais , Liberação Controlada de Fármacos , Géis , Interações Hidrofóbicas e Hidrofílicas , Absorção Intestinal , Masculino , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Permeabilidade , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley
18.
FASEB J ; 29(12): 5044-58, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26293690

RESUMO

Alzheimer's disease (AD) is associated with a magnesium ion (Mg(2+)) deficit in the serum or brain. However, the mechanisms regulating the roles of Mg(2+) in the pathologic condition of AD remain unknown. We studied whether brain Mg(2+) can decrease ß-amyloid (Aß) deposition and ameliorate the cognitive decline in a model of AD, the APPswe/PS1DE9 transgenic (Tg) mouse. We used a recently developed compound, magnesium-L-threonate (MgT), for a treatment that resulted in enhanced clearance of Aß in an anterior pharynx-defective (APH)-1α/-1ß-dependent manner. To further explore how MgT treatment inhibits cognitive decline in APP/PS1 Tg mice, the critical molecules for amyloid precursor protein (APP) cleavage and signaling pathways were investigated. In neurons, ERK1/2 and PPARγ signaling pathways were activated by MgT treatment, which in turn suppressed (by >80%) the expression of APH-1α/-1ß, which is responsible for the deposition of Aß and potentially contributes to the memory deficit that occurs in AD. More important, Aß oligomers in the cerebrospinal fluid (CSF) further promoted the expression of APH-1α/-1ß (by >2.5-fold), which enhances the γ-cleavage of APP and Aß deposition during AD progression. These findings provide new insights into the mechanisms of AD progression and are instrumental for developing better strategies to combat the disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Transtornos Cognitivos/prevenção & controle , Endopeptidases/metabolismo , Magnésio/farmacologia , Presenilina-1/genética , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Aprendizagem em Labirinto , Proteínas de Membrana , Camundongos , Camundongos Transgênicos
19.
Sci Rep ; 5: 10412, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25992485

RESUMO

MMP-1 expression is detected in fluid shear stress (20 dyn/cm(2))-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1ß, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2(+/-) transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Animais , Células Cultivadas , Condrócitos/citologia , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Interleucina-1beta/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resistência ao Cisalhamento , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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