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1.
Nat Nanotechnol ; 15(2): 131-137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31907442

RESUMO

To date, effective control over the electrochemical reduction of CO2 to multicarbon products (C ≥ 2) has been very challenging. Here, we report a design principle for the creation of a selective yet robust catalytic interface for heterogeneous electrocatalysts in the reduction of CO2 to C2 oxygenates, demonstrated by rational tuning of an assembly of nitrogen-doped nanodiamonds and copper nanoparticles. The catalyst exhibits a Faradaic efficiency of ~63% towards C2 oxygenates at applied potentials of only -0.5 V versus reversible hydrogen electrode. Moreover, this catalyst shows an unprecedented persistent catalytic performance up to 120 h, with steady current and only 19% activity decay. Density functional theory calculations show that CO binding is strengthened at the copper/nanodiamond interface, suppressing CO desorption and promoting C2 production by lowering the apparent barrier for CO dimerization. The inherent compositional and electronic tunability of the catalyst assembly offers an unrivalled degree of control over the catalytic interface, and thereby the reaction energetics and kinetics.

2.
Mater Sci Eng C Mater Biol Appl ; 108: 110386, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923940

RESUMO

Therapeutic peptide, NuBCP-9 (N9) as a Bcl-2 functional converter, has been demonstrated to have the remarkable anticancer efficiency in Bcl-2-abundant cancer. However, it faced technical challenges in clinical use, such as the low bioavailability, the easily-destroyed bio-stability, and the insusceptibility to cellular interior. With the potential of mesoporous silica nanoparticles (MSNs) as the promising delivery vehicle of therapeutic macromolecules, we developed a kind of MSNs with the surface coating of folic acid (FA) for cancer cell targeting and with the macropore loading of N9 peptide for cancer therapy. Our results showed that the functional MSNs had the relatively greater biosafety than the naked MSNs in zebrafish models, leading to less than 30% embryo of death at 200 µg/ml, which could further specifically target the folate receptor (FR)-overexpressed cervical cancer HeLa cells instead of FR-negative normal embryonic kidney HEK 293T cells in a FA-competitive manner. N9 peptide with the delivery of functional MSNs could be internalized by HeLa cells, and co-localized with mitochondria in a Bcl-2-dependent manner. Moreover, N9 peptide delivered by FA-modified MSNs displayed the excellent anticancer efficiency with great selectivity, inducing approximately 52% HeLa cells into apoptosis. In summary, our results illustrated the potential of functional MSNs with large pore size as an efficient nanocarrier for the intracellular delivery of peptide drugs with targeting proteins to realize cancer therapy.

3.
Theranostics ; 10(3): 1230-1244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31938062

RESUMO

Rationale: Glycogen synthase kinase-3ß (GSK-3ß) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3ß can confer tumor growth. However, the expression and function of GSK-3ß in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3ß in HCC. Methods: We firstly clarified the expression of GSK-3ß in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3ß could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3ß in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Results: We demonstrated that GSK-3ß is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3ß confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3ß is correlated with reduced expression of retinoic acid receptor-ß (RARß), which is caused by GSK-3ß-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARß promoter. Overexpression of functional GSK-3ß impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3ß by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARß by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARß. Conclusions: Our findings demonstrate that GSK-3ß is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3ß may be a promising strategy for HCC treatment in clinic.

5.
Cancer Lett ; 469: 340-354, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31629930

RESUMO

Therapeutic biomacromolecules are confronted with in vivo challenges of low bio-stability and poor tumor tissue-penetration. Herein, we report for the first time, our development and characterization of a hybrid nanocomposite for delivering a Bcl-2-converting peptide (NuBCP9, N9 hereafter) and testing its efficacy alone or together with doxorubicin (DOX). The hybrid nanocomposite is composed of the internal large pore sized-mesoporous silica nanoparticles (MSNs) and the external highly-branched polyamidoamine (PAMAM) dendrimers, into which N9 peptide and DOX were encapsulated for the different sub-cellular delivery to treat drug-resistant cancer. The nanocomposite possessed the particle and pore sizes of ~37 nm and ~8 nm, which displayed the superior tumor penetration capacity over naked MSNs both in cultured-3D tumor sphere and in live animal models. Moreover, the dual drug nanocomposite exhibited a great synergistic anticancer effect on Bcl-2-positive cancer cells in vitro and animals with the negligible toxic side effects. The tumor inhibition rate of the nanocomposite (89%) was five times as much as the two drugs combination. This design provides a new effective, safe and versatile strategy to fabricate large pore-sized MSNs with the organic-inorganic hybrid framework to concurrently transport therapeutic peptides and chemotherapeutics to the specific sub-cellular locations for the synergistic cancer therapy and drug resistance reversal, which has significant impact on the development of improved cancer therapeutics.

6.
Eur J Med Chem ; 177: 171-187, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132532

RESUMO

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a Kd of 0.87 µM was found to be less toxic than celastrol and could be a hit molecule for further optimization.


Assuntos
Anti-Inflamatórios/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/toxicidade , Sítios de Ligação , Desenho de Drogas , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Relação Estrutura-Atividade , Fator 2 Associado a Receptor de TNF/metabolismo , Triterpenos/síntese química , Triterpenos/metabolismo , Triterpenos/toxicidade , Peixe-Zebra
7.
Nat Nanotechnol ; 14(7): 705-711, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31133663

RESUMO

The urgent need for safer batteries is leading research to all-solid-state lithium-based cells. To achieve energy density comparable to liquid electrolyte-based cells, ultrathin and lightweight solid electrolytes with high ionic conductivity are desired. However, solid electrolytes with comparable thicknesses to commercial polymer electrolyte separators (~10 µm) used in liquid electrolytes remain challenging to make because of the increased risk of short-circuiting the battery. Here, we report on a polymer-polymer solid-state electrolyte design, demonstrated with an 8.6-µm-thick nanoporous polyimide (PI) film filled with polyethylene oxide/lithium bis(trifluoromethanesulfonyl)imide (PEO/LiTFSI) that can be used as a safe solid polymer electrolyte. The PI film is nonflammable and mechanically strong, preventing batteries from short-circuiting even after more than 1,000 h of cycling, and the vertical channels enhance the ionic conductivity (2.3 × 10-4 S cm-1 at 30 °C) of the infused polymer electrolyte. All-solid-state lithium-ion batteries fabricated with PI/PEO/LiTFSI solid electrolyte show good cycling performance (200 cycles at C/2 rate) at 60 °C and withstand abuse tests such as bending, cutting and nail penetration.

8.
Nat Commun ; 10(1): 1463, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931933

RESUMO

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.


Assuntos
Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Interleucina-6/imunologia , Receptor X Retinoide alfa/genética , Fator de Transcrição STAT3/imunologia , Animais , Carcinogênese/imunologia , Colite/imunologia , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/imunologia , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Células HCT116 , Humanos , Inflamação , Macrófagos/imunologia , Camundongos , NF-kappa B/imunologia , Receptor X Retinoide alfa/imunologia , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Fator 6 Associado a Receptor de TNF/imunologia
9.
Br J Pharmacol ; 176(14): 2559-2572, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30943581

RESUMO

BACKGROUND AND PURPOSE: Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-α (RXRα) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXRα modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization. EXPERIMENTAL APPROACH: Our previously established ApoE-/- mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003. KEY RESULTS: K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-κB subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, IκBα degradation, and transcription of NF-κB target genes. In addition, K-80003 inhibited NF-κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXRα cytoplasmic translocation. CONCLUSIONS AND IMPLICATIONS: K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-κB proinflammatory pathway. Thus, targeting RXRα-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.

10.
Mar Drugs ; 17(3)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893778

RESUMO

Five new ergostanes, penicisteroids D-H (1-5), were isolated from the liquid culture of the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475, along with 27 known compounds. The structures of the new steroids were established mainly on the basis of extensive analysis of 1D and 2D NMR as well as HRESIMS data. Moreover, the absolute configurations of 1 were confirmed unambiguously by the single-crystal X-ray crystallography. Compounds 2 and 4⁻7 showed moderate antiproliferative effects selectively against 12 different cancer cell lines with IC50 values of around 5 µM. Compounds 2 and 6, potent RXRα binders with Kd values of 13.8 and 12.9 µM, respectively, could induce apoptosis by a Retinoid X Receptor (RXR)-α-dependent mechanism by regulating RXRα transcriptional expression and promoting the poly-ADP-ribose polymerase (PARP) cleavage. Moreover, they could inhibit proliferation by cell cycle arrest at the G0/G1 phase.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Ergosterol/farmacologia , Penicillium/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/análogos & derivados , Ergosterol/química , Ergosterol/isolamento & purificação , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Sedimentos Geológicos/microbiologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Mol Cancer Ther ; 18(5): 886-899, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926635

RESUMO

Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF3 +MeSO3 - (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77- and Bcl-2-dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

12.
Environ Pollut ; 247: 812-823, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30731306

RESUMO

A conversion of the global terrestrial carbon sink to a source is critically dependent on the microbially mediated decomposition of soil organic matter (SOM). We have developed a detailed, process-based, mechanistic model for simulating SOM decomposition and its associated processes, based on Microbial Kinetics and Thermodynamics, called the MKT model. We formulated the sequential oxidation-reduction potential (ORP) and chemical reactions undergoing at the soil-water zone using dual Michaelis-Menten kinetics. Soil environmental variables, as required in the MKT model, are simulated using one of the most widely used watershed-scale models - the soil water assessment tool (SWAT). The MKT model was calibrated and validated using field-scale data of soil temperature, soil moisture, and N2O emissions from three locations in the province of Saskatchewan, Canada. The model evaluation statistics show good performance of the MKT model for daily soil N2O simulations. The results show that the proposed MKT model can perform better than the more widely used process-based and SWAT-based models for soil N2O simulations. This is because the multiple processes of microbial activities and environmental constraints, which govern the availability of substrates to enzymes were explicitly represented. Most importantly, the MKT model represents a step forward from conceptual carbon pools at varying rates.


Assuntos
Poluentes Atmosféricos/análise , Biodegradação Ambiental , Dióxido de Nitrogênio/análise , Microbiologia do Solo , Carbono , Meio Ambiente , Monitoramento Ambiental , Cinética , Óxido Nitroso/análise , Oxirredução , Saskatchewan , Solo/química , Termodinâmica , Água
13.
Eur J Med Chem ; 164: 562-575, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30634084

RESUMO

Nuclear receptor RXRα plays an important role in many biological and pathological processes. The nongenomic action of RXRα is implicated in many cancers. K-8008, a non-canonical RXRα ligand derived from sulindac, inhibits the TNFα-activated PI3K/AKT pathway by mediating the interaction between a truncated form of RXRα (tRXRα) and the p85α regulatory subunit of PI3K and exerts potent anticancer activity in animal model. Herein we report our studies of a novel series of K-8008 analogs as potential anticancer agents targeting RXRα. Two compounds 8b and 18a were identified to have slightly stronger binding to RXRα and improved apoptotic activities in breast cancer cells.


Assuntos
Antineoplásicos/síntese química , Desenho de Drogas , Receptor X Retinoide alfa , Tetrazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Humanos , Ligantes , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/metabolismo , Fator de Necrose Tumoral alfa
14.
Bioorg Med Chem Lett ; 29(5): 707-712, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30670347

RESUMO

The orphan nuclear receptor Nur77 (also known as TR3 or nerve growth factor-induced clone B NGFI-B) functions as a nuclear transcription factor in the regulation of target gene expression and plays a critical role in the regulation of differentiation, proliferation, apoptosis, and survival of many different cell types. Recent studies demonstrate that Nur77 also involves many important physiological and pathological processes including cancer, inflammation and immunity, cardiovascular diseases, and bone diseases. Our previous studies showed that cardiac glycosides could induce the expression of Nur77 protein and its translocation from the nucleus to the cytoplasm and subsequent targeting to mitochondria, leading to apoptosis of cancer cells. In order to probe the Nur77 protein inducting pathway, we designed and synthesized a series of novel biotinylated cardiac glycosides from ß-Antiarin and α-Antiarin, two typical cardiac glycosides from the plant of Antiaris toxicaria. The induction of Nur77 protein expression of these biotinylated cardiac glycosides and their inhibitory effects on NIH-H460 cancer cell proliferation were evaluated. Results displayed that some biotinylated cardiac glycosides could significantly induce the expression of Nur77 protein comparable with their parent compounds ß-Antiarin and α-Antiarin. Also, their streptavidin binding activities were evaluated. Among them, biotinylated cardiac glycosides P4b and P5a exhibited significant effect on the induction of Nur77 expression along with high binding capacity with streptavidin, suggesting that they can be used as probes for probing Nur77 protein inducting pathway.


Assuntos
Biotina/química , Glicosídeos Cardíacos/química , Glicosídeos Cardíacos/síntese química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Animais , Glicosídeos Cardíacos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Sondas Moleculares
15.
Bioorg Chem ; 85: 413-419, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30665035

RESUMO

Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.


Assuntos
Atorvastatina/farmacologia , Multimerização Proteica/efeitos dos fármacos , Receptor X Retinoide alfa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Atorvastatina/química , Atorvastatina/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Células MCF-7 , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Estabilidade Proteica/efeitos dos fármacos , Sulindaco/análogos & derivados , Sulindaco/metabolismo
17.
Mol Pharm ; 16(2): 480-488, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-29995422

RESUMO

Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1, and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid ß (Aß)-protein clearance in the brain of an Alzheimer's disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methoxyl, hydroxyl, and methoxy groups in 2- or 4-position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxyl in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4-position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aß plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4-position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aß plaques in AD mouse model.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Naftalenos/uso terapêutico , Nitrocompostos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Receptor X Retinoide alfa/metabolismo , Doença de Alzheimer/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Naftalenos/química , Nitrocompostos/química , Placa Amiloide/metabolismo
18.
J Cell Mol Med ; 23(1): 155-166, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30370662

RESUMO

Matriptase is an epithelia-specific membrane-anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor-1 (HAI-1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI-1 complex formation determines the intensity and duration of matriptase activity. 3-Cl-AHPC, 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid, is an adamantly substituted retinoid-related molecule and a ligand of retinoic acid receptor γ (RARγ). 3-Cl-AHPC is of strong anti-cancer effect but with elusive mechanisms. In our current study, we show that 3-Cl-AHPC time- and dose- dependently induces matriptase/HAI-1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3-Cl-AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3-Cl-AHPC inhibits matriptase-mediated cleavage of pro-HGF through matriptase/HAI-1 complex induction, resulting in the suppression of pro-HGF-stimulated signalling and cell scattering. Although 3-Cl-AHPC binds to RARγ, its induction of matriptase/HAI-1 complex is not RARγ dependent. Together, our data demonstrates that 3-Cl-AHPC down-regulates matriptase activity through induction of matriptase/HAI-1 complex formation in a RARγ-independent manner, providing a mechanism of 3-Cl-AHPC anti-cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI-1 complex induction using small molecules.

19.
Nanoscale Res Lett ; 13(1): 362, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430270

RESUMO

I-III-VI2 compounds have shown great interests in the application of functional semiconductors. Among them, Cu(In,Ga)S2 has been a promising candidate due to its excellent optoelectronic properties. Although the polymorphs of Cu(In,Ga)S2 have been attracted extensive attentions, the efforts to developing the methodologies for phase-controlled synthesis of them are rare. In this paper, we reported a phase-selective synthesis of CIGS nanoparticles with metastable phases via simply changing the composition of solvents. For the wet chemistry synthesis, the microstructure of the initial nuclei is decisive to the crystal structure of final products. In the formation of Cu(In,Ga)S2, the solvent environment is the key factor, which could affect the coordination of monomers and influence the thermodynamic conditions of Cu-S nucleation. Moreover, wurtzite and zincblende Cu(In,Ga)S2 nanoparticles are selectively prepared by choosing pure en or its mixture with deionized water as reaction solvent. The as-synthesized wurtzite Cu(In,Ga)S2 possess a band gap of 1.6 eV and a carrier mobility of 4.85 cm2/Vs, which indicates its potential to construct a heterojunction with hexagonal-structured CdS for solar cells.

20.
Micromachines (Basel) ; 9(12)2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487394

RESUMO

Engine health monitoring is very important to maintain the life of engines, and the power supply to sensor nodes is a key issue that needs to be solved. The piezoelectric vibration energy harvester has attracted much attention due to its obvious advantages in configuration, electromechanical conversion efficiency, and output power. However, the narrow bandwidth has restricted its practical application. A self-powered engine health monitoring system was proposed in this paper, and an L-shaped wideband piezoelectric energy harvester was designed and implemented. The L-shaped beam-mass structure and the piezoelectric bimorph cantilever beam structure was combined to form the wideband piezoelectric energy harvester configuration, which realized effective output at both resonance points. The theoretical model and finite element simulation analysis of the wideband piezoelectric energy harvester were proposed and the parameters were optimized based on that to meet the requirement of the vibration frequency of the engine. The experimental results show that the proposed energy harvester can be applied into the automobile engine health monitoring system. Engine signal analysis results also demonstrate that the proposed system can be used for engine health monitoring.

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