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1.
J Am Chem Soc ; 144(13): 6059-6070, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35333507

RESUMO

Triplet ground-state organic molecules are of interest with respect to several emerging technologies but usually show limited stability, especially as thin films. We report an organic diradical, consisting of two Blatter radicals, that possesses a triplet ground state with a singlet-triplet energy gap, ΔEST ≈ 0.4-0.5 kcal mol-1 (2J/k ≈ 220-275 K). The diradical possesses robust thermal stability, with an onset of decomposition above 264 °C (TGA). In toluene/chloroform, glassy matrix, and fluid solution, an equilibrium between two conformations with ΔEST ≈ 0.4 kcal mol-1 and ΔEST ≈ -0.7 kcal mol-1 is observed, favoring the triplet ground state over the singlet ground-state conformation in the 110-330 K temperature range. The diradical with the triplet ground-state conformation is found exclusively in crystals and in a polystyrene matrix. The crystalline neutral diradical is a good electrical conductor with conductivity comparable to the thoroughly optimized bis(thiazolyl)-related monoradicals. This is surprising because the triplet ground state implies that the underlying π-system is cross-conjugated and thus is not compatible with either good conductance or electron delocalization. The diradical is evaporated under ultra-high vacuum to form thin films, which are stable in air for at least 18 h, as demonstrated by X-ray photoelectron and electron paramagnetic resonance (EPR) spectroscopies.


Assuntos
Elétrons , Condutividade Elétrica , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Modelos Moleculares , Conformação Molecular
2.
J Am Chem Soc ; 144(2): 626-647, 2022 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-34982552

RESUMO

Open-shell macromolecules (i.e., polymers containing radical sites either along their backbones or at the pendant sites of repeat units) have attracted significant attention owing to their intriguing chemical and physical (e.g., redox, optoelectronic, and magnetic) properties, and they have been proposed and/or implemented in a wide range of potential applications (e.g., energy storage devices, electronic systems, and spintronic modules). These successes span multiple disciplines that range from advanced macromolecular chemistry through nanoscale structural characterization and on to next-generation solid-state physics and the associated devices. In turn, this has allowed different scientific communities to expand the palette of radical-containing polymers relatively quickly. However, critical gaps remain on many fronts, especially regarding the elucidation of key structure-property-function relationships that govern the underlying electrochemical, optoelectronic, and spin phenomena in these materials systems. Here, we highlight vital developments in the history of open-shell macromolecules to explain the current state of the art in the field. Moreover, we provide a critical review of the successes and bring forward open opportunities that, if solved, could propel this class of materials in a meaningful manner. Finally, we provide an outlook to address where it seems most likely that open-shell macromolecules will go in the coming years. Our considered view is that the future of radical-containing polymers is extremely bright and the addition of talented researchers with diverse skills to the field will allow these materials and their end-use devices to have a positive impact on the global science and technology enterprise in a relatively rapid manner.

3.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151

RESUMO

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Assuntos
Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
4.
Phytomedicine ; 93: 153776, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34666285

RESUMO

BACKGROUND: Traditional Chinese herbal patches (TCHPs) characterized by good patient adherence and few side effects have been widely used in the clinic. However, their bioactive transdermal components, which are key to the quality and efficacy, have rarely been investigated. PURPOSE: Establishing an approach to probe the bioactive transdermal components of TCHPs, using Gutong patch (GTP) as a case study. STUDY DESIGN AND METHODS: GTP constituents were identified using ultrahigh-pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). The identified GTP constituents were transferred to an ultrahigh-pressure liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) method in a dynamic multiple reaction monitoring (dMRM) mode for sensitively targeted analysis of transdermal components present at low concentrations. The ex vivo transdermal components were rapidly probed using a percutaneous permeation model and the release kinetics of marker components was assessed to evaluate the release behavior of GTP. The in vivo transdermal components were then studied in a rat model of arthritis and the changes in concentration of 15 representative bioactive transdermal components with time were well revealed. RESULTS: A total of 120 phytochemical constituents have been identified in GTP extracts and 61 ex vivo transdermal components were targetedly detected. The release kinetics of GTP were evaluated by eight marker components and fitted to a zero-order kinetic model. In vivo, 62 and 40 transdermal components were observed in the skin and subcutaneous tissues of arthritic rats, respectively. The concentration-time changes of 15 representative transdermal components with documented bioactivities have been successfully exhibited after GTP administration. CONCLUSION: We established a feasible approach to probe the bioactive transdermal components of TCHPs efficiently. The integration of mass spectrometry profiling and targeted detection in dMRM mode enabled a comprehensive investigation of phytochemical constituents and their transdermal delivery, thus addressing the challenge of direct probing of diverse transdermal components present at low concentrations. This approach could be used to rapidly probe the bioactive components and understand the mechanism of TCHPs.


Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Administração Cutânea , Animais , China , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/análise , Ratos
5.
Nano Lett ; 21(18): 7839-7844, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34469174

RESUMO

Sn-based halide perovskites are promising for thermoelectric (TE) device applications because of their high electrical conductivity as well as the low thermal conductivity associated with their soft lattices. However, conventional three-dimensional Sn-based perovskites are not stable under typical TE device operating conditions. Here, we report a stable two-dimensional Sn-based perovskite for thermoelectric energy conversion by incorporating bulky conjugated ligands. We demonstrate a thin film with a large power factor of 5.42 ± 3.07 (average) and 7.07 (champion) µW m-1 K-2 at 343 K with an electrical conductivity of 5.07 S cm-1 and a Seebeck coefficient of 118.1 µV K-1. Importantly, these thin films show excellent operational stability (i.e., for over 100 h) at 313 K. This work suggests that the novel hybrid two-dimensional perovskites are a promising platform for thermoelectric energy conversion applications.

6.
Math Biosci Eng ; 18(5): 4943-4960, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34517471

RESUMO

Tumor segmentation using magnetic resonance imaging (MRI) plays a significant role in assisting brain tumor diagnosis and treatment. Recently, U-Net architecture with its variants have become prevalent in the field of brain tumor segmentation. However, the existing U-Net models mainly exploit coarse first-order features for tumor segmentation, and they seldom consider the more powerful second-order statistics of deep features. Therefore, in this work, we aim to explore the effectiveness of second-order statistical features for brain tumor segmentation application, and further propose a novel second-order residual brain tumor segmentation network, i.e., SoResU-Net. SoResU-Net utilizes a number of second-order modules to replace the original skip connection operations, thus augmenting the series of transformation operations and increasing the non-linearity of the segmentation network. Extensive experimental results on the BraTS 2018 and BraTS 2019 datasets demonstrate that SoResU-Net outperforms its baseline, especially on core tumor and enhancing tumor segmentation, illuminating the effectiveness of second-order statistical features for the brain tumor segmentation application.


Assuntos
Neoplasias Encefálicas , Processamento de Imagem Assistida por Computador , Neoplasias Encefálicas/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Neuroimagem
7.
Talanta ; 228: 122238, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33773740

RESUMO

Phosphate esters and anhydrides have great significance in the field of biochemical research and medical therapy. The genetic materials (DNA or RNA), most of the coenzymes, many intermediary metabolites, such as nucleotides and glycosyl phosphates in vivo are phosphodiesters, phosphoric acid or phosphates, respectively. It is important to monitor endogenous active phosphate metabolites for investigating many biological processes or drug mechanism. However, the detection and determination of those free active phosphate metabolites are challenged due to their unstable and easily hydrolyzed property and relatively low sensitivity, especially diphosphates and triphosphates. In the current study, we successfully developed a strategy by 3-aminomethyl pyridine (AMPy) derivatization coupled with hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) for simultaneous determination of multiple types of phosphate metabolites with good stability in 48 h and 29 to 126-fold improvement of the limit of detection (LOD). Based on the diagnostic fragment ions of different types of AMPy-derivatized phosphate metabolites, characteristic MRM ion pairs were successfully performed for global profiling of the phosphate metabolites in phosphate ester/anhydride metabolic network, including nucleotide/deoxynucleotide mono/di/triphosphates, glycosyl mono/diphosphates, and other key phosphates, such as 5-phosphoribosyl-1-pyrophosphate (PRPP), SAICARP and FAICARP in HPF, HUVEC and PBMCs cells without standards. The developed strategy greatly expanded the coverage of applying a single derivatization reaction to analyze active phosphate metabolites. Finally, the established method was performed to investigate the phosphate esters and anhydrides based on a glioma rat model. For the first time, phosphate metabolites were comprehensively characterized based on phosphate ester and anhydride metabolic network, covering nucleotide metabolism, glycolysis and pentose phosphate pathways, etc. The results demonstrated that the applicability of the method could be extended to a wider range of active phosphate compounds and could facilitate to related applications in the future studies.


Assuntos
Glioma , Espectrometria de Massas em Tandem , Anidridos , Animais , Cromatografia Líquida , Ésteres , Interações Hidrofóbicas e Hidrofílicas , Redes e Vias Metabólicas , Ratos
8.
J Shoulder Elbow Surg ; 30(9): 2065-2072, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33484831

RESUMO

BACKGROUND: Bone grafts have been used for augmentation and improving stability of reduced fractures in proximal humeral fractures. The aim of this study was to analyze the clinical and radiological outcomes after the use of cancellous bone allografts (CAs) for augmentation in 3- or 4-part proximal humeral fractures, and compare with fibular strut allografts (FAs). METHODS: Between November 2016 and February 2018, 55 patients, followed for at least 1 year, with 3- or 4-part proximal humeral fractures fixed with locking plates were included and grouped according to the type of allograft bone used for augmentation. In this retrospective analysis, we assessed and compared the clinical and radiological outcomes of the 2 groups, using the visual analog scale score, the Constant-Murley score (CMS), the disability of the arm, shoulder, and hand (DASH) score, the range of movement, neck-shaft angle (NSA), humeral head height (HHH), and the changes of NSA and HHH, as well as recording any complications. The repeatedly measured clinical and radiological outcomes were analyzed by linear mixed models. The differences in outcomes between groups at the final follow-up were compared using Student's t test. RESULTS: There were 28 patients in the CA group and 27 patients in the FA group with an average follow-up of 14.5 months. The mean age of all patients was 64 (36-86). Nonsignificant group effects were observed on CMS (ß = -8.792, P = .216), DASH (ß = 1.329, P = .094), NSA (ß = 1.432, P = .752), and HHH (ß = 1.660, P = .628). At the final follow-up, the patients in the CA group showed no significant differences in visual analog scale (1.8 vs. 2.2, P = .276), CMS (81.5 vs. 75.4, P = .072), and DASH (11.0 vs. 13.5, P = .235) scores compared with the FA group. There were no significant differences in the change of NSA (6 vs. 4, P = .387) or HHH (1 vs. 2, P = .261). CONCLUSIONS: Patients with 3- or 4-part proximal humeral fractures treated with locking plates combined with CAs have good clinical and radiographic outcomes, similar to those treated with FAs.


Assuntos
Osso Esponjoso , Fraturas do Ombro , Aloenxertos , Placas Ósseas , Fixação Interna de Fraturas , Humanos , Cabeça do Úmero , Estudos Retrospectivos , Fraturas do Ombro/diagnóstico por imagem , Fraturas do Ombro/cirurgia , Resultado do Tratamento
9.
Transl Cancer Res ; 10(9): 4125-4147, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35116710

RESUMO

BACKGROUND: Gasdermins (GSDMs) are a class of proteins related to pyrolysis and in humans, consist of GSDMA, GSDMB, GSDMC, GSDMD, DFNA5, and DFNB59. The inflammatory factors and cell contents released during pyrolysis can recruit immune cells and change the microenvironment. However, to date, there is a paucity of studies examining the relationship between GSDMs and the immune microenvironment in tumors. Therefore, this current report analyzed the expression of GSDM genes in tumors and their relationship with the immune microenvironment. METHODS: Apply GSCALite and GEPIA2 online analysis tools to analyze the gene expression levels and the Single nucleotide variant (SNV), copy number variation (CNV), and methylation characteristics of GSDM genes respectively. Use R software or TISIDB online analysis tool to carry out the correlation analysis required in the article. Furthermore, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to examine the role of these GSDM genes in various cancers. RESULTS: The results demonstrated that CNV can cause an increase in GSDM gene expression, and methylation can inhibit GSDM gene expression. The elevated expression of GSDMA, GSDMB, GSDMC, GSDMD, and DFNA5 in some or most tumors was often accompanied by elevated immune scores, increased immune cell infiltration, and high expression of major histocompatibility complex (MHC) molecules, chemokines and their receptors, and immune checkpoint-related genes. However, DFNB59 was often negatively correlated with these indicators in tumors. GSDMD was the most highly expressed GSDM protein in various normal tissues and tumors, and showed the strongest correlation with immune microenvironment-related genes. Moreover, the methylation of GSDMD was accompanied by low immune cell infiltration, low expression of MHC molecule-related genes, low expression of chemokines and receptor-related genes, and low expression of immune checkpoint-related genes. CONCLUSIONS: Therefore, the expression of GSDM-related genes is associated with the tumor immune microenvironment. The GSDM genes, especially GSDMD, may be used as therapeutic targets to predict or change the tumor microenvironment and as biomarkers to predict the therapeutic efficacy of immune checkpoint inhibitors.

10.
J Pharm Anal ; 11(6): 764-775, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35028182

RESUMO

There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments. Here, the anti-MI mechanism and material basis of Ginkgo biloba L. extract (GBE) were studied from the perspective of energy metabolism flux regulation. Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes. It showed that [U-13C] glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes, but the opposite was seen for the downstream metabolites, while their total cellular concentrations were increased. This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources. A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction. It showed that bilobalide protected against impaired mitochondrial aerobic respiration. MFA also showed that bilobalide significantly modulated the TCA cycle flux, reduced abnormal metabolite accumulation, and balanced the demand of different carbon sources. Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells. Bilobalide's efficacy was verified by in vivo experiments in rats. This is the first report to show that bilobalide, the active ingredient of GBE, protects against MI by rescuing impaired TCA cycle flux. This provides a new mechanism and potential drug treatment for MI. It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.

11.
Bone Joint J ; 102-B(12): 1629-1635, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33249912

RESUMO

AIMS: The aim of this study was to explore why some calcar screws are malpositioned when a proximal humeral fracture is treated by internal fixation with a locking plate, and to identify risk factors for this phenomenon. Some suggestions can be made of ways to avoid this error. METHODS: We retrospectively identified all proximal humeral fractures treated in our institution between October 2016 and October 2018 using the hospital information system. The patients' medical and radiological data were collected, and we divided potential risk factors into two groups: preoperative factors and intraoperative factors. Preoperative factors included age, sex, height, weight, body mass index, proximal humeral bone mineral density, type of fracture, the condition of the medial hinge, and medial metaphyseal head extension. Intraoperative factors included the grade of surgeon, neck-shaft angle after reduction, humeral head height, restoration of medial support, and quality of reduction. Adjusted binary logistic regression and multivariate logistic regression models were used to identify pre- and intraoperative risk factors. Area under the curve (AUC) analysis was used to evaluate the discriminative ability of the multivariable model. RESULTS: Data from 203 patients (63 males and 140 females) with a mean age of 62 years (22 to 89) were analyzed. In 49 fractures, the calcar screw was considered to be malpositioned; in 154 it was in the optimal position. The rate of malpositioning was therefore 24% (49/203). No preoperative risk factor was found for malpositioning of the calcar screws. Only the neck-shaft angle was found to be related to the risk of screw malpositioning in a multivariate model (with an AUC of 0.72). For the fractures in which the neck-shaft angle was reduced to between 130° and 150°, 91% (133/46) of calcar screws were in the optimal position. CONCLUSION: The neck-shaft angle is the key factor for the appropriate positioning of calcar screws when treating a proximal humeral fracture with a locking plate. We recommend reducing the angle to between 130° and 150°. Cite this article: Bone Joint J 2020;102-B(12):1629-1635.


Assuntos
Fixação Interna de Fraturas/métodos , Úmero/cirurgia , Fraturas do Ombro/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Placas Ósseas , Parafusos Ósseos , Feminino , Fixação Interna de Fraturas/efeitos adversos , Fixação Interna de Fraturas/instrumentação , Humanos , Úmero/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fraturas do Ombro/diagnóstico por imagem , Adulto Jovem
12.
Int J Mol Sci ; 21(14)2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32707731

RESUMO

Activation of the nod-like receptor 3 (NLRP3) inflammasomes is crucial for immune defense, but improper and excessive activation causes inflammatory diseases. We previously reported that Cbl plays a pivotal role in suppressing NLRP3 inflammasome activation by inhibiting Pyk2-mediated apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. Here, we showed that Cbl dampened NLRP3 inflammasome activation by inhibiting glycolysis, as demonstrated with Cbl knockout cells and treatment with the Cbl inhibitor hydrocotarnine. We revealed that the inhibition of Cbl promoted caspase-1 cleavage and interleukin (IL)-1ß secretion through a glycolysis-dependent mechanism. Inhibiting Cbl increased cellular glucose uptake, glycolytic capacity, and mitochondrial oxidative phosphorylation capacity. Upon NLRP3 inflammasome activation, inhibiting Cbl increased glycolysis-dependent activation of mitochondrial respiration and increased the production of reactive oxygen species, which contributes to NLRP3 inflammasome activation and IL-1ß secretion. Mechanistically, inhibiting Cbl increased surface expression of glucose transporter 1 (GLUT1) protein through post-transcriptional regulation, which increased cellular glucose uptake and consequently raised glycolytic capacity, and in turn enhanced NLRP3 inflammasome activation. Together, our findings provide new insights into the role of Cbl in NLRP3 inflammasome regulation through GLUT1 downregulation. We also show that a novel Cbl inhibitor, hydrocortanine, increased NLRP3 inflammasome activity via its effect on glycolysis.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Transporte Biológico Ativo , Membrana Celular/metabolismo , Técnicas de Inativação de Genes , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Glicólise , Células HEK293 , Humanos , Inflamassomos/imunologia , Mitocôndrias/metabolismo , Modelos Biológicos , Fosforilação Oxidativa , Proteínas Proto-Oncogênicas c-cbl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-cbl/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
13.
Int J Immunopathol Pharmacol ; 34: 2058738420923907, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32462951

RESUMO

Shenzhiling oral liquid (SZL) is a Traditional Chinese Medicine (TCM) compound to be approved by the China Food and Drug Administration (CFDA) (Z20120010) for the treatment of mild-to-moderate Alzheimer's disease (AD). However, its mechanism in early AD is not clear. We studied its mechanism in protecting myelin. Three-month-old APPswe/PS1dE9double transgenic mice were used as AD model and wild-type C57BL/6 mice were used as control. After 3-month intervention, the Morris water maze was used to detect behavioural changes. Myelin mTOR pathway (PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR), myelin basic protein (MBP) and postsynaptic density protein 95 (PSD95) were detected by immunohistochemistry and western blot and reverse transcriptase polymerase chain reaction (RT-PCR). After 3 months of SZL treatment, compared with the model group (M), SZL medium-dose (SM) and SZL low-dose groups (SL) exhibited increased staying and crossing results in Morris water maze (P < 0.05). Compared with M, PI3K-positive cells in SM and SL groups were increased (P < 0.01), p-PI3K expression increased in the Donepezil group (D), SZL high-dose group (SH) and SM (P < 0.05); number of Akt-positive cells and Akt expression in D, SM and SL were increased (P < 0.01, P < 0.05); number of p-Akt- and mTOR-positive cells and mTOR expression in all drug-treated groups were significantly increased (P < 0.01); p-Akt and p-mTOR expression increased in all drug-treated groups (P < 0.05, P < 0.01); MBP expression in D and SH increased (P < 0.05), while in SM and SL it increased more significantly (P < 0.01); and PSD95 expression in D, SM and SL was increased (P < 0.05). RT-PCR results showed that compared with M, PI3K mRNA and Akt mRNA expression in all drug-treated groups increased, but there was no statistical difference (P > 0.05), mTOR mRNA expression in all the drug-treated groups increased significantly (P < 0.01) and MBP mRNA and PSD95 mRNA expression in D and SH increased (P < 0.05). SZL oral liquid could play a role in myelin protection in early AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Bainha de Mielina/patologia , Transdução de Sinais/efeitos dos fármacos , Animais , Transtornos Cognitivos/prevenção & controle , Transtornos Cognitivos/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Aprendizagem em Labirinto , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Básica da Mielina/metabolismo , Proteína Oncogênica v-akt/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos
14.
Pharmacol Res ; 152: 104636, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31926275

RESUMO

Dengzhan Shengmai (DZSM) is a proprietary Chinese medicine for remarkable curative effect as a treatment of cerebrovascular diseases, such as chronic cerebral hypoperfusion (CCH) and dementia based on evidence-based medicine, which have been widely used in the recovery period of ischemic cerebrovascular diseases. The purpose of this study was to investigate the active substances and mechanism of DZSM against CCH. Integrative metabolomic and proteomic studies were performed to investigate the neuroprotective effect of DZSM based on CCH model rats. The exposed components of DZSM in target brain tissue were analysed by a high-sensitivity HPLC-MS/MS method, and the exposed components were tested on a glutamate-induced neuronal excitatory damage cell model for the verification of active ingredients and mechanism of DZSM. Upon proteomic and metabolomic analysis, we observed a significant response in DZSM therapy from the interconnected neurotransmitter transport pathways including glutamatergic and GABAergic synapses. Additionally, DZSM had a significant regulatory effect on glutamate and GABA-related proteins including vGluT1 and vIAAT, suggested that DZSM could be involved in the vesicle transport of excitatory and inhibitory neurotransmitters in the pre-synaptic membrane. DZSM could also regulated the metabolism of arachidonic acid (AA), phospholipids, lysophospholipids and the expression of phospholipase A2 in post-synaptic membrane. The results of glutamate-induced neuronal excitatory injury cell model experiment for verification of active ingredients and mechanism of DZSM showed that there are five active ingredients, and among them, 4,5 caffeoylquinic acid (4,5-CQA) and scutellarin (SG) could simultaneously affect the GABAergic and glutamatergic synaptic metabolism as well as the related receptors, the NR2b subunit of NMDA and the α1 subunit of GABAA. The active ingredients of DZSM could regulate the over-expression of the NMDA receptor, enhance the expression of the GABAA receptor, resist glutamate-induced neuronal excitatory damage, and finally maintain the balance of excitatory and inhibitory synaptic metabolism dominated by glutamate and GABA. Furtherly, we compared the efficacy of DZSM, 4,5-CQA, SG and the synergistic effect of 4,5-CQA and SG, and the results showed that all the groups significantly improved cell viability compared with the model group (p < 0.001). The western blot results showed that DZSM, 4,5-CQA, SG and 4,5-CQA/SG co-administration groups could significantly regulate the expression of receptors (GABAA α1 and NR2b subunit of NMDA) and synaptic-related proteins, such as Sv2a, Syp, Slc17a7, bin1 and Prkca, respectively. These results proved DZSM and its active ingredients (4,5-CQA and SG) had the effect of regulating glutamatergic and GABAergic synapses. Finally, membrane potential FLIPR assay of 4,5-CQA and SG was used for GABRA1 activity test, and it was found that the two compounds could increase GABA-induced activation of GABRA1 receptor (GABA 10 µM) in a dose-dependent manner with EC50 value of 48.74 µM and 29.77 µM, respectively. Manual patch clamp method was used to record NMDA NR1/NR2B subtype currents, and scutellarin could cause around 10 % blockade at 10 µM (p<0.05 compared with the control group). These studies provided definitive clues of the mechanism for the neuroprotective effect of DZSM for CCH treatment and the active compounds regulating glutamatergic and GABAergic synapses. Additionally, 4,5-CQA and SG might be potential drugs for the treatment of neurodegenerative disease related to CCH.


Assuntos
Apigenina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Glucuronatos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Ácido Quínico/análogos & derivados , Animais , Apigenina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Medicamentos de Ervas Chinesas/farmacologia , Glucuronatos/farmacologia , Ácido Glutâmico/fisiologia , Masculino , Metabolômica , Fármacos Neuroprotetores/farmacologia , Proteômica , Ácido Quínico/farmacologia , Ácido Quínico/uso terapêutico , Ratos Sprague-Dawley , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia
15.
ACS Biomater Sci Eng ; 6(3): 1438-1448, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33455371

RESUMO

Developing a new cost-effective and reliable approach used for the detection of uric acid (UA) with no requirement of uricase is still very challenging. Herein, an easily realized, cost-effective, and uricase-free approach is reported for selective colorimetric biosensing of UA utilizing polypyrrole (PPy)-coated polyoxometalate-encapsulated fourfold helical metal-organic frameworks Ag5[bimt]2[PMo12O40]·2H2O (Ag5PMo12) as a monolithic peroxidase mimic. It is demonstrated that the as-obtained Ag5PMo12@PPy possesses excellent peroxidase-like activity originated from the synergistic effect to induce catalytic oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to green oxTMB in the presence of H2O2. Then, the green oxTMB can be selectively converted to colorless TMB induced by UA; thus, UA can inhibit the catalytic oxidation of TMB. Based on these results, a uricase-free colorimetric biosensor for UA is achieved with a linear detection range of 1-50 µM and a detection limit of 0.47 µM. More importantly, the developed biosensor is suited for simple-operated and good reliable UA detection in clinical samples, showing promising application ability in clinical diagnosis and relative fields.


Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Colorimetria , Peróxido de Hidrogênio , Polímeros , Pirróis , Compostos de Tungstênio , Urato Oxidase , Ácido Úrico
16.
Dalton Trans ; 49(1): 79-88, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31799571

RESUMO

Rechargeable lithium-ion batteries (LIBs) for potentially low-cost and high-energy-density storage have been intensively researched to meet ever-growing demands. Achieving higher storages and understanding the transporting and storing diffusion process of Li ions are still great challenges. Herein, a porous crystalline polyoxometalate-based metal-organic framework (POM@MOF), H2[Cu(Htrz)5(H2O)2][MoCuO26]0.5·3H2O, with defect sites as a LIB electrode material is reported. The Li-ion diffusion process in the material was investigated using ex situ X-ray photoelectron spectroscopy (XPS) and off-line powder X-ray diffraction (PXRD), indicating that O atoms of POM nano-clusters can be regarded as Li-ion acceptors (storage sites); meanwhile the defect sites (uncoordinated N atoms or -N-H groups) in the crystalline material also participate in the Li-ion storage. The reported porous crystalline POM@MOF material with defects delivers a remarkable Li-ion storage capacity of ca. 700 mA h g-1 in 200 cycles at a current density of 100 mA g-1.

17.
Cytokine ; 127: 154951, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31837587

RESUMO

Psoriasis is a chronic inflammatory skin disease that affects about 2% of the general population. Activation of the Absent in Melanoma 2 (AIM2) inflammasome is crucial for immune defense, but it can also cause inflammatory and autoimmune diseases, including psoriasis. We currently lack an AIM2 inflammasome inhibitor that could be used therapeutically. Here, we show that EFLA 945, a safe product of red grape vine leaf extracts, can restrict AIM2 inflammasome activation. Mechanistically, EFLA945 prevents DNA entry into THP-1-derived macrophages, and thereby inhibits cytoplasmic DNA-dependent apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, caspase-1 activation, and the secretion of interleukin (IL)-1ß and IL-18. The major phytochemicals of EFLA 945, resveratrol and peonidin 3-O-glucoside (P3G), appear to be the potential bioactive compounds responsible for its ability to restrict AIM2-dependent IL-1ß secretion. Importantly, in an in vivo mouse model, EFLA 945 attenuates imiquimod (IMQ)-induced psoriasis-related pro-inflammatory responses in topical psoriatic skin, including caspase-1 activation, IL-1ß maturation, and IL-17 production, and decreases the severity of psoriasis. Together, these results demonstrate that the safe natural product, EFLA 945, can restrict the AIM2 inflammasome activation through preventing DNA entry and may prove beneficial for treating psoriasis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Inflamassomos/metabolismo , Extratos Vegetais/farmacologia , Psoríase/tratamento farmacológico , Animais , Linhagem Celular , Citoplasma/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Folhas de Planta/química , Psoríase/metabolismo , Células Th1 , Vitis/química
18.
Mol Cell Proteomics ; 19(1): 142-154, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31723016

RESUMO

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1ß. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (p = 0.037) and ATP5B (p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Intervalo Livre de Doença , Complexo I de Transporte de Elétrons/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , ATPases Mitocondriais Próton-Translocadoras/genética , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Fosforilação Oxidativa , Proteômica/métodos , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/genética
19.
Onco Targets Ther ; 12: 9309-9318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807011

RESUMO

Background: Dysregulation of long non-coding RNAs (lncRNAs) is closely related with the progression of cancer in humans. The functional and regulatory roles of lncRNAs in colorectal cancer (CRC) are still largely unclear. The purpose of this study is to explore the function of lncRNA STARD13-AS in CRC. Methods: The bioinformatics tool "GEPIA" was used to predict the potential expression of STARD13-AS in CRC. qRT-PCR was used to evaluate the relative expression level of STARD13-AS in CRC cells lines and tissues samples. The functional involvement of STARD13-AS in the CRC cells was assessed using MTT assay, flow cytometry, and Transwell assay. The expression levels of cyclin D, cyclin E, E-cadherin, N-cadherin, and vimentin were assessed using Western blot. Results: Bioinformatics prediction and qRT-PCR results showed that STARD13-AS expression was decreased in CRC tissues. Patients with low STARD13-AS expression exhibited distant and lymphatic metastasis as well as enhancement in tumor size. STARD13-AS expression was downregulated in CRC cell lines compared to normal human colon mucosal epithelial cell line NCM460 and STARD13-AS expression in SW620 and LoVo cell lines was lowest. Moreover, we observed that while STARD13-AS overexpression suppressed the cell cycle, proliferation, migration, and invasion, while promoted apoptosis both in LoVo and SW620 cells. In addition, STARD13-AS overexpression inhibited Cyclin E, Cyclin D, N-cadherin and vimentin expression, and promoted E-cadherin expression both in LoVo and SW620 cells. Conclusion: Expression of STARD13-AS suppresses cell proliferation and metastasis in CRC, suggesting that STARD13-AS might act as a potential target for CRC treatment.

20.
Tissue Eng Regen Med ; 16(6): 653-665, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31824827

RESUMO

Background: With the popularity of laparoscopic cholecystectomy, common bile duct injury has been reported more frequently. There is no perfect method for repairing porcine biliary segmental defects. Methods: After the decellularization of human arterial blood vessels, the cells were cultured with GFP+ (carry green fluorescent protein) porcine bile duct epithelial cells. The growth and proliferation of porcine bile duct epithelial cells on the human acellular arterial matrix (HAAM) were observed by hematoxylin-eosin (HE) staining, electron microscopy, and immunofluorescence. Then, the recellularized human acellular arterial matrix (RHAAM) was used to repair biliary segmental defects in the pig. The feasibility of it was detected by magnetic resonance cholangiopancreatography, liver function and blood routine changes, HE staining, immunofluorescence, real-time quantitative PCR (RT-qPCR), and western blot. Results: After 4 weeks (w) of co-culture of HAAM and GFP+ porcine bile duct epithelial cells, GFP+ porcine bile duct epithelial cells grew stably, proliferated, and fused on HAAM. Bile was successfully drained into the duodenum without bile leakage or biliary obstruction. Immunofluorescence detection showed that GFP-positive bile duct cells could still be detected after GFP-containing bile duct cells were implanted into the acellular arterial matrix for 8 w. The implanted bile duct cells can successfully resist bile invasion and protect the acellular arterial matrix until the newborn bile duct is formed. Conclusion: The RHAAM can be used to repair biliary segmental defects in pigs, which provides a new idea for the clinical treatment of common bile duct injury.


Assuntos
Artérias/citologia , Células Epiteliais/citologia , Animais , Artérias/metabolismo , Artérias/transplante , Doenças dos Ductos Biliares/terapia , Ductos Biliares/citologia , Colangiopancreatografia por Ressonância Magnética , Técnicas de Cocultura , Ducto Colédoco/diagnóstico por imagem , Ducto Colédoco/patologia , Células Epiteliais/metabolismo , Células Epiteliais/transplante , Humanos , Queratina-7/metabolismo , Testes de Função Hepática , Suínos
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