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1.
Artigo em Inglês | MEDLINE | ID: mdl-32175289

RESUMO

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease and hepatocellular carcinoma. Current antiviral therapy does not effectively eradicate HBV and further investigations into the mechanisms of viral infection are needed to enable the development of new therapeutic agents. The sodium-taurocholate cotransporting polypeptide (NTCP) has been identified as a functional receptor for HBV entry in liver cells. However, the NTCP receptor is not sufficient for entry and other membrane proteins contribute to modulate HBV entry. This study seeks to understand how the NTCP functions in HBV entry. Herein we show that knockdown of the cell-cell adhesion molecule, E-cadherin significantly reduced infection by HBV particles and entry by HBV pseudoparticles in infected liver cells and cell lines. The glycosylated NTCP localizes to the plasma membrane through interaction with E- cadherin, which increases interaction with the preS1 portion of the Large HBV surface antigen. Our study contributes novel insights that advance knowledge of HBV infection at the level of host cell binding and viral entry.

2.
Mikrochim Acta ; 187(4): 243, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32206934

RESUMO

A nanoplatform based on metal-organic frameworks (MOFs) and lambda exonuclease (λ exo) for the fluorimetric determination of T4 polynucleotide kinase (T4 PNK) activity and inhibition is described. Fe-MIL-88 was selected as the nanomaterial because of its significant preferential binding ability to single-stranded DNA (ssDNA) over double-stranded DNA (dsDNA) and its quenching property. The synthesized Fe-MIL-88 was characterized by transmission electron microscope, scanning electron microscope, and X-ray photoelectron spectroscopy. In the presence of T4 PNK, FAM-labeled dsDNA (FAM-dsDNA) is phosphorylated on its 5'-terminal. λ exo then recognizes and cleaves the phosphorylated strand yielding FAM-labeled ssDNA (FAM-ssDNA). The fluorescence of the produced FAM-ssDNA is quenched due to Fe-MIL-88's absorbing on FAM-ssDNA. On the contrary, in the absence of T4 PNK, the phosphorylation and cleavage processes cannot take place. Therefore, the fluorescence of FAM-dsDNA still remains. The fluorescence intensity is detected at the maximum emission wavelength of 524 nm using the maximum excitation wavelength of 488 nm. The assay of T4 PNK based on the fluorescence quenching of FAM-ssDNA achieves a linear relationship in the range 0.01-5.0 U mL-1 with a detection limit of 0.0089 U mL-1 in buffer. The assay exhibits excellent performance for T4 PNK activity determination in a complex biological matrix. The results also reveal the ability of the assay for T4 PNK inhibitor screening. Graphical abstract Schematic presentation of a nanoplatform based on Fe-MIL-88 and coupled exonuclease reaction for the fluorimetric determination of T4 polynucleotide kinase activity. FAM-ssDNA, FAM-labeled single-stranded DNA; cDNA, complementary DNA; λ exo, lambda exonuclease;T4 PNK, T4 polynucleotide kinase.

3.
J Phys Chem Lett ; 11(4): 1364-1369, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32000486

RESUMO

A method using machine learning (ML) is proposed to describe metal growth for simulations, which retains the accuracy of ab initio density functional theory (DFT) and results in a thousands-fold reduction in the computational time. This method is based on atomic energy decomposition from DFT calculations. Compared with other ML methods, our energy decomposition approach can yield much more information with the same DFT calculations. This approach is employed for the amorphous sodium system, where only 1000 DFT molecular dynamics images are enough for training an accurate model. The DFT and neural network potential (NNP) are compared for the dynamics to show that similar structural properties are generated. Finally, metal growth experiments from liquid to solid in a small and larger system are carried out to demonstrate the ability of using NNP to simulate the real growth process.

4.
J Neurochem ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976561

RESUMO

Acid-sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of ~pH 6, whereas its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na+ and Ca2+ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na+ and Ca2+ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na+ and Ca2+ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na+ and Ca2+ waves that propagate to mitochondria. Inhibiting ASIC1a with Psalmotoxin 1 or ASIC1a gene knockout blocked not only the cytosolic but also the mitochondrial Na+ and Ca2+ signals. Moreover, physiological activation of ASIC1a by this pH shift enhances mitochondrial respiration and evokes mitochondrial Na+ signaling even in digitonin-permeabilized neurons. Altogether our results indicate that ASIC1a is critical in linking physiological extracellular pH stimuli to mitochondrial ion signaling and metabolic activity and thus is an important metabolic sensor.

5.
Chem Commun (Camb) ; 56(16): 2423-2426, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31994543

RESUMO

A highly sensitive laser-induced fluorescence detection system with real-time imaging focusing instead of the use of fluorescent reagents were developed for the detection of analytes in nanocapillaries. A cylindrical lens was adopted for the shaping of a laser beam to increase its spatial resolution. The limit of detection with a capillary having a radius of 440 nm was 6.76 yoctomoles (or four molecules) for fluorescein, and 84.5 yoctomoles (or 51 molecules) for FAM-labeled Hsa-miR-17. The designed system exhibited high sensitivity and stability for femtoliters of sample and was hence indicated to be suitable for analyses of single cells.

6.
Nat Commun ; 11(1): 475, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980622

RESUMO

We reported previously that acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1) to its C terminus (CT), independent of its ion-conducting function. Here we show that the N-terminus (NT) of ASIC1a interacts with its CT to form an auto-inhibition that prevents RIPK1 recruitment/activation under resting conditions. The interaction involves glutamate residues at distal NT and is disrupted by acidosis. Expression of mutant ASIC1a bearing truncation or glutamate-to-alanine substitutions at distal NT causes constitutive cell death. The NT-CT interaction is further disrupted by N-ethylmaleimide-sensitive fusion ATPase (NSF), which associates with ASIC1a-NT under acidosis, facilitating RIPK1 interaction with ASIC1a-CT. Importantly, a membrane-penetrating synthetic peptide representing the distal 20 ASIC1a NT residues, NT1-20, reduced neuronal damage in both in vitro model of acidotoxicity and in vivo mouse model of ischemic stroke, demonstrating the therapeutic potential of targeting the auto-inhibition of ASIC1a for neuroprotection against acidotoxicity.

7.
Food Chem ; 308: 125590, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31644970

RESUMO

A novel fluorescent nanoprobe was for the first time developed for the efficient detection of ferrocyanide ions ([Fe(CN)6]4-) based on nitrogen (N), sulfur (S) and chlorine (Cl) co-doped carbon nanoparticles (N,S,Cl-CNPs). The N,S,Cl-CNPs were fabricated through a simple and ultrafast acid-base neutralization method. The sensing mechanism was based on the quenching effect of [Fe(CN)6]4- on the fluorescence emission of N,S,Cl-CNPs via dynamic interaction. The N,S,Cl-CNPs were found to show high selectivity and sensitivity towards [Fe(CN)6]4- detection with two good linear relationships were achieved in the concentration ranges of 0.01-1.0 µg/mL and 1.0-50.0 µg/mL, respectively, and the detection limits are as low as 3.3 and 21.8 ng/mL, respectively. The proposed fluorescence method was successfully applied for [Fe(CN)6]4- analyses in food samples with high accuracy. The results of this study indicate the great application prospects of N,S,Cl-CNPs for [Fe(CN)6]4- detection in complex food matrix.


Assuntos
Carbono/química , Ferrocianetos/análise , Nanopartículas , Cloro/química , Ferrocianetos/química , Fluorescência , Análise de Alimentos , Limite de Detecção , Nitrogênio/química , Espectrometria de Fluorescência/métodos , Enxofre/química
8.
J Neurosci Res ; 98(1): 201-211, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30895638

RESUMO

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

9.
Int J Oncol ; 55(5): 1019-1032, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31793654

RESUMO

Hepatitis B virus (HBV) has been revealed to be involved in the development of hepatocellular carcinoma. However, the mechanism remains to be fully elucidated. Smad­interacting protein 1 (SIP1) is a transcriptional repressor, which serves a pivotal role in cell metastasis. In the present study, the role of SIP1 in HBx­induced hepatocyte EMT and cancer aggressiveness was examined. It was found that HBV X protein (HBx) increased the expression of SIP1 and recruited it to the promoter of E­cadherin, resulting in depression of the transcription of E­cadherin. Histone deacetylase 1 was also found to be involved in the repressive complex formation. Furthermore, in an orthotopic tumor transplantation model in vivo, HBx promoted tumor growth and metastasis, whereas the knockdown of SIP1 attenuated the effect of HBx. These results indicate a novel mechanism for the development of HBV­related liver cancer.

10.
Integr Cancer Ther ; 18: 1534735419890917, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31855073

RESUMO

Background: Current treatment of osteosarcoma is limited in part by side effects and low tolerability, problems generally avoided with traditional Chinese medicine. Ganoderma lucidum, a traditional Chinese medicine with antitumor effects, offers a potential alternative, but little is known about its molecular mechanisms in osteosarcoma cells. Objective: To investigate the effect of G lucidum on osteosarcoma cells and its mechanism. Methods: Osteosarcoma MG63 and U2-OS cells were treated with G lucidum, followed by assays for cell proliferation (Cell Counting Kit-8), colony formation, and apoptosis (Alexa Fluor 647-Annexin V/propidium iodide, flow cytometry). Migration and invasion of cells were assessed by wound healing and Transwell invasion assays, and the effect of G lucidum on Wnt/ß-catenin signal transduction was studied by real-time quantitative polymerase chain reaction, western blot, and dual-luciferase assay. Results: G lucidum inhibited the proliferation, migration, and invasion, and induced apoptosis of human osteosarcoma MG63 and U2-OS cells. Dual-luciferase assay showed that G lucidum suppressed the transcriptional activity of T-cell factor/lymphocyte enhancer factor in the Wnt/ß-catenin signaling pathway. Moreover, G lucidum blocked Wnt/ß-catenin signaling by inhibiting the Wnt co-receptor LRP5 and Wnt-related target genes, such as ß-catenin, cyclin D1, C-Myc, MMP-2, and MMP-9. At the same time, when Wnt/ß-catenin was inhibited, the expression of E-cadherin was upregulated. Conclusions: Our results suggest that G lucidum broadly suppresses osteosarcoma cell growth by inhibiting Wnt/ß-catenin signaling.

11.
FEBS J ; 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31736227

RESUMO

Endoplasmic reticulum (ER) stress and autophagy dysfunction contribute to the establishment and progression of diverse pathologies. Proteolytic activation of the transcription factor nSREBP1 is induced under ER stress; however, little is known about how SREBP1 and its nuclear active form nSREBP1 influence autophagy and unfolded protein response (UPR) activation in osteosarcoma cells. Our research focused on the effect of SREBP1/nSREBP1 upon apoptosis and autophagy during ER stress and the molecular mechanisms involved. Here, we showed that nSREBP1 binds to the promoter of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and then regulates ER stress, cell growth, cell apoptosis, and autophagy through the PERK signaling pathway. nSREBP1 increased PERK gene expression and phosphorylation. nSREBP1 was further demonstrated to activate ER stress response through stimulatory effects on PERK signaling. Overexpression of SREBP1 increased its cleavage and release of nSREBP1; therefore, the effect of SREBP1 is achieved through the enhancement of the expression of nSREBP1. Overexpression of SREBP1/nSREBP1 amplifies PERK-associated cell cycle stagnation with G1 phase arresting, S phase reducing, and G2-M phase delaying. LV-SREBP1/nSREBP1 can also bolster PERK's ER stress-associated pro-apoptotic effects. LV-SREBP1/nSREBP1 and LV-PERK can activate autophagy in ER stress response, along with the overexpression of SREBP1/nSREBP1 and PERK. This resulted in amplification of PERK-related changes to cell proliferation and ER stress-mediated apoptosis and autophagy, with the biological effect of nSREBP1 relying on PERK, which makes up one of the three branches of the UPR signaling pathway. This study reveals important roles for SREBP1/nSREBP1 in PERK signaling under ER stress. Furthermore, nSREBP1, the nuclear active form of SREBP1, is able to robustly augment the effects of PERK. Description of the link between PERK and SREBP1/nSREBP1 function offers an improved understanding of the ER stress response and insight into the biological function of SREBP1/nSREBP1.

12.
AAPS PharmSciTech ; 21(1): 6, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754916

RESUMO

The aim of the study is to investigate the feasibility of fabricating FDM 3D-printed gastric floating tablets with low infill percentages and the effect of infill percentage on the properties of gastric floating tablets in vitro. Propranolol hydrochloride was selected as a model drug, and drug-loaded polyvinyl alcohol (PVA) filaments were produced by hot melt extrusion (HME). Ellipsoid-shaped gastric floating tablets with low infill percentage of 15% and 25% (namely E-15 and E-25) were then prepared respectively by feeding the extruded filaments to FDM 3D printer. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) were employed to characterize the filaments and 3D-printed tablets, and a series of evaluations were performed to the 3D-printed tablets, including the weight variation, drug content, hardness, in vitro floating behavior, and drug release of the tablets. The SEM results showed that the drug-loaded filaments and 3D-printed tablets appeared intact without defects, and the printed tablets were composed of filaments deposited uniformly layer by layer. The model drug and the excipients were thermally stable under the process temperature of extruding and printing, with a small amount of drug crystals dispersing in the drug-loaded filaments and 3D-printed tablets. Both E-15 and E-25 could float on artificial gastric fluids without any lag time and released in a sustained manner. Compared with E-15, the E-25 presented less weight variation, higher tablet hardness, shorter floating time, and longer drug release time.


Assuntos
Portadores de Fármacos/síntese química , Excipientes/síntese química , Impressão Tridimensional , Comprimidos/síntese química , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria/métodos , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Excipientes/farmacocinética , Álcool de Polivinil/síntese química , Álcool de Polivinil/farmacocinética , Propranolol/síntese química , Propranolol/farmacocinética , Comprimidos/farmacocinética , Difração de Raios X/métodos
13.
Mikrochim Acta ; 186(12): 818, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748845

RESUMO

A turn-on ratiometric fluorescent assay is described for the determination of the activity of enzymes participating in ascorbic acid-forming reactions. Blue-emitting carbon dots (bCDs; with excitation/emission wavelength at 380/450 nm) serve as fluorescent indicator. Their fluorescence is reduced by Fe3+ ions via an inner filter effect. Yellow-emitting CDs (yCDs; with excitation/emission wavelength at 380/550 nm) serve as internal reference because their fluorescence is insensitive to Fe3+. Upon exposure to ascorbic acid (AA), Fe3+ is reduced to Fe2+. Hence, the fluorescence of the bCDs is restored. Thus, enzymes participating in AA-related reactions such as α-glucosidase (α-Glu) and alkaline phosphatase (ALP) can be determined. α-Glu activity was quantified in the range from 0.13 to 6.70 U mL-1, and ALP activity was determined between 2.0 and 130 U L-1. Endowed with excellent sensitivity, selectivity and low background signals, the method may also be used to screen the inhibitors of α-Glu and ALP. Graphical abstractSchematic representation of a redox modulated ratiometric fluorometric method based on the use of dual-color carbon dots for determination of the activity of enzymes participating in ascorbic acid-related reactions. Blue-emitting carbon dots (bCDs) serve as fluorescent indicator while yellow-emitting CDs (yCDs) serve as internal reference.

14.
Chin Med J (Engl) ; 132(19): 2362-2372, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567373

RESUMO

OBJECTIVE: Premature ejaculation (PE) is regarded as one of the most common male sexual dysfunctions. This review introduced several pharmaceutical and surgical methods for the management of PE. The definition, etiology, behavioral, and psychological therapy of PE were also discussed. DATA SOURCES: "Premature," "ejaculation," or "sexual dysfuction" were used as the medical subject headings (MeSH) to obtain relevant articles before June 2019 on Pubmed, Google Scholar and CNKI. Most articles used were written in English and several Chinese articles were also cited. STUDY SELECTION: Full-text articles of retrospective/prospective/randomized controlled trials were analyzed. Animal experiments and letters were excluded. RESULTS: There are four PE sub-types: lifelong PE, acquired PE, natural variable PE, and subjective PE. Behavioral therapy, psychotherapy, medication, topical anesthetics, and surgery are currently used for the treatment of PE. However, all the above treatments have limitations. Therefore, novel ways should be investigated to more efficiently control PE. CONCLUSIONS: The pharmaceutical therapy that is currently being used in clinical practice for the management of PE is still the main choice globally due to its good efficacy. Surgery may be a choice for patients who are resistant to medication. However, it should be performed cautiously.

15.
Pathol Oncol Res ; 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31606786

RESUMO

Tumor-infiltrating immune cells engage in an extensive crosstalk with tumors and act as two-edged swords by inhibiting or promoting cancer growth. Therefore, identifying the density and prognostic values of tumor-infiltrating immune cells will provide valuable tips for cancer treatments. In this study, we identified the density of tumor inflammatory infiltrates and the number of tumor-infiltrating immune cells, including CD3+, CD4+, CD8+, FoxP3+ T cells and CD1a+ dendritic cells (DCs) in 153 tongue squamous cell carcinomas (TSCC). High inflammatory cell infiltration was associated with better overall survival (OS) and disease free survival (DFS). Moreover, the number of CD3+, CD4+, FoxP3+ and CD1a+ cells were associated with tumor differentiation (P<0.001) and the number of FoxP3+, CD1a+ cells and CD8+/FoxP3+ ratios were also associated with tumor stage (P<0.01, P<0.01, P<0.05). In addition, patients with higher CD1a+ DCs had better OS and increased CD8+/FoxP3+ ratios were associated with improved OS and DFS (P = 0.037; P = 0.047; P = 0.033). In conclusion, our results indicated that tumor-infiltrating CD1a+ DCs and CD8+/FoxP3+ ratios were associated with favorable clinical outcomes but not independent prognostic factors for TSCC patients.

16.
EBioMedicine ; 48: 81-91, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31631041

RESUMO

BACKGROUND: Histological assessment of resected margins has some drawbacks. We therefore aimed to identify a panel of metabolic markers for evaluating the surgical margins of oral squamous cell carcinoma during surgery. METHODS: A total of 28 case of OSCC samples were enrolled in the study. Gas chromatography-mass spectrometry based untargeted metabolic analysis was employed to acquire the metabolic perturbation of the distance-related surgical margins in the development group. The acquired MS data were then subjected to univariate and multivariate analysis by MetaboAnalyst. Ultra-high performance liquid chromatography-tandem mass spectrometerbased targeted metabolomics for quantitative analysis of the validation group was performed to verify the results of the development group. Another 60 OSCC patients with dysplastic surgical margins were used to further validate the results of the development group by immunohistochemical examination of key enzyme expression, and correlate them with clinicopathological parameters and clinical outcomes. FINDINGS: We finally identified 4 amino acids as negative margin markers, and 6 amino acids as dysplastic margin markers. IHC analysis showed that asparagine synthetase positive expression in dysplastic surgical margins and its higher expression was correlated with tumor recurrence and local relapse-free survival. INTERPRETATIONS: We developed a panel of metabolic molecular markers to supplement the evaluation of negative and dysplastic margins. FUND: This study was supported by Nanjing Municipal Key Medical Laboratory Constructional Project Funding (Since 2012); Center of Nanjing Clinical Medicine Tumor (Since 2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

17.
Med Gas Res ; 9(3): 127-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552875

RESUMO

Microglia participate in bi-directional control of brain repair after stroke. Previous studies have demonstrated that hydrogen protects brain after ischemia/reperfusion (I/R) by inhibiting inflammation, but the specific mechanism of anti-inflammatory effect of hydrogen is poorly understood. The goal of our study is to investigate whether inhalation of high concentration hydrogen (HCH) is able to attenuate I/R-induced microglia activation. Eighty C57B/L male mice were divided into four groups: sham, I/R, I/R + HCH and I/R + N2/O2 groups. Assessment of animals happened in "blind" matter. I/R was induced by occlusion of middle cerebral artery for one hour). After one hour, filament was withdrawn, which induced reperfusion. Hydrogen treated I/R animals inhaled mix of 66.7% H2 balanced with O2 for 90 minutes, starting immediately after initiation of reperfusion. Control animals (N2/O2) inhaled mix in which hydrogen was replaced with N2 for the same time (90 minutes). The brain injury, such as brain infarction and development of brain edema, as well as neurobehavioral deficits were determined 23 hours after reperfusion. Effect of HCH on microglia activation in the ischemic penumbra was investigated by immunostaining also 23 hours after reperfusion. mRNA expression of inflammation related genes was detected by PCR. Our results showed that HCH attenuated brain injury and consequently reduced neurological dysfunction after I/R. Furthermore, we demonstrated that HCH directed microglia polarization towards anti-inflammatory M2 polarization. This study indicates hydrogen may exert neuroprotective effects by inhibiting the microglial activation and regulating microglial polarization. This study was conducted in agreement with the Animal Care and Use Committee (IACUC) and Institutional Animal Care guidelines regulation (Shanghai Jiao Tong University, China (approval No. A2015-011) in November 2015.

18.
Mol Med Rep ; 20(4): 3131-3139, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432112

RESUMO

Advanced glycation end products (AGEs) have been reported to serve an important role in the stiffening of cardiac tissues and myocardial cell injury. Serious myocardial cell injury can result in various heart diseases with high mortality. Halofuginone (HF), which possesses marked anti­inflammatory and antifibrotic effects, has recently been applied to inhibit the effects of cardiac stress. The present study aimed to investigate the potential effects of HF and its underlying mechanism in the treatment of AGEs­induced H9C2 cardiomyocyte damage. The western blot results of the present study demonstrated that HF may reduce the expression levels of myocardial injury markers, including myoglobin, creatine kinase MB and cardiac troponin I. In addition, flow cytometric analysis indicated that the production of reactive oxygen species (ROS) was significantly decreased by HF. Additionally, endoplasmic reticulum (ER) stress was suppressed in response to treatment with HF, as observed by low expression levels of ER stress­associated proapoptotic proteins (CCAAT/enhancer­binding protein homologous protein and cleaved caspase­12); overexpression of prosurvival proteins (growth arrest and DNA damage­inducible protein GADD34 and binding immunoglobulin protein) was also reported. Furthermore, the expression levels of microtubule­associated proteins 1A/1B light chain 3B (LC3)II/LC3I and Beclin 1 were elevated, whereas P62 expression levels were reduced following treatment with HF. These findings, together with immunofluorescence staining of LC3, indicated that HF may induce autophagy. Finally, the protective effects of HF on AGEs­treated H9C2 cells were reversed following treatment with the inhibitor 3­methyladenine, as indicated by inhibition of autophagy, and increases in apoptosis, ROS production and the ER stress response. Collectively, the findings of the present study suggested that the protective effects of HF against AGEs­induced myocardial cell injury may be associated with the induction of autophagy and amelioration of ROS­mediated ER stress and apoptosis. These findings may contribute to the development of a novel therapeutic method to inhibit the progression of myocardial cell injury.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Produtos Finais de Glicação Avançada/toxicidade , Miócitos Cardíacos/metabolismo , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Linhagem Celular , Miócitos Cardíacos/patologia , Ratos
19.
Mikrochim Acta ; 186(8): 506, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270632

RESUMO

Phosphorus and nitrogen dually-doped carbon quantum dots (PN-CQDs) were prepared from sucrose, 85% phosphoric acid and 1,2-ethylenediamine as the sources for carbon, phosphorus and nitrogen, respectively. The PN-CQDs possess good water solubility and favorable biocompatibility. The excitation/emission peaks are at 365/451 nm, but bright blue, green, or red emissions are found depending on whether the excitation wavelengths of the laser are set to 408 nm, 488 nm, or 543 nm, respectively. Fluorescence is quenched by both vitamin B12 (VB12) and Co(II) by a combination of inner filter effect and static quenching. The PN-CQDs are shown to be useful nanoprobes for determination of VB12 and Co(II). Response to VB12 is linear in the range of 2.0-31 µM. The response to Co(II) is linear in two ranges, viz. from 1.7-12 µM and from 28 to 141 µM. The limit of detection of VB12 and Co(II) are 3.0 nM and 29.4 nM, respectively. The nanoprobe was successfully applied to the analyses of VB12 in drug samples and of Co(II) in spiked water samples, and it gave satisfactory results. The nanoprobe was also applied to the determination of VB12 and Co(II) in human hepatocarcinoma cells (type SMMC7721), human pulmonary epithelial cells (type BEAS-2B), human adenocarcinoma cells (type A549), and human pheochromocytoma cells (type PC12), respectively. Graphical abstract Schematic presentation of the quenching of the fluorescence of phosphorus and nitrogen dually-doped carbon quantum dots (PN-CQDs) by vitamin B12 (VB12) and Co(II).

20.
Arthritis Res Ther ; 21(1): 173, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307506

RESUMO

OBJECTIVE: To evaluate contextual effects in the form of placebo responses (PRs) for patient-reported pain and function and objectively measured function in osteoarthritis (OA) clinical trials. METHODS: Two authors independently searched major electronic databases from inception to 20 May 2019. Included studies were randomized, placebo-controlled OA trials of pharmacological agents reporting both patient-reported and objectively measured outcomes. PRs for each type of outcome measure were compared by standardized mean differences (SMDs). The placebo response ratio (PRR) assessed the placebo to treatment effect size. The effect sizes of PRs and PRRs were pooled using a random effects model. RESULTS: Twenty-one trials met the inclusion criteria; 20 were double-blinded with one not reporting on blinding status. Compared with patients' self-reported outcome (PRO) pain, PRs were significantly lower for PRO function (SMD - 0.16 [95% CI = - 0.28, - 0.05], p = 0.006), objectively measured muscle strength (SMD - 0.34 [95% CI - 0.58, - 0.10], p = 0.006), and range of motion (SMD = - 0.31 [95% CI = - 0.54, - 0.08], p = 0.008) function. Generally, PRs for function outcomes (patient-reported and objectively measured) were similar. The overall PRR for different measures ranged from the smallest (most favorable) for walking time/distance (0.30, 95% CI 0.16 to 0.43) to the largest for PRO pain (0.44, 95% CI 0.23 to 0.65). CONCLUSION: Function measures both subjective and objective had less contextual effects than pain measures in OA trials. Our results support the OMERACT-OARSI recommendations to include measures of physical function in all clinical trials of hip and knee OA and suggest that a greater use of function measures might enhance the success rates of pharmacological OA trials. Increasing the availability of mobile health apps should facilitate the acquisition of measured function data.

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