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1.
PLoS Genet ; 16(2): e1008597, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32032354

RESUMO

Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) to centromeres is essential for faithful chromosome segregation. Mislocalization of CENP-A leads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression and mislocalization of CENP-A has been observed in many cancers and this correlates with increased invasiveness and poor prognosis. Yet genes that regulate CENP-A levels and localization under physiological conditions have not been defined. In this study we used a genome-wide genetic screen to identify essential genes required for Cse4 homeostasis to prevent its mislocalization for chromosomal stability. We show that two Skp, Cullin, F-box (SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 and Cdc4 interact and cooperatively regulate proteolysis of endogenous Cse4 and prevent its mislocalization for faithful chromosome segregation under physiological conditions. The interaction of Met30 with Cdc4 is independent of the D domain, which is essential for their homodimerization and ubiquitination of other substrates. The requirement for both Cdc4 and Met30 for ubiquitination is specifc for Cse4; and a common substrate for Cdc4 and Met30 has not previously been described. Met30 is necessary for the interaction between Cdc4 and Cse4, and defects in this interaction lead to stabilization and mislocalization of Cse4, which in turn contributes to CIN. We provide the first direct link between Cse4 mislocalization to defects in kinetochore structure and show that SCF-mediated proteolysis of Cse4 is a major mechanism that prevents stable maintenance of Cse4 at non-centromeric regions, thus ensuring faithful chromosome segregation. In summary, we have identified essential pathways that regulate cellular levels of endogenous Cse4 and shown that proteolysis of Cse4 by SCF-Met30/Cdc4 prevents mislocalization and CIN in unperturbed cells.

2.
Anal Biochem ; 593: 113611, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035040

RESUMO

Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are both tenofovir (TFV) prodrugs, with the same active intracellular metabolite, TFV-diphosphate (TFV-DP). TAF delivers TFV-DP to target cells more efficiently and at lower doses than TDF, thereby substantially reducing systemic exposure to TFV, which results in improved bone and renal safety relative to TDF. As such, the method developed for the determination of TFV following TAF administration involved two key differences from determination of TFV following TDF administration. First, human plasma samples (500 µL) immediately upon collection were treated with 20% formic acid (40 µL) (plasma: formic acid ratio of 100:8) to minimize hydrolysis of TAF to TFV, and thereby avoided overestimation of TFV concentrations. Second, various TFV validation tests were conducted in the presence of TAF to mimic the high TAF:TFV ratios in clinical samples collected within ~2 h after dosing. The method for determination of TFV was developed and validated at a US lab and followed FDA and EMA guidelines. To support global clinical studies of TAF, the method was cross-validated (one-way) between the US lab and a China lab and was successfully used for TFV determination in plasma samples from a clinical study that involved healthy Chinese subjects.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31934802

RESUMO

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.

4.
Nano Lett ; 20(1): 284-291, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31794217

RESUMO

One-dimensional defects in two-dimensional (2D) materials can be particularly damaging because they directly impede the transport of charge, spin, or heat and can introduce a metallic character into otherwise semiconducting systems. Current characterization techniques suffer from low throughput and a destructive nature or limitations in their unambiguous sensitivity at the nanoscale. Here we demonstrate that dark-field second harmonic generation (SHG) microscopy can rapidly, efficiently, and nondestructively probe grain boundaries and edges in monolayer dichalcogenides (i.e., MoSe2, MoS2, and WS2). Dark-field SHG efficiently separates the spatial components of the emitted light and exploits interference effects from crystal domains of different orientations to localize grain boundaries and edges as very bright 1D patterns through a Cerenkov-type SHG emission. The frequency dependence of this emission in MoSe2 monolayers is explained in terms of plasmon-enhanced SHG related to the defect's metallic character. This new technique for nanometer-scale imaging of the grain structure, domain orientation and localized 1D plasmons in 2D different semiconductors, thus enables more rapid progress toward both applications and fundamental materials discoveries.

5.
Mol Immunol ; 117: 110-121, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765840

RESUMO

Although granulocyte colony-stimulating factor(G-CSF) has pathogenic roles in several immune inflammatory diseases, its role in periodontitis has not been investigated. Here we detected local expression of G-CSF using public datasets in the Gene Expression Omnibus (GEO) database, and immune cell infiltration into gingival tissue was estimated based on single-sample gene set enrichment analysis (ssGSEA). G-CSF expression and neutrophil infiltration were also confirmed by human gingival biopsies analysis. Moreover, anti-G-CSF neutralizing antibody was locally administrated to investigate the effects of G-CSF neutralization on neutrophils infiltration and periodontal tissue destruction in periodontitis mice model. Two public datasets (GSE10334 and GSE16134), which included 424 patients with periodontitis and 133 health controls, were used in the analysis. Markedly increased immune cell infiltration and G-CSF expression in gingival tissues were found in the periodontitis group as compared to the control group. The higher expression of G-CSF was correlated with higher infiltration of immune cells, especially with neutrophil infiltration. Analysis of gingival biopsies further confirmed high neutrophil infiltration and G-CSF expression. In addition, anti-G-CSF antibody-treated mice with periodontitis showed significantly reduced alveolar bone resorption and neutrophil infiltration when compared with periodontitis mice treated with isotype control antibody. Also, anti-G-CSF antibody treatment significantly reduced mRNA expression of CXC chemokines (CXCL1, CXCL2 and CXCL3), interleukin 1ß (IL-1ß), IL-6, matrix metalloproteinases 9, receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG) ratio and osteoclasts number in periodontal tissues. In summary, neutrophil infiltration and G-CSF expression levels were significantly increased in inflamed gingival tissues. G-CSF neutralization in periodontal inflammation could alleviate neutrophil infiltration and periodontal tissue destruction in experimental periodontitis.

6.
J Sep Sci ; 43(2): 406-417, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31633862

RESUMO

Zhi-Zi-Hou-Po Decoction, consisting of Gardenia jasminoides Ellis, Magnolia officinalis Rehd. et Wils., and Citrus aurantium L, is a classical Traditional Chinese Medicine formula for the treatment of depression. In order to make good and rational use of this formula in the future, a sensitive, selective, and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed for simultaneous determination of two iridoid glycosides (geniposide and genipin gentiobioside), two lignans (honokiol and magnolol), four flavonoid glycosides (isonaringin, naringin, hesperidin, and neohesperidin), the major bioactive constituents of Zhi-Zi-Hou-Po Decoction, in rat plasma using paeoniflorin as internal standard. Plasma samples were pretreated by a simple protein precipitation with acetonitrile. Chromatographic separation was performed on a shim-pack XR-ODS C18 column (75 × 3.0 mm, 2.2 µm) using gradient elution with mobile phase consisting of 0.1% formic acid aqueous solution and acetonitrile at a flow rate of 0.5 mL/min. Mass spectrometric detection was conducted on a 3200 QTRAP mass spectrometry equipped with electrospray ionization source in negative ionization mode. Quantification was performed using multiple reactions monitoring mode. Calibration curves exhibited good linearity (r > 0.9947) over a wide concentration range for all analytes, and the lower limits of quantification were 10, 5, 1, 5, 1, 5, 1, and 5 ng/mL for geniposide, genipin gentiobioside, honokiol, magnolol, isonaringin, naringin, hesperidin, and neohesperidin, respectively. The intraday and interday precisions at three quality control levels were less than 12.3% and the accuracies ranged from -11.2 to 10.7%. Extraction recovery, matrix effect, and stability were satisfactory in rat plasma. The validated method was successfully applied to a pharmacokinetic study of the eight analytes after oral administration of Zhi-Zi-Hou-Po decoction to rats.

7.
Surg Endosc ; 34(1): 384-395, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30972621

RESUMO

BACKGROUND: The number of publications of systematic reviews and meta-analyses (MAs) on robotic surgery have been increasing, including many investigating the same topic. Their quality and extent of overlap remains unclear. We assessed the quality of the MAs in this area and investigated the extent of their overlap. METHODS: Relevant studies were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases up to August 1, 2017. Reporting and methodological quality levels were assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Assessment of Multiple Systematic Reviews (AMSTAR) checklists. A thorough investigation of the extent of overlap was performed. RESULTS: In total, 90 MAs in 5 surgical subspecialties were included after full-text review. The mean reporting and methodological quality scores were 22.5 (83.2%) and 7.6 (69.2%), respectively. Authors from university-affiliated institutions and the presence of statistician or epidemiologist coauthors were associated with better-reporting quality scores. The topics with the most overlapping MAs (all ≥ 6) were robot-assisted thyroidectomy, prostatectomy, gastrectomy, colectomy, and fundoplication. 36 (40%) of the included MAs cited previous MAs on the same topic. Among the 7 MAs comparing robot-assisted radical prostatectomy to the open procedure, most (6/7) drew the same conclusion. 50 to 86% of MAs on this topic included the same trials as primary studies. CONCLUSION: Conducting multiple overlapping MAs with identical conclusions on the same topic that are of suboptimal quality may be a waste of resource and effort. Authors from university-affiliated institutes and experts in epidemiology and statistics are more likely to conduct MAs that have better quality. More guidelines and registries are needed to avoid overlapping MAs.

8.
Mol Med Rep ; 21(1): 508-516, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746394

RESUMO

Depression is often triggered by prolonged exposure to psychosocial stressors and associated with coronary heart disease (CHD). Matrix metalloproteinases (MMPs) are involved in the pathogenesis of various emotional and cardiovascular disorders. The purpose of this study was to investigate whether Kai­Xin­San (KXS), which may terminate the signaling of MMPs, exerts antidepressant­like and cardioprotective effects in a myocardial infarction (MI) plus depression rat model. Rats were randomly assigned to five groups: A normal control (control group), a celisc­injection of isopropyl adrenaline group (ISO group), depression (depression group), an ISO + depression (depression + ISO group), and an ISO + depression group treated with intragastric administration of 1,785 mg/kg KXS (KXS group). Behavioral changes, echocardiography, biochemical index, matrix metalloproteinase (MMP) and apoptosis­related proteins were assessed. Compared with the depression + ISO group, KXS significantly improved stress­induced alterations of behavioral parameters and protected the heart by enlarging the left ventricular (LV) fractional shortening (FS) and LV ejection fraction (EF). Moreover, KXS significantly attenuated ISO + depression­induced MMP­2 and MMP­9 expression at the mRNA and protein level and decreased TIMP in the heart compared to the complex model group. Myocardial apoptosis was significantly attenuated by KXS by regulating the Bcl­2/Bax axis. These results indicated that MI comorbid with depression may damage the MMP balance in the central and peripheral system, and KXS may have a direct anti­depressive and cardio­protective effect by regulating the level of MMPs and associated myocardial apoptosis. It is promising to further explore the clinical potential of KXS for the therapy or prevention of MI plus depression comorbidity disease.

9.
Mol Divers ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792660

RESUMO

The present work describes the in vitro antibacterial evaluation of some new pyrimidine derivatives. Twenty-two target compounds were designed, synthesized and preliminarily explored for their antimicrobial activities. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungal including drug-resistant pathogens. Compound 7c presented the most potent inhibitory activities against Gram-positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924) and the fungus Candida albicans 7535, with an MIC of 2.4 µmol/L. Compound 7c was also the most potent, with MICs of 2.4 or 4.8 µmol/L against four multidrug-resistant, Gram-positive bacterial strains. The toxicity evaluation of the compounds 7c, 10a, 19d and 26b was assessed in human normal liver cells (L02 cells). Molecular docking simulation and analysis suggested that compound 7c has a good interaction with the active cavities of dihydrofolate reductase (DHFR). In vitro enzyme study implied that compound 7c also displayed DHFR inhibition.

10.
Obes Surg ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781938

RESUMO

PURPOSE: White adipose tissue (WAT) browning plays a crucial role in energy metabolism. However, it remains unclear whether WAT browning is involved in the adipose reduction following sleeve gastrectomy (SG). Adiponectin is upregulated after Roux-en-Y gastric bypass surgery. The role of adiponectin in SG was further investigated in the current study. MATERIALS AND METHODS: Diabetic Sprague Dawley rats were randomly divided into control, sham + libitum, sham + food restriction, and sleeve groups. Browning markers, including uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor (PPAR) γ, and PPARγ coactivator-1 alpha (PGC-1α), were examined 4 weeks after the operation. RESULTS: UCP1, PPARγ, and PGC-1α expression were significantly higher in the sleeve group compared to the other study groups. The adipose tissue of the sleeve group exhibited tissue weight loss and additional morphological browning features. In addition, adiponectin expression in the sleeve group was significantly increased. Adiponectin upregulated the expression of the browning genes and sirtuin 1 (SIRT1) in 3T3-L1 adipocytes. SIRT1 could increase the WAT browning levels, revealing that adiponectin induced the browning process via the upregulation of SIRT1. Furthermore, SIRT1 represented a positive regulatory feedback loop for adiponectin. SIRT1 activated adenosine monophosphate-activated protein kinase (AMPK), which can mediate WAT browning. Inhibition of the AMPK signaling pathway by dorsomorphin decreased UCP1, PPARγ, and PGC-1α expression. However, additional studies are needed to understand the relationship between adiponectin and glucose homeostasis. CONCLUSIONS: Sleeve gastrectomy increased adiponectin levels, which in turn upregulated SIRT1. Thus, SIRT1 may function as an endocrine signal to mediate WAT browning.

11.
J Forensic Sci ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738462

RESUMO

Sudden cardiac death (SCD) is an unexpected death caused by a sudden loss of cardiac function, which is currently a global public health problem. Evaluation of the agonal cardiac function of the deceased is a quite important task for the diagnosis of SCD in forensic medicine. Brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are currently considered as significant biomarkers for the diagnosis of heart failure in both clinical and forensic practices. To investigate the postmortem evaluation roles of postmortem BNP and NT-proBNP levels for SCD, the present study meta-analyzed eight related studies from Embase, Cochrane Library, PubMed, China Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang Data. Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included literature, and the meta-analysis was performed by RevMan 5.3.5 software. Postmortem NT-proBNP in pericardial fluid showed higher levels in the SCD group than that of the non-SCD group with the weighted mean difference = 3665.74, 95% confidence interval: 1812.89-5518.59, and p = 0.0001. However, postmortem levels of BNP in pericardial fluid and NT-proBNP in serum revealed no statistical difference between SCD and non-SCD subjects. The results of present meta-analysis demonstrated that postmortem NT-proBNP in the pericardial fluid could be used as an ancillary indicator for evaluation of agonal cardiac function in forensic medicine.

12.
J Cell Physiol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31637729

RESUMO

Aberrant fibrogenesis impairs the architectural and functional homeostasis of the kidneys. It also predicts poor diagnosis in patients with end-stage renal disease (ESRD). Renal tubular epithelial cells (RTEC) can trans-differentiate into myofibroblasts to produce extracellular matrix proteins and contribute to renal fibrosis. Connective tissue growth factor (CTGF) is a cytokine upregulated in RTECs during renal fibrosis. In the present study, we investigated the regulation of CTGF transcription by megakaryocytic leukemia 1 (MKL1). Genetic deletion or pharmaceutical inhibition of MKL1 in mice mitigated renal fibrosis following the unilateral ureteral obstruction procedure. Notably, MKL1 deficiency in mice downregulated CTGF expression in the kidneys. Likewise, MKL1 knockdown or inhibition in RTEs blunted TGF-ß induced CTGF expression. Further, it was discovered that MKL1 bound directly to the CTGF promoter by interacting with SMAD3 to activate CTGF transcription. In addition, MKL1 mediated the interplay between p300 and WDR5 to regulate CTGF transcription. CTGF knockdown dampened TGF-ß induced pro-fibrogenic response in RTEs. MKL1 activity was reciprocally regulated by CTGF. In conclusion, we propose that targeting the MKL1-CTGF axis may generate novel therapeutic solutions against aberrant renal fibrogenesis.

13.
Nanoscale ; 11(43): 20667-20675, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31642452

RESUMO

Retinal ischemia-reperfusion (I/R) injuries are involved in the universal pathological processes of many ophthalmic diseases, including glaucoma, diabetic retinopathy, and retinal arterial occlusion. The reason is that the ischemia-reperfusion injury is accompanied by the abnormal accumulation of reactive oxygen species (ROS), which can cause damage to retinal ganglion cells (RGCs), promote their apoptosis, and finally lead to the irreversible loss of the visual field. RGCs are specialized projection neurons that are situated in the inner retinal surface of the eye, and they transmit visual images into certain areas of the brain in the form of action potentials. Therefore, any damage that affects the viability of RGCs can cause visual field defects or even irreversible vision loss. There is no effective drug treatment in clinical practice for the loss of the visual field that is caused by the oxidation and apoptosis of RGCs. Hence, finding a drug with neuroprotective and antioxidant functions is urgently needed. As a new type of nanomaterial, tetrahedral framework nucleic acids (tFNAs) exhibit outstanding biocompatibility and have been shown in our previous studies to participate in the positive regulation of cell behavior. In this experiment, we first established a cellular model of oxidative stress in RGCs with tert-butyl peroxide (TBHP). Then, we primarily explored the antioxidant and neuroprotective effects of tFNAs after TBHP-induced oxidative stress and the main mechanisms by which the tFNAs function. Our research showed that tFNAs could reduce the production of reactive oxygen species (ROS) in cells and protect the cells from oxidative stress by regulating intracellular oxidation-related enzymes. In addition, tFNAs could simultaneously improve oxidative stress-induced apoptosis significantly via affecting the expression of apoptosis-related proteins. Finally, we confirmed by western blotting that the mechanism by which tFNAs prevent damage caused by oxidative stress involves activating the Akt/Nrf2 pathway. Our findings provide new ideas for the prevention and treatment of a series of diseases that are caused by oxidative stress to RGCs.

14.
Pharm Biol ; 57(1): 710-716, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622118

RESUMO

Context: Methicillin-resistant Staphylococcus aureus (MRSA) is a very harmful bacterium. Oridonin, a component in Rabdosia rubescens (Hemsl.) Hara (Lamiaceae), is widely used against bacterial infections in China. Objective: We evaluated oridonin effects on MRSA cell membrane and wall, protein metabolism, lactate dehydrogenase (LDH), DNA and microscopic structure. Materials and methods: Broth microdilution and flat colony counting methods were used to measure oridonin minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against USA300 strain. Electrical conductivity and DNA exosmosis were analysed to study oridonin effects (128 µg/mL) on cell membrane and wall for 0, 1, 2, 4 and 6 h. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was used to detect effects on soluble protein synthesis after 6, 10 and 16 h. LDH activity was examined with an enzyme-linked immunosorbent assay. Effects of oridonin on USA300 DNA were investigated with DAPI staining. Morphological changes in MRSA following oridonin treatment were determined with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results: Oridonin MIC and MBC values against USA300 were 64 and 512 µg/mL, respectively. The conductivity and DNA exosmosis level of oridonin-treated USA300 improved by 3.20±0.84% and increased by 58.63 ± 1.78 µg/mL, respectively. LDH and soluble protein levels decreased by 30.85±7.69% and 27.51 ± 1.39%, respectively. A decrease in fluorescence intensity was reported with time. Oridonin affected the morphology of USA300. Conclusions: Oridonin antibacterial mechanism was related to changes in cell membrane and cell wall permeability, disturbance in protein and DNA metabolism, and influence on bacterial morphology. Thus, oridonin may help in treating MRSA infection.

15.
Front Oncol ; 9: 823, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508374

RESUMO

The toxicity and side effects of traditional chemotherapeutic drugs are the main causes of chemotherapy failure. To improve the specificity and selectivity of chemotherapeutic drugs for tumor cells, a novel redox-sensitive polymer prodrug, polyethylene glycol-poly (ß-benzyl-L-aspartate) (PEG-PBLA)-SS-paclitaxel (PPSP), was designed and synthesized in this study. The PPSP micelle was manufactured via high-speed dispersion stirring and dialysis. The particle size and zeta potential of this prodrug micelle were 63.77 ± 0.91 nm and -25.8 ± 3.24 mV, respectively. The micelles were uniformly distributed and presented a spherical morphology under a transmission electron microscope. In the tumor physiological environment, the particle size of the PPSP micelles and the release rate of paclitaxel (PTX) were significantly increased compared with those of mPEG-PBLA-CC-PTX (PPCP) micelles, reflecting the excellent redox-sensitive activity of the PPSP micelles. The inhibitory effect of PPSP on HepG2, MCF-7 and HL-7702 cell proliferation was investigated with MTT assays, and the results demonstrated that PPSP is superior to PTX with respect to the inhibition of two tumor cell types at different experimental concentration. Simultaneously PPSP has lower toxicity against HL-7702 cells then PTX and PPCP. Moreover, the blank micelle from mPEG-PBLA showed no obvious toxicity to the two tumor cells at different experimental concentrations. In summary, the redox-sensitive PPSP micelle significantly improved the biosafety and the anti-tumor activity of PTX.

16.
J Transl Med ; 17(1): 268, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412888

RESUMO

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune disorder mainly characterized by exocrine gland injury. Costimulatory molecules play an important role in immune-regulatory networks. Although B7 family costimulatory molecules were previously discovered in human salivary gland epithelial (HSGE) cells in pSS, the effects of the B7 family member B7-H3 (CD276) have not been well elucidated. Thus, this study aimed to investigate the role and mechanism of B7-H3 in HSGE cells in pSS. METHODS: The expression of B7-H3, B7-H1, PD-1 in serum, saliva and salivary gland were examined by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Immunofluorescence was used to test the expression and distribution of B7-H3, AQP5 and CK-8 in salivary gland tissues. Flow cytometry, Cell Counting Kit 8 (CCK-8) and western blot (WB) were performed to research the apoptotic, proliferative and inflammatory effects of B7-H3 in primary HSGE cells and HSGE cell lines. RESULTS: Our results showed that the expression of PD-1, B7-H1 and B7-H3 in peripheral blood, and salivary glands in pSS patients was higher than that in healthy controls, which was positive correlation with the grade of the salivary glands. The expression of B7-H3 in saliva was higher in pSS patients than that in healthy controls, which was detected with the most significant difference of them. The expression of B7-H3 in primary HSGE cells of pSS patients was significantly higher than healthy controls. B7-H3 increased activity of NF-κB pathway and promoted inflammation of HSGE cells, decreasing the expression of AQP5. Furthermore, B7-H3 overexpression inhibited proliferation and induced apoptosis in HSGE cell lines. CONCLUSION: B7-H3 could promote inflammation and induce apoptosis of HSGE cells by activating NF-κB pathway, which might be a promising therapeutic target for pSS.

17.
ACS Appl Mater Interfaces ; 11(36): 32787-32797, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424187

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by a series of progressive motor disorders. PD is caused by dysfunction of basal ganglia, decrease of dopaminergic neurons in substantia nigra, and abnormal accumulation of Lewy bodies and Lewy neurites. Antiparkinsonian agents, which are currently used for treatment of PD, exhibit unsatisfactory effects on disease control. In recent years, tetrahedral framework nucleic acids (TFNAs) have been considered as multifunctional nanomaterials, and their scope of application has been extended to a wide range of areas. In previous studies, TFNAs were shown to exert positive effects on various cell types in processes such as cell proliferation, cell differentiation, and apoptosis. In the present study, we explored the role of TFNAs in the treatment and prevention of PD in vitro and elucidated its underlying mechanisms of action. On the basis of the experiments conducted, we demonstrated that TFNAs could inhibit and repair the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of PC12 cells through decreasing the accumulation of α-synuclein, one of the characteristic biomarkers of PD. Genes and proteins related to the AKT/PI3K signaling and mitochondrial apoptotic pathways were examined to further support this finding. Most importantly, TFNAs exhibited unexpected neuroprotective and neurorestorative effects on PC12 cells, providing a novel approach for reducing the neuropathological changes caused by PD.

18.
Nat Commun ; 10(1): 3283, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337765

RESUMO

Control of atomic-scale interfaces between materials with distinct electronic structures is crucial for the design and fabrication of most electronic devices. In the case of two-dimensional materials, disparate electronic structures can be realized even within a single uniform sheet, merely by locally applying different vertical gate voltages. Here, we utilize the inherently nano-structured single layer and bilayer graphene on silicon carbide to investigate lateral electronic structure variations in an adjacent single layer of tungsten disulfide (WS2). The electronic band alignments are mapped in energy and momentum space using angle-resolved photoemission with a spatial resolution on the order of 500 nm (nanoARPES). We find that the WS2 band offsets track the work function of the underlying single layer and bilayer graphene, and we relate such changes to observed lateral patterns of exciton and trion luminescence from WS2.

19.
Int J Oncol ; 55(2): 451-461, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268161

RESUMO

Gastric cancer (GC) is one of the most common cancers worldwide and results in the second greatest rate of cancer­associated mortality globally. Multidrug resistance (MDR) often develops during the chemotherapy, resulting in the failure of treatment. To investigate the molecular mechanism of MDR, the roles of microRNA (miR)­1 were studied in GC. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to investigate the expression levels of miR­1 and sorcin in SGC7901/ADM and SGC7901/VCR cell lines. The effect of miR­1 on the half maximal inhibitory concentration (IC50), cell apoptosis rates and drug accumulation was uncovered by MTT assay and flow cytometric analysis. Furthermore, dual­luciferase assay and western blotting were used to determine the target of miR­1 in GC. It was demonstrated that miR­1 was highly downregulated in MDR GC cell lines, including SGC7901/ADM and SGC7901/VCR. Overexpression of miR­1 in MDR GC cells decreased IC50, but increased the cell apoptosis rates and promoted the drug accumulation in cancer cells. Dual­luciferase activity assay indicated that sorcin was the target of miR­1 in GC. In addition, overexpression of sorcin could partially reverse the effect of miR­1 in MDR GC cells. The role of miR­1 in MDR GC cells makes it a potential therapeutic target for a successful clinical outcome.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Células Tumorais Cultivadas , Vincristina/farmacologia
20.
Peptides ; 119: 170080, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31260713

RESUMO

Nesfatin-1 is an anorexic peptide derived from nucleobindin 2 (NUCB2). An increase in hypothalamic nesfatin-1 inhibits feeding behavior and promotes weight loss. However, the effects of weight loss on hypothalamic nesfatin-1 levels are unclear. In this study, obese rats lost weight in three ways: Calorie Restriction diet (CRD), Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). We found an increase in nesfatin-1 serum and cerebrospinal fluid levels after weight loss in obese Sprague-Dawley (SD) rats. Moreover, weight loss also increased hypothalamic melanocortin 3/4 receptor (MC3/4R) and extracellular regulated kinase phosphorylation (p-ERK) signaling. Third ventricle administration of antisense morpholino oligonucleotide (MON) against the gene encoding NUCB2 inhibited hypothalamic nesfatin-1 and p-ERK signaling, increased food intake and reduced body weight loss in SG and RYGB obese rats. Third ventricle administration of SHU9119 (MC3/4R blocker) blocked hypothalamic MC3/4R, inhibited p-ERK signaling, increased food intake and reduced body weight loss in SG and RYGB obese rats. These findings indicate that weight loss leads to an increase in hypothalamic nesfatin-1. The increase in hypothalamic nesfatin-1 participates in regulating feeding behavior through the MC3/4R-ERK signaling especially after SG and RYGB.

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