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1.
Bioorg Chem ; 98: 103737, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32193031

RESUMO

PI3Kα has been identified as an ideal target to treat with PIK3CA gene mutation disease, including drugs such as Alpelisib and Copanlisib. Five purine analogues and four thiazole analogues were designed and synthesized. Their enzymaticactivity against PI3Ka/ß/γ/δ were tested, respectively. All compounds showed excellent selectivity in modulating PI3Ka activity, and parts of the compounds showed good inhibition. Meanwhile, we used Autodock 4.2 to explore the binding mode of the most potential compound Tg with the target protein. In addition, DFT was used to calculate the HOMO-LUMO maps of the compounds Tf, Tg and positive control. This paper will provide some useful information for further drug design of PI3Kα inhibitors.

3.
J Neurol ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008072

RESUMO

BACKGROUND AND PURPOSE: This study aimed at developing a radiomics signature (R score) as prognostic biomarkers based on penumbra quantification and to validate the radiomics nomogram to predict the clinical outcomes for thrombolysis for acute ischemic stroke (AIS) patients. METHODS: In total, 168 patients collected from seven centers were retrospectively included. A score of mismatch was defined as MIS. Based on a short-term clinical label, 456 radiomics features were evaluated with feature selection methods. R score was constructed with the selected features. To compare the predictive capabilities of the clinical factors, MIS, and R score, three nomograms were developed and evaluated, according to the short-term clinical assessment on day 7. Finally, the radiomics nomogram was validated by predicting the 3-month clinical outcomes of AIS patients, in an external cohort. RESULTS: R scores were found to be significantly higher in patients with favorable clinical outcomes in both training and validation datasets. The predictive value of the radiomics nomogram estimating favorable clinical outcomes was modest, with a concordance index (C-index) of 0.695 [95% confidence interval (CI) 0.667-0.723) in an external validation dataset. In addition, the area under curve (AUC) of the radiomics nomogram predicting favorable clinical outcome reached 0.886 (95% CI 0.809-0.963) on day 7 and 0.777 (95% CI 0.666-0.888) at 3 months. CONCLUSIONS: The radiomics signature is an independent biomarker for estimating the clinical outcomes in AIS patients. By improving the individualized prediction of the clinical outcome for AIS patients 3 months after onset, the radiomics nomogram adds more value to the current clinical decision-making process.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32091099

RESUMO

OBJECTIVES: The emergence and spread of plasmid-encoded tet(X3/X4) genes that confer high-level tigecycline and eravacycline resistance in Escherichia coli and Acinetobacter spp. pose serious threats to human and animal health. We developed a rapid and robust assay to detect Tet(X3/X4) in Gram-negative bacteria based on eravacycline degradation by the presence of the Tet(X) enzyme in the test strain. METHODS: This tetracycline inactivation method (TIM) is based on the degradation of eravacycline by the Tet(X3/X4)-producing strain, which results in reduced eravacycline activity against an acid-producing thermophile Bacillus stearothermophilus indicator strain. For Tet(X)-negative strains, eravacycline retains its antimicrobial activity. Coupled with a pH-sensitive dye (bromocresol purple), the reduced colorimetric inhibition zone can be measured to determine the production of Tet(X3/X4). One hundred and eighteen isolates, including 30 tet(X4)-positive E. coli, 30 tet(X3)-positive Acinetobacter spp. and 58 tet(X)-negative E. coli and Acinetobacter spp., were examined to evaluate the performance of this TIM. RESULTS: The sensitivity and specificity for E. coli carrying tet(X4) was 96.7% and 100%, respectively, and for Acinetobacter spp. carrying tet(X3) both were 100%. The TIM assay can be completed within 6.5 h. CONCLUSIONS: The TIM is a simple, rapid and cost-effective method for the detection of plasmid-mediated high-level tigecycline resistance in E. coli and Acinetobacter spp.

6.
Sci Rep ; 10(1): 302, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942003

RESUMO

We have previously demonstrated that a recombinant Listeria ivanovii (LI) strain expressing the ESAT-6 or Ag85C protein of Mycobacterium tuberculosis (Mtb) as a tuberculosis (TB) vaccine candidates induced antigen-specific cellular immune responses after intravenous immunization of mice. However, whether such recombinant strains could induce desired immune responses in the lung, where TB infection occurs, is not clear. In this paper, C57BL/6 J mice were intranasally vaccinated with attenuated LIΔactAplcB-Rv3875 (Δ refers to gene deletion in the bacterial genome) or LIΔactAplcB-Rv0129c, the two vaccine candidates that utilize LI as an antigen delivery vector. Bacterial load in the target organs, histological changes in the infected organs, the percentage of specific cytokine-secreting T cells in the lung and spleen, IgG levels in the serum and secretory IgA (SIgA) levles in bronchoalveolar lavage (BAL) fluid were determined at specific days post inoculation (dpi). The results showed that both strains were mainly confined to the lung and were eliminated at 10 dpi. The histological damage caused by the infection in the lung was slight and recovered by day 5. Intranasal vaccination of the mice twice at an interval of 4 weeks notably elicited TB antigen-specific CD4+ and CD8+ T cell responses in the lung and SIgA secretion in the pulmonary mucosa, and significantly enhanced the percentage of double-functional CD8+ T cells (IFN-γ+ TNF-α+ CD8+). To our knowledge, this is the first report regarding the used of LI vector vaccines to induce promising lung-localized cellular and humoral immune responses by intranasal vaccination. These data suggest that LI could be a novel and promising live vector to construct an intranasal vaccine against respiratory diseases.

7.
J Phys Chem B ; 124(1): 253-265, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31790253

RESUMO

The force-extension relationship of single polymer chains is an essential component underlying the development of macroscopic constitutive models for elastomers. In this work, we present a model for the force-extension relationship beyond the consideration of classical entropic elasticity, by accounting for bond deformation on the chain's backbone. Parameters in this model are mostly molecular parameters for bond stretching, bending, and breaking already available in the literature, thereby limiting the parameters that need to be extracted from fitting experimental data to a minimum. In addition, an extension of the model is made to include the effects of mechanophores: molecules that react under the application of a mechanical force. This has endowed the model with the capability of predicting the mechanophore reaction as well as chain scission. The model is applied and compared to experimental data, in a range of scenarios: reproducing the measured force-extension relationship for PDMS chains, calculating the rate dependent fracture energy of PDMS films, and predicting the force-extension relationship caused by the unfolding of mechanophore domains. For the last example, it was demonstrated that this type of chain has the potential to be utilized to design elastomers with substantially enhanced strength and toughness.

8.
Curr Cancer Drug Targets ; 20(1): 76-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31433759

RESUMO

BACKGROUND: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. MATERIALS AND METHODS: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. RESULTS: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. CONCLUSION: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.

9.
Free Radic Biol Med ; 146: 70-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31626947

RESUMO

We found recently that benzohydroxamic acid (BHA) could detoxify the chlorinated quinoid carcinogens via an unusual Lossen rearrangement reaction. However, it is not clear what would happen when the nitrogen hydrogen of BHA was substituted with methyl and other alkyl groups. Here we show that N-methyl benzohydroxamic acid (N-MeBHA, a simple model compound for the classic iron-chelator deferoxamine, which is a typical N-alkyl trihydroxamic acid) could react with 2,5-dichloro-1,4-benzoquinone (DCBQ) to form a relatively stable initial carbon-oxygen bonding conjugation intermediate CBQ-O-N-MeBHA. However, the major final product was identified, unexpectedly, as a carbon-nitrogen bonding conjugate CBQ(OH)-N(CH3)-COAr, which is the rearranged isomer of CBQ-O-N-MeBHA. Interestingly, a new 18-line nitrogen-centered radical and a carbon-centered quinone ketoxy radical were observed by the ESR spin-trapping method, which was further confirmed by HPLC-MS and 15N-isotope labeling methods. We further found that both new DNA adducts and DNA strand breaks could be produced by the reactive nitrogen-centered radical. Taken together, we propose that the reaction between DCBQ and N-MeBHA was not via the Lossen rearrangement, but rather through a novel radical homolysis and recoupling pathway. Analogous results were observed for other chlorinated quinones and N-alkyl hydroxamic acids including the widely-used trihydroxamate iron-chelating drug deferoxamine. This represents the first report of unexpected radical pathway for the reaction between chlorinated quinones and N-alkyl hydroxamic acids under normal physiological conditions, which may have broad biological and environmental significance for future study of carcinogenic chloroquinones and hydroxamic acid drugs.

10.
Pancreatology ; 20(1): 95-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786057

RESUMO

OBJECTIVES: FOLFIRINOX (FFX) or abraxane plus gemcitabine (AG)-based chemotherapy is used widely as firstline treatment for patients with pancreatic cancer. However, their use in the elderly is discouraged because of adverse events. More clinical data about the therapeutic response and tolerability to FFX or AG in elderly patents (over 70 years old) are required. METHODS: Patients with advanced pancreatic cancer (n = 203; 131 metastatic pancreatic cancer patients (MPC) and 72 locally advanced pancreatic cancer patients (LAPC)) were treated using modified-FFX (mFFX) or AG and mFFX sequentially. The patients were grouped according to their age, patients below 70 years old and patients above 70 years old. The objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse events were compared between the groups. RESULTS: The ORRs in the elderly and in patients below 70 were similar (30.0% versus 32.3%). The median OS and PFS were also similar between the groups (mOS 13.3 m vs 12.7 m, p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS mPFS 10.6 m vs 10.3 m, p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293)). However, the elderly patients suffered a higher incidence of severe adverse events (50% vs. 28.3%). CONCLUSIONS: These data could provide guidance for chemotherapy use in elderly patients with advanced pancreatic cancer. Age did not affect treatment outcome; however, supportive treatment is very important for elderly patients receiving chemotherapy.

11.
Support Care Cancer ; 28(3): 979-1010, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31813021

RESUMO

INTRODUCTION: Weight loss in cancer patients is a worrisome constitutional change predicting disease progression and shortened survival time. A logical approach to counter some of the weight loss is to provide nutritional support, administered through enteral nutrition (EN) or parenteral nutrition (PN). The aim of this paper was to update the original systematic review and meta-analysis previously published by Chow et al., while also assessing publication quality and effect of randomized controlled trials (RCTs) on the meta-conclusion over time. METHODS: A literature search was carried out; screening was conducted for RCTs published in January 2015 up until December 2018. The primary endpoints were the percentage of patients achieving no infection and no nutrition support complications. Secondary endpoints included proportion of patients achieving no major complications and no mortality. Review Manager (RevMan 5.3) by Cochrane IMS and Comprehensive Meta-Analysis (version 3) by Biostat were used for meta-analyses of endpoints and assessment of publication quality. RESULTS: An additional seven studies were identified since our prior publication, leading to 43 papers included in our review. The results echo those previously published; EN and PN are equivalent in all endpoints except for infection. Subgroup analyses of studies only containing adults indicate identical risks across all endpoints. Cumulative meta-analysis suggests that meta-conclusions have remained the same since the beginning of publication time for all endpoints except for the endpoint of infection, which changed from not favoring to favoring EN after studies published in 1997. There was low risk of bias, as determined by assessment tool and visual inspection of funnel plots. CONCLUSIONS: The results support the current European Society of Clinical Nutrition and Metabolism guidelines recommending enteral over parenteral nutrition, when oral nutrition is inadequate, in adult patients. Further studies comparing EN and PN for these critical endpoints appear unnecessary, given the lack of change in meta-conclusion and low publication bias over the past decades.

12.
Nanoscale ; 12(2): 1032-1045, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31845926

RESUMO

Cell entry of polymeric nanoparticles (NPs) bearing polynucleotides is an important stage for successful gene delivery. In this work, we addressed the influence of cell membrane lipids on the integrity and configurational changes of NPs composed of short interfering ribonucleic acid (siRNA) and polyethylenimine. We focused on NPs derived from two different PEIs, unmodified low molecular weight PEI and linoleic acid (LA)-substituted PEI, and their interactions with two membrane lipids (zwitterionic 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) and anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS)). Our experiments showed that POPS liposomes interacted strongly with both types of NPs, which caused partial dissociation of the NPs. POPC liposomes, however, did not induce any dissociation. Consistent with the experiments, steered molecular dynamics simulations showed a stronger interaction between the NPs and the POPS membrane than between the NPs and the POPC membrane. Lipid substitution on the PEIs enhanced the stability of the NPs during membrane crossing; lipid association between PEIs of the LA-bearing NPs as well as parallel orientation of the siRNAs provided protection against their dissociation (unlike NPs from native PEI). Our observations provide valuable insight into the integrity and structural changes of PEI/siRNA NPs during membrane crossing which will help in the design of more effective carriers for nucleic acid delivery.

13.
Biomed Pharmacother ; 121: 109248, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734579

RESUMO

LncRNA NEAT1 is reported as a crucial oncogene in multiple cancers. But, its biological role in bladder cancer is barely understood. Therefore, we concentrated on the function and role of NEAT1 in bladder cancer. Firstly, NEAT1 expression in bladder cancer cells was determined and it was displayed NEAT1 was significant elevated. NEAT1 was knockdown and overexpressed in T24 and J82 cells. Then it was indicated that NEAT1 silence greatly inhibited bladder cancer cell proliferation with an increased ratio of apoptotic cells and severe cell cycle arrest. Overexpression of NEAT1 exhibited a reversed process in bladder cancer cells. Additionally, in vivo experiments were employed using establishment of nude mice models. NEAT1 knockdown inhibited bladder cancer growth while increase of NEAT1 promoted bladder cancer development in vivo. By employing the bioinformatics analysis, we speculated that miR-410 was as a downstream target of NEAT1. Then, the targeting association between them was proved in our research and we implicated miR-410 was dramatically restrained in bladder cancer cells. Meanwhile, it was exhibited that miR-410 was negatively regulated by NEAT1. Apart from these, HMGB1 was speculated as a downstream target of miR-410. Dual-luciferase reporter assay was used to prove the correlation between miR-410 and HMGB1. Up-regulation of miR-410 restrained HMGB1 levels and NEAT1 can regulate HMGB1 level via sponging miR-410. To sum up, we implied NEAT1/miR-410/HMGB1 axis participated in bladder cancer.

14.
J Cell Physiol ; 235(2): 1120-1128, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31294463

RESUMO

The long noncoding RNA MEG3 is a significant tumor-suppressive gene in various tumors. But its biological role in bladder cancer remains uninvestigated. Herein, the biological mechanism of MEG3 in bladder cancer pathogenesis was explored. First, the expression of MEG3 in bladder cancer cells was examined, and we found that it was significantly reduced. In addition, in bladder cancer cells, we observed htat miR-494 was increased. Then, MEG3 was overexpressed in UMUC3 and SW780 cells and it could negatively modulate miR-494 expression. Bladder cancer cell proliferation was repressed, cell apoptosis was triggered and meanwhile, the cell cycle was remarkably arrested by the overexpression of MEG3. Moreover, the increase of MEG3 suppressed bladder cancer cell migration and invasion capacity. MEG3 can sponge miR-494 and the binding sites between them were confirmed by carrying out a series of functional assays. Furthermore, PTEN was speculated as a putative target of miR-494. Meanwhile, we found that miR-494 inhibitors induced PTEN. Finally, in vivo assays were conducted to prove that MEG3 can restrain bladder tumor growth by modulating miR-494 and PTEN. In conclusion, it was suggested MEG3 can interact with miR-494 to regulate PTEN in bladder cancer development.

15.
J Magn Reson Imaging ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31867839

RESUMO

BACKGROUND: In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required. PURPOSE: To develop a radiomic nomogram based on MR radiomics to stratify patients preoperatively and potentially improve clinical practice. STUDY TYPE: Retrospective. POPULATION: We enrolled 303 patients from two medical centers. Patients with a disease-free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126). FIELD STRENGTH/SEQUENCE: 3.0T axial T1 -weighted (T1 -w), T2 -weighted (T2 -w), contrast-enhanced T1 -weighted (CET1 -w). ASSESSMENT: ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19-9, and radiomic-related features of ER were assessed. In addition, to determine the intra- and interobserver reproducibility of radiomic features extraction, the intra- and interclass correlation coefficients (ICC) were calculated. STATISTICAL TESTS: The area under the receiver-operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit. RESULTS: The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19-9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19-9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort). DATA CONCLUSION: The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019.

16.
Medicine (Baltimore) ; 98(51): e18490, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861033

RESUMO

To generate a nomogram to predict posthepatectomy liver failure (PHLF), we attempted to elucidate salient risk factors in patients with hepatocellular carcinoma (HCC).We performed a retrospective review of 665 patients with HCC who received hepatectomy in 2 academic institutions in China. Independent risk factors for PHLF were identified from putative demographic, intrinsic, biochemical, surgery-related, and volumetric data. A predictive nomogram was formulated based on relevant risk factors, and we compared this with existing models.We identified clinical signs of portal hypertension (P = .023), serum total bilirubin (P = .001), serum creatinine (P = .039), and intraoperative hemorrhage (P = .015) as being important risk factors in predicting PHLF. The nomogram had a C-index of 0.906 for the externally validated data. The nomogram displayed better predictive value than 2 of the other most cited models (C-indices of 0.641 and 0.616, respectively) in the current cohort. Additionally, we were able to patients into low- (<10%), intermediate- (10-30%), and high-risk (≥30%) groups based on the nomogram. This allows us to facilitate person-specific management.Here, we constructed a simple nomogram for prediction of PHLF in patients with HCC weighted by independent risk factors. Further prospective studies are required to confirm the predictive ability of our nomogram.


Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Falência Hepática/epidemiologia , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Idoso , China/epidemiologia , Feminino , Humanos , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos
17.
Singapore Med J ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31680182

RESUMO

INTRODUCTION: Dihydroartemisinin (DHA) is a first-line antimalarial drug with relatively low toxicity. DHA has been speculated to possess a broad-spectrum antitumour effect. However, the potential value of DHA for the treatment of endometrial carcinoma or cervical cancer is unclear. METHODS: We used human endometrial cancer cells and cervical cancer cells to assess whether DHA alone or when combined with cisplatin would induce cell death. We aimed to elucidate the role of autophagy in DHA-induced cytotoxicity in both endometrial and cervical cancer cells, as well as explore the impact of DHA treatment on cell proliferation, apoptosis and autophagy. RESULTS: DHA alone or in combination with cisplatin induced cell death in a dose- and time-dependent manner. Caspase-3 mRNA and cleaved caspase-3 protein levels were markedly elevated following DHA treatment either in the presence or absence of cisplatin, suggesting a role of apoptosis in DHA-induced cell death. DHA treatment activated the autophagic pathway, as evidenced by increased monodansylcadaverine-positive staining, elevated microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, and enhanced p62/sequestosome 1 degradation. Inhibition of autophagy by 3-methyladenine further enhanced the cytotoxicity of DHA towards tumour cells. mRNA levels of transferrin receptor (TfR) were suppressed upon DHA treatment and knockdown of TfR by RNA interference caused further DHA induction of cancer cell death. CONCLUSION: Our results suggest a clinical value for DHA in the treatment of endometrial carcinoma and cervical cancer. Our data reveals possible anticancer mechanisms of DHA that involve regulating apoptosis, autophagy pathway and levels of TfR.

18.
Int J Nanomedicine ; 14: 8345-8360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695371

RESUMO

Background: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Isoflavonas/farmacologia , Micelas , Mitocôndrias/metabolismo , Miócitos Cardíacos/patologia , Fosfinas/química , Animais , Cátions , Linhagem Celular , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Isoproterenol , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos
19.
Science ; 366(6465): 645-648, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672899

RESUMO

The propensity of metals to form irregular and nonplanar electrodeposits at liquid-solid interfaces has emerged as a fundamental barrier to high-energy, rechargeable batteries that use metal anodes. We report an epitaxial mechanism to regulate nucleation, growth, and reversibility of metal anodes. The crystallographic, surface texturing, and electrochemical criteria for reversible epitaxial electrodeposition of metals are defined and their effectiveness demonstrated by using zinc (Zn), a safe, low-cost, and energy-dense battery anode material. Graphene, with a low lattice mismatch for Zn, is shown to be effective in driving deposition of Zn with a locked crystallographic orientation relation. The resultant epitaxial Zn anodes achieve exceptional reversibility over thousands of cycles at moderate and high rates. Reversible electrochemical epitaxy of metals provides a general pathway toward energy-dense batteries with high reversibility.

20.
Int J Nanomedicine ; 14: 7489-7502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571860

RESUMO

Background: 3,5,4'-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated. Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated. Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues. Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Micelas , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Disponibilidade Biológica , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Camundongos Endogâmicos BALB C , Fosfatidiletanolaminas/efeitos adversos , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Polímeros/química , Ratos Sprague-Dawley , Resultado do Tratamento
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