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1.
Nanoscale ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674617

RESUMO

As a new kind of porous material, zeolitic imidazolate frameworks (ZIF-8) are built from zinc ions and 2-methylimidazolate and possess unique merits including high porosity, good structural regularity and tunability, adjustable surface functionality and intrinsic pH induced biodegradability. These advantages endow ZIF-8 with multiple functionalities and stimuli-responsive controlled release of loaded payloads by endogenous or exogenous means. In this review, we will summarize the recent advancement of ZIF-8 as nanocarriers for the loading of various molecules including chemotherapeutic drugs, photosensitizers, photothermal agents, and proteins to fabricate multifunctional nanocomposites for synergistic cancer therapy. In addition, the challenges and future developments in this area will be highlighted.

2.
Sci Rep ; 9(1): 15962, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685901

RESUMO

Fe-Mn-C-Al alloy is a new steel grade of TWIP steel developed in recent years. It has an excellent combination of elongation and tensile strength, as well as good anti-delayed fracture property. However, the crack sensitivity of this new TWIP steel has not been reported yet. In this study, differential thermal analysis (DTA) method was used, combined with professional thermodynamic software ThermoCalc to analyze the solidification behavior for Fe-Mn-C-Al alloys with different chemical compositions. Based on this, the crack sensitivity of TWIP steel is further determined. Through this study, it was found that Fe-Mn-C-Al TWIP steel may have a solidification sequence with high crack sensitivity, belonging to hypo-peritectic steel. Moreover, it was found that the carbon content has a large influence on the solidification behavior, and the manganese content also affects the solidification sequence. It can make the phase transition sequence of the solidification process change significantly, which may avoid the solidification behavior of hypo-peritectic reaction. The analysis results by thermodynamic software ThermoCalc are in good agreement with the experimental results. It displays thermoCalc can be a cost-effective way to develop Fe-Mn-C-Al TWIP steel. It is of great significance for shortening the development period of new Fe-Mn-C-Al steel grades.

3.
J Surg Oncol ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691290

RESUMO

BACKGROUND: Open surgery for hilar cholangiocarcinoma (HCCA) has already been widely reported and analyzed. However, the laparoscopic technique for treating HCCA remains controversial because of the lack of radicality and poor assessment of the resectability of hilar structures without direct palpation. The aim of this study was to provide detailed surgical procedures and photographs of this technically demanding operation, describe our experience in assessing resectability before and during surgery, and confirm the radicality of laparoscopic resection of Bismuth type III and IV HCCA. METHODS: From November 2016 to November 2018, nine patients received laparoscopic resection of Bismuth type III or IV HCCA in our department. RESULTS: Laparoscopic right hepatectomy was performed in four patients, and laparoscopic left hepatectomy was performed in five patients. Negative margins were achieved in all patients. Complications were found in two (22.22%) patients, with bile leakage and hepatic insufficiency each in one patient. The patient developing hepatic insufficiency had persistent and ongoing liver failure and finally expired. CONCLUSION: The radicality of laparoscopic resection for Bismuth type III and IV HCCA can be technically improved through extended lymphadenectomy, visual assessment of hilar structures, and frozen section techniques.

6.
Circulation ; 140(14): 1170-1184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31567014

RESUMO

BACKGROUND: Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS: Aortic arches containing plaques developed in Ldlr-/- mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS: Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS: Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

7.
Food Funct ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31620755

RESUMO

Most current research on food-relevant Pickering emulsions has been conducted using inorganic or food-compatible organic particles as emulsifiers. A key challenge is maintaining a favourable structure while being able to resist displacement or destabilisation by surfactants and controlling transport of substrates during digestion. Liposome stabilised emulsions have demonstrated some potential for being smart, responsive delivery systems for poorly available bioactives and drugs. We developed a liposome-stabilized oil-in-water Pickering emulsion utilising macromolecular crowding- with polyethylene glycol (PEG). They were pH-controllable and had surfactant-dependent deformability whilst displaying dual delivery routes from both the liposome and oil phases. Dynamic light scattering, confocal microscopy and emulsion stability measurements indicated the liposomes containing 10% PEG at neutral pH remained intact at the interface for extended time. Various degrees of interfacial coverage still existed in the presence of PEG, under acidic environment and with added bile salts. Emulsions with added PEG maintained a more integrated structure after in vitro oral-gastric digestion, and showed greater lipolysis with more free fatty acids (14.7 ± 0.5% for with PEG vs. 12.7 ± 0.1% for without PEG) released during in vitro intestinal digestion. These Pickering emulsions could provide a flexible approach to controlled release under a broad range of conditions.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31567715

RESUMO

BACKGROUND AND AIM: Open surgery remains the major approach to treat hepatocellular carcinoma, and laparoscopy-assisted liver resection has been recommended as a superior treatment. However, the efficacy of laparoscopic surgery versus open surgery for cirrhotic patients is under debate. Therefore, the aim of this meta-analysis was to compare the clinical outcomes of laparoscopic and open resection of hepatocellular carcinoma in patients with cirrhosis. METHODS: Electronic databases were searched for eligible literature updated on November 2018. After rigorous review of quality, the data were extracted from eligible trials. All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. RESULTS: Fourteen trials met the inclusion criteria. According to the pooled result of surgery duration, laparoscopic surgery was associated with significantly shorter hospital stay [STD mean difference (SMD) = -0.61, 95% confidence interval -0.89 to -0.32; P < 0.0001], lower intraoperative blood loss (SMD = -0.56, 95% confidence interval -0.99 to -0.12; P = 0.01), fewer complications (odds ratio = 0.38, 95% confidence interval 0.28 to 0.52; P < 0.00001) and lower transfusion rate (odds ratio = 0.58, 95% confidence interval 0.36-0.93; P = 0.02). Nevertheless, there was no remarkable difference in operative time (SMD = 0.17, 95% confidence interval -0.25 to -0.59; P = 0.42) between the two groups. The pooled analysis of overall survival showed that laparoscopic surgery did not achieve benefit compared with open surgery (P = 0.02). Moreover, the pooled results of three subgroups indicated that laparoscopic surgery was associated with significantly better disease-free survival (P < 0.05). CONCLUSION: The current analysis indicates that laparoscopic liver resection for hepatocellular carcinoma improved intraoperative and disease-free survival, with similar overall survival compared to the open procedure. Laparoscopic surgery may serve as a safe and feasible alternative for selected hepatocellular carcinoma patients with cirrhosis.

9.
Mar Drugs ; 17(9)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484443

RESUMO

Phytoplankton are primary producers in the marine ecosystem, where phosphorus is often a limiting factor of their growth. Hence, they have evolved strategies to recycle phosphorus by replacing membrane phospholipids with phosphorus-free lipids. However, mechanisms for replacement of lipid classes remain poorly understood. To improve our understanding, we performed the lipidomic and transcriptomic profiling analyses of an oleaginous marine microalga Nannochloropsis sp. PJ12 in response to phosphorus depletion (PD) and replenishing. In this study, by using (liquid chromatography couple with tandem mass spectrometry) LC-MS/MS-based lipidomic analysis, we show that membrane phospholipid levels are significantly reduced upon PD, while phosphorus-free betaine lipid levels are increased. However, levels of phosphorus-free photosynthetic galactolipid and sulfolipid are not increased upon PD, consistent with the reduced photosynthetic activity. RNA-seq-based transcriptomic analysis indicates that enzymes involved in phospholipid recycling and phosphorus-free lipid synthesis are upregulated, supporting the lipidomic analysis. Furthermore, enzymes involved in FASII (type II fatty acid synthesis) elongation cycle upon PD are transcriptionally downregulated. EPA (eicosapentaenoic acid) level decrease upon PD is revealed by both GC-MS (gas chromatography coupled with mass spectrometry) and LC-MS/MS-based lipidomic analyses. PD-induced alteration is reversed after phosphorus replenishing. Taken together, our results suggest that the alteration of lipid classes upon environmental change of phosphorus is a result of remodeling rather than de novo synthesis in Nannochloropsis sp. PJ12.

10.
Int Immunopharmacol ; 76: 105882, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520991

RESUMO

Vitamin A (VA) is an anti-inflammatory agent that is important in modulating and balancing the immune system. The present study aimed to investigate the immunoregulatory effects of vitamin A supplement (VAS) in C57BL/6J mice infected with Plasmodium yoelii 17XL (P.y17XL) or Plasmodium berghei ANKA (P.bANKA). Following VA treatment, parasitaemia decreased, but survival rate did not significantly change during P.y17XL infection. However, in P.bANKA infected C57BL/6J mice, VA pretreatment decreased parasitaemia, and a lag in cerebral malaria (CM) was observed during the early stages of infection. Furthermore, VA pretreatment was also demonstrated to upregulate MHCII expression in dendritic cells (DCs), downregulate Th1 and Tregs, and downregulate TNF-α and IFN-γ production. The results of the current study indicated that VAS downregulated the inflammation response in CM, but did not exhibit an immunoregulatory effect against P.y17XL infection. VAS protected the onset of CM by reducing inflammation, and was also correlated with the downregulation of Th1 by modifying the function of DCs and Tregs. However, no significant effect was observed during P.y17XL infection.

11.
Bioorg Med Chem Lett ; 29(20): 126665, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31495556

RESUMO

Pyruvate dehydrogenase kinases (PDKs) act as negative modulator of mitochondrial pyruvate dehydrogenase complex (PDC) and play a crucial role in the regulation of oxidative glycolysis, which recently have been considered as a potential drug target for varying types of cancer and diabetes. Herein, we describe the discovery and biological validation of novel anti-osteosarcoma therapeutics targeting PDK2. We identified 14 anti-osteosarcoma compounds from an in-house small molecule library, which were then evaluated in a PDK2 kinase inhibition assay. We found that compounds with 2-((4-oxo-6-((4-phenylpiperazin-1-yl)methyl)-4H-pyran-3-yl)oxy)acetamide moiety showed promising inhibitory potencies to PDK2. Especial for 12, which bound to PDK2 with a Kd value of 2.3 µM, and inhibited PDK2 activity with an EC50 value of 1.1 µM. In addition, 12 selectively inhibited PDK2, the selectivity indexes are 10.6, 22.0, and 60.9 for PDK2 as compared to PDK1, 2 and 4, respectively. The MTT assay suggested that 12 reduced MG-63 cancer cell proliferation with an IC50 value of 4.7 µM. All these observations indicated that 12 was a novel anti-osteosarcoma therapeutic, which deserved for further investigation.

12.
Nanomedicine ; 23: 102085, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31442580

RESUMO

Osteosarcoma (OS) is the most common malignant bone tumor with high metastasis and mortality. Neoadjuvant chemotherapy is an effective therapeutic regimen, but the clinical application is limited by the unsatisfactory efficacies and considerable side effects. In this study, the reduction-responsive polypeptide micelles based on methoxy poly(ethylene glycol)-block-poly(S-tert-butylmercapto-L-cysteine) copolymers (mPEG113-b-PBMLC4, P4M, and mPEG113-b-PBMLC9, P9M) were developed to control the delivery of doxorubicin (DOX) in OS therapy. Compared to free DOX, P4M/DOX and P9M/DOX exhibited 2.6 and 3.5 times increase in the area under the curve of pharmacokinetics, 1.6 and 2.0 times increase in tumor accumulation, and 1.6 and 1.7 times decrease of the distribution in the heart. Moreover, the selective accumulation of micelles, especially P9M/DOX, in tumors induced stronger antitumor effects on both primary and lung metastatic OSs with less systematic toxicity. These micelles with smart responsiveness to intracellular microenvironments are highly promising for the targeted delivery of clinical chemotherapeutic drugs in cancer therapy.

13.
J Natl Cancer Inst ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400201

RESUMO

BACKGROUND: Isocitrate dehydrogenase (IDH)-wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, while only 27% of IDH-WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood. METHODS: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests. RESULTS: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knockdown or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; HR = 3.94 (95%CI=1.87-8.28), p<.001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, p=.03), which decreased dramatically after surgery. CONCLUSION: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31420655

RESUMO

Until recently, the polymyxin antibiotics were sparingly used due to dose limiting toxicities. However, the lack of therapeutic alternatives for infections caused by highly resistant Gram-negative bacteria has led to the increased use of the polymyxins. Unfortunately, in the last decade the world has witnessed increased rates of polymyxin resistance, which is likely in part due to its irrational use in human and veterinary medicine. The spread of polymyxin-resistance has been aided by the dissemination of the transferable polymyxin-resistance gene, mcr, in humans and the environment. The mortality of colistin-resistant bacteria infections varies in different reports. However, poor clinical outcome was associated with prior colistin treatment, illness severity, complications and multidrug resistance. Detection of polymyxin-resistance in the clinic is possible through multiple robust and practical tests including broth microdilution susceptibility testing, chromogenic agar testing, and molecular biology assays. There are multiple risk factors that increase a person's risk for infection with a polymyxin-resistant bacteria including age, prior colistin treatment, hospitalization and ventilator support. For patients that are determined to be infected by polymyxin-resistant bacteria, various antibiotic treatment options currently exist. The rising trend of polymyxin-resistance threatens patient care and warrants an effective control.

15.
Org Lett ; 21(16): 6418-6422, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31368713

RESUMO

An attractive method for the synthesis of indoline-7-carboxylates through RhCl3-catalyzed C-H carbonylation of indolines with CO and alcohols was developed. The copper-based oxidant and removable pyrimidyl directing group played important roles in achieving high-level yields of the title products. Based on control experiments, a possible catalytic cycle was proposed.

16.
J BUON ; 24(3): 1075-1080, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424663

RESUMO

PURPOSE: Breast cancer causes significant mortality in women world over. The lack of efficient and reliable biomarkers and therapeutic targets impedes the treatment of breast cancer. Herein, the role and therapeutic potential of miR-155 was investigated in different breast cancer cell lines Methods: Cell viability was determined by WST-1 and colony formation assays. Transfections were performed by Lipofectamine 2000 reagent. Cell cycle analysis was carried out by flow cytometry and apoptosis was detected by AO (acridine orange)/EB (ethidium bromide) staining. Cell migration and cell invasion were determined by wound healing assay. RNA and protein expressions were determined by qRT-PCR and western blotting, respectively. RESULTS: miR-155 was significantly upregulated in all the breast cancer cells. Suppression of miR-155 in SK-BR-3 cells inhibited the growth and colony formation. The inhibition of SK-BR-3 cell proliferation was found to trigger apoptotic cell death and cell cycle arrest. Induction of apoptosis was also accompanied with enhancement of cytochrome c, Bax caspase 3, 8 and 9and inhibition of Bcl-2. Besides, suppression of miR-155 resulted in the decrease of cell migration and invasion. Bioinformatic analysis revealed MAPK7 to be the potential target of miR-155. The MAPK7 expression was also upregulated in all the breast cancer cells and suppression of miR-155 resulted in its downregulation. CONCLUSION: Taken together, miR-155 may prove essential in the management of breast cancer.

17.
J Antimicrob Chemother ; 74(11): 3184-3189, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31360994

RESUMO

OBJECTIVES: To characterize the complete sequences of four plasmids in MCR-1-producing clinical Escherichia coli strain D72, and to depict the formation mechanism and characteristics of the cointegrate plasmid derived from the pD72-mcr1 and pD72-F33 plasmids. METHODS: The genetic profiles of plasmids in strain D72 and its transconjugant were determined by conjugation, S1-PFGE, Southern hybridization, WGS analysis and PCR. Plasmid sequences were analysed with bioinformatic tools. The traits of the fusion plasmid were characterized by cointegration, stability and conjugation assays. RESULTS: Strain D72, belonging to ST1114, contained four plasmids, including mcr-1-carrying pD72-mcr1, blaCTX-M-55-carrying pD72-F33, blaTEM-238-bearing pD72-IncP and pD72-IncX1 carrying aph(3')-Ia, qnrS2 and floR. A single plasmid, pD72C, in the transconjugant was found to be larger than any plasmid in the original strain D72. Sequence analysis showed that pD72C was the fusion product of pD72-mcr1 and pD72-F33, and the recombinant event involved an intermolecular replicative mechanism. Plasmid fusion occurred at a frequency of 1.75 × 10-4 cointegrates per transconjugant. The fusion plasmid presented a high stability and conjugation frequency of 8.00 × 10-3. CONCLUSIONS: To our knowledge, this is the first report of the IS26-mediated fusion of an IncN1-F33:A-:B- plasmid and an mcr-1-carrying phage-like plasmid, providing evidence for the important role of IS26 in the recombination of plasmids. The biological advantages of the fusion plasmid indicated that the fusion event presumably plays a potential role in the dissemination of mcr-1.

18.
Anal Chem ; 91(16): 10541-10548, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31313574

RESUMO

The photothermally induced resonance AFM-IR technique (denoted as PTIR) is a promising and still developing analytical method that can provide nanoscale chemical and topographical information. Herein, by taking advantage of a customized PTIR system with either top-down or bottom-up incidence mode for a quantum cascade laser (QCL), we explore how the surface-enhanced IR absorption (SEIRA) effect due to the Au-coated AFM tip and/or substrate may affect the PTIR signals from 25 to 580 nm thick p-nitrobenzoic acid (PNBA) samples, as a function of sample thickness, incidence mode, laser polarization, and Au film morphology. By analysis of the νas(NO2) band intensity, it is revealed that the SEIRA effect may increase the PTIR signals by 1.5-8.3 times, with that from the Au-coated substrate being greater than that from the Au-coated tip. Nevertheless, the overall PTIR signal goes up monotonically over the entire thickness range for the top-down incidence mode, while it increases and then decreases with the sample thickness for the bottom-up incidence mode. The p-polarized laser enhances the PTIR signal more than does the s-polarized laser, especially on the Au-coated substrate. The significant loss of the PTIR signal of a PNBA sample corroborates the substantial loss of the SEIRA effect of an annealed Au film. The present work may promote the application of the SEIRA effect to the PTIR technique and provides hints for developing the PTIR technique into a more versatile analytical tool.

20.
Neuroendocrinology ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31261148

RESUMO

BACKGROUND: Serine/threonine kinase 33 (STK33) has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in pancreatic neuroendocrine tumour (PNET) and the underlying mechanisms. METHODS: PNET specimens and adjacent non-tumorous pancreatic tissues from 84 patients who underwent curative surgery for PNET were stained by immunochemistry for STK33. The relationships among STK33 expression, clinicopathological parameters and clinical prognosis were statistically analysed. MTT, scratching, transwell and apoptosis assays were employed to detect the effects of STK33 knockdown (siSTK33) or STK33 overexpression (pSTK33) on major oncogenic properties of cells of two PNET cell lines (BON and QGP-1), and real-time PCR and western blot were used to examine the expression of relevant genes. RESULTS: Relative to its expression in normal pancreatic tissue, STK33 was over-expressed in PNET specimens. Furthermore, STK33 expression was significantly associated with WHO classification (P < 0.001), AJCC stage (P < 0.001), lymph node metastasis (P < 0.001), tumour size (P = 0.022), sex (P = 0.003), perineural invasion (P < 0.001), and shorter disease free survival of patients with PNET (P < 0.001). Enforced STK33 expression promoted PNET cell proliferation, migration, and invasion and tumour growth and inhibited cell apoptosis, whereas STK33 depletion exerted the opposite effects. Mechanistic studies revealed that STK33 promoted growth and progression of PNET via activation of the PI3K/AKT/mTOR pathway. CONCLUSIONS: STK33 plays important roles in the tumour growth and progression of PNET via activation of the PI3K/AKT/mTOR pathway and has potential as a therapeutic target to improve PNET treatment.

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