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1.
Chem Commun (Camb) ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31912821

RESUMO

A photothermal and immune co-therapy strategy based on natural melanin nanoparticles was developed for treating primary and abscopal breast cancers.

2.
Mol Cancer ; 19(1): 3, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906946

RESUMO

BACKGROUND: Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. METHODS: qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. RESULTS: Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. CONCLUSIONS: Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.

3.
Cancer Lett ; 474: 15-22, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31917160

RESUMO

The gut microbiota forms a symbiotic relationship with the host and benefits the body in many critical aspects of life. However, immune system defects, alterations in the gut microbiota and environmental changes can destroy this symbiotic relationship and may lead to diseases, including cancer. Due to the anatomic and functional connection of the gut and liver, increasing studies show the important role of the gut microbiota in the carcinogenesis of hepatocellular carcinoma (HCC). In this manuscript, we review the available evidence and analyze some potential mechanisms of the gut microbiota, including bacterial dysbiosis, lipopolysaccharide (LPS), and genotoxins, in the progression and promotion of HCC. Furthermore, we discuss the possible therapeutic applications of probiotics, chemotherapy modulation, immunotherapy, targeted drugs and fecal microbiota transplantation (FMT) in targeting the gut microbiota.

4.
Anal Chem ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31927942

RESUMO

Cerebral ischemia reperfusion injury (CIRI) is closely related to lipid peroxidation. Malondialdehyde (MDA), as a biomarker of lipid peroxidation, is prone to addition with biomacromolecules, resulting in the secondary cerebral injury. However, desirable tools for in vivo determining cerebral MDA are scarce. Thus, we devised an innovative polymer carbon dots carbonized by benzoyl hydrazine and named it BH-PCDs. BH-PCDs covered with hydrazine groups, directly forming in one-pot. The functional nanoparticle specifically identifies MDA via photo-induced electron transfer (PET) mechanism from other similar biological species, especially reactive carbonyl species. BH-PCDs afforded several valuable traits of a simple preparation, large two-photon absorption cross-section, exceptional biocompatibility, as well as the ability of traversing blood brain barrier. Relying on BH-PCDs, we real-time portrayed the increased cerebral MDA under CIRI. Furthermore, combining with a commercial indicator of superoxide anion (O2•-), O2•- regulated MDA level under CIRI was visualized in vivo. Moreover, we demonstrated MDA inactivated glutamine synthetase under CIRI, mediating glutamate level. Overall, we provide a perspective nanolight serviceable for treating CIRI and revealing the physiopathology mechanism of brain MDA in future.

5.
Aging (Albany NY) ; 12(1): 825-843, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31929112

RESUMO

BACKGROUND: The correlation between superoxide dismutase 2 (SOD2) V16A variant and urological cancer susceptibility has been widely studied, however, with divergent results. RESULTS: Totally, 9,910 cancer patients and 11,239 control subjects were enrolled. V16A variant is associated with an increased susceptibility to urological cancer (A-allele vs. V-allele: OR = 1.06, 95% CI = 1.00 - 1.13, P = 0.047; AA+AV vs. VV: OR = 1.09, 95% CI = 1.02 - 1.16, P = 0.008), especially for prostate cancer (PCa). Serum SOD2 level of PCa patients with VV+VA genotypes was lower than in those with AA genotypes. SOD2 expression is downregulated in both prostate and bladder cancer, as compared to the control. Furthermore, SOD2 was found to be downregulated in more advanced PCa participants, as compared to the ones in early stages. PCa subjects with low SOD2 expression displayed a shorter disease-free survival (DFS) time compared to that of the high SOD2 expression counterparts. CONCLUSIONS: The SOD2 V16A variant may be associated with increased urological cancer susceptibility, especially for prostate cancer. METHODS: A pooled analysis utilizing odds ratios (ORs), in silico tools and ELISA was adopted to demonstrate this association. We also used immunohistochemical staining (IHS) to assess SOD2 expression.

6.
Pancreas ; 49(1): 111-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31856086

RESUMO

OBJECTIVES: The mechanisms underlying pathogenesis of acute pancreatitis (AP) are still not completely understood. An early, critical feature of AP is aberrant calcium (Ca) signaling, termed Ca overload, within pancreatic acinar cells. This study aimed to develop a model system in rats for AP induction to study the contribution of the Na-Ca exchanger 1 (NCX1) ion channel in AP pathogenesis. METHODS: To establish a rat model of AP induction, cerulein or L-arginine were intraperitoneally injected and tissue was histologically analyzed by hematoxylin and eosin staining. A cell culture-based model for AP induction was similarly created through cerulein treatment of AR42J cells. Induction of AP was also examined following exposure to the NXC1-targeted inhibitor KB-R7943. The expression of each gene was detected by Western blotting, immunofluorescence, immunohistochemistry, or quantitative reverse transcription polymerase chain reaction. Transcriptional regulation by nuclear factor (NF)-κB was detected using an NCX1 promoter-fusion dual luciferase reporter system. Cytosolic Ca was measured using a fluorescent calcium indicator. RESULTS: We found that cerulein induced NCX1 expression via activation of nuclear factor NF-κB, which potentially binds to the NCX1 promoter to induce its transcription. CONCLUSIONS: Our findings reveal a regulatory pathway through NF-κB/NCX1 governing Ca overload in AP development, thus providing potential targets for AP treatment.

7.
Anal Chem ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820623

RESUMO

Drug-induced liver injury (DILI) can cause liver failure and even death in severe cases, gravely threatening human health. The treatment of DILI remains a clinical challenge, mainly due to the lack of efficient and accurate diagnosis. Therefore, developing accurate diagnosis approach is imperative to boost the timely treatment for DILI. As the primary organ of iron storage, liver's functions are tightly linked to iron homeostasis. Thus, monitoring iron homeostasis is promising for the diagnosis and treatment of DILI. Hence, we reported a new near-infrared fluorescent probe (LCy7) that enables real-time and in vivo visualizing of Fe2+ in drug-induced liver injury. In this design, Fe2+ would bind to the N4O ligand in LCy7 and conduce to the C-O bond broken in the presence of O2, which restore the masked QCy7 emitting luminous near-infrared fluorescence. Utilizing LCy7, the increase in Fe2+ was distinctly witnessed in hepatocytes under endoplasmic reticulum stress by acetaminophen (APAP) stimulation. In vivo near-infrared fluorescence imaging revealed the conspicuous rise in Fe2+ in the liver of mice during APAP-induced liver injury. We further unprecedentedly disclosed that endoplasmic reticulum stress was accompanied with the overload of Fe2+ in injured liver of these mice. Collectively, this work will facilitate a greater understanding of the pathogenesis of DILI, and also provide a powerful new tool for DILI diagnosis and treatment.

8.
J Mol Biol ; 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31821812

RESUMO

Prion diseases, such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, are fatal neurodegenerative diseases that affect many mammals including humans, and are caused by the misfolding of prion protein (PrP). A naturally occurring protective polymorphism G127V in human PrP has recently been found to greatly attenuate prion diseases, but the mechanism has remained elusive. We herein report that the hydrophobic chain introduced in G127V significantly inhibits amyloid fibril formation by human PrP, highlighting the protective effect of the G127V polymorphism. We further introduce an amino acid with a different hydrophobic chain (Ile) at the same position and find that G127I has similar protective effects as G127V. Moreover, we show that these two neutralizing mutations, G127V and G127I, significantly decrease the human PrP cytotoxicity resulting from PrP fibril formation, mitochondrial damage, and elevated ROS production enhanced by a strong prion-prone peptide PrP 106-126. These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases.

9.
Exp Ther Med ; 18(6): 4740-4746, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31798703

RESUMO

Bosentan is an effective drug for the treatment of pulmonary arterial hypertension (PAH). The aim of the present meta-analysis was to examine the evidence concerning the efficacy and safety of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type 5 (PDE-5) inhibitors for treating PAH. Eligible published studies were collected from Embase, PubMed, The Cochrane Library and the www.clinicaltrials.gov website. Heterogeneity was assessed using the Cochran Q-statistic test. Results were presented as risk ratios or mean differences with 95% confidence intervals (CI). A total of five studies, comprising 310 patients were included for analysis. No significant improvements in six-minute walk distance (6MWD; mean difference, 16.43 m), clinical worsening (risk ratio, 0.54) and the World Health Organization functional classification (class I: risk ratio, 1.17; class II: risk ratio, 1.18) were observed in patients treated with bosentan in combination with prostacyclin analogues or PDE-5 inhibitors. However, a significant reduction in the mean pulmonary artery pressure (mPAP; 95% CI: -17.06, -6.83; P<0.0001) following bosentan combination therapy was observed. Comparisons of adverse event rates in the bosentan combination therapy (55.6%) and monotherapy (51.8%) suggested that there is no reduction in adverse events (risk ratio, 1.10). The results indicated that bosentan combined with prostacyclin analogues or PDE-5 inhibitors may not improve 6MWD, cardiac function, clinical worsening and adverse events. However, bosentan combined with prostacyclin analogues or PDE-5 inhibitor therapy was able to significantly reduce mPAP compared with the effect of bosentan monotherapy.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31825209

RESUMO

Hydroxide ion (OH-) adsorption process is critical for accelerating the half-reactions of both metal-air batteries and direct methanol fuel cells in alkaline media. This study designs a rational catalyst/co-catalyst by constructing the readily-available OH- adsorption sites to boost oxygen evolution reaction (OER) and methanol oxidation reaction (MOR). Cobalt selenide coated nickel selenide nano-rods are in-situ grown on nickel foam to obtain CoSe/NiSe-nrs/NF via a one-pot solvothermal synthesis route. CoSe-0.2/NiSe-nrs/NF (Co/Ni molar ratio of 0.26) exhibits an excellent OER activity (overpotential of 310 mV at 100 mA cm-2 and tafel slope of 58.3 mV dec-1). The differently-oriented CoSe/NiSe-nrs with velutipes-like structure and metallic property provide a promising electrical conductivity for charge transfer. In situ X-ray diffraction tests verify the crystallization of active ß-NiOOH during OER, and the crystallized NiOOH/CoOOH contributes to the excellent OER cycling stability in alkaline media. Synergistic effects between CoSe and NiSe-nrs/NF can balance the formation of NiOOH/CoOOH heterostructures to govern the exposure of available active sites. NiOOH/CoOOH as highly active component can energetically adsorb OH- to promote OER. CoSe/NiSe-nrs/NFs as a low Pt-loading (0.5 wt.%) support offer the mutually beneficial interactions for promoting co-catalytic and COads (poisonous intermediate) co-oxidation activities towards MOR. Electrochemically active surface area and mass activity of Pt/CoSe-0.2/NiSe-nrs/NF are 85 m2 gpt-1 and 1437.1 mA mgpt-1, respectively, which are much higher than those of commercial Pt/C (10.0 wt.%). OH- absorbed on NiOOH/CoOOH structure eliminates COads on Pt surface via bi-functional mechanisms to improve MOR activity. This study provides a promising reference for designing the versatile catalysts for energy conversion.

11.
Chem Commun (Camb) ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829350

RESUMO

We report a cancer cell membrane-camouflaged nanoreactor based on a GOx decorated TiO2@MnO2 core-shell structure for enhanced radiotherapy against cancer metastasis. The nanoreactor could specifically target tumor tissues, catalytically oxidize glucose to generate H2O2, and generate abundant ROS under X-ray irradiation.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31865025
13.
Chem Commun (Camb) ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31850458

RESUMO

A homotypic cancer cell membrane camouflaged MOF-based nanoreactor with the photothermal-starvation effect has been developed for synergistic suppression of intracellular defensive systems for enhanced cancer treatment.

14.
J Mater Chem B ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31850470

RESUMO

A novel dual-targeted CeO2-DNA nanosensor by modifying with folic acid (FA) and CD36 antibody was designed. This fluorescent nanosensor enables noninvasive imaging of alterations in H2O2 in vitro and in vivo with good sensitivity and selectivity, accurately evaluating the inflammation level and providing early warning of plaque vulnerability.

15.
Mol Cancer ; 18(1): 185, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31849331

RESUMO

BACKGROUND: Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies. Aberrant expression of CBX8 has been identified in many types of cancer, but the cause of this aberrant CBX8 expression and whether CBX8 is associated with stemness properties in CC remain unknown. METHODS: qRT-PCR and IHC were applied to examine CBX8 levels in normal and chemoresistant CC tissues. Cancer cell stemness and chemosensitivity were evaluated by spheroid formation, colony formation, Western blot and flow cytometry assays. RNA-seq combined with ChIP-seq was used to identify target genes, and ChIP, IP and dual luciferase reporter assays were applied to explore the underlying mechanisms. RESULTS: CBX8 was significantly overexpressed in chemoresistant CC tissues. In addition, CBX8 could promote stemness and suppress chemosensitivity through LGR5. Mechanistic studies revealed that CBX8 activate the transcription of LGR5 in a noncanonical manner with assistance of Pol II. CBX8 recruited KMT2b to the LGR5 promoter, which maintained H3K4me3 status to promote LGR5 expression. Moreover, m6A methylation participated in the upregulation of CBX8 by maintaining CBX8 mRNA stability. CONCLUSIONS: Upon m6A methylation-induced upregulation, CBX8 interacts with KMT2b and Pol II to promote LGR5 expression in a noncanonical manner, which contributes to increased cancer stemness and decreased chemosensitivity in CC. This study provides potential new therapeutic targets and valuable prognostic markers for CC.

16.
Opt Express ; 27(24): 35349-35361, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31878705

RESUMO

We study the correlations between the driving signal reflection on the traveling wave electrodes and the modulated signal characteristics of silicon Mach-Zehnder modulators (MZM). Correlation coefficients are introduced for systematic and quantitative analysis. The signal-to-noise ratio, extinction ratio, and bit error rate show similar correlation behaviors with the mean reflection magnitude over proper frequency ranges, whereas the correlation behaviors of the temporal parameters can be complex. Partial correlation coefficients can be introduced to help remove the influence of other factors. Some relevant fabrication variation scenarios in the underlying structures are discussed, and potential approaches to mitigating the effects of such variations are suggested.

17.
J Vis Exp ; (152)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31710030

RESUMO

Manual vascular reconstruction training is essential for a beginner surgeon. However, an optimal training system for vascular reconstruction in vitro has yet to be developed. In this study, we introduce an in vitro training and testing system using a magnetic anchoring technique with which a trainee can practice manual vascular reconstruction individually. Additionally, this system can also be used to test the quality of the reconstruction. The described system includes a vascular reconstruction training machine, magnetic tractors, and a magnetic suture puller. In this manuscript, we detail an end-to-end vein anastomosis using porcine right and left iliac veins. To identify the potential damage caused by a magnetic suture puller on the suture, we created three groups with six segments of 4-0 polypropylene sutures each: a control group with no intervention on the polypropylene suture, a group in which the polypropylene suture is manually pulled with sterile gloves 20x, and a magnetic puller group in which the magnetic puller pulled the polypropylene suture 20x. These groups were tested by light microscopy and breaking strength tests, and the effect of reconstruction was assessed. In the light microscopy test, the control group was less likely to be damaged (p < 0.05) and the number of damaged points of the manual group and magnetic puller group were similar (p > 0.05). The results of the breaking strength test were compared across groups and no significant difference was observed (p > 0.05). The end-to-end anastomosis of the porcine iliac veins was successfully performed using this training system, and the reconstructed veins could undergo 2.0 kPa perfusion pressure. Using this training and testing system the trainee can practice manual vascular reconstruction in vitro individually with the aid of magnetic tractors and a magnetic suture puller, and the quality of the reconstruction can be tested.

18.
Hematol Oncol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31701557

RESUMO

Immortalized cell lines are useful for deciphering the pathogenesis of acute leukemia and developing novel therapeutic agents against this malignancy. In this study, a new human myeloid leukemia cell line YBT-5 was established. After more than 1-year cultivation from the bone marrow of a patient with acute monocytic leukemia, YBT cell line was established. Then a subclone, YBT-5, was isolated from YBT using single cell sorting. Morphological and cytogenetical characterizations of the YBT-5 cell line were determined by cytochemical staining, flow cytometry analysis, and karyotype analysis. Molecular features were identified by transcriptomic analysis and reverse transcription-polymerase chain reaction. To establish a tumor model, 5 × 106 YBT-5 cells were injected subcutaneously in nonobese diabetic/severe combined immune-deficiency (NOD/SCID) mice. DOT1L has been proposed as a potential therapeutic target for KMT2A-related leukemia; therefore, to explore the potential application of this new cell line, its sensitivity to a specific DOT1L inhibitor, EPZ004777 was measured ex vivo. The growth of YBT-5 does not depend on granulocyte-macrophage colony-stimulating factor. Cytochemical staining showed that α-naphthyl acetate esterase staining was positive and partially inhibited by sodium fluoride, while peroxidase staining was negative. Flow cytometry analysis of YBT-5 cells showed positive myeloid and monocytic markers. Karyotype analysis of YBT-5 showed 48,XY,+8,+8. The breakpoints between KMT2A exon 10 and exon 11 (KMT2A exon 10/11) and MLLT3 exon 5 and exon 6 (MLLT3 exon 5/6) were identified, which was different from all known breakpoint locations, and a novel fusion transcript KMT2A exon 10/MLLT3 exon 6 was formed. A tumor model was established successfully in NOD/SCID mice. EPZ004777 could inhibit the proliferation and induce the differentiation of YBT-5 cells. Therefore, a new acute monocytic leukemia cell line with clear biological and molecular features was established and may be used in the research and development of new agents targeting KMT2A-associated leukemia.

19.
Dalton Trans ; 48(48): 17763-17769, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31773120

RESUMO

Covalent organic frameworks (COFs) have been utilized as molecular sieves to adsorb or remove or separate a wide range of substances. Herein, a new carboxyl-containing COF (COF-COOH) is fabricated from the polymerization of 1,3,5-triformylphloroglucinol (TP) and 4,4'-diamino-[1,1'-biphenyl]-3,3'-dicarboxylic acid (DBA). COF-COOH displays good adsorption performance on Congo red (CR) through hydrogen bonds and π-π stacking interactions. Through post-modification with Ca2+/Ni2+ ions, the adsorption capacity of COF-COOCa/COF-COONi to CR is improved, which is due to the coordinated metal cations having a positive contribution to the electrostatic interactions. At 25 °C, the maximum adsorption amount of COF-COOCa and COF-COONi to CR is 704.23 mg g-1 and 781.25 mg g-1, respectively. The removal efficiency of COF-COOCa to CR is 95% and that of COF-COONi is 96%. This demonstrates that the new metal ion-assisted COFs are viable adsorbents to remove dye pollutants, which are harmful to the environment and to human health, from wastewater.

20.
ACS Appl Mater Interfaces ; 11(48): 44999-45006, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31714050

RESUMO

High recurrence and metastasis rates are the major causes of the high mortality of hepatocellular carcinoma (HCC). Circulating tumor cells (CTCs) disseminating into the bloodstream play an essential role in cancer metastasis. However, since HCC-CTCs are extremely rare, limitations of current detection methods impede accurate discerning of HCC-CTCs under complicated biological context. Here, a dual-targeting functionalized reduced graphene oxide film (DTFGF) for specifically identifying HCC-CTCs was created via coinstantaneous targeting epithelial cell adhesion molecule (EpCAM) and HCC cell-specific asialoglycoprotein receptor (ASGPR). Anti-EpCAM antibodies and galactose-rhodamine-polyacrylamide nanoparticles (Gal-Rh-PAA NPs) specifically recognizing ASGPR are modified on the surface of a graphene film that quenches the rhodamine fluorescence. HCC-CTCs can be captured by anti-EpCAM antibodies and endocytose Gal-Rh-PAA NPs, recovering the rhodamine fluorescence. Profiting from the accuracy of dual-targeting, less handling steps, and high resolution of fluorescence imaging, a simple, rapid, and low-cost HCC-CTC enumeration method is established with excellent sensitivity and selectivity than conventional methods. Using DTFGFs, as low as five HCC-CTCs were detected in a 1 mL blood sample. Further results revealed that larger HCC-CTC quantities indicate more advanced stages of HCC in patients. Overall, this work holds great promise for the early diagnosis, prognosis, and therapeutic evaluation of HCC.

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