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1.
Chem Commun (Camb) ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475103

RESUMO

A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97 : 3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.

2.
Bioorg Med Chem ; 32: 115999, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33444848

RESUMO

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC50 values of 0.64 and 0.63 µM, which were better than that of gemcitabine (1.40 µM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.

3.
Ying Yong Sheng Tai Xue Bao ; 32(1): 261-270, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33477234

RESUMO

The rapid urbanization has greatly changed the spatial pattern and function of regional habitats, profoundly affected the material flow and energy flow between habitats, and also posed a serious threat to habitats and biodiversity. Here, we used InVEST model, landscape index and multiple linear regression to systematically analyze the spatial and temporal variation and influencing factors for the impacts of urbanization on habitat quality in the Loess Plateau and the densely populated areas from 1990 to 2018. The results showed that the urban expansion of Loess Plateau significantly affected habitat quality. Between 1990 and 2018, the area of construction land increased by 49.6%, resulting in a 5.2% reduction in the total area of habitat patch. After 2010, the urban patch area increased, but the patch density and fragmentation decreased, resulting in a spatial pattern of "high outside and low inside" for urban habitat quality. The rate of urban expansion in densely populated areas was significantly negatively correlated with the habitat quality. The average value of habitat quality in the region dropped by 2.7%, whereas the level of habitat degradation increased by 33.4%. The level of habitat quality was unstable, and patches with high-level habitats were easily converted to lower level. The conversion rates of Lanzhou, Xi'an-Xianyang and Taiyuan were 12.9%, 2.9% and 1.7%, respectively. There were eight influencing factors that could effectively explain the spatial variation of habitat quality (R2=68.7%). Among those factors, population density and distance to roads were the main factors for the fragmentation of habitats, while slope, GDP and precipitation had positive effects on the optimization of habitat spatial patterns.

4.
Theranostics ; 11(2): 878-892, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391510

RESUMO

Purpose: To identify extracellular vesicle (EV)-delivered microRNAs in the patient's serum as indicators for bone-metastatic prostate cancer. Methods: First, the profiling change of serum EV-delivered miRNAs in patients with either benign prostatic hyperplasia (BPH), non-bone metastatic prostate cancer or bone-metastatic prostate cancer was detected by microRNA deep sequencing assay and microRNA-chip array assay, respectively. Second, the candidates were further confirmed using TaqMan microRNA assay in two independent validation cohorts of total 176 patients with either BPH, non-bone metastatic prostate cancer or bone metastatic prostate cancer to seek the most valuable microRNA(s). Results: Through microRNA deep sequencing and microRNA-chip array, we found 4 prospective EV-delivered miRNAs including miR-181a-5p with significantly upregulated expression in bone metastatic groups than in non-bone metastatic prostate cancer groups (p < 0.05). In the validation cohorts, logistic regression analysis was performed to evaluate the diagnostic association of candidates with bone metastasis, which indicated that miR-181a-5p was significantly associated with bone metastatic prostate cancer. Furthermore, accuracy estimate of each candidate for the diagnosis of bone metastatic prostate cancer was quantified using the area under the receiver-operating characteristic curve (AUC), which identified miR-181a-5p as the best biomarker with the AUCs of 85.6% for diagnosis of prostate cancer and 73.8% for diagnosis of bone metastatic prostate cancer. Conclusion: EV-delivered miR-181a-5p from patient's serum is a promising diagnostic biomarker for bone metastatic prostate cancer.

5.
Adv Healthc Mater ; : e2001953, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33448140

RESUMO

Probiotics are closely related to human health. However, it is hard to find an appropriate disintegration mode for encapsulation to balance the survival, release, and adhesion of probiotics simultaneously during the current colon-targeted oral delivery, which leads to limited colonization. In this study, an enzyme-triggered fuse-like microcapsule is constructed using alginate and protamine via the electrostatic droplet combined with the layer by layer self-assembly. The multilayer microcapsule can protect the probiotics in the stomach and disintegrate layer by layer under the catalysis of trypsin in the intestine. The formulation with two protamine layers showed the best protection for Escherichia coli MG1655 (EM) during the oral delivery; as well the minimal release at the gastric pH value but a burst release after 1 h at the intestinal pH value. In particular, the adhesion strength of EM is improved with the increase of the layer number. In vivo experiments demonstrate that the EM enters into the stationary phase within 12 h in the colon. Moreover, the blood biochemistry and histological analysis demonstrates the safety of the microcapsule formulation. It can be concluded that this microcapsule can help the probiotics survive during the delivery, then release and colonize in the colon.

6.
Sci Total Environ ; 750: 142308, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33182201

RESUMO

Compared to homogeneous soils, soil heterogeneity is thought to promote plant species diversity through niche differentiation. The number of patch types within the heterogeneous soil (i.e. the difference in soil configurational heterogeneity) may also play a key role in regulating plant diversity. However, most empirical studies examining heterogeneity-diversity relationships involved only two contrasting types of patches. Moreover, the shape of heterogeneity-diversity relationships may also be changed by background soil fertility. To test how soil heterogeneity and number of patch types within the heterogeneous soil influence plant community evenness and their potential dependence on background soil fertility, we constructed plant communities consisting of four plant species in low- and high-nutrient soils, and manipulated the soils in heterogeneous configurations consisting of two or four types of soil patches and in a homogeneous condition where these soil patches were homogenized. Neither evenness of the plant community nor the difference in competitive ability between plants within the community was significantly different between the homogeneous soil and the heterogeneous soils, suggesting that soil heterogeneity overall had no effect on community evenness. However, evenness was higher and the difference in competitive ability between plants was lower in the heterogeneous soils with four types of soil patches than in the heterogeneous soils with two types of soil patches and also in the low-nutrient soils than in the high-nutrient soils. These results suggest that lowering soil fertility and increasing soil configurational heterogeneity can promote plant community evenness through reducing the difference in competitive ability between plant species within the community.


Assuntos
Plantas , Solo , Microbiologia do Solo
7.
Nat Methods ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288960

RESUMO

Circular RNAs (circRNAs) produced from back-spliced exons are widely expressed, but individual circRNA functions remain poorly understood owing to the lack of adequate methods for distinguishing circRNAs from cognate messenger RNAs with overlapping exons. Here, we report that CRISPR-RfxCas13d can effectively discriminate circRNAs from mRNAs by using guide RNAs targeting sequences spanning back-splicing junction (BSJ) sites featured in RNA circles. Using a lentiviral library that targets sequences across BSJ sites of highly expressed human circRNAs, we show that a group of circRNAs are important for cell growth mostly in a cell-type-specific manner and that a common oncogenic circRNA, circFAM120A, promotes cell proliferation by preventing the mRNA for family with sequence similarity 120A (FAM120A) from binding the translation inhibitor IGF2BP2. Further application of RfxCas13d-BSJ-gRNA screening has uncovered circMan1a2, which has regulatory potential in mouse embryo preimplantation development. Together, these results establish CRISPR-RfxCas13d as a useful tool for the discovery and functional study of circRNAs at both individual and large-scale levels.

8.
Med Hypotheses ; : 110327, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33277104

RESUMO

Stroke is associated with high mortality and extremely high disability rate. Regulating ferroptosis seems to be a promising way to treat ischemic stroke. After stroke, vasogenic edema exerts a mechanical force on surrounding structures, which could activate the mechanosensitive PIEZO1 channel. Our previous research has found that brain cortex PIEZO1 expression was increased in the rat model of middle cerebral artery occlusion (MCAO), and PIEZO1 regulated oxygen-glucose deprivation/reoxygenation (OGD/R) injury in neurons through the calcium signaling. Considering recent studies has identified HIF1α as an essential protein in PIEZO1/calcium signaling, ferroptosis regulation and cerebral ischemia, we herein hypothesize that PIEZO1 might be involved in cerebral ischemia-reperfusion injury through ferroptosis regulation.

9.
J Integr Plant Biol ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33325122

RESUMO

In eukaryotes, MEDIATOR is a conserved multi-subunit complex that links transcription factors and RNA polymerase II and that thereby facilitates transcriptional initiation. Although the composition of MEDIATOR has been well studied in yeast and mammals, relatively little is known about the composition of MEDIATOR in plants. By affinity purification followed by mass spectrometry, we identified 28 conserved MEDIATOR subunits in Arabidopsis thaliana, including putative MEDIATOR subunits that were not previously validated. Our results indicated that MED34, MED35, MED36, and MED37 are not Arabidopsis MEDIATOR subunits, as previously proposed. Our results also revealed that two homologous CBP/p300 histone acetyltransferases, HAC1 and HAC5 (HAC1/5) are in fact plant-specific MEDIATOR subunits. The MEDIATOR subunits MED8 and MED25 (MED8/25) are partially responsible for the association of MEDIATOR with HAC1/5., MED8/25 and HAC1/5 co-regulate gene expression and thereby affect flowering time and floral development. Our in vitro observations indicated that MED8 and HAC1 form liquid-like droplets by phase separation, and our in vivo observations indicated that these droplets co-localize in the nuclear bodies at a subset of nuclei. The formation of liquid-like droplets is required for MED8 to interact with RNA polymerase II. In summary, we have identified all of the components of Arabidopsis MEDIATOR and revealed the mechanism underlying the link of histone acetylation and transcriptional regulation. This article is protected by copyright. All rights reserved.

10.
Cytotherapy ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33334686

RESUMO

BACKGROUND AIMS: Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment strategy in solid tumors. In vivo cell tracking techniques can help us better understand the infiltration, persistence and therapeutic efficacy of CAR T cells. In this field, magnetic resonance imaging (MRI) can achieve high-resolution images of cells by using cellular imaging probes. MRI can also provide various biological information on solid tumors. METHODS: The authors adopted the amino alcohol derivatives of glucose-coated nanoparticles, ultra-small superparamagnetic particles of iron oxide (USPIOs), to label CAR T cells for non-invasive monitoring of kinetic infiltration and persistence in glioblastoma (GBM). The specific targeting CARs included anti-human epidermal growth factor receptor variant III and IL13 receptor subunit alpha 2 CARs. RESULTS: When using an appropriate concentration, USPIO labeling exerted no negative effects on the biological characteristics and killing efficiency of CAR T cells. Increasing hypointensity signals could be detected in GBM models by susceptibility-weighted imaging MRI ranging from 3 days to 14 days following the injection of USPIO-labeled CAR T cells. In addition, nanoparticles and CAR T cells were found on consecutive histopathological sections. Moreover, diffusion and perfusion MRI revealed significantly increased water diffusion and decreased vascular permeability on day 3 after treatment, which was simultaneously accompanied by a significant decrease in tumor cell proliferation and increase in intercellular tight junction on immunostaining sections. CONCLUSION: These results establish an effective imaging technique that can track CAR T cells in GBM models and validate their early therapeutic effects, which may guide the evaluation of CAR T-cell therapies in solid tumors.

11.
Commun Biol ; 3(1): 778, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328604

RESUMO

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

12.
Zhongguo Zhong Yao Za Zhi ; 45(21): 5219-5225, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350238

RESUMO

This study aimed to clarify the microbial diversity, dominant species and the change of community structures in the fermentation of Liushenqu(Massa Medicata Fermentata), and explore the material foundation of its pharmacodynamics effect. On the basis of standardizing the fermentation process, Massa Medicata Fermentata was prepared by screening and optimizing the recipes and the standard formula issued by the Ministry. The community structure and growth process of fungi and bacteria in the samples at five time points(0, 17, 41, 48, 65 h) in the fermentation process of Massa Medicata Fermentata were analyzed by using isolation and culture of eight different media and high-throughput DNA sequencing technology. The results indicated that the samples of the two recipes pre-sented high microbial diversity at the initial fermentation stage, with Aspergillus spp. as the dominant species. As the fermentation process goes forward, Saccharomycopsis fibuligera and Rhizopus oryzae soon became dominant species from 17 h after fermentation commencement point to the fermentation end, while the other species were inhibited at a lower level from 17 h. The species diversity of bacteria in the initial fermentation samples was also high, and Enterobacter was the dominant species. Enterobacter cloacae, Pediococcus pentosaceus and Cronobacter sakazakii became dominant bacterial species 17 h after fermentation commencement, while the species diversity was decreased. Our results will be a scientific basis for promoting the fermentation process of Massa Medicata Fermentata by using pure microbial cultures.


Assuntos
Medicamentos de Ervas Chinesas , Microbiota , Fermentação , Fungos/genética , Saccharomycopsis
13.
Fitoterapia ; 149: 104804, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33309970

RESUMO

A series of novel myricetin derivatives containing benzimidazole skeleton were constructed. The structure of compound 4g was further corroborated via X-ray single crystal diffractometer. The antimicrobial bioassays showed that all compounds exhibited potent inhibitory activities against Xanthomonas axonopodis pv. Citri (Xac), Ralstonia solanacearum (Rs) and Xanthomonas oryzae pv. Oryzae (Xoo) in vitro. Significantly, compound 4q showed the best inhibitory activities against Xoo, with the EC50 value of 8.2 µg/mL, which was better than thiodiazole copper (83.1 µg/mL) and bismerthiazol (60.1 µg/mL). In vivo experimental studies showed that compound 4q can treat rice bacterial leaf blight at 200 µg/mL, and the corresponding curative and protection efficiencies were 45.2 and 48.6%, respectively. Meanwhile, the antimicrobial mechanism of the compounds 4l and 4q were investigated through scanning electron microscopy (SEM). Studies showed that compounds 4l or 4q can cause deformation or rupture of Rs or Xoo cell membrane. These results indicated that novel benzimidazole-containing myricetin derivatives can be used as a potential antibacterial reagent.

14.
Mol Pharm ; 17(12): 4603-4615, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33175556

RESUMO

Cancer nanovaccines have been widely explored to enhance immunotherapy efficiency, in which the significant irritation of antigen-specific cytotoxic T cells (CTLs) is the critical point. In this study, we developed a pH and reduction dual-sensitive nanovaccine (PMSN@OVA-MPN) composed of two parts. The inner part was made up of polyethyleneimine (PEI)-modified mesoporous silica nanoparticles (MSNs) loaded with model antigen ovalbumin (OVA) and the outer part was made up of disulfide bond-involved metal-phenolic networks (MPNs) as a protective corona. In vitro release experiments proved that PMSN@OVA-MPN could intelligently release OVA in the presence of reductive glutathione, but not in neutral phosphate-buffered saline (PBS). Moreover, in vitro cell assays indicated that the nanovaccine promoted not only the OVA uptake efficiency by DC2.4 cells but also antigen lysosome escape due to the proton sponge effect of PEI. Furthermore, in vivo animal experiments indicated that PMSN@OVA-MPN induced a large tumor-specific cellular immune response so as to effectively inhibit the growth of an existing tumor. Finally, the immune memory effect caused by the nanovaccine afforded conspicuous prophylaxis efficacy in neonatal tumors. Hence, the multifunctional vaccine delivery system prepared in this work exhibits a great application potential in cancer immunotherapy and offers a platform for the development of nanovaccines.

15.
Medicine (Baltimore) ; 99(48): e23417, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33235121

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the top 10 malignant tumors worldwide and poses a great threat to human life and health, the prevention and treatment of which has become the focus and difficulty of medical research. With its unique advantages, traditional Chinese medicine (TCM) is widely used in the prevention and treatment of postoperative recurrence and metastasis of GC as well as the improvement of patients' quality of life. The aim of this study is to elucidate the curative effect and the underlying mechanism of Yiqi Huayu Jiedu (YQHYJD) decoction. METHODS/DESIGN: This is a prospective, multicenter, randomized controlled trial continuing 3 years. Two hundred ninety-eight eligible patients will be randomly divided into 2 groups, the chemotherapy combined with placebo and the chemotherapy combined with YQHYJD group at a ratio of 1:1. All patients will receive the treatment for 6 months and follow up for 3 years. The primary outcomes are disease-free survival, and 1-year, 2-year, 3-year progression-free survival rate, while the secondary outcomes are tumor makers, TCM syndrome score, quality of life score, overall chemotherapy completion rate, intestinal flora diversity test, immune function (T, B lymphocyte subsets and NK cells) test. The Security index includes blood, urine and stool routine, electrocardiogram, liver function (ALT), and renal function (BUN, Scr). All of these outcomes will be analyzed at the end of the trial. DISCUSSION: This research will provide the valuable evidence for the efficacy and safety of Yiqi Huayu Jiedu decoction in postoperative GC. Furthermore, it will be helpful to form a higher level of evidence-based medical basis for TCM in the treatment of GC recurrence and metastasis. TRIAL REGISTRATION: ChiCTR2000039038.

16.
Comput Biol Med ; 128: 104104, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33220590

RESUMO

BACKGROUND AND OBJECTIVE: To automatically identify and locate various types and states of the ureteral orifice (UO) in real endoscopy scenarios, we developed and verified a real-time computer-aided UO detection and tracking system using an improved real-time deep convolutional neural network and a robust tracking algorithm. METHODS: The single-shot multibox detector (SSD) was refined to perform the detection task. We trained both the SSD and Refined-SSD using 447 resectoscopy images with UO and tested them on 818 ureteroscopy images. We also evaluated the detection performance on endoscopy video frames, which comprised 892 resectoscopy frames and 1366 ureteroscopy frames. UOs could not be identified with certainty because sometimes they appeared on the screen in a closed state of peristaltic contraction. To mitigate this problem and mimic the inspection behavior of urologists, we integrated the SSD and Refined-SSD with five different tracking algorithms. RESULTS: When tested on 818 ureteroscopy images, our proposed UO detection network, Refined-SSD, achieved an accuracy of 0.902. In the video sequence analysis, our detection model yielded test sensitivities of 0.840 and 0.922 on resectoscopy and ureteroscopy video frames, respectively. In addition, by testing Refined-SSD on 1366 ureteroscopy video frames, the sensitivity achieved a value of 0.922, and a lowest false positive per image of 0.049 was obtained. For UO tracking performance, our proposed UO detection and tracking system (Refined-SSD integrated with CSRT) performed the best overall. At an overlap threshold of 0.5, the success rate of our proposed UO detection and tracking system was greater than 0.95 on 17 resectoscopy video clips and achieved nearly 0.95 on 40 ureteroscopy video clips. CONCLUSIONS: We developed a deep learning system that could be used for detecting and tracking UOs in endoscopy scenarios in real time. This system can simultaneously maintain high accuracy. This approach has great potential to serve as an excellent learning and feedback system for trainees and new urologists in clinical settings.

17.
J Agric Food Chem ; 68(49): 14426-14437, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33216530

RESUMO

The pyrazole-4-carboxamide scaffold containing a flexible amide chain has emerged as the molecular skeleton of highly efficient agricultural fungicides targeting succinate dehydrogenase (SDH). Based on the above vital structural features of succinate dehydrogenase inhibitors (SDHI), three types of novel pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether moiety were rationally conceived under the guidance of a virtual docking comparison between bioactive molecules and SDH. Consistent with the virtual verification results of a molecular docking comparison, the in vitro antifungal bioassays indicated that the skeleton structure of title compounds should be optimized as an N'-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide scaffold. Strikingly, N'-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide derivatives 11o against Rhizoctonia solani, 11m against Fusarium graminearum, and 11g against Botrytis cinerea exhibited excellent antifungal effects, with corresponding EC50 values of 0.14, 0.27, and 0.52 µg/mL, which were obviously better than carbendazim against R. solani (0.34 µg/mL) and F. graminearum (0.57 µg/mL) as well as penthiopyrad against B. cinerea (0.83 µg/mL). The relative studies on an in vivo bioassay against R. solani, bioactive evaluation against SDH, and molecular docking were further explored to ascertain the practical value of compound 11o as a potential fungicide targeting SDH. The present work provided a non-negligible complement for the structural optimization of antifungal leads targeting SDH.

18.
Hemoglobin ; : 1-5, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148073

RESUMO

Genetic recombination between homologous sequences on the human globin gene clusters can lead to the creation of fusion genes. In this study, we report the detection of an α-globin fusion gene by using real-time polymerase chain reaction (qPCR)-based multicolor melting curve analysis (MMCA). The carriers of this fusion gene had a mild α-thalassemia phenotype with a normal hemoglobin (Hb) value and borderline hematological indices. Sequence analysis revealed that the mutant gene was the result of a fusion between the α2 and ψα1 genes. Our results indicate that the MMCA has the ability to detect the fusion gene, which is helpful for genetic counseling in thalassemia prevalent areas.

19.
Arch Med Res ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33162186

RESUMO

INTRODUCTION: Osteosarcoma, the most prevalent primary malignancy of the bone, is often presented with high-grade subclinical metastatic disease that metastasizes at very early stages. Exosomes, as molecular information carriers, may play a potent role in the occurrence and development of tumors through oncogenic molecular reprogramming of tumor-associated macrophages (TAMs). In this study, we will investigate the effect of osteosarcoma-derived exosomes on the polarization of TAMs and decipher its underlying molecular mechanism. MATERIAL AND METHODS: Osteosarcoma-derived exosomes from MG63 cells were isolated and characterized by transmission electron microscopy, and nano-particle size analysis. Double fluorescence staining was performed to confirm the macrophages phagocytosis of exosomes. Western blot, qRT-PCR, and transwell assays were conducted to assess the effect of exosomes on migration, invasion, and macrophage differentiation. The mouse model of osteosarcoma was established to evaluate the effects of exosomes on lung metastasis in vivo. RESULTS: MG63 exosomes were successfully isolated and verified to be phagocytized by macrophages through fluorescence confocal microscopy. The results revealed that osteosarcoma cells could induce M2 type differentiation of macrophages largely through Tim-3 mediated by exosomes, which in turn could promote the migration, invasion, epithelial-mesenchymal transition (EMT), and lung metastasis of osteosarcoma cells through the secretion of cytokines including IL-10, TGF-ß, and VEGF. CONCLUSIONS: Our results demonstrated that osteosarcoma-derived exosomes induced M2 polarization of macrophages and promoted the invasion and metastasis of tumors through Tim-3; besides, the study also suggests a novel therapeutic target for future studies.

20.
Int J Biol Sci ; 16(16): 3200-3209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162825

RESUMO

Malignant glioma is the most common brain tumor in adults. Despite the great advances in anti-glioma treatments which have led to significant improvement in clinical outcomes, tumor recurrence remains the major cause of mortality. Increased cancer cell stemness and invasiveness are correlated with glioma progression. By searching the Cancer Genome Atlas, we showed that the expression of miR-7156-3p is significantly decreased in glioma tissues compared to the normal brain, and the decreased level of miR-7156-3p is closely correlated with glioma grade and patient survival. Clinical study consistently confirmed that miR-7156-3p is negatively correlated with glioma grade. Cell culture and animal experiments revealed that inhibition of miR-7156-3p effectively stimulates glioma cell stemness, invasion, and growth. In contrast, the augmentation of miR-7156-3p inhibits these phenotypes. Using Next-generation sequencing combined with target prediction approach, Homeobox D13 (HOXD13) is identified as the target gene of miR-7156-3p and further validated by luciferase reporter assay and cell transfection experiments. Additional in vitro and animal experiments demonstrated that miR-7156-3p regulates glioma cell stemness, invasion, and growth by mediating HOXD13. In conclusion, our findings provide new insight into the regulation of glioma stemness and invasiveness and may propose a potential strategy for anti-glioma treatment. Moreover, miR-7156-3p may serve as a candidate biomarker for predicting glioma progression in clinical practice.

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