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1.
Cancer Cell Int ; 21(1): 648, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863167

RESUMO

BACKGROUND: Osteosarcoma (OS) patients with lung metastasis have poor prognoses, and effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking. Hence, it is critical to elucidate the underlying mechanisms of OS metastasis and to identify additional new effective treatment strategies for patients. METHODS: Differential expression and functional analyses were performed to identify key genes and relevant signaling pathways associated with OS lung metastasis. The expression of CCR9 in OS cell lines and tissues was measured by RT-qPCR, western blotting and immunohistochemistry. Cell migration and invasion were assessed by wound healing and Transwell Matrigel invasion assays, respectively. The regulatory relationship between CCR9 and the Wnt/ß-catenin signaling pathway was further evaluated by rescue experiments. RESULTS: The expression of CCR9 was elevated in OS cell lines and patients with lung metastasis. CCR9 promoted MG63 and HOS cell migration and invasion by activating the Wnt/ß-catenin signaling pathway. Furthermore, knockdown of CCR9 repressed epithelial-mesenchymal transition (EMT) by downregulating mesenchymal markers (N-cadherin and Vimentin) and EMT-associated transcription factors (twist and snail) and upregulating an epithelial marker (E-cadherin). CONCLUSIONS: Our findings suggest that CCR9 promotes EMT by activating Wnt/ß-catenin pathways to promote OS metastasis. CCR9 may be a promising therapeutic target to inhibit lung metastasis and serve as a novel prognostic marker for OS.

2.
ACS Omega ; 6(50): 34989-35001, 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34963980

RESUMO

The adiabatic spontaneous combustion period of coal is an important index for the macroscopic characterization of coal spontaneous combustion, and it is affected by many internal and external factors. There are several methods to study it, but there are various shortcomings to these methods. Some require too much time, while others have too many interfering factors. To quickly obtain the accurate adiabatic spontaneous combustion period of coal, a rapid contrastive experimental method was designed. In this method, the coal samples of the experimental and control groups were the same, and air and nitrogen were used as control atmospheres. A theoretical calculation method for the adiabatic spontaneous combustion period based on this method is proposed. The experimental results showed that during the temperature-programmed coal spontaneous combustion experiment, the increase in the coal temperature was due to physical and chemical heating. Physical heating is the heating effect of the temperature-programmed furnace body and the heated gas on the coal sample. Chemical heating includes oxidative exothermic heating promoted by physical and adiabatic oxidation heating. The adiabatic oxidative heat release can be determined by the oxidation heat release in the air atmosphere minus the oxidation heat release corresponding to the coal sample temperature in the nitrogen environment at the same period. The adiabatic spontaneous combustion period of coal can be calculated from the adiabatic oxidation heat release. Our results provide a rapid contrastive experimental method to quickly obtain the accurate adiabatic spontaneous combustion period of coal.

3.
Materials (Basel) ; 14(22)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34832402

RESUMO

In this work, a visible-light-driven BiOCl/Bi2WO6 photocatalyst was obtained via a facile hydrothermal method and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive spectrometry (EDS), X-ray photoelectron spectroscopy (XPS), ultraviolet/visible light diffuse reflection spectroscopy (UV/Vis), and photocurrent (PC). BiOCl/Bi2WO6 was modified with (3-chloro-2-hydroxypropyl) trimethyl ammonium chloride to obtain the cationized BiOCl/Bi2WO6. Cotton fabric was pretreated with sodium hydroxide (NaOH) and sodium chloroacetate solution to obtain carboxymethylated cotton fabric, which was further reacted with cationized BiOCl/Bi2WO6 to achieve finished cotton fabric. The cotton fabrics were characterized by Fourier-transform infrared spectroscopy (FT-IR), XRD, SEM, and EDS. The photocatalytic activity of the BiOCl/Bi2WO6 photocatalyst and cotton fabrics was assessed by photocatalytic degradation of MB (methylene blue) solution under simulated visible light. The self-cleaning property of cotton fabrics was evaluated by removing MB solution and red-wine stains. Results revealed that the coated cotton fabrics exhibited appreciable photocatalytic and self-cleaning performance. In addition, anti-UV studies showed that the finished cotton fabrics had remarkable UV blocking properties in the UVA and UVB regions. Therefore, the finished cotton fabric with BiOCl/Bi2WO6 can provide a framework for the development of multifunctional textiles.

4.
Front Psychol ; 12: 719754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721172

RESUMO

This research analysed the integration of innovation and entrepreneurship education for students, majoring in digital media art design. Using a grounded theory approach, we investigated the experiences of two research groups: five leaders of digital media art design courses in colleges and universities, and five successful entrepreneurs who had majored in digital media art design and had achieved significantly in the industry after graduation. From the two dimensions of 'innovation' and 'entrepreneurship', as well as the two perspectives of 'implementer' and 'party', semi-structured interviews were conducted on the core competencies that innovation and entrepreneurship talents should have the methods and experience of innovation and entrepreneurship education, the difficulties and problems in the implementation of innovation and entrepreneurship education, the need for talent among enterprises and the factors affecting entrepreneurship success. By analysing and clustering the data, we were able to comprehensively identify the main problems and aspects that require more attention in terms of cultivating innovative and entrepreneurial talents in the digital media art design major. Based on the grounded theory research method, this paper established a theoretical model, outlining the innovation of the digital media art design major and the entrepreneurship education reform path. The key internal elements of the model include mechanisms for professional talent training, curriculum integration, teacher team construction and resource support. The school-enterprise cooperation mechanism is recognised as the key external element for innovation and entrepreneurship education reform. The results provide direction for future education and teaching reform, as well as professional input for the digital media art design major. The findings encourage those involved in the digital media art design major to cultivate more high-level, pioneering professionals, so as to adapt to the transformation and upgrading of economic and social development in the context of a growing digital economy.

5.
Plant Physiol Biochem ; 169: 224-235, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34808465

RESUMO

Basic/helix-loop-helix (bHLH) transcription factors are involved in various metabolic and physiological processes in plants. Sweetpotato (Ipomoea batatas (L.) Lam.) is an important crop in China but is highly susceptible to cold stress. However, little information on the bHLH gene family is available, and the function of this family in response to cold stress has not been revealed in sweetpotato. Here, 110 IbbHLHs were identified and classified into 17 categories based on phylogenetic relationships, conserved motifs and gene structure analyses. Except for 5 IbbHLHs, 90 IbbHLHs were putative E-box-binding proteins including 70 IbbHLHs belonging to G-box, whereas 15 IbbHLHs were putative non-E box-binding proteins based on DNA-binding analysis. In total, 37 pairs of segmental duplicated genes and 5 pairs of tandem duplication genes were identified within the IbbHLH gene family. The transcript level of 20 IbbHLHs was regulated by cold stress based on RNA-seq data, and 8 genes were selected for further quantitative real-time PCR (qRT-PCR) analysis. IbHLH8 and IbHLH92 are involved in network interaction with several genes related to abiotic and biotic stresses under cold treatment. IbbHLH79, an ICE1-like gene, was isolated and overexpressed in sweetpotato. The IbbHLH79 protein can activate the CBF (C-repeat Binding Factor) pathway, and IbbHLH79-overexpressing transgenic plants display enhanced cold tolerance. Taken together, these results provide valuable information on the IbbHLH gene family; in addition, several IbbHLHs may regulate cold stress, and the results suggest IbbHLH79 will be useful for molecular breeding of enhanced cold tolerance in sweetpotato.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34742603

RESUMO

Our aim was to evaluate the clinical effect and feasibility of immediate implant placement combined with flap surgery with no bone grafting and non-submerged healing in the maxillary molar area. Thirty-five patients with failed single teeth in the molar area were selected. After minimally invasive extraction of the tooth, the flaps were elevated, and an implant inserted immediately; thereafter a healing abutment was connected. The mucoperiosteal flaps were sutured around the abutment without tension, and a permanent repair was performed six months later. During the study period, the implant survival rate, cone-beam computed tomography (CBCT) data, torque value, and the results of a subjective satisfaction survey conducted with a visual analogue scale (VAS), were evaluated to assess the procedure's therapeutic effect and feasibility. All 35 teeth were successfully implanted immediately after flap surgery. The mean (SD) torque value was 42.79 (5.70) N∙cm at the time of placement. During the six-month follow up and after one year of restoration, all 35 teeth showed no loosening, shedding of implants and restoration, or inflammation around the site. The mean (SD) value of the bony space around the implant immediately after the operation was 2.47 (0.56) mm. The bony spaces were filled with new bone after six months postoperatively. The mean (SD) VAS for satisfaction was 8.71 (1.05). Immediate implant placement combined with flap surgery without bone grafting and non-submerged healing is feasible for the maxillary molar area and produces a satisfactory clinical effect.

7.
Mol Ther Nucleic Acids ; 26: 557-574, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34631285

RESUMO

Expansion in vitro prior to mesenchymal stem cells (MSCs) application is a necessary process. Functional and genomic stability has a crucial role in stem-cell-based therapies. However, the exact expression and co-expressed profiles of coding and non-coding RNAs in human bone marrow (BM)-MSCs in vitro aging are still lacking. In the present studies, the change of morphology, immunophenotype, and capacity of proliferation, differentiation, and immunoregulation of MSCs at passage (P) 4, P6, P8, P10, and P12 were investigated. RNA sequencing identified that 439 mRNAs, 65 long noncoding RNAs (lncRNAs), 59 microRNAs (miRNAs), and 229 circular RNAs (circRNAs) were differentially expressed (DE) in P12 compared with P4, with a similar trend in P6. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) identified several significant biological processes and pathways, including binding, ossification, and Wnt and PPAR signaling pathways. Interaction and co-expression/localization analyses were performed for DE mRNAs and lncRNAs, and several key lncRNAs, circRNAs, and important pathways like autophagy and mitophagy were identified in the competing endogenous RNA (ceRNA) network. Some key RNAs found in the bioinformatics analysis were validated. Our studies indicate that replicative senescence of MSCs is a continuous process, including widespread alterations in biological characteristics and global gene expression patterns that need to be considered before therapeutic applications of MSCs.

8.
Dentomaxillofac Radiol ; : 20210272, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34644186

RESUMO

OBJECTIVE: To investigate the size and morphology of the temporomandibular joint (TMJ) articular disc and condyle in young asymptomatic adults by using magnetic resonance imaging (MRI) and to provide a reference for clinical diagnosis and scientific study of temporomandibular disorders (TMD). METHODS: Overall, 93 undergraduate volunteers without TMD were enrolled from the freshmen pool at the Qingdao University. All participants underwent MRI of the oblique sagittal and oblique coronal TMJ planes. The articular disc and condyle were subsequently measured, and their morphology was evaluated. The obtained data were then grouped and analyzed statistically. Finally, intragroup correlation coefficient (ICC) was used to evaluate the interobserver measurement reliability. RESULTS: We totally received 186 TMJ imaging samples. Based on our analysis, disc's anterior band in young asymptomatic adult females were thicker than males of the same age (p = 0.024). Moreover, the media-lateral dimensions of the condylar head of adult females were shorter than males of equal age (P<0.001). The bilateral articular disc morphology was the same in 72.4% of subjects while the condylar morphology was the same in 63.4% of participants. Finally, using measurement reliability assessment, we demonstrated that our conclusions are reliable (ICC ≥0.7). CONCLUSION: The thickness of the anterior band of the disc and the media-lateral dimensions of the condylar head were gender-related. Additionally, the morphology of the bilateral articular disc and condyle was different among the subset of young asymptomatic adults.

9.
Nat Commun ; 12(1): 5373, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508078

RESUMO

Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m6A modification in ELMO1 3'UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , Espondilite Anquilosante/patologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Biópsia , Medula Óssea/patologia , Estudos de Casos e Controles , Diferenciação Celular/genética , Movimento Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Cultura Primária de Células , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/genética , Microtomografia por Raio-X , beta-Glucanas/administração & dosagem , beta-Glucanas/efeitos adversos
10.
ACS Omega ; 6(30): 19409-19418, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34368528

RESUMO

Significant volume shrinkage and drying cracking of high-water-content lignite will occur during low-temperature drying. To determine the variation behaviors of the drying shrinkage rate and desiccation crack surface width in the process of low-temperature drying, low-temperature and low-humidity drying experiments were conducted, and the variations of the surface widths of the desiccation crack with time and water content of old lignite were examined. The results showed that the slow drying of lignite at low temperatures caused significant volume shrinkage and desiccation crack formation, and the occurrence and development of desiccation cracks were highly nonuniform. Three stages of the variation of surface widths of the desiccation cracks were observed with the water content decrease: an initial rapid increase stage, a second slow decrease stage, and a final stable stage, and the average width of the desiccation cracks increased in a Gaussian function. The higher the evaporation rate and volume drying shrinkage rate, the lower the surface width of the desiccation cracks under low-temperature drying conditions. To achieve safe and green mining, storage, transportation, processing, and utilization of lignite, the moisture content of old lignite should be controlled to be above 13-15%.

11.
Am J Transl Res ; 13(6): 6873-6880, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306438

RESUMO

OBJECTIVE: This study aimed to explore the efficacy of Bailing capsules combined with losartan to treat diabetic glomerulosclerosis (DG) and the combination's effect on blood and urine biochemistry. METHODS: 160 DG patients admitted to our hospital were recruited as the study cohort and randomly divided into a control group and an observation group (n=80 in each group). The control group was treated with losartan, and the observation group was treated with losartan and Bailing capsules. The efficacy, diastolic blood pressure (DBP), systolic blood pressure (SBP), blood creatinine (Scr), 24 h urine protein (24 h UP), blood urea nitrogen (BUN), urine microalbumin (mALB), urine ß2 microglobulin (ß2-MG), glomerular filtration rates (GFR), TCM scores, serum superoxide dismutase (SOD), reactive oxygen species (ROS), 8-hydroxydeoxyguanine (8-OHdG), hypersensitive C-reactive protein (hs-CRP), transforming growth factor ß1 (TGF-ß1), and the serum amyloid A (SAA) levels were compared between the two groups. RESULTS: The overall effective rate was higher in the observation group (91.25%) than it was in the control group (78.75%) (P<0.05). After the treatment, the DBP, SBP, Scr, 24 h UP, BUN, mALB, and ß2-MG levels were lower, and the GFR was higher in the observation group than in the control group (P<0.01). The TCM points were lower in the observation group than they were in the control group (P<0.01). The observation group also showed higher serum SOD and lower ROS, 8-OHdG, hs-CRP, TGF-ß1, and SAA levels than the control group (P<0.01). The differences in the incidences of adverse reactions between the two groups were not significantly different (P>0.05). CONCLUSION: Bailing capsules combined with losartan in the treatment of diabetic glomerulosclerosis can improve the therapeutic efficacy, improve the blood and urine biochemical indexes, the renal function, and the clinical symptoms, reduce the oxidative stress, improve the microinflammatory state, and delay the progression of the disease without increasing the adverse reactions.

12.
Toxicol Mech Methods ; 31(8): 609-618, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34167444

RESUMO

Aristolochic acid (AA) are persistent soil pollutants in the agricultural fields of the Balkan Peninsula. Preparations containing aristolochic acid are widely used for anti-inflammatory, diuretic, etc. To study the hepatotoxicity of aristolochic acid, 80 healthy SD rats were selected and divided into 20 mg/kg- AA group, 4 mg/kg-AA group, and 2 mg/kg-AA group and blank group, 20 rats per group. Mainly tested the body weight, liver function, liver tissue oxidative stress and pathological changes of liver tissue in rats. The ALT and AST activities in the serum of the rats in the administration groups were increased compared with the blank group. The activity of MDA in the administration groups was higher than that in the blank group; the activities of SOD, T-AOC and GSH-PX were significantly lower than those in the blank group. HE tissue sections also found that the administration groups showed varying degrees of hepatocyte boundary blur, nuclear fragmentation, and fibrosis tendency. Transmission electron microscopy showed that the mitochondria of the rat liver became more and more severely damaged with the increase of dose. Compared with the blank group, the mRNA expression of Bax, Caspase-9 and Caspase-3 in the administration groups were determined, while the mRNA expression of the Bcl-2 was increased. And compared with the blank control group, the expression levels of apoptotic proteins caspase-9 and caspase-3 increased significantly in the 20 mg/kg-AA group. Aristolochic acid can induce liver injury in rats through oxidative stress pathway and mitochondrial apoptosis pathway.


Assuntos
Apoptose , Estresse Oxidativo , Animais , Ácidos Aristolóquicos , Fígado/metabolismo , Mitocôndrias , Ratos , Ratos Sprague-Dawley
13.
Clin Transl Med ; 11(6): e429, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34185419

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are the major source of osteoblasts. Long noncoding RNAs (lncRNAs) are abundantly expressed RNAs that lack protein-coding potential and play an extensive regulatory role in cellular biological activities. However, the regulatory network of lncRNAs in MSC osteogenesis needs further investigation. METHODS: QRT-PCR, western blot, immunofluorescence, and immunohistochemistry assays were used to determine the levels of relevant genes. The osteogenic differentiation capability was evaluated by using Alizarin Red S (ARS) staining, alkaline phosphatase activity assays, hematoxylin & eosin staining or micro-CT. RNA fluorescence in situ hybridization (FISH) and RNAscope were used to detect HHAS1 expression in cells and bone tissue. A microarray assay was performed to identify differentially expressed microRNAs. RNA immunoprecipitation and RNA pull-down were used to explore the interactions between related proteins and nucleic acids. RESULTS: The level of lncRNA HHAS1 increased during bone marrow-derived MSC (BMSC) osteogenesis and was positively related to the levels of osteogenic genes and ARS intensity. HHAS1 was located in both the cytoplasm and the nucleus and was expressed in human bone tissue. HHAS1 facilitated BMSC osteogenic differentiation by downregulating miR-204-5p expression and enhancing the level of RUNX family transcription factor 2 (RUNX2). In addition, interferon regulatory factor 2 (IRF2) was increased during BMSC osteogenic differentiation and interacted with the promoter of HHAS1, which resulted in the transcriptional activation of HHAS1. Furthermore, IRF2 and HHAS1 helped improve bone defect repair in vivo. CONCLUSIONS: Our study identified a novel lncRNA, HHAS1, that facilitates BMSC osteogenic differentiation and proposed a role for the IRF2/HHAS1/miR-204-5p/RUNX2 axis in BMSC osteogenesis regulation. These findings help elucidate the regulatory network of BMSC osteogenesis and provide potential targets for clinical application.

14.
Opt Lett ; 46(12): 2803-2806, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34129544

RESUMO

Measuring the complex field of ultrashort pulse lasers plays a fundamental role in light wavefront manipulation and nonlinear phenomena investigation; yet, it still constitutes a challenge for both full-field and high-resolution characterization due to the short coherent length. We proposed and implemented an off-axis interference system with a delay-line sweeping technique to overcome the fringe contrast degradation caused by the envelope mismatch between interfering pulses, resulting in an increased effective analysis area. The effectiveness of the proposed method was first demonstrated by measuring a complex field generated by a phase-only spatial light modulator, where a four-pixel binning technique was adopted for both amplitude and phase modulation; then it was used for the measurement of the second harmonic generation signal of a urea crystal sample. The experimental results show that the proposed method is capable of measuring complex fields having fine features within the full field. The proposed technique can be applied for strongly scattering medium refocusing and adaptive optics, where measuring the complex field of ultrashort pulse lasers is essential.

15.
Cell Death Dis ; 12(6): 578, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34088896

RESUMO

N6-methyladenosine (m6A) modification is widespread in messenger RNAs and increasing evidence suggests the crucial roles of m6A in cell differentiation and tissue development. However, whether m6A modulates the osteogenic differentiation of mesenchymal stem cells (MSCs) has not been fully elucidated. Here we show that conditional knockout of the demethylase Alkbh5 in bone marrow MSCs strengthened bone mass in mice. Loss- and gain-of-function studies demonstrated that ALKBH5 negatively regulates the osteogenic differentiation of MSCs in vitro. At a mechanistic level, meRIP-seq and RNA-seq in MSCs following knockdown of ALKBH5 revealed changes in transcripts of PRMT6 containing consensus m6A motifs required for demethylation by ALKBH5. Furthermore, we found that ALKBH5 accelerates the degradation rate of PRMT6 mRNA in an m6A-dependent manner, and that the ALKBH5-PRMT6 axis regulates the osteogenesis of MSCs, mainly through activation of the PI3K/AKT pathway. Thus, our work reveals a different facet of the novel ALKBH5-PRMT6 axis that modulates the osteogenic differentiation of MSCs, which can serve as a target to improve the clinical use of MSCs.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas Nucleares/metabolismo , Osteócitos/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteócitos/citologia , Osteogênese
16.
Stem Cell Reports ; 16(4): 926-939, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33798448

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate-like unconventional T cells that are abundant in humans and have attracted increasing attention in recent years. Mesenchymal stem cells (MSCs) are crucial regulators of immune cells. However, whether MAIT cells are regulated by MSCs is unclear. Here, we explored the effect of MSCs on MAIT cells and revealed the underlying mechanism. We found that MSCs did not influence the proliferation of MAIT cells but strikingly induced an activated phenotype with an increased expression of CD69, TNF-α, IFN-γ, and granzyme B. Moreover, MSCs activated MAIT cells in a TCR-MR1-independent mechanism through MSC-secreted IL-15. We revealed that MSC-derived IL-15 activated MAIT cells by enhancing autophagy activity, which was abolished by the autophagy inhibitor 3-methyladenine. Based on our findings, MAIT cells are activated by MSCs through IL-15-induced autophagy, which may help elucidate the mechanisms underlying some immune responses and diseases and provide guidance for future research.

17.
Cancer Biol Med ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710817

RESUMO

OBJECTIVE: Therapy for hepatocellular carcinoma (HCC) is a major challenge, and targeted therapies provide only a modest benefit in terms of overall survival. Treatment with antibodies to programmed cell death protein 1 (PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20% of patients with advanced HCC. Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy. METHODS: Tumor-bearing mice were treated with Agrocybe aegerita galectin (AAGL) alone or in combination with anti-PD-1, and the tumor sizes and lifespans of mice were determined. Transcriptome analysis, cytokine analysis, flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen, and molecular and cellular analyses of tumors were used to define the underlying mechanisms. RESULTS: AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner. Furthermore, AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers; this effect was associated with the activation and migration of T cells and macrophages, in agreement with the in vitro results. Importantly, the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy. CONCLUSIONS: The results showed that AAGL induced the activation and migration of lymphocytes to the liver, and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.

19.
Hum Mol Genet ; 30(3-4): 277-293, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33355648

RESUMO

Ankylosing spondylitis (AS) is a rheumatic disease with pathological osteogenesis that causes bony ankylosis and even deformity over time. Mesenchymal stem cells (MSCs) are multipotent stem cells that are the main source of osteoblasts. We previously demonstrated that enhanced osteogenic differentiation of MSCs from AS patients (ASMSCs) is related to pathological osteogenesis in AS. However, the more concrete mechanism needs further exploration. Super enhancers (SEs) are dense clusters of stitched enhancers that control cell identity determination and disease development. Single-nucleotide polymorphisms (SNPs) regulate the formation and interaction of SEs and denote genes accounting for AS susceptibility. Via integrative analysis of multiomic data, including histone 3 lysine 27 acetylation (H3K27ac), chromatin immunoprecipitation sequencing (ChIP-seq), SNPs and RNA sequencing (RNA-seq) data, we discovered a transcription network mediated by AS SNP-adjacent SEs (SASEs) in ASMSCs and identified key genes, such as Toll-like receptor 4 (TLR4), interleukin 18 receptor 1 (IL18R1), insulin-like growth factor binding protein 4 (IGFBP4), transportin 1 (TNPO1) and proprotein convertase subtilisin/kexin type 5 (PCSK5), which are pivotal in osteogenesis and AS pathogenesis. The SASE-regulated network modulates the enhanced osteogenic differentiation of ASMSCs by synergistically activating the PI3K-Akt, NF-kappaB and Hippo signaling pathways. Our results emphasize the crucial role of the SASE-regulated network in pathological osteogenesis in AS, and the preferential inhibition of ASMSC osteogenic differentiation by JQ1 indicates that SEs may be attractive targets in future treatment for new bone formation in AS.


Assuntos
Redes Reguladoras de Genes , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Transdução de Sinais , Espondilite Anquilosante/genética , Diferenciação Celular , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação , Humanos , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Células-Tronco Mesenquimais/fisiologia , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 5/genética , Análise de Sequência de RNA , Espondilite Anquilosante/fisiopatologia , Receptor 4 Toll-Like/genética , beta Carioferinas/genética
20.
Clin Transl Med ; 10(7): e227, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33252864

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stem cells that can differentiate via osteogenesis and adipogenesis. The mechanism underlying MSC lineage commitment still remains incompletely elucidated. Understanding the regulatory mechanism of MSC differentiation will help researchers induce MSCs toward specific lineages for clinical use. In this research, we intended to figure out the long noncoding RNA (lncRNA) that plays a central role in MSC fate determination and explore its application value in tissue engineering. METHODS: The expression pattern of lncRNAs during MSC osteogenesis/adipogenesis was detected by microarray and qRT-PCR. Lentivirus and siRNAs were constructed to regulate the expression of lncRNA repressor of adipogenesis (ROA). MSC osteogenesis/adipogenesis was evaluated by western blot and alizarin red/oil red staining. An adipokine array was used to select the paracrine/autocrine factor PTX3, followed by RNA interference or recombinant human protein stimulation to confirm its function. The activation of signaling pathways was also detected by western blot, and a small molecule inhibitor, SCH772984, was used to inhibit the activation of the ERK pathway. The interaction between ROA and hnRNP A1 was detected by RNA pull-down and RIP assays. Luciferase reporter and chromatin immunoprecipitation assays were used to confirm the binding of hnRNP A1 to the PTX3 promotor. Additionally, an in vivo adipogenesis experiment was conducted to evaluate the regulatory value of ROA in tissue engineering. RESULTS: In this study, we demonstrated that MSC adipogenesis is regulated by lncRNA ROA both in vitro and in vivo. Mechanistically, ROA inhibits MSC adipogenesis by downregulating the expression of the key autocrine/paracrine factor PTX3 and the downstream ERK pathway. This downregulation was achieved through transcription inhibition by impeding hnRNP A1 from binding to the promoter of PTX3. CONCLUSIONS: ROA negatively regulates MSC adipogenesis through the hnRNP A1-PTX3-ERK axis. ROA may be an effective target for modulating MSCs in tissue engineering.

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