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1.
Circ J ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34629373

RESUMO

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an effective therapy for atrial fibrillation (AF). However, it the problem of AF recurrence remains. This study investigates whether a deep convolutional neural network (CNN) can accurately predict AF recurrence in patients with AF who underwent RFCA, and compares CNN with conventional statistical analysis.Methods and Results:Three-hundred and ten patients with AF after RFCA treatment, including 94 patients with AF recurrence, were enrolled. Nine variables are identified as candidate predictors by univariate Cox proportional hazards regression (CPH). A CNNSurv model for AF recurrence prediction was proposed. The model's discrimination ability is validated by a 10-fold cross validation method and measured by C-index. After back elimination, 4 predictors are used for model development, they are N-terminal pro-BNP (NT-proBNP), paroxysmal AF (PAF), left atrial appendage volume (LAAV) and left atrial volume (LAV). The average testing C-index is 0.76 (0.72-0.79). The corresponding calibration plot appears to fit well to a diagonal, and the P value of the Hosmer-Lemeshow test also indicates the proposed model has good calibration ability. The proposed model has superior performance compared with the DeepSurv and multivariate CPH. The result of risk stratification indicates that patients with non-PAF, higher NT-proBNP, larger LAAV and LAV would have higher risks of AF recurrence. CONCLUSIONS: The proposed CNNSurv model has better performance than conventional statistical analysis, which may provide valuable guidance for clinical practice.

2.
Mol Plant Pathol ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633738

RESUMO

Several MYB transcription factors are known to play important roles in plant resistance to environmental stressors. However, the mechanism governing the involvement of MYBs in regulating tobacco mosaic virus (TMV) resistance in plants is still unclear. In this study, we found that not only is Nicotiana benthamiana MYB4-like involved in defence against TMV, but also that the ethylene pathway participates in MYB4L-mediated resistance. Transcription of NbMYB4L was up-regulated in N. benthamiana infected with TMV. Silencing of NbMYB4L led to intensified TMV replication, whereas overexpression of NbMYB4L induced significant resistance to TMV. Transcription of NbMYB4L was greater in 1-aminocyclopropanecarboxylic acid (ACC, ethylene precursor)-pretreated plants but lower when the ethylene signalling pathway was blocked during TMV infection. Gene expression analysis showed that the transcription of NbMYB4L was largely suppressed in ETHYLENE INSENSITIVE 3-like 1(EIL1)-silenced plants. The results of electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) experiments indicated that NbEIL1 could directly bind to two specific regions of the NbMYB4L promoter. Furthermore, a luciferase assay revealed that NbEIL1 significantly induced the reporter activity of the MYB4L promoter in N. benthamiana. These results point to NbEIL1 functioning as a positive regulator of NbMYB4L transcription in N. benthamiana against TMV. Collectively, our work reveals that EIL1 and MYB4L constitute a coherent feed-forward loop involved in the robust regulation of resistance to TMV in N. benthamiana.

3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(5): 754-758, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34622588

RESUMO

Objective: To explore the effect of polystyrene (PS) and PS-polyvinylpyrrolidone (PVP) electrospun materials on the adhesion ability of Porphyromonas gingivalis( P. gingivalis), a common periodontal pathogen. Methods: PS and PS-PVP electrospun materials were prepared with stainless steel needles in high-voltage electric field. The growth and adhesion of P. gingivalis on the surface of different materials were observed with scanning electron microscope (SEM). The changes in the amount of P. gingivalis biofilm formed on the surface of different materials were measured according to viable colony forming units (CFU). The effect of surface charge of the different materials on the adhesion ability of P. gingivalis was determined through changing the charge properties on the surface of the electrospun materials. Results: SEM images showed that both PS and PS-PVP can be used to form electrospun fibers with a diameter of 0.2 µm. SEM images and CFU counts of the biofilm at 24 h and 48 h showed that there was a smaller amount of P. gingivalis biofilm on the surface of the two materials ( P<0.05). After treatment with tetrabutylammonium bromide (TBAB), the surface charge of the PS-PVP electrospun material changed from being negatively charged to being positively charged, and the amount of bacterial adhesion on the surface increased significantly in comparison to that of untreated PS and PS-PVP materials ( P<0.05). Conclusion: PS and PS-PVP electrospun materials can be used to reduce the adhesion ability of P. gingivalis on the surface of different materials, and this ability may be related to the surface charge properties of the materials.


Assuntos
Porphyromonas gingivalis , Povidona , Biofilmes , Fibras na Dieta , Poliestirenos , Povidona/farmacologia
4.
Genes Genomics ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623609

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in DN pathogenesis. OBJECTIVE: The purpose of the present study was to explore the role and mechanism of lncRNA tetratricopeptide repeat domain 2B antisense RNA 1 (TTC28-AS1) in DN. METHODS: Cell viability and apoptosis were assessed by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of TTC28-AS1, miR-320a and CD2-associated protein (CD2AP) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-8 were gauged by enzyme-linked immunosorbent assay (ELISA). Targeted relationship between miR-320a and TTC28-AS1 or CD2AP was evaluated by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Our data indicated that high glucose (HG) induced HK-2 cell damage by the repression of cell viability and autophagy and the enhancement of cell apoptosis, fibrosis and pro-inflammatory cytokines production. TTC28-AS1 was down-regulated and miR-320a was up-regulated in HG-induced HK-2 cells. TTC28-AS1 overexpression or miR-320a knockdown alleviated HG-induced damage in HK-2 cells. MiR-320 was a molecular mediator of TTC28-AS1 in regulating HG-induced HK-2 cell damage. Moreover, TTC28-AS1 functioned as a post-transcriptional regulator of CD2AP expression by miR-320a. MiR-320a knockdown relieved HG-induced damage in HK-2 cells by up-regulating CD2AP. CONCLUSIONS: Our findings suggest that TTC28-AS1 attenuates HG-induced damage in HK-2 cells at least partially by targeting the miR-320a/CD2AP axis, highlighting its role as a promising therapeutic approach for DN treatment.

5.
Appl Opt ; 60(22): 6351-6356, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34612868

RESUMO

We demonstrate broadband mid-infrared cascaded stimulated Raman scattering (SRS) and flat supercontinuum (SC) generation in a chalcogenide optical fiber made from As2S5 glass. By using a 2 µm nanosecond laser as the pump source, mid-infrared cascaded SRS up to six orders ranging from 2149 to 3425 nm was experimentally observed, and this all-fiber Raman laser operating at 3.43 µm was realized for the first time to our knowledge. By introducing a 2 µm femtosecond laser as the excited source, the broadband flat mid-infrared SC with the spectral range of ∼10dB (from ∼1030 to 3441 nm) was observed. Our results verify that the As2S5 optical fibers possess promising applications for tunable mid-infrared Raman fiber lasers and SC light sources pumped by 2 µm pulsed lasers.

6.
Bioengineered ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652258

RESUMO

Stanford type A aortic dissection (TAAD) is one of the most dangerous vascular diseases worldwide, and the mechanisms of its development remain unclear. Further molecular pathology studies may contribute to a comprehensive understanding of TAAD and provide new insights into diagnostic markers and potential therapeutic targets. Recent studies have identified that ferroptosis, a form of cell death, may play a previously unrecognized role in influencing the development of TAAD. In this study, we explored the pathological role of ferroptosis in TAAD by performing bioinformatics analyses. Gene set enrichment analysis (GSEA) showed that the ferroptosis-related gene (FRG) set was significantly different between normal and TAAD aortic samples at an overall level (p < 0.001). Further Gene Ontology (GO) enrichment analysis found that FRGs may influence the response to oxygen levels, transition metal ion homeostasis, and the response to hypoxia by regulating oxidoreductase activity and post-transcriptional ubiquitination modifications, which may regulate cellular ferroptosis and contribute to the structural abnormalities that render patients susceptible to TAAD. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the HIF-1 signaling pathway may be a key pathway regulating cellular ferroptosis in TAAD development. We further identified six key genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, MYC) from differentially expressed FRGs in TAAD by constructing a protein-protein interaction (PPI) network, all key genes were upregulated in TAAD. Four of the key genes (CA9, IL6, CDKN1A, and HIF1A) were demonstrated to be correlated with cigarette smoke extract-induced ferroptosis in aortic vascular smooth muscle cells. These results suggest that ferroptosis is one of the essential pathological processes in the development of TAAD, and some FRGs affect TAAD development by mediating cellular ferroptosis, which provides deepening insights into the molecular mechanisms and potential therapeutic targets of TAAD.

7.
Sci Total Environ ; 806(Pt 3): 150409, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34599953

RESUMO

This study focused on the resource recovery of sludge treatment by quantifying the environmental contributions, identifying the influential factors, and comparing different scenarios. Life cycle assessment (LCA) of sewage sludge treatment was carried out to estimate the environmental impacts of six scenarios: (1) co-digestion of sludge and food waste; (2) co-gasification of sludge and woody waste; (3) co-incineration of sludge and used oil; (4) landfilling; (5) incineration; and (6) anaerobic digestion combined with incineration. Results demonstrate that the resource recovery had a substantial contribution to the environmental performance of the sludge treatment, while the degree of contribution was largely affected by various treatment scenarios and diverse impact categories. To gain deep insight into the parameters related to resource recovery, sensitivity analysis was performed to investigate the influence of the parameters on the LCA results, including the organic content, conversion efficiency of organic matter to methane, and other energy conversion efficiencies. After integrating the inventory variation of those parameters into the decision process via the Monte Carlo simulation, results indicate that no obviously superior scenario could be identified. Conversely, when parameter uncertainty was not considered, co-gasification of sludge and woody waste exhibited the most preferable environmental performance. Overall, this study demonstrates that considering the parameter uncertainty of resource recovery will contribute to a more transparent evaluation process, but will inevitably increase the complexity of the decision-making process based on LCA results because it is difficult to determine a sludge treatment scenario that decisively outperforms the others.

8.
Chin J Dent Res ; 24(3): 143-152, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491008

RESUMO

Tooth eruption is closely linked to the normal development of dentition and proper establishment of occlusion. Disturbances in tooth eruption may affect oral physiological functions, facial contour and aesthetics; it is therefore important to understand the eruption process. This process is a complex biological event involving dynamic changes at the tissue and cellular levels. It is guided by anatomical structures as well as biological and molecular factors that result in the movement of the tooth to its final functional position in the oral cavity. Evidence increasingly suggests that stem cells contribute to tooth development and eruption. Multiple stem cell populations have been discovered in teeth and in their supporting tissues, such as dental follicle precursor cells, orofacial bone-/bone marrow-derived mesenchymal stem cells, periodontal ligament stem cells, stem cells from the apical papilla and dental pulp stem cells. These stem cells exhibit distinct differentiation capacities and are closely linked to alveolar bone remodelling, periodontium development and root formation during the eruption process. The present review summarises the current knowledge of the characteristics and functions of orofacial stem cells in tooth eruption, with a particular focus on recent discoveries concerning their lineage allocation and regulatory mechanisms.


Assuntos
Erupção Dentária , Dente , Diferenciação Celular , Ligamento Periodontal , Células-Tronco
9.
Invest New Drugs ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499335

RESUMO

BACKGROUND: Over the past few years, dramatic breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution for non-small cell lung cancer (NSCLC). While only some patients present a favorable response to this treatment. It is urgent to explore the potential molecular mechanisms underlying the regulation of tumor immune microenvironment in the process of immunotherapy. Lysine acetyltransferase 2B (KAT2B) plays a crucial role in the regulation of gene expression at the post-transcriptional level by acetylation, and is associated with many types of cancer. METHODS: RNA-sequencing data, genetic mutation data, and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then subjected to immune characteristics, gene expression, survival, genetic alteration, enrichment analyses. RESULTS: KAT2B expression correlated positively with infiltrating levels of multiple immune cells and mRNA expression levels of immune checkpoint genes in NSCLC. Furthermore, KAT2B expression was downregulated in tumor tissues, and low KAT2B expression was associated with unsatisfactory efficacy of immune checkpoint blockade (ICB) and poor prognosis of patients with lung adenocarcinoma. Moreover, there were higher somatic genes mutation frequency in patients with low expression of KAT2B. Finally, functional enrichment analysis suggested that KAT2B was mainly linked to the regulation of immune cells and interferon - gamma (IFN-γ) mediated signaling pathways, response to IFN-γ, antigen processing and presentation. CONCLUSION: This is the first comprehensive study to disclose that KAT2B is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and response to immunotherapy in NSCLC.

10.
Nat Prod Res ; : 1-8, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542359

RESUMO

A new glyoxylate-containing benzene derivative, methyl 2-(4-hydroxy-3-(3'-methyl-2'-butenyl)phenyl)-2-oxoacetate (1), together with ten known compounds (2-11), were isolated from the marine algicolous fungus, Aspergillus sp. SCSIO 41304. Their planar structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analysis and comparing with literature data. Compound 1 was isolated as a new fungal secondary metabolite, possessing a methyl glyoxylate moiety R-CO-CO-OCH3, which is rare in natural sources. All the isolated compounds (1-11) were tested for their antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among these compounds, aspulvinone H (4) showed moderate inhibition against AChE and PL with IC50 values of 25.95 and 47.06 µM, respectively. Further molecular docking simulation exhibited that compound 4 could well bind to the catalytic pockets of the AChE and PL.

11.
Nano Lett ; 21(19): 7998-8007, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34529430

RESUMO

With the aging of the population, postmenopausal osteoporosis becomes increasingly widespread and severe as fractures caused by osteoporosis may lead to permanent disabilities and even death. Inspired by extracellular vesicles that participate in bone remodeling, we present a biomimicking polymer vesicle for bone-targeted ß-estradiol (E2) delivery. This vesicle is self-assembled from a poly(ε-caprolactone)28-block-poly[(l-glutamic acid)7-stat-(l-glutamic acid-alendronic acid)4] (PCL28-b-P[Glu7-stat-(Glu-ADA)4]) diblock copolymer. The alendronic acid (ADA) on the coronas endows the polymer vesicles with a high bone affinity and acts synergistically with E2 to achieve an enhanced therapeutic effect. As confirmed with ovariectomized osteoporosis rat models, bone loss was significantly reversed as the recovery rates of total BMD (bone mineral density) and trabecular BMD were 70.4% and 99.3%, respectively. Overall, this work provides fresh insight into the treatment of osteoporosis.


Assuntos
Osteoporose , Polímeros , Animais , Densidade Óssea , Osso e Ossos , Osteoporose/tratamento farmacológico , Ratos
12.
Orthop Surg ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34585838

RESUMO

OBJECTIVE: To investigate three-dimensional distribution of bone-resorptive lesions based on the three-pillar classification and its effect on the disease progression of osteonecrosis of the femoral head (ONFH). METHODS: A total of 194 femoral head CT images from 117 patients diagnosed with ARCO stage II and III ONFH were retrospectively reviewed from April 2014 to February 2019. Three-dimensional structures of the femoral head and the bone-resorptive lesions were reconstructed. Using the three-pillar classification and coronal plane of the femoral head, we divided each femoral head into six regions to observe the location characteristics of bone-resorption lesions, and explore the destruction of different areas of the femoral head by the bone-resorptive lesions. Then the hips were divided into two groups based on whether they contained bone-resorption lesions and compared the difference of stage II and stage III between the two groups. RESULTS: The regional distribution revealed 39 (27.27%), 55 (38.46%), six (4.20%), 23 (16.08%), 17 (11.89%) and three (2.10%) bone-resorptive lesions in regions I, II, III, IV, V and VI respectively. The lateral pillar, AL (I + IV), contained 44.76% of the lesions, central pillar, C (II + V), 48.95%, and medial pillar, M (III + VI), 6.29%. Moreover, there were 81.82% bone-resorption lesions in anterolateral pillar, AL (I + II + IV), and 18.18% in posteromedial pillar, PM (III + V + VI). In all ONFH hips, the lateral pillar of 81(88.04%) femoral heads were affected, the central pillar of 84 (91.30%) femoral heads were affected, and the medical pillar of 29 (31.52%) femoral heads were affected. The ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions (76.09% vs 30.39%, P < 0.001). CONCLUSIONS: This study demonstrated that the bone-resorption lesions are mainly distributed in the lateral and central pillar of the femoral head, and the two pillars of the femoral head are usually involved by bone-resorption lesions. Furthermore, the ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions, suggesting that the bone-resorption lesions might accelerate the progression of ONFH.

13.
Mil Med Res ; 8(1): 51, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34517915

RESUMO

To determine the prevalence and clinical features of olfactory and taste disorders among coronavirus disease 2019 (COVID-19) patients in China. A cross-sectional study was performed in Wuhan from April 3, 2020 to April 15, 2020. A total of 187 patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) completed face-to-face interviews or telephone follow-ups. We found that the prevalence of olfactory and taste disorders was significantly lower in the Chinese cohort than in foreign COVID-19 cohorts. Females were more prone to olfactory and taste disorders. In some patients, olfactory and taste disorders precede other symptoms and can be used as early screening and warning signs.


Assuntos
COVID-19/complicações , Transtornos do Olfato/etiologia , Olfato , Distúrbios do Paladar/etiologia , Paladar , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/epidemiologia , Prevalência , SARS-CoV-2 , Fatores Sexuais , Distúrbios do Paladar/epidemiologia , Adulto Jovem
14.
Fitoterapia ; 155: 105036, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34536535

RESUMO

Two novel aporphine-derived alkaloids, aporaloids A and B (1 and 2), together with eight known biogenetically related alkaloids (3-10), two known isoquinoline alkaloids (3 and 4), and six known aporphinoid alkaloids (5-10) were isolated from the stems of Fissistigma glaucescens. Their structures were elucidated using comprehensive spectroscopic methods. Compounds 1 and 2 represent the rare example of a six-membered lactone ring aporphine-derived alkaloids from natural products. The inhibitory activities of all compounds against four cancer cell lines were evaluated. Aporaloids A and B (1 and 2) showed broad spectrum cytotoxic activities.

15.
Int J Nurs Stud ; 123: 104074, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536908

RESUMO

BACKGROUND: Head and neck cancer treatment destroys nerves and/or organs associated with swallowing. Previous studies have investigated the efficacy of exercises for muscles used in swallowing before treatment in reducing disuse atrophy and delaying the occurrence of muscle fibrosis. However, the rehabilitation effects of training and the optimal intervention strategy are unknown. OBJECTIVES: To establish evidence for the efficacy of prophylactic swallowing interventions in reducing aspiration and restoring oral intake in patients with head and neck cancer with dysphagia. METHODS: We searched electronic databases (PubMed, Embase, Cochrane and MEDLINE) for studies published up to June 2021 reporting outcomes following prophylactic swallowing interventions in patients with head and neck cancer with dysphagia and the related influencing factors. The methodological quality of the literature was assessed using the Joanna Briggs Institute appraisal tools. RESULTS: The search identified 1468 articles, and 13 studies were eventually included. Four categories involving 12 different swallowing interventions were classified. Regarding the descriptive analysis of the rehabilitation effects across all studies, in terms of oropharyngeal safety, five studies showed that swallowing interventions reduced the risk of aspiration, penetration or residue. In terms of oral intake and tube feeding dependence, four studies demonstrated reduced time to return to oral intake in the intervention group compared with the control group. In terms of intervention adherence, three studies showed that speech-language pathologist- and nurse-supervised training was a potential promoter of adherence, and five studies showed that the negative factors affecting adherence included pain, fatigue, forgetting, smoking, decreased exercise motivation, side effects of radiotherapy and distance to the rehabilitation site. CONCLUSIONS: Preventive swallowing interventions may be effective at reducing aspiration, improving swallowing function, and restoring oral intake. However, due to the lack of standardization and consistency of interventions and measurement results, which prevented the production of a best practice guide, future rigorous methodological trials will be needed to determine the most effective interventions for maximizing exercise adherence over the long term.


Assuntos
Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Deglutição , Transtornos de Deglutição/prevenção & controle , Terapia por Exercício , Humanos
16.
Adv Mater ; 33(37): e2008613, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34338371

RESUMO

Many drug delivery systems end up in the lysosome because they are built from covalent or kinetically inert supramolecular bonds. To reach other organelles, nanoparticles hence need to either be made from a kinetically labile interaction that allows re-assembly of the nanoparticles inside the cell following endocytic uptake, or, be taken up by a mechanism that short-circuits the classical endocytosis pathway. In this work, the intracellular fate of nanorods that self-assemble via the Pt…Pt interaction of cyclometalated platinum(II) compounds, is studied. These deep-red emissive nanostructures (638 nm excitation, ≈700 nm emission) are stabilized by proteins in cell medium. Once in contact with cancer cells, they cross the cell membrane via dynamin- and clathrin-dependent endocytosis. However, time-dependent confocal colocalization and cellular electron microscopy demonstrate that they directly move to mitochondria without passing by the lysosomes. Altogether, this study suggests that Pt…Pt interaction is strong enough to generate emissive, aggregated nanoparticles inside cells, but labile enough to allow these nanostructures to reach the mitochondria without being trapped in the lysosomes. These findings open new venues to the development of bioimaging nanoplatforms based on the Pt…Pt interaction.

17.
World J Gastroenterol ; 27(28): 4667-4686, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366628

RESUMO

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Proteína 1 de Ligação a Y-Box
18.
Virchows Arch ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448895

RESUMO

In recent years, breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution, which has been shown to improve the prognosis of patients with hepatocellular carcinoma (HCC). Immune infiltrates represent a major component of tumor microenvironment (TME), and play an essential role in both tumor progression and therapeutic response. The major unmet challenge in tumor immunotherapy is exploring the intrinsic and extrinsic mechanisms of TME promoting the management of HCC. Lysyl oxidase like 3 (LOXL3) participates in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic fibers. It has been reported that LOXL3 is associated with the development and tumorigenesis of multiple types of cancer. RNA sequencing data and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) databases, then subjected to gene expression, tumor microenvironment, survival, enrichment analyses utilizing R packages. In this study, we first found that LOXL3 gene was upregulated in tumor tissues compared with the normal tissues. Furthermore, LOXL3 expression is positively correlated with the infiltration of multiple immune cells and the expression of immune checkpoint genes in HCC. Meanwhile, high LOXL3 expression predicted poor outcomes of the patients with HCC. Functional enrichment analysis suggested that LOXL3 was mainly linked to extracellular structure and matrix organization, cell-cell adhesion, and T cell activation. This is the first comprehensive study to indicate that LOXL3 is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and immunotherapy in HCC.

19.
ACS Biomater Sci Eng ; 7(9): 4509-4520, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34346208

RESUMO

Searching for drug carries with controlled release and good biocompatibility has always been one of the research hotspots and difficulties. Herein, core-sheath nanofibrous mats (NFs) consisting of biocompatible poly(ethylene oxide) (PEO, core) and poly(l-lactic acid) (PLLA, sheath) for drug delivery were fabricated via coaxial electrospinning strategy. The nontoxic layered silicate rectorite (REC) with 0.5-1 wt % amount was introduced in the sheath for sustained drug delivery. Layered REC could be intercalated with PLLA macromolecule chains, leading to the densified structure for loading and keeping doxorubicin hydrochloride (DOX) while reversibly capturing and releasing DOX to delay the drug migration due to its high cation activity. The addition of REC in NFs could delay the initial burst release of DOX and prolong the residence time from 12 to 96 h. Moreover, DOX-loaded core-sheath NFs had in vitro culture with strong antitumor activity, which was confirmed by cytotoxicity results and live and dead assay. HepG2 tumor-bearing xenograft further demonstrated the tumor-suppression effect and the excellent safety of the DOX-loaded core-sheath NFs in vivo. The constructed NFs as drug carriers showed great potential in the local treatment of solid tumors.


Assuntos
Nanofibras , Silicatos de Alumínio , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Minerais
20.
Ecotoxicol Environ Saf ; 224: 112686, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34438274

RESUMO

Cadmium is a carcinogenic heavy metal that poses a severe threat to human beings. The underlying mechanism, however, remains elusive. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in mRNA that regulates RNA metabolism. Emerging evidence shows that m6A is involved in the pathogenesis of various cancers. In this study, human bronchial epithelial BEAS-2B cells were transformed by exposing to 2 µM of cadmium for 20 weeks to investigate the role of m6A in cadmium carcinogenesis. We found the level of m6A in mRNA was significantly decreased in cadmium-transformed BEAS-2B cells, and this change was regulated by m6A demethylase ALKBH5. ALKBH5 was significantly upregulated in the middle and late stages of cell transformation at week 8, 12, 16 and 20. Knockdown of ALKBH5 in cadmium-transformed cells alleviated cell proliferation, migration, invasion, and anchorage-independent growth, but co-transfection with ALKBH5 siRNA and PTEN siRNA restored the inhibitory effects of ALKBH5 knockdown on those transformation properties. ALKBH5 decreased the m6A level of PTEN mRNA, resulting in its instability and reduction of PTEN protein expression. These results indicate that ALKBH5-mediated demethylation m6A at PTEN mRNA is involved in cadmium-induced cell transformation. Our study provides a new perspective for the involvement of m6A modification in cadmium carcinogenesis.

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