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BACKGROUND: The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis. METHODS AND RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α). CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.
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Neoplasias de la Mama , Endonucleasas de ADN Solapado , Factor de Transcripción STAT3 , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Endonucleasas de ADN Solapado/genética , Endonucleasas de ADN Solapado/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Animales , RatonesRESUMEN
OBJECTIVES: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.
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Anodoncia , Secuenciación del Exoma , Cara , Discapacidad Intelectual , Micrognatismo , Mutación Missense , Cuello , Factores de Transcripción SOXC , Animales , Femenino , Humanos , Masculino , Ratones , Anomalías Múltiples/genética , Anodoncia/genética , Cara/anomalías , Deformidades Congénitas de la Mano/genética , Hibridación Fluorescente in Situ , Micrognatismo/genética , Cuello/anomalías , Factores de Transcripción SOXC/genéticaRESUMEN
INTRODUCTION: Although the 9-minute mean withdrawal time (m-WT) is often reported to be associated with the optimal adenoma detection rate (ADR), no randomized trials of screening colonoscopy have confirmed the impact of a 9-minute m-WT on adenoma miss rate (AMR) and ADR. METHODS: A multicenter tandem trial was conducted in 11 centers. Seven hundred thirty-three asymptomatic participants were randomized to receive segmental tandem screening colonoscopy with a 9-minute withdrawal, followed by a 6-minute withdrawal (9-minute-first group, 9MF, n = 366) or vice versa (6-minute-first group, 6MF, n = 367). The primary outcome was the lesion-level AMR. RESULTS: The intention-to-treat analysis revealed that 9MF significantly reduced the lesion-level (14.5% vs 36.6%, P < 0.001) and participant-level AMR (10.9% vs 25.9%, P < 0.001), advanced adenoma miss rate (AAMR, 5.3% vs 46.9%, P = 0.002), multiple adenomas miss rate (20.7% vs 56.5%, P = 0.01), and high-risk adenomas miss rate (14.6% vs 39.5%, P = 0.01) of 6MF without compromising detection efficiency ( P = 0.79). In addition, a lower false-negative rate for adenomas ( P = 0.002) and high-risk adenomas ( P < 0.05), and a lower rate of shortening surveillance schedule ( P < 0.001) were also found in 9MF, accompanying with an improved ADR in the 9-minute vs 6-minute m-WT (42.3% vs 33.5%, P = 0.02). The independent inverse association between m-WT and AMR remained significant even after adjusting ADR, and meanwhile, 9-minute m-WT was identified as an independent protector for AMR and AAMR. DISCUSSION: In addition to increasing ADR, 9-minute m-WT also significantly reduces the AMR and AAMR of screening colonoscopy without compromising detection efficiency.
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Adenoma , Colonoscopía , Humanos , Adenoma/diagnósticoRESUMEN
OBJECTIVES: To explore the effect of exosomal miR-126 derived from stem cells from the apical papilla (SCAPs) under hypoxia on human umbilical vein endothelial cell (HUVEC) angiogenesis. METHODS: miR-126 mimics plasmids were used to upregulate miR-126 in SCAPs. Internalization of PKH26-labeled exosomes was examined by fluorescent microscopy. CCK-8 assay, Transwell assay, scratch assay, tube formation assay, and Matrigel plug assay were performed to detect the effects of exosomes on the angiogenic ability of HUVECs. The luciferase reporter assay and rescue assay were performed to examine the relationship between miR-126 and sprouty-related, EVH1 domain-containing protein 1 (SPRED1). The involvement of SPRED1 and the extracellular signal-regulated kinase (ERK) signaling pathway was evaluated by western blotting. RESULTS: miR-126 expression was upregulated in SCAPs and in SCAP-derived exosomes under hypoxia. miR-126 expression was increased in HUVECs when cocultured with SCAP-derived exosomes. Induced overexpression of miR-126 in hypoxic SCAPs and secreted exosomes resulted in enhanced angiogenesis both in vitro and in vivo. Western blot analysis revealed that miR-126-mediated SPRED1 downregulation induced activation of ERK signaling. CONCLUSIONS: Under hypoxic conditions, exosomes derived from SCAPs can promote HUVEC angiogenesis through expression of miR-126, which subsequently suppresses SPRED1 and activates the ERK signaling pathway.
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Exosomas , MicroARNs , Humanos , MicroARNs/metabolismo , Exosomas/metabolismo , Células Madre/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proliferación Celular , Hipoxia/metabolismoRESUMEN
BACKGROUND: Accumulated evidence suggests that M2-like polarized macrophages plays an important role in reducing inflammation, promoting and accelerating wound healing process and tissue repair. Thus, M2-like TAMs (Tumour-associated macrophages) was an appealing target for therapy intervention. METHOD: Flow cytometry and RT-PCR assay were used to detect the polarization of macrophages induced by Medrysone, and the rat corneal mechanical injury model was established to evaluate the efficacy of Medrysone in cornel repair. RESULTS: Here we found that Medrysone enhanced IL-4 induced M2 polarization of macrophages, as illustrated by increased expression of CD206, up-regulation of M2 marker mRNAs. Medrysone promoted VEGF and CCL2 secretion in IL-4 induced M2-like polarization. IL-4 triggered STAT6 activation was further enhanced by Medrysone and silencing of STAT6 partially abrogated the stimulatory effect of Medrysone. Medrysone improved migration-promoting feature of M2-like macrophages, as indicated by increased migration of endothelial cells. Further, Medrysone promoted corneal injury repair by inducing M2 polarization of macrophages in vivo. CONCLUSION: Our study suggest that Medrysone promotes corneal injury repair by inducing the M2 polarization of macrophages, providing a theoretical basis for the application of Medrysone in the treatment of corneal injury.
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Lesiones de la Cornea , Células Endoteliales , Ratas , Animales , Interleucina-4/farmacología , Interleucina-4/metabolismo , Macrófagos/metabolismoRESUMEN
The internal gear pump is simple in structure, small in size and light in weight. It is an important basic component that supports the development of hydraulic system with low noise. However, its working environment is harsh and complex, and there are hidden risks related to reliability and exposure of acoustic characteristics over the long term. In order to meet the requirements of reliability and low noise, it is very necessary to make models with strong theoretical value and practical significant to accurately monitor health and predict the remaininglife of the internal gear pump. This paper proposed a multi-channel internal gear pump health status management model based on Robust-ResNet. Robust-ResNet is an optimized ResNet model based on a step factor h in the Eulerian approach to enhance the robustness of the ResNet model. This model was a two-stage deep learning model that classified the current health status of internal gear pumps, and also predicted the remaining useful life (RUL) of internal gear pumps. The model was tested in an internal gear pump dataset collected by the authors. The model was also proven to be useful in the rolling bearing data from Case Western Reserve University (CWRU). The accuracy results of health status classification model were 99.96% and 99.94% in the two datasets. The accuracy of RUL prediction stage in the self-collected dataset was 99.53%. The results demonstrated that the proposed model achieved the best performance compared to other deep learning models and previous studies. The proposed method was also proven to have high inference speed; it could also achieve real-time monitoring of gear health management. This paper provides an extremely effective deep learning model for internal gear pump health management with great application value.
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BACKGROUND: Vascular cell adhesion molecule (VCAM-1) mediates pulpitis via regulating interleukin (IL)-1ß. microRNA (miR)-126 was reported to regulate the VCAM-1 under many different pathophysiological circumstances. We investigated variations of miR-126 and VCAM-1 in inflamed patient pulp tissues and determined potential roles of miR-126 in pulpitis using human dental pulp cells (hDPCs) in vitro. METHODS: We quantitatively measured the transcripts of miR-126 and VCAM-1 in inflamed human pulp tissues using qRT-PCR and compared with those from healthy human pulp tissues. In addition, we transfected miR-126 in hDPCs using plasmid DNA (pDNA)-encoding miR-126 delivered by polyethylenimine (PEI) nanoparticles. RESULTS: The irreversible pulpitis significantly reduced miR-126 and increased the transcript of VCAM-1 in pulp tissues (p < 0.05). pDNA-encoding miR-126 delivered PEI nanoparticles and effectively upregulated the expression of miR-126 in hDPCs (p < 0.05). The overexpression of miR-126 could effectively suppress the transcripts and protein levels of VCAM-1 and IL-1ß induced by Pg-LPS at 100ng/mL in DPCs (p < 0.05). CONCLUSIONS: miR-126 is involved in pulpitis and downregulated the VCAM-1 and IL-1ß in DPCs. miR-126 may be a potential target to attenuate the inflammation of pulpitis.
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MicroARNs , Pulpitis , Células Cultivadas , Pulpa Dental , Humanos , Interleucina-1beta/genética , Lipopolisacáridos/farmacología , MicroARNs/genética , Pulpitis/inducido químicamente , Pulpitis/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
BACKGROUND: Aiming at the poor quality of small lectures due to the lack of lecturing skills of the clinical teachers in residency standardized training, the Teaching and Training Department of Shanghai East Hospital set up a continuous improvement project of lecturing skills for the clinical teachers to search for effective ways to improve lecture quality, then the effect was evaluated. METHODS: Based on the ADDIE model of training design, the department conducted the project in accordance with a process of analysis, design, development, implementation and evaluation. A special course "Clinical Teacher Presentation Training" (CTPT) was developed to convey and train the 5 key behaviors in presentation to improving lecture quality of the clinical teachers. Ninety-nine clinical teachers who give lectures to the residents were recruited as subjects for the project. Adopted the model of "intensive training + practice transference" to strengthen lecturing skills, and applied the Kirkpatrick Four Levels to evaluate the effect of the project from multi-role and multi-stage. RESULTS: The training satisfaction of the CTPT course from the subjects reaches 100%. The subjects have a high degree of knowledge acquisition through CTPT and the knowledge of the 5 key behaviors has been actually used in their lectures at the stage of practice transference. Comparing the data before training and after transference, it is found that the average increasing of the subjects' 5 key behavior scores made by teaching secretaries is 14.12 points (14.12%) and that of the subjects' self-efficacy scores is 9.31 points (9.31%); the performance values were modeling based on the scores from different types of evaluators and increased by an average of 12.61 points (12.61%); and the star ratings of the overall performance increased by an average of 1.17 points (23.4%). The results showed statistically difference (P < 0.001). CONCLUSIONS: The project effectively promoted the improvement of the clinical teachers' lecturing skills and the quality of small lectures.
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Internado y Residencia , China , Competencia Clínica , Humanos , EnseñanzaRESUMEN
The COVID-19 pandemic has exposed emergent vulnerability to adolescents' mental health. This longitudinal study investigated the association between coping at the peak of the COVID outbreak (T1) and Post-Traumatic Stress Disorder (PTSD) symptoms concurrently, and at the remission periods of COVID in China three months (T2) and six months (T3) later in a sample of 6th to 12th-grade students (N = 782). The results showed that forward-focus coping was negatively associated with PTSD symptoms across all three timepoints and predicted reduced risk for more PTSD symptoms at T2, and trauma-focus coping was positively associated with PTSD symptoms across all three timepoints and predicted higher risk of PTSD symptoms both at T2 and T3. There was an interaction effect of trauma-focus coping and T1 symptoms on later symptoms (T3) - trauma-focus coping was more detrimental for those who had more initial symptoms. The results showed the beneficial effects of future-oriented coping and harmful effects of trauma-focus coping for Chinese youth during the epidemic. Clinical implications of the results were discussed.
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BACKGROUND: Streptococcus mutans is the principal etiological agent of human dental caries. The major virulence factors of S. mutans are acid production, acid tolerance, extracellular polysaccharide (EPS) synthesis and biofilm formation. The aim of this study is to evaluate the effect of resveratrol, a natural compound, on virulence properties of S. mutans. RESULTS: Resveratrol at sub-MIC levels significantly decreased acid production and acid tolerance, inhibited synthesis of water-soluble polysaccharide and water-insoluble polysaccharide, compromised biofilm formation. Related virulence gene expression (ldh, relA, gtfC, comDE) was down-regulated with increasing concentrations of resveratrol. CONCLUSIONS: Resveratrol has an inhibitory effect on S. mutans cariogenic virulence properties and it represents a promising anticariogenic agent.
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Resveratrol/farmacología , Streptococcus mutans/patogenicidad , Virulencia/efectos de los fármacos , Ácidos/metabolismo , Proteínas Bacterianas/genética , Biopelículas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Polisacáridos Bacterianos/metabolismo , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/genética , Streptococcus mutans/metabolismoRESUMEN
BACKGROUND: The mortality and morbidity rates of pancreatic adenocarcinoma have been increasing over the past two decades, and an understanding of the mechanisms underlying pancreatic adenocarcinoma progression is urgently needed. The long non-coding RNA ZFAS1 has been demonstrated to be an oncogene in some cancers, but its function and mechanism in pancreatic adenocarcinoma remain unclear. METHODS: The ZFAS1 expression level in pancreatic adenocarcinoma was predicted by bioinformatic analysis, and the expression level of ZFAS1 in pancreatic adenocarcinoma tissue samples and cell lines was further detected by quantitative real-time PCR and in situ hybridization. The functions of ZFAS1 in pancreatic adenocarcinoma in vitro and in vivo were investigated by further bioinformatic analysis. Dual-luciferase reporter assays were used to confirm the binding of ZFAS1/miR-3924 and miR-3924/ROCK2, and rescue assays were performed to further investigate the underlying mechanism. RESULTS: ZFAS1 overexpression in pancreatic adenocarcinoma was predicted and experimentally verified. ZFAS1 silencing inhibited pancreatic adenocarcinoma metastasis in vitro and in vivo. The competing endogenous RNA mechanism of ZFAS1 was also identified. CONCLUSIONS: Our results demonstrated the promotive effect of ZFAS1 on pancreatic adenocarcinoma metastasis and suggested its potential role as a novel regulator of ROCK2.
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This article reports a clinical case of a boy who underwent an avulsion of the upper right central incisor at 8 years old. The avulsed tooth was kept in the socket for 11 years after replantation. The clinical and radiographic findings after 14 years revealed a complete root resorption, but alveolar bone volume is adequate for future implantation from the recent tomography scans view, even in labial area where alveolar bone morphology is poor.
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Avulsión de Diente/cirugía , Reimplante Dental , Niño , Humanos , Incisivo , Masculino , Resorción Radicular , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND/AIMS: RECQL1, a member of the human RECQ helicase family, participates in DNA repair. Recent reports showed that RECQL1 silencing in cancer cells resulted in mitotic catastrophe, which prevented tumor growth in murine models. However, its therapeutic potential has never been examined in tongue squamous cell carcinoma (SCC). METHODS: To explore the role of RECQL1 in the development of tongue SCC, we used RNA interference technology to silence RECQL1 in SCC-9 and SCC-15 human tongue SCC cell lines, and to subsequently evaluate its effects both in vitro and in vivo. RESULTS: After RECQL1 was silenced in SCC cells by siRNA, we observed downregulation of RECQL1 mRNA and protein in cancer cells. RECQL1 is one of the predicted miR-203 targets, and we found that miR-203 downregulated the expression of RECQL1 at the post-transcriptional level. RECQL1-shRNA or miR-203 overexpression inhibited SCC-9 cell growth. In addition, there was accumulation of cells in the sub-G1 fraction and increased apoptosis 72 h post-transfection. In addition, knockdown of RECQL1 led to a strong anticancer effect, as the tumorigenicity of SCC-9 cells was inhibited in vivo. Moreover, we found that two immunosuppressive factors were also significantly downregulated upon RECQL1 knockdown or miR-203 overexpression in vitro. CONCLUSION: Collectively, these results indicate that RECQL1 plays an important regulatory role in cancer cell proliferation and tumor progression.
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Carcinoma de Células Escamosas/metabolismo , RecQ Helicasas/metabolismo , Neoplasias de la Lengua/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Silenciador del Gen/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , RecQ Helicasas/antagonistas & inhibidores , RecQ Helicasas/genética , Relación Estructura-Actividad , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/patologíaRESUMEN
PURPOSE: Using different chain lengths of PEG as linkers to develop a novel folate (FA) and TAT peptide co-modified doxorubicin (DOX)-loaded liposome (FA/TAT-LP-DOX) and evaluate its potential for tumor targeted intracellular drug delivery. METHODS: FA/TAT-LP-DOX was prepared by pH gradient method and post-insertion method and the optimal ligand density was screened by MTT assay. In vitro evaluation was systematically performed through cytotoxicity assay, cellular uptake studies, subcellular localization and cellular uptake mechanism in folate receptor (FR) over-expressing KB tumor cells. In vivo tumor targeted delivery of FA/TAT-LP-DOX was also studied by in vivo fluorescence imaging in a murine KB xenograft model. RESULTS: The particle size and zeta potential determination indicated that FA and TAT were successfully inserted into the liposome and cationic TAT peptide was completely shielded. With the optimal ligand density (5% of FA and 2.5% TAT), the FA/TAT-LP-DOX exhibited improved cytotoxity and cellular uptake efficiency compared with its single-ligand counterparts (FA-LP-DOX and PEG/TAT-LP-DOX). Competitive inhibition and uptake mechanism experiments revealed that FA and TAT peptide played a synergistic effect in facilitating intracellular transport of the liposome, and association between FA and FA receptors activated this transport process. In vivo imaging further demonstrated the superiority of FA/TAT-LP in tumor targeting and accumulation. CONCLUSIONS: Folate and TAT peptide co-modified liposome using different chain lengths of PEG as linkers may provide a useful strategy for specific and efficient intracellular drug delivery.
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Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Ácido Fólico/química , Productos del Gen tat/química , Liposomas/química , Liposomas/farmacocinética , Péptidos/química , Péptidos/farmacocinética , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Células KB , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Polietilenglicoles , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nanocellulose, as a nanoscale polymer material, has garnered significant attention worldwide due to its numerous advantages including excellent biocompatibility, thermal stability, non-toxicity, large specific surface area, and good hydrophilicity. Various methods can be employed for the preparation of nanocellulose. Traditional approaches such as mechanical, chemical, and biological methods possess their own distinct characteristics and limitations. However, with the growing deterioration of our living environment, several green and environmentally friendly preparation techniques have emerged. These novel approaches adopt eco-friendly technologies or employ green reagents to achieve environmental sustainability. Simultaneously, there is a current research focus on optimizing traditional nanocellulose preparation methods while addressing their inherent drawbacks. The combination of mechanical and chemical methods compensates for the limitations associated with using either method alone. Nanocellulose is widely used in wound dressings owing to its exceptional properties, which can accelerate the wound healing process and reduce patient discomfort. In this paper, the principle, advantages and disadvantages of each preparation method of nanocellulose and the research findings in recent years are introduced Moreover, this review provides an overview of the utilization of nanocellulose in wound dressing applications. Finally, the prospective trends in its development alongside corresponding preparation techniques are discussed.
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Celulosa , Polímeros , Humanos , Celulosa/química , Estudios Prospectivos , Vendajes , Cicatrización de HeridasRESUMEN
Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1-/- mice (8-10 weeks old), impaired NK cell bioactivity was shown in methionine-choline-diet (MCD)-fed UCP1-/- mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1flox/flox-NCR1cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1-/- NK cells. Transcriptions of mitophagy-associated molecules in UCP1-/- NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NKWT cells, PA-treated NKWT cells, or physiologic NKKO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 µM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.
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Células Asesinas Naturales , Cirrosis Hepática , Necroptosis , Enfermedad del Hígado Graso no Alcohólico , Proteína Desacopladora 1 , Animales , Proteína Desacopladora 1/metabolismo , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratones , Humanos , Necroptosis/efectos de los fármacos , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , LípidosRESUMEN
Trefoil factor 3 (TFF3) is a member of the TFF-domain peptide family and essential in regulating cell migration and maintaining mucosal integrity in gastrointestinal tract. However, the role of TFF3 and its downstream regulating mechanisms in cancer cell migration remain unclear. We previously reported that TFF3 prolonged the up-regulation of Twist protein to modulate IL-8 secretion in intestinal epithelial cells. In this study, we investigated the role of Twist protein in TFF3-induced migration of SGC7901 cells. While Twist was activated by TFF3, siRNA-mediated knockdown of Twist abolished TFF3-induced cell migration. Furthermore, the migration related marker CK-8 as well as ZO-1 and MMP-9 was also regulated by TFF3 via a Twist-dependent mechanism. Our study suggests that Twist, as an important potential downstream effector, plays a key role in TFF3-modulated metastasis in gastric cancer and can be a promising therapeutic target against intestinal-type gastric cancer.
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Movimiento Celular , Proteínas Nucleares/metabolismo , Péptidos/metabolismo , Transducción de Señal , Neoplasias Gástricas/fisiopatología , Proteína 1 Relacionada con Twist/metabolismo , Línea Celular , Humanos , Neoplasias Gástricas/patología , Factor Trefoil-3RESUMEN
BACKGROUND: Oral cancer develops through multi-stages: from normal to mild (low grade) dysplasia (LGD), moderate dysplasia, and severe (high grade) dysplasia (HGD), to carcinoma in situ (CIS) and finally invasive oral squamous cell carcinomas (OSCC). Clinical and histological assessments are not reliable in predicting which precursor lesions will progress. The aim of this study was to assess the potential of a noninvasive approach to assess progress risk of oral precancerous lesions. METHODS: We first used microRNA microarray to profile progressing LGD oral premaligant lesions (OPLs) from non-progressing LGD OPLs in order to explore the possible microRNAs deregulated in low grade OPLs which later progressed to HGD or OSCC. We then used RT-qPCR to detect miRNA targets from the microarray results in saliva samples of these patients. RESULTS: We identified a specific miRNA signature that is aberrantly expressed in progressing oral LGD leukoplakias. Similar expression patterns were detected in saliva samples from these patients. CONCLUSIONS: These results show promise for using saliva miRNA signature for monitoring of cancer precursor lesions and early detection of disease progression.
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Biomarcadores de Tumor/genética , Carcinoma in Situ/genética , Carcinoma de Células Escamosas/genética , Leucoplasia Bucal/genética , MicroARNs/genética , Neoplasias de la Boca/genética , Lesiones Precancerosas/genética , Saliva , Anciano , Carcinoma in Situ/patología , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Femenino , Humanos , Leucoplasia Bucal/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Lesiones Precancerosas/patología , Medición de RiesgoRESUMEN
LKB1, a tumour suppressor, plays key roles in cell polarity, cell growth and energy metabolism. 14-3-3 proteins bind to LKB1 and suppress its functions. A chimera containing 14-3-3ζ and its binding region in LKB1 was constructed and the chimeric protein LKB1-14-4-3ζ was purified and crystallized. The crystal of LKB1-14-4-3ζ diffracted to 2.9 Å resolution and belonged to space group R32, with unit-cell parameters a = b = 130.262, c = 264.960 Å. Structure determination and refinement are in progress.
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Proteínas 14-3-3/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Recombinantes de Fusión/química , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Cristalización , Cristalografía por Rayos X , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
BACKGROUND: Abnormal expression of early growth response gene 1 (Egr-1) and ß-catenin may play a crucial role in the development and progression of human cancer. However, little is known about the expression and underlying molecular mechanisms in which Egr-1 and ß-catenin are involved in the development and progression of gastric cancer. AIMS: The purpose of this study was to elucidate the potential relationship between Egr-1 and ß-catenin expression in gastric cancer, which contributes to finding new molecular carcinogenesis as a potential therapeutic target for gastric cancer. METHODS: In a sample of 102 cases of human gastric cancer, the expression of Egr-1 and ß-catenin was detected using immunohistochemistry. Egr-1 gene was transfected into gastric cancer SGC7901 cells and its role in proliferation and cell invasion was detected by MTT assay, flow cytometry, wound-healing and transwell invasion assay. Western blot analysis was used to study the expression of ß-catenin and cyclin D1 proteins. RESULTS: Upregulated Egr-1 and ß-catenin protein expression were strongly correlated with cancer progression and depth of invasion in gastric cancer. ß-catenin, present mainly in cytoplasmic and nucleus of gastric cancer cells, was also positively correlated with Egr-1 expression in gastric cancer. Furthermore, the overexpression of Egr-1 upregulated ß-catenin expression level, promoted cell proliferation, increased cell population in S-phase and enhanced gastric cancer cell migration and invasion in vitro. CONCLUSIONS: Egr-1 might contribute to gastric cancer proliferation and invasion through activation of the ß-catenin signaling pathway.