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BACKGROUND AND AIMS: Liver fibrosis is a leading indicator for increased mortality and long-term comorbidity in NASH. Activation of HSCs and excessive extracellular matrix production are the hallmarks of liver fibrogenesis. Tyrosine kinase receptor (TrkB) is a multifunctional receptor that participates in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, the regulatory network and therapeutic potential of TrkB were explored in the progression of hepatic fibrosis. METHODS AND RESULTS: The protein level of TrkB was decreased in mouse models of CDAHFD feeding or carbon tetrachloride-induced hepatic fibrosis. TrkB suppressed TGF-ß-stimulated proliferation and activation of HSCs in 3-dimensional liver spheroids and significantly repressed TGF-ß/SMAD signaling pathway either in HSCs or in hepatocytes. The cytokine, TGF-ß, boosted Nedd4 family interacting protein-1 (Ndfip1) expression, promoting the ubiquitination and degradation of TrkB through E3 ligase Nedd4-2. Moreover, carbon tetrachloride intoxication-induced hepatic fibrosis in mouse models was reduced by adeno-associated virus vector serotype 6 (AAV6)-mediated TrkB overexpression in HSCs. In addition, in murine models of CDAHFD feeding and Gubra-Amylin NASH (GAN), fibrogenesis was reduced by adeno-associated virus vector serotype 8 (AAV8)-mediated TrkB overexpression in hepatocytes. CONCLUSION: TGF-ß stimulated TrkB degradation through E3 ligase Nedd4-2 in HSCs. TrkB overexpression inhibited the activation of TGF-ß/SMAD signaling and alleviated the hepatic fibrosis both in vitro and in vivo . These findings demonstrate that TrkB could be a significant suppressor of hepatic fibrosis and confer a potential therapeutic target in hepatic fibrosis.
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Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Factor de Crecimiento Transformador beta , Animales , Ratones , Tetracloruro de Carbono , Células Estrelladas Hepáticas/metabolismo , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Proteínas Tirosina Quinasas Receptoras , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismoRESUMEN
AIM: The present study aimed to investigate healthcare professionals' perceptions and experiences in caring for cervical cancer patients. The present study was also designed to assess the healthcare professionals' attitudes toward cervical cancer screening and its prevention. METHODS: A cross-sectional quantitative descriptive study was conducted, and 540 participants (240 nurses and 300 doctors), from different hospitals of Pakistan have been selected and interviewed. RESULTS: Data was collected using structured questionnaires and SPSS was used to statistically analyze the data. Participants in the present study are questioned with respect to age, gender, and work experience. The mean age of the participants is 35 years. Among them, 41% of participants are < 35 years of age and 59% are > 35 years of age. In the case of gender, 22% of participants are males and 78% are females. 47% of the participants have work experience < 20 years and 53% have work experience > 20 years. Data from the present study showed that most of the nurses are less educated (basic education of middle and matric degree) with a simple diploma in nursing and midwifery. Nurses and doctors do not have any knowledge/experience of the patient's psychological counselling. Participants are also questioned with respect to HPV vaccination, 39% of nurses and 62% of doctors are vaccinated. The difference in vaccination frequency of participants was observed as statistically significant (p < 0.0001). In the case of treatment modalities, doctors have statistically more knowledge about the pap smear (p < 0.0001), cervical biopsy (p < 0.0001), colposcopy (p < 0.0001), and visual application after acetic acid application (p < 0.0001) compared to nurses. Data analysis showed that Pap smear was performed significantly higher in married females compared to unmarried (p < 0.0001). CONCLUSION: our study provides a comprehensive and in-depth perspective of the nurses and doctors for cervical cancer patients. Cervical cancer prevalence is increasing due to inadequate knowledge and awareness among healthcare professionals. Improvement can be brought about by the regular use of treatment modalities in unmarried females also.
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Macrophages play critical roles in wound healing process. They switch from "classically activated" (M1) phenotype in the early inflammatory phase to "alternatively activated" (M2) phenotype in the later healing phase. However, the dynamic process of macrophage phenotype switching in diabetic wounds burdened with bacteria is unclear. In this report, Pseudomonas aeruginosa, frequently detected in diabetic foot ulcers, was inoculated into cutaneous wounds of db/db diabetic mice to mimic bacterium-infected diabetic wound healing. We observed that P. aeruginosa infection impaired diabetic wound healing and quickly promoted the expression of pro-inflammatory genes (M1 macrophage markers) tumor necrosis factor-α (tnf-α), interleukin-1ß (il-1ß) and il-6 in wounds. The expression of markers of M2 macrophages, including il-10, arginase-1, and ym1 were also upregulated. In addition, similar gene expression patterns were observed in macrophages isolated directly from wounds. Immunostaining showed that P. aeruginosa infection increased both the ratios of M1 and M2 macrophages in wounds compared with that in control groups, which was further confirmed by in vitro culturing macrophages with P. aeruginosa and skin fibroblast conditioned medium. However, the ratios of the expression levels of pro-inflammatory genes to anti-inflammatory gene il-10 was increased markedly in P. aeruginosa infected wounds and macrophages compared with that in control groups, and P. aeruginosa prolonged the presence of M1 macrophages in the wounds. These data demonstrated that P. aeruginosa in diabetic wounds activates a mixed M1/M2 macrophage phenotype with an excessive activation of M1 phenotype or relatively inadequate activation of M2 phenotype.
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Macrófagos/microbiología , Fenotipo , Infecciones por Pseudomonas/microbiología , Cicatrización de Heridas/fisiología , Animales , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiología , Expresión Génica/fisiología , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment.
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Hepatocellular carcinoma (HCC) as a main type of primary liver cancers has become one of the most deadly tumors because of its high morbidity and poor prognosis. Fucoidan is a family of natural, heparin-like sulfated polysaccharides extracted from brown algae. It is not only a widely used dietary supplement, but also participates in many biological activities, such as anti-oxidation, anti-inflammation and anti-tumor. However, the mechanism of fucoidan induced inhibition of HCC is elusive. In our study, we demonstrated that fucoidan contributes to inhibiting cell proliferation in vivo and in vitro, restraining cell motility and invasion and inducing cell cycle arrest and apoptosis. According to High-Throughput sequencing of long-non-coding RNA (lncRNA) in MHCC-97H cells treated with 0.5 mg/mL fucoidan, we found that 56 and 49 lncRNAs were correspondingly up- and down-regulated. LINC00261, which was related to the progression of tumor, was highly expressed in fucoidan treated MHCC-97H cells. Moreover, knocking down LINC00261 promoted cell proliferation by promoting the expression level of miR-522-3p, which further decreased the expression level of downstream SFRP2. Taken together, our results verified that fucoidan effectively inhibits the progression of HCC via causing lncRNA LINC00261 overexpression.
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Pancreatic cancer is a common malignant tumor with a high incidence and mortality rate. The prognosis of patients with pancreatic cancer is considerably poor due to the lack of effective treatment in clinically. Despite numerous studies have revealed that baicalein, a natural product, is responsible for suppressing multiple cancer cells proliferation, motility and invasion. The mechanism by which baicalein restraining pancreatic cancer progression remains unclear. In this study, we firstly verified that baicalein plays a critical role in inhibiting pancreatic tumorigenesis in vitro and in vivo. Then we analyzed the alteration of microRNAs (miRNAs) expression levels in Panc-1 cells incubated with DMSO, 50 and 100 µM baicalein by High-Throughput sequencing. Intriguingly, we observed that 20 and 39 miRNAs were accordingly up- and down-regulated through comparing Panc-1 cells exposed to 100 µM baicalein with the control group. Quantitative PCR analysis confirmed that miR-139-3p was the most up-regulated miRNA after baicalein treatment, while miR-196b-5p was the most down-regulated miRNA. Further studies showed that miR-139-3p induced, miR-196b-5p inhibited the apoptosis of Panc-1 cells via targeting NOB1 and ING5 respectively. In conclusion, we demonstrated that baicalein is a potent inhibitor against pancreatic cancer by modulating the expression of miR-139-3p or miR-196b-5p.
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Non-small cell lung cancer (NSCLC) has the highest morbidity and mortality among all carcinomas. However, it is difficult to diagnose in the early stage, and current therapeutic efficacy is not ideal. Although numerous studies have revealed that Ailanthone (Aila), a natural product, can inhibit multiple cancers by reducing cell proliferation and invasion and inducing apoptosis, the mechanism by which Aila represses NSCLC progression in a time-dependent manner remains unclear. In this study, we observed that most long noncoding RNAs (lncRNAs) were either notably up- or downregulated in NSCLC cells after treatment with Aila. Moreover, alterations in lncRNA expression induced by Aila were crucial for the initiation and metastasis of NSCLC. Furthermore, in our research, expression of DUXAP8 was significantly downregulated in NSCLC cells after treatment with Aila and regulated expression levels of EGR1. In conclusion, our findings demonstrate that Aila is a potent natural suppressor of NSCLC by modulating expression of DUXAP8 and EGR1.
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As an important regulatory mechanism at the posttranscriptional level in metazoans, adenosine deaminase acting on RNA (ADAR)-induced A-to-I RNA editing modification of double-stranded RNA has been widely detected and reported. Editing may lead to non-synonymous amino acid mutations, RNA secondary structure alterations, pre-mRNA processing changes, and microRNA-mRNA redirection, thereby affecting multiple cellular processes and functions. In recent years, researchers have successfully developed several bioinformatics software tools and pipelines to identify RNA editing sites. However, there are still no widely accepted editing site standards due to the variety of parallel optimization and RNA high-seq protocols and programs. It is also challenging to identify RNA editing by normal protocols in tumor samples due to the high DNA mutation rate. Numerous RNA editing sites have been reported to be located in non-coding regions and can affect the biosynthesis of ncRNAs, including miRNAs and circular RNAs. Predicting the function of RNA editing sites located in non-coding regions and ncRNAs is significantly difficult. In this review, we aim to provide a better understanding of bioinformatics strategies for human cancer A-to-I RNA editing identification and briefly discuss recent advances in related areas, such as the oncogenic and tumor suppressive effects of RNA editing.
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BACKGROUND: Several studies have explored the prognostic value of sirtuin 3 (SIRT3) in various cancers, but obtained inconsistent results. The current systematic review and meta-analysis was conducted to investigate the association between SIRT3 expression and prognosis in various cancers. METHODS: PubMed, Embase, Web of Science and the Cochrane Library were comprehensively retrieved by the end of September 29, 2017. All the relevant studies were checked and included in the meta-analysis if they met the inclusion criteria. RESULTS: A total of 17 studies involving 2,865 patients were included in the systematic review and meta-analysis. The results indicated that SIRT3 expression was not significantly associated with overall survival (OS) (hazard ratio [HR]=0.87, 95% CI=0.59-1.29, P=0.50) and disease-free survival (HR=0.87, 95% CI=0.57-1.31, P=0.50) in total various cancers. However, significant relationship between SIRT3 expression and OS in specific cancers was detected, including chronic lymphocytic leukemia (CLL) (HR=0.48, 95% CI=0.26-0.89, P=0.019), hepatocellular carcinoma (HCC) (HR=0.56, 95% CI=0.42-0.74, P<0.001), pancreatic carcinoma (PC) (HR=0.55, 95% CI=0.30-1.00, P=0.049), renal cell carcinoma (RCC) (HR=0.13, 95% CI=0.02-0.98, P=0.048), breast cancer (BC) (HR=2.53, 95% CI=1.83-3.67, P<0.001), colon cancer (CC) (HR=1.87, 95% CI=1.12-3.26, P=0.022) and non-small-cell lung cancer (NSCLC) (HR=2.20, 95% CI=1.38-3.50, P=0.001). Moreover, SIRT3 expression was obviously associated with tumor size (odds ratio [OR]=1.41, 95% CI=1.02-1.94, P=0.04), tumor differentiation (OR=1.52, 95% CI=1.08-2.16, P=0.02) and clinical stage (OR=2.07, 95% CI=1.23-3.46, P=0.01) in HCC. CONCLUSION: SIRT3 was distinctly related to the OS in specific cancers. SIRT3 was an unfavorable prognostic factor in BC, CC and NSCLC; however, it was also a favorable prognostic factor in CLL, HCC, PC and RCC, especially in HCC.
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BACKGROUNDS: Plenty of studies have been conducted to explore the prognostic value of LncRNA AFAP1-AS1 in various cancers, however, with contradictory outcomes. The aim of the current study was to explore the prognostic value of high LncRNA AFAP1-AS1 expression in various cancers. METHODS: PubMed, EMBASE, Web of Science, Cochrane library, China National Knowledge Internet (CNKI) and Wan-fang database were comprehensively retrieved, and all the relevant studies were included into the study. RESULTS: A total of 21 studies involving 2179 patients were finally included into the systematic review and meta-analysis. Compared to low LncRNA AFAP1-AS1 expression, high LncRNA AFAP1-AS1 expression was significantly related to shorter OS (HRâ¯=â¯2.02, 95%CIâ¯=â¯1.51-2.70, Pâ¯<â¯0.001; I2â¯=â¯78%), DFS(HRâ¯=â¯1.80, 95%CIâ¯=â¯1.16-2.80, Pâ¯=â¯0.009; I2â¯=â¯0%), RFS (HRâ¯=â¯2.90, 95%CIâ¯=â¯1.79-4.69, Pâ¯<â¯0.001; I2â¯=â¯38%)and PFS(HRâ¯=â¯2.18, 95%CIâ¯=â¯1.62-2.92, Pâ¯<â¯0.001; I2â¯=â¯0%) in patients with various cancers. Besides, high LncRNA AFAP1-AS1 expression was significantly associated with smoking (Pâ¯<â¯0.001), advanced clinical stage (Pâ¯<â¯0.001), larger tumor size (Pâ¯<â¯.001), earlier tumor metastasis (Pâ¯<â¯0.001), earlier lymph nodal involvement (Pâ¯=â¯0.002) and vascular invasion (Pâ¯<â¯0.001) in various cancers. CONCLUSIONS: Cancer patients with high LncRNA AFAP1-AS1 expression had shorter OS, DFS, RFS and PFS compared to those with low expression. Moreover, high LncRNA AFAP1-AS1 expression was significantly related to advanced clinical stage, larger tumor size, earlier tumor metastasis, earlier lymph nodal involvement and vascular invasion. High LncRNA AFAP1-AS1 expression was an unfavorable prognostic factor in various cancers.