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Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease caused by the destruction of the intestinal mucosal epithelium that affects a growing number of people worldwide. Although the etiology of IBD is complex and still elucidated, the role of dysbiosis and dysregulated proteolysis is well recognized. Various studies observed altered composition and diversity of gut microbiota, as well as increased proteolytic activity (PA) in serum, plasma, colonic mucosa, and fecal supernatant of IBD compared to healthy individuals. The imbalance of intestinal microecology and intestinal protein hydrolysis were gradually considered to be closely related to IBD. Notably, the pivotal role of intestinal microbiota in maintaining proteolytic balance received increasing attention. In summary, we have speculated a mesmerizing story, regarding the hidden role of PA and microbiota-derived PA hidden in IBD. Most importantly, we provided the diagnosis and therapeutic targets for IBD as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Proteolisis , Enfermedades Inflamatorias del Intestino/terapia , Intestinos , Mucosa Intestinal , DisbiosisRESUMEN
BACKGROUND: Astroviruses (AstVs) are single-stranded RNA viruses that have been detected in a wide range of mammals and birds. They are associated with numerous interspecies transmissions and viral recombination events, posing a threat to human and animal health. METHODS: We collected 1,333 samples from wild animals, including bats, rodents, wild boars, and birds, from various states and cities in the Yunnan Province, China, between 2020 and 2023 to investigate the presence of AstVs. AstVs were detected using a polymerase chain reaction targeting the RdRp gene. Finally, the Molecular Evolutionary Genetics Analysis software was used to construct the phylogenetic tree. RESULTS: The overall positivity rate for AstVs was 7.12% in four species, indicating their widespread occurrence in the region. High genetic diversity among AstVs was observed in different animal species, suggesting the potential for interspecies transmission, particularly among rodents and birds. Additionally, we identified a novel AstV strain and, for the first time, provided information on the presence of bastroviruses in Yunnan, China. CONCLUSIONS: The widespread distribution and high genetic diversity of AstVs, along with the observed potential for interspecies transmission, highlight the importance of further investigation and surveillance in the region. The findings emphasize the need for increased attention to AstVs and their potential impact on human and animal health in Yunnan and other regions.
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Infecciones por Astroviridae , Quirópteros , Virus ARN , Animales , Humanos , Animales Salvajes , Infecciones por Astroviridae/epidemiología , Infecciones por Astroviridae/veterinaria , Filogenia , China/epidemiología , Mamíferos , RoedoresRESUMEN
PURPOSE: Malignant ascites (MA) often occurs in recurrent abdominal malignant tumors, and the large amount of ascites associated with cancerous peritonitis not only leads to severe abdominal distension and breathing difficulties, but also reduces the patient's quality of life and ability to resist diseases, which usually makes it difficult to carry out anti-cancer treatment. The exploration of MA treatment methods is also a key link in MA treatment. This article is going to review the treatment of MA, to provide details for further research on the treatment of MA, and to provide some guidance for the clinical treatment of MA. METHOD: This review analyzes various expert papers and summarizes them to obtain the paper. RESULT: There are various treatment methods for MA, including systemic therapy and local therapy. Among them, systemic therapy includes diuretic therapy, chemotherapy, immunotherapy, targeted therapy, anti angiogenic therapy, CAR-T, and vaccine. Local therapy includes puncture surgery, peritoneal vein shunt surgery, acellular ascites infusion therapy, radioactive nuclide intraperitoneal injection therapy, tunnel catheter, and intraperitoneal hyperthermia chemotherapy. And traditional Chinese medicine treatment has also played a role in enhancing efficacy and reducing toxicity to a certain extent. CONCLUSION: Although there has been significant progress in the treatment of MA, it is still one of the clinical difficulties. Exploring the combination or method of drugs with the best therapeutic effect and the least adverse reactions to control MA is still an urgent problem to be solved.
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Carcinoma , Neoplasias Peritoneales , Humanos , Ascitis/etiología , Ascitis/terapia , Calidad de Vida , Recurrencia Local de Neoplasia , Inmunoterapia , ChinaRESUMEN
Mulberry leaf is a widely used protein feed and is often used as a strategy to reduce feed costs and improve meat quality in the livestock industry. However, to date, there is a lack of research on the improvement of meat quality using mulberry leaves, and the exact mechanisms are not yet known. The results showed that fermented mulberry leaves significantly reduced backfat content but had no significant effect on intramuscular fat (IMF). Lipidomic analysis showed that 98 and 303 differential lipid molecules (p < 0.05) were identified in adipose and muscle tissues, respectively, including triglycerides (TG), phosphatidylcholine, phosphatidylethanolamine, sphingolipids, and especially TG; therefore, we analysed the acyl carbon atom number of TG. The statistical results of acyl with different carbon atom numbers of TG in adipose tissue showed that the acyl group containing 13 carbon atoms (C13) in TG was significantly upregulated, whereas C15, C16, C17, and C23 were significantly downregulated, whereas in muscle tissue, the C12, C19, C23, C25, and C26 in TG were significantly downregulated. Acyl changes in TG were different for different numbers of carbon atoms in different tissues. We found that the correlations of C (14-18) in adipose tissue were higher, but in muscle tissue, the correlations of C (18-26) were higher. Through pathway enrichment analysis, we identified six and four metabolic pathways with the highest contributions of differential lipid metabolites in adipose and muscle tissues respectively. These findings suggest that fermented mulberry leaves improve meat quality mainly by inhibiting TG deposition by downregulating medium- and short-chain fatty acids in backfat tissue and long-chain fatty acids in muscle tissue.
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Tejido Adiposo , Alimentación Animal , Dieta , Fermentación , Morus , Músculo Esquelético , Animales , Morus/química , Porcinos , Tejido Adiposo/metabolismo , Tejido Adiposo/química , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Alimentación Animal/análisis , Dieta/veterinaria , Metabolismo de los Lípidos , Lípidos/química , Lipidómica , Fenómenos Fisiológicos Nutricionales de los Animales , Hojas de la Planta/químicaRESUMEN
Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL.
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Linfoma de Células B Grandes Difuso , Humanos , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia Tirosina Quinasa/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Transducción de Señal , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
The development of information technology puts forward huge demand for electronic materials with high dielectric constants; first-principles calculations and simulations have been demonstrated as an efficient technique for screening and exploring novel dielectric materials. In the present study, first-principles calculations combined with density functional perturbation theory are employed to study the dielectric properties of two newly discovered layered nitrides SrHfN2 and SrZrN2 under strain. By analyzing the evolution of lattice distortion, dielectric constant, Born effective charge, and phonon modes along with the applied strain, we find that the biaxial strain and isotropic strain can effectively modulate the dielectric constant. The two nitrides SrHfN2 and SrZrN2 are dynamically stable up to biaxial tensile strains of 2.1% and 1.8%, and the dielectric constants have been enlarged to about 500 and 2000. Furthermore, the dielectric constant is dramatically enhanced by 15 (9) times to a maximum value of â¼2600 (2700) under an isotropic tensile strain of 1.2% (0.7%) for SrHfN2 (SrZrN2), which is mainly due to the softening of the lowest-frequency infrared-active phonon mode and the increasing octahedral distortion degree. Particularly, the ionic contribution of the dielectric constant shows very remarkable anisotropy and plays a dominant role in the change of the dielectric constant, whose in-plane components exhibit giant enhancement by 18 (10) times for SrHfN2 (SrZrN2). This work not only sheds light on the experimentally observed high dielectric constants of SrHfN2 and SrZrN2, but also provides an effective route to regulate the anisotropic dielectric constants by applied strain, which indicates promising applications in optical and electronic devices.
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Long noncoding RNAs (lncRNAs) are critical regulators of inflammation with great potential as new therapeutic targets. However, the role of lncRNAs in early atherosclerosis remains poorly characterized. This study aimed to identify the key lncRNA players in activated endothelial cells (ECs). The lncRNAs in response to pro-inflammatory factors in ECs were screened through RNA sequencing. ICAM-1-related non-coding RNA (ICR) was identified as the most potential candidate for early atherosclerosis. ICR is essential for intercellular adhesion molecule-1 (ICAM1) expression, EC adhesion and migration. In a high fat diet-induced atherosclerosis model in mice, ICR is upregulated in the development of atherosclerosis. After intravenous injection of adenovirus carrying shRNA for mouse ICR, the atherosclerotic plaque area was markedly reduced with the declined expression of ICR and ICAM1. Mechanistically, ICR stabilized the mRNA of ICAM1 in quiescent ECs; while under inflammatory stress, ICR upregulated ICAM1 in a nuclear factor kappa B (NF-κB) dependent manner. RNA-seq analysis showed pro-inflammatory targets of NF-κB were regulated by ICR. Furthermore, the chromatin immunoprecipitation assays showed that p65 binds to ICR promoter and facilitates its transcription. Interestingly, ICR, in turn, promotes p65 accumulation and activity, forming a positive feedback loop to amplify NF-κB signaling. Preventing the degradation of p65 using proteasome inhibitors rescued the expression of NF-κB targets suppressed by ICR. Taken together, ICR acts as an accelerator to amplify NF-κB signaling in activated ECs and suppressing ICR is a promising early intervention for atherosclerosis through ICR/p65 loop blockade.
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Aterosclerosis , ARN Largo no Codificante , Animales , Aterosclerosis/genética , Células Endoteliales/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Ratones , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that disturbs the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development, affecting more and more people around the world. Despite the multiple factors that account for IBS remaining incompletely studied, emerging evidence demonstrated the abnormal changes in gut microbiota and bile acids (BAs) metabolism closely associated with IBS. Moreover, microbiota drives significant modifications for BAs, consisting of deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, esterification, and so on, while BAs, in turn, affect the microbiota directly or indirectly. In light of the complex connection among gut microbiota, BAs, and IBS, it is urgent to review the latest research progress in this field. In this review, we described the disorders of intestinal microecology and BAs profiles in IBS-D and also highlighted the cross-talk between gut microbiota and BAs in the context of IBS-D. Integrating these, we suggest that new therapeutic strategies targeting the microbiota-BAs axis for IBS-D, even for other related diseases caused by bacteria-bile acid dysbiosis should be expected.
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Microbioma Gastrointestinal , Síndrome del Colon Irritable , Humanos , Síndrome del Colon Irritable/metabolismo , Ácidos y Sales Biliares , Disbiosis , DiarreaRESUMEN
The scattering enhancement technique has shown prominent potential in various regimes such as satellite communication, Radar Cross Section (RCS) camouflage, and remote sensing. Currently, the scattering enhancement devices based on the metasurface have shown advantages in light weight and better performance. These metasurfaces always possess complex structure, it is hard to achieve through the tradition trial-and-error method which relies on the full-wave numerical simulation. In this paper, a new method combining the machine learning and the evolution optimization algorithm is proposed to design the metasurface retroreflector (MRF) for arbitrary direction incident wave. In this method, a predicting model and a generative inverse design model are constructed and trained, the predicting model is used to evaluate the fitness of each offspring in the genetic algorithm (GA), the generative model is used to initialize the first offspring of the GA by inverse generate the MRF based on the requirements of the designer. With the assistance of these two machine learning models, the evolution optimization algorithm is employed to find the optimal design of the MRF. This approach enables automatic solution of electromagnetic inverse design problems and opens the way to facilitate the optimization of other metadevices.
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BACKGROUND: To explore the clinical effect of filling the preaponeurotic fat with autologous fine particles fat under direct vision to correct the sunken upper eyelid after double eyelid surgery. METHODS: From June 2017 to May 2020, 134 cases of sunken upper eyelid after double eyelid surgery were treated by sharp needle injection of autologous fine particles fat under direct vision, and the surgical effect of each case was analyzed and evaluated. RESULTS: The sunken upper eyelid was corrected, the appearance was satisfactory, the shape was in good state, and there was no lump and obvious displacement of the transplanted fat. And in the sunken upper eyelid group after double eyelid surgery, 5 patients had severe upper eyelid adhesions and lost plenty of preaponeurotic fat; among them, 4 patients underwent secondary repair surgery, and one did not. CONCLUSION: The sharp needle injection method of filling autologous fat in the preaponeurotic fat under direct vision can accurately correct the sunken upper eyelid and replenish the preaponeurotic fat. The positioning is accurate, the filling amount is easy to control, and the transplanted fat particles survive well. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Blefaroplastia , Procedimientos de Cirugía Plástica , Blefaroplastia/métodos , Párpados/cirugía , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Biomedical named entity recognition is one of the most essential tasks in biomedical information extraction. Previous studies suffer from inadequate annotated datasets, especially the limited knowledge contained in them. METHODS: To remedy the above issue, we propose a novel Biomedical Named Entity Recognition (BioNER) framework with label re-correction and knowledge distillation strategies, which could not only create large and high-quality datasets but also obtain a high-performance recognition model. Our framework is inspired by two points: (1) named entity recognition should be considered from the perspective of both coverage and accuracy; (2) trustable annotations should be yielded by iterative correction. Firstly, for coverage, we annotate chemical and disease entities in a large-scale unlabeled dataset by PubTator to generate a weakly labeled dataset. For accuracy, we then filter it by utilizing multiple knowledge bases to generate another weakly labeled dataset. Next, the two datasets are revised by a label re-correction strategy to construct two high-quality datasets, which are used to train two recognition models, respectively. Finally, we compress the knowledge in the two models into a single recognition model with knowledge distillation. RESULTS: Experiments on the BioCreative V chemical-disease relation corpus and NCBI Disease corpus show that knowledge from large-scale datasets significantly improves the performance of BioNER, especially the recall of it, leading to new state-of-the-art results. CONCLUSIONS: We propose a framework with label re-correction and knowledge distillation strategies. Comparison results show that the two perspectives of knowledge in the two re-corrected datasets respectively are complementary and both effective for BioNER.
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Bases del Conocimiento , Almacenamiento y Recuperación de la InformaciónRESUMEN
The hyper-inflammatory response is thought to be a major cause of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Although multiple cytokines are reportedly associated with disease severity, the key mediators of SARS-CoV-2 induced cytokine storm and their predictive values have not been fully elucidated. The present study analyzed maximal and early (within 10 days after disease onset) concentrations of 12-plex cytokines in plasma. We found consistently elevated plasma levels of IL-6, IL-8 and IL-5 in patients who were deceased compared with those who had mild/moderate or severe disease. The early plasma concentrations of IFN-a and IL-2 positively correlated with the length of the disease course. Moreover, correlation network analysis showed that IL-6, IL-8, and IL-5 located at the center of an inter-correlated cytokine network. These findings suggested that IL-8, IL-6, IL-5 might play central roles in cytokine storms associated with COVID-19 and that the early detection of multiple plasma cytokines might help to predict the prognosis of this disease.
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COVID-19/patología , Síndrome de Liberación de Citoquinas/patología , Citocinas/sangre , Síndrome de Dificultad Respiratoria/patología , SARS-CoV-2/inmunología , Anciano , Correlación de Datos , Femenino , Humanos , Interferón-alfa/sangre , Interleucina-2/sangre , Interleucina-5/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that affects 3.8-9.2% of the world population. It affects the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development. Presently, a large number of studies have shown that compared to healthy individuals, the composition and diversity of gut microbiota in IBS patients have changed, and the proteolytic activity (PA) in fecal supernatant and colonic mucosa of IBS patients has also increased. These findings indicate that the imbalance of intestinal microecology and intestinal protein hydrolysis is closely related to IBS. Furthermore, the intestinal flora is a key substance that regulates the PA and is associated with IBS. The current review described the intestinal microecology and intestinal proteolytic activity of patients with IBS and also discussed the effect of intestinal flora on PA. In summary, this study proposed a pivotal role of gut microbiota and PA in IBS, respectively, and provided an in-depth insight into the diagnosis and treatment targets of IBS as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.
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Microbioma Gastrointestinal , Síndrome del Colon Irritable , Heces , Humanos , Mucosa IntestinalRESUMEN
Etoposide-induced protein 2.4 (EI24), located on the endoplasmic reticulum (ER) membrane, has been proposed to be an essential autophagy protein. Specific ablation of EI24 in neuronal and liver tissues causes deficiency of autophagy flux. However, the molecular mechanism of the EI24-mediated autophagy process is still poorly understood. Like neurons and hepatic cells, pancreatic ß cells are also secretory cells. Pancreatic ß cells contain large amounts of ER and continuously synthesize and secrete insulin to maintain blood glucose homeostasis. Yet, the effect of EI24 on autophagy of pancreatic ß cells has not been reported. Here, we show that the autophagy process is inhibited in EI24-deficient primary pancreatic ß cells. Further mechanistic studies demonstrate that EI24 is enriched at the ER-mitochondria interface and that the C-terminal domain of EI24 is important for the integrity of the mitochondria-associated membrane (MAM) and autophagy flux. Overexpression of EI24, but not the EI24-ΔC mutant, can rescue MAM integrity and decrease the aggregation of p62 and LC3II in the EI24-deficient group. By mass spectrometry-based proteomics following immunoprecipitation, EI24 was found to interact with voltage-dependent anion channel 1 (VDAC1), inositol 1,4,5-trisphosphate receptor (IP3R), and the outer mitochondrial membrane chaperone GRP75. Knockout of EI24 impairs the interaction of IP3R with VDAC1, indicating that these proteins may form a quaternary complex to regulate MAM integrity and the autophagy process.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia , Retículo Endoplásmico/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocondrias/metabolismo , Proteínas Nucleares/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Sistemas CRISPR-Cas , Células Cultivadas , Femenino , Células HEK293 , Humanos , Células Secretoras de Insulina/citología , Masculino , Ratones , Proteínas Nucleares/genética , Canal Aniónico 1 Dependiente del Voltaje/metabolismoRESUMEN
In the published article, few errors were noticed and this has been corrected with this erratum publication.
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Aluminum (Al) toxicity is a major yield-limiting factor for crops in acidic soils. In this work, we have investigated the potential role of spermidine (Spd) on Al toxicity in rice chloroplasts. Exogenous Spd markedly reduced Al concentration and elevated other nutrient elements such as Mn, Mg, Fe, K, Ca, and Mo in chloroplasts of Al-treated plants. Meanwhile, Spd further activated arginine decarboxylase (ADC) activity of key enzyme in polyamine (PA) synthesis, and enhanced PA contents in chloroplasts. Spd application dramatically addressed Al-induced chlorophyll (Chl) losses, inhibited thylakoid membrane protein complexes degradation, especially photosystem II (PSII), and significantly depressed the accumulations of superoxide radical (O2·-), hydrogen peroxide (H2O2), and malondialdehyde (MDA) in chloroplasts. Spd addition activated antioxidant enzyme activities and decreased soluble sugar content in chloroplasts compared with Al treatment alone. Spd not only reversed the inhibition of photosynthesis-related gene transcript levels induced by Al toxicity, but diminished the increased expression of Chl catabolism-related genes. Furthermore, Chl fluorescence analysis showed that Spd protected PSII reaction centers and photosynthetic electron transport chain under Al stress, thus improving photosynthetic performance. These results suggest that PAs are involved in Al tolerance in rice chloroplasts and can effectively protect the integrity and function of photosynthetic apparatus, especially PSII, by mitigating oxidative damage induced by Al toxicity.
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Aluminio/toxicidad , Complejo de Proteína del Fotosistema II/efectos de los fármacos , Sustancias Protectoras/farmacología , Espermidina/farmacología , Aluminio/metabolismo , Antioxidantes/metabolismo , Clorofila/metabolismo , Cloroplastos/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Malondialdehído/metabolismo , Fotosíntesis/efectos de los fármacos , Complejo de Proteína del Fotosistema II/metabolismo , Poliaminas/metabolismo , Espermidina/metabolismoRESUMEN
Regorafenib, a multiple kinase inhibitor, is recently approved for treatment of patients with advanced hepatocellular carcinoma (HCC). Previous studies demonstrated that regorafenib was a mitochondrial toxicant, which associated with the impairment of mitochondria. Sirt3 is involved in the regulation of mitochondrial function in cancers. This study aimed to investigate the mechanism of Sirt3 involved in the mitochondrial dysfunction which associated with regorafenib treatment in liver cancer cells. We found regorafenib inhibited Sirt3 and p-ERK expression in HCC cells in a dose-dependent manner. Bioinformatics analysis showed that Sirt3 expression was down-regulated in liver cancer tissues and its low expression was correlated with worse overall survival (OS) in liver cancer patients. After transfected with Sirt3 overexpression plasmid, we found that Sirt3 sensitized liver cancer cells to regorafenib and resulted in much more apoptosis with a significant increase of ROS level. However, exogenous antioxidant could not weaken the apoptosis. Mitochondrial membrane potential assay indicated that Sirt3 overexpression accelerated the mitochondrial depolarization process induced by regorafenib and aggravated mitochondrial injury. Cellular oxygen consumption assay showed that mitochondrial dysfunction was caused by the damage of the electron transport chain. The results demonstrated that Sirt3 overexpression promoted the increase of ROS and apoptosis induced by regorafenib through the acceleration of mitochondrial dysfunction by impairing function of the electron transport chain in liver cancer cells. Our studies verified the functional role of Sirt3 in regorafenib treatment and suggested that regorafenib accompanied with Sirt3 activator as a novel treatment strategy for HCC.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Sirtuina 3/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chronic hyperlipidemia causes the dysfunction of pancreatic ß-cells, such as apoptosis and impaired insulin secretion, which are aggravated in the presence of hyperglycemia. The underlying mechanisms, such as endoplasmic reticulum (ER) stress, oxidative stress and metabolic disorders, have been reported before; however, the time sequence of these molecular events is not fully understood. Here, using isobaric labeling-based mass spectrometry, we investigated the dynamic proteomes of INS-1 cells exposed to high palmitate in the absence and presence of high glucose. Using bioinformatics analysis of differentially expressed proteins, including the time-course expression pattern, protein-protein interaction, gene set enrichment and KEGG pathway analysis, we analyzed the dynamic features of previously reported and newly identified lipotoxicity- and glucolipotoxicity-related molecular events in more detail. Our temporal data highlight cholesterol metabolism occurring at 4 h, earlier than fatty acid metabolism that started at 8 h and likely acting as an early toxic event highly associated with ER stress induced by palmitate. Interestingly, we found that the proliferation of INS-1 cells was significantly increased at 48 h by combined treatment of palmitate and glucose. Moreover, benefit from the time-course quantitative data, we identified and validated two new molecular targets: Setd8 for cell replication and Rhob for apoptosis, demonstrating that our temporal dataset serves as a valuable resource to identify potential candidates for mechanistic studies of lipotoxicity and glucolipotoxicity in pancreatic ß-cells.
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Glucosa/toxicidad , Células Secretoras de Insulina/metabolismo , Lípidos/toxicidad , Proteómica/métodos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ontología de Genes , N-Metiltransferasa de Histona-Lisina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Palmitatos/toxicidad , Fenotipo , Proteoma/metabolismo , Ratas , Reproducibilidad de los Resultados , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Proteína de Unión al GTP rhoB/metabolismoRESUMEN
The molecular mechanism in pancreatic ß cells underlying hyperlipidemia and insulin insufficiency remains unclear. Here, we find that the fatty acid-induced decrease in insulin levels occurs due to a decrease in insulin translation. Since regulation at the translational level is generally mediated through RNA-binding proteins, using RNA antisense purification coupled with mass spectrometry, we identify a novel insulin mRNA-binding protein, namely, DDX1, that is sensitive to palmitate treatment. Notably, the knockdown or overexpression of DDX1 affects insulin translation, and the knockdown of DDX1 eliminates the palmitate-induced repression of insulin translation. Molecular mechanism studies show that palmitate treatment causes DDX1 phosphorylation at S295 and dissociates DDX1 from insulin mRNA, thereby leading to the suppression of insulin translation. In addition, DDX1 may interact with the translation initiation factors eIF3A and eIF4B to regulate translation. In high-fat diet mice, the inhibition of insulin translation happens at an early prediabetic stage before the elevation of glucose levels. We speculate that the DDX1-mediated repression of insulin translation worsens the situation of insulin resistance and contributes to the elevation of blood glucose levels in obese animals.
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ARN Helicasas DEAD-box/metabolismo , Ácidos Grasos/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animales , Ácidos Grasos no Esterificados/metabolismo , Técnicas de Silenciamiento del Gen , Glucosa/metabolismo , Islotes Pancreáticos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Oligonucleótidos Antisentido/genética , Palmitatos/metabolismo , Fosforilación , Unión Proteica , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/metabolismo , Ratas , Transducción de SeñalRESUMEN
The SKA (Square Kilometer Array) radio telescope will become the most sensitive telescope by correlating a huge number of antenna nodes to form a vast array of sensors in a region over one hundred kilometers. Faceting, the wide-field imaging algorithm, is a novel approach towards solving image construction from sensing data where earth surface curves cannot be ignored. However, the traditional processor of cloud computing, even if the most sophisticated supercomputer is used, cannot meet the extremely high computation performance requirement. In this paper, we propose the design and implementation of high-efficiency FPGA (Field Programmable Gate Array) -based hardware acceleration of the key algorithm, faceting in SKA by focusing on phase rotation and gridding, which are the most time-consuming phases in the faceting algorithm. Through the analysis of algorithm behavior and bottleneck, we design and optimize the memory architecture and computing logic of the FPGA-based accelerator. The simulation and tests on FPGA are done to confirm the acceleration result of our design and it is shown that the acceleration performance we achieved on phase rotation is 20× the result of the previous work. We then further designed and optimized an efficient microstructure of loop unrolling and pipeline for the gridding accelerator, and the designed system simulation was done to confirm the performance of our structure. The result shows that the acceleration ratio is 5.48 compared to the result tested on software in gridding parts. Hence, our approach enables efficient acceleration of the faceting algorithm on FPGAs with high performance to meet the computational constraints of SKA as a representative vast sensor array.