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Aurora kinase B (AURKB) is known to play a carcinogenic role in a variety of cancers, but its underlying mechanism in liver cancer is unknown. This study aimed to investigate the role of AURKB in hepatocellular carcinoma (HCC) and its underlying molecular mechanism. Bioinformatics analysis revealed that AURKB was significantly overexpressed in HCC tissues and cell lines, and its high expression was associated with a poorer prognosis in HCC patients. Furthermore, downregulation of AURKB inhibited HCC cell proliferation, migration, and invasion, induced apoptosis, and caused cell cycle arrest. Moreover, AURKB downregulation also inhibited lung metastasis of HCC. AURKB interacted with DExH-Box helicase 9 (DHX9) and targeted its expression in HCC cells. Rescue experiments further demonstrated that AURKB targeting DHX9 promoted HCC progression through the PI3K/AKT/mTOR pathway. Our results suggest that AURKB is significantly highly expressed in HCC and correlates with patient prognosis. Targeting DHX9 with AURKB promotes HCC progression via the PI3K/AKT/mTOR pathway.
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Aurora Quinase B , Carcinoma Hepatocelular , Proliferação de Células , RNA Helicases DEAD-box , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apoptose , Aurora Quinase B/metabolismo , Aurora Quinase B/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Progressão da Doença , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM2.5) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM2.5 exposure (PM) group, the concentrated PM2.5 treated with low-dose DES (DL) group, and the concentrated PM2.5 treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM2.5 for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM2.5 exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM2.5-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM2.5-induced IR.
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Poluentes Atmosféricos , Resistência à Insulina , Feminino , Animais , Camundongos , Material Particulado/toxicidade , Desipramina/farmacologia , Camundongos Endogâmicos C57BL , Fígado , Poluentes Atmosféricos/toxicidadeRESUMO
The high conductivities and good mechanical properties of hydrogel electrolyte films are critical for energy storage devices with high flexibility, fast redox kinetics, and long life. Herein, a low water content (6.63 wt%) hydrogel film is prepared, and a favorable environment is created, with an electrochemical stability window of 2.26 V and a high ionic conductivity of 2.6 mS cm-1 . The hydrogel film exhibits good folding ability, low in-plane swelling, and anti-freezing abilities. These properties are benefitted by immobilizing free water molecules on the abundant oxygenic groups of polymer fibers in the hydrogel film, offering a unique 3D channel to allow Li+ to quickly transport along the polymer network. Therefore, the hydrogel film-based all-in-one flexible cell exhibits stable cycling performance with a retention of 81.8% of the initial capacity after 500 cycles at room temperature and 66.2% of capacity retention at -30 °C. Furthermore, the full cell with high cathode loading (≈21 mg cm-2 ) exhibits a high areal capacity of 2.5 mAh cm-2 (≈119 mAh g-1 ). The overall merits of flexible all-in-one quasi-solid-state batteries demonstrate high potential to be used for power wearable electronics.
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Recent studies have shown a strong correlation between ambient fine particulate matter (PM2.5) exposure and diabetes risk, including abnormal lipid accumulation and systemic insulin resistance (IR). Hawthorn total flavonoids (HF) are the main groups of active substances in Hawthorn, which showed anti-hyperlipidemic and anti-hyperglycemic effects. Therefore, we hypothesized that HF may attenuate PM2.5-induced IR and abnormal lipid accumulation. Female C57BL/6 N mice were randomly assigned to the filtered air exposure (FA) group, concentrated PM2.5 exposure (PM) group, PM2.5 exposure maintained on a low-dose HF diet (LHF) group, and PM2.5 exposure maintained on a high-dose HF diet (HHF) group for an 8-week PM2.5 exposure using a whole-body exposure device. Body glucose homeostasis, lipid profiles in the liver and serum, and enzymes responsible for hepatic lipid metabolism were measured. We found that exposure to PM2.5 impaired glucose tolerance and insulin sensitivity. In addition, triacylglycerol (TAG) in serum elevated, whereas hepatic TAG levels were decreased after PM2.5 exposure, accompanied by inhibited fatty acid uptake, lipogenesis, and lipolysis in the liver. HF administration, on the other hand, balanced the hepatic TAG levels by increasing fatty acid uptake and decreasing lipid export, leading to alleviated systemic IR and hyperlipidemia in PM2.5-exposed mice. Therefore, HF administration may be an effective strategy to protect against PM2.5-induced IR and metabolic abnormalities of lipids.
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Poluentes Atmosféricos , Crataegus , Resistência à Insulina , Feminino , Animais , Camundongos , Material Particulado , Flavonoides , Camundongos Endogâmicos C57BL , Lipídeos , Ácidos GraxosRESUMO
Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.
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Doença de Parkinson , Rotenona , Humanos , Rotenona/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Autofagia , Inflamação , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/farmacologia , Poli(ADP-Ribose) Polimerase-1/genéticaRESUMO
The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor-A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T-helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representing a potential therapeutic target for airway epithelial barrier dysfunction in asthma.
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Asma , Pyroglyphidae , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular , Asma/induzido quimicamente , Dermatophagoides pteronyssinus , Citocinas , Modelos Animais de DoençasRESUMO
Background: The high prevalence, morbidity and mortality, and disease heterogeneity of chronic obstructive pulmonary disease (COPD) result in the scattered data derived from patient visits in different medical units. The huge cost of integrating the scattered data for analysis and modeling, as well as the legal demand for patient privacy protection lead to the emergence of data island. Objectives: On the premise of protecting patient privacy, integrating scattered data of patients from different medical units for high-quality modeling is beneficial to promoting the development of digital health. Based on this, we develop a distributed COPD disease diagnosis system termed COPD average federated learning (COPD_AVG_FL) using FedAvg. Methods: First, to build the COPD_AVG_FL, the clinical data of COPD patients from the real world is collected and the data pre-processing is performed to clean the incorrect data, outlier samples and missing values. Then, a classical federated learning architecture is designed as COPD_AVG_FL. Finally, to evaluate the established COPD_AVG_FL system, we develop Centralized Machine Learning (CML). Conclusions: Our results suggest that, with the assistance of COPD_AVG_FL, the absolute improvement rates are 13.4% (accuracy), 13.3% (precision), 12.8% (recall), 13.1% (F1-Score) and 12.9% (AUC) on the test data, respectively. The decoupling between model training and raw training data protects the patients' privacy, and helps to securely integrate more COPD data from different medical units to generate a more comprehensive model COPD_AVG_FL. This approach promotes the landing of wise information technology of medicine for COPD in the real clinical world. Code for our model will be made available at https://github.com/Cczhh/COPD_AVG_FL/tree/master.
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Changes in calcium signalling are crucial for the development of glioma cells. Whether mitochondrial calcium balance is involved in glial cell development is still unknown. Mitochondrial Calcium Uniporter (MCU) plays an important role in regulating glioma progression. In this work, we found that MCU and p38 expression were positively correlated with glioma grade and the degree tumour progression. MCU increases glioma cell migration by upregulating p38. Furthermore, p38 promotes glioma progression by activating Transcription Factor EB (TFEB)-mediated autophagy. Thus, MCU promotes glioma cell migration by activating autophagy in a p38/TFEB pathway-dependent manner, which provides a theoretical basis for new therapeutic targets for gliomas.
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To simply, quickly, and efficiently separate circulating tumor cells from blood has always been an enormous challenge. Leveraging the principle of inertial focusing, we here designed a simply structured microfluidic chip that maintained excellent CTC separation efficiency with high robustness and low velocity sensitivity across a broad velocity range. The parameter configuration of the chip was systematically examined, especially the most influential parameters such as the arc radius and arc angle. With optimal parameters, the designed chip achieved an outstanding particle separation efficiency of 99.8% and, more importantly, enabled the efficient separation and enrichment of CTCs in blood samples. This design can be readily integrated with other functional modules for further sample processing, serving as a promising tool for cancer diagnosis and therapeutics.
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The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 µg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 µg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.
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Multiple myeloma is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete monoclonal immunoglobulins in the bone marrow. Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein extracted from the seeds of the edible plant Momordica charantia L., which has a variety of biological activities. This study aimed to investigate the inhibitory effect of α-MMC on the proliferation of multiple myeloma MM.1S cells and the molecular mechanism of MM.1S cell death induced through the activation of cell signal transduction pathways. The cell counting kit-8 (CCK-8) assay was used to determine the inhibitory effect of α-MMC on the proliferation of MM.1S cells and its toxic effect on normal human peripheral blood mononuclear cells (PBMCs). The effect of α-MMC on the MM.1S cells' morphology was observed via inverted microscope imaging. The effects of α-MMC on the MM.1S cell cycle, mitochondrial membrane potential (MMP), and apoptosis were explored using propidium iodide, JC-1, annexin V- fluorescein isothiocyanate/propidium iodide fluorescence staining, and flow cytometry (FCM) analysis. Western blot was used to detect the expressions levels of apoptosis-related proteins and MAPK-signaling-pathway-related proteins in MM.1S cells induced by α-MMC. The results of the CCK-8 showed that in the concentration range of no significant toxicity to PBMCs, α-MMC inhibited the proliferation of MM.1S cells in a time-dependent and concentration-dependent manner, and the IC50 value was 13.04 and 7.518 µg/mL for 24 and 48 h, respectively. Through inverted microscope imaging, it was observed that α-MMC induced a typical apoptotic morphology in MM.1S cells. The results of the FCM detection and analysis showed that α-MMC could arrest the MM.1S cells cycle at the G2 phase, decrease the MMP, and induce cell apoptosis. Western blot analysis found that α-MMC upregulated the expression levels of Bax, Bid, cleaved caspase-3, and cleaved PARP, and downregulated the expression levels of Mcl-1. At the same time, α-MMC decreased the expression levels of p-c-Raf, p-MEK1/2, p-ERK1/2, p-MSK1, and p-P90RSK, and increased the expression levels of p-p38, p-SPAK/JNK, p-c-Jun, and p-ATF2. The above results suggest that α-MMC can inhibit the proliferation of multiple myeloma MM.1S cells. MAPK cascade signaling is involved in the growth inhibition effect of α-MMC on MM.1S cells via cycle arrest and mitochondrial-pathway-dependent apoptosis.
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We report the effect of dimethyl sulfoxide (DMSO) on the stability of the four-stranded structures formed by the oligodeoxyribonucleotides d[5'-AGGG(TTAGGG)3-3'] (HTel), d[5'-(GGGT)3GGG-3'] (G3T), d[5'-GGTTGGTGTGGTTGG-3] (TBA), d[5'-GGGGTTTTGGGG-3'] (Oxy-1.5), and d[5'-TGGGGT-3'] (TG4T). In these measurements, influence of the co-solvent was assessed by the change in the mid-point of the heat-induced unfolding, Tm, by monitoring the change in the UV absorption of the sample. Increasing concentrations of DMSO led to an increase in the Tm from the folded to unfolded states. We have also studied the effect of the denaturant urea and mixtures of urea and DMSO on the stability of the intramolecular HTel and the intermolecular TG4T G-quadruplexes. Consistent with earlier data, we found that urea destabilized the folded G-quadruplex structure; the Tm decreases with increasing urea concentration. However, in solutions containing both urea and DMSO, we observed that the two co-solvents off-set the destabilizing and stabilizing effect, respectively, of one another. That is, in solutions containing urea, increasing concentrations of DMSO led to the increase of the Tm of the G-quadruplex structure. This effect is observed in solutions containing sodium, potassium, or ammonium as the ion that stabilizes the folded G-quadruplex structure. The complementary effect of the two co-solvents presumably arises from differential interactions between urea and DMSO and the oligonucleotide or the cations involved in the stabilization of the G-quadruplexes. These results highlight the importance of co-solutes and co-solvents in systems containing guanine-rich DNA, particularly experimental processes that require DMSO.
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Quadruplex G , DNA/química , Dimetil Sulfóxido , Conformação de Ácido Nucleico , Solventes , Ureia/químicaRESUMO
Rabies is an infectious disease of animal origin with a high mortality rate. In the early stages of rabies, the rabies virus (RABV) is usually undetectable in saliva and cerebrospinal fluid (CSF). In addition, there are still no effective drugs and treatments. Here, we present a case in which blood purification alleviated multisystem failures. The patient was a 45-year-old woman who presented with the fear of water and wind, restlessness, and hyperactivity. RABV was detected in her saliva by high-throughput sequencing Next Generation Sequencing (NGS) and polymerase chain reaction (PCR). Based on typical clinical symptoms and the result of NGS and PCR, the patient was diagnosed as a confirmed case of rabies. Hemodialysis combined with antiviral therapy and intensive care unit (ICU) treatment can effectively relieve circulatory failure, respiratory failure, and renal failure. Finally, she died of brain death on the 34th day of admission. The case report showed that blood purification was positive for rabies-induced organ failure. Blood purification combined with antiviral therapy can prolong the lives of patients with rabies to some extent.
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Vírus da Raiva , Raiva , Animais , Feminino , Humanos , Raiva/terapia , Raiva/diagnóstico , Vírus da Raiva/genética , Reação em Cadeia da Polimerase , Saliva , Antivirais/uso terapêuticoRESUMO
Rotenone, a component of pesticides, is widely used in agriculture and potentially causes Parkinson's disease (PD). However, the regulatory mechanisms of rotenone-induced PD are unclear. Here, we revealed a novel feedback mechanism of p38-Parkin-ROS regulating rotenone-induced PD. Rotenone treatment led to not only the activation of p38 but also Parkin inactivation and reactive oxygen species (ROS) overproduction in SN4741 cells. Meanwhile, p38 activation regulated Parkin phosphorylation at serine 131 to disrupt Parkin-mediated mitophagy. Notably, both p38 inhibition and Parkin overexpression decreased ROS levels. Additionally, the ROS inhibitor N-acetyl-l-cysteine (NAC) inhibited p38 and activated Parkin-mediated mitophagy. Both p38 inhibition and the ROS inhibitor NAC exerted a protective effect by restoring cell death and mitochondrial function in rotenone-induced PD models. Based on these results, the p38-Parkin-ROS signaling pathway is involved in neurodegeneration. This pathway represents a valuable treatment strategy for rotenone-induced PD, and our study provides basic research evidence for the safe use of rotenone in agriculture.
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Inseticidas , Transtornos Parkinsonianos/induzido quimicamente , Espécies Reativas de Oxigênio , Rotenona , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Retroalimentação Fisiológica , Inseticidas/toxicidade , Camundongos , Transtornos Parkinsonianos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rotenona/toxicidade , Transdução de Sinais , Ubiquitina-Proteína Ligases/genéticaRESUMO
Osteopontin (OPN) is a secreted, non-collagenous, sialic acid-rich protein which functions by mediating cell-matrix interactions and cellular signaling via binding with integrins and CD44 receptors. An increasing number of studies have shown that OPN plays an important role in controlling cancer progression and metastasis. OPN was found to be expressed in many human cancer types, and in some cases, its over-expression was shown to be directly associated with poor patient prognosis. In vitro cancer cell line and animal model studies have clearly indicated that OPN can function in regulating the cell signaling that ultimately controls the oncogenic potential of various cancers. Previous studies in our laboratory demonstrated that OPN is highly expressed in human osteosarcoma (OS) cell line OS-732. In this study, we successfully reduced the tumorigenecity of OS-732 cells xenotransplanted into nude mice, using the antisense human OPN (hOPN) RNA expression vector.
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Osteopontina/genética , Osteossarcoma/genética , Osteossarcoma/terapia , RNA Antissenso/uso terapêutico , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteossarcoma/patologiaRESUMO
AIM: To examine the role of nucleostemin in the growth regulation of gastric cancer, liver cancer and other cancers. METHODS: RT-PCR was used to clone the fragment of nucleostemin cDNA from HEK 293 cells. Eighteen kinds of malignant tumor tissues including gastric adenocarcinoma and liver cancer tissues, 3 kinds of benign tumor tissues, 3 kinds of benign hyperplastic tissues and normal tissues were employed to examine nucleostemin gene expression by RT-PCR, Slot blot, Northern blot and in situ hybridization. RESULTS: We successfully cloned a 570 bp fragment of nucleostemin-cDNA from HEK-293 cells. All detected malignant tumor tissues, benign tumor tissues, and benign hyperplastic tissues had high levels of nucleostemin expression. Nucleostemin was also expressed in human placenta tissue at a high level. In terminally differentiated normal human adult kidney and mammary gland tissues, no nucleostemin expression could be detected. CONCLUSION: Nucleostemin can help regulate the proliferation of both cancer cells and stem cells. It might play an important role in the growth regulation of gastric cancer, liver cancer and other cancers.