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Hepatocellular carcinoma (HCC) is a common malignant tumor with a complex immune evasion mechanism posing a challenge to treatment. The role of the S100A10 gene in various cancers has garnered significant attention. This study aims to elucidate the impact of S100A10 on CD8+ T cell exhaustion via the cPLA2 and 5-LOX axis, thereby elucidating its role in immune evasion in HCC. By analyzing the HCC-related data from the GEO and TCGA databases, we identified differentially expressed genes associated with lipid metabolism and developed a prognostic risk model. Subsequently, through RNA-seq and PPI analyses, we determined vital lipid metabolism genes and downstream factors S100A10, ACOT7, and SMS, which were significantly correlated with CD8+ T cell infiltration. Given the most significant expression differences, we selected S100A10 for further investigation. Both in vitro and in vivo experiments were conducted, including co-culture experiments of CD8+ T cells with MHCC97-L cells, Co-IP experiments, and validation in an HCC mouse model. S100A10 was significantly overexpressed in HCC tissues and potentially regulates CD8+ T cell exhaustion and lipid metabolism reprogramming through the cPLA2 and 5-LOX axis. Silencing S100A10 could inhibit CD8+ T cell exhaustion, further suppressing immune evasion in HCC. S100A10 may activate the cPLA2 and 5-LOX axis, initiating lipid metabolism reprogramming and upregulating LTB4 levels, thus promoting CD8+ T cell exhaustion in HCC tissues, facilitating immune evasion by HCC cells, ultimately impacting the growth and migration of HCC cells. This research highlights the critical role of S100A10 via the cPLA2 and 5-LOX axis in immune evasion in HCC, providing new theoretical foundations and potential targets for diagnosing and treating HCC.
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Araquidonato 5-Lipoxigenase , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Evasão Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Humanos , Animais , Camundongos , Araquidonato 5-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/genética , Linhagem Celular Tumoral , Proteínas S100/metabolismo , Proteínas S100/genética , Fosfolipases A2 Citosólicas/metabolismo , Fosfolipases A2 Citosólicas/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos C57BL , Exaustão das Células TRESUMO
BACKGROUND: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation. METHODS: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein. RESULTS: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation. CONCLUSION: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA.
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Aneurisma da Aorta Abdominal , Armadilhas Extracelulares , Ferroptose , Glutationa , Mitocôndrias , Miócitos de Músculo Liso , Proteína-Arginina Desiminase do Tipo 4 , Ferroptose/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/induzido quimicamente , Animais , Camundongos , Armadilhas Extracelulares/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/genética , Humanos , Glutationa/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Proteína-Arginina Desiminase do Tipo 4/genética , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Masculino , Modelos Animais de Doenças , Estresse Oxidativo , Neutrófilos/metabolismo , Neutrófilos/patologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Angiotensina II/metabolismoRESUMO
Mitochondria are important for the activation of endothelial cells and the process of angiogenesis. NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8) is a protein that plays a critical role in the function of mitochondrial Complex I. We aimed to investigate the potential involvement of NDUFS8 in angiogenesis. In human umbilical vein endothelial cells (HUVECs) and other endothelial cell types, we employed viral shRNA to silence NDUFS8 or employed the CRISPR/Cas9 method to knockout (KO) it, resulting in impaired mitochondrial functions in the endothelial cells, causing reduction in mitochondrial oxygen consumption and Complex I activity, decreased ATP production, mitochondrial depolarization, increased oxidative stress and reactive oxygen species (ROS) production, and enhanced lipid oxidation. Significantly, NDUFS8 silencing or KO hindered cell proliferation, migration, and capillary tube formation in cultured endothelial cells. In addition, there was a moderate increase in apoptosis within NDUFS8-depleted endothelial cells. Conversely, ectopic overexpression of NDUFS8 demonstrated a pro-angiogenic impact, enhancing cell proliferation, migration, and capillary tube formation in HUVECs and other endothelial cells. NDUFS8 is pivotal for Akt-mTOR cascade activation in endothelial cells. Depleting NDUFS8 inhibited Akt-mTOR activation, reversible with exogenous ATP in HUVECs. Conversely, NDUFS8 overexpression boosted Akt-mTOR activation. Furthermore, the inhibitory effects of NDUFS8 knockdown on cell proliferation, migration, and capillary tube formation were rescued by Akt re-activation via a constitutively-active Akt1. In vivo experiments using an endothelial-specific NDUFS8 shRNA adeno-associated virus (AAV), administered via intravitreous injection, revealed that endothelial knockdown of NDUFS8 inhibited retinal angiogenesis. ATP reduction, oxidative stress, and enhanced lipid oxidation were detected in mouse retinal tissues with endothelial knockdown of NDUFS8. Lastly, we observed an increase in NDUFS8 expression in retinal proliferative membrane tissues obtained from human patients with proliferative diabetic retinopathy. Our findings underscore the essential role of the mitochondrial protein NDUFS8 in regulating endothelial cell activation and angiogenesis.
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Angiogênese , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Serina-Treonina Quinases TOR/metabolismo , RNA Interferente Pequeno/farmacologia , Lipídeos/farmacologia , Trifosfato de Adenosina/farmacologia , Proliferação de Células/genética , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismoRESUMO
BACKGROUND: Solute carrier family 38 member 5 (SLC38A5), as an amino acid transporter, play a vital role in cellular biological processes. In this study, we analyzed the function of SLC38A5 and its potential mechanism in breast cancer (BC) progression. METHODS: The expression of SLC38A5 in cancer and adjacent-normal tissues was analyzed by qRT-PCR and Western blot, and its correlation with patient prognosis was analyzed. The immunohistochemical staining of cancer tissues and adjacent-normal tissues was performed on SLC38A5-positive specimens. BC mice were successfully applied to examine the role of SLC38A5 on tumor proliferation using the CCK-8 assay. In BC cells and mouse tumor tissues, SLC38A5 and PCNA expression were determined by Western blotting. RESULTS: The study found that SLC38A5 was highly expressed in BC patients and associated with a poor survival. SLC38A5 silencing inhibited BC cell viability and glutamine uptake. In addition, SLC38A5 overexpression promoted BC cell viability via the glutamine metabolism. SLC38A5 inhibited cisplatin chemosensitivity in BC cells. Importantly, SLC38A5 silencing inhibited tumor growth in vivo. CONCLUSION: Our findings suggest that SLC38A5 enhances BC cell viability by glutamine metabolism, inhibits the chemical sensitivity of cisplatin in BC cells, and promotes tumor growth, emphasizing the clinical relevance of SLC38A5 in BC management as a novel potential therapeutic target.
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Sistemas de Transporte de Aminoácidos Neutros , Neoplasias da Mama , Humanos , Animais , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Glutamina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Sistemas de Transporte de Aminoácidos Neutros/uso terapêuticoRESUMO
Immune checkpoint inhibitors such as monoclonal antibodies have been used recently with greater effect for the management of non-small cell lung cancer (NSCLC). Sintilimab, a fully human IgG4 monoclonal antibody is specific for the immune checkpoint protein programmed cell death receptor-1 (PD-1). It is a common medication adopted for treating Hodgkin's lymphoma and NSCLC. The adverse effects associated with the use of monoclonal antibodies should be closely monitored and in the current report, the use of sintilimab for treating NSCLC led to skin-associated adverse effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Genetic testing showed that genes such as KRAS, CREBBP, NTRK1, RAF1, and TP53 were mutated. Initial visible symptom included the formation of a vesicular rash on the skin that had spread to the upper limbs, chest, and dorsum 1 week after the administration of sintilimab. The patient received anti-inflammatory agents to prevent worsening of the rashes and further infections. When the vesicles in back and limbs enlarged and the neck skin began to desquamate, the patient was diagnosed with Stevens-Johnson syndrome and sintilimab-induced toxic epidermal necrolysis. Toxic epidermal necrolysis was diagnosed via clinical symptoms and physical examination. The patient also reported the symptoms of oral mucositis. As soon as the dose of sintilimab was reduced to 20 mg/day, the skin-associated condition of the patient began to improve. Although the lump in the lungs decreased considerably 45 days after initial administration of sintilimab, the medication was stopped from use as soon as the skin-related symptoms improved after its withdrawal. This report suggests that close monitoring, personal care, and proper use of medications such as sintilimab should be implemented to avoid such rare skin-associated toxicities as an adverse effect.
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Triple-negative breast Cancer (TNBC) is a highly malignant cancer with unclear pathogenesis. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) vitally influence tumor onset and progression. Thus, this research aimed to identify distinct subgroups of CAF using single-cell and TNBC-related information from the GEO and TCGA databases, respectively. The primary aim was to establish a novel predictive model based on the CAF features and their clinical relevance. Moreover, the CAFs were analyzed for their immune characteristics, response to immunotherapy, and sensitivity to different drugs. The developed predictive model demonstrated significant effectiveness in determining the prognosis of patients with TNBC, TME, and the immune landscape of the tumor. Of note, the expression of GPR34 was significantly higher in TNBC tissues compared to that in other breast cancer (non-TNBC) tissues, indicating that GPR34 plays a crucial role in the onset and progression of TNBC. In summary, this research has yielded a novel predictive model for TNBC that holds promise for the accurate prediction of prognosis and response to immunotherapy in patients with TNBC.
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PURPOSE: Recent studies have revealed an increase in the incidence rate of non-alcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC). Furthermore, the association of Sphingosine 1-phosphate receptor 2 (S1PR2) with various types of tumours is identified, and the metabolism of conjugated bile acids (CBAs) performs an essential function in the onset and development of HCC. However, the association of CBA and S1PR2 with NAFLD-HCC is unclear. METHODS: The relationship between the expression of S1PR2 and the prognosis of patients suffering from NAFLD-HCC was investigated by bioinformatics techniques. Subsequently, the relationship between S1PR2 and the biological behaviours of HCC cell lines Huh 7 and HepG2 was explored by conducting molecular biology assays. Additionally, several in vivo animal experiments were carried out for the elucidation of the biological impacts of S1PR2 inhibitors on HCC cells. Finally, We used Glycodeoxycholic acid (GCDA) of CBA to explore the biological effects of CBA on HCC cell and its potential mechanism. RESULTS: High S1PR2 expression was linked to poor prognosis of the NAFLD-HCC patients. According to cellular assay results, S1PR2 expression could affect the proliferation, invasion, migration, and apoptosis of Huh 7 and HepG2 cells, and was closely associated with the G1/G2 phase of the cell cycle. The experiments conducted in the In vivo conditions revealed that the overexpression of S1PR2 accelerated the growth of subcutaneous tumours. In addition, JTE-013, an antagonist of S1PR2, effectively inhibited the migration and proliferation of HCC cells. Furthermore, the bioinformatics analysis highlighted a correlation between S1PR2 and the PI3K/AKT/mTOR pathway. GCDA administration further enhanced the expression levels of p-AKT, p-mTOR, VEGF, SGK1, and PKCα. Moreover, both the presence and absence of GCDA did not reveal any significant change in the levels of S1PR2, p-AKT, p-mTOR, VEGF, SGK1, and PKCα proteins under S1PR2 knockdown, indicating that CBA may regulates the PI3K/AKT/mTOR pathway by mediating S1PR2 expression. CONCLUSION: S1PR2 is a potential prognostic biomarker in NAFLD-HCC. In addition, We used GCDA in CBAs to treat HCC cell and found that the expression of S1PR2 was significantly increased, and the expression of PI3K/AKT/mTOR signalling pathway-related signal molecules was also significantly enhanced, indicating that GCDA may activate PI3K/AKT/mTOR signalling pathway by up-regulating the expression of S1PR2, and finally affect the activity of hepatocellular carcinoma cells. S1PR2 can be a candidate therapeutic target for NAFLD-HCC. Collectively, the findings of this research offer novel perspectives on the prevention and treatment of NAFLD-HCC.
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Background: Bronchoalveolar lavage fluid (BALF) exosomes possess different properties in different diseases, which are mediated through microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), among others. By sequencing the differentially expressed lncRNAs in BALF exosomes, we seek potential targets for the diagnosis and treatment of acute lung injury (ALI). Methods: Considering that human and rat genes are about 80% similar, ALI was induced using lipopolysaccharide in six male Wistar rats, with six rats as control (all weighing 200 ± 20 g and aged 6-8 weeks). BALF exosomes were obtained 24 h after ALI. The exosomes in BALF were extracted by ultracentrifugation. The differential expression of BALF exosomal lncRNAs in BALF was analyzed by RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the functions of differentially expressed lncRNAs, which were confirmed by reverse transcription-polymerase chain reaction. Results: Compared with the control group, the ALI group displayed a higher wet/dry ratio, tumor necrosis factor-α levels, and interleukin-6 levels (all P < 0.001). The airway injection of exosomes in rats led to significant infiltration by neutrophils. A total of 2,958 differentially expressed exosomal lncRNAs were identified, including 2,524 upregulated and 434 downregulated ones. Five lncRNAs confirmed the reliability of the sequencing data. The top three GO functions were phagocytic vesicle membrane, regulation of receptor biosynthesis process, and I-SMAD binding. Salmonella infection, Toll-like receptor signaling pathway, and osteoclast differentiation were the most enriched KEGG pathways. The lncRNA-miRNA interaction network of the five confirmed lncRNAs could be predicted using miRDB. Conclusions: BALF-derived exosomes play an important role in ALI development and help identify potential therapeutic targets related to ALI.
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Lesão Pulmonar Aguda , Exossomos , MicroRNAs , RNA Longo não Codificante , Humanos , Masculino , Ratos , Animais , Exossomos/genética , RNA Longo não Codificante/genética , Líquido da Lavagem Broncoalveolar , Reprodutibilidade dos Testes , Ratos Wistar , MicroRNAs/genética , Redes Reguladoras de Genes , Análise de Sequência de RNA , Lesão Pulmonar Aguda/genéticaRESUMO
Resveratrol is a kind of iPolyphenols widely existing in herbal medicine. Here we aim to investigate whether resveratrol can reduce the degree of myocardial ischemia/reperfusion (IR) injury and inhibit the development of oxidative stress, and elucidate the molecular mechanism of resveratrol in protecting myocardial cells. The primary rat cardiomyocytes were used to establish an ischemia/reperfusion model in vitro, and a series of routine biochemical experiments were conducted to explore the antioxidant and anti-apoptotic effects of resveratrol in myocardial ischemia-reperfusion injury. Compared with that of the simulated ischemia-refusion (SIR) group, cell viability in the SIR and resveratrol co-treatment groups increased significantly (P < 0.001), the release of lactate dehydrogenase (LDH) and creatine kinase MB (CKMB) decreased, the positive rate of reactive oxygen species (ROS) in cardiomyocytes decreased, and the concentration of catalase and glutathione peroxidase increased significantly (P < 0.001). Besides, resveratrol can activate PI3K/AKT signaling pathway. PI3K siRNA can inhibit the PI3K/AKT signaling mediated by resveratrol. The addition of resveratrol can significantly increase the activity of mitochondrial superoxide dismutase (SOD) and reduce the malondialdehyde (MDA), which indicates that the oxidative damage of mitochondria induced by resveratrol was significantly weakened. The mitochondrial functional changes induced by resveratrol can be reversed by PI3K siRNA. In conclusion, our study shows that resveratrol can reduce ROS in cardiomyocytes by PI3K/AKT signaling pathway activation, and effectively inhibit the apoptosis of cardiomyocytes, thus having a direct protective effect on cardiomyocytes under SR.
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Apoptose , Mitocôndrias/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Polifenóis/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Animais Recém-Nascidos , Sobrevivência Celular , Creatina Quinase Forma MB/biossíntese , L-Lactato Desidrogenase/antagonistas & inibidores , Masculino , Malondialdeído/química , Miócitos Cardíacos/citologia , RNA Interferente Pequeno/metabolismo , Ratos , Espécies Reativas de Oxigênio , Resveratrol/farmacologia , Transdução de SinaisRESUMO
BACKGROUND: Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exos) exhibit various roles in breast cancer development. The molecular mechanisms underlying hucMSC-exos in breast cancer cells are not fully clear. In the current study, we set out to investigate the downstream signaling pathways of hucMSC-exos in MCF-7 cells, a commonly used cell line to study breast cancer. METHODS: hucMSC-exos' effects on MCF-7 cells were examined using immunocytochemistry. An inhibitor and a mimic of miR-21-5p were administered. The mRNA and protein levels of ZNF367 were analyzed using real-time quantitative reverse transcription PCR (qRT-PCR)and western blotting. Transwell assays were used to measure invasion and migration. Dual-luciferase assays were performed to investigate the binding sites between miR-21-5p and ZNF367. To manipulate expression, an overexpressing of ZNF367 approach was utilized. RESULTS: We confirmed that hucMSC-exos can be internalized by MCF-7 cells. hucMSC-exos dramatically inhibited migration and invasion behaviors through downregulation of ZNF367 and upregulation of miR-21-5p. miR-21-5p directly binds on 3'UTR of ZNF367. miR-21-5p mimic partially abolished overexpressed ZNF367-induced migration and invasion. In breast cancer tissues, there was a negative correlation between miR-21-5p and ZNF367 levels. The similar results were also obtained in human breast cancer MDA-MB-231 cells. CONCLUSION: husMSC-exos are anti-oncogenic in MCS-7 cells. husMSC-exos suppress ZNF367 expression and promote miR-21-5p expression. miR-21-5p opposes ZNF367's actions during breast cancer development. miR-21-5p direct binds ZNF367 3'UTR to inhibit ZNF367 expression. The interaction between miR-21-5p and ZNF367 may serve as a future therapeutic approach to improve breast cancer prognosis.
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Neoplasias da Mama/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Células MCF-7 , MicroRNAs/genética , Cordão Umbilical/metabolismoRESUMO
Sulfur has become one of the most promising positive electrode materials for lithium sulfur batteries due to its high theoretical capacity and high energy density (2500 Wh kg-1). The use of common nonpolar carbon/sulfur composites has proved to be a good way to improve the performance, but they still cannot efficiently trap highly polar lithium polysulfides due to the weak interactions between nonpolar carbon and polar polysulfides. Herein, we report a new strategy of using polar cysteamine groups to trap polar polysulfides, leading to greatly enhanced capacity of â¼920 mAh g-1 at 1 C with a high Coulombic efficiency of â¼99.1%, and a long cycle life of over 600 cycles with a capacity retention higher than 80%. Importantly, in situ UV/Vis spectroscopy was employed to identify intermediates during cycling, which demonstrates the constructed unique polar cysteamine functionalized carbon nanotubes (CNTs) can greatly reduce the production of polysulfides and suppress the shuttle effect. The broken-bond model of linear polysulfane during cycling was further demonstrated by density functional theory calculations. The present strategy of using polar cysteamine-functionalized CNTs to trap soluble intermediates is promising and has significant potential for the development of highly efficient lithium sulfur batteries.
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OBJECTIVE: Calcium channel blockers, such as dihydropyridines, are commonly used to inhibit enhanced activity of vascular CaV1.2 channels in hypertension. However, patients who are insensitive to such treatments develop calcium channel blocker-resistant hypertension. The function of CaV1.2 channel is diversified by alternative splicing, and the splicing factor PTBP (polypyrimidine tract-binding protein) 1 influences the utilization of mutually exclusive exon 8/8a of the CaV1.2 channel during neuronal development. Nevertheless, whether and how PTBP1 makes a role in the calcium channel blocker sensitivity of vascular CaV1.2 channels, and calcium channel blocker-induced vasodilation remains unknown. Approach and Results: We detected high expression of PTBP1 and, inversely, low expression of exon 8a in CaV1.2 channels (CaV1.2E8a) in rat arteries. In contrast, the opposite expression patterns were observed in brain and heart tissues. In comparison to normotensive rats, the expressions of PTBP1 and CaV1.2E8a channels were dysregulated in mesenteric arteries of hypertensive rats. Notably, PTBP1 expression was significantly downregulated, and CaV1.2E8a channels were aberrantly increased in dihydropyridine-resistant arteries compared with dihydropyridine-sensitive arteries of rats and human. In rat vascular smooth muscle cells, PTBP1 knockdown resulted in shifting of CaV1.2 exon 8 to 8a. Using patch-clamp recordings, we demonstrated a concomitant reduction of sensitivity of CaV1.2 channels to nifedipine, due to the higher expression of CaV1.2E8a isoform. In vascular myography experiments, small interfering RNA-mediated knockdown of PTBP1 attenuated nifedipine-induced vasodilation of rat mesenteric arteries. CONCLUSIONS: PTBP1 finely modulates the sensitivities of CaV1.2 channels to dihydropyridine by shifting the utilization of exon 8/8a and resulting in changes of responses in dihydropyridine-induced vasodilation.
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Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Resistência a Medicamentos , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Hipertensão/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Processamento Alternativo , Animais , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Éxons , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Potenciais da Membrana , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
The limited efficacy of chemotherapy with Taxol (TAX) and cisplatin (DDP) in triple-negative breast cancer (TNBC) has prompted the investigation of combined therapies. Previous studies demonstrated that microRNA (miR)-31-5p is involved in various biological processes. In the present study, it was hypothesized that the overexpression of miR-31-5p may enhance the efficacy of chemotherapy. The expression levels of miR-31-5p in the TNBC cell lines MDA-MB-231 and MDA-MB-468 were measured using reverse transcription-quantitative PCR following transfection with miR-31-5p mimic or inhibitor. A Cell Counting Kit-8 and flow cytometry assays suggested that the overexpression of miR-31-5p inhibited cell proliferation and promoted apoptosis, and these effects were reversed by transfecting a miR-31-5p inhibitor into MDA-MB-231 and MDA-MB-468 cells. Furthermore, the overexpression of miR-31-5p increased the sensitivity of cells to chemotherapy, which exhibited an increase in apoptosis and in the expression level of Bax, and a decrease in the expression level of Bcl-2. Chemotherapy resistance induced by miR-31-5p inhibitor could be reversed by inhibiting the AKT signaling pathway in MDA-MB-231 and MDA-MB-468 cells. In conclusion, the present preclinical results indicated that targeting miR-31-5p may enhance the efficacy of TAX- and DDP-mediated chemotherapy in TNBC.
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BACKGROUND: Preeclampsia (PE) is a severe pregnancy complication and is an important cause for maternal and child death, premature delivery, and limited intrauterine growth and development. The aim of this study was to investigate the role of NGAL and cystatin C, alone and in combination, for early prediction of PE at 10 - 14 weeks of gestation. METHODS: Serum levels of NGAL and cystatin C were assessed in women at 10 - 14 weeks of gestation who subsequently developed PE (n = 128) and normal pregnancy outcome (n = 183). Comparison of clinical characteristics, NGAL, and cystatin C levels between normal pregnancy and PE groups were analyzed using Mann-Whitney test. The receiver operating characteristic curve (ROC curve) was used to analyze the value of serum NGAL and cystatin C levels in predicting PE. RESULTS: The levels of cystatin C and NGAL in the serum were significantly higher in the PE group [0.64 mg/L (0.52 - 0.78)] and [34.9 ng/mL (24.4 - 55.2), respectively] than in the normal pregnancy group [0.56 mg/L (0.49 - 0.65)] and [20.2 ng/mL (13.8 - 26.9), respectively]. ROC curve analysis showed that serum NGAL levels predicted the area under the curve in the PE period 0.739 (95% CI: 0.618 to 0.860). Serum cystatin C levels predicted the area under the curve in the PE period 0.722 (95% CI: 0.592 to 0.853). The combination of serum NGAL and cystatin C levels predicted the area under the curve in the PE period 0.877 (95% CI: 0.811 to 0.943). CONCLUSIONS: NGAL and cystatin C levels in serum appear to be ideal biomarkers for PE prediction at 10 - 14 weeks. The combination of NGAL and cystatin C will also be more valuable in discriminating patients at risk of developing PE from other pregnancy complications early in gestation.
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Biomarcadores/sangue , Cistatina C/sangue , Lipocalina-2/sangue , Pré-Eclâmpsia/sangue , Adulto , Feminino , Idade Gestacional , Humanos , Pré-Eclâmpsia/diagnóstico , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Prognóstico , Curva ROC , Adulto JovemRESUMO
PURPOSE: Physical activity (PA) during and after cancer treatment is associated with improved cancer- and non-cancer-related outcomes. We assessed for predictors of change in PA levels among cancer survivors. METHODS: Adult cancer survivors from a comprehensive cancer center completed a one-time questionnaire retrospectively assessing PA levels before, during, and after cancer treatment along with their perceptions of PA. Multivariable logistic regression models evaluated the association of clinico-demographics variables and perceptions of PA with changes in whether patients were meeting PA guidelines after cancer diagnosis. RESULTS: Among the 1003 patients, 319 (32%) met moderate to vigorous PA (MVPA) guidelines before diagnosis. Among those meeting guidelines before diagnosis, 50% still met guidelines after treatment; 12% not meeting MVPA guidelines initially met them after treatment/at follow-up. Among patients meeting guidelines before diagnosis, better ECOG performance status at follow-up, receiving curative therapy, and spending a longer time on PA initially were each associated with meeting guidelines at follow-up. After controlling for other variables, perceiving that PA improves quality of life (adjusted odds ratio, aOR = 11.09, 95%CI [1.42-86.64], P = 0.02) and overall survival (aOR = 8.52, 95%CI [1.12-64.71], P = 0.04) was each associated with meeting MVPA guidelines during/after treatment, in patients who did not meet guidelines initially. Only 13% reported receiving counseling, which was not associated with PA levels. Common reported barriers to PA included fatigue, lacking motivation, and being too busy. CONCLUSIONS: Patient perceptions of PA benefits are strongly associated with improving PA levels after a cancer diagnosis. Clinician counseling should focus on patient education and changing patient perceptions.
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Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Exercício Físico , Neoplasias/psicologia , Neoplasias/reabilitação , Percepção , Adulto , Idoso , Atitude Frente a Saúde , Aconselhamento , Exercício Físico/fisiologia , Exercício Físico/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
Neuroblastoma is a major contributor of cancer-specific mortality. Although remarkable enhancement has been achieved in the treatment of neuroblastoma in patients with early stage disease, limited progress has been made in the treatment of patients with high-risk neuroblastoma. Thus, innovative approaches are required to achieve further improvements in neuroblastoma patient survival outcomes. The major alkaloid obtained from Sophora flavescens Ait, matrine, has been shown to counteract malignancy in various kinds of cancers. In the current study, we evaluated the effects of matrine on the migration and proliferation of neuroblastoma cells. Cell cycle analysis coupled with Transwell and wound healing experiments showed that matrine triggers G2/M cell cycle arrest and suppresses neuroblastoma migration. This effect of matrine is due to upregulation of TRB3 expression followed by inhibition of the PI3K/AKT activation. Consistent with the in vitro data, growth of xenograft cancer was also suppressed by matrine. Our results indicate that matrine inhibits neuroblastoma cell proliferation and migration by enhancing TRB3 expression, suggesting that matrine may serve as a promising agent for the treatment of neuroblastoma.
Assuntos
Alcaloides/farmacologia , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Neuroblastoma/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinolizinas/farmacologia , Proteínas Repressoras/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Proteínas de Ciclo Celular/genética , Humanos , Camundongos , Camundongos SCID , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , MatrinasRESUMO
We introduce a new method for fabricating unique on-chip supercapacitors based on CuO/polypyrrole core/shell nanosheet arrays by means of direct electrochemical co-deposition on interdigital-like electrodes. The prepared all-solid-state device demonstrates exceptionally high specific capacitance of 1275.5 F cm(-3) (â¼40 times larger than that of CuO-only supercapacitors) and high-energy-density of 28.35 mWh cm(-3), which are both significantly greater than other solid-state supercapacitors. More importantly, the device maintains approximately 100% capacity retention at 2.5 A cm(-3) after 3000 cycles. The in situ co-deposition of CuO/polypyrrole nanosheets on interdigital substrate enables effective charge transport, electrode fabrication integrity, and device integration. Because of their high energy, power density, and stable cycling stability, these newly developed on-chip supercapacitors permit fast, reliable applications in portable and miniaturized electronic devices.
RESUMO
PURPOSE: Improved cancer screening and treatment have led to a greater focus on cancer survivorship care. Older cancer survivors may be a unique population. We evaluated whether older cancer survivors (age ≥ 65 years) had lifestyle behaviors, attitudes, and knowledge distinct from younger survivors. PATIENTS AND METHODS: Adult cancer survivors with diverse cancer subtypes were recruited from Princess Margaret Cancer Centre (Toronto, Ontario, Canada). Multivariable models evaluated the effect of age on smoking, alcohol, and physical activity habits, attitudes toward and knowledge of these habits on cancer outcomes, and lifestyle information and recommendations received from health care providers, adjusted for sociodemographic and clinicopathologic covariates. RESULTS: Among the 616 survivors recruited, 23% (n = 139) were older. Median follow-up since diagnosis was 24 months. Older survivors were more likely ex-smokers and less likely current smokers than younger survivors, but they were less likely to know that smoking could affect cancer treatment (adjusted odds ratio [OR], 0.53; P = .007) or prognosis (adjusted OR, 0.53; P = .008). Older survivors were more likely to perceive alcohol as improving overall survival (adjusted OR, 2.39; P = .02). Rates of meeting moderate-to-vigorous physical activity guidelines 1 year before diagnosis (adjusted OR, 0.55; P = .02) and maintaining and improving their exercise levels to meet these guidelines after diagnosis (adjusted OR, 0.48; P = .02) were lower in older survivors. Older and younger cancer survivors reported similar rates of receiving lifestyle behavior information from health care providers (P = .36 to .98). CONCLUSION: Older cancer survivors reported being less aware of the impact of smoking on their overall health, more likely perceived alcohol as beneficial to survival, and were less likely to meet exercise goals compared with younger survivors. Survivorship programs need to consider age when counseling on lifestyle behaviors.
Assuntos
Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Estilo de Vida , Neoplasias/terapia , Sobreviventes/psicologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora , Educação de Pacientes como Assunto , Fumar , Adulto JovemRESUMO
AIMS AND BACKGROUND: Ovarian cancer (OC) is the most lethal gynecologic malignancy. This study aims to explore the molecular mechanisms of OC and identify potential molecular targets for OC treatment. METHODS AND STUDY DESIGN: Microarray gene expression data (GSE14407) including 12 normal ovarian surface epithelia samples and 12 OC epithelia samples were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) between 2 kinds of ovarian tissue were identified by using limma package in R language (|log2 fold change| gt;1 and false discovery rate [FDR] lt;0.05). Protein-protein interactions (PPIs) and known OC-related genes were screened from COXPRESdb and GenBank database, respectively. Furthermore, PPI network of top 10 upregulated DEGs and top 10 downregulated DEGs was constructed and visualized through Cytoscape software. Finally, for the genes involved in PPI network, functional enrichment analysis was performed by using DAVID (FDR lt;0.05). RESULTS: In total, 1136 DEGs were identified, including 544 downregulated and 592 upregulated DEGs. Then, PPI network was constructed, and DEGs CDKN2A, MUC1, OGN, ZIC1, SOX17, and TFAP2A interacted with known OC-related genes CDK4, EGFR/JUN, SRC, CLI1, CTNNB1, and TP53, respectively. Moreover, functions about oxygen transport and embryonic development were enriched by the genes involved in the network of downregulated DEGs. CONCLUSIONS: We propose that 4 DEGs (OGN, ZIC1, SOX17, and TFAP2A) and 2 functions (oxygen transport and embryonic development) might play a role in the development of OC. These 4 DEGs and known OC-related genes might serve as therapeutic targets for OC. Further studies are required to validate these predictions.
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Biologia Computacional , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Ovarianas/metabolismo , Fatores de Transcrição SOXF/genética , Fator de Transcrição AP-2/genética , Fatores de Transcrição/genética , Regulação para Baixo , Feminino , Desenvolvimento Fetal , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Análise em Microsséries , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Oxigênio/metabolismo , Fatores de Transcrição SOXF/metabolismo , Fator de Transcrição AP-2/metabolismo , Fatores de Transcrição/metabolismo , Regulação para CimaRESUMO
The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.