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BACKGROUND: Pancreatic cancer (PanCa), ranked as the 4th leading cause of cancer-related death worldwide, exhibits an dismal 5-year survival rate of less than 5â¯%. Chronic pancreatitis (CP) is a known major risk factor for PanCa. Brusatol (BRT) possesses a wide range of biological functions, including the inhibition of PanCa proliferation. However, its efficacy in halting the progression from CP to pancreatic carcinogenesis remains unexplored. METHODS: We assess the effects of BRT against pancreatic carcinogenesis from CP using an experimentally induced CP model with cerulein, and further evaluate the therapeutic efficacy of BRT on PanCa by employing Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mouse model. RESULTS: Our finding demonstrated that BRT mitigated the severity of cerulein-induced pancreatitis, reduced pancreatic fibrosis and decreased the expression of α-smooth muscle actin (α-SMA), which is a biomarker for pancreatic fibrosis. In addition, BRT exerted effects against cerulein-induced pancreatitis via inactivation of NLRP3 inflammasome. Moreover, BRT significantly inhibited tumor growth and impeded cancer progression. CONCLUSIONS: The observed effect of BRT on impeding pancreatic carcinogenesis through targeting NLRP3 inflammasome suggests its good potential as a potential agent for treatment of PanCa.
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Proteína 3 que Contém Domínio de Pirina da Família NLR , Neoplasias Pancreáticas , Pancreatite Crônica , Animais , Masculino , Camundongos , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinogênese/genética , Ceruletídeo , Modelos Animais de Doenças , Fibrose , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Pancreatite Crônica/patologia , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/metabolismo , Pancreatite Crônica/genética , Quassinas , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
This study aims to investigate the mechanism of total saponins of Paridis Rhizoma in inducing the ferroptosis of MCF-7 cells and provide a theoretical basis for the clinical treatment of breast cancer with total saponins of Paridis Rhizoma. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the effects of different concentrations of total saponins of Paridis Rhizoma on the proliferation of MCF-7 cells. A phase contrast inverted microscope was used to observe the morphological changes of MCF-7 cells. The colony formation assay was employed to test the colony formation of MCF-7 cells. The lactate dehydrogenase(LDH) release test was conducted to determine the cell membrane integrity of MCF-7 cells. The cell scratch assay was employed to examine the migration of MCF-7 cells. After that, the level of reactive oxygen species(ROS) in MCF-7 cells was observed by an inverted fluorescence microscope, and the content of Fe~(2+) in MCF-7 cells was detected by the corresponding kit. Transmission electron microscopy was employed to observe the mitochondrial ultrastructure of MCF-7 cells. Western blot was employed to determine the expression of ferroptosis-related proteins, such as p53, solute carrier family 7 member 11(SLC7A11), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long-chain family member 4(ACSL4), and transferrin receptor protein 1(TFR1) in MCF-7 cells. The results showed that 1.5, 3, 4.5, 6, 7.5, and 9 µg·mL~(-1) total saponins of Paridis Rhizoma significantly inhibited the proliferation of MCF-7 cells, with the IC_(50) of 4.12 µg·mL~(-1). Total saponins of Paridis Rhizoma significantly damaged the morphology of MCF-7 cells, leading to the formation of vacuoles and the gradual shrinkage and detachment of cells. Meanwhile, total saponins of Paridis Rhizoma inhibited the colony formation of MCF-7 cells, destroyed the cell membrane(leading to the release of LDH), and shortened the migration distance of MCF-7 cells. Total saponins of Paridis Rhizoma treatment significantly increased the content of ROS, induced oxidative damage, and led to the accumulation of Fe~(2+) in MCF-7 cells. Furthermore, total saponins of Paridis Rhizoma changed the mitochondrial structure, increased the mitochondrial membrane density, led to the decrease or even disappear of ridges, promoted the expression of p53 protein, down-regulated the expression of SLC7A11 and GPX4, and up-regulated the expression of ACSL4 and TFR1. In summary, total saponins of Paridis Rhizoma can significantly inhibit the proliferation and migration of MCF-7 cells and destroy the cell structure by inducing ferroptosis.
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Neoplasias da Mama , Ferroptose , Espécies Reativas de Oxigênio , Rizoma , Saponinas , Humanos , Saponinas/farmacologia , Saponinas/química , Ferroptose/efeitos dos fármacos , Células MCF-7 , Rizoma/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Espécies Reativas de Oxigênio/metabolismo , Feminino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Proliferação de Células/efeitos dos fármacos , Primulaceae/químicaRESUMO
Encapsulating enzymes within metal-organic frameworks has enhanced their structural stability and interface tunability for catalysis. However, the small apertures of the frameworks restrict their effectiveness to small organic molecules. Herein, we present a green strategy directed by visible linker micelles for the aqueous synthesis of MAF-6 that enables enzymes for the catalytic asymmetric synthesis of chiral molecules. Due to the large pore aperture (7.6 Å), double the aperture size of benchmark ZIF-8 (3.4 Å), MAF-6 allows encapsulated enzyme BCL to access larger substrates and do so faster. Through the optimization of surfactants' effect during synthesis, BCL@MAF-6-SDS (SDS = sodium dodecyl sulfate) displayed a catalytic efficiency (Kcat/Km) that was 420 times greater than that of BCL@ZIF-8. This biocomposite efficiently catalyzed the synthesis of drug precursor molecules with 94-99% enantioselectivity and nearly quantitative yields. These findings represent a deeper understanding of de novo synthetic encapsulation of enzyme in MOFs, thereby unfolding the great potential of enzyme@MAF catalysts for asymmetric synthesis of organics and pharmaceuticals.
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The development of drug delivery systems with high drug loading capacity, low leakage at physiological pH, and rapid release at the lesion sites remains an ongoing challenge. In this work, core-shell poly(6-O-methacryloyl-D-galactose)@poly(tert-butyl methacrylate) (PMADGal@PtBMA) nanoparticles (NPs) of sub-50 nm are facilely synthesized by reversible addition-fragmentation chain transfer (RAFT) soap-free emulsion polymerization with the assistance of 12-crown-4. A hydrophilic poly(methacrylic acid) (PMAA) core can then be revealed after deprotection of the tert-butyl groups, which is negatively charged and can adsorb nearly 100% of incubated doxorubicin (DOX) from a solution at pH 7.4. The physical shrinkage of PMAA chains below pH 6.0 endows the core with the squeezing effect, therefore realizing rapid drug release. It is demonstrated that the DOX release rate of PMADGal@PMAA NPs at pH 5 was 4 times that at pH 7.4. Cellular uptake experiments confirm the high targeting ability of the galactose modified PMADGal shell to human hepatocellular carcinoma (HepG2) cells. The fluorescence intensity of DOX in HepG2 cells is 4.86 times that of HeLa cells after 3 h incubation. Moreover, 20% cross-linked NPs show the highest uptake efficiency by HepG2 cells due to their moderate surface charge, size and hardness. In summary, both the core and the shell of PMADGal@PMAA NPs promise the rapid site-specific release of DOX in HepG2 cells. This work provides a facile and an effective strategy to synthesize core-shell NPs for hepatocellular carcinoma targeting therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Células HeLa , Polímeros , Neoplasias Hepáticas/tratamento farmacológico , Doxorrubicina/farmacologia , Concentração de Íons de HidrogênioRESUMO
BACKGROUND: Neuroinflammation after aneurysmal subarachnoid hemorrhage (aSAH) leads to poor outcome of patients. High mobility group box 1 (HMGB1) contributes to inflammation through binding to receptors for advanced glycation end-products (RAGE) in various diseases. We aimed to determine the production of these two factors after aSAH and their relationship with clinical features. METHODS: HMGB1 and soluble RAGE (sRAGE) levels in cerebrospinal fluid (CSF) of aSAH patients and controls were measured, and their temporal courses were observed. The correlation between early concentrations (days 1-3) and clinical symptoms assessed by disease severity scores, neuroinflammation estimated by CSF IL-6 levels, as well as prognosis evidenced by delayed cerebral ischemia (DCI) and 6-month adverse outcome was investigated. Finally, combined analysis of early levels for predicting prognosis was confirmed. RESULTS: CSF HMGB1 and sRAGE levels were higher in aSAH patients than in controls (P < 0.05), and the levels decreased from higher early to lower over time. Their early concentrations were positively associated with disease severity scores, IL-6 levels, DCI and 6-month poor outcome (P < 0.05). HMGB1 ≥ 6045.5 pg/ml (OR = 14.291, P = 0.046) and sRAGE ≥ 572.0 pg/ml (OR = 13.988, P = 0.043) emerged as independent predictors for DCI, while HMGB1 ≥ 5163.2 pg/ml (OR = 7.483, P = 0.043) and sRAGE ≥ 537.3 pg/ml (OR = 12.653, P = 0.042) were predictors for 6-month poor outcome. Combined analysis of them improved predictive values of adverse prognosis. CONCLUSION: CSF HMGB1 and sRAGE levels of aSAH patients were increased early and then varied dynamically, which might act as potential biomarkers for poor outcome, especially when co-analyzed.
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Isquemia Encefálica , Proteína HMGB1 , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Interleucina-6 , Doenças Neuroinflamatórias , Prognóstico , Biomarcadores/líquido cefalorraquidiano , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/complicações , Infarto Cerebral/complicaçõesRESUMO
Galactosylated core-shell nanoparticles (NPs) with diameters of sub-50 nm were fabricated in one pot by reversible addition-fragmentation chain transfer (RAFT) soap-free emulsion polymerization. Their galactosylated shells and acidic cores endow them with high targeting and drug loading efficiencies, respectively. Morever, the physical shrinkage and cleavage of the disulfide cross-linked NPs can realize the rapid release of loaded doxorubicin (DOX) under pH 5.0 and reduced glutathione (GSH) conditions. The combination of these excellent properties resulted in an even lower IC50 of DOX-loaded NPs than free DOX, demonstrating that this platform would be promising in targeting the therapy of hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Doxorrubicina/uso terapêutico , Nanopartículas/química , Concentração de Íons de HidrogênioRESUMO
AIM: To explore the prevalence and related factors influencing diabetes stigma among Chinese young and middle-aged patients with type 2 diabetes. DESIGN: A cross-sectional, quantitative study was conducted through questionnaires. METHODS: A total of 453 young and middle-aged patients with type 2 diabetes were recruited. Questionnaire survey was conducted with convenience sampling from September 2019 to December 2020. This included demographic questionnaire, Type 2 Diabetes Stigma Assessment Scale (DSAS-2) and Connor-Davidson Resilience Scale (CD-RISC). The STROBE checklist was applied as the reporting guideline for this study. RESULTS: The scores of diabetes stigma and resilience of patients were 48.18 ± 14.52 and 66.02 ± 7.18, respectively. Diabetes stigma was negatively correlated with resilience, the correlation coefficient was -0.581. The results showed that the complications, diabetes year, monthly income and insulin treatment are important factors affecting stigma. In addition, it is resilience that was a protective factor of diabetes stigma, explaining 27.2% of the variance in diabetes stigma.
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Diabetes Mellitus Tipo 2 , Resiliência Psicológica , Pessoa de Meia-Idade , Humanos , Estudos Transversais , Psicometria , Inquéritos e QuestionáriosRESUMO
M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in the context of EBI are not yet fully understood. In this study, firstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation, and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further confirmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This finding provided new insights for the treatment of EBI.
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GABAergic neurons in the vestibular nuclei (VN) participate in multiple vital vestibular sensory processing allowing for the maintenance and rehabilitation of vestibular functions. However, although the important role of GABA in the central vestibular system has been widely reported, the underlying neural circuits between VN GABAergic neurons and other brain functional regions remain elusive, which limits the further study of the underlying mechanism. Hence, it is necessary to elucidate neural connectivity based on outputs and inputs of GABAergic neurons in the VN. This study employed a modified rabies virus retrograde tracing vector and cre-dependent adeno-associated viruses (AAVs) anterograde tracing vector, combined with a transgenic VGAT-IRES-Cre mice, to map the inputs and outputs of VN GABAergic neurons in the whole brain. We found that 51 discrete brain regions received projections from VN GABAergic neurons in the whole brain, and there were 77 upstream nuclei innervating GABAergic neurons in the VN. These nuclei were mainly located in four brain regions, including the medulla, pons, midbrain, and cerebellum. Among them, VN GABAergic neurons established neural circuits with some functional nuclei in the whole brain, especially regulating balance maintenance, emotion control, pain processing, sleep and circadian rhythm regulation, and fluid homeostasis. Therefore, this study deepens a comprehensive understanding of the whole-brain neural connectivity of VN, providing the neuroanatomical information for further research on the neural mechanism of the co-morbidities with vestibular dysfunction.
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Oxygen is an essential molecule for animal respiration, growth, and survival. Unlike in terrestrial environments, contamination and climate change have led to the frequent occurrence of hypoxia in aquatic environments, thus impacting aquatic animal survival. However, the adaptative mechanisms underlying fish responses to environmental hypoxia remain largely unknown. Here, we used large yellow croaker ( Larimichthys crocea) and large yellow croaker fry (LYCF) cells to investigate the roles of the Hif-1α/Hsf1/Hsp70 signaling pathway in the regulation of cellular redox homeostasis, and apoptosis. We confirmed that hypoxia induced the expression of Hif-1α, Hsf1, and Hsp70 in vivo and in vitro. Genetic Hsp70 knockdown/overexpression indicated that Hsp70 was required for maintaining redox homeostasis and resisting oxidative stress in LYCF cells under hypoxic stress. Hsp70 inhibited caspase-dependent intrinsic apoptosis by maintaining normal mitochondrial membrane potential, enhancing Bcl-2 mRNA and protein expression, inhibiting Bax and caspase3 mRNA expression, and suppressing caspase-3 and caspase-9 activation. Hsp70 suppressed caspase-independent intrinsic apoptosis by inhibiting nuclear translocation of apoptosis-inducing factor (AIF) and disturbed extrinsic apoptosis by inactivating caspase-8. Genetic knockdown/overexpression of Hif-1α and dual-luciferase reporter assay indicated that Hif-1α activated the Hsf1 DNA promoter and enhanced Hsf1 mRNA transcription. Hsf1 enhanced Hsp70 mRNA transcription in a similar manner. In summary, the Hif-1α/Hsf1/Hsp70 signaling pathway plays an important role in regulating redox homeostasis and anti-apoptosis in L. crocea under hypoxic stress.
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Fatores de Transcrição de Choque Térmico/metabolismo , Homeostase/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/farmacologia , Perciformes/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose , Linhagem Celular , Clonagem Molecular , Biologia Computacional , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/genética , Homeostase/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxirredução , Oxigênio/química , Perciformes/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Água/químicaRESUMO
The large yellow croaker (Larimichthys crocea), which is an economically important mariculture fish in China, is often exposed to environmental hypoxia. Reactive oxygen species (ROS) homeostasis is essential for the maintenance of normal physiological conditions in an organism. Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish. Furthermore, the sources of ROS overproduction in marine fish under hypoxic stress are poorly known. In this study, we investigated the effects of hypoxia on redox homeostasis in L. crocea and the impact of impaired redox homeostasis on fish. We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L. crocea and its cell line (large yellow croaker fry (LYCF) cells). We subsequently detected a marked increase in the antioxidant systems of the fish. However, imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress. Cell viability showed a remarkable decrease while oxidative indicators, such as malondialdehyde, protein carbonylation, and 8-hydroxy-2 deoxyguanosine, showed a significant increase after hypoxia, accompanied by tissue damage. N-acetylcysteine (NAC) reduced ROS levels, alleviated oxidative damage, and improved cell viability in vitro. Appropriate uptake of ROS scavengers (e.g., NAC and elamipretide Szeto-Schiller-31) and inhibitors (e.g., apocynin, diphenylene iodonium, and 5-hydroxydecanoate) may be effective at overcoming hypoxic toxicity. Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.
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Antioxidantes/metabolismo , Peixes/metabolismo , Estresse Oxidativo/fisiologia , Oxigênio/química , Oxigênio/metabolismo , Espécies Reativas de Oxigênio , Animais , Linhagem Celular , Sobrevivência Celular , Meio Ambiente , Homeostase , NADPRESUMO
BACKGROUND: In 2017 Tuta absoluta was identified as an invasive species in China. Due to its rapid geographic expansion and the severe crop damage it causes, T. absoluta poses a serious threat to China's tomato production industry. To determine its geographic distribution and host range, intensive surveys and routine monitoring were conducted across the Chinese mainland between 2018 and 2019. The population colonization coefficient (PCC; ratio of colonized sites and prefectures) and population occurrence index (POI; ratio of infested host species and PCCs) were calculated. RESULTS: In northwestern China, T. absoluta populations established in Xinjiang exhibited a medium PCC value (~0.03). In southwestern China, populations in Yunnan and its five neighboring provinces exhibited high (~0.50 in Yunnan and Guizhou), or low (<0.02 in Guangxi, Sichuan, Hunan, and Chongqing) PCC values. In the Chinese mainland, infestations of four crop plant species (tomato, eggplant, potato, and Chinese lantern) and two wild plant species (black nightshade and Dutch eggplant) were identified; tomatoes were infested in every colonized province. Chinese lantern and Dutch eggplant are potentially novel hosts. Yunnan, Guizhou, and Xinjiang experienced the most serious damage (POI). In southwestern China, observed damage significantly decreased with increased distance from the first discovery site of T. absoluta to the farthest county of an infested province increased. CONCLUSION: T. absoluta populations are well-established and could potentially spread to other regions of China. The present study helps to inform the establishment of better pest management guidelines and strategies in China and tomato-producing regions worldwide. © 2021 Society of Chemical Industry.
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Mariposas , Solanum lycopersicum , Animais , China/epidemiologia , Surtos de Doenças , Especificidade de Hospedeiro , Larva , América do SulRESUMO
Stearoyl-CoA-desaturase 1 (SCD1) deficiency mediates apoptosis in colorectal cancer cells by promoting ceramide de novo synthesis. The mechanisms underlying the cross-talk between SCD1 and ceramide synthesis have not been explored. We treated colorectal cancer cells with an SCD1 inhibitor and examined the effects on gene expression, cell growth, and cellular lipid contents. The main effect of SCD1 inhibition on the fatty acid contents of colorectal cancer cells was a decrease in monounsaturated fatty acids (MUFAs). RNA sequencing (RNA-seq) showed that the most intense alteration of gene expression after SCD1 inhibition occurred in the NF-κB signaling pathway. Further experiments revealed that SCD1 inhibition resulted in increased levels of phosphorylated NF-κB p65 and increased nuclear translocation of NF-κB p65. Treatment with an NF-κB inhibitor eliminated several effects of SCD1 inhibition, mainly including overexpression of serine palmitoyltransferase1 (SPT1), elevation of dihydroceramide contents, and suppression of cell growth. Furthermore, treatment with supplemental oleate counteracted the SCD1-induced NF-κB activation and downstream effects. In summary, our data demonstrate that the NF-κB pathway plays a role in SCD1 deficiency-induced ceramide de novo synthesis in colorectal cancer cells, and that reduced MUFA levels contribute to the course.
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Ceramidas/metabolismo , NF-kappa B/metabolismo , Estearoil-CoA Dessaturase/deficiência , HumanosRESUMO
The complete mitochondrial genome of a predominant parasitoid, Necremnus tutae (Hymenoptera: Eulophidae) (GenBank accession number MT916846) is 15,252 bp in length, and contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes, and an A + T-rich region. The overall base composition is 38.86% for A, 7.14% for C, 8.57% for G, and 45.43% for T, with a high AT bias of 84.29%. ATA, ATT, ATG were initiation codons and TAA and T were termination codons. All the 22 tRNAs displayed a typical cloverleaf secondary structure, except for trnS1 and trnR which lacked the dihydrouracil (DHU) arm. Phylogenetic analyses were performed using 13 PCGs showed that N. tutae is closely related to Tenthredo tienmushana, which in accordance with the traditional classification.
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Sorafenib (SOR) resistance remains a major obstacle in the effective treatment of hepatocellular carcinoma (HCC). A number of long noncoding RNAs (lncRNAs) are responsible for this chemoresistance. This study aimed to reveal the essential function of a recently defined lncRNA, lncRNA-POIR, in the epithelial-mesenchymal transition (EMT) and SOR sensitivity of HCC cells. SOR-induced cytotoxicity was analyzed via cell counting kit-8 and ethynyl-2'-deoxyuridine incorporation assays, whereas immunoblotting and confocal immunofluorescence were used to determine the expression levels of EMT markers. Furthermore, loss- or gain-of-function approaches were used to demonstrate the role of lncRNA-POIR/miR-182-5p on EMT and SOR sensitivity in HCC. The direct interaction between lncRNA-POIR and miR-182-5p was verified using a luciferase reporter assay. We found that knockdown of lncRNA-POIR sensitized HCC cells to SOR and simultaneously reversed EMT. As expected, miR-182-5p was confirmed as the downstream target of lncRNA-POIR. Moreover, miR-182-5p overexpression clearly reversed EMT and promoted SOR-induced cytotoxicity in representative HCC cells, whereas miR-182-5p downregulation played a contrasting role; miR-182-5p knockdown abolished the modulatory effects of lncRNA-POIR siRNA on EMT and SOR sensitivity. Together, these pieces of data suggest that lncRNA-POIR promotes EMT progression and suppresses SOR sensitivity simultaneously by sponging miR-182-5p. Thus, we proposed a compelling rationale for the use of lncRNA-POIR as a promising predictor of SOR response and as a potential therapeutic target for HCC treatment in the future.
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Carcinoma Hepatocelular/tratamento farmacológico , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , Sorafenibe/farmacologia , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células Tumorais CultivadasRESUMO
Background: Aortic valve sclerosis (AVSc), a common precursor to calcific aortic valve disease, may progress into advanced aortic stenosis with hemodynamic instability. However, plasma biomarkers of such a subclinical condition remain lacking. Since impaired fibrinolysis featuring dysregulated tissue plasminogen activator (t-PA) is involved in several cardiovascular diseases, we investigated whether endogenous t-PA was also associated with AVSc. Methods: Plasma t-PA levels were measured in 295 consecutive patients undergoing standard echocardiography and Doppler flow imaging. Multiple logistic regression analyses were used to assess the association between t-PA and AVSc. Receiver operating characteristic curve analysis was performed for determining the diagnostic value of t-PA for AVSc. The performance of adding t-PA to clinical signatures of AVSc was evaluated. Concentration of t-PA was assessed in human sclerotic and non-sclerotic aortic valves by histology and immunohistochemistry analysis. Results: Plasma t-PA was higher in patients with AVSc than in non-AVSc counterparts (median, 2063.10 vs. 1403.17 pg/mL, p < 0.01). C-statistics of plasma t-PA for discriminating AVSc was 0.698 (95%CI: 0.639-0.758). The performance of t-PA for identifying AVSc was better among male and non-hypertensive patients [C-statistics (95%CI): 0.712 (0.634-0.790) and 0.805 (0.693-0.916), respectively]. Combination of t-PA and clinical factors improved classification of the patients (category-free NRI: 0.452, p < 0.001; IDI: 0.020, p = 0.012). The concentration of t-PA was three times higher in sclerotic compared to non-sclerotic aortic valves. Conclusion: Elevated circulating t-PA level confers an increased risk for AVSc. Further prospective studies with larger sample size are needed to examine if t-PA could serve as a diagnostic clinical marker for AVSc.
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Aquatic vegetation is an important part of lake ecosystems and plays a vital role in improving water quality and maintaining biodiversity. At present, China's lakes are facing eutrophication and the degradation of aquatic vegetation. The monitoring of temporal and spatial variations in aquatic vegetation and elucidating the main influencing factors are of great significance for protecting aquatic vegetation and restoring eutrophic lake ecosystems. Therefore, we introduced the Vegetation Present Frequency (VPF) method to extract data on aquatic vegetation and combined this with meteorological factors and human activities to analyze the temporal and spatial in Lake Hongze based on MODIS data from 2007 to 2017. The VPF of aquatic vegetation in Lake Hongze showed clear seasonal and interannual variations. The VPF was significantly higher in spring and summer than in autumn and winter (P<0.05, one way-ANOVA). The maximum VPF of 0.43 occurred in June but the minimum VPF of 0.21 was recorded in January. The VPF from April to October, during the growing season of aquatic vegetation, was significantly higher than in other months. The annual mean VPF of the northern lake area (Z1) decreased significantly (R2=0.56, P<0.01), ranging from the highest value of 0.50 in 2008 to the lowest value of 0.27 in 2016 (a decrease of 45.8%), indicating a significant loss of aquatic vegetation. Spatially, the VPF of Lake Hongze decreases from the coastal zone to the open water, and the VPF values of the northern (Z1) and western sub-lakes (Z2) are higher than that of other lakes segments (Z3-Z5). The interannual variation in VPF for the entire lake was not significantly affected by annual mean temperature, annual precipitation, annual mean wind speed, or annual sunshine duration (P>0.05), indicating that meteorological factors have little influence on interannual variation of aquatic vegetation in this lake. However, total suspended matter concentration was significantly negatively correlated with VPF in Z1 area (R2=0.48, P<0.01), with strong sand-mining activities occurring in this area. These results indicate that the increase of total suspended matter concentrations caused by sand mining is an important driving factor in the decline of aquatic vegetation in the Z1 segment.
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The frequency and amplitude of heat waves are predicted to increase under future climate change conditions. We still lack a detailed understanding of how changes in the frequency and amplitude of heat waves are linked to the life history traits and biocontrol efficiency of host-feeding parasitoids. In the present study, we simulated a series of heat waves as a function of amplitude and frequency to investigate the effects on the life history traits of the host-feeding parasitoid Eretmocerus hayati. We found that both the amplitude and frequency of heat waves significantly affected the adult phenotypes. In the low-amplitude heat wave group, the frequency of heat waves did not change the life history traits of the parasitoid; however, when the heat amplitude reached 42 °C, medium (four times/week) and high frequencies (seven times/week) of heat waves detrimentally affected these parameters. Hence, these findings suggest that to obtain optimal biological control with this parasitoid, we need to carefully monitor heat wave pattern (especially the amplitude and frequency) over the short term (usually 7-10 days) before releasing a host-feeding parasitoid.
RESUMO
BACKGROUND: Nelson Bay orthoreovirus (NBV) was first isolated over 40 years ago from a fruit bat in Australia. Normally, NBV does not cause human diseases, but recently several NBV strains have been associated with human respiratory tract infections, thus attracting clinical attention. Autophagy, an evolutionarily conserved process in eukaryotic cells, degrades intracellular substrates, participates in multiple physiological processes, and maintains cellular homeostasis. In addition, autophagy is intimately involved in viral infection. METHODS: A new strain of NBV, isolated from a patient with a respiratory tract infection who returned to Japan from Bali, Indonesia, in 2007, was used in this study. NBV was rescued using a reverse genetics system involving cotransfection of BHK cells with 11 plasmids (pT7-L1 MB, pT7-L2 MB, pT7-L3 MB, pT7-M1 MB, pT7-M2 MB, pT7-M3 MB, pT7-S1 MB, pT7-S2 MB, pT7-S3 MB, pT7-S4 MB, and pcDNA3.1-T7), yielding NBV-MB. Recovered viruses were confirmed by immunofluorescence. The effect of NBV-MB on autophagy was evaluated by measuring the LC3-I/II proteins by immunoblot analysis after infection of BHK cells. Furthermore, after treatment with rapamycin (RAPA), 3-methyladenine (3-MA), chloroquine (CQ), or plasmid (GFP-LC3) transfection, the changes in expression of the LC3 gene and the amount of LC3-I/II protein were examined. In addition, variations in viral titer were assayed after treatment of BHK cells with drugs or after transfection with plasmids pCAGM3 and pCAGS3, which encode virus nonstructural proteins µNS and σNS, respectively. RESULTS: NBV-MB infection induced autophagy in host cells; however, the level of induction was dependent on viral replication. Induction of autophagy increased viral replication. By contrast, inhibiting autophagy suppressed NBV replication, albeit not significantly. The NBV-MB nonstructural protein µNS was involved in the induction of autophagy with viral infection. CONCLUSIONS: NBV-MB infection triggered autophagy. Also, the NBV nonstructural protein µNS may contribute to augmentation of autophagy upon viral infection.
Assuntos
Autofagia , Interações entre Hospedeiro e Microrganismos , Orthoreovirus/fisiologia , Replicação Viral , Linhagem Celular , Células HEK293 , Humanos , Infecções por Reoviridae/virologia , Genética Reversa , Carga Viral , Proteínas Virais/genéticaRESUMO
Parasitoids are insects (usually wasps or flies) that lay eggs within or on other insects (their hosts). Host-feeding parasitoids lay eggs to parasitize the host and feed directly on the host for nourishment. Temperature is the most critical factor affecting insect behavioral responses. Few studies have focused on the impacts of variable temperatures across different life stages on the behaviors of host-feeding parasitoids. This study investigated the effects of temperature experienced during the preadult and adult stages on the life history traits and life table parameters of females of a host-feeding parasitoid, Eretmocerus hayati. Our results show that the temperatures experienced during the preadult and adult stages significantly change life history traits (immature development, adult longevity, host feeding and fecundity). Increasing the preadult temperature resulted in shorter development times for immature stages of the parasitoid, and decreasing the temperature during the adult stage increased reproduction and longevity. Most importantly, we found that host-feeding events changed with temperature rather than life stage. The daily host-feeding ability of the parasitoid increased with increasing temperature at all temperatures except the stress temperature (34 °C). Furthermore, switching temperatures at the immature stage and adult stage can increase the values of life table parameters, with the highest intrinsic rate of increase (r) occurring in the 30/26 °C treatment. This study provides new insight into the mass rearing of parasitic natural enemies.