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BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. METHODS: Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. RESULTS: ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. CONCLUSION: This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.
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Adenocarcinoma , Neoplasias Pancreáticas , Animais , Camundongos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Antígeno B7-H1/metabolismo , Transferases/uso terapêutico , Receptor de Morte Celular Programada 1 , Camundongos Endogâmicos C57BL , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.
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Transtorno Depressivo Maior , Habenula , Camundongos , Animais , Masculino , Habenula/fisiologia , Adenosina/farmacologia , Neurônios/metabolismo , Hipotálamo/metabolismo , Receptor A2A de Adenosina/metabolismoRESUMO
Stick-slip behavior between friction pairs causes severe vibration problems such as abrasion and noise pollution, leading to material loss and deterioration in human health. This phenomenon is extremely complex because the surfaces of friction pairs have various asperities with different sizes. Therefore, it is of importance to understand the scale effect of asperities on the stick-slip behavior. Here, we selected four kinds of zinc-coated steels with multiscale surface asperities as a presentative example to reveal what types of asperities play the key role in affecting the stick-slip behavior. It is discovered that the stick-slip behavior is dominated by the density of small-scale asperities rather than large-scale asperities. High-density small-scale asperity increases the potential energy between asperities of the friction pairs, which leads to stick-slip behavior. It is suggested that decreasing the density of small-scale asperity on the surface significantly suppresses the stick-slip behavior. The present study reveals the scale effect of surface asperities on the stick-slip behavior and thus could offer a pathway to tailoring the surface topography of a wide range of materials for suppressing the stick-slip behavior.
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Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the "inflammation-MMP9-angiogenesis" cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV.
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Neovascularização de Coroide , Pontos Quânticos , Humanos , Camundongos , Animais , Idoso , Metaloproteinase 9 da Matriz/uso terapêutico , Minociclina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Sistemas de Liberação de Medicamentos , Inibidores da Angiogênese/uso terapêutico , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Immune checkpoint blockade (ICB) therapy targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients with pancreatic cancer remain resistant to ICB. Moreover, there is a lack of optimal biomarkers for the prediction of response to this therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, termed zinc finger Asp-His-His-Cys-type palmitoyltransferases (ZDHHC), which precisely control various cancer-related protein functions and represent promising drug targets for cancer therapy. Here, we revealed that tumor cell-intrinsic ZDHHC9 was overexpressed in pancreatic cancer tissues and associated with impaired anti-tumor immunity. In syngeneic pancreatic tumor models, the knockdown of ZDHHC9 expression suppressed tumor progression and prolonged survival time of mice by modifying the immunosuppressive ('cold') to proinflammatory ('hot') tumor microenvironment. Furthermore, ZDHHC9 deficiency sensitized anti-PD-L1 immunotherapy mainly in a CD8+ T cell dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in pancreatic tumors. Collectively, our findings indicate that ZDHHC9 overexpression in pancreatic tumors is a mechanism involved in the inhibition of host anti-tumor immunity and highlight the importance of inactivating ZDHHC9 as an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy against pancreatic cancer.
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Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Camundongos , Aciltransferases/genética , Imunoterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMO
The adenosine A2A receptor (A2AR), a G protein-coupled receptor, is involved in numerous and varied physiological and pathological processes, including inflammation, immune responses, blood flow, and neurotransmission. Accordingly, it has become an important drug target for the treatment of neuropsychiatric disorders. However, the exact brain distribution of A2AR in regions outside the striatum that display relatively low levels of endogenous A2AR expression has hampered the exploration of A2AR functions under both physiological and pathological conditions. To further study the detailed distribution of the A2AR in low-expression regions, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice) via CRISPR/Cas9 technology. Here, using CRISPR/Cas9 technology, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice). The A2AR-tag mice exhibited normal locomotor activity and emotional state. Consistent with previous studies, A2AR fluorescence was widely detected in the striatum, nucleus accumbens, and olfactory tubercles, with numerous labeled cells being evident in these regions in the A2AR-tag mouse. Importantly, we also identified the presence of a few but clearly labeled cells in heterogeneous brain regions where A2AR expression has not previously been unambiguously detected, including the lateral septum, hippocampus, amygdala, cerebral cortex, and gigantocellular reticular nucleus. The A2AR-tag mouse represents a novel useful genetic tool for monitoring the expression of A2AR and dissecting its functions in brain regions other than the striatum.
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Retinopathy of prematurity (ROP) is characterized by pathological angiogenesis and associated inflammation in the retina and is the leading cause of childhood blindness. MiRNA-223 (miR-223) drives microglial polarization toward the anti-inflammatory phenotype and offers a therapeutic approach to suppress inflammation and consequently pathological neovascularization. However, miRNA-based therapy is hindered by the low stability and non-specific cell-targeting ability of delivery systems. In the present study, we developed folic acid-chitosan (FA-CS)-modified mesoporous silica nanoparticles (PMSN) loaded with miR-223 to regulate retinal microglial polarization. The FA-CS/PMSN/miR-223 nanoparticles exhibited high stability and loading efficiency, achieved targeted delivery, and successfully escaped from lysosomes. In cultured microglial cells, treatment with FA-CS/PMSN/miR-223 nanoparticles upregulated the anti-inflammatory gene YM1/2 and IL-4RA, and downregulated the proinflammatory genes iNOS, IL-1ß, and IL-6. Notably, in a mouse oxygen-induced retinopathy model of ROP, intravitreally injected FA-CS/PMSN/miR-223 nanoparticles (1 µg) decreased the retinal neovascular area by 52.6%. This protective effect was associated with the reduced and increased levels of pro-inflammatory (M1) and anti-inflammatory (M2) cytokines, respectively. Collectively, these findings demonstrate that FA-CS/PMSN/miR-223 nanoparticles provide an effective therapeutic strategy for the treatment of ROP by modulating the miR-223-mediated microglial polarization to the M2 phenotype.
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Quitosana , MicroRNAs , Retinopatia da Prematuridade , Animais , Quitosana/uso terapêutico , Modelos Animais de Doenças , Ácido Fólico , Humanos , Imunomodulação , Recém-Nascido , Inflamação , Interleucina-6 , Camundongos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Neovascularização Patológica , Oxigênio/uso terapêutico , Retinopatia da Prematuridade/tratamento farmacológico , Retinopatia da Prematuridade/patologia , Dióxido de Silício/uso terapêuticoRESUMO
Glioblastoma (GBM), an aggressive primary tumor, is common in humans, accounting for 12-15% of all intracranial tumors, and has median survival of fewer than 15 months. Since a growing body of evidence suggests that conventional drugs are ineffective against GBM, our goal is to find emerging therapies that play a role in its treatment. This research constructs a risk model to predict the prognosis of GBM patients. A set of genes associated with GBM was taken from a GBM gene data bank, and clinical information on patients with GBM was retrieved from the Cancer Genome Atlas (TCGA) data bank. One-way Cox and Kaplan-Meier analyses were performed to identify genes in relation to prognosis. Groups were classified into high and low expression level of PTEN expression. Prognosis-related genes were further identified, and multi-factor Cox regression analysis was used to build risk score equations for the prognostic model to construct a survival prognostic model. The area under the ROC curve suggested that the pattern had high accuracy. When combined with nomogram analysis, GJB2 was considered an independent predictor of GBM prognosis. This study provides a potential prognostic predictive biological marker for GBM patients and confirms that GJB2 is a key gene for GBM progression.
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HCLS1-associated protein X-1 (HAX1), an anti-apoptotic molecular, overexpresses in glioma. However, the role of HAX1 in glioma cell surviving in hypoxic environment remains unclear. Western blotting, qRT-PCR, Transwell assay, TUNEL assay, wounding healing assay, clone formation, tumour xenograft model and immunohistochemical staining were used to investigate the role of HAX1 in glioma. HAX1 regulated by HIF-1α was increased in glioma cells cultured in hypoxia. Silencing of HAX1 could cause an increased apoptosis of glioma cells cultured in hypoxia. Silencing of HAX1 also decreased the proliferation, migration and invasion of glioma cells cultured in hypoxia. Increased mitochondrial fission could prevent glioma cells from the damage induced by HAX1 knockdown in hypoxia. Furthermore, HAX1 was found to regulate glioma cells through phosphorylated AKT/Drp signal pathway. In conclusion, our study suggested that HAX1 promoted survival of glioma cells in hypoxic environment via AKT/Drp signal pathway. Our study also provided a potential therapeutic target for glioma.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Glioma/etiologia , Glioma/patologia , Hipóxia/genética , Dinâmica Mitocondrial/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fatores de Iniciação em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioma/metabolismo , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
Nickel (Ni+2) accumulation in wastewater treatment sludge poses a potential environmental risk with biosolids-land application. An incubation experiment was conducted to evaluate the effect of nanoparticles of zero-valent iron (nZVI) on Ni+2 sorption in biosolids-treated agricultural soils. Two application rates of biosolids (0, 5%, w/w) and four treatment levels (0, 1, 5, and 10 g/kg) of nZVI were examined, either separately or interactively. The results of this study showed significant differences in Ni+2 sorption capacity between different nZVI treatments. The initial Ni+2 concentration in biosolids-amended soil significantly affected Ni sorption in the soil treated with nZVI. The "H-shape" of sorption isotherm in nZVI-treated soil reflects strong interaction between the Ni concentration and the nZVI treatment, while the C-shape of sorption isotherm in biosolids-amended soil without the nZVI treatment indicates intermediate affinity for Ni+2 sorption. Nickel retention in soil was increased with the increase of nZVI levels. The removal efficiency of Ni+2 by nZVI from solution was increased with the increase of pH from 5 to 11 and reached a maximum of 99.56% at pH 11 and nZVI treatment of 10 g/kg. The Ni+2 desorption rate decreased from 92 to 7, 4, and 1% with increasing nZVI treatment levels from 0 to 1, 5, and 10 g/kg, respectively, with a soil Ni+2 concentration of 50 mg/L. The maximum adsorption capacity (?max) of 10 g/kg nZVI-treated soil was 333.3 mg/g, which was much higher than those from the other treatments of 0 (5 mg/g), 1 (25 mg/g), and 5 g/kg (125 mg/g). The underlying mechanism for Ni+2 immobilization using nZVI in an aquatic environment is controlled by a sorption process, reduction of metal ion to zero-valent metal, as well as (co)precipitation. Moreover, increasing the nZVI treatment level in biosolids-amended soil significantly decreased bioavailable Ni+2 concentrations in the soil.
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Progranulin (PGRN) is an autocrine growth factor and has important effects on regulation of cell growth, motility, tissue repair and embryonic development. Recent years, several researches found the expression of PGRN was at higher levels in a number of cancer cells and its high levels are associated with poor outcome of patients. More and more studies investigated the role of PGRN in cancer and found PGRN exerted various biological functions in cancer cells, such as promoting proliferation, inhibiting apoptosis, inducing migration and invasion of cells, accelerating angiogenesis and enhancing the effectiveness of chemoresistance and radiation. Now the effects of PGRN have been demonstrated in several cancers, including breast cancer, lung cancer, and bladder cancer. In addition, several signaling pathways and molecules are involved in the effects of PGRN on cancer cells, including Akt, mitogen-activated protein kinase (MAPK), vascular endothelial growth factor (VEGF) and cyclin D1. Therefore, PGRN is probably a significant diagnostic and prognostic biomarker for cancer and may be a potential target for anti-cancer therapy. Here, we reviewed the advancing field of PGRN in cancer as well as several signaling pathways activated by PGRN and confirmed PGRN is a key role in cancer. Moreover, future studies are still necessary to elucidate the biological functions and signaling pathways of PGRN in cancer.
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Genetic factors play an important role in the pathogenesis of ischemic stroke. Of these, epigenetic modifications provide a new direction for the study of ischemic stroke pathogenesis. This study aimed to determine the correlation between DNA methylation of the gene encoding S-adenosylhomocysteine hydrolase (AHCY) and the risk of ischemic stroke in 64 ischemic stroke patients and 138 patients with traumatic brain injury (control group). The methylation level of AHCY was analyzed using quantitative methylation-specific polymerase chain reaction. Statistically significant differences in AHCY methylation levels were observed between the case group [medians (interquartile range): 0.13% (0.09%, 0.27%)] and the control group [0.06% (0.00%, 0.17%), p < 0.0001], and these associations remained significant in both male (p = 0.003) and female (p = 0.0005) subjects. A subgroup analysis by age revealed a considerably higher percentage of methylated AHCY in the case group than the control group in all age groups (age < 60 years, p = 0.007; age ≥ 60 years, p < 0.0001). A receiver operating characteristic (ROC) curve analysis revealed a trend toward a role for AHCY methylation as an indicator of risk in all ischemic patients [area under the curve (AUC) = 0.70, p = 0.0001], male patients (AUC = 0.67, p = 0.004), and female patients (AUC = 0.75, p = 0.0002). Our study confirmed a significant association between the AHCY DNA methylation level and the risk of ischemic stroke, suggesting that this gene methylation pattern may be a potential diagnostic marker of ischemic stroke.
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Adenosil-Homocisteinase/metabolismo , Isquemia Encefálica/genética , Metilação de DNA , AVC Isquêmico/genética , Adenosil-Homocisteinase/genética , Idoso , Área Sob a Curva , Biomarcadores , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Curva ROCRESUMO
Cerebral vasospasm is the major cause of a poor outcome after aneurysmal subarachnoid hemorrhage (aSAH), and effective treatments for vasospasm are limited. The purpose of this study was to research the impact of electroacupuncture (EA) on cerebral vasospasm and the outcomes of patients with aSAH. A total of 60 age- and sex-matched aSAH patients were collected from Ningbo First Hospital between December 2015 and June 2017. All patients were given a basic treatment of nimodipine and randomized into two groups. The study group was treated with EA therapy on the Baihui (GV20) acupoint, and the control group was given mock transcutaneous electrical nerve stimulation. Cerebral vasospasm was measured by computed tomographic perfusion (CTP) and transcranial doppler (TCD). The mean flow velocity (MFV) in the middle cerebral artery (MCA), cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) of the patients were analyzed. The CBV and MTT exhibited significant differences between the study and control groups on the 1st (p = 0.026 and p = 0.001), 7th (p = 0.020 and p < 0.001), and 14th (p = 0.001 and p < 0.001) day after surgery, whereas CBF exhibited statistical significance only on the 14th day after surgery (p = 0.002). The MFV in MCA were significantly reduced after EA treatment in all patients (all p < 0.001). Additionally, the MFV in the MCA in patients treated with EA were considerably reduced compared with those of the control group (3rd day p = 0.046; 5th day, p = 0.010; 7th day, p < 0.001). Moreover, better outcomes were noted in the EA-treated group for the 1st month (p < 0.001) and 3rd month (p = 0.001) after surgery than in the control group. In conclusion, EA represents a potential method to treat cerebral vasospasm after aSAH and can improve the outcomes of patients with aSAH.
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Cereals and soybeans are the main food sources for the majority of Chinese. This study evaluated the effects of four common cooking methods including steaming, boiling, frying, and milking on selenium (Se) content and speciation in seven selenium bio-fortified cereals and soybeans samples. The Se concentrations in the selected samples ranged from 0.91 to 110.8 mg/kg and selenomethionine (SeMet) was detected to be the main Se species. Total Se loss was less than 8.1% during the processes of cooking except milking, while 49.1% of the total Se was lost in milking soybean for soy milk due to high level of Se in residuals. It was estimated that about 13.5, 24.0, 3.1, and 46.9% of SeMet were lost during the processes of steaming, boiling, frying, and milking, respectively. Meanwhile, selenocystine (SeCys2) and methylselenocysteine (SeMeCys) were lost completely from the boiled cereals. Hence, steaming and frying were recommended to cook Se-biofortified cereals in order to minimize the loss of Se.
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Culinária/métodos , Grão Comestível/química , Alimentos Fortificados , Glycine max/química , Selênio/análise , China , Cistina/análogos & derivados , Cistina/análise , Análise de Alimentos , Compostos Organosselênicos/análise , Selenocisteína/análogos & derivados , Selenocisteína/análise , Selenometionina/análise , Leite de Soja/químicaRESUMO
The present study investigated the beneficial role of selenium (Se) in protecting oilseed rape (Brassica napus L.) plants from cadmium (Cd+2) and lead (Pb+2) toxicity. Exogenous Se markedly reduced Cd and Pb concentration in both roots and shoots. Supplementation of the medium with Se (5, 10, and 15 mg kg-1) alleviated the negative effect of Cd and Pb on growth and led to a decrease in oxidative damages caused by Cd and Pb. Furthermore, Se-enhanced superoxide free radicals ([Formula: see text]), hydrogen peroxide (H2O2), and lipid peroxidation, as indicated by malondialdehyde accumulation, but decreased superoxide dismutase and glutathione peroxidase activities. Meanwhile, the presence of Cd and Pb in the medium affected Se speciation in shoots. The results suggest that Se could alleviate Cd and Pb toxicity by preventing oxidative stress in oilseed rape plant.
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In order to investigate the interrelationship between particulate matter (PM) size and in vitro toxicological effects of mainstream cigarette smoke, PM sized between 10 nm and 10 µm in mainstream cigarette smoke was sampled and divided into six stages. The in vitro cytotoxicity, genotoxicity and cell inhibition effects of PM were assessed by the neutral red cytotoxicity assay, Salmonella mutagenicity assay, micronucleus test and flow cytometry analysis, respectively. The results showed that all test samples were cytotoxic in the neutral red cytotoxicity assay. The IC50 values in the small-sized groups were significantly lower than those in the large-sized groups. Most test samples were mutagenic in the Salmonella mutagenicity assay (TA98 with S9 and TA100 with S9) and increased the frequency of micronucleated cells. Most PM disturbed the normal progression of the cell cycle, resulting in the accumulation of cells in the G0/G1 phase and the induction of apoptosis. In these tests, PM of a large size induced less toxicity compared with PM of a small size. These findings suggest that most PM samples induced toxicity in vitro, and PM of a small size was more toxic than PM of a large size.
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Nicotiana , Tamanho da Partícula , Fumaça/efeitos adversos , Animais , Apoptose , Células CHO , Ciclo Celular , Cricetinae , Cricetulus , Citometria de Fluxo , Técnicas In Vitro , Testes para Micronúcleos , Testes de ToxicidadeRESUMO
Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I(2) = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I(2) = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I(2) = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I(2) = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01-1.20, P = 0.023, I(2) = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I(2) = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.
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Linfotoxina-alfa/genética , Neoplasias/genética , Polimorfismo Genético , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias/diagnóstico , Neoplasias/patologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Viés de Publicação , RiscoRESUMO
Silver, zinc oxide, and titanium dioxide nanoparticles are used as sterilisation materials to enhance the performance of disinfectants. We investigated the respiratory tract immune toxicity ("immunotoxicity") of these nanoparticles in vivo and in vitro, and we explored the relationships between particle size, particle shape, chemical composition, chemical stability and the toxicological effects of these typical nanoparticles in rats. In vivo, the rats were exposed to nanoparticles by intratracheal instillation. Exposure to nanoparticles caused an increase in oxidative injury to the lungs and disorders in regulating the cytokine network, which were detected in the bronchoalveolar lavage fluid, suggesting that oxidative stress might be important for inducing the respiratory immunotoxicity of nanoparticles. In vitro, the phagocytic function of alveolar macrophages (AMs) was dose-dependently reduced by nanoparticles, and ZnO nanoparticles induced greater cytotoxicity than the silver and titanium-dioxide nanoparticles, which were coincident with the results of multiple measurements, such as a cell viability assay by WST-8 and LDH measurements. Comparative analyses demonstrated that particle composition and chemical stability most likely had a primary role in the biological effects of different nanoparticles.
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Macrófagos Alveolares/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Titânio/toxicidade , Óxido de Zinco/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/química , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Glutationa/metabolismo , L-Lactato Desidrogenase/metabolismo , Macrófagos Alveolares/patologia , Macrófagos Alveolares/fisiologia , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Ratos , Ratos Wistar , Sistema Respiratório , Esterilização , Superóxido Dismutase/metabolismo , Sais de Tetrazólio/metabolismoRESUMO
Oxidative stress is a major factor contributing to endothelial cell damage. Single-wall carbon nanotubes (SWCNTs) have oxidative properties; however, the oxidative effects of SWCNTs on endothelial cells are not fully understood. In the present study, we investigated the effects of oxidative stress induced by SWCNTs on rat aortic endothelial cells (RAECs). Various markers of cellular damage were assessed, such as biochemical and ES immunity indexes, and DNA and protein damage. Our findings suggest that RAEC endured oxidative damage following SWCNT exposure. Specifically, after SWCNTs exposure, non-enzymatic antioxidant glutathione was activated prior to superoxide dismutase activation in order to defend against oxidative stress. Additionally, it was found that as SWCNT concentration increased, so did the stress protein, heme oxygenase-1 (HO-1), expression levels. These changes may induce RAEC damage, and result in many serious diseases.