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Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.
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Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Desenho Universal , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/química , COVID-19 , Vacinas contra COVID-19 , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/imunologia , Receptores Virais/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/química , SARS-CoV-2 , Células Sf9 , Organismos Livres de Patógenos Específicos , Spodoptera , Transfecção , Vacinação/métodos , Células Vero , Vacinas ViraisRESUMO
Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.
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Células-Tronco Mesenquimais , Osteoporose , Humanos , Camundongos , Animais , Osteogênese/genética , Envelhecimento/metabolismo , Senescência Celular , Diferenciação Celular/genética , Osteoporose/metabolismo , Células da Medula Óssea , Proteína 1 de Ligação a Y-Box/metabolismoRESUMO
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
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Caspase 8/metabolismo , Doenças Hereditárias Autoinflamatórias/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Células HEK293 , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Generalized anxiety disorder (GAD) is a common anxiety disorder experiencing psychological and somatic symptoms. Here, we explored the link between the individual variation in functional connectome and anxiety symptoms, especially psychological and somatic dimensions, which remains unknown. In a sample of 118 GAD patients and matched 85 healthy controls (HCs), we used multivariate distance-based matrix regression to examine the relationship between resting-state functional connectivity (FC) and the severity of anxiety. We identified multiple hub regions belonging to salience network (SN) and default mode network (DMN) where dysconnectivity associated with anxiety symptoms (P < 0.05, false discovery rate [FDR]-corrected). Follow-up analyses revealed that patient's psychological anxiety was dominated by the hyper-connectivity within DMN, whereas the somatic anxiety could be modulated by hyper-connectivity within SN and DMN. Moreover, hypo-connectivity between SN and DMN were related to both anxiety dimensions. Furthermore, GAD patients showed significant network-level FC changes compared with HCs (P < 0.01, FDR-corrected). Finally, we found the connectivity of DMN could predict the individual psychological symptom in an independent GAD sample. Together, our work emphasizes the potential dissociable roles of SN and DMN in the pathophysiology of GAD's anxiety symptoms, which may be crucial in providing a promising neuroimaging biomarker for novel personalized treatment strategies.
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Conectoma , Humanos , Conectoma/métodos , Rede de Modo Padrão , Imageamento por Ressonância Magnética/métodos , Transtornos de Ansiedade/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
The number of individuals with underlying medical conditions has been increasing steadily. These individuals are relatively vulnerable to harmful external factors. But it has not been proven that the effects of hazardous chemicals may differ depending on their physicochemical properties. This study determines the toxic effects of two chemicals with high indoor exposure risk and different physicochemical properties on an underlying disease model. A pulmonary arterial hypertension (PAH) model was constructed by a single subcutaneous injection of monocrotaline (MCT; 60â¯mg/kg) into Sprague-Dawley rats. After three weeks, formaldehyde (FA; 2.5â¯mg/kg) and polyhexamethylene guanidine (PHMG; 0.05â¯mg/kg) were administered once via intratracheal instillation, and rats were necropsied one week later. Exposure to FA and PHMG affected organ weight and the Fulton and toxicity indices in rats induced with PAH. FA promoted bronchial injury and aggravated PAH, while PHMG only induced alveolar injury. Additionally, the differentially expressed genes were altered following exposure to FA and PHMG, as were the associated diseases (cardiovascular disease and pulmonary fibrosis, respectively). In conclusion, inhaled chemicals with different physicochemical properties can cause damage to organs, such as the lungs and heart, and can aggravate underlying diseases. This study elucidates indoor inhaled exposure-induced toxicities and alerts patients with pre-existing diseases to the harmful chemicals.
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Two undescribed germacrane-type sesquiterpenoids, salcasins A (1) and B (2), together with three known compounds (3-5) were isolated and identified from the whole plant of Salvia cavaleriei var. simplicifolia Stib. The structures of the undescribed compounds were elucidated on the basis of spectroscopic methods, such as HR-ESI-MS, 1D and 2D NMR data. The relative configurations of 1 and 2 were established by analyzing their NOESY spectra as well as by 13C NMR calculations with DP4+ probability analyses. The absolute configurations of 1 and 2 were determined by comparing experimental and calculated ECD spectra. Furthermore, the inâ vivo anti-Alzheimer's disease activities of 1-5 were evaluated using Caenorhabditis elegans AD pathological model. Among all isolated compounds, salcasin A (1) significantly delayed AD-like symptoms of worm paralysis, which may be a potential anti-AD candidate agent.
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Doença de Alzheimer , Caenorhabditis elegans , Salvia , Sesquiterpenos de Germacrano , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Salvia/química , Caenorhabditis elegans/efeitos dos fármacos , Sesquiterpenos de Germacrano/farmacologia , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/isolamento & purificação , Estrutura Molecular , Conformação Molecular , Modelos Animais de DoençasRESUMO
Cigarette smoke induces an inflammatory response in the lungs by recruiting inflammatory cells, leading to lung diseases such as lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Existing inhalation exposure methods for assessing the adverse effects of cigarette smoke require expensive equipment and are labor-intensive. Therefore, we attempted to develop a novel method to assess these adverse effects using intratracheal instillation (ITI) of whole cigarette smoke condensate (WCSC). The WCSC (0, 5, 10, or 20 mg/mL) was administered by ITI once daily for 6 or 12 days using an automatic video instillator. Repeated WCSC ITI increased the lung weight, and monocyte chemoattractant protein-1 (MCP-1), neutrophil, and lymphocyte levels within bronchoalveolar lavage fluid compared to the control. In the histopathological analysis of the lung tissue, a mild inflammatory response was observed in the 6 and 12 days 20 mg/mL WCSC exposure groups. The genome-wide RNA-seq expression patterns revealed that inflammatory and immune response-related genes, such as the chemokine signaling pathway, Th1/Th2 cell differentiation, and cytokine-cytokine receptor interaction, were employed following WCSC exposure. In addition, MCP-1 was time-dependent and increased in the 10 mg/mL exposure group compared to the control group. These results suggested that the WCSC might induce the potential pulmonary inflammatory response. Furthermore, we proposed that ITI may be a rapid and effective method of evaluating the adverse effects of WCSC within a short exposure period (less than 2 weeks), and it can be used to evaluate cigarette inhalation toxicity studies as an alternative method.
Assuntos
Fumar Cigarros , Pneumopatias , Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Pulmão , Doença Pulmonar Obstrutiva Crônica/metabolismo , Pneumopatias/patologia , Líquido da Lavagem BroncoalveolarRESUMO
BACKGROUND: Schizophrenia is a common mental disorder that seriously affects patients' daily lives and brings heavy psychological and economic burdens to their families and society. The oral problems of patients with schizophrenia are gradually gaining attention, among which dental caries are among the most common oral diseases. Sex differences may be related not only to the various clinical symptoms of schizophrenia but also to different oral hygiene statuses; therefore, the main purpose of this paper is to investigate sex differences related to influencing factors for dental caries in patients with schizophrenia. METHOD: Inpatients with schizophrenia over 18 years old were included in this study, and multidimensional indicators such as demographics, symptom and cognitive impairment assessments, medications, and the caries index of decayed, missing, and filled teeth (DMFT) were collected. An analysis of sex-based influential factors for dental caries in schizophrenia patients was performed. RESULTS: Four-hundred and ninety-six patients with schizophrenia were included, with a mean age of 46.73 ± 12.23 years, of which 142 were females and 354 were males. The mean DMFT was significantly higher in males (8.81 ± 8.50) than in females (5.63 ± 6.61, p < 0.001), and the odd ratio of caries in males to females was significantly higher as well (OR = 2.305, p < 0.001). The influential factors of caries in male patients were independently associated with age and smoking status, in which current smokers were at the highest risk for developing caries, and different smoking statuses had various influencing factors for caries. The influencing factors for caries in female patients were independently associated with age, antipsychotic dose, PANSS-positive symptoms, and MMSE levels. CONCLUSION: Our findings suggest sex differences exist among influential factors for caries in patients with schizophrenia. These risk factors may even be associated with and affect the treatment and prognosis of psychiatric symptoms in patients. Therefore, oral hygiene management of patients with schizophrenia should be enhanced. These differential factors provide new visions and ideas for formulating individual interventions, treatments, and care priorities.
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Antipsicóticos , Cárie Dentária , Transtornos Psicóticos , Esquizofrenia , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Esquizofrenia/tratamento farmacológico , Cárie Dentária/complicações , Cárie Dentária/epidemiologia , Transtornos Psicóticos/tratamento farmacológico , Antipsicóticos/uso terapêutico , Fatores de Risco , PrevalênciaRESUMO
BACKGROUND: Using nanotechnology to improve the efficiency of tumor treatment represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements of complex tumor treatment. RESULTS: In this paper, a programmed-triggered nanoplatform (APP NPs), which is sequentially responsive to light and hypoxia, is rationally integrated for photoacoustic (PA) imaging-guided synergistic cancer photo-chemotherapy. The nanoplatform is constructed by in situ hybridization of dopamine monomer in the skeleton of PCN-224 and loading prodrug banoxantrone (AQ4N). Upon first-stage irradiation with a 660 nm laser, cellular internalization was effectively promoted by a photosensitizer-mediated photochemical effect. Furthermore, under second-stage irradiation, APP NPs exhibit a notably high photothermal conversion efficiency and sufficient reactive oxygen species (ROS) production for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively, which not only triggers rapid intercellular drug release but also consequently aggravates tumor hypoxia levels, and aggravated hypoxia can further active the cytotoxicity of AQ4N for chemotherapy. Both in vitro and in vivo studies confirm that the dual-stage light guided photo-chemotherapy strategy exhibits a greatly enhanced anticancer effects and superior therapeutic safety. CONCLUSION: This work represents a versatile strategy to construct a dual-stage light induced PDT/PTT and hypoxia-activated chemotherapy nanoplatform and will be promising for the development of multistimuli-responsive nanosystems with programmable functions for precise cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Hipóxia/tratamento farmacológico , Linhagem Celular TumoralRESUMO
BACKGROUND: Increasing body fat or decreasing muscle and bone mass were associated with worse health outcomes in the adult population. The effects of nickel exposure on body composition are not known. The aim of the current study was to investigate the relationship between urinary nickel levels and body compositions. MATERIALS AND METHODS: Two thousand seven hundred sixty-two participants were included in the analysis from the National Health and Nutrition Examination Surveys of 2017-2018 after excluding participants who have missing data on urinary nickel and those with missing all body mass component data. We used weighted generalized linear models to explore the relationship between urinary nickel and body mass components under interpolating missing covariable values. Simultaneously, sensitivity analyses and subgroup analysis were conducted to verify stability of analysis result. Curve fitting and saturation effect analysis were used to explore the possible nonlinear relationship between urine nickel and body compositions. RESULTS: Among the 2,762 participants, the average urinary nickel level was 1.58 ug/L. The weighted generalized linear models, the sensitivity analyses and subgroup analyses found no significant linear relationship between urinary nickel and body compositions. For body weight, BMI, TLM, ALM, TRF, TOF and BMC, the urine nickel saturation effect values were 0.76, 0.74, 0.5, 0.67, 0.64, 0.48, and 0.45 ug/L, respectively. For each 1 ug/L rise in urinary nickel levels at levels below the turning point, body weight increases (ß = 9.06, 95% CI = 2.75, 15.36, p = 0.01), BMI increases (ß = 3.20, 95% CI = 1.36, 5.05, p = < 0.001), TLM decreases (ß = -47.39, 95% CI = -97.38, 2.59, p = 0.06), ALM decreases (ß = -37.25, 95% CI = -63.25, -11.24, p = 0.01), TRF increases (ß = 20.68, 95% CI = 1.50, 39.86, p = 0.03), TOF increases (ß = 57.92, 95% CI = -0.12, 115.95, p = 0.05), and BMC decreases (ß = -6.84, 95% CI = -12.64, -1.04, p = 0.02). CONCLUSIONS: In summary, our study demonstrated that a dose-response relationship exists between urinary nickel and body compositions, with a low inflection point level of urinary nickel for the saturation effect.
Assuntos
Composição Corporal , Níquel , Adulto , Estados Unidos/epidemiologia , Humanos , Estudos Transversais , Tecido Adiposo , Aumento de PesoRESUMO
In order to investigate the flavour characteristics of aromatic, glutinous, and nonaromatic rice, gas chromatography-ion mobility spectrometry (GC-IMS) was used to analyse the differences in volatile organic compounds (VOCs) amongst different rice varieties. The results showed that 103 signal peaks were detected in these rice varieties, and 91 volatile flavour substances were identified. Amongst them, 28 aldehydes (28.89~31.17%), 24 alcohols (34.85~40.52%), 14 ketones (12.26~14.74%), 12 esters (2.30~4.15%), 5 acids (7.80~10.85%), 3 furans (0.30~0.68%), 3 terpenes (0.34~0.64%), and 2 species of ethers (0.80~1.78%) were detected. SIMCA14.1 was used to perform principal component analysis (PCA) and orthogonal partial least squares discriminant analysis, and some potential character markers (VIP > 1) were further screened out of the 91 flavour substances identified based on the variable important projections, including ethanol, 1-hexanol, hexanal, heptanal, nonanal, (E)-2-heptenal, octanal, trans-2-octenal, pentanal, acetone, 6-methyl-5-hepten-2-one, ethyl acetate, propyl acetate, acetic acid, and dimethyl sulphide. Based on the established fingerprint information, combined with principal component analysis and orthogonal partial least squares discriminant analysis, different rice varieties were also effectively classified, and the results of this study provide data references for the improvement in aromatic rice varieties.
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Safety and efficacy are essential in the process of disease treatment. However, off-label medication use is inevitable because various medications do not contain regulatory labels for pediatric use. We aimed to examine off-label medication use and analyze the risk factors correlated with adverse drug reactions (ADRs). This study was performed retrospectively using electronic medical data from a pediatric intensive care unit (PICU) of a tertiary hospital in Korea from July 2019 to June 2020. A total 6,183 prescribed medications from 502 PICU patients were examined in the present study. A total of 80% were infants or children, and 96.0% of them were treated with off-label medications. It was discovered that 4,778 off-label cases (77.2%) of the top 100 drugs had prescriptions with dosage (67.8%). Drugs prescribed to patients admitted to the cardiothoracic department (odds ratio [OR], 3.248; p = 0.019), total number of medications (OR, 1.116; p = 0.001), and length of PICU stay of ≥ 7 days (OR, 4.981; p = 0.008) were significantly associated with ADRs. ADRs were noted to be more severe in off-label use (p = 0.0426). For appropriate medication use, evidence regarding the safety of off-label medications is required and ultimately reflected in the official regulation.
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BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.
Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/radioterapia , Linhagem Celular Tumoral , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Cobre/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Ferro/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Camundongos , Tolerância a Radiação/genéticaRESUMO
Pulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.
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Adenocarcinoma de Pulmão/patologia , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Proteína A Associada a Surfactante Pulmonar/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Proteína A Associada a Surfactante Pulmonar/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Benzalkonium chloride (BKC) is a prototypical quaternary ammonium disinfectant. Previously, we suggested a no lethal dose level (0.005%) and an LD50 range (0.5-0.05%) of BKC following a single pharyngeal aspiration. Herein, we exposed BKC repeatedly by pharyngeal aspiration for 14 days (0.005 and 0.01%, female mice, total five times with interval of two days, 5 mice/group) and 28 days (0, 0.001, 0.005, and 0.01%, male and female mice, weekly, 16 mice/sex/group). Death following 14 days-repeated exposure did not occur. Meanwhile, chronic pathological lesions were observed in the lung tissues of mice exposed to BKC for 28 days. The total number of bronchial alveolar lavage cells increased, and pulmonary homeostasis of immunologic messenger molecules was disturbed. Following, we investigated BKC-induced cellular responses using human bronchial epithelial cells. The cytotoxicity increased rapidly with concentration. Lysosomal volume, NO production, and lipid peroxidation increased in BKC-treated cells, whereas intracellular ROS level decreased accompanying structural and functional damage of mitochondria. We also found that BKC affected the expression level of immune response, DNA damage, and amino acid biosynthesis-related molecules. More interestingly, lamellar body- and autophagosome-like structures were notably observed in cells exposed to BKC, and necrotic and apoptotic cell death were identified accompanying cell accumulation in the G2/M phase. Therefore, we suggest that repeated respiratory exposure of BKC causes pulmonary inflammation and lung tissue damage and that dead and damaged cells may contribute to the inflammatory response. In addition, the formation process of lamellar body-like structures may function as a key toxicity mechanism.
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Pneumonia , Surfactantes Pulmonares , Animais , Compostos de Benzalcônio/toxicidade , Feminino , Homeostase , Pulmão , Masculino , Camundongos , Pneumonia/induzido quimicamenteRESUMO
OBJECTIVE: To reveal the possible routine of brain network dynamic alterations in patients with mesial temporal lobe epilepsy (mTLE) and to establish a predicted model of seizure recurrence during interictal periods. METHODS: Seventy-nine unilateral mTLE patients with hippocampal sclerosis and 97 healthy controls from two centers were retrospectively enrolled. Dynamic brain configuration analyses were performed with resting-state functional magnetic resonance imaging (MRI) data to quantify the functional stability over time and the dynamic interactions between brain regions. Relationships between seizure frequency and ipsilateral hippocampal module allegiance were evaluated using a machine learning predictive model. RESULTS: Compared to the healthy controls, patients with mTLE displayed an overall higher dynamic network, switching mainly in the epileptogenic regions (false discovery rate [FDR] corrected p-FDR < .05). Moreover, the dynamic network configuration in mTLE was characterized by decreased recruitment (intra-network communication), and increased integration (inter-network communication) among hippocampal systems and large-scale higher-order brain networks (p-FDR < .05). We further found that the dynamic interactions between the hippocampal system and the default-mode network (DMN) or control networks exhibited an opposite distribution pattern (p-FDR < .05). Strikingly, we showed that there was a robust association between predicted seizure frequency based on the ipsilateral hippocampal-DMN dynamics model and actual seizure frequency (p-perm < .001). SIGNIFICANCE: These findings suggest that the interictal brain of mTLE is characterized by dynamical shifts toward unstable state. Our study provides novel insights into the brain dynamic network alterations and supports the potential use of DMN dynamic parameters as candidate neuroimaging markers in monitoring the seizure frequency clinically during interictal periods.
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Epilepsia do Lobo Temporal , Mapeamento Encefálico , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , ConvulsõesRESUMO
BACKGROUND: Bisphenol A (BPA) exposure and its structural analogs (BPS and BPF) might cause endocrine alterations and adverse physiological effects. Few studies to date have directly explored the association between its structural analogs (BPS, BPF) and sex hormones in adult male participants. Therefore, we aimed to assess the associations between BPA, BPS, BPF, and sex hormones in American adult men. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey 2011-2016. We excluded participants without data available on sex hormones and urinary bisphenols. Furthermore, participants consuming sex hormone medications were excluded. Multivariable regression models were performed to assess the association between bisphenols and sex hormones. RESULTS: In this study, 2367 participants were included. Of 2367, in 1575 participants, the data on BPS and BPF were available. We found that a per unit increase in BPF was associated with 0.575 ng/dL higher total testosterone (TT) (Model 2: 95% CI: 0.047, 1.103, P = 0.033). However, there was no significant association between BPA or BPS and TT. Furthermore, increased BPA and BPS levels were associated with higher levels of sex hormone-binding globulin (SHBG) (Model 2: ß = 0.364, 95% CI: 0.158, 0.571; ß = 0.25, 95% CI: 0.071, 0.429, respectively). Additionally, participants in the highest BPA exposure quartile (quartile 4) had 4.072 nmol/L higher levels of SHBG than those in quartile 1 (Model 2: 95% CI: 0.746, 7.397, P = 0.017; P for trend =0.005). Both BPA and BPS were negatively associated with free testosterone (FT, nmol/L) after full adjustment (Model 2, ß = - 0.01%, P = 0.0211, P = 0.0211; Model 2, ß = - 0.01%, P = 0.0258, respectively). However, BPF was positively associated with FT (Model 2, ß = 0.0029%, P = 0.0028). CONCLUSION: Our study indicated that exposure to both BPA and its substitutions could alter sex hormone levels. This finding supports the possibility that human exposure to bisphenols at environmental levels might affect the endogenous hormone balance.
Assuntos
Compostos Benzidrílicos , Testosterona , Adulto , Humanos , Masculino , Inquéritos Nutricionais , Hormônios Esteroides GonadaisRESUMO
PURPOSE: The aim of this study is to determine the association between mental disorders and strabismus in South Korean children and adolescents. METHODS: Using data from the Korean National Health Claims Database from 2011 to 2017, the prevalence rates of mental illnesses and odds ratio were calculated. Children and adolescents (1-19 years) with strabismus and their randomly selected nonstrabismic age- and sex-matched controls (1:1) were enrolled. The odds ratios were adjusted for preterm birth, cerebral palsy, and mental retardation. Subgroup analysis was performed according to sex and the type of strabismus. RESULTS: A total of 327,076 subjects (male, 158,597; female, 168,479) identified as strabismus patients were enrolled. After adjusting for preterm birth, cerebral palsy, and mental retardation, the corrected odds ratio of overall mental illness was 1.10 (95% CI, 1.08-1.12) for the strabismus group compared to the controls: 1.7 (95% CI, 1.62-1.78) for developmental disorder, 1.36 (95% CI, 1.27-1.45) for pervasive developmental disorder (autism), 1.14 (95% CI, 1.10-1.17) for attention-deficit hyperactivity disorder (ADHD), 1.15 (95% CI, 1.05-1.27) for obsessive-compulsive disorder (OCD), 1.08 (95% CI, 1.05-1.11) for pediatric behavioral and emotional disorders, 0.93 (95% CI, 0.88-0.99) for post-traumatic stress disorder (PTSD), and 0.85 (95% CI, 0.82-0.89) for tic disorder. CONCLUSION: South Korean children and adolescents with strabismus had a higher relative risk for various types of mental disorders such as a developmental disorder, autism, ADHD, and OCD than the controls, whereas they had a relatively lower risk of tic disorder.
Assuntos
Transtornos Mentais , Estrabismo , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Mentais/epidemiologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Nascimento Prematuro , República da Coreia/epidemiologia , Estrabismo/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Tique/epidemiologiaRESUMO
Polyhexamethylene guanidine phosphate (PHMG-P), a cationic biocide, is widely used in household products due to its strong bactericidal activity and low toxicity. However, it causes fatal lung damage when inhaled. In this study, we investigated why PHMG-P causes fatal lung injury when inhaled, and demonstrated that the disruption of membrane integrity through ionic interaction-a molecular initiating event of PHMG-P-determines toxicity. Mice were injected intravenously with 0.9 or 7.2 mg/kg PHMG-P (IV group), or instilled intratracheally with 0.9 mg/kg PHMG-P (ITI group); they were euthanatized at 4 h and on days 1 and 7 after treatment. Increased total BAL cell count and proinflammatory cytokine production, along with fibrotic changes in the lungs, were detected in the ITI group only. Levels of hepatic enzymes and hepatic serum amyloid A mRNA expression were markedly upregulated in the 7.2 mg/kg IV and ITI groups at 4 h or day 1 after treatment, but returned to baseline. No pathological findings were detected in the heart, liver, or kidneys. To simulate the IV injection, A549, THP-1, and HepG2 cells were treated with PHMG-P in cell culture media supplemented with different serum concentrations. Increased serum concentration was associated with an increase in cell viability. These results support the idea that direct contact between PHMG-P and cell membranes is necessary for PHMG-induced toxicity.
Assuntos
Desinfetantes , Lesão Pulmonar , Animais , Desinfetantes/toxicidade , Guanidinas/toxicidade , Pulmão/patologia , Lesão Pulmonar/patologia , CamundongosRESUMO
Objective: To establish a method for quantitative analysis of haloacetic acids (HAAs), disinfection byproducts, in tap water with reversed-phase ultra-performance liquid chromatography-quadrupole-orbitrap high resolution mass spectrometry. Methods: Tap water samples were collected and 0.70 g/L ascorbic acid was added to eliminate residual chlorine. Then, the water samples were directly injected into the instrument for analysis after filtration. After separation on a pentafluorobenzene (PFP) column with an inner diameter of 1.0 mm at a higher linear velocity and a lower volume flow rate compared with those of a narrow-bore column, nine HAAs, namely, monochloroacetic acid (MCAA), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), bromochloroacetic acid (BCAA), dibromoacetic acid (DBAA), trichloroacetic acid (TCAA), bromodichloroacetic acidï¼BDCAA), chlorodibromoacetic acid (CDBAA) and tribromoacetic acid (TBAA), were examined by negative electrospray ionization and full MS/dd-MS 2 acquisition mode. In order to adjust for the matrix effect, matrix matching calibration curves were used to quantitate the nine HAAs. Results: Good linearity was obtained for each of the nine HAAs within their respective linear ranges. The detection limits and quantification limits of the method were 0.020-1.0 µg/L and 0.060-3.0 µg/L. The recoveries were 69.8%-119%. Conclusion: The proposed method showed strengths in separation speed and qualitative accuracy. It did not require for complicated pretreatment procedures and can meet the need of tap water sample analysis.