RESUMO
Cigarette smoke is a common global environmental pollutant. Asthma, the most frequent allergic airway disease, is related to maternal exposure to cigarette smoke. Our previous studies demonstrated that prenatal exposure to nicotine (PNE), the major active product of smoking, impairs fetal thymopoiesis and CD4+ T cell development after birth. This study aimed to investigate whether PNE contributes to asthma susceptibility through CD4+ T cell development alterations. First, A PNE model was established by administering 3 mg/kg/day nicotine to maternal mice, and then an ovalbumin-induced asthma model was established in the offspring. Further, ß-catenin and downstream pathways were inhibited in vitro to confirm the molecular mechanisms underlying the phenotype observed during the in vivo phase. The results showed that PNE induced Th2 and Th17 biases at developmental checkpoints and aggravated asthma symptoms in the offspring. In fetuses, PNE up-regulated α7 nAChR, activated PI3K-AKT, promoted ß-catenin level increase, and established potential Th2- and Th17-biased gene expression patterns during thymopoiesis, which persisted after birth. Similar results were also observed in 1 µM nicotine-treated thymocytes in vitro. Moreover, inhibiting PI3K-AKT by LY294002 abrogated nicotine-mediated ß-catenin level increase and thymopoiesis abnormalities, and an α7 nAChR antagonist (α-btx) also reversed nicotine-induced PI3K-AKT activation. Our findings provide strong evidence that PNE is a risk factor for T cell deviation and postnatal asthma, and revealed that nicotine-induced ß-catenin level increase induces thymopoiesis abnormalities.
Assuntos
Asma , Efeitos Tardios da Exposição Pré-Natal , Animais , Asma/induzido quimicamente , Asma/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Feminino , Humanos , Camundongos , Nicotina/metabolismo , Nicotina/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vitaminas , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69-CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69-CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.
Assuntos
Substâncias Perigosas/toxicidade , Nicotina/toxicidade , Timócitos/fisiologia , Animais , Autofagia/efeitos dos fármacos , Proteína 10 de Linfoma CCL de Células B , Proteína Beclina-1 , Feminino , Feto , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timócitos/imunologia , VitaminasRESUMO
The application of acupuncture and moxibustion in alleviating the adverse effects of chemotherapy drugs has been widely recognized at home and abroad, but the studies have been rarely summarized for the enhanced anti-tumor effect and its mechanism of acupuncture and moxibustion to synergize the chemotherapy drugs. This paper reviewed the clinical and basic studies on the synergism of chemotherapy with acupuncture and moxibustion in recent years. It was found that chemotherapy synergized with acupuncture and moxibustion can suppress cancer to a certain extent and improve the quality of life in patients. The effect mechanism of acupuncture and moxibustion combined with chemotherapy drugs is related to promoting tumor cell apoptosis, improving the immune and vascular microenvironment, and advancing chemotherapy drug enrichment on the affected area. It provides the evidences and ideas for enhancing the effect of chemotherapy by delivering acupuncture and moxibustion as an adjuvant therapy.
Assuntos
Terapia por Acupuntura , Antineoplásicos , Moxibustão , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Animais , Terapia CombinadaRESUMO
OBJECTIVES: The purpose of this paper is to ascertain the effect and mechanism of Radix Isatidis polysaccharide (RIP) on obesity. METHODS: High fat diet (HFD)-induced obese rats and the MDI-induced 3T3-L1 adipocyte cells were established to evaluate the ameliorated obesity effect and mechanism from RIP. KEY FINDINGS: Experiments in vivo show that oral administration of RIP has significant preventive effects on HFD-induced obesity and metabolic disorders in rats. With treatment of RIP (20, 40 and 80 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels and antioxidant enzyme activity were progressively improved. On the other hand, the treatment of 3T3-L1 cells with RIP (25, 50 and 100 mg/L) led to a decrease in lipid accumulation and glucose consumption. In addition, during adipogenesis in 3T3-L1 cells, RIP remarkably down-regulated mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase and glycerol-3-phosphate dehydrogenase. Furthermore, after RIP treatment, the protein expression of PPARγ, C/EBPα, FAS, HMG-CoA reductase and acetyl-CoA synthetase-1 (AceCS1) were significantly decreased and the expression of p-AMPK was increased. CONCLUSION: These results highlight the potential of RIP for obesity interventions and suggest that RIP inhibited adipocyte differentiation and lipid synthesis by activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway and down-regulating the expression of major adipogenic transcription factors, PPARγ, C/EBPα, etc.
Assuntos
Fármacos Antiobesidade , Dieta Hiperlipídica , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Adipogenia , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas , Lipídeos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/prevenção & controle , PPAR gama/metabolismo , Polissacarídeos/farmacologia , RatosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC), usually known as hepatoma, is the third leading cause of cancer mortality globally. Early detection of HCC helps in its treatment and increases survival rates. OBJECTIVE: The aim of this study is to develop a deep learning model, using the trend and severity of each medical event from the electronic health record to accurately predict the patients who will be diagnosed with HCC in 1 year. METHODS: Patients with HCC were screened out from the National Health Insurance Research Database of Taiwan between 1999 and 2013. To be included, the patients with HCC had to register as patients with cancer in the catastrophic illness file and had to be diagnosed as a patient with HCC in an inpatient admission. The control cases (non-HCC patients) were randomly sampled from the same database. We used age, gender, diagnosis code, drug code, and time information as the input variables of a convolution neural network model to predict those patients with HCC. We also inspected the highly weighted variables in the model and compared them to their odds ratio at HCC to understand how the predictive model works. RESULTS: We included 47,945 individuals, 9553 of whom were patients with HCC. The area under the receiver operating curve (AUROC) of the model for predicting HCC risk 1 year in advance was 0.94 (95% CI 0.937-0.943), with a sensitivity of 0.869 and a specificity 0.865. The AUROC for predicting HCC patients 7 days, 6 months, 1 year, 2 years, and 3 years early were 0.96, 0.94, 0.94, 0.91, and 0.91, respectively. CONCLUSIONS: The findings of this study show that the convolutional neural network model has immense potential to predict the risk of HCC 1 year in advance with minimal features available in the electronic health records.
RESUMO
BACKGROUND: Although most current medication error prevention systems are rule-based, these systems may result in alert fatigue because of poor accuracy. Previously, we had developed a machine learning (ML) model based on Taiwan's local databases (TLD) to address this issue. However, the international transferability of this model is unclear. OBJECTIVE: This study examines the international transferability of a machine learning model for detecting medication errors and whether the federated learning approach could further improve the accuracy of the model. METHODS: The study cohort included 667,572 outpatient prescriptions from 2 large US academic medical centers. Our ML model was applied to build the original model (O model), the local model (L model), and the hybrid model (H model). The O model was built using the data of 1.34 billion outpatient prescriptions from TLD. A validation set with 8.98% (60,000/667,572) of the prescriptions was first randomly sampled, and the remaining 91.02% (607,572/667,572) of the prescriptions served as the local training set for the L model. With a federated learning approach, the H model used the association values with a higher frequency of co-occurrence among the O and L models. A testing set with 600 prescriptions was classified as substantiated and unsubstantiated by 2 independent physician reviewers and was then used to assess model performance. RESULTS: The interrater agreement was significant in terms of classifying prescriptions as substantiated and unsubstantiated (κ=0.91; 95% CI 0.88 to 0.95). With thresholds ranging from 0.5 to 1.5, the alert accuracy ranged from 75%-78% for the O model, 76%-78% for the L model, and 79%-85% for the H model. CONCLUSIONS: Our ML model has good international transferability among US hospital data. Using the federated learning approach with local hospital data could further improve the accuracy of the model.
RESUMO
OBJECTIVES: The objective of this paper was to explore the effects of Radix isatidis polysaccharide (RIP) extracted from Radix isatis on alleviating insulin resistance. METHODS: The insulin resistance models of 3T3-L1 preadipocytes and type 2 diabetic rats were established to evaluate the insulin resistance activity of RIP. KEY FINDINGS: Radix isatidis polysaccharide within the concentration range of 25-100 µg/ml could reduce cell supernatant glucose and TNF-α levels (P < 0.01) and increase the expression of PI-3K P85, Glut4, IRS-1 and Akt protein in symptoms of IR 3T3-L1 preadipocytes. In the meantime, RIP contributed to relieve the weight loss of diabetic rats whose liver weight and liver index were decreased due to the effects of RIP. Experiments in rats also showed that RIP had capacity in reduced serum TC, TG, LDL-C, FFA, FBG, FINS, MDA, ALT, AST activities and increased serum HDL-C, SOD, ISI (P < 0.05 or 0.01). In addition, the oral glucose tolerance in rats was improved (P < 0.05) and liver damage was restored due to RIP. CONCLUSIONS: Radix isatidis polysaccharide significantly alleviates insulin resistance in 3T3-L1 preadipocytes and type 2 diabetic rats. These beneficial effects of RIP may associate with their roles in improving the glucose metabolism, lipid metabolism and oxidative stress.