Stigmasterol alleviates airway inflammation in OVA-induced asthmatic mice via inhibiting the TGF-ß1/Smad2 and IL-17A signaling pathways.

Stigmasterol is a common dietary phytosterol with high nutritional value and physiological activity. In this study, we evaluated the effects of stigmasterol on inflammatory cytokines and the TGF-ß1/Smad2 and IL-17A signaling pathway in an ovalbumin (OVA)-induced asthma mouse model. Stigmasterol treatment improved airway remodeling. In addition, it significantly attenuated the symptoms of asthma attacks, reduced the number of macrophages, lymphocytes, neutrophils, and eosinophils in BALF and inflammatory cytokines, including IL-1ß, IL-5, IL-6, and IL-13. It further decreased the level of IL-17A in BALF, serum and spleen. Spleen single-cell suspension analysis via flow cytometry showed that IL-17A level was consistent with the results obtained in BALF, serum and spleen. Stigmasterol decreased the protein expression levels of TGF-ß, p-Smad2 and IL-17A in the spleen, by increasing the protein expression level of IL-10. After 24 h of co-culture of TGF-ß, IL-6 and stigmasterol, the level of IL-17 in CD4+ T cell supernatant was lower relative to levels in the group without stigmasterol. Meanwhile, stigmasterol treatment attenuated the expression level of TGF- ß, p-Smad2 and IL-17A proteins in CD4+ T cells and enhanced the expression levels of IL-10 protein. These data suggested that stigmasterol inhibited the TGF-ß1/Smad2 and IL-17A signaling pathway to achieve anti-asthmatic effects in the OVA-induced asthma mouse model. Collectively, the results of this study are that stigmasterol has achieved preliminary efficacy in the non-clinical laboratory, further studies are needed to consider the clinical application of stigmasterol.

Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice.

Oscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention.

SFRP5 Partially Inhibits the Proliferation and Migration of Airway Smooth Muscle Cells in Children with Asthma by Regulating the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND: Childhood asthma is a chronic inflammatory disease of the respiratory tract characterized by bronchial inflammation, airway hyperresponsiveness, airflow disorder, and obstruction. Secreted frizzled-related protein 5 (SFRP5) may be associated with respiratory inflammatory diseases. This study investigated the effect of SFRP5 on human airway smooth muscle cells (HASMCs) to provide new ideas for treating asthma. METHODS: A total of 30 children with asthma and 30 children who had a physical examination at the same time were selected and divided into asthma and healthy groups. Serum SFRP5 levels were determined by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR). Lipofectamine 2000™ regent was used to transfect the SFRP5 overexpression plasmid (pc-SFRP5) or corresponding negative control (pc-NC) into HASMCs. HASMCs were treated with 10 µg/L platelet-derived growth factor-BB (PDGF-BB), which is an inducer to mimic the asthma-like condition at the cellular level of childhood asthma. HASMCs were divided into control, PDGF-BB (PDGF-BB treatment), PDGF-BB+pc-NC (pc-NC transfection and PDGF-BB treatment), and PDGF-BB+pc-SFRP5 (pc-SFRP5 transfection and PDGF-BB treatment) groups. Cell proliferation was measured by 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assay. Cell migration was detected by Transwell assay. The protein expression was detected by western blot. RESULTS: Serum SFRP5 expression in the asthmatic group was decreased versus the healthy group (p < 0.0001). Induction of PDGF-BB decreased SFRP5 expression in HASMCs (p < 0.01). SFRP5 expression in the pc-SFRP5 group was increased (p < 0.01). The proliferation and migration of HASMCs increased after PDGF-BB treatment (p < 0.001, p < 0.0001), indicating that the asthma model was successfully inducted in vitro. Moreover, the expression of ß-catenin, cellular-myelocytomatosis viral oncogene (c-Myc), and cyclinD1 proteins in HASMCs increased after PDGF-BB treatment (p < 0.0001). SFRP5 overexpression partly inhibited PDGF-BB-induced proliferation, migration, and expressions of ß-catenin, c-Myc, and cyclinD proteins in HASMCs (p < 0.01, p < 0.001, p < 0.0001). CONCLUSIONS: Serum SFRP5 expression decreases in children with asthma. SFRP5 overexpression partially inhibits PDGF-BB-induced HASMC proliferation and migration by regulating the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt)/ß-catenin pathway.

Establishment of a diagnostic model based on immune-related genes in children with asthma.

Objective: Allergic asthma is driven by an antigen-specific immune response. This study aimed to identify immune-related differentially expressed genes in childhood asthma and establish a classification diagnostic model based on these genes. Methods: GSE65204 and GSE19187 were downloaded and served as training set and validation set. The immune cell composition was evaluated with ssGSEA algorithm based on the immune-related gene set. Modules that significantly related to the asthma were selected by WGCNA algorithm. The immune-related differentially expressed genes (DE-IRGs) were screened, the protein-protein interaction network and diagnostic model of DE-IRGs was constructed. The pathway and immune correlation analysis of hub DE-IRGs was analyzed. Results: Eight immune cell types exhibited varying levels of abundance between the asthma and control groups. A total of 112 differentially expressed immune-related genes (DE-IRGs) was identified. Through the application of four ranking methods (MCC, MNC, DEGREE, and EPC), 17 hub DE-IRGs with overlapping significance were further selected. Subsequently, 8 optimized were identified using univariate logistic regression analysis and the LASSO regression algorithm, based on which a robust diagnostic model was constructed. Notably, TNF and CD40LG emerged as direct participants in asthma-related signaling pathways, displaying a positive correlation with the immune cell types of immature B cells, activated B cells, activated CD8 T cells, activated CD4 T cells, and myeloid-derived suppressor cells. Conclusion: The diagnostic model constructed using the DE-IRGs (CCL5, CCR5, CD40LG, CD8A, IL2RB, PDCD1, TNF, and ZAP70) exhibited high and specific diagnostic value for childhood asthma. The diagnostic model may contribute to the diagnosis of childhood asthma.

An Empirical Mode Decomposition Fuzzy Forecast Model for Air Quality.

Air quality has a significant influence on people's health. Severe air pollution can cause respiratory diseases, while good air quality is beneficial to physical and mental health. Therefore, the prediction of air quality is very important. Since the concentration data of air pollutants are time series, their time characteristics should be considered in their prediction. However, the traditional neural network for time series prediction is limited by its own structure, which makes it very easy for it to fall into a local optimum during the training process. The empirical mode decomposition fuzzy forecast model for air quality, which is based on the extreme learning machine, is proposed in this paper. Empirical mode decomposition can analyze the changing trend of air quality well and obtain the changing trend of air quality under different time scales. According to the changing trend under different time scales, the extreme learning machine is used for fast training, and the corresponding prediction value is obtained. The adaptive fuzzy inference system is used for fitting to obtain the final air quality prediction result. The experimental results show that our model improves the accuracy of both short-term and long-term prediction by about 30% compared to other models, which indicates the remarkable efficacy of our approach. The research of this paper can provide the government with accurate future air quality information, which can take corresponding control measures in a targeted manner.

An Empirical Mode Decomposition Fuzzy Forecast Model for COVID-19.

At present, the Corona Virus Disease 2019 (COVID-19) is ravaging the world, bringing great impact on people's life safety and health as well as the healthy development of economy and society, so the research on the prediction of the development trend of the epidemic is crucial. In this paper, we focus on the prevention and control of epidemic using the relevant technologies in the field of artificial intelligence and signal analysis. With the unknown principle of epidemic transmission, we first smooth out the complex and variable epidemic data through the empirical mode decomposition model to obtain the change trends of epidemic data at different time scales. On this basis, the change trends under different time scales are trained using an extreme learning machine to obtain the corresponding prediction values, and finally the epidemic prediction results are obtained by fitting through Adaptive Network-based Fuzzy Inference System. The experimental results show that the algorithm has good learning ability, especially in the prediction of time-series sequences can guarantee the accuracy rate while having low time complexity. Therefore, this paper not only plays a theoretical support for epidemic prevention and control, but also plays an important role in the construction of public emergency health system in the long run.

Sensitive quantitation of ESR1 mutations in cell-free DNA from breast cancer patients using base-specific invasive reaction assisted qPCR.

Acquired estrogen receptor 1 (ESR1) mutation is being promoted as a key mechanism of resistance to endocrine therapies in breast cancers. It is significative to monitor ESR1 mutations in real time, which provide an opportunity to alter therapy as these mutations emerge. Previous assays based on next-generation sequencing (NGS) and digital PCR (dPCR) usually due to high costs and complicated workflows hampered their clinical adoption in general medical institutions. Here, we proposed a new strategy using base-specific invasive reaction assisted qPCR measure for ESR1 mutations in cfDNA. Two pivotal steps involved in this strategy are target-specific signal generation and the quantification without adding any internal reference or making standard calibration curves. The strategy enabled a high specificity of 0.1% (better than traditional NGS-based method) and a minimum sensitivity of 0.1 copies µL-1. As validation, with the strategy, cfDNA from endocrine therapy-resistant breast cancers and untreated ones were successfully analyzed (20% mutation rate (2/10) with mutation abundance of 0.54-1.65% vs. 0% mutation rate (0/5)). By virtue of cost-effective, highly flexible and precise, the strategy could be readily implemented in general laboratory, showing promising application perspectives in analysis of other types of mutations.

Corrigendum: Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

[This corrects the article DOI: 10.3389/fphar.2018.00410.].

Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and mildly decreased liver fibrosis, but exhibited no effect on hepatic steatosis/macrovesicular vacuolation. In conclusion, we found the progression of NASH hepatic steatosis/macrovesicular vacuolation, and inflammation eventually lead to hepatocyte death and fibrosis. Life style change and current pharmacotherapies in development may be effective in treating NASH, but their effects on NASH-induced fibrosis may be mild. Since fibrosis is known to be an independent risk for decompensated cirrhosis, cardiovascular events, and mortality, our study suggests that effective anti-fibrosis therapy should be an essential component of the combined pharmacotherapy for advanced NASH.

[Efficacy observation of chronic obstructive pulmonary disease due to lung and kidney deficiency treated with acupoint-catgut-embedding therapy combined western medication].

OBJECTIVE: To observe the clinical efficacy of acupoint-catgut-embedding therapy combined conventional western medication on chronic obstructive pulmonary disease (COPD) at stable stage due to lung and kidney deficiency. METHODS: The cases were randomized into observation group and control group, 30 cases in each one. In control group, the conventional western medication was administered. In observation group, on the basis of conventional western medication, the catgut-embedding therapy was applied at Dingchuan (EX-B 1), Feishu (BL 13), Shenshu (BL 23), Fenglong (ST 40) and Zusanli (ST 36). The total attack frequency of acute exacerbation of COPD (AECOPD), the attack frequency of AECOPD at moderate or above moderate stage and TCM syndrome score were compared before treatment and 6 months after treatment in two groups. RESULTS: The total effective rate was 93.3% (28/30) in observation group and was 90.0% (27/30) in control group, indicating equivalent efficacy between two groups. 6 months after treatment, in two groups, the total attack frequency of AECOPD and the attack frequency of AECOPD at moderate or above moderate stage were reduced remarkably as compared with those before treatment (P < 0.01, P < 0.05). The total attack frequency of AECOPD in observation group was reduced remarkably as compared with that in control group (P < 0.05). The scores of cough, expectoration and chest oppression as well as the total score of TCM syndrome were reduced remarkably after treatment in observation group (all P < 0.01). CONCLUSION: Integrated therapy of acupoint-catgut-embedding and conventional medication has similar efficacy as simple medication. But, the combination of acupoint-catgut-embedding therapy and western medication can reduce the attack frequency of AECOPD and improve in cough, chest oppression and other symptoms in patients with COPD at stable stage effectively.