Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice.

BACKGROUND: Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. METHODS: In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. RESULTS: The plasma levels and hypothalamic mRNA levels of IL-1ß and TNF-α were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the nucleus accumbens (NAc) and insula. Moreover, microglial activation in the ARC, anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice. CONCLUSIONS: Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.

The selective lipoprotein-associated phospholipase A2 inhibitor darapladib triggers irreversible actions on glioma cell apoptosis and mitochondrial dysfunction.

Although the development of a therapeutic strategy for glioblastoma multiforme (GBM), the most aggressive type of brain tumor in adults, is in progress, the prognosis is still limited. In this study, we evaluated the anti-glioma effects of darapladib, a selective reversible inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is encoded by the PLA2G7 gene and serves as a predictive biomarker of sub-clinical inflammation in cardiovascular diseases. The three glioma cell lines (rat C6 glioma cell line, human U87MG, and human U251MG) and an ex vivo brain tissue slice-glioma cell co-culture system were used to validate the inhibitory effect of darapladib on the expansion of glioma cells. Exposure to darapladib at doses higher than 5 µM induced profound cytotoxicity in C6, U87MG, and U251MG. Moreover, the colony formation ability of the glioma cell lines was significantly repressed after the addition of darapladib. Although darapladib did not reduce the generation of the Lp-PLA2 downstream molecule, arachidonic acid (AA), in the glioma cells, this small compound triggered mitochondrial membrane depolarization and cell apoptosis in these glioma cells. In addition, transient exposure to darapladib induced the upregulation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) levels, but reduced phosphorylation of AKT/PKB (protein kinase B). The results from an ex vivo brain slice culture system further confirmed the effective inhibition of darapladib on the expansion of glioma cells. In conclusion, darapladib acts as a potential anti-glioma compound via the induction of mitochondrial membrane depolarization and cell apoptosis, and the inhibition of AKT signaling in glioma cells.

Down-regulation of interleukin-33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression.

Interleukin-33 (IL-33), a member of the IL1 family, has been found to be expressed in oligodendrocytes (OLGs) and released as an alarmin from injured OLGs to work on other glial cell-types in the central nervous system. However, its functional role in OLGs remains unclear. Herein, we present that IL-33 was mainly expressed in the nucleus of CC1+ -oligodendrocytes (OLGs) in mouse and rat corpus callosum, as well as NG2+ -oligodendrocyte precursor cells (OPCs). The in vitro study indicated that the amount of IL-33 expressing in OPCs was higher when compared to that detected in OLGs. Results from the experiments using lentivirus-mediated shRNA delivery against IL-33 expression (IL33-KD) in OPCs showed that IL33-KD reduced the differentiation of OLGs into mature OLGs along with the down-regulation of OLG differentiation-related genes and mature OLG marker proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Alternatively, we observed reduced differentiation of OLGs that were prepared from the brains of IL-33 gene knockout (IL33-KO) mice with anxiolytic-like behavior. Observations were correlated with the results showing lower levels of MBP and PLP in IL33-KO cultures than those detected in the control cultures prepared from wildtype (WT) mice. Transmission Electron Microscopy (TEM) analysis revealed that the myelin structures in the corpus callosum of the IL33-KO mice were impaired compared to those observed in the WT mice. Overall, this study provides important evidence that declined expression of IL-33 in OPCs suppresses the maturation of OLGs. Moreover, gene deficiency of IL-33 can disrupt OLG maturation and interfere with myelin compaction. Cover Image for this issue: doi: 10.1111/jnc.14522.

Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus.

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.

[Systematically review of modified Sanzi Yangqin Decoction for treating acute exacerbation of chronic obstructive pulmonary disease].

The randomized controlled trials( RCTs) about modified Sanzi Yangqin Decoction in the treatment of patients with exacerbation of chronic obstructive pulmonary disease( AECOPD) were collected from 7 databases( PubMed,CNKI,etc.) till December25,2018 from their inception. All the studies searched were strictly evaluated and independently screened by two researchers according to the inclusion and exclusion criteria,and the methodological quality of included studies was evaluated. In order to systematically review the efficacy and safety of modified Sanzi Yangqin Decoction for treating AECOPD,the Meta-analysis and trial sequential analysis were conducted by using Stata/SE 14. 0 and TSA 0. 9. 5. 10 Beta,respectively. A total of 22 RCTs involving 2 012 patients were included. The results of Meta-analysis suggested that: as compared with the control group,the clinical symptoms in AECOPD patients were improved( RR = 1. 19,95%CI[1. 15,1. 24],P = 0); the pulmonary functions including forced expiratory volume in one second( FEV_1)( SMD= 0. 96,95%CI[0. 39,1. 52],P= 0. 001),the percentage of forced expiratory volume in one second( FEV_1%)( SMD =0. 80,95%CI[0. 20,1. 41],P = 0. 009),forced vital capacity( FVC)( SMD = 0. 69,95% CI[0. 06,1. 31],P = 0. 032),first seconds breathing volume percentage of forced vital capacity( FEV_1/FVC) were improved( SMD = 0. 81,95%CI[0. 64,0. 97],P = 0);the arterial oxygen partial pressure( PaO_2) was improved( SMD= 0. 87,95%CI[0. 41,1. 32],P= 0); the arterial partial pressure of carbon dioxide( PaCO_2) was decreased( SMD =-0. 91,95%CI[-1. 33,-0. 49],P = 0) in the trial group. In addition,the incidence of adverse reactions in the experimental group was low,and there were no serious adverse events. The trial sequential analysis( TSA) showed that the studies included in the improvement of clinical efficacy had passed the conventional and TSA threshold at the same time,further confirming the efficacy of trial group. This research showed that,conventional Western medicine treatment,combined with modified Sanzi Yangqin Decoction in treating acute exacerbation patients with chronic obstructive pulmonary disease could improve the clinical efficiency and pulmonary functions,improve the PaO_2,decrease the PaCO_2,with a high safety. However,the quality of existing research is low,requiring more high quality clinical trials for further validation.

Mechanosensitive store-operated calcium entry regulates the formation of cell polarity.

Ca(2+) -mediated formation of cell polarity is essential for directional migration which plays an important role in physiological and pathological processes in organisms. To examine the critical role of store-operated Ca(2+) entry, which is the major form of extracellular Ca(2+) influx in non-excitable cells, in the formation of cell polarity, we employed human bone osteosarcoma U2OS cells, which exhibit distinct morphological polarity during directional migration. Our analyses showed that Ca(2+) was concentrated at the rear end of cells and that extracellular Ca(2+) influx was important for cell polarization. Inhibition of store-operated Ca(2+) entry using specific inhibitors disrupted the formation of cell polarity in a dose-dependent manner. Moreover, the channelosomal components caveolin-1, TRPC1, and Orai1 were concentrated at the rear end of polarized cells. Knockdown of TRPC1 or a TRPC inhibitor, but not knockdown of Orai1, reduced cell polarization. Furthermore, disruption of lipid rafts or overexpression of caveolin-1 contributed to the downregulation of cell polarity. On the other hand, we also found that cell polarity, store-operated Ca(2+) entry activity, and cell stiffness were markedly decreased by low substrate rigidity, which may be caused by the disorganization of actin filaments and microtubules that occurs while regulating the activity of the mechanosensitive TRPC1 channel.

Interleukin-33 has the protective effect on oligodendrocytes against impairment induced by cuprizone intoxication.

Our prior investigations have demonstrated the pivotal role of IL-33 in facilitating the maturation of oligodendrocytes (OLs), prompting our interest in exploring its potential therapeutic effects. In this study, our focus was directed towards deciphering the functions of interleukin-33 (IL-33) in established demyelinating mouse model induced by the feeding of cuprizone (CPZ)-containing diet. We observed the reduction in corpus callosal adenomatous polyposis coli (APC)+ OLs with IL-33 expression in mice subjected to CPZ feeding for durations of 6 and 8 weeks. In parallel, the levels of IL-33 in the corpus callosum declined after CPZ-containing diet. Furthermore, we conducted experiments utilizing primary oligodendrocyte precursor cells (OPCs) and mature OLs, which were exposed to CPZ. A decrease in the expression of myelin basic protein (MBP) was evident in the cultures of mature OLs after treatment with CPZ. Additionally, both IL-33 mRNA and protein levels exhibited downregulation. To counteract the diminished IL-33 levels induced by CPZ, we employed a lentiviral vector to overexpress IL-33 in OLs. Intriguingly, the overexpression of IL-33 (IL33OE) in OLs resulted in a more distinct membranous morphology following CPZ treatment when compared to that observed in OL Mock cultures. Moreover, MBP protein levels in the presence of CPZ were higher in IL33OE OLs than that detected in OL Mock cultures. These findings collectively indicate that IL-33 possesses the capability to mitigate CPZ-induced damage and bolster OL homeostasis. In summary, our study underscores the importance of IL-33 in the context of demyelinating diseases, shedding light on its potential therapeutic implications for fostering remyelination and preserving OL function.

Interleukin-6 Inhibits Expression of miR-204-5p, a Regulator of Oligodendrocyte Differentiation: Involvement of miR-204-5p in the Prevention of Chemical-Induced Oligodendrocyte Impairment.

Oligodendrocytes (OLs) form myelin sheaths around axons in the central nervous system (CNS) facilitate the propagation of action potentials. The studies have shown that the differentiation and maturation of OLs involve microRNA (miR) regulation. The recent findings have addressed that miR-204 regulates OL differentiation in culture. In this study, through in situ hybridization in combination with immunohistochemistry, we showed that microRNA-204-5p in the corpus callosum was mainly expressed in OLs immunoreactive with adenomatous polyposis coli (APC), an OL marker. We also found miR-204-5p expression in mature OLs was suppressed by the addition of interleukin-6 (IL-6). Moreover, IL-6-induced inhibition of miR-204-5p expression was blocked by the addition of the inhibitors specific for p38 mitogen-activated protein kinase (p38MAPK) or phosphatidylinositol 3-kinase (PI3K) pathway. We further utilized a rat model by feeding cuprizone (CPZ)-containing diet for 3 weeks to induce demyelination and gliosis in the corpus callosum, as well as the upregulation of IL-6 gene expression significantly. Despite that miR-204-5p expression in the corpus callosum was not altered after feeding by CPZ for 3 weeks, its expression was increased and IL-6 transcription was decreased in the corpus callosum of the recovery group that was fed by CPZ for the first 2 weeks and by the regular diet for one more week. Our data demonstrate that miR-204-5p expression in OLs declined under the influence of the inflamed microenvironment. The findings that an increase in miR-204-5p and declined IL-6 expression observed in the recovery group might be involved with OL repair in the corpus callosum, and also shed light on a potential role for miR-204-5p in OL homeostasis following the white matter injury.

Potential of semen coicis in enhancing the anti-tumor effects of PD-1 inhibitor on A549 cell lines by blocking the PI3K-AKT-mTOR pathway.

BACKGROUND: The objective of this research was to investigate how the combination of semen coicis extract and PD-1 inhibitors can potentially work together to enhance the anti-tumor effects, with a focus on understanding the underlying mechanism. METHODS: We obtained the active components and specific targets of semen coicis in the treatment of NSCLC from various databases, namely TCMSP, GeneCard, and OMIM. By utilizing the STRING database and Cytoscape software, we established a protein interaction network (PPI) for the active ingredient of semen coicis and the target genes related to NSCLC. To explore the potential pathways involved, we conducted gene ontology (GO) and biological pathway (KEGG) enrichment analyses, which were further supported by molecular docking technology. Additionally, we conducted cyto-inhibition experiments to verify the inhibitory effects of semen coicis alone or in combination with a PD-1 inhibitor on A549 cells, along with examining the associated pathways. Furthermore, we investigated the synergistic mechanism of these two drugs through cytokine release experiments and the PD-L1 expression study on A549 cells. RESULTS: Semen coicis contains two main active components, Omaine and (S)-4-Nonanolide. Its primary targets include PIK3R1, PIK3CD, PIK3CA, AKT2, and mTOR. Molecular docking experiments confirmed that these ingredients and targets form stable bonds. In vitro experiments showed that semen coicis demonstrates inhibitory effects against A549 cells, and this effect was further enhanced when combined with PD-1 inhibitors. PCR and WB analysis confirmed that the inhibition of the PI3K-AKT-mTOR pathway may contribute to this effect. Additionally, semen coicis was observed to decrease the levels of IFN-γ, IL-6, and TNF-α, promoting the recovery of the human anti-tumor immune response. And semen coicis could inhibit the induced expression of PD­L1 of A549 cells stimulated by IFN­Î³ as well. CONCLUSION: Semen coicis not only has the ability to kill tumor cells directly but also alleviates the immunosuppression found in the tumor microenvironment. Additionally, it collaboratively enhances the effectiveness of PD-1 inhibitors against tumors by blocking the activation of PI3K-AKT-mTOR.

Prospects for the Protective Mechanisms and Compounds of Bufei Huoxue Capsule against COVID-19 Convalescence: Evaluation of Integrating UHPLC-HRMS Analysis and Network Pharmacology Strategy.

INTRODUCTION: Most COVID-19 survivors are troubled with chronic persistent symptoms, which have currently no definitive treatments. Bufei Huoxue (BFHX) capsule exerts clinical benefit, while the material basis and molecular mechanism remain unclear. AIM: The study aimed to elucidate the protective mechanisms of BFHX capsules against COVID-19 convalescence. UHPLC-HRMS and various databases were employed to explore potential compounds and targets. PPI, MCODE, transcription factor (TF), and miRNA analyses were conducted to receive hub targets and corresponding upstream regulators. METHOD: Molecular docking was applied to verify the binding activity of compound and target. Further, GO, KEGG, WIKI, and Reactome analyses were performed, and compound-targetsymptom and gene-disease networks were constructed. A total of 127 compounds and 313 targets were acquired. A sum of 10 hub targets were screened and showed good binding affinities with critical compounds. RESULT: MLLT1, CBFB, and EZH2 were identified as key TFs, and hsa-mir-146a-5p, hsa-mir- 26b-5p, and hsa-mir-24-3p were predicted to be important miRNAs. BFHX capsule may alleviate the symptoms by targeting TNF, IL-6, IFNG, and TGF-ß1. Besides, BFHX capsule may exert a therapeutic effect on respiratory disease (especially pulmonary fibrosis and lung infection) and multi-system damage during COVID-19 convalescence by regulating cytokine-cytokine receptor interaction, as well as TGF-ß, TNF, and Toll-like receptor signaling pathways. CONCLUSION: In summary, BFHX capsule may exert a therapeutic effect on multi-system damages during COVID-19 convalescence through multiple compounds (such as albiflorin, isopsoralen, and neobavaisoflavone), multiple targets (such as TNF, IL-6, and EGF) and multiple pathways (TGF-ß, TNF, and Toll-like receptor signaling pathways).

Bronchial epithelial transcriptomics and experimental validation reveal asthma severity-related neutrophilc signatures and potential treatments.

Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma.

Exploration of COVID-19 Pandemic Prevention Behaviors among Healthcare Workers.

Since the outbreak of COVID-19, the pandemic has become an important topic of global public health. To reduce the rapid spread of the pandemic, compliance with preventive behaviors has become one of the important guidelines from the World Health Organization (WHO). Healthcare workers stand on the frontline for pandemic prevention, and preventive behaviors are essential measures to protect their health and safety. The purpose of this study was to propose an integrative model that explained and predicted COVID-19 preventive behaviors among healthcare workers. The study integrated workplace safety climate and the health belief model (HBM) to verify the impact of workplace safety climate and health belief factors on the safety attitude, safety compliance, and safety satisfaction of healthcare workers performing COVID-19 pandemic prevention behaviors. A cross-sectional study was conducted from March to August 2021 with a self-administered online questionnaire. The sample of the study was drawn from healthcare workers of a famous medical institution in Taipei City as research subjects. After collecting 273 valid questionnaires and verifying them through the analysis of structural equation modeling (SEM), the findings revealed that workplace safety climate had an impact on health belief factors, and then health belief factors had impacts on safety attitudes. In addition, safety attitude affected safety compliance, while safety compliance further affected safety satisfaction. The study showed that workplace safety climate can strengthen healthcare workers' health beliefs and further affect their safety attitudes, safety compliance, and safety satisfaction. The study attempted to propose a model of healthcare workers' pandemic prevention behaviors as a reference for medical facility administrators in real practice.

Modeling Kaempferol as a Potential Pharmacological Agent for COVID-19/PF Co-Occurrence Based on Bioinformatics and System Pharmacological Tools.

Objective: People suffering from coronavirus disease 2019 (COVID-19) are prone to develop pulmonary fibrosis (PF), but there is currently no definitive treatment for COVID-19/PF co-occurrence. Kaempferol with promising antiviral and anti-fibrotic effects is expected to become a potential treatment for COVID-19 and PF comorbidities. Therefore, this study explored the targets and molecular mechanisms of kaempferol against COVID-19/PF co-occurrence by bioinformatics and network pharmacology. Methods: Various open-source databases and Venn Diagram tool were applied to confirm the targets of kaempferol against COVID-19/PF co-occurrence. Protein-protein interaction (PPI), MCODE, key transcription factors, tissue-specific enrichment, molecular docking, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to clarify the influential molecular mechanisms of kaempferol against COVID-19 and PF comorbidities. Results: 290 targets and 203 transcription factors of kaempferol against COVID-19/PF co-occurrence were captured. Epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase SRC (SRC), mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 8 (MAPK8), RAC-alpha serine/threonine-protein kinase (AKT1), transcription factor p65 (RELA) and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) were identified as the most critical targets, and kaempferol showed effective binding activities with the above critical eight targets. Further, anti-COVID-19/PF co-occurrence effects of kaempferol were associated with the regulation of inflammation, oxidative stress, immunity, virus infection, cell growth process and metabolism. EGFR, interleukin 17 (IL-17), tumor necrosis factor (TNF), hypoxia inducible factor 1 (HIF-1), phosphoinositide 3-kinase/AKT serine/threonine kinase (PI3K/AKT) and Toll-like receptor signaling pathways were identified as the key anti-COVID-19/PF co-occurrence pathways. Conclusion: Kaempferol is a candidate treatment for COVID-19/PF co-occurrence. The underlying mechanisms may be related to the regulation of critical targets (EGFR, SRC, MAPK3, MAPK1, MAPK8, AKT1, RELA, PIK3CA and so on) and EGFR, IL-17, TNF, HIF-1, PI3K/AKT and Toll-like receptor signaling pathways. This study contributes to guiding development of new drugs for COVID-19 and PF comorbidities.

Insights into potential mechanisms of asthma patients with COVID-19: A study based on the gene expression profiling of bronchoalveolar lavage fluid.

BACKGROUND: The 2019 novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a major challenge threatening the global healthcare system. Respiratory virus infection is the most common cause of asthma attacks, and thus COVID-19 may contribute to an increase in asthma exacerbations. However, the mechanisms of COVID-19/asthma comorbidity remain unclear. METHODS: The "Limma" package or "DESeq2" package was used to screen differentially expressed genes (DEGs). Alveolar lavage fluid datasets of COVID-19 and asthma were obtained from the GEO and GSV database. A series of analyses of common host factors for COVID-19 and asthma were conducted, including PPI network construction, module analysis, enrichment analysis, inference of the upstream pathway activity of host factors, tissue-specific analysis and drug candidate prediction. Finally, the key host factors were verified in the GSE152418 and GSE164805 datasets. RESULTS: 192 overlapping host factors were obtained by analyzing the intersection of asthma and COVID-19. FN1, UBA52, EEF1A1, ITGB1, XPO1, NPM1, EGR1, EIF4E, SRSF1, CCR5, PXN, IRF8 and DDX5 as host factors were tightly connected in the PPI network. Module analysis identified five modules with different biological functions and pathways. According to the degree values ranking in the PPI network, EEF1A1, EGR1, UBA52, DDX5 and IRF8 were considered as the key cohost factors for COVID-19 and asthma. The H2O2, VEGF, IL-1 and Wnt signaling pathways had the strongest activities in the upstream pathways. Tissue-specific enrichment analysis revealed the different expression levels of the five critical host factors. LY294002, wortmannin, PD98059 and heparin might have great potential to evolve into therapeutic drugs for COVID-19 and asthma comorbidity. Finally, the validation dataset confirmed that the expression of five key host factors were statistically significant among COVID-19 groups with different severity and healthy control subjects. CONCLUSIONS: This study constructed a network of common host factors between asthma and COVID-19 and predicted several drugs with therapeutic potential. Therefore, this study is likely to provide a reference for the management and treatment for COVID-19/asthma comorbidity.

Identification of Molecular Markers Related to Immune Infiltration in Patients with Severe Asthma: A Comprehensive Bioinformatics Analysis Based on the Human Bronchial Epithelial Transcriptome.

Background: Severe asthma (SA), a heterogeneous inflammatory disease characterized by immune cell infiltration, is particularly difficult to treat and manage. The airway epithelium is an important tissue in regulating innate and adaptive immunity, and targeting airway epithelial cell may contribute to improving the efficacy of asthma therapy. Methods: Bioinformatics methods were utilized to identify the hub genes and signaling pathways involved in SA. Experiments were performed to determine whether these hub genes and signaling pathways were affected by the differences in immune cell infiltration. Results: The weighted gene coexpression network analysis identified 14 coexpression modules, among which the blue and salmon modules exhibited the strongest associations with SA. The blue module was mainly enriched in actomyosin structure organization and was associated with regulating stem cell pluripotency signaling pathways. The salmon module was mainly involved in cornification, skin development, and glycosphingolipid biosynthesis-lacto and neolacto series. The protein-protein interaction network and module analysis identified 11 hub genes in the key modules. The CIBERSORTx algorithm revealed statistically significant differences in CD8+ T cells (P = 0.013), T follicular helper cells (P = 0.002), resting mast cells (P = 0.004), and neutrophils (P = 0.002) between patients with SA and mild-moderate asthma patients. Pearson's correlation analysis identified 11 genes that were significantly associated with a variety of immune cells. We further predicted the utility of some potential drugs and validated our results in external datasets. Conclusion: Our results may help provide a better understanding of the relationship between the airway epithelial transcriptome and clinical data of SA. And this study will help to guide the development of SA-targeted molecular therapy.

Inhibitory Effects of Trifluoperazine on Peripheral Proinflammatory Cytokine Expression and Hypothalamic Microglia Activation in Obese Mice Induced by Chronic Feeding With High-Fat-Diet.

Microglia and astrocytes are the glial cells of the central nervous system (CNS) to support neurodevelopment and neuronal function. Yet, their activation in association with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called as gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in obese individuals and animal models. Thus, reduction in peripheral and central inflammation is considered as a strategy to lessen the abnormality of obesity-associated metabolic indices. In this study, we reported that acute peripheral challenge by inflammagen lipopolysaccharide (LPS) upregulated the expression of hypothalamic dopamine type 2 receptor (D2R) mRNA, and chronic feeding by high-fat-diet (HFD) significantly caused increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that an FDA-approved antipsychotic drug named trifluoperazine (TFP), a D2R inhibitor was able to suppress LPS-stimulated activation of microglia and effectively inhibited LPS-induced peripheral inflammation, as well as hypothalamic inflammation. Further findings showed daily peripheral administration intraperitoneally (i.p.) by TFP for 4 weeks was able to reduce the levels of plasma tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in accompany with lower levels of plasma glucose and insulin in obese mice receiving HFD for 16 weeks when compared those in obese mice without TFP treatment. In parallel, the activation of microglia and astrocytes in the ARC was also inhibited by peripheral administration by TFP. According to our results, TFP has the ability to suppress HFD-induced ARC gliosis and inflammation in the hypothalamus.

Enhanced Microglia Activation and Glioma Tumor Progression by Inflammagen Priming in Mice with Tumor Necrosis Factor Receptor Type 2 Deficiency.

Despite the fact that accumulation of microglia, the resident macrophages of the central nervous system (CNS) are the main feature of glioblastoma, the role of microglia in the progression of glioma is still arguable. Based on the correlation of inflammation with tumor progression, in this study, we attempt to determine if peripheral inflammation aggravates glioma expansion and the activation of microglia associated with the tumor. Experimental animals were administered intraperitoneally by inflammagen lipopolysaccharide (LPS) for 7 days (LPS priming) before intracerebral implantation of glioma cells. Moreover, a reduced level of tumor necrosis factor receptor type 2 (TNFR2) that is restricted to immune cells, neurons, and microglia has been found in patients with glioblastoma through the clinic analysis of monocyte receptor expression. Thus, in addition to wildtype (WT) mice, heterogeneous TNFR2 gene deficiency (TNFR2+/-) mice and homogeneous TNFR2 gene knockout (TNFR2-/-) mice were used in this study. The results show that peripheral challenge by LPS, Iba1+- or CD11b+-microglia increase in numbers in the cortex and hippocampus of TNFR2-/- mice, when compared to WT or TNFR2+/- mice. We further conducted the intracerebral implantation of rodent glioma cells into the animals and found that the volumes of tumors formed by rat C6 glioma cells or mouse GL261 glioma cells were significantly larger in the cortex of TNFR2-/- mice when compared to that measured in LPS-primed WT or LPS-primed TNFR2+/- mice. Ki67+-cells were exclusively clustered in the tumor of LPS-primed TNFR2-/- mice. Microglia were also extensively accumulated in the tumor formed in LPS-primed TNFR2-/- mice. Accordingly, our findings demonstrate that aggravation of microglia activation by peripheral inflammatory challenge and a loss of TNFR2 function might lead to the promotion of glioma growth.

A Practical Strategy for Exploring the Pharmacological Mechanism of Luteolin Against COVID-19/Asthma Comorbidity: Findings of System Pharmacology and Bioinformatics Analysis.

Asthma patients may increase their susceptibility to SARS-CoV-2 infection and the poor prognosis of coronavirus disease 2019 (COVID-19). However, anti-COVID-19/asthma comorbidity approaches are restricted on condition. Existing evidence indicates that luteolin has antiviral, anti-inflammatory, and immune regulation capabilities. We aimed to evaluate the possibility of luteolin evolving into an ideal drug and explore the underlying molecular mechanisms of luteolin against COVID-19/asthma comorbidity. We used system pharmacology and bioinformatics analysis to assess the physicochemical properties and biological activities of luteolin and further analyze the binding activities, targets, biological functions, and mechanisms of luteolin against COVID-19/asthma comorbidity. We found that luteolin may exert ideal physicochemical properties and bioactivity, and molecular docking analysis confirmed that luteolin performed effective binding activities in COVID-19/asthma comorbidity. Furthermore, a protein-protein interaction network of 538 common targets between drug and disease was constructed and 264 hub targets were obtained. Then, the top 6 hub targets of luteolin against COVID-19/asthma comorbidity were identified, namely, TP53, AKT1, ALB, IL-6, TNF, and VEGFA. Furthermore, the enrichment analysis suggested that luteolin may exert effects on virus defense, regulation of inflammation, cell growth and cell replication, and immune responses, reducing oxidative stress and regulating blood circulation through the Toll-like receptor; MAPK, TNF, AGE/RAGE, EGFR, ErbB, HIF-1, and PI3K-AKT signaling pathways; PD-L1 expression; and PD-1 checkpoint pathway in cancer. The possible "dangerous liaison" between COVID-19 and asthma is still a potential threat to world health. This research is the first to explore whether luteolin could evolve into a drug candidate for COVID-19/asthma comorbidity. This study indicated that luteolin with superior drug likeness and bioactivity has great potential to be used for treating COVID-19/asthma comorbidity, but the predicted results still need to be rigorously verified by experiments.

Application of Artificial Intelligence in the Establishment of an Association Model between Metabolic Syndrome, TCM Constitution, and the Guidance of Medicated Diet Care.

BACKGROUND: This study conducted exploratory research using artificial intelligence methods. The main purpose of this study is to establish an association model between metabolic syndrome and the TCM (traditional Chinese medicine) constitution using the characteristics of individual physical examination data and to provide guidance for medicated diet care. METHODS: Basic demographic and laboratory data were collected from a regional hospital health examination database in northern Taiwan, and artificial intelligence algorithms, such as logistic regression, Bayesian network, and decision tree, were used to analyze and construct the association model between metabolic syndrome and the TCM constitution. Findings. It was found that the phlegm-dampness constitution (90.6%) accounts for the majority of TCM constitution classifications with a high risk of metabolic syndrome, and high cholesterol, blood glucose, and waist circumference were statistically significantly correlated with the phlegm-dampness constitution. This study also found that the age of patients with metabolic syndrome has been advanced, and shift work is one of the risk indicators. Therefore, based on the association model between metabolic syndrome and TCM constitution, in the future, metabolic syndrome can be predicted through the syndrome differentiation of the TCM constitution, and relevant medicated diet care schemes can be recommended for improvement. CONCLUSION: In order to increase the public's knowledge and methods for mitigating metabolic syndrome, in the future, nursing staff can provide nonprescription medicated diet-related nursing guidance information via the prediction and assessment of the TCM constitution.

Hericium erinaceus mycelium and its small bioactive compounds promote oligodendrocyte maturation with an increase in myelin basic protein.

Oligodendrocytes (OLs), myelin-producing glia in the central nervous system (CNS), produce a myelin extension that enwraps axons to facilitate action potential propagation. An effective approach to induce oligodendrogenesis and myelination is important to foster CNS development and promote myelin repair in neurological diseases. Hericium (H.) erinaceus, an edible and culinary-medicinal mushroom, has been characterized as having neuroprotective activities. However, its effect on OL differentiation has not yet been uncovered. In this study using oligodendrocyte precursor cell (OPC) cultures and an ex vivo cerebellar slice system, we found that the extract from H. erinaceus mycelium (HEM) not only promoted the differentiation of OPCs to OLs in the differentiation medium, but also increased the level of myelin basic protein (MBP) on neuronal fibers. Moreover, daily oral administration of HEM into neonatal rat pups for 7 days enhanced MBP expression and OLs in the corpus callosum of the postnatal rat brain. The effect of HEM-derived bioactive compounds, the diterpenoid xylosides erinacine A (HeA) and HeC and a sesterterpene with 5 isoprene units called HeS, were further evaluated. The results showed that HeA and HeS more potently stimulated MBP expression in OLs and increased the number of OLs. Moreover, overlap between MBP immunoreactivity and neuronal fibers in cultured cerebellar tissue slices was significantly increased in the presence of HeA and HeS. In summary, our findings indicate that HEM extract and its ingredients HeA and HeS display promising functional effects and promote OL maturation, providing insights into their potential for myelination in neurodevelopmental disorders.