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.
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.
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.
•Systemic review and meta-analysis assessing the efficacy of tocilizumab for treatment of severe COVID-19.•All-cause mortality was similar between tocilizumab and control groups (16.3% vs. 24.1%; ...RR = 0.62).•Risk of ICU admission was similar between tocilizumab and control groups (35.0% vs. 15.8%; RR = 1.51).•Requirement for mechanical ventilation was similar between tocilizumab and control groups (32.4% vs. 28.6%; RR = 0.82).•There is no conclusive evidence that tocilizumab provides any additional benefit to patients with severe COVID-19.
This systemic review and meta-analysis aimed to assess the efficacy of tocilizumab for the treatment of severe coronavirus disease 2019 (COVID-19). Candidate studies up to 24 May 2020 were identified from PubMed, Cochrane Library, Embase, medRxiv and bioRxiv. Treatment outcomes included mortality, risk of intensive care unit (ICU) admission and the requirement for mechanical ventilation (MV). Seven retrospective studies involving 592 adult patients with severe COVID-19, including 240 in the tocilizumab group and 352 in the control group, were enrolled. All-cause mortality of severe COVID-19 patients among the tocilizumab group was 16.3% (39/240), which was lower than that in the control group (24.1%; 85/352). However, the difference did not reach statistical significance risk ratio (RR) = 0.62, 95% confidence interval (CI) 0.31–1.22; I2 = 68%. Additionally, risk of ICU admission was similar between the tocilizumab and control groups (35.1% vs. 15.8%; RR = 1.51, 95% CI 0.33–6.78; I2 = 86%). The requirement for MV was similar between the tocilizumab and control groups (32.4% vs. 28.6%; RR = 0.82, 95% CI 0.14–4.94; I2 = 91%). However, these non-significant differences between the tocilizumab and control groups may have been the result of baseline characteristics of the tocilizumab group, which were more severe than those of the control group. Based on low-quality evidence, there is no conclusive evidence that tocilizumab would provide any additional benefit to patients with severe COVID-19. Therefore, further recommendation of tocilizumab for COVID-19 cases should be halted until high-quality evidence from randomised controlled trials is available.
Following the global trend of reducing animal testing, various reconstructed human epidermis (RHE) models for skin irritation test (SIT) have been developed, verified, validated and included in OECD ...TG 439. We developed a new RHE called EPiTRI and a SIT method using EPiTRI (EPiTRI-SIT model) following the OECD guidelines. EPiTRI possesses morphological, biochemical and physiological properties similar to human epidermis with well-differentiated multilayered viable cells with barrier function. The EPiTRI-SIT model was tested for 20 reference chemicals in Performance Standard of OECD TG 439 (GD 220), showing good predictive capacity with 100% sensitivity, 70% specificity and 85% accuracy. EPiTRI had sensitivity in detecting di-n-propyl disulphate, as an irritant chemical (UN GHS Category 2), whereas most validated reference methods detected it as a non-irritant. An international validation study of EPiTRI-SIT was conducted in four laboratories to confirm the within- and between-laboratory reproducibility, as well as predictive capacity. The phase I/II within-laboratory and between-laboratory reproducibility was 100%/95% and 95%, respectively. The overall sensitivity, specificity and accuracy of EPiTRI-SIT was 96%, 70% and 83%, respectively, which fulfilled the OECD criteria. Thus, EPiTRI, meets the criteria of Performance Standards of OECD TG 439 (GD 220) and is suitable for screening irritating chemicals in vitro.
•Structure and function of new reconstructed human epidermis,EPiTRI, similar to human epidermis.•International validation study of EPiTRI-SIT meets the acceptance criteria of OECD GD 220.•EPiTRI-SIT classify di-n-propyl disulphide as an irritant whereas VRMs as non-irritant chemical.
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-1β (IL-1β) 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.
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.
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.
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%CI1. 15,1. 24,P = 0); the pulmonary functions including forced expiratory volume in one seco
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