Chinese medicine Xuebijing (XBJ) has proven to be effective in the treatment of mild coronavirus disease 2019 (COVID-19) cases. But the bioactive compounds and potential mechanisms of XBJ for ...COVID-19 prevention and treatment are unclear. This study aimed to examine the potential effector mechanisms of XBJ on COVID-19 based on network pharmacology.
We searched Chinese and international papers to obtain the active ingredients of XBJ. Then, we compiled COVID-19 disease targets from the GeneCards gene database and via literature searches. Next, we used the SwissTargetPrediction database to predict XBJ's effector targets and map them to the abovementioned COVID-19 disease targets in order to obtain potential therapeutic targets of XBJ. Cytoscape software version 3.7.0 was used to construct a "XBJ active-compound-potential-effector target" network and protein-protein interaction (PPI) network, and then to carry out network topology analysis of potential targets. We used the ClueGO and CluePedia plugins in Cytoscape to conduct gene ontology (GO) biological process (BP) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of XBJ's effector targets. We used AutoDock vina and PyMOL software for molecular docking.
We obtained 144 potential COVID-19 effector targets of XBJ. Fourteen of these targets-glyceraldehyde 3-phosphate dehydrogenase (
), albumin (
), tumor necrosis factor (
), epidermal growth factor receptor (
), mitogen-activated protein kinase 1 (
), Caspase-3 (
), signal transducer and activator of transcription 3 (
),
, prostaglandin-endoperoxide synthase 2 (
),
, interleukin-2 (
), estrogen receptor 1 (
), and
had degree values > 40 and therefore could be considered key targets. They participated in extracellular signal-regulated kinase 1 and 2 (
,
) cascade, the T-cell receptor signaling pathway, activation of
activity, cellular response to lipopolysaccharide, and other inflammation- and immune-related BPs. XBJ exerted its therapeutic effects through the renin-angiotensin system (RAS), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB),
, phosphatidylinositol-4, 5-bisphosphate 3-kinase (
)-protein kinase B (
)-vascular endothelial growth factor (VEGF), toll-like receptor (TLR), TNF, and inflammatory-mediator regulation of transient receptor potential (TRP) signaling pathways to ultimately construct a "drug-ingredient-target-pathway" effector network. The molecular docking results showed that the core 18 effective ingredients had a docking score of less than - 4.0 with those top 10 targets.
The active ingredients of XBJ regulated different genes, acted on different pathways, and synergistically produced anti-inflammatory and immune-regulatory effects, which fully demonstrated the synergistic effects of different components on multiple targets and pathways. Our study demonstrated that key ingredients and their targets have potential binding activity, the existing studies on the pharmacological mechanisms of XBJ in the treatment of sepsis and severe pneumonia, could explain the effector mechanism of XBJ in COVID-19 treatment, and those provided a preliminary examination of the potential effector mechanism in this disease.
An efficient technique using citric acid and glucose based natural deep eutectic solvent (G-C-NADES) was developed to obtain ultrahigh deamidated wheat gluten (UDWG) (deamidation degree (DD) > 90%). ...FTIR and 1H NMR indicated intensive hydrogen bonds (HBs) in G-C-NADES supermolecules. Quantum chemical calculations and molecular dynamic simulations demonstrated that 10 wt % diluted G-C-NADES still had a myriad of HBs. Physicochemical results showed UDWG had DD up to 92.45% after G-C-NADES deamidation, that is, 22% higher than citric-acid-DWG with a weak degree of hydrolysis (1.75%). Conformational characterization demonstrated the obvious conversion from α-helix to β-sheet via FTIR, the least amount of disulfide bonds by Raman spectra, and more exposure of tryptophan residues by fluorescence measurement for UDWG. It is proven that enhanced accessible conformation of WG reached with HBs of G-C-NADESs could contribute to the improvement on nucleophilic attack of deamidation, declaring that G-C-NADES might be a potential solvent for obtaining an ultrahigh deamidation for WG to successfully guarantee the safety of wheat gluten based cereal food regarding to lowering its allergy.
Rivaling the Himalaya in relief, the Longmen Shan is probably one of the most enigmatic mountain ranges in the world: high mountains reach more than 4000 m relief but without adjacent foreland ...subsidence and with only slow active convergence. What are geological and geodynamic processes that built the Longmen Shan? Coseismic deformation associated with the 2008 Wenchuan earthquake could hold clues to answer these questions. The primary features associated with the 2008 Wenchuan earthquake rupture have been narrowly distributed coseismic deformation and predominantly vertical displacements that could be interpreted as the result of slips on high‐angle listric seismogenic faults. Deep sounding seismic reflection profiling across the seismogenic faults indeed reveals high‐angle listric reverse faulting in the brittle upper crust and east‐dipping reflectors that we interpret as ductile shearing, in the viscous lower crust. In conjunction with a visco‐elastic finite element modeling of coseismic displacements associated with the Wenchuan earthquake, we show that the high‐angle listric nature of earthquake faults produces insignificant horizontal shortening across the fault and facilitates upward slips along the fault that both explain the localized coseismic deformation and vertical displacement, as well as the presence of high mountains without adjacent foreland flexure. We suggest that the formation of the Longmen Shan may be better understood in terms of partitioned lithospheric pure‐shear thickening in which upward high‐angle listric faulting of brittle upper crust is linked to thickening of the more viscous lithospheric mantle through downward ductile shearing of rheologically deformable lower crust.
Key Points
The Wenchuan earthquake produces narrow deformation zone and predominant vertical slip
Seismic reflection shows listric reverse faults and ductile shears in upper and lower crust
High‐angle listric faults result in minor horizontal contraction and facilitate upward slips
Proteases secreted by Trichinella spiralis intestinal infective larvae (IIL) play an important role in larval invasion and pathogenesis. However, the mechanism through which proteases mediate larval ...invasion of intestinal epithelial cells (IECs) remains unclear. A novel T. spiralis trypsin (TsTryp) was identified in IIL excretory/secretory (ES) proteins. It was an early and highly expressed protease at IIL stage, and had the potential as an early diagnostic antigen. The aim of this study was to investigate the biological characteristics of this novel TsTryp, its role in larval invasion of gut epithelium, and the mechanisms involved.
TsTryp with C-terminal domain was cloned and expressed in Escherichia coli BL21 (DE3), and the rTsTryp had the enzymatic activity of natural trypsin, but it could not directly degrade gut tight junctions (TJs) proteins. qPCR and western blotting showed that TsTryp was highly expressed at the invasive IIL stage. Immunofluorescence assay (IFA), ELISA and Far Western blotting revealed that rTsTryp specifically bound to IECs, and confocal microscopy showed that the binding of rTsTryp with IECs was mainly localized in the cytomembrane. Co-immunoprecipitation (Co-IP) confirmed that rTsTryp bound to protease activated receptors 2 (PAR2) in Caco-2 cells. rTsTryp binding to PAR2 resulted in decreased expression levels of ZO-1 and occludin and increased paracellular permeability in Caco-2 monolayers by activating the extracellular regulated protein kinases 1/2 (ERK1/2) pathway. rTsTryp decreased TJs expression and increased epithelial permeability, which could be abrogated by the PAR2 antagonist AZ3451 and ERK1/2 inhibitor PD98059. rTsTryp facilitated larval invasion of IECs, and anti-rTsTryp antibodies inhibited invasion. Both inhibitors impeded larval invasion and alleviated intestinal inflammation in vitro and in vivo.
TsTryp binding to PAR2 activated the ERK1/2 pathway, decreased the expression of gut TJs proteins, disrupted epithelial integrity and barrier function, and consequently mediated larval invasion of the gut mucosa. Therefore, rTsTryp could be regarded as a potential vaccine target for blocking T. spiralis invasion and infection.
Parapneumonic pleural effusion (PPE) is a common complication in patients with pneumonia. Timely and accurate diagnosis of PPE is of great value for its management. Measurement of biomarkers in ...circulating and pleural fluid have the advantages of easy accessibility, short turn-around time, objectiveness and low cost and thus have utility for PPE diagnosis and stratification. To date, many biomarkers have been reported to be of value for the management of PPE. Here, we review the values of pleural fluid and circulating biomarkers for the diagnosis and stratification PPE. The biomarkers discussed are C-reactive protein, procalcitonin, presepsin, soluble triggering receptor expressed on myeloid cells 1, lipopolysaccharide-binding protein, inflammatory markers, serum amyloid A, soluble urokinase plasminogen activator receptor, matrix metalloproteinases, pentraxin-3 and cell-free DNA. We found that none of the available biomarkers has adequate performance for diagnosing and stratifying PPE. Therefore, further work is needed to identify and validate novel biomarkers, and their combinations, for the management of PPE.
Background:
Pleural fluid (PF) carcinoembryonic antigen (CEA) is a widely used diagnostic marker for malignant pleural effusion (MPE). Recent studies revealed that PF to serum CEA was also a ...promising diagnostic parameter for MPE.
Objective:
We aimed to investigate whether PF to serum CEA ratio and delta CEA (PF minus serum CEA) provided added value to PF CEA in diagnosing MPE.
Methods:
Patients with pleural effusion in a retrospective cohort (BUFF) and a prospective cohort (SIMPLE) were included. The clinical characteristics of the patients were extracted from their medical records. The diagnostic value of CEA ratio and delta CEA was estimated by a receiver operating characteristics (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).
Results:
A total of 148 patients in the BUFF cohort and 164 patients in the SIMPLE cohort were enrolled. The BUFF cohort had 46 MPE patients and 102 benign pleural effusion (BPE) patients, and the SIMPLE cohort had 85 MPE patients and 79 BPE patients. In both cohorts, MPE patients had significantly higher PF CEA, serum CEA, CEA ratio, and delta CEA. The area under ROC curves (AUCs) of PF CEA, CEA ratio, and delta CEA were 0.78 (95% CI: 0.67–0.88), 0.80 (95% CI: 0.72–0.89) and 0.83 (95% CI: 0.75–0.91) in the BUFF cohort, and 0.89 (95% CI: 0.83–0.94), 0.86 (95% CI: 0.80–0.92), and 0.84 (95% CI: 0.78–0.91) in the SIMPLE cohort. The differences between the AUCs of PF CEA, CEA ratio, and delta CEA did not reach statistical significance. The continuous NRI and IDI of CEA ratio and delta CEA were <0.
Conclusion:
CEA ratio and delta value cannot provide added diagnostic value to PF CEA. The simultaneous determination of serum and PF CEA should not be adopted in clinical practice.
Errors are inherent in all biological systems. Errors in protein translation are particularly frequent giving rise to a collection of protein quasi-species, the diversity of which will vary according ...to the error rate. As mistranslation rates rise, these new proteins could produce new phenotypes, although none have been identified to date. Here, we find that mycobacteria substitute glutamate for glutamine and aspartate for asparagine at high rates under specific growth conditions. Increasing the substitution rate results in remarkable phenotypic resistance to rifampicin, whereas decreasing mistranslation produces increased susceptibility to the antibiotic. These phenotypic changes are reflected in differential susceptibility of RNA polymerase to the drug. We propose that altering translational fidelity represents a unique form of environmental adaptation.
Blastocystis is a common zoonotic intestinal protozoan and causes a series of gastrointestinal symptoms in humans and animals via the fecal–oral route, causing economic losses and posing public ...health problems. At present, the prevalence and genetic structure of Blastocystis in sheep and pigs in Shanxi province remains unknown. Thus, the present study collected 492 sheep fecal samples and 362 pig fecal samples from three representative counties in northern, central and southern Shanxi province for the detection of Blastocystis based on its SSU rRNA gene. The results showed that the overall prevalence of Blastocystis in the examined sheep and pigs were 16.26% and 14.09%, respectively. Sequences analyses showed that four known subtypes (ST5, ST10, ST14 and ST30) in sheep and two subtypes (ST1 and ST5) in pigs were detected in this study, with ST5 being the predominate subtype among the study areas. Phylogenetic analysis showed that the same subtypes were clustered into the same branch. This study reveals that sheep and pigs in Shanxi province are hosts for multiple Blastocystis subtypes, including the zoonotic subtypes (ST1 and ST5), posing a risk to public health. Baseline epidemiological data are provided that help in improving our understanding of the role of zoonotic subtypes in Blastocystis transmission.
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