Zika virus (ZIKV) infection is a public health emergency and host innate immunity is essential for the control of virus infection. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase-1 to facilitate interleukin-1β (IL-1β) secretion. Here we report that ZIKV stimulates IL-1β secretion in infected patients, human PBMCs and macrophages, mice, and mice BMDCs. The knockdown of NLRP3 in cells and knockout of NLRP3 in mice inhibit ZIKV-mediated IL-1β secretion, indicating an essential role for NLRP3 in ZIKV-induced IL-1β activation. Moreover, ZIKV NS5 protein is required for NLRP3 activation and IL-1β secretion by binding with NLRP3 to facilitate the inflammasome complex assembly. Finally, ZIKV infection in mice activates IL-1β secretion, leading to inflammatory responses in the mice brain, spleen, liver, and kidney. Thus we reveal a mechanism by which ZIKV induces inflammatory responses by facilitating NLRP3 inflammasome complex assembly and IL-1β activation.

Glycyrrhetinic acid (GA), a triterpene saponins, has been widely proven to have multiple medicinal properties. Our study aimed to figure out the protective effect of GA on acute lung injury (ALI) and the underlying mechanism. The LPS-induced ALI model mice were intratracheally administrated with 10 mg/kg LPS. Pretreatment with GA (10, 20, 40 mg/kg, i.g.) ameliorated acute lung injury pathological damage, macrophage infiltration and lung edema. In the lung tissue, immunofluorescence (IF) and Immunohistochemistry (IHC) were performed to detect macrophage Nod-like receptor 3 (Nlrp3) inflammasome activation and interleukin-1β (IL-1β) protein expression. In macrophages, the co-localization of Nlrp3 with caspase-1 and Nlrp3 with ASC were assessed by IF. The translational and transcriptional level of Nlrp3, cle-caspase-1 and apoptosis-associated speck-like protein containing CARD (ASC), were examined by Western blot and Real time PCR (RT-PCR). The protein expression of Cle-caspase-1 was remarkably suppressed via sh-Nlrp3 transfection compared with LPS groups. GA notably attenuated ALI by inhibiting Nlrp3 formation and activation. Furthermore, GA downregulated the production of reactive oxygen species (ROS) and the phosphorylation level of PI3K and AKT in macrophages. These findings indicate that GA ameliorated ALI in mice by suppressing the activation of Nlrp3 inflammasome which may be mediated by ROS-PI3K/AKT pathway. GA may serve as a promising agent for the attenuation of ALI-related inflammation and pathology.

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.

Background: 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. Methods: 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. Results: We obtained 144 potential COVID-19 effector targets of XBJ. Fourteen of these targets-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), albumin (ALB), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), Caspase-3 (CASP3), signal transducer and activator of transcription 3 (STAT3), MAPK8, prostaglandin-endoperoxide synthase 2 (PTGS2), JUN, interleukin-2 (IL-2), estrogen receptor 1 (ESR1), and MAPK14 had degree values > 40 and therefore could be considered key targets. They participated in extracellular signal–regulated kinase 1 and 2 (ERK1, ERK2) cascade, the T-cell receptor signaling pathway, activation of MAPK 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), MAPK, phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt)-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. Conclusion: 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.