Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma

We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma.Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly(I:C)/LyoVec or infection-related cytokine TNF-αto induce expression of cytokines/chemokines/adhesion molecules.House dust mite(HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo.IL-38 significantly inhibited induced proinflammatory IL-6,IL-1β,CCL5,and CXCL10 production,and antiviral interferon-βand intercellular adhesion molecule-1 expression in the coculture system.Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1,STAT3,p38 MAPK,ERK1/2,and NF-κB pathways,and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13.Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4,IL-5,and IL-13 in the bronchoalveolar lavage fluid(BALF)and lung homogenates.Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia,together with reduced Th2,Th17,and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs,spleen,and lymph nodes.IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice,together with significantly decreased CCR3^(+) eosinophil numbers in the BALF and lungs,and a reduced percentage of human CD4^(+)CRTH2^(+)Th2 cells in the lungs and mediastinal lymph nodes.Together,our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.

Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors

Background:SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology.However,rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology.Polyoxometalates(POMs)are inorganic compounds that were previously shown to target the high-mobility group(HMG)of SOX proteins at nanomolar concentrations.In continuation of this work,we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs.Results:The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates.Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class.Further,organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity.The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.Conclusion:Polyoxometalates are highly potent,nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family.However,binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families.Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR.In summary,our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies,to address the substantial challenges involved in achieving target selectivity.

A Hashing-Based Framework for Enhancing Cluster Delineation of High-Dimensional Single-Cell Profiles

Although many methods have been developed to explore the function of cells by clustering high-dimensional(HD)single-cell omics data,the inconspicuously differential expressions of biomarkers of proteins or genes across all cells disturb the cell cluster delineation and downstream analysis.Here,we introduce a hashing-based framework to improve the delineation of cell clusters,which is based on the hypothesis that one variable with no significant differences can be decomposed into more diversely latent variables to distinguish cells.By projecting the original data into a sparse HD space,fly and densefly hashing preprocessing retain the local structure of data,and improve the cluster delineation of existing clustering methods,such as PhenoGraph.Moreover,the analyses on mass cytometry dataset show that our hashing-based framework manages to unveil new hidden heterogeneities in cell clusters.The proposed framework promotes the utilization of cell biomarkers and enriches the biological findings by introducing more latent variables.