ABSTRACT
Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2 activating composition PB125(R) downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-Cov-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL1-beta, IL6, TNF-, the cell adhesion molecules ICAM1, VCAM1, and E-selectin, and a group of IFN-{gamma}-induced genes. Many of these cytokines have been specifically identified in the "cytokine storm" observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.
ABSTRACT
Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.
Subject(s)
Hypertension, Pulmonary/etiology , Interleukin-6/metabolism , Schistosoma mansoni/pathogenicity , Animals , Disease Models, Animal , Familial Primary Pulmonary Hypertension , Gene Expression Profiling , Humans , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Interleukin-6/deficiency , Interleukin-6/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , NFATC Transcription Factors/metabolism , Pulmonary Artery/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Schistosomiasis mansoni/complications , Signal TransductionABSTRACT
OBJECTIVE: To reveal the characteristics of gene expression in adrenal gland of H22 tumor mice with typical syndromes and in different liver cancer stages. METHODS: By the quantitative four diagnosis and syndrome differentiation methods and GeneChip Mouse Exon 1.0 ST Array, we observed adrenal gland gene expression in H22 tumor mice with pathogenic factor-toxin predominance syndrome and qi deficiency syndrome in the earlier stage, yang-qi deficiency syndrome in the intermediate stage, and qi-yin-yang deficiency syndrome in the advanced stage. Genes highly expressed and remarkably different were analyzed in this study. RESULTS: A total of seventy-three up-regulated coincident genes and twenty-six down-regulated coincident genes in different stages were investigated in the study. Up-regulated coincident genes included Hp, C3, Anxa1, Procr, C2, Il4ra, Cd14, Ptprc, Cd52, C4b, Eno3, Xdh, Gpx3, and so on. Down-regulated coincident genes included nervous system function-related genes such as Plp1, Mbp, Aldh1a1, Cck, Atn1, genes associated with electrolyte metabolism such as Aldh1a1 and Slc22a17, genes related to signal transduction such as Cxcr4, Spag5 and Stmn3, etc, and genes related to transcriptional control and protein biosynthesis such as Hspa1a, Dnajb1, Thra, Hhex and so on. CONCLUSION: With the development of the tumorigenesis, the symptoms and signs and differentially expressed genes in adrenal gland of H22 tumor mice can be measured. Up-regulated and down-regulated coincident genes may be the features of H22 tumor mice different from those of normal mice.
