Nuclear factor of activated T cells 5 (NFAT5), a Rel/nuclear factor- (NF-) κB family member, is the only known gene regulator of the mammalian adaptive response to osmotic stress. Exposure to elevated glucose increases the expression and nuclear translocation of NFAT5, as well as NFAT5-driven transcriptional activity in vivo and in vitro. Increased expression of NFAT5 is closely correlated with the progression of diabetes in patients. The distinct structure of NFAT5 governs its physiological and pathogenic roles, indicating its opposing functions. The ability of NFAT5 to maintain cell homeostasis and proliferation is impaired in patients with diabetes. NFAT5 promotes the formation of aldose reductase, pathogenesis of diabetic vascular complications, and insulin resistance. Additionally, NFAT5 activates inflammation at a very early stage of diabetes and induces persistent inflammation. Recent studies revealed that NFAT5 is an effective therapeutic target for diabetes. Here, we describe the current knowledge about NFAT5 and its relationship with diabetes, focusing on its diverse regulatory functions, and highlight the importance of this protein as a potential therapeutic target in patients with diabetes.

Asthma is a heterogeneous disease characterized by symptoms of chronic inflammation and airway structural and functional changes. It affects about 300 million people worldwide and causes 250 000 deaths annually, but its symptoms can be greatly relieved by regular use of inhaled glucocorticoids (GCs). GCs exert their function through interacting with glucocorticoid receptors (GRs). Diosgenin is a naturally occurring steroidal saponin abundantly present in many medicinal plants, including Dioscorea nipponica, which shares a similar steroidal structure with GC. In this study, ovalbumin (OVA)-induced asthmatic mice and primary tracheal epithelial cells (TECs) were used as research models. ELISAs were applied to measure the secretion of TNF-α, IL-1β, and IL-6, while quantitative PCR and western blotting were applied to evaluate expression of GRs SLPI, TTP, GILZ, MKP-1, and NF-κB. Our data demonstrated that diosgenin suppressed the secretion of TNF-α, IL-1β, and IL-6 by enhancing the expression of GRs, SLPI, GILZ, and MKP-1, and inhibiting the expression of HSP70. These data provide some evidence on the molecular mechanism of diosgenin, which might facilitate its clinical applications.

Purpose. Dioscorea nipponica Makino (DNM) is a traditional herb with multiple medicinal functions. This study is aimed at exploring the therapeutic effects of DNM on asthma and the underlying mechanisms involving RKIP-mediated MAPK signaling pathway. Methods. An ovalbumin-induced asthma model was established in mice, which was further administrated with DNM and/or locostatin (RKIP inhibitor). ELISA was performed to detect the serum titers of OVA-IgE and OVA-IgG1, bronchoalveolar lavage fluid (BALF) levels of inflammation-related biomarkers, and tissue levels of oxidative stress-related biomarkers. The expression of RKIP was measured by quantitative real-time PCR, Western blot, immunohistochemistry, and immunofluorescence. HE staining was used to observe the pathological morphology of lung tissues. The protein expression of MAPK pathway-related proteins was detected by Western blot. Results. Compared with the controls, the model mice exhibited significantly higher serum titers of OVA-IgE and OVA-IgG1, BALF levels of IL-6, IL-8, IL-13, TGF-β1, and MCP-1, tissue levels of MDA and ROS, lower BALF levels of IL-10 and IFN-γ, and tissue level of GSH. DNM relieved the allergic inflammatory response and oxidative stress in the model mice. DNM also recovered the downregulation of RKIP and the pathological injury of lung tissues in asthma mice. In addition, the Raf-1/MEK/MAPK/ERK pathway in the model mice was blocked by DNM. Silencing of RKIP by locostatin weakened the relieving effects of DNM on asthma through activating the Raf-1/MEK/MAPK/ERK pathway. Conclusion. DNM relieves asthma via blocking the Raf-1/MEK/MAPK/ERK pathway that mediated by RKIP upregulation.

Background. In this study, network pharmacological methods were used to analyze the targets of Rhizoma Dioscoreae Nipponicae (RDN) and investigate the potential underlying mechanism of RDN in the treatment of asthma. Methods. Asthma-related targets were obtained from the GeneCards and DisGeNET databases. The bioactive components of RDN were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database, and the targets of these compounds were predicted using the BATMAN-TCM database. The network of RDN component targets was constructed using Cytoscape. A protein-protein interaction (PPI) network was constructed in Cytoscape to determine the potential targets of RDN for the treatment of asthma. The hub genes of RDN in the treatment of asthma were screened using network topological parameters. Gene ontology (GO) and the KEGG pathways were analyzed. Molecular docking and in vivo experiments were performed to validate the network pharmacology results. Results. A total of four bioactive components and 55 targets were identified. The results of the enrichment analysis suggested that the treatment of asthma with RDN involved signaling pathways, such as those related to systemic lupus erythematosus, alcoholism, viral carcinogenesis, the cell cycle, prostate cancer, transcriptional misregulation in cancer, hepatitis B, thyroid hormone signaling, and PI3K-AKT signaling, as well as other signaling pathways. Molecular docking showed that the active components of RDN could stably bind to the predicted target. In vivo experiments showed that RDN could regulate the expression of target genes and inhibit the activation of the PI3K-AKT signaling pathway. Conclusion. To a certain extent, this study reveals the potential bioactive components and molecular mechanisms of RDN in the treatment of asthma and provides new insights for the development of new drugs for asthma.

Acute lung injury (ALI) is a critical illness with no current effective treatment. Caveolin-1 indirectly activates inflammation-associated signaling pathways by inhibiting endothelial nitric oxide synthase (eNOS). This induces an imbalance between pro- and anti-inflammatory cytokine levels, which are involved in the pathogenesis of ALI. The compound Chinese prescription Qi-Dong-Huo-Xue-Yin (QDHXY) is efficacious for ALI treatment via an anti-inflammatory effect; however, the exact underlying mechanism is unknown. Therefore, we explored the protective effect of QDHXY against lipopolysaccharide- (LPS-) induced ALI in mice. Histopathological changes in mouse lung tissues were studied. Furthermore, alterations in the serum levels of pro- and anti-inflammatory cytokines were investigated. The levels of tumor necrosis factor- (TNF-)α, interleukin- (IL-) 6, IL-1β, and interferon-γ-induced protein 10 in bronchoalveolar lavage fluid were measured. Additionally, the expression levels of myeloid differentiation factor 88 (MyD88), caveolin-1, and eNOS were assessed. QDHXY significantly reduced lung infiltration with inflammatory cells and the production of serum pro- and anti-inflammatory cytokines and inhibited the expression of TNF-α, IL-1β, caveolin-1, and MyD88 but not eNOS. These indicate that QDHXY significantly improved the balance between pro- and anti-inflammatory cytokine levels, possibly by inhibiting the caveolin-1 signaling pathway. Therefore, QDHXY may be a potential treatment for ALI.