LncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas.

Arteriovenous fistulas (AVFs) are the most common vascular access points for hemodialysis (HD), but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia (NIH). Our previous studies have revealed a highly conserved LncRNA-LncDACH1 as an important regulator of cardiomyocyte and fibroblast proliferation. Herein, we find that LncDACH1 regulates NIH in AVF in male mice with conditional knockout of smooth muscle cell-specific LncDACH1 and in male mice model of AVF with LncDACH1 overexpression by adeno-associated virus. Mechanistically, silence of LncDACH1 activates p-AKT through promoting the expression of heat shock protein 90 (HSP90) and serine/arginine-rich splicing factor protein kinase 1 (SRPK1). Moreover, LncDACH1 is transcriptionally activated by transcription factor KLF9 that binds directly to the promoter region of the LncDACH1 gene. In this work, during AVF NIH, LncDACH1 is downregulated by KLF9 and promotes NIH through the HSP90/ SRPK1/ AKT signaling axis.

Identifying the Therapeutic and Prognostic Role of the CD8+ T Cell-Related Gene ALDH2 in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSC) is a widely known malignancy which is usually diagnosed late and has a poor prognosis. This study focuses on finding a new gene linked with CD8+ T cell infiltration as a prognostic marker for patients with HNSC. Differential analysis of transcriptomic data was performed between HNSC and control tissues from TCGA and GEO database. The CD8+ T cell infiltration score was quantified using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) algorithms were used to identify key modules associated with CD8+ T cell infiltration. Kaplan-Meier (K-M) survival analysis was used to compare overall survival (OS) between the 2 groups. Univariate and multivariate Cox analyses were used to assess independent prognostic markers. The results showed CD8+ T cell infiltration score was an independent favorable prognostic marker in HNSC. Differential analysis and WGCNA identified 93 differential gene related to high CD8+ T infiltration. Amog the 93 genes, ALDH2 was an independent favorable prognostic marker in HNSC. ALDH2 expression was found to be much lower in HNSC, and patients with low ALDH2 expression had higher T stage and N stage. The correlation analysis showed that ALDH2 was linked with immune cell infiltration in the tumor microenvironment of HNSC. Patients having increased expression of ALDH2 tend to be sensitive to immune checkpoint inhibitors (ICIs). In addition, we showed the relationship between ALDH2 expression and chemotherapeutic drug sensitivity. In conclusion, this study identified ALDH2 as a prognostic marker, associated with CD8+ T cell infiltration in HNSC.

A 4-Benzene-Indol Derivative Alleviates LPS-Induced Acute Lung Injury Through Inhibiting the NLRP3 Inflammasome.

Acute lung injury (ALI) is a common complication of critical illness that could frequently lead to acute respiratory distress syndrome and other serious clinical consequences. Sepsis is one of the major and most common inducements among all causes of ALI. Due to its high incidence and mortality rate and also the complexity in treatment, sepsis-related ALI has become an urgent clinical problem waiting to be solved effectively. At present, only the protective ventilation strategy, restrictive fluid management, and antibiotics application are measures that can improve the prognosis with evidence-based medical proof. No pharmacological treatment is currently available to protect or significantly reverse the prognosis. Seeking for effective interventions measures for sepsis-related ALI is one of the most necessitous research directions. In this research, a conspicuous discovery of treatment-related translational use for a 4-benzene-indol derivative was elaborated by screening a large number of chemical compounds. The results showed that 4-benzene-indol derivative could not only suppress the activation of NLRP3 inflammasome both in vitro and alleviate LPS-induced ALI in vivo but also suppress the NLRP3 inflammasome in human myeloid leukemia mononuclear cells (THP-1) cell lines. Mechanistically, 1,2-diol blocks the NLRP3 inflammasome activation by disrupting NLRP3-NEK7 interaction and the subsequent NLRP3 inflammasome assembly and activation. To summarize, this research indicated that the newly-discovered 4-benzene-indol derivative targets NLRP3 inflammasome signaling, which consequently alleviates sepsis-related ALI. Collectively, the 4-benzene-indol derivative may serve as a potential therapeutic drug and NLRP3 inflammasome signaling would be a novel pharmaceutical target for clinical treatment of sepsis-related ALI.

An 8-Hydroxy-Quinoline Derivative Protects Against Lipopolysaccharide-Induced Lethality in Endotoxemia by Inhibiting HMGB1-Mediated Caspase-11 Signaling.

Sepsis, an inflammatory syndrome secondary to infection, is the leading cause of in-hospital lethality. It is evidenced that LPS, the major pathological component of the Gram-negative bacteria membrane, predominantly contributes to the pathogenesis of sepsis. Cytoplasmic lipopolysaccharide (LPS) can be sensed by the noncanonical inflammasome and triggers the oligomerization of caspase-11, resulting in pyroptosis and lethal immune responses in sepsis. A previous study has shown that hepatocyte-released high mobility group box 1 (HMGB1) mediates caspase-11-dependent lethality in sepsis by delivering extracellular LPS into the cytosol. Here, we established a phenotypic screening system using recombinant HMGB1 plus LPS in mouse peritoneal macrophages, identifying a novel 8-hydroxyquinoline derivative named 7-[phenyl (pyridin-2-ylamino) methyl] quinolin-8-ol (8-ol, NSC84094) that can specifically inhibit HMGB1-mediated caspase-11 signaling. 8-ol targets directly to HMGB1 and changes the secondary conformation, consequently disrupting the interaction between LPS and HMGB1 and inhibiting the HMGB1-mediated delivery of LPS into the cytosol. Intervention of 8-ol significantly reduced the release of IL-1α and IL-1ß and protected against caspase-11-mediated organ injury and lethality in endotoxemic mice. Thus, this study clearly suggests that the HMGB1-caspase-11 pathway is a potential drug target in lethal immune disorders and might open a new avenue in the treatment of sepsis.

A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis.

Caspase-11, a cytosolic lipopolysaccharide (LPS) receptor, mediates lethal immune responses and coagulopathy in sepsis, a leading cause of death worldwide with limited therapeutic options. We previously showed that over-activation of caspase-11 is driven by hepatocyte-released high mobility group box 1 (HMGB1), which delivers extracellular LPS into the cytosol of host cells during sepsis. Using a phenotypic screening strategy with recombinant HMGB1 and peritoneal macrophages, we discovered that FeTPPS, a small molecule selectively inhibits HMGB1-mediated caspase-11 activation. The physical interaction between FeTPPS and HMGB1 disrupts the HMGB1-LPS binding and decreases the capacity of HMGB1 to induce lysosomal rupture, leading to the diminished cytosolic delivery of LPS. Treatment of FeTPPS significantly attenuates HMGB1- and caspase-11-mediated immune responses, organ damage, and lethality in endotoxemia and bacterial sepsis. These findings shed light on the development of HMGB1-targeting therapeutics for lethal immune disorders and might open a new avenue to treat sepsis.

Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties.

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

Identification of biomarkers and drug repurposing candidates based on an immune-, inflammation- and membranous glomerulonephritis-associated triplets network for membranous glomerulonephritis.

BACKGROUND: Membranous glomerulonephritis (MGN) is a common kidney disease. Despite many evidences support that many immune and inflammation-related genes could serve as effective biomarkers and treatment targets for MGN patients, the potential associations among MGN-, immune- and inflammation-related genes have not been sufficiently understood. METHODS: Here, a global immune-, inflammation- and MGN-associated triplets (IIMATs) network is constructed and analyzed. An integrated and computational approach is developed to identify dysregulated IIMATs for MGN patients based on expression and interaction data. RESULTS: 45 dysregulated IIMATs are identified in MGN by above method. Dysregulated patterns of these dysregulated IIMATs are complex and various. We identify four core clusters from dysregulated IIMATs network and some of these clusters could distinguish MGN and normal samples. Specially, some anti-cancer drugs including Tamoxifen, Bosutinib, Ponatinib and Nintedanib could become candidate drugs for MGN based on drug repurposing strategy follow IIMATs. Functional analysis shows these dysregulated IIMATs are associated with some key functions and chemokine signaling pathway. CONCLUSIONS: The present study explored the associations among immune, inflammation and MGN. Some effective candidate drugs for MGN were identified based on immune and inflammation. Overall, these comprehensive results provide novel insights into the mechanisms and treatment of MGN.

Comprehensive identification of immune-associated biomarkers based on network and mRNA expression patterns in membranous glomerulonephritis.

BACKGROUND: Membranous glomerulonephritis (MGN) is the most common cause of nephrotic syndrome in adult patients. Despite extensive evidences suggested that many immune-related genes could serve as effective biomarkers in MGN, the potential has not been sufficiently understood because of most previous studies have concentrated on individual gene and not the entire interaction network. METHODS: Here, we integrated multiple levels of data containing immune-related genes, MGN-related genes, protein-protein interaction (PPI) networks and gene expression profiling data to construct an immune or MGN-directed neighbor network (IOMDN network) and an MGN-related genes-directed network (MGND network). RESULTS: Our analysis suggested that immune-related genes in the PPI network have special topological characteristics and expression pattern related to MGN. We also identified five network modules which showed tighter network structure and stronger correlation of expression. In addition, functional and drug target analyses of genes in modules indicated that the potential mechanism for MGN. CONCLUSIONS: Collectively, these results indicated that the strong associations between immune and MGN and showed the potential of immune-related genes as novel diagnostic and therapeutic targets for MGN.