NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer.

BACKGROUND: Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8+ T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition. METHODS: This study used spontaneous adenoma-developing ApcMin/+, macrophage-specific Act1-knockdown (anti-Act1), and ApcMin/+; anti-Act1 (AA) mice. Histological analysis was performed on CRC tissues of patients and mice. CRC patients' data retrieved from the TCGA dataset were analyzed. Primary cell isolation, co-culture system, RNA-seq, and fluorescence-activated cell sorting (FACS) were used. RESULTS: By TCGA and TISIDB analysis, the downregulation of Act1 expression in tumor tissues of CRC patients negatively correlated with accumulated CD68+ macrophages in the tumor. Relative expression of EMT markers in the tumor enriched ACT1lowCD68+ macrophages of CRC patients. AA mice showed adenoma-adenocarcinoma transition, TAMs recruitment, and CD8+ T cell infiltration in the tumor. Macrophages depletion in AA mice reversed adenocarcinoma, reduced tumor amounts, and suppressed CD8+ T cell infiltration. Besides, macrophage depletion or anti-CD8a effectively inhibited metastatic nodules in the lung metastasis mouse model of anti-Act1 mice. CRC cells induced activation of IL-6/STAT3 and IFN-γ/NF-κB signaling and the expressions of CXCL9/10, IL-6, and PD-L1 in anti-Act1 macrophages. Anti-Act1 macrophages facilitated epithelial-mesenchymal-transition and CRC cells' migration via CXCL9/10-CXCR3-axis. Furthermore, anti-Act1 macrophages promoted exhaustive PD1+ Tim3+ CD8+ T cell formation. Anti-PD-L1 treatment repressed adenoma-adenocarcinoma transition in AA mice. Silencing STAT3 in anti-Act1 macrophages reduced CXCL9/10 and PD-L1 expression and correspondingly inhibited epithelial-mesenchymal-transition and CRC cells' migration. CONCLUSIONS: Act1 downregulation in macrophages activates STAT3 that promotes adenoma-adenocarcinoma transition via CXCL9/10-CXCR3-axis in CRC cells and PD-1/PD-L1-axis in CD8+ T cells.

Salt-Sensitive Ileal Microbiota Plays a Role in Atrial Natriuretic Peptide Deficiency-Induced Cardiac Injury.

Atrial natriuretic peptide (ANP) activity deficiency contributes to salt-sensitive hypertension in humans and mice. However, the role of ileal microbiota in salt sensitivity in ANP deficiency-related cardiac injury has not been investigated yet. This study used ANP-/- mice to analyze the role of the salt-sensitive ileal microbiome on cardiac injury. ANP-/- mice showed an increase in blood pressure (BP), the heart weight/body weight (HW/BW) ratio, and cardiac hypertrophy compared with wild-type (WT) mice. ANP deficiency did not impact the histological structure but reduced occludin expression in the ileum. Antibiotics significantly relieved BP and cardiac hypertrophy in ANP-/- mice. A high-salt diet (HSD) increased BP, the HW/BW ratio, and cardiac hypertrophy/fibrosis in WT and ANP-/- mice, and an HSD treatment in ANP-/- mice exacerbated these cardiac parameters. The HSD markedly decreased muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of WT and ANP-/- mice. Furthermore, the HSD increased the level of TLR4 and IL-1ß in ANP-/- mice ileum compared with WT mice. Antibiotics reduced the HW/BW ratio, cardiac hypertrophy/fibrosis, and the level of TLR4 and IL-1ß in the ileum, and rescued the muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of HSD-ANP-/- mice. Importantly, ANP deficiency induced the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum on the NSD diet, which was only observed in HSD-induced WT mice but not in WT mice on the NSD. Besides, the HSD significantly enhanced the sum of the percentage of the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum of ANP-/- mice. Ileal microbiota transfer (IMT) from ANP-/- mice to healthy C57BL/6J mice drove Lactobacillus johnsonii and Lactobacillus reuteri colonization in the ileum, which manifested an increase in BP, the HW/BW ratio, cardiac hypertrophy, and ileal pathology compared with IMT from WT mice. The HSD in C57BL/6J mice with IMT from ANP-/- mice drove the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum and further exacerbated the cardiac and ileal pathology. Our results suggest that salt-sensitive ileal microbiota is probably related to ANP deficiency-induced cardiac injury.

LncRNA Gas5 regulates Fn1 deposition via Creb5 in renal fibrosis.

Aim: Although studies on lncRNAs in renal fibrosis have focused on target genes and functions of lncRNAs, a comprehensive interaction analysis of lncRNAs is lacking. Materials & methods: Differentially expressed genes in renal fibrosis were screened, and the interaction between lncRNAs and miRNAs was searched. Results: We constructed a ceRNA network associated with renal fibrosis, by which we found the transcription factor Creb5, a target gene of lncRNA Gas5 that might regulate extracellular Fn1 deposition. Conclusion: Our study not only provides a theoretical basis for the ceRNA regulation mechanism of Gas5 but also provides experimental evidence supporting the use of Gas5 targeting in the treatment of renal fibrosis.

Effects of ferric ion on the photo-treatment of nonionic surfactant Brij35 washing waste containing 2,2',4,4'-terabromodiphenyl ether.

The effects of ferric iron on the photo-treatment of simulated BDE-47 (2,2',4,4'- terabromodiphenyl ether)-Brij35 (Polyoxyethylene lauryl ether) washing waste were studied to evaluate the influences of ferric iron on BDE-47 removal and Brij35 recovery. The results show that Fe3+ accelerated BDE-47 degradation at lower concentrations (<0.5 mM) but attenuated it at higher concentrations (0.5-5 mM) and that Brij35 loss was increased with increasing Fe3+. These results likely are caused by changes in the rate of •OH production due to the ferric ion, association of Fe3+ and electron transfer from Brij35, and light attenuation at high concentration. The BDE-47 and Brij35 had different degradation rates at different pH values and at different dissolved oxygen concentrations. The BDE-47 products were identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The results indicated that BDE-47 transformed into mainly lower-brominated products, a few bromodibenzofurans, some rearrangement products, and some hydroxylated polybrominated diphenyl ethers. A series of Brij35 oxidization products were detected by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS), including hydroxylation products, carboxylation products, and some hydrophilic chain-breaking products. Brij35 was mainly oxidized by Fe3+ and/or reactive oxygen species (ROS) with the final products of CO2 and H2O. The iron ions apparently cycled from ferric to ferrous ions in the micelles such that the Fe3+-Brij35 complex dominated the main redox reaction, leading to both BDE-47 and Brij35 degradation. It appears that in any applied soil washing system, the ferric ions in the washing waste need to be removed because of the adverse effects on BDE-47 removal and eluate reuse.