OTUD1 Deficiency Alleviates LPS-Induced Acute Lung Injury in Mice by Reducing Inflammatory Response.

The ovarian tumor (OTU) family consists of deubiquitinating enzymes thought to play a crucial role in immunity. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) pose substantial clinical challenges due to severe respiratory complications and high mortality resulting from uncontrolled inflammation. Despite this, no study has explored the potential link between the OTU family and ALI/ARDS. Using publicly available high-throughput data, 14 OTUs were screened in a simulating bacteria- or LPS-induced ALI model. Subsequently, gene knockout mice and transcriptome sequencing were employed to explore the roles and mechanisms of the selected OTUs in ALI. Our screen identified OTUD1 in the OTU family as a deubiquitinase highly related to ALI. In the LPS-induced ALI model, deficiency of OTUD1 significantly ameliorated pulmonary edema, reduced permeability damage, and decreased lung immunocyte infiltration. Furthermore, RNA-seq analysis revealed that OTUD1 deficiency inhibited key pathways, including the IFN-γ/STAT1 and TNF-α/NF-κB axes, ultimately mitigating the severity of immune responses in ALI. In summary, our study highlights OTUD1 as a critical immunomodulatory factor in acute inflammation. These findings suggest that targeting OTUD1 could hold promise for the development of novel treatments against ALI/ARDS.

Design, Synthesis, And Evaluation Of Cyanopyridines As Anti-Colorectal Cancer Agents Via Inhibiting STAT3 Pathway.

BACKGROUND: Colorectal cancer is one of the common malignant tumors. Cyanopyridine and aminocyanopyridine having a carbon-nitrogen bond have been shown to have significant anticancer effects. STAT3 is a promising therapeutic target in multiple cancers. However, there are currently no effective STAT3 inhibitors in clinical practice for the treatment of colorectal cancer. MATERIALS AND METHODS: We screened 27 cyanopyridines for their anticancer activity by cell viability. The HCT-116, RKO, and DLD-1 cell lines were used to evaluate the anti-colorectal cancer effect of 3n. Scratch experiments and colony formation assays were used for the assessment of cell migration and proliferation capacity. Phosphorylated STAT3, STAT3, MCL-1, and Survivin levels were assessed by Western blot analysis. RESULTS: In this study, we synthesized 27 cyanopyridines and screened their anticancer activities in three human tumor cells, HCT-116, Hela229, and A375. We found that 2-amino-3-cyanopyridine 3n has better anticancer activity with IC50 values in the low micromolar range. Furthermore, 3n significantly inhibited the migration and colony formation of colorectal cancer cells. Mechanistically, 3n inhibited the expression of STAT3 phosphorylation in a dose- and time-dependent manner. CONCLUSION: 3n is worth of further investigations toward the discovery of STAT3 inhibitor as a drug candidate for cancer therapy.