MARCH9 Mediates NOX2 Ubiquitination to Alleviate NLRP3 Inflammasome-Dependent Pancreatic Cell Pyroptosis in Acute Pancreatitis.

OBJECTIVE: The pathogenesis of acute pancreatitis mainly involves NLRP3 inflammasome-mediated pancreatic cell injury, although regulators of this inflammasome machinery are still not fully identified. Membrane-associated RING-CH 9 (MARCH9) is a member of MARCH-type finger proteins, which regulates innate immunity through catalyzing polyubiquitination of critical immune factors. The aim of present research is to examine the function of MARCH9 in acute pancreatitis. METHODS: Cerulein-induced acute pancreatitis was established on pancreatic cell line AR42J and rat model. Reactive oxygen species (ROS) accumulation and NLRP3 inflammasome-dependent cell pyroptosis in pancreas were examined by flow cytometry. RESULTS: MARCH9 was downregulated by cerulein, but overexpressing MARCH9 could inhibit NLRP3 inflammasome activation and ROS accumulation, thus suppressing pancreatic cell pyroptosis and mitigating pancreatic injury. We further uncovered that the mechanism underlying such an effect of MARCH9 is through mediating the ubiquitination of NADPH oxidase-2, whose deficiency reduces cellular ROS accumulation and inflammasome formation. CONCLUSIONS: Our results suggested that MARCH9 suppresses NLRP3 inflammasome-mediated pancreatic cell injury through mediating the ubiquitination and degradation of NADPH oxidase-2, which compromises ROS generation and NLRP3 inflammasomal activation.

A risk signature of necroptosis-related lncRNA to predict prognosis and probe molecular characteristics for male with bladder cancer.

Bladder cancer (BC) is a frequently diagnosed cancer with high mortality. Male patients have a higher risk of developing BC than female patients. As a type of caspase-independent cell death, necroptosis plays a significant role in the occurrence and progression of BC. The aberrant function of long non-coding RNAs (lncRNAs) plays an indispensable role in GI. However, the relationship between lncRNA and necroptosis in male patients with BC remains unclear. The clinical information and RNA-sequencing profiles of all BC patients were retrieved from The Cancer Genome Atlas Program. A total of 300 male participants were selected for the study. We conducted to identify the necroptosis-related lncRNAs (NRLs) by Pearson correlation analysis. Subsequently, least absolute shrinkage and selection operator Cox regression were conducted to establish a risk signature with overall survival-related NRLs in the training set and to validate it in the testing set. Finally, we verified the effectiveness of the 15-NRLs signature in prognostic prediction and therapy via survival analysis, receiver operating characteristic curve analysis, and Cox regression. Furthermore, we analyzed the correlation between the signature risk score and pathway enrichment analysis, immune cell infiltration, anticancer drug sensitivity, and somatic gene mutations. We developed 15-NRLs (AC009974.1, AC140118.2, LINC00323, LINC02872, PCAT19, AC017104.1, AC134312.5, AC147067.2, AL139351.1, AL355922.1, LINC00844, AC069503.1, AP003721.1, DUBR, LINC02863) signature, and divided patients into a high-risk group and low-risk group through the median risk score. Kaplan-Meier and receiver operating characteristic curves showed that the prognosis prediction had satisfactory accuracy. Cox regression analysis indicated that the 15-NRLs signature was a risk factor independent of various clinical parameters. Additionally, immune cell infiltration, half-maximal inhibitory concentration, and somatic gene mutations differed significantly among different risk subsets, implying that the signature could assess the clinical efficacy of chemotherapy and immunotherapy. This 15-NRLs risk signature may be helpful in assessing the prognosis and molecular features of male patients with BC and improve treatment modalities, thus can be further applied clinically.