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  • Title: MZB1 regulates cellular proliferation, mitochondrial dysfunction, and inflammation and targets the PI3K-Akt signaling pathway in acute pancreatitis.
    Author: Xu M, Feng Y, Xiang X, Liu L, Tang G.
    Journal: Cell Signal; 2024 Jun; 118():111143. PubMed ID: 38508349.
    Abstract:
    BACKGROUND: Acute pancreatitis (AP) is a pathological condition characterized by the premature release and activation of trypsinogens and other enzyme precursors. In severe cases, the mortality rates are in the range of 20-30% and may even be as high as 50%. Though various prophylaxes are available for AP, the mechanism of its progression is unclear. Marginal zone B and B-1 cell-specific protein 1 (MZB1) is found in the endoplasmic reticulum (ER) where it is expressed exclusively in the B cells there. MZB1 promotes proliferation, inhibits apoptosis, invasion, and inflammation, and mitigates mitochondrial damage in cells. However, the importance of MZB1 in AP has not yet been determined. METHODS: Differentially expressed genes (DEGs) between healthy pancreatic cells and those affected by AP were identified using datasets from Gene Expression Omnibus (GEO) datasets. Relative differences in MZB1 expression between normal and diseased tissues and cells were validated in vivo using a rat AP model induced with 4% (w/v) sodium taurocholate and in vitro using the AR42J rat pancreatic cell line exposed to caerulein (CAE). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2`-deoxyuridine (EdU) assays were performed to detect and compare normal and pathological cell proliferation. Flow cytometry was employed to assess and compare cellular apoptosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) were applied to evaluate the apoptotic factors Bax and Bcl. The inflammatory factors interleukin (IL)-6 and IL-1β were quantified using Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR techniques. Mitochondrial function was evaluated using assays for reactive oxygen species (ROS) and tetramethylrhodamine methyl ester (TMRM). WB and qRT-PCR were utilized to measure the expression levels of the PI3K-Akt signaling pathway, followed by a rescue experiment involving the inhibitor of wortmannin. RESULTS: MZB1 was upregulated in the AP cases screened from the GEO datasets, the rat AP model, and the AR42J cells exposed to CAE. Overexpression of MZB1 enhanced the growth and supressed the cell death of AR42J cells while also activating the PI3K-Akt signaling pathway. MZB1 knockdown led to mitochondrial dysfunction and exacerbated inflammation. The rescue experiment demonstrated that MZB1 enhanced proliferation and inhibited apoptosis, mitochondrial dysfunction, and inflammation in pancreatic cells through the PI3K-Akt pathway. CONCLUSIONS: AP cells and tissues exhibited markedly elevated levels of MZB1 expression compared to their healthy counterparts. MZB1 overexpression promoted proliferation and supressed apoptosis, mitochondrial dysfunction, and inflammation in pancreatic cells through the positive regulation of the PI3K-Akt signaling pathway.
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