Hyperlipidemia exacerbates acute pancreatitis via interactions between P38MAPK and oxidative stress

  • Cell Signal. 2024 Nov 4:125:111504. doi: 10.1016/j.cellsig.2024.111504.
Minhao Qiu  1 ,  Yining Huang  1 ,  Xiaoying Zhou  1 ,  Junyu Yu  1 ,  Jianmin Li  2 ,  Wei Wang  3 ,  Maddalena Zippi  4 ,  Sirio Fiorino  5 ,  Wandong Hong  6
Affiliations
  • 1. Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China.
  • 2. Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China.
  • 3. School of Mental Health, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: [email protected].
  • 4. Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy.
  • 5. Medicine Department, Internal Medicine Unit, Budrio Hospital Azienda USL, 40054 Bologna, Budrio, Italy. Electronic address: [email protected].
  • 6. Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 39505288 DOI: 10.1016/j.cellsig.2024.111504
Abstract

Background: The mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood.

Aims: To investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP.

Methods: In AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2). GeneMANIA has been used for the prediction of potential interaction mechanisms. Validation was carried out using an experimental AP model and a bi-directional Mendelian randomization (MR) analysis.

Results: Compared to mild AP, patients with severe AP had higher gene expression of MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. GeneMANIA revealed 77.6 % physical interactions among MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. Our results indicated that HLAP group had a more severe pancreatic injury, a stronger inflammatory response with higher serum levels of TNF-α, IL-6 and IL-1β in comparison with the AP group, which were significantly mitigated in HLAP-Pi group. Furthermore, SB 203580 inhibited increasing levels of malondialdehyde (MDA) in serum and of inducible nitric oxide synthase (iNOS), P38MAPK, p-P38MAPK and NF-κB p65 in pancreatic tissue as well as decreasing serum values of SOD and GSH-PX in HLAP group. MR analysis suggested that MAPK14 levels were negatively associated with the SOD levels, by using the inverse variance weighted (IVW) method (b = -0.193: se = 0.225; P = 1.03e-17). Reverse MR analysis indicated that SOD was negatively associated with the MAPK14 levels in the IVW analysis (b = -0.163: se = 0.020; P = 1.38e-15).

Conclusion: Interactions between P38MAPK and oxidative stress may play an important role in the pathogenesis of HLAP.

Keywords
Acute pancreatitis; Bioinformatics; Hyperlipidemia; Mendelian randomization; Pathogenesis.
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