The molecular mechanism of PLD2-mediated regulation of apoptosis and cell edema in pancreatic cells via the Nrf2/NF-κB pathway.
Cell edema
Nrf2/NF-κB
Pan-apoptosis
Pancreatic cells
Phospholipase D2
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
26 Oct 2024
26 Oct 2024
Historique:
received:
10
05
2024
accepted:
11
10
2024
medline:
27
10
2024
pubmed:
27
10
2024
entrez:
27
10
2024
Statut:
epublish
Résumé
This study aimed to elucidate the molecular mechanisms by which PLD2 controls apoptosis and edema in pancreatic cells via the Nrf2/NF-κB pathway. AR42J rat pancreatic cells were treated with 10 nM mitomycin to create an in vitro pancreatitis model (model group), with a control group receiving phosphate-buffered saline. Cells were transfected with a PLD2 overexpression plasmid using Lipofectamine 3000, forming the PLD2 overexpression group. PLD2 protein expression was assessed by Western blotting, and TNF-α, IL-6, and IL-10 levels were measured by RT-qPCR. Nrf2/NF-κB protein expressions were also analyzed. Apoptosis and necrosis were evaluated using Annexin V-FITC/PI staining and the LDH release test. Cell edema was assessed by cell volume, ion content, and membrane damage. Western blotting was used to analyze pan-apoptosis-related proteins. PLD2 expression was lower in the model group compared to controls (P < 0.05) but higher in the PLD2 overexpression group (P < 0.05). TNF-α, IL-6, and IL-10 levels were elevated in the model group (P < 0.05) and reduced in the PLD2 overexpression group (P < 0.05). Nrf2 expression decreased in the model group but increased with PLD2 overexpression (P < 0.05). NF-κB expression increased in the model group but decreased with PLD2 overexpression (P < 0.05). Apoptosis and necrosis rates were higher in the model group (P < 0.05) but lower in the PLD2 overexpression group (P < 0.05). Cell volume, Na + content, and LDH release increased in the model group (P < 0.05) but decreased with PLD2 overexpression (P < 0.05). RIPK1 expression decreased in the model group (P < 0.05) but increased with PLD2 overexpression (P < 0.05). CASP8, FADD, and ZBP1 levels were higher in the model group (P < 0.05) and reduced with PLD2 overexpression (P < 0.05). PLD2 exerts a protective effect in acute pancreatitis by activating Nrf2 and inhibiting NF-κB, reducing apoptosis, cell swelling, and membrane damage. This highlights potential therapeutic targets for pancreatic inflammation.
Identifiants
pubmed: 39461986
doi: 10.1038/s41598-024-76274-4
pii: 10.1038/s41598-024-76274-4
doi:
Substances chimiques
NF-E2-Related Factor 2
0
NF-kappa B
0
Phospholipase D
EC 3.1.4.4
Nfe2l2 protein, rat
0
phospholipase D2
EC 3.1.4.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25563Informations de copyright
© 2024. The Author(s).
Références
Lin, Y. et al. Astragaloside IV ameliorates Streptozotocin Induced pancreatic β-Cell apoptosis and dysfunction through SIRT1/P53 and Akt/GSK3β/Nrf2 signaling pathways. Diabetes Metabolic Syndrome Obesity: Targets Therapy. 15, 131–140 (2022).
doi: 10.2147/DMSO.S347650
pubmed: 35046684
Ghasemzadeh Rahbardar, M. & Hosseinzadeh, H. A review of how the saffron (Crocus sativus) petal and its main constituents interact with the Nrf2 and NF-κB signaling pathways. Naunyn. Schmiedebergs Arch. Pharmacol. 396 (9), 1879–1909 (2023).
doi: 10.1007/s00210-023-02487-5
pubmed: 37067583
Aslan, A. et al. The impact of ellagic acid on some apoptotic gene expressions: A new perspective for the regulation of pancreatic Nrf-2/NF-κB and Akt/VEGF signaling in CCl(4)-induced pancreas damage in rats. Immunopharmacol. Immunotoxicol. 43 (2), 145–152 (2021).
doi: 10.1080/08923973.2020.1869255
pubmed: 33455449
Banks, P. A. et al. Classification of acute pancreatitis–2012: Revision of the Atlanta classification and definitions by international consensus. Gut. 62 (1), 102–111 (2013).
doi: 10.1136/gutjnl-2012-302779
pubmed: 23100216
Majidi, S., Golembioski, A., Wilson, S. L. & Thompson, E. C. Acute pancreatitis: Etiology, pathology, diagnosis, and treatment. South. Med. J. 110 (11), 727–732 (2017).
doi: 10.14423/SMJ.0000000000000727
pubmed: 29100225
Wu, T. et al. Lentinan protects against pancreatic β-cell failure in chronic ethanol consumption-induced diabetic mice via enhancing β-cell antioxidant capacity. J. Cell. Mol. Med. 25 (13), 6161–6173 (2021).
doi: 10.1111/jcmm.16529
pubmed: 33837638
pmcid: 8256364
Gupta, P. et al. Dietary pomegranate supplement alleviates murine pancreatitis by modulating Nrf2-p21 interaction and controlling apoptosis to survival switch. J. Nutr. Biochem. 66, 17–28 (2019).
doi: 10.1016/j.jnutbio.2018.12.009
pubmed: 30708236
Li, W. et al. Polysaccharides from Opuntia milpa alta alleviate alloxan-induced INS-1 cells apoptosis via reducing oxidative stress and upregulating Nrf2 expression. Nutr. Res. (New York NY). 77, 108–118 (2020).
doi: 10.1016/j.nutres.2020.02.004
Wu, H., Chen, H. & Zhou, R. Phospholipase D2 targeted by mir-5132-5p alleviates cerulein-induced acute pancreatitis via the Nrf2/NFκB pathway. Immun. Inflamm. Dis. 11 (5), e831 (2023).
doi: 10.1002/iid3.831
pubmed: 37249288
pmcid: 10227361
Baumel-Alterzon, S. et al. Nrf2 regulates β-Cell Mass by suppressing β-Cell death and promoting β-Cell proliferation. Diabetes. 71 (5), 989–1011 (2022).
doi: 10.2337/db21-0581
pubmed: 35192689
pmcid: 9044139
Liang, F. et al. Cinchonine-induced cell death in pancreatic cancer cells by downregulating RRP15. Cell. Biol. Int. 47 (5), 907–919 (2023).
doi: 10.1002/cbin.11987
pubmed: 36682038
Katsu-Jiménez, Y. et al. Absence of TXNIP in humans leads to lactic acidosis and low serum methionine linked to deficient respiration on pyruvate. Diabetes. 68 (4), 709–723 (2019).
doi: 10.2337/db18-0557
pubmed: 30755400
Cao, X. Y. et al. The protective effects of a novel polysaccharide from Lentinus edodes mycelia on islet β (INS-1) cells damaged by glucose and its transportation mechanism with human serum albumin. Int. J. Biol. Macromol. 134, 344–353 (2019).
doi: 10.1016/j.ijbiomac.2019.05.033
pubmed: 31075333
Liang, C. et al. PIN1 maintains Redox Balance via the c-Myc/NRF2 Axis to counteract Kras-Induced mitochondrial respiratory Injury in Pancreatic Cancer cells. Cancer Res. 79 (1), 133–145 (2019).
doi: 10.1158/0008-5472.CAN-18-1968
pubmed: 30355620
Zhao, Q., Wei, Y., Pandol, S. J., Li, L. & Habtezion, A. STING signaling promotes inflammation in experimental acute pancreatitis. Gastroenterology. 154 (6), 1822–1835e1822 (2018).
doi: 10.1053/j.gastro.2018.01.065
pubmed: 29425920
Wang, S. et al. Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. Autophagy. 15 (11), 1954–1969 (2019).
doi: 10.1080/15548627.2019.1596486
pubmed: 30894069
pmcid: 6844531
Mohammad, J. et al. JNK inhibition blocks piperlongumine-induced cell death and transcriptional activation of heme oxygenase-1 in pancreatic cancer cells. Apoptosis: Int. J. Program. cell. Death. 24 (9–10), 730–744 (2019).
doi: 10.1007/s10495-019-01553-9
Terasaki, M. et al. A marine carotenoid of fucoxanthinol accelerates the growth of human pancreatic cancer PANC-1 cells. Nutr. Cancer. 74 (1), 357–371 (2022).
doi: 10.1080/01635581.2020.1863994
pubmed: 33590779
Lu, Y. et al. Double-negative T cells inhibit proliferation and invasion of human pancreatic cancer cells in co-culture. Anticancer Res. 39 (11), 5911–5918 (2019).
doi: 10.21873/anticanres.13795
pubmed: 31704815
Zhang, Q. et al. Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model. Neoplasia (New York NY). 22 (6), 242–252 (2020).
doi: 10.1016/j.neo.2020.03.002
Gong, J. H. et al. Dexamethasone enhances the antitumor efficacy of Gemcitabine by glucocorticoid receptor signaling. Cancer Biol. Ther. 21 (4), 332–343 (2020).
doi: 10.1080/15384047.2019.1702399
pubmed: 31906826
pmcid: 7515523
Xu, C., Zhang, M., Zhang, G., Yan, S. & Yan, W. Hydrogen Sulfide improves functional recovery in Rat traumatic spinal cord Injury Model by inducing nuclear translocation of NF-E2-related factor 2. Biol. Pharm. Bull. 44 (8), 1093–1100 (2021).
doi: 10.1248/bpb.b21-00259
pubmed: 34334495
Kha, M. L., Hesse, L., Deisinger, F. & Sipos, B. The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ∆Zip2. Oncogene. 38 (9), 1461–1476 (2019).
doi: 10.1038/s41388-018-0518-3
pubmed: 30302023
Shi, Z. et al. The LipoxinA4 receptor agonist BML-111 ameliorates intestinal disruption following acute pancreatitis through the Nrf2-regulated antioxidant pathway. Free Radic. Biol. Med. 163, 379–391 (2021).
doi: 10.1016/j.freeradbiomed.2020.12.232
pubmed: 33383086
Yin, Q. H., Zhou, Y. & Li, Z. H. Y. miR-373 suppresses cell proliferation and apoptosis via regulation of SIRT1/PGC-1α/NRF2 axis in pancreatic cancer. Cell. J. 23 (2), 199–210 (2021).
pubmed: 34096221
pmcid: 8181315
Ding, Y. et al. Preclinical validation of silibinin/albumin nanoparticles as an applicable system against acute liver injury. Acta Biomater. 146, 385–395 (2022).
doi: 10.1016/j.actbio.2022.04.021
pubmed: 35460909
Wu, L. L. et al. NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis. J. cell. Commun. Signal. 13 (1), 99–112 (2019).
doi: 10.1007/s12079-018-0479-x
pubmed: 30030687
Naganna, C. M., Prasad, K. Y., Mahendra, V. P., Ganesan, P. & Kumar, R. Vanillic acid potentiates insulin secretion and prevents pancreatic β-cells cytotoxicity under H(2)O(2)-induced oxidative stress. Mol. Biol. Rep. 50 (2), 1311–1320 (2023).
doi: 10.1007/s11033-022-08046-0
pubmed: 36454432
Huang, S. et al. Tamoxifen inhibits cell proliferation by impaired glucose metabolism in gallbladder cancer. J. Cell. Mol. Med. 24 (2), 1599–1613 (2020).
doi: 10.1111/jcmm.14851
pubmed: 31782270