Skip to main content
Log in

Crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

The anti-inflammatory and anti-apoptotic properties of crocetin have been widely demonstrated in numerous diseases. However, the exact role and mechanism of crocetin in acute pancreatitis have not been elucidated. Thus, this paper aims at exploring whether crocetin could be used to alleviate acute pancreatitis and further demonstrating the underlying mechanisms. Cell viability of caerulein-induced pancreatic exocrine cell line AR42J treated with crocetin was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT). Apoptosis and inflammation of these treated cells were detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), western blot and enzyme linked immunosorbent assay (ELISA). The expression of sirtuin-1 (SIRT1) was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. After knockdown of SIRT1, cell viability, apoptosis and inflammation were measured again by corresponding kits. Finally, the NF-κB nuclear translocation and proteins in the NF-κB signaling were examined. Crocetin remarkably suppressed the apoptosis and inflammation of caerulein-induced AR42J cells. The decreased expression of SIRT1 was increased in caerulein-induced AR42J cells after exposure to crocetin. After knockdown of SIRT1, the alleviative effects of crocetin were found to be canceled in these cells. Furthermore, SIRT1 knockdown promoted the NF-κB signal transduction. On the whole, we presented the first evidence for the importance of SIRT1-NF-κB axis in acute pancreatitis and proposed that crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Saeed SA (2020) Acute pancreatitis in children: updates in epidemiology, diagnosis and management. Curr Probl Pediatr Adolesc Health Care. https://doi.org/10.1016/j.cppeds.2020.100839

    Article  PubMed  Google Scholar 

  2. Rickes S, Uhle C (2009) Advances in the diagnosis of acute pancreatitis. Postgrad Med J 85:208–212

    Article  CAS  Google Scholar 

  3. Algul H, Schmid RM (2009) Acute pancreatitis: etiology, diagnosis and therapy. Med Monatsschr Pharm 32:242–247

    PubMed  Google Scholar 

  4. Rasul A, Yu B, Khan M, Zhang K, Iqbal F, Ma T, Yang H (2012) Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways. Int J Oncol 40:1153–1161

    Article  CAS  Google Scholar 

  5. Sreekanth GP, Chuncharunee A, Yenchitsomanus PT, Limjindaporn T (2020) Crocetin improves dengue virus-induced liver injury. Viruses. https://doi.org/10.3390/v12080825

    Article  PubMed  PubMed Central  Google Scholar 

  6. Khan MB, Hoda MN, Ishrat T, Ahmad S, Moshahid Khan M, Ahmad A, Yusuf S, Islam F (2012) Neuroprotective efficacy of Nardostachys jatamansi and crocetin in conjunction with selenium in cognitive impairment. Neurol Sci 33:1011–1020

    Article  Google Scholar 

  7. Yang R, Vernon K, Thomas A, Morrison D, Qureshi N, Way CW III, Van. (2011) Crocetin reduces activation of hepatic apoptotic pathways and improves survival in experimental hemorrhagic shock. JPEN J Parenter Enteral Nutr 35:107–113

    Article  CAS  Google Scholar 

  8. Ahmad AS, Ansari MA, Ahmad M, Saleem S, Yousuf S, Hoda MN, Islam F (2005) Neuroprotection by crocetin in a hemi-parkinsonian rat model. Pharmacol Biochem Behav 81:805–813

    Article  CAS  Google Scholar 

  9. Zhuang X, Dong A, Wang R, Shi A (2018) Crocetin treatment inhibits proliferation of colon cancer cells through down-regulation of genes involved in the inflammation. Saudi J Biol Sci 25:1767–1771

    Article  CAS  Google Scholar 

  10. Farghali H, Kemelo MK, Canova NK (2019) SIRT1 modulators in experimentally induced liver injury. Oxid Med Cell Longev 2019:8765954

    Article  Google Scholar 

  11. Chen Q, Li J, Ma J, Yang X, Ni M, Zhang Y, Li X, Lin Z, Gong F (2020) Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1-autophagy signalling pathway. J Cell Mol Med 24:5341–5351

    Article  CAS  Google Scholar 

  12. Lv C, He Y, Wei M, Xu G, Chen C, Xu Z, Ding Z (2020) CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-kappaB/p53 axis. Biosci Rep. https://doi.org/10.1042/BSR20200092

  13. Di Emidio G, Rossi G, Bonomo I, Alonso GL, Sferra R, Vetuschi A, Artini PG, Provenzani A, Falone S, Carta G, D’Alessandro AM, Amicarelli F, Tatone C (2017) The natural carotenoid crocetin and the synthetic tellurium compound AS101 protect the ovary against cyclophosphamide by modulating SIRT1 and mitochondrial markers. Oxid Med Cell Longev 2017:8928604

    Article  Google Scholar 

  14. Xue BH, Liu Y, Chen H, Sun Y, Yu WL (2020) A novel function of IRF9 in acute pancreatitis by modulating cell apoptosis, proliferation, migration, and suppressing SIRT1-p53. Mol Cell Biochem 472:125–134

    Article  CAS  Google Scholar 

  15. Rossi G, Placidi M, Castellini C, Rea F, D’Andrea S, Alonso GL, Gravina GL, Tatone C, Di Emidio G, D’Alessandro AM (2021) Crocetin mitigates irradiation injury in an in vitro model of the pubertal testis: focus on biological effects and molecular mechanisms. Molecules. https://doi.org/10.3390/molecules26061676

    Article  PubMed  PubMed Central  Google Scholar 

  16. Abdelzaher WY, Ahmed SM, Welson NN, Marraiki N, Batiha GE, Kamel MY (2021) Vinpocetine ameliorates L-arginine induced acute pancreatitis via Sirt1/Nrf2/TNF pathway and inhibition of oxidative stress, inflammation, and apoptosis. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2020.110976

    Article  PubMed  Google Scholar 

  17. Chen TH, Wang JJ (2018) Niacin pretreatment attenuates ischemia and reperfusion of pancreas-induced acute pancreatitis and remote lung injury through suppressing oxidative stress and inflammation and activation of SIRT1. Transplant Proc 50:2860–2863

    Article  CAS  Google Scholar 

  18. Fung C, Svystun O, Fouladi DF, Kawamoto S (2020) CT imaging, classification, and complications of acute pancreatitis. Abdom Radiol (NY) 45:1243–1252

    Article  Google Scholar 

  19. Najenson AC, Courreges AP, Perazzo JC, Rubio MF, Vatta MS, Bianciotti LG (2018) Atrial natriuretic peptide reduces inflammation and enhances apoptosis in rat acute pancreatitis. Acta Physiol (Oxf). https://doi.org/10.1111/apha.12992

    Article  Google Scholar 

  20. Wang N, Ma J, Ren Y, Xiang S, Jia R (2019) Secreted klotho from exosomes alleviates inflammation and apoptosis in acute pancreatitis. Am J Transl Res 11:3375–3383

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhatia M (2004) Apoptosis of pancreatic acinar cells in acute pancreatitis: is it good or bad? J Cell Mol Med 8:402–409

    Article  CAS  Google Scholar 

  22. Dong N, Dong Z, Chen Y, Gu X (2020) Crocetin alleviates inflammation in MPTP-induced Parkinson’s disease models through improving mitochondrial functions. Parkinsons Dis 2020:9864370

    PubMed  PubMed Central  Google Scholar 

  23. Liu P, Xue Y, Zheng B, Liang Y, Zhang J, Shi J, Chu X, Han X, Chu L (2020) Crocetin attenuates the oxidative stress, inflammation and apoptosisin arsenic trioxide-induced nephrotoxic rats: Implication of PI3K/AKT pathway. Int Immunopharmacol. https://doi.org/10.1016/j.intimp.2020.106959

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang Y, Yu W, Shi C, Hu P (2020) Crocetin attenuates sepsis-induced cardiac dysfunction via regulation of inflammatory response and mitochondrial function. Front Physiol 11:514

    Article  Google Scholar 

  25. Liu Y, Liang Y, Zheng B, Chu L, Ma D, Wang H, Chu X, Zhang J (2020) Protective effects of crocetin on arsenic trioxide-induced hepatic injury: involvement of suppression in oxidative stress and inflammation through activation of Nrf2 signaling pathway in rats. Drug Des Devel Ther 14:1921–1931

    Article  CAS  Google Scholar 

  26. Yang M, Mao G, Ouyang L, Shi C, Hu P, Huang S (2020) Crocetin alleviates myocardial ischemia/reperfusion injury by regulating inflammation and the unfolded protein response. Mol Med Rep 21:641–648

    CAS  PubMed  Google Scholar 

  27. Diao SL, Sun JW, Ma BX, Li XM, Wang D (2018) Influence of crocetin on high-cholesterol diet induced atherosclerosis in rats via anti-oxidant activity together with inhibition of inflammatory response and p38 MAPK signaling pathway. Saudi J Biol Sci 25:493–499

    Article  CAS  Google Scholar 

  28. Bonkowski MS, Sinclair DA (2016) Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17:679–690

    Article  CAS  Google Scholar 

  29. Kulkarni SR, Soroka CJ, Hagey LR, Boyer JL (2016) Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis. Hepatology 64:2151–2164

    Article  CAS  Google Scholar 

  30. Del Campo JA, Gallego P, Grande L (2018) Role of inflammatory response in liver diseases: therapeutic strategies. World J Hepatol 10:1–7

    Article  Google Scholar 

  31. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380

    Article  CAS  Google Scholar 

  32. Dai Y, Rahmani M, Dent P, Grant S (2005) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25:5429–5444

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chuan He.

Ethics declarations

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, L., He, C. Crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB. J Nat Med 76, 410–418 (2022). https://doi.org/10.1007/s11418-021-01597-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-021-01597-9

Keywords

Navigation