Ginsenoside Rg3 ameliorates acute pancreatitis by activating the NRF2/HO‑1‑mediated ferroptosis pathway

Shan,Yuqiang; Li,Jiaotao; Zhu,Akao; Kong,Wencheng; Ying,Rongchao; Zhu,Weiming

doi:10.3892/ijmm.2022.5144

Ginsenoside Rg3 ameliorates acute pancreatitis by activating the NRF2/HO‑1‑mediated ferroptosis pathway

Authors:
- Yuqiang Shan
- Jiaotao Li
- Akao Zhu
- Wencheng Kong
- Rongchao Ying
- Weiming Zhu
View Affiliations

Affiliations: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China, Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China, Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
Published online on: May 16, 2022 https://doi.org/10.3892/ijmm.2022.5144
Article Number: 89
Copyright: © Shan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute pancreatitis (AP) is an inflammatory disorder that has been associated with systemic inflammatory response syndrome. Ginsenoside Rg3 is a major active component of Panax ginseng, which has been demonstrated to exert potent protective effects on hyperglycemia and diabetes. However, it remains to be determined whether Rg3 ameliorates AP. Thus, an in vitro AP cell model was established in the present study by exposing AR42J cells to cerulein (Cn). AR42J cell viability was increased in the Rg3‑treated group as compared with the Cn‑exposed group. Simultaneously, the number of dead AR42J cells was decreased in the Rg3‑treated group compared with the group treated with Cn only. Furthermore, following treatment with Rg3, the production of malondialdehyde (MDA) and ferrous ion (Fe²⁺) in the AR42J cells was reduced, accompanied by increased glutathione (GSH) levels. Western blot analysis revealed that the decrease in glutathione peroxidase 4 (GPX4) and cystine/glutamate transporter (xCT) levels induced by Cn were reversed by Rg3 treatment in the AR42J cells. Mice treated with Cn exhibited increased serum amylase levels, as well as increased levels of TNFα, IL‑6, IL‑1β, pancreatic MDA, reactive oxygen species (ROS) and Fe²⁺ production. Following Rg3 treatment, ROS accumulation and cell death were decreased in the pancreatic tissues compared with the AP group. Furthermore, in the pancreatic tissues of the AP model, the expression of nuclear factor‑erythroid factor 2‑related factor 2 (NRF2)/heme oxygenase 1 (HO‑1)/xCT/GPX4 was suppressed. In comparison, the NRF2/HO‑1/xCT/GPX4 pathway was activated in pancreatic tissues following Rg3 administration. Taken together, the present study, to the best of our knowledge, is the first to reveal a protective role for Rg3 in mice with AP by suppressing oxidative stress‑related ferroptosis and the activation of the NRF2/HO‑1 pathway.

View Figures

View References

1	Gliem N, Ammer-Herrmenau C, Ellenrieder V and Neesse A: Management of severe acute pancreatitis: An update. Digestion. 102:503–507. 2021. View Article : Google Scholar
2	Petrov MS and Yadav D: Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol. 16:175–184. 2019. View Article : Google Scholar :
3	Wang J, Chen G, Gong H, Huang W, Long D and Tang W: Amelioration of experimental acute pancreatitis with Dachengqi Decoction via regulation of necrosis-apoptosis switch in the pancreatic acinar cell. PLoS One. 7:e401602012. View Article : Google Scholar : PubMed/NCBI
4	Huang DY, Li Q, Shi CY, Hou CQ, Miao Y and Shen HB: Dexmedetomidine attenuates inflammation and pancreatic injury in a rat model of experimental severe acute pancreatitis via cholinergic anti-inflammatory pathway. Chin Med J (Engl). 133:1073–1079. 2020. View Article : Google Scholar
5	Schepers NJ, Bakker OJ, Besselink MG, Ahmed Ali U, Bollen TL, Gooszen HG, van Santvoort HC and Bruno MJ; Dutch Pancreatitis Study Group: Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis. Gut. 68:1044–1051. 2019. View Article : Google Scholar
6	Jain S, Mahapatra SJ, Gupta S, Shalimar Shalimar and Garg PK: Infected pancreatic necrosis due to multidrug-resistant organisms and persistent organ failure predict mortality in acute pancreatitis. Clin Transl Gastroenterol. 9:1902018. View Article : Google Scholar : PubMed/NCBI
7	Schneider L, Jabrailova B, Strobel O, Hackert T and Werner J: Inflammatory profiling of early experimental necrotizing pancreatitis. Life Sci. 126:76–80. 2015. View Article : Google Scholar : PubMed/NCBI
8	Yu H, Guo P, Xie X, Wang Y and Chen G: Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 21:648–657. 2017. View Article : Google Scholar :
9	Hassannia B, Vandenabeele P and Vanden Berghe T: Targeting ferroptosis to iron out cancer. Cancer Cell. 35:830–849. 2019. View Article : Google Scholar : PubMed/NCBI
10	Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, et al: Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 16:1180–1191. 2014. View Article : Google Scholar : PubMed/NCBI
11	Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ma D, Li C, Jiang P, Jiang Y, Wang J and Zhang D: Inhibition of ferroptosis attenuates acute kidney injury in rats with severe acute pancreatitis. Dig Dis Sci. 66:483–492. 2021. View Article : Google Scholar
13	Wei S, Qiu T, Yao X, Wang N, Jiang L, Jia X, Tao Y, Wang Z, Pei P, Zhang J, et al: Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway. J Hazard Mater. 384:1213902020. View Article : Google Scholar
14	Hu S, Zhu Y, Xia X, Xu X, Chen F, Miao X and Chen X: Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal Cell Pathol (Amst). 2019:38157862019.
15	Zou J, Su H, Zou C, Liang X and Fei Z: Ginsenoside Rg3 suppresses the growth of gemcitabine-resistant pancreatic cancer cells by upregulating lncRNA-CASC2 and activating PTEN signaling. J Biochem Mol Toxicol. 34:e224802020. View Article : Google Scholar : PubMed/NCBI
16	Chen F, Chen Y, Kang X, Zhou Z, Zhang Z and Liu D: Anti-apoptotic function and mechanism of ginseng saponins in Rattus pancreatic beta-cells. Biol Pharm Bull. 35:1568–1573. 2012. View Article : Google Scholar
17	Yuan HD, Kim JT, Kim SH and Chung SH: Ginseng and diabetes: The evidences from in vitro, animal and human studies. J Ginseng Res. 36:27–39. 2012. View Article : Google Scholar : PubMed/NCBI
18	Kim YJ, Park SM, Jung HS, Lee EJ, Kim TK, Kim TN, Kwon MJ, Lee SH, Rhee BD, Kim MK and Park JH: Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress. Islets. 8:57–64. 2016. View Article : Google Scholar : PubMed/NCBI
19	Kim M, Ahn BY, Lee JS, Chung SS, Lim S, Park SG, Jung HS, Lee HK and Park KS: The ginsenoside Rg3 has a stimulatory effect on insulin signaling in L6 myotubes. Biochem Biophys Res Commun. 389:70–73. 2009. View Article : Google Scholar : PubMed/NCBI
20	Jeong YK and Kim H: A mini-review on the effect of docosahexaenoic acid (DHA) on cerulein-induced and hypertriglyceridemic acute pancreatitis. Int J Mol Sci. 18:22392017. View Article : Google Scholar :
21	Xian Y, Wu Y, He M, Cheng J, Lv X and Ren Y: Sleeve gastrectomy attenuates the severity of cerulein-induced acute pancreatitis in obese rats. Obes Surg. 31:4107–4117. 2021. View Article : Google Scholar : PubMed/NCBI
22	Hagar HH, Almubrik SA, Attia NM and Aljasser SN: Mesna alleviates cerulein-induced acute pancreatitis by inhibiting the inflammatory response and oxidative stress in experimental rats. Dig Dis Sci. 65:3583–3591. 2020. View Article : Google Scholar : PubMed/NCBI
23	Malla SR, Krueger B, Wartmann T, Sendler M, Mahajan UM, Weiss FU, Thiel FG, De Boni C, Gorelick FS, Halangk W, et al: Early trypsin activation develops independently of autophagy in caerulein-induced pancreatitis in mice. Cell Mol Life Sci. 77:1811–1825. 2020. View Article : Google Scholar
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
25	Dodson M, Castro-Portuguez R and Zhang DD: NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 23:1011072019. View Article : Google Scholar : PubMed/NCBI
26	Gao Z, Sui J, Fan R, Qu W, Dong X and Sun D: Emodin protects against acute pancreatitis-associated lung injury by inhibiting NLPR3 inflammasome activation via Nrf2/HO-1 signaling. Drug Des Devel Ther. 14:1971–1982. 2020. View Article : Google Scholar : PubMed/NCBI
27	Wu K, Yao G, Shi X, Zhang H, Zhu Q, Liu X, Lu G, Hu L, Gong W, Yang Q and Ding Y: Asiaticoside ameliorates acinar cell necrosis in acute pancreatitis via toll-like receptor 4 pathway. Mol Immunol. 130:122–132. 2021. View Article : Google Scholar
28	Chen X, Yu C, Kang R, Kroemer G and Tang D: Cellular degradation systems in ferroptosis. Cell Death Differ. 28:1135–1148. 2021. View Article : Google Scholar : PubMed/NCBI
29	Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S, Gao Y, Chen X, Sui X and Li G: The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 127:1101082020. View Article : Google Scholar : PubMed/NCBI
30	Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W and Wang J: Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 23:4900–4912. 2019. View Article : Google Scholar : PubMed/NCBI
31	Wei X, Chen J, Su F, Su X, Hu T and Hu S: Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. Int Immunol. 24:465–471. 2012. View Article : Google Scholar : PubMed/NCBI
32	Lee IS, Uh I, Kim KS, Kim KH, Park J, Kim Y, Jung JH, Jung HJ and Jang HJ: Anti-inflammatory effects of ginsenoside Rg3 via NF-ĸB pathway in A549 cells and human asthmatic lung tissue. J Immunol Res. 2016:75216012016. View Article : Google Scholar
33	Tsai K, Wang SS, Chen TS, Kong CW, Chang FY, Lee SD and Lu FJ: Oxidative stress: An important phenomenon with pathogenetic significance in the progression of acute pancreatitis. Gut. 42:850–855. 1998. View Article : Google Scholar : PubMed/NCBI
34	Pereda J, Sabater L, Aparisi L, Escobar J, Sandoval J, Viña J, López-Rodas G and Sastre J: Interaction between cytokines and oxidative stress in acute pancreatitis. Curr Med Chem. 13:2775–2787. 2006. View Article : Google Scholar : PubMed/NCBI
35	Booth DM, Murphy JA, Mukherjee R, Awais M, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Petersen OH, Sutton R and Criddle DN: Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology. 140:2116–2125. 2011. View Article : Google Scholar : PubMed/NCBI
36	Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, Jiang F and Peng ZY: Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019:50808432019. View Article : Google Scholar : PubMed/NCBI
37	Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, et al: Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 171:273–285. 2017. View Article : Google Scholar : PubMed/NCBI
38	Armstrong JA, Cash N, Soares PM, Souza MH, Sutton R and Criddle DN: Oxidative stress in acute pancreatitis: Lost in translation? Free Radic Res. 47:917–933. 2013. View Article : Google Scholar : PubMed/NCBI
39	Dong H, Qiang Z, Chai D, Peng J, Xia Y, Hu R and Jiang H: Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1. Aging (Albany NY). 12:12943–12959. 2020. View Article : Google Scholar
40	Yuan Y, Zhai Y, Chen J, Xu X and Wang H: Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 Axis. Biomolecules. 11:9232021. View Article : Google Scholar : PubMed/NCBI
41	Liu X, Zhu Q, Zhang M, Yin T, Xu R, Xiao W, Wu J, Deng B, Gao X, Gong W, et al: Isoliquiritigenin ameliorates acute pancreatitis in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway. Oxid Med Cell Longev. 2018:71615922018. View Article : Google Scholar : PubMed/NCBI