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2026 Vol.39, Issue 3 Preview Page
Dual Anti-Neuroinflammatory and Neuroprotective Actions of a Wild-Simulated Ginseng Aerial-Underground Blend in SIM-A9 Microglia and SH-SY5Y Neurons
Hyeok Jin Choi1†
,
Yurry Um2†
,
Jeong Won Choi1
,
So Jung Park1
,
Gyeong Eun Im1
,
Yeong-Bae Yun3
,
Sang Hun Lee4
,
Jin Boo Jeong5
1Graduate Student, Department of Forest Science, Gyeongkuk National University, Andong 36729, Korea
2Researcher, Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju 36040, Korea
3Post-doc, Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju 36040, Korea
4Post-Master’s Researcher, Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju 36040, Korea
5Professor, Department of Forest Science, Gyeongkuk National University, Andong 36729, Korea
*Corresponding Author
†These authors contributed equally to this work.
1 June 2026. pp. 132-146
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Abstract

Wild-simulated ginseng contains tissue-dependent ginsenosides, but defined-ratio blends of aerial and underground parts have rarely been evaluated for both anti-neuroinflammatory and neuroprotective effects. Here, a 1:1 (w/w) blend of aerial (WSGL) and underground (WSGR) extracts, termed WSGLR, was prepared and tested in microglial and neuronal cell models. Ginsenoside profiling showed distinct part-specific compositions, suggesting complementary phytochemical properties. In SIM-A9 microglia, WSGLR was selected through comparative screening and significantly reduced LPS-induced NO production and iNOS expression without cytotoxicity. Mechanistically, WSGLR suppressed p38/JNK MAPK and NF-κB p65 activation, while ERK1/2 remained unaffected. WSGLR also promoted nuclear Nrf2 accumulation and HO-1 expression, and inhibition of HO-1 largely reversed its NO-suppressive effect. In addition, WSGLR induced early PI3K phosphorylation, and PI3K inhibition attenuated Nrf2 nuclear translocation and HO-1 upregulation, indicating that PI3K acts upstream of Nrf2/HO-1 activation. In SH-SY5Y cells, WSGLR protected against Aβ25-35-induced toxicity by improving viability, reducing LDH release and ROS generation, and normalizing apoptosis-related proteins. These findings indicate that WSGLR exerts dual anti-neuroinflammatory and neuroprotective effects through suppression of p38/JNK–NF-κB signaling and activation of PI3K-dependent Nrf2/HO-1 pathways.

Keywords
Anti-neuroinflammation
Neuroprotection
Wild-simulated ginseng
References
1

Brown, G. and A. Bal-Price. 2003. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol. Neurobiol. 27:325-355.

10.1385/MN:27:3:325
2

Cai, Y., J. Liu, B. Wang, M. Sun, and H. Yang. 2022. Microglia in the neuroinflammatory pathogenesis of Alzheimer’s disease and related therapeutic targets. Front. Immunol. 13:856376.

10.3389/fimmu.2022.85637635558075PMC9086828
3

He, M., C. Park, Y. Shin, J. Kim, and E. Cho. 2023. N-feruloyl serotonin attenuates neuronal oxidative stress and apoptosis in Aβ25-35-treated human neuroblastoma SH-SY5Y cells. Molecules 28:1610.

10.3390/molecules2804161036838597PMC9963151
4

Heneka, M.T., M.J. Carson, J. El Khoury, G.E. Landreth, F. Brosseron, D.L. Feinstein, A.H. Jacobs, T. Wyss-Coray, J. Vitorica, R.M. Ransohoff, K. Herrup, S.A. Frautschy, B. Finsen, G.C. Brown, A. Verkhratsky, K. Yamanaka, J. Koistinaho, E. Latz, A. Halle, G.C. Petzold, T. Town, D. Morgan, M.L. Shinohara, V.H. Perry, C. Holmes, N.G. Bazan, D.J. Brooks, S. Hunot, B. Joseph, N. Deigendesch, O. Garaschuk, E. Boddeke, C.A. Dinarello, J.C. Breitner, G.M. Cole, D.T. Golenbock, and M.P. Kummer. 2015. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14:388-405.

10.1016/S1474-4422(15)70016-525792098PMC5909703
5

Hu, J.F., X.Y. Song, S.F. Chu, J. Chen, H.J. Ji, X.Y. Chen, Y.H. Yuan, N. Han, J.T. Zhang, and N.H. Chen. 2011. Inhibitory effect of ginsenoside Rg1 on lipopolysaccharide-induced microglial activation in mice. Brain Res. 1374:8-14.

10.1016/j.brainres.2010.11.069
6

Hu, Y., Y. He, Z. Niu, T. Shen, J. Zhang, X. Wang, W. Hu, and J.Y. Cho. 2021. A review of the immunomodulatory activities of polysaccharides isolated from Panax species. J. Ginseng Res. 46:23-32.

10.1016/j.jgr.2021.06.00335058724PMC8753523
7

Iizumi, T., S. Takahashi, K. Mashima, K. Minami, Y. Izawa, T. Abe, T. Hishiki, M. Suematse, M. Kajimura, and N. Suzuki. 2016. A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system. J. Neuroinflammation 13:99.

10.1186/s12974-016-0564-027143001PMC4855896
8

Jamornwan, S., T. Chokpanuwat, K. Uppakara, T. Laorob, U. Wichai, P. Ketsawatsomkron, and W. Saengsawang. 2022. Nitro capsaicin suppressed microglial activation and TNF-α-induced brain microvascular endothelial cell damage. Biomedicine 10:2680.

10.3390/biomedicines1011268036359200PMC9687943
9

Kang, C.H., M.J. Kim, M.J. Seo, Y.H. Choi, W.S. Jo, K.T. Lee, Y.K. Jeong, and G.Y. Kim. 2013. 5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharide-stimulated BV2 microglia via NF-κB suppression and Nrf-2-dependent heme oxygenase-1 induction. Food Chem. Toxicol. 57:119-125.

10.1016/j.fct.2013.03.019
10

Kang, O.J. and J.S. Kim. 2016. Comparison of ginsenoside contents in different parts of Korean ginseng (Panax ginseng C.A. Meyer). Prev. Nutr. Food Sci. 24:389-392.

10.3746/pnf.2016.21.4.38928078264PMC5216893
11

Kim, J.H. 2014. Brain-derived neurotrophic factor exerts neuroprotective actions against amyloid β-induced apoptosis in neuroblastoma cells. Exp. Ther. Med. 8:1891-1895.

10.3892/etm.2014.203325371750PMC4218707
12

Kim, K.H., D. Lee, H.L. Lee, C.E. Kim, K. Jung, and K.S. Kang. 2018. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J. Ginseng Res. 42:239-247.

10.1016/j.jgr.2017.03.01129989012PMC6035378
13

Kozina, A., G. Herer-Alonso, A. Díaz, G. Flores, and J. Guevara. 2024. Effect of the aggregation state of amyloid-beta (25-35) on the brain oxidative stress in vivo. PLoS One 19:0610258.

10.1371/journal.pone.031025839471144PMC11521274
14

Lee, K.W., S.Y. Jung, S.M. Choi, and E.J. Yang. 2012. Effects of ginsenoside Re on LPS-induced inflammatory mediators in BV2 microglial cells. BMC Complement. Altern. Med. 12:196.

10.1186/1472-6882-12-19623102375PMC3517379
15

Lee, S., K. Youn, and M. Jun. 2018. Major compounds of red ginseng oil attenuate Aβ25-35-induced neuronal apoptosis and inflammation by modulating MAPK/NF-κB pathway. Food Funct. 9:4122-4134.

10.1039/C8FO00795K
16

Lee, S., K. Youn, W.S. Seong, C.T. Ho, and M. Jun. 2017. Protective effects of red ginseng oil against Aβ25-35-induced neuronal apoptosis and inflammation in PC12 cells. Int. J. Mol. Sci. 18:2218.

10.3390/ijms1810221829065557PMC5666897
17

Lee, S.H., J.W. Choi, H.J. Choi, S.J. Park, J.H. Hwang, Y.S. Kim, K. Hwang, and J.B. Jeong. 2025. Anti-inflammatory activity of Cirsium nipponicum extracts via inhibition of JNK and NF-κB signaling and activation of ROS/PI3K/Nrf2/HO-1 pathways in RAW264.7 cells. Korean J. Plant Res. 38:1-9.

18

Lull, M.E. and M.L. Block. 2010. Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354-365.

10.1016/j.nurt.2010.05.01420880500PMC2951017
19

Madhi, I., J.H. Kim, J.E. Shin, and Y. Kim. 2021. Ginsenoside Re exhibits neuroprotective effects by inhibiting neuroinflammation via CAMK/MAPK/NF‑κB signaling in microglia. Mol. Med. Rep. 24:698.

10.3892/mmr.2021.1233734368872PMC8365412
20

Nagamoto-Combs, K., J. Kulas, and C.K. Combs. 2014. A novel cell line from spontaneously immortalized murine microglia. J. Neurosci. Methods 233:187-198.

10.1016/j.jneumeth.2014.05.02124975292PMC4140094
21

Roh, S.S., G.J. Lee, B. Kim, B.K. Hwang, H. Kim, Y.H. Chang, J.K. Yoou, and Y.S. Ju. 2023. Analysis of chemical components for aerial and underground parts of wild ginseng and evaluation of skin anti-aging efficacy. Kor. J. Herbology 38:85-89.

10.6116/KJH.2023.38.5.85
22

Sarlus, H. and M.T. Heneka. 2017. Microglia in Alzheimer's disease. J. Clin. Invest. 127:3240-3249.

10.1172/JCI9060628862638PMC5669553
23

Xu, X., H. Li, X. Hou, D. Li, S. He. C. Wan, P. Yin, M. Liu, F. Liu, and J. Xu. 2015. Punicalagin induces Nrf2/HO-1 expression via upregulation of PI3K/AKT pathway and inhibits LPS-induced oxidative stress in RAW264.7 macrophages. Mediators Inflamm. 2015:380218.

10.1155/2015/38021825969626PMC4417599
24

Yuste, J.E., E. Tarragon, C.M. Campuzano, and F. Ros-Bernal. 2015. Implications of glial nitric oxide in neurodegenerative diseases. Frontiers in Cellular Neuroscience 9:322.

10.3389/fncel.2015.0032226347610PMC4538301
25

Zhang, F., S. Tang, L. Zhao, X. Yang, Y. Yau, Z. Hou, and P. Xue. 2021. Stem-leaves of Panax as a rich and sustainable source of less-polar ginsenosides: comparison of ginsenosides from Panax ginseng, American ginseng and Panax notoginseng prepared by heating and acid treatment. Journal of Ginseng Research 45:163-175.

10.1016/j.jgr.2020.01.00333437168PMC7790872
Information
  • Publisher :The Plant Resources Society of Korea
  • Publisher(Ko) :한국자원식물학회
  • Journal Title :Korean Journal of Plant Resources
  • Journal Title(Ko) :한국자원식물학회지
  • Volume : 39
  • No :3
  • Pages :132-146
  • Received Date : 2026-02-03
  • Revised Date : 2026-02-20
  • Accepted Date : 2026-02-22
  • DOI :https://doi.org/10.7732/kjpr.2026.39.3.132
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