All Issue

2026 Vol.39, Issue 3 Preview Page
Anti-neuroinflammatory and Neuroprotective Effects of 11S,17S-DiHDHA in SIM-A9 and SH-SY5Y Cells
Jin Boo Jeong1
1Professor, Department of Forest Science, Gyeongkuk National University, Andong 36729, Korea
*Corresponding Author
1 June 2026. pp. 147-161
PDF XML Citation
Abstract

This study investigated the anti-neuroinflammatory and neuroprotective effects of 11S,17S-DiHDHA in SIM-A9 and SH-SY5Y cells. 11S,17S-DiHDHA suppressed NO production by downregulating iNOS expression and inhibited the LPS-induced activation of p38, JNK, and NF-κB signaling pathways. It activated the PI3K/Nrf2/HO-1 signaling pathway, which was essential for NO inhibition, as demonstrated by Nrf2 knockdown and HO-1 inhibition assays. In SH-SY5Y cells, 11S,17S-DiHDHA effectively mitigated Aβ25-35-induced cytotoxicity, apoptosis, and ROS accumulation. Specifically, it preserved cell viability, reduced LDH release, and attenuated the dysregulation of apoptosis-related proteins by suppressing Bax expression and restoring Bcl-2 levels. Additionally, 11S,17S-DiHDHA significantly inhibited Aβ25-35-induced ROS generation, suggesting its potential role in oxidative stress mitigation. These findings indicate that 11S,17S-DiHDHA exerts its neuroprotective effects through the activation of the PI3K/Nrf2/HO-1 pathway and inhibition of MAPK/NF-κB signaling. Collectively, our results suggest that 11S,17S-DiHDHA may serve as a promising therapeutic candidate for neurodegenerative diseases by modulating neuroinflammatory and oxidative stress pathways.

Keywords
Alzheimer’s disease
11S,17S-DiHDHA
Neuroinflammation
Neuroprotection
References
1

Antony, R., W.J. Lukiw, and N.G. Bazan. 2010. Neuroprotectin D1 induces dephosphorylation of Bcl-xL in a PP2A-dependent manner during oxidative stress and promotes retinal pigment epithelial cell survival. J. Biol. Chem. 285:18301-18308.

10.1074/jbc.M109.09523220363734PMC2881755
2

Asatryan, A. and N.G. Bazan. 2017. Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. J. Biol. Chem. 292:12390-12397.

10.1074/jbc.R117.78307628615451PMC5535015
3

Belayev, L., S.H. Hong, H. Menghani, S.J. Marcell, A. Obenaus, R.S. Freitas, L. Khoutorova, V. Balaszczuk, B. Jun, R.B. Oriá, and N. Bazan. 2018. Docosanoids promote neurogenesis and angiogenesis, blood-brain barrier integrity, penumbra protection, and neurobehavioral recovery after experimental ischemic stroke. Mol. Neurobiol. 55:7090-7106.

10.1007/s12035-018-1136-329858774PMC6054805
4

Brown, M.R., S.E. Radford, and E.W. Hewitt. 2020. Modulation of β-Amyloid fibril formation in Alzheimer’s disease by microglia and infection. Front. Mol. Neurosci. 13:609073.

10.3389/fnmol.2020.60907333324164PMC7725705
5

Cagnol, S. and J.C. Chambard. 2010. ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J. 277:2-21.

10.1111/j.1742-4658.2009.07366.x
6

Chao, C.C., S. Hu, T.W. Molitor, E.G. Shaskan, and P.K. Peterson. 1992. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J. Immunol. 149:2736-2741.

10.4049/jimmunol.149.8.2736
7

Cheignon, C., M. Tomas, D. Bonnefont-Rousselot, P. Faller, C. Hureau, and F. Collin. 2018. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 14:450-464.

10.1016/j.redox.2017.10.01429080524PMC5680523
8

Chen, H., Y. Zeng, D. Wang, Y. Li, J. Xing, Y. Zeng, Z. Liu, X. Zhou, and H. Fan. 2024 Neuroinflammation of microglial regulation in Alzheimer’s disease : Therapeutic approaches. Molecules 29:1478.

10.3390/molecules2907147838611758PMC11013124
9

Chen, W.F., Y.H. Shih, H.C. Liu, C.I. Cheng, C.I. Chang, C.Y. Chen, I.P. Lin, M.Y. Lin, and C.H. Lee. 2022. 6-methoxyflavone suppresses neuroinflammation in lipopolysaccharide- stimulated microglia through the inhibition of TLR4/MyD88/p38 MAPK/NF-κB dependent pathways and the activation of HO-1/NQO-1 signaling. Phytomedicine 99:154025.

10.1016/j.phymed.2022.154025
10

Coleman, J.W. 2001. Nitric oxide in immunity and inflammation. Int. Immunopharmacol. 1:1397-406.

10.1016/S1567-5769(01)00086-8
11

Heneka, M.T., M.J. Carson, J. El-Kkoury, 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
12

Hwang, H.J., T.W. Jung, J.W. Kim, J.A. Kim, Y.B. Lee, S.H. Hong, E. Roh, K.M. Choi, S.H. Baik and H.J. Yoo. 2019. Protectin DX prevents H2O2-mediated oxidative stress in vascular endothelial cells via an AMPK-dependent mechanism. Cell. Signal. 53:14-21.

10.1016/j.cellsig.2018.09.011
13

Iwuchukwu, I., D. Nguyen, A. Shirazian, A. Asatryan, B. Jun, and N.G, Bazan. 2022. Neuroprotectin D1, a lipid anti-inflammatory mediator, in patients with intracerebral hemorrhage. Biochimie 195:16-18.

10.1016/j.biochi.2021.12.017
14

Kaminska, B., A. Gozdz, M. Zawadzka, A. Ellert-Miklaszewska, and M. Lipko. 2009. MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target. Anat. Rec. 292:1902-1913.

10.1002/ar.21047
15

Kumari, S., R. Dhapola, and D.H. Reddy. 2023 Apoptosis in Alzheimer’s disease: insight into the signaling pathways and therapeutic avenues. Apoptosis 28:943-957.

10.1007/s10495-023-01848-y
16

Kyriakis, J.M. and J. Avruch. 2012. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev. 92:689-737.

10.1152/physrev.00028.2011
17

Lagarde, M., M. Guichardant, and N. Bernoud-Hubac. 2020. Anti-inflammatory and anti-virus potential of poxytrins, especially protectin DX. Biochimie 179:281-284.

10.1016/j.biochi.2020.09.00832956736PMC7499149
18

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.

19

Liy, P.M., N.N.A. Puzi, S. Jose, and S. Vidyadaran. 2021. Nitric oxide modulation in neuroinflammation and the role of mesenchymal stem cells. Exp. Biol. Med. 246:2399-2406.

10.1177/153537022199705233715528PMC8606960
20

Luo, J.F., X.Y. Shen, C.K. Lio, Y. Dai, C.S. Cheng, J.X. Liu, Y.D. Yao, Y. Yu, Y. Xie, P. Luo, X.S. Yao, Z.Q. Liu, and H. Zhou, H. 2018. Activation of Nrf2/HO-1 pathway by nardochinoid C inhibits inflammation and oxidative stress in lipopolysaccharide-stimulated macrophages. Front. Pharmacol. 9:911.

10.3389/fphar.2018.0091130233360PMC6131578
21

Mairuae, N., J.R. Connor, B. Buranrat, and S.Y. Lee. 2019. Oroxylum indicum (L.) extract protects human neuroblastoma SH‑SY5Y cells against β‑amyloid‑induced cell injury. Mol. Med. Rep. 20:1933-1942.

10.3892/mmr.2019.10411
22

Muthaiyah, B., M.M. Essa, V. Chauhan, and A. Chauhan. 2011. Protective effects of walnut extract against amyloid beta peptide-induced cell death and oxidative stress in PC12 cells. Neurochem. Res. 36:2096-2103.

10.1007/s11064-011-0533-z21706234PMC3183245
23

Nguyen, N.M., M.T.H. Duong, P.L. Nguyen, B.P. Bui, H.C. Ahn, and J. Cho. 2022. Efonidipine inhibits JNK and NF-κB pathway to attenuate inflammation and cell migration induced by lipopolysaccharide in microglial cells. Biomol. Ther. 30:455-464.

10.4062/biomolther.2022.07635993250PMC9424335
24

O’Rourke, S.A., L.C. Shanley, and A. Dunne. 2024. The Nrf2-HO-1 system and inflammaging. Front. Immunol. 15:1457010.

10.3389/fimmu.2024.145701039380993PMC11458407
25

Oh, C.W., S.E. Kim, J. Lee, and D.K. Oh. 2022. Bioconversion of C20-and C22-polyunsaturated fatty acids into 9S, 15S-and 11S,17S-dihydroxy fatty acids by Escherichia coli expressing double-oxygenating 9S-lipoxygenase from Sphingopyxis macrogoltabida.  J. Biosci. Bioeng. 134:14-20.

10.1016/j.jbiosc.2022.04.001
26

Olivera, G.C., X. Ren, S.K. Vodnala, J. Lu, L. Coppo, C. Leepiyasakulchai, A. Holmgren, K. Kristensson, and M.E. Rottenberg. 2016. Nitric oxide protects against infection-induced neuroinflammation by preserving the stability of the blood-brain barrier. PLOS Path. 12:e1005442.

10.1371/journal.ppat.100544226915097PMC4767601
27

Ponce, J., A. Ulu, C. Hanson, E. Cameron-Smith, J. Bertoni, J. Wuebker, A. Fisher, K.C. Siu, V. Marmelat, J. Adamec, and D. Bhatti. 2022. Role of specialized pro-resolving mediators in reducing neuroinflammation in neurodegenerative disorders. Front. Aging Neurosci. 14:780811.

10.3389/fnagi.2022.78081135250536PMC8891627
28

Querfurth, H.W. and F.M. LaFerla. 2010. Alzheimer’s disease. N. Engl. J. Med. 362:329-344.

10.1056/NEJMra0909142
29

Reed, J.C. 1994. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124:1-6.

10.1083/jcb.124.1.18294493PMC2119888
30

Selkoe, D.J. and J. Hardy. 2016. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8:595-608.

10.15252/emmm.20160621027025652PMC4888851
31

Shih, R.H., C.Y. Wang, and C.M. Yang. 2015. NF-kappaB signaling pathways in neurological inflammation: A mini review. Front. Mol. Neurosci. 8:77.

10.3389/fnmol.2015.0007726733801PMC4683208
32

Sobue, A., O. Komine, and K. Yamanaka. 2023. Neuroinflammation in Alzheimer’s disease: microglial signature and their relevance to disease. Inflamm. Regen. 43:26.

10.1186/s41232-023-00277-337165437PMC10170691
33

Valente, M., M. Dentoni, F. Bellizzi, F. Kuris, and G.L. Gigli. 2022. Specialized pro-resolving mediators in neuroinflammation: Overview of studies and perspectives of clinical applications. Molecules 27:4836.

10.3390/molecules2715483635956787PMC9370036
34

Weekman, E.M., T.L. Sudduth, E.L. Abner, G.J. Popa, M.D. Mendenhall, H.M. Brothers, K. Braun, A. Greenstein, and D.M. Wilcock. 2014. Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice. J. Neuroinflammation 11:127.

10.1186/1742-2094-11-12725062954PMC4128532
35

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
36

Zhang, Q., J. Liu, H. Duan, R. Li, W. Peng, and C. Wu. 2021. Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J. Adv. Res. 34:43-63.

10.1016/j.jare.2021.06.02335024180PMC8655139
37

Zvěřová, M. 2019. Clinical aspects of Alzheimer’s disease. Clin. Biochem. 72:3-6.

10.1016/j.clinbiochem.2019.04.015
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 :147-161
  • Received Date : 2026-01-28
  • Accepted Date : 2026-03-12
  • DOI :https://doi.org/10.7732/kjpr.2026.39.3.147
Journal Informaiton Korean Journal of Plant Resources Korean Journal of Plant Resources
Online Submission
  • NRF
  • KOFST
  • KISTI Current Status
  • KISTI Cited-by
  • crosscheck
  • orcid
  • ccl
Journal Informaiton Journal Informaiton - close