Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative
Abstract
:1. Introduction
2. Results
2.1. Design of SB140
2.2. SB140 Exerts Immunomodulatory Effects on Microglial Cells but Not on MDC
2.3. SB140 Activates Nrf2 in Microglial Cells and MDC
2.4. SB140 Exerts Immunomodulatory Effects on T Cells
3. Discussion
4. Materials and Methods
4.1. SB140
4.2. Cells and Cell Cultures
4.3. Viability Assays
4.4. Detection of NO Release
4.5. ELISA
4.6. Flow Cytometry
4.7. Reverse Transcription−Real-Time Polymerase Chain Reaction
4.8. Statistics
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Bjedov, S.; Bekić, S.; Marinović, M.; Škorić, D.; Pavlović, K.; Ćelić, A.; Pteri, E.; Sakač, M. Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain. J. Serbian Chem. Soc. 2023, 88, 123–139. [Google Scholar] [CrossRef]
- Dinkova-Kostova, A.T.; Holtzclaw, W.D.; Wakabayashi, N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 2005, 44, 6889–6899. [Google Scholar] [CrossRef] [PubMed]
- Dodson, M.; de la Vega, M.R.; Cholanians, A.B.; Schmidlin, C.J.; Chapman, E.; Zhang, D.D. Modulating NRF2 in Disease: Timing Is Everything. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 555–575. [Google Scholar] [CrossRef] [PubMed]
- Krishnarajah, S.; Becher, B. TH Cells and Cytokines in Encephalitogenic Disorders. Front. Immunol. 2022, 13, 822919. [Google Scholar] [CrossRef] [PubMed]
- Alakhras, N.S.; Kaplan, M.H. Dendritic Cells as a Nexus for the Development of Multiple Sclerosis and Models of Disease. Adv. Biol. 2023, 7, e2300073. [Google Scholar] [CrossRef] [PubMed]
- Radandish, M.; Khalilian, P.; Esmaeil, N. The Role of Distinct Subsets of Macrophages in the Pathogenesis of MS and the Impact of Different Therapeutic Agents on These Populations. Front. Immunol. 2021, 12, 667705. [Google Scholar] [CrossRef] [PubMed]
- Luo, C.; Jian, C.; Liao, Y.; Huang, Q.; Wu, Y.; Liu, X.; Zou, D.; Wu, Y. The role of microglia in multiple sclerosis. Neuropsychiatr. Dis. Treat. 2017, 13, 1661–1667. [Google Scholar] [CrossRef] [PubMed]
- Moehle, M.S.; West, A.B. M1 and M2 immune activation in Parkinson’s Disease: Foe and ally? Neuroscience 2015, 302, 59–73. [Google Scholar] [CrossRef] [PubMed]
- Ho, M.S. Microglia in Parkinson’s Disease. Adv. Exp. Med. Biol. 2019, 1175, 335–353. [Google Scholar] [CrossRef]
- Munawara, U.; Catanzaro, M.; Xu, W.; Tan, C.; Hirokawa, K.; Bosco, N.; Dumoulin, D.; Khalil, A.; Larbi, A.; Lévesque, S.; et al. Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer’s disease. Immun. Ageing 2021, 18, 29. [Google Scholar] [CrossRef]
- Miao, J.; Ma, H.; Yang, Y.; Liao, Y.; Lin, C.; Zheng, J.; Yu, M.; Lan, J. Microglia in Alzheimer’s disease: Pathogenesis, mechanisms, and therapeutic potentials. Front. Aging Neurosci. 2023, 15, 1201982. [Google Scholar] [CrossRef]
- Brandes, M.S.; Gray, N.E. NRF2 as a Therapeutic Target in Neurodegenerative Diseases. ASN Neuro. 2020, 12, 1759091419899782. [Google Scholar] [CrossRef]
- Saha, S.; Buttari, B.; Profumo, E.; Tucci, P.; Saso, L. A Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer’s and Parkinson’s Diseases. Front. Cell. Neurosci. 2022, 15, 787258. [Google Scholar] [CrossRef]
- Gopal, S.; Mikulskis, A.; Gold, R.; Fox, R.J.; Dawson, K.T.; Amaravadi, L. Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies. Mult. Scler. 2017, 23, 1875–1883. [Google Scholar] [CrossRef]
- Kobayashi, E.H.; Suzuki, T.; Funayama, R.; Nagashima, T.; Hayashi, M.; Sekine, H.; Tanaka, N.; Moriguchi, T.; Motohashi, H.; Nakayama, K.; et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 2016, 7, 11624. [Google Scholar] [CrossRef]
- Koh, K.; Kim, J.; Jang, Y.J.; Yoon, K.; Cha, Y.; Lee, H.J.; Kim, J. Transcription factor Nrf2 suppresses LPS-induced hyperactivation of BV-2 microglial cells. J. Neuroimmunol. 2011, 233, 160–167. [Google Scholar] [CrossRef]
- Morzadec, C.; Macoch, M.; Sparfel, L.; Kerdine-Römer, S.; Fardel, O.; Vernhet, L. Nrf2 expression and activity in human T lymphocytes: Stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone. Free. Radic. Biol. Med. 2014, 71, 133–145. [Google Scholar] [CrossRef]
- van der Veen, R.C.; Dietlin, T.A.; Dixon Gray, J.; Gilmore, W. Macrophage-derived nitric oxide inhibits the proliferation of activated T helper cells and is induced during antigenic stimulation of resting T cells. Cell. Immunol. 2000, 199, 43–49. [Google Scholar] [CrossRef]
- Alleva, D.G.; Burger, C.J.; Elgert, K.D. Tumor-induced macrophage tumor necrosis factor-alpha production suppresses autoreactive T cell proliferation. Immunobiology 1993, 188, 430–445. [Google Scholar] [CrossRef]
- Tsukamoto, H.; Fujieda, K.; Senju, S.; Ikeda, T.; Oshiumi, H.; Nishimura, Y. Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity. Cancer Sci. 2018, 109, 523–530. [Google Scholar] [CrossRef]
- Cheng, L.; Wang, J.; Li, X.; Xing, Q.; Du, P.; Su, L.; Wang, S. Interleukin-6 induces Gr-1+CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice. PLoS ONE 2011, 6, e17631. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; Saeed, A.F.U.H.; Liu, Q.; Jiang, Q.; Xu, H.; Xiao, G.G.; Rao, L.; Duo, Y. Macrophages in immunoregulation and therapeutics. Signal Transduct. Target. Ther. 2023, 8, 207. [Google Scholar] [CrossRef]
- Stojanović, N.M.; Randjelović, P.J.; Maslovarić, A.; Kostić, M.; Raičević, V.; Sakač, M.; Bjedov, S. How do different bile acid derivatives affect rat macrophage function—Friends or foes? Chem. Biol. Interact. 2023, 383, 110688. [Google Scholar] [CrossRef] [PubMed]
- Kaskow, B.J.; Baecher-Allan, C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8, a029025. [Google Scholar] [CrossRef]
- Momcilović, M.; Miljković, Z.; Popadić, D.; Miljković, D.; Mostarica-Stojković, M. Kinetics of IFN-gamma and IL-17 expression and production in active experimental autoimmune encephalomyelitis in Dark Agouti rats. Neurosci. Lett. 2008, 447, 148–152. [Google Scholar] [CrossRef]
- Pierson, E.; Simmons, S.B.; Castelli, L.; Goverman, J.M. Mechanisms regulating regional localization of inflammation during CNS autoimmunity. Immunol. Rev. 2012, 248, 205–215. [Google Scholar] [CrossRef] [PubMed]
- Lazarević, M.; Djedovic, N.; Stanisavljević, S.; Dimitrijević, M.; Stegnjaić, G.; Krishnamoorthy, G.; Mostarica Stojković, M.; Miljković, Đ.; Jevtić, B. Complete Freund’s adjuvant-free experimental autoimmune encephalomyelitis in Dark Agouti rats is a valuable tool for multiple sclerosis studies. J. Neuroimmunol. 2021, 354, 577547. [Google Scholar] [CrossRef] [PubMed]
- Djedovic, N.; Mansilla, M.J.; Jevtić, B.; Navarro-Barriuso, J.; Saksida, T.; Martínez-Cáceres, E.M.; Miljković, Ð. Ethyl Pyruvate Induces Tolerogenic Dendritic Cells. Front. Immunol. 2019, 10, 157. [Google Scholar] [CrossRef] [PubMed]
- Miljković, D.; Blaževski, J.; Petković, F.; Djedović, N.; Momčilović, M.; Stanisavljević, S.; Jevtić, B.; Mostarica Stojković, M.; Spasojević, I. A comparative analysis of multiple sclerosis-relevant anti-inflammatory properties of ethyl pyruvate and dimethyl fumarate. J. Immunol. 2015, 194, 2493–2503. [Google Scholar] [CrossRef]
- Morgenstern, C.; Lastres-Becker, I.; Demirdöğen, B.C.; Costa, V.M.; Daiber, A.; Foresti, R.; Motterlini, R.; Kalyoncu, S.; Arioz, B.I.; Genc, S.; et al. Biomarkers of NRF2 signalling: Current status and future challenges. Redox Biol. 2024, 72, 103134. [Google Scholar] [CrossRef]
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Bjedov, S.; Stegnjaić, G.; Stanisavljević, S.; Lazarević, M.; Pilipović, I.; Sakač, M.; Miljković, Đ. Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative. Int. J. Mol. Sci. 2024, 25, 7136. https://doi.org/10.3390/ijms25137136
Bjedov S, Stegnjaić G, Stanisavljević S, Lazarević M, Pilipović I, Sakač M, Miljković Đ. Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative. International Journal of Molecular Sciences. 2024; 25(13):7136. https://doi.org/10.3390/ijms25137136
Chicago/Turabian StyleBjedov, Srđan, Goran Stegnjaić, Suzana Stanisavljević, Milica Lazarević, Ivan Pilipović, Marija Sakač, and Đorđe Miljković. 2024. "Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative" International Journal of Molecular Sciences 25, no. 13: 7136. https://doi.org/10.3390/ijms25137136