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Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress
Open accessAbstract
Docosahexaenoic acid (DHA) is a lipid peroxidation target in oxidative injury to retinal pigment epithelium (RPE) and retina. Photoreceptor and synaptic membranes share the highest content of DHA of all cell membranes. This fatty acid is required for RPE functional integrity; however, it is not known whether specific mediators generated from DHA contribute to its biological significance. We used human ARPE-19 cells and demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin D1 (NPD1)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1beta, or by supplying DHA. Under these conditions, there is a time-dependent release of endogenous free DHA followed by NPD1 formation, suggesting that phospholipase A(2) releases the mediator's precursor. Added NPD1 potently counteracted H(2)O(2)/tumor necrosis factor alpha oxidative-stress-triggered apoptotic RPE DNA damage. NPD1 also up-regulated the antiapoptotic proteins Bcl-2 and Bcl-x(L) and decreased proapoptotic Bax and Bad expression. Moreover, NPD1 (50 nM) inhibited oxidative-stress-induced caspase-3 activation. NPD1 also inhibited IL-1beta-stimulated expression of cyclooxygenase 2 promoter transfected into ARPE-19 cells. Overall, NPD1 protected RPE cells from oxidative-stress-induced apoptosis, and we predict that it will similarly protect neurons. This lipid mediator therefore may indirectly contribute to photoreceptor cell survival as well. Because both RPE and photoreceptor cells die in retinal degenerations, our findings contribute to the understanding of retinal cell survival signaling and potentially to the development of new therapeutic strategies.
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“DHA then ends up amounting to more than 50% of OS phospholipid fatty acyl chains and therefore DHA-containing phospholipids in the retina and other cells are reservoirs for docosanoids (Bazan et al., 1984; Mukherjee et al., 2004).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Mukherjee et al., 2004
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“In fact, NPD1 also induces the anti-apoptotic Bcl-2 family of proteins Bcl-2 and Bcl-xl in oxidatively challenged human RPE cells (Mukherjee et al., 2004) and promotes cytoprotection.”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Mukherjee et al., 2004
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First total synthesis of 7(S),16(R),17(S)-Resolvin D2, a potent anti-inflammatory lipid mediator
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Figueroa, J. D., Cordero, K., Baldeosingh, K., Torrado, A. I., Walker, R. L., Miranda, J. D., & León, M. A. D. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2011.2141 · Cited by 63
“Moreover, DHA activates both Akt and CREB, which have been associated with neuroprotection and myelin stability in vitro and in vivo (Akbar et al., 2005; Mukherjee et al., 2004; Salvati et al., 2008; Wu et al., 2008).”
Sharma, A. K., & Rohrer, B. (2007) · Current Eye Research · doi:10.1080/02713680601161238 · Cited by 61
Chang, Y.-L., Chen, S., Kao, C.-L., Hung, S., Ding, D., Yu, C.-C., Chen, Y., Ku, H., Lin, C.-P., Lee, K.-H., et al. (2011) · Cell Transplantation · doi:10.3727/096368911x580572 · Cited by 64
Belayev, L., Mukherjee, P. K., Balaszczuk, V., Calandria, J. M., Obenaus, A., Khoutorova, L., Hong, S., & Bazan, N. G. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.55 · Cited by 60
“Neuroectoderm-derived post-mitotic retinal pigment epithelial (RPE) cells are protected by NPD1 when exposed to UOS.(11) Also, during early reperfusion after cerebral ischemia NPD1 synthesis increases in the brain.”
InfluentialER Stress and Effects of DHA as an ER Stress Inhibitor
Begum, G., Harvey, L. D., Dixon, C. E., & Sun, D. (2013) · Translational Stroke Research · doi:10.1007/s12975-013-0282-1 · Cited by 57
“DHA is metabolized into a number of bioactive compounds termed as protectins and resolvins that are capable of not only of resolving inflammation but also providing neuroprotection [68].”
Matesanz, N., Park, G. S. H., McAllister, H., Leahey, W. J., Devine, A. B., McVeigh, G. E., Gardiner, T. A., & McDonald, D. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5339 · Cited by 59
“In addition to reducing the concentration of AA-derived eicosanoids, the same enzymes (LOX and COX) produce specific EPA- or DHA-derived bioactive eicosanoids that are less inflammatory, have fewer growth-promoting properties, and have more antiapoptotic properties and antiangiogenic activity than their -6 PUFA–derive…”
Kotlyarov, S. N., & Котлярова, А. А. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312803 · Cited by 59
“PD1 was first described in brain and retinal tissues as neuroprotectin D1 (NPD1), which was considered to be a mediator of protection against oxidative stress [149,150].”
Arab, K., Rossary, A., Soulère, L., & Steghens, J. (2006) · British Journal Of Nutrition · doi:10.1017/bjn20061910 · Cited by 58
“The potential for preventive actions in CVDwas recently bolstered by the finding that PUFA, especially n-3 PUFA, have a protective effect on ischaemia–reperfusion in neuroprotection and an anti-inflammatory action (Pepe & McLennan, 2002; Mukherjee et al. 2004).”
Persistence of Essential Fatty Acid Deficiency in Cystic Fibrosis Despite Nutritional Therapy
Aldamiz-Echevarria, L. J., Prieto, J. A., Andrade, F., Elorz, J., Sojo, A., Lage, S., Sanjurjo, P., Vázquez, C., & Rodríguez‐Soriano, J. (2009) · Pediatric Research · doi:10.1203/pdr.0b013e3181b4e8d3 · Cited by 58
PUFA and oxidative stress. Differential modulation of the cell response by DHA
Nunzio, M. D., Valli, V., & Bordoni, A. (2016) · International Journal of Food Sciences and Nutrition · doi:10.1080/09637486.2016.1201790 · Cited by 58
“According to many in vivo (Mas et al. 2010; Patten et al. 2013) and in vitro (Mukherjee et al. 2004; Gonz alez-P eriz et al. 2006) studies, DHA appears the only fatty acid not increasing cell susceptibility to H2O2, although its effect is not ascribable to a stronger induction of antioxidant…”
Bhattacharjee, S., Jun, B., Belayev, L., Heap, J., Kautzmann, M.-A., Obenaus, A., Menghani, H., Marcell, S. J., Khoutorova, L., Yang, R., et al. (2017) · Science Advances · doi:10.1126/sciadv.1700735 · Cited by 57
Hall, J. C. E., Priestley, J. V., Perry, V. H., & Michael-Titus, A. T. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07726.x · Cited by 58
“…metabolite of DHA, is rapidly generated, that is, within 5–10 h, following either mobilization of endogenous DHA from phospholipids through phospholipase activity, or following acute administration of a bolus of DHA (Marcheselli et al. 2003; Mukherjee et al. 2004; Belayev et al. 2005).”
Lipids as targets for novel anti-inflammatory therapies
Huwiler, A., & Pfeilschifter, J. M. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.06.008 · Cited by 60
Ocular cytochrome P450s and transporters: roles in disease and endobiotic and xenobiotic disposition
Nakano, M., Lockhart, C. M., Kelly, E. J., & Rettie, A. E. (2014) · Drug Metabolism Reviews · doi:10.3109/03602532.2014.921190 · Cited by 59
“anti-inflammatory lipid mediators (Bazan et al., 2010; Mukherjee et al., 2004; Serhan et al., 2004).”
Duvall, M. G., Brüggemann, T. R., & Levy, B. D. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.04.003 · Cited by 58
“Finally, a number of SPMs reduce epithelial barrier disruption and protect against epithelial cell apoptosis (de Paiva et al., 2012; Erdinest et al., 2014; Mukherjee et al., 2004; Wang et al., 2012).”
Ho, C. F., Ismail, N. B., Koh, J. K.-Z., Gunaseelan, S., Low, Y. H., Ng, Y., Chua, J. J. E., & Ong, W. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2573-0 · Cited by 56
Markworth, J. F., Brown, L. A., Lim, E. Y., Castor‐Macias, J. A., Larouche, J. A., Macpherson, P. C. D., Davis, C. S., Aguilar, C. A., Maddipati, K. R., & Brooks, S. V. (2021) · Aging Cell · doi:10.1111/acel.13393 · Cited by 60
The essential role of docosahexaenoic acid and its derivatives for retinal integrity
Swinkels, D., & Baes, M. I. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108440 · Cited by 56
Bazan, N. G. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-74904-4_3 · Cited by 56
“to show that human RPE cells in primary culture also synthesize NPD1, initially described in the ARPE-19 cell line ( Mukherjee et al., 2004 ).”
Yin, H., Liu, W., Goleniewska, K., Porter, N. A., Morrow, J. D., & Peebles, R. S. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.05.033 · Cited by 56
“[65].”
Neuroprotectin D1 Reduces the Severity of Herpes Simplex Virus–Induced Corneal Immunopathology
Rajasagi, N. K., Reddy, P. B. J., Mulik, S., Gjorstrup, P., & Rouse, B. T. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12152 · Cited by 53
Aursnes, M., Tungen, J. E., Vik, A., Dalli, J., & Hansen, T. V. (2013) · Organic & Biomolecular Chemistry · doi:10.1039/c3ob41902a · Cited by 53
Docosahexaenoic acid accumulation in thraustochytrids: search for the rationale
Jain, R., Raghukumar, S., Sambaiah, K., Kumon, Y., & Nakahara, T. (2007) · Marine Biology · doi:10.1007/s00227-007-0608-1 · Cited by 52
“One of the possible roles of DHA and other PUFAs in storage lipids is that of antioxidants when a cell is subjected to oxidative stress, as during starvation (Dukanan et al. 2000; Mukherjee et al. 2004 ).”
Hennebelle, M., Champeil‐Potokar, G., Lavialle, M., Vancassel, S., & Denis, I. (2014) · Nutrition Reviews · doi:10.1111/nure.12088 · Cited by 53
Lipids and Lipidomics in Brain Injury and Diseases
Adibhatla, R. M., Hatcher, J. F., & Dempsey, R. J. (2006) · The AAPS Journal · doi:10.1208/aapsj080236 · Cited by 52
Knöchel, C., Voß, M., Grüter, F., Alves, G. S., Matura, S., Sepanski, B., Stäblein, M., Wenzler, S., Prvulovic, D., Carvalho, A. F., et al. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666150630173047 · Cited by 52
“Resolvins, docosatriens and neuroprotectins metabolised from DHA are also of anti-inflammatory action [53, 54], but may have additional neuroprotective mechanisms [55-57].”
Krutmann, J., & Humbert, P. G. (2010) · Springer eBooks · doi:10.1007/978-3-642-12264-4 · Cited by 82
Brain Protection in Schizophrenia, Mood and Cognitive Disorders
Ritsner, M. S. (2010) · Springer eBooks · doi:10.1007/978-90-481-8553-5 · Cited by 50
Hansen, T. V., Dalli, J., & Serhan, C. N. (2017) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2017.06.003 · Cited by 51
Bazan, N. G. (2012) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2012.08.008 · Cited by 54
“The selective endowment in omega-3 essential fatty acids (docosahexaenoyl – DHA- chains of membrane phospholipids, 22C and 6 double bonds) in synapses, photoreceptors and other membranes of the nervous system [5, 6, 7, 8, 9, 10, 11, 12] is being explored based on the bioactivity of the docosanoid synthesized from DHA…”
Stark, D. T., & Bazan, N. G. (2011) · Molecular Neurobiology · doi:10.1007/s12035-011-8174-4 · Cited by 49
“Since photoreceptor survival is dependent on RPE cell integrity, the protection of RPE cells has important implications in vision and AMD.”
InfluentialHacıoğlu, G., Seval, Y., Tanrιöver, G., Özsoy, Ö., Saka, E., Balkan, S., & Ağar, A. (2012) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.2012.0032 · Cited by 50
Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders
Nebbioso, M., Regno, P. D., Gharbiya, M., Sacchetti, M., Plateroti, R., & Lambìase, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081764 · Cited by 49
Metadata
- Authors
- Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N., & Bazan, N. G.
- Affiliations
- Louisiana State University (US)
- Corresponding author
- Bazan, Nicolas G.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-05-19
- Volume
- 101
- Issue
- 22
- Pages
- 8491-8496
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC420421
- OpenAlex
- W1739691545
- Cited by
- 753
- References
- 50
- Citations by year
- 2026: 22 · 2025: 14 · 2024: 13 · 2023: 14 · 2022: 24 · 2021: 20 · 2020: 34 · 2019: 23 · 2018: 25 · 2017: 34 · 2016: 24 · 2015: 35 · 2014: 42 · 2013: 52 · 2012: 42
- FWCI
- 44.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Huntsman Cancer Institute
- University of Leicester
- National Institutes of Health (4r37gm038765-19, GM 38765)
- National Eye Institute (EY05121, R01EY005121)
- National Institute of General Medical Sciences (GM 38765, R01GM038765, R37-GM038765)
- National Center for Research Resources (P20RR-16816, P20RR016816)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- neuroprotectin D1, docosahexaenoic acid, retinal pigment epithelium, oxidative stress, apoptosis, phospholipase A2, cyclooxygenase-2, Bcl-2 family proteins, caspase-3, IL-1β, photoreceptor survival, retinal degeneration, lipid mediators
- MeSH terms
- Cell Line, Docosahexaenoic Acids, Epithelial Cells, Humans, Interleukin-1, Isoenzymes, Membrane Proteins, Pigment Epithelium of Eye, Prostaglandin-Endoperoxide Synthases, Lipid Peroxidation, Molecular Structure, Apoptosis, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Caspases, Cyclooxygenase 2, Caspase 3, DNA Fragmentation
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