Current and Recent Research at the Nicolas Bazan Laboratory
The research is focused on understanding cellular and molecular mechanisms of homeostasis in the brain and retina, particularly aiming to uncover rules that sustain successful aging. Therefore, experimental approaches aim to prevent, ameliorate, and cure Alzheimer’s disease (AD), age-related macular degeneration, stroke, Parkinson’s, TBI and other neurological conditions. The projects have led to the uncovering of new gene regulation and necessary proteins for cell survival at the onset of brain and retina neurodegenerations. Ongoing projects include the understanding of mechanisms that preserve photoreceptors and retinal pigment epithelial (RPE) cells’ functional integrity for decades in healthy eyes despite their hostile environment (light exposure, high oxygen consumption, the formation of highly reactive retinoids, the abundance of peroxidation-susceptible polyunsaturated fatty acids, and other adversities).
We are also following similar events likely to operate to sustain successful brain aging.
Our laboratory has begun to uncover molecular principles involved in the retention/conservation of the omega-3 fatty acid family member, docosahexaenoic acid (DHA), necessary for cell survival signaling in RPE cells and photoreceptors. Our lab contributed to the discovery of the cell survival mediator, neuroprotectin D1 (NPD1), and coined its name. Under conditions of uncompensated oxidative stress, NPD1 is made on demand from DHA when disruptors of homeostasis evolve, and the initial response needs to be modulated to protect cell integrity. NPD1 is the first biologically active mediator of the novel docosanoid family. Our lab is studying neurotrophins (mainly PEDF) as agonists for the synthesis of this mediator in RPE cells. Recently we uncovered that 15-lipoxygenase-1 (15-LOX-1) is the enzyme that catalyzes NPD1 synthesis, that it targets protein phosphatase 2A (PP2A) to regulate anti-/pro-apoptotic proteins during uncompensated oxidative stress, and that it regulates proteostasis as well. Our lab identified the transcription of pro-inflammatory genes as a target of NPD1 and demonstrated that the CA1 hippocampal area from short post-mortem, early-stage Alzheimer’s patients displays a 25-fold loss of NPD1 as well as of the enzyme for the synthesis of this lipid mediator.
A central theme of the lab is understanding early responses to uncompensated oxidative stress, neuroinflammation, mutation expression, and conditions that recapitulate neurodegenerative diseases and stroke to gain insight into endogenous protective mechanisms. A common thread of concepts includes homeostatic regulation, necessary proteins, and genetic and epigenetic events.
Our lab is placing efforts to identify and define the significance of novel lipid mediators and other regulators of cell integrity and survival. Most of the known lipid mediators are derived from 18-22C length FA precursors, including prostaglandins and NPD1. However, we recently discovered a new mediator family named elovanoids (ELVs) formed from 32C or 34C length FA precursors. These precursors are made by photoreceptor-specific ELOVL4. Our lab continues to explore novel mediators using our experience to decipher detailed structure and stereochemistry, along with approaches to further define pro-homeostatic neuroprotective mediators of low abundance that also arrest senescence gene programming and senescence-activated secretory phenotype (SASP) upon cellular homeostasis disruptions.
In February 2020, our lab expanded its interests to include new approaches using lipid mediators to counteract SARS-CoV-2 cell entrance and inflammatory damage. We use primary cultures of human alveoli and human nasal cells. We prepared and characterized the RBD of the viral spike glycoprotein by complexing it with the fluorescent Alexa Fluor 546 and defined conditions for binding and internalization of the labeled protein in the primary cultures. We then sub-cloned an
ORF for the entire spike protein into a carrier vector containing the mCHERRY tag. We developed a quantitative assessment of cell surface binding and internalization of tag RBD of viral spike protein or recombinant entire spike protein from SARS-CoV-2 using confocal microscopy and IMARIS Cell/Batch module. We also adapted other methods from our lab for this project, including assessment of protein abundance by Jess technology, droplet digital PCR for gene expression, and LC-MS/MS-based lipidomic analysis.
Our lab explores how the pro-homeostatic lipid mediators ELVs attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) as well as of the SARS-CoV-2 virus in human primary alveoli cells in culture. We are exploring how very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA,n-3) activate ELV biosynthesis in lung cells and how both ELVs and their precursors reduce the binding to RBD. Experiments are testing how ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulate defensive proteins against lung damage. In addition, we have experimental approaches to define how ELVs and their precursors decreased the signal of spike (S) protein found in SARS-CoV-2 infected cells, suggesting that the lipids curb viral infection. These studies open up avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.
Our lab is also studying a pipeline of novel analgesics that we discovered. Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. We are studying novel compounds that avoid oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI). This is a key mechanism for hepatotoxicity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these compounds represent a novel, non-narcotic therapeutic pipeline.
Impact of my research as of 03/25/2021: >490 peer-reviewed publications (PubMed), plus monographs, books, and chapters, an h-index of 100 (Google Scholar), an i10-index of 427, and >40,001 citations to my work (Google Scholar).
Publications 2017-2021 (with links)
Retina, RPE and photoreceptors
Bazan NG. J Lipid Res. 2021 Mar 1:100058. doi: 10.1194/jlr.TR120001137. Online ahead of print. PMID: 33662383 Free article. Review.
Das Y, Swinkels D, Kocherlakota S, Vinckier S, Vaz FM, Wever E, van Kampen AHC, Jun B, Do KV, Moons L, Bazan NG, Van Veldhoven PP, Baes M. Front Cell Dev Biol. 2021 Feb 2;9:632930. doi: 10.3389/fcell.2021.632930. eCollection 2021.PMID: 33604342 Free PMC article.
Li S, Gordon WC, Bazan NG, Jin M. Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32114-32123. doi: 10.1073/pnas.2012623117. Epub 2020 Nov 30. PMID: 33257550
Vidal E, Jun B, Gordon WC, Maire MA, Martine L, Grégoire S, Khoury S, Cabaret S, Berdeaux O, Acar N, Bretillon L, Bazan NG. J Lipid Res. 2020 Dec;61(12):1733-1746. doi: 10.1194/jlr.RA120001057. Epub 2020 Oct 30. PMID: 33127836 Free article.
Bazan NG. J Lipid Res. 2020 Oct 26:jlr.TR120001137. doi: 10.1194/jlr.TR120001137. Online ahead of print. PMID: 33106370 Free article.
Langbøl M, Saruhanian S, Baskaran T, Tiedemann D, Mouhammad ZA, Toft-Kehler AK, Jun B, Vohra R, Bazan NG, Kolko M. J Clin Med. 2020 Sep 15;9(9):2979. doi: 10.3390/jcm9092979. PMID: 32942740 Free PMC article.
Leslie CE, Rosencrans RF, Walkowski W, Gordon WC, Bazan NG, Ryan MJ, Farris HE. Front Behav Neurosci. 2020 Jan 21;13:293. doi: 10.3389/fnbeh.2019.00293. eCollection 2019. PMID: 32076402 Free PMC article.
Kautzmann MI, Gordon WC, Jun B, Do KV, Matherne BJ, Fang Z, Bazan NG. FASEB J. 2020 Jan;34(1):912-929. doi: 10.1096/fj.201902359R. Epub 2019 Nov 28. PMID: 31914617 Free PMC article.
Do KV, Kautzmann MI, Jun B, Gordon WC, Nshimiyimana R, Yang R, Petasis NA, Bazan NG. Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24317-24325. doi: 10.1073/pnas.1912959116. Epub 2019 Nov 11. PMID: 31712409 Free PMC article.
Bazan NG, Gordon WC. Neuron. 2019 Feb 20;101(4):548-550. doi: 10.1016/j.neuron.2019.02.004. PMID: 30790533 Free article.
Rosencrans RF, Leslie CE, Perkins KA, Walkowski W, Gordon WC, Richards-Zawacki CL, Bazan NG, Farris HE. J Comp Neurol. 2018 Dec 15;526(18):3045-3057. doi: 10.1002/cne.24531. Epub 2018 Oct 31. PMID: 30198557
Dhingra A, Bell BA, Peachey NS, Daniele LL, Reyes-Reveles J, Sharp RC, Jun B, Bazan NG, Sparrow JR, Kim HJ, Philp NJ, Boesze-Battaglia K. Front Cell Neurosci. 2018 Oct 8;12:351. doi: 10.3389/fncel.2018.00351. eCollection 2018. PMID: 30349463 Free PMC article.
Li S, Sato K, Gordon WC, Sendtner M, Bazan NG, Jin M. J Biol Chem. 2018 Sep 28;293(39):15256-15268. doi: 10.1074/jbc.RA118.004008. Epub 2018 Aug 16. PMID: 30115683 Free PMC article.
Elison JR, Weinstein JE, Sheets KG, Regan CE Jr, Lentz JJ, Reinoso M, Gordon WC, Bazan NG. Curr Eye Res. 2018 Jun;43(6):821-827. doi: 10.1080/02713683.2018.1454476. Epub 2018 Apr 11. PMID: 29641916 Free PMC article.
Shaw LC, Li Calzi S, Li N, Moldovan L, Sengupta-Caballero N, Quigley JL, Ivan M, Jun B, Bazan NG, Boulton ME, Busik J, Neu J, Grant MB.Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):858-869. doi: 10.1167/iovs.17-23034.PMID: 29490339 Free PMC article.
Knott EJ, Gordon WC, Jun B, Do K, Bazan NG. Cell Mol Neurobiol. 2018 May;38(4):901-917. doi: 10.1007/s10571-017-0565-2. Epub 2017 Nov 24. PMID: 29177613 Free PMC article.
Jun B, Mukherjee PK, Asatryan A, Kautzmann MA, Heap J, Gordon WC, Bhattacharjee S, Yang R, Petasis NA, Bazan NG. Sci Rep. 2017 Jul 13;7(1):5279. doi: 10.1038/s41598-017-05433-7. PMID: 28706274 Free PMC article.
Belayev L, Obenaus A, Mukherjee PK, Knott EJ, Khoutorova L, Reid MM, Roque CR, Nguyen L, Lee JB, Petasis NA, Oria RB, Bazan NG. Brain Circ. 2020 Dec 29;6(4):260-268. doi: 10.4103/bc.bc_36_20. eCollection 2020 Oct-Dec. PMID: 33506149 Free PMC article.
Belayev L, Hong SH, Freitas RS, Menghani H, Marcell SJ, Khoutorova L, Mukherjee PK, Reid MM, Oria RB, Bazan NG. CNS Neurosci Ther. 2020 Nov;26(11):1155-1167. doi: 10.1111/cns.13444. Epub 2020 Aug 5. PMID: 32757264 Free PMC article.
Iwuchukwu I, Nguyen D, Beavers M, Tran V, Sulaiman W, Fannin E, Lasseigne L, Ramsay E, Wilson J, Bazan NG. Mol Neurobiol. 2020 May;57(5):2346-2357. doi: 10.1007/s12035-020-01872-y. Epub 2020 Feb 10. PMID: 32040835
Belayev L, Hong SH, Menghani H, Marcell SJ, Obenaus A, Freitas RS, Khoutorova L, Balaszczuk V, Jun B, Oriá RB, Bazan NG. Mol Neurobiol. 2018 Aug;55(8):7090-7106. doi: 10.1007/s12035-018-1136-3. Epub 2018 Jun 1. PMID: 29858774 Free PMC article.
Bhattacharjee S, Jun B, Belayev L, Heap J, Kautzmann MA, Obenaus A, Menghani H, Marcell SJ, Khoutorova L, Yang R, Petasis NA, Bazan NG. Sci Adv. 2017 Sep 27;3(9):e1700735. doi: 10.1126/sciadv.1700735. eCollection 2017 Sep. PMID: 28959727 Free PMC article.
Belayev L, Mukherjee PK, Balaszczuk V, Calandria JM, Obenaus A, Khoutorova L, Hong SH, Bazan NG. Cell Death Differ. 2017 Jun;24(6):1091-1099. doi: 10.1038/cdd.2017.55. Epub 2017 Apr 21. PMID: 28430183 Free PMC article.
Lipid Mediators (not included in other groups of publications)
Elovanoids are novel pro-homeostatic modulators of inflammatory responses and neuroprotection.
Do KV, Bazan NG. Lifestyle Genom. 2021. Review. [in press]
Hong S, Lu Y, Morita M, Saito S, Kobayashi Y, Jun B, Bazan NG, Xu X, Wang Y. Synlett. 2019 Feb;30(3):343-347. doi: 10.1055/s-0037-1612011. Epub 2019 Jan 14. PMID: 31086432 Free PMC article.
Bazan NG. Mol Aspects Med. 2018 Dec;64:18-33. doi: 10.1016/j.mam.2018.09.003. Epub 2018 Oct 1. PMID: 30244005 Free PMC article. Review.
Gordon WC, López VG, Bhattacharjee S, Gil DR, Díaz JA, de la Losa FP, Peláez RP, Ferrer CT, Bacchini GS, Jun B, Varoqui H, Bazan NG. Dermatol Ther (Heidelb). 2018 Mar;8(1):111-126. doi: 10.1007/s13555-018-0223-8. Epub 2018 Feb 16. PMID: 29453524 Free PMC article.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG,et all. Cell Death Differ. 2018 Mar;25(3):486-541. doi: 10.1038/s41418-017-0012-4. Epub 2018 Jan 23. PMID: 29362479 Free PMC article. Review.
Nishimura K, Sakaguchi T, Nanba Y, Suganuma Y, Morita M, Hong S, Lu Y, Jun B, Bazan NG, Arita M, Kobayashi Y. J Org Chem. 2018 Jan 5;83(1):154-166. doi: 10.1021/acs.joc.7b02510. Epub 2017 Dec 27. PMID: 29224348
Connolly NMC, Theurey P, Adam-Vizi V, Bazan NG, et all. Cell Death Differ. 2018 Mar;25(3):542-572. doi: 10.1038/s41418-017-0020-4. Epub 2017 Dec 11. PMID: 29229998 Free PMC article. Review.
Asatryan A, Bazan NG. J Biol Chem. 2017 Jul 28;292(30):12390-12397. doi: 10.1074/jbc.R117.783076. Epub 2017 Jun 14. PMID: 28615451 Free PMC article.
Bazan NG, Carman GM.J Biol Chem. 2017 Jul 28;292(30):12373-12374. doi: 10.1074/jbc.R117.801753. Epub 2017 Jun 14.PMID: 28615440 Free PMC article.
Pham TL, He J, Kakazu AH, Calandria J, Do KV, Nshimiyimana R, Petasis NA, Bazan HEP, Bazan NG. Res Sq. 2020 Aug 11:rs.3.rs-55764. doi: 10.21203/rs.3.rs-55764/v1. Preprint. PMID: 32818210 Free PMC article.
Elovanoid-N32 or RvD6-isomer decrease ACE2 and binding of S protein RBD after injury or INFγ in the eye.
Pham TL, He J, Kakazu AH, Calandria J, Do KV, Nshimiyimana R, Petasis NA, Bazan HEP, Bazan NG. Res Sq 2020. https://doi.org/10.21203/rs.3.rs-55764/v1.
Elovanoids downregulate canonical SARS-CoV-2 cell-entry mediators and enhance protective signaling in human alveolar cells.
Calandria J, Bhattacharjee S, Kautzmann M-A, Asatryan A, Gordon WC, Do KV, Jun B, Mukherjee PK, Petasis NA, Bazan NG. Res Sq 2020. https://doi.org/10.21203/rs.3.rs-75121/v1
Bazan HA, Bhattacharjee S, Burgos C, Recio J, Abet V, Pahng AR, Jun B, Heap J, Ledet AJ, Gordon WC, Edwards S, Paul D, Alvarez-Builla J, Bazan NG. Eur J Med Chem. 2020 Sep 15;202:112600. doi: 10.1016/j.ejmech.2020.112600. Epub 2020 Jun 30. PMID: 32629335 Free PMC article.
Das M, Bhattacharjee S, Fronczek FR, Bazan NG, Trudell ML. Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3798-3801. doi: 10.1016/j.bmcl.2018.09.020. Epub 2018 Sep 17. PMID: 30327145
Cornea/anterior segment of the eye
Pham TL, Kakazu AH, He J, Jun B, Bazan NG, Bazan HEP. Sci Rep. 2020 Mar 12;10(1):4582. doi: 10.1038/s41598-020-61390-8. PMID: 32165657 Free PMC article.
Pham TL, He J, Kakazu AH, Jun B, Bazan NG, Bazan HEP. J Biol Chem. 2017 Nov 10;292(45):18486-18499. doi: 10.1074/jbc.M117.801472. Epub 2017 Sep 26. PMID: 28972155 Free PMC article.
Some of the N. Bazan Lab earlier Discoveries
A novel key molecular mechanism leading to visual degeneration and blindness.
This research reveals events that may be harnessed for prevention, as well as to slow down progression, of retinal degenerative diseases. The paper is published in Nature Communication (Rice et al., Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival.Nat Commun. 2015 Mar 4;6:6228. See link for more.
Novel gene-regulated neuroprotection disease-modifying mechanism for vision and stroke
This research led to the finding that gene interactions determine whether cells live or die in the retina and brain. It has uncovered a stereospecific mediator that targets gene interactions leading to cell survival relevant to retinal degenerative diseases, including age-related macular degeneration. Moreover, they also found that this key event halts progression of experimental ischemic stroke damage by activating a neuronal selective event. The molecular mechanisms identified seem to be critical for vision (RPE-photoreceptor cell) and brain integrity (selectively neuronal). The paper is published online in Cell Death & Differentiation, a Nature journal athttp://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014233a.html. See link for more.
Discovery of neuronal architecture protection by neuroprotection D1 in a novel Parkinson’s disease dish model
In a recent report published by our lab, we developed a model of Parkinson’s disease in a dish using the primary mesencephalic neurons in culture from mouse. This model has the advantage of focusing on neurons affected by the disease and to be able to chemically damage the neuronal architecture, recapitulating aspects of the disease process. In addition, the model can be used to identify novel disease-modifying molecular mechanisms and to screen potentially useful therapeutic agents. In fact, using this model, we discovered that the lipid mediator neuroprotectin D1 (D1) remarkably protects the neuronal architecture. See link for more.
Protection of hippocampal dendritic spines and synaptic plasticity in experimental epilepsy by a docosanoid
In a recent publication, the lab reported the uncovering of naturally-occurring molecules hippocampal neuronal networks in the pilocarpine post-status epilepticus model of limbic epileptogenesis. The data demonstrate that the docosahexaenoic acid (DHA)-derived docosanoid mediator, neuroprotectin D1 (NPD1), prevents experimental epileptogenesis. The paper reports that the structure and function of hippocampal neuronal networks are restored by measuring brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis, and we found that systemically-injected NPD1 led to a reduction in spontaneous recurrent seizures. The results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis, which may contribute to the development of anti-epileptogenic therapeutic strategies. See link for more.
Targeting Neuroprotection in Epilepsy by a Docosanoid
In an editorial update, the lab published in the journal Future Neurology highlights regarding the therapeutic potential of neuroprotectin D1 (NPD1) for epilepsy. NPD1 is a docosanoid mediator because it is derived from docosahexaenoic acid (DHA) and displays neuroprotective and pro-homeostatic bioactivity. Emphasis is placed on depicting this docosanoid as a major cell survival mediator made “on demand.” This article also discusses ways to effectively deliver NPD1 to the brain, or to enhance its bioavailability, which could contribute to a therapeutic paradigm shift by enhancing the intrinsic potential of brain cells to protect and repair themselves in epilepsy. See link for more.