Sean S. Davies, Ph.D.

Associate Professor

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Faculty Appointments
Associate Professor of Pharmacology
Ph.D., MAJOR IN EXPERIMENTAL PATHOLOGY, University of Utah, Salt Lake City, UtahB.S., CHEMISTRY, University of Utah, Salt Lake City, Utah
Office Address
506A RRB
Clinical Pharmacology
2220 Pierce Ave
Nashville, TN 6602
Research Description

Our lab's mission is to develop novel and highly sustainable therapeutic interventions for chronic diseases in order to improve human health. We do this by investigating the role of lipid mediators in modulating physiological and pathophysiological processes, and then using this knowledge to design novel interventions to modulate these processes.


Recent studies have suggested a critical role for gut microbiota in human health. Difference in bacterial species associated with the gut appear to be causally linked to adiposity and insulin resistance, which have in turn been linked to oxidative stress and inflammation and eventual vascular disease. Because the exact species of bacteria and bacterial metabolites that modulate health are only now beginning to be elucidated, we have taken an alternative approach of genetically modifying bacterial species associated with the mammalian gut to produce therapeutic metabolites (small molecules like lipids and peptides) that reduce oxidative stress and inflammation in the host. We hypothesize this approach can be used as a novel drug delivery system for treating chronic disease. Our current research focus on two proof of concept therapeutic compounds: N-acyl phosphatidylethanolamine (NAPE) and an ApoAI mimetic peptide (4F). Excitingly, probiotic bacteria engineered to express high levels of NAPE protect against the development of obesity and glucose intolerance in mice fed a high fat diet. We are exploring the mechanisms underlying this effect and the critical parameters for NAPE delivery and efficacy.


Oxidative stress has been implicated in atherosclerosis, diabetes, neurodegenerative diseases, and various cancers. Peroxidation of lipids generates highly reactive aldehydes including malondialdehyde (MDA), acrolein, 4-hydroxynonenal, and isolevuglandins (IsoLG, also given trivial name of isoketals). These lipid aldehydes react with proteins and phosphatidylethanolamine (PE) to exert their effects.

We have developed small molecule primary amines that selectively scavenge IsoLG and closely related dicarbonyls. Because these scavenger only alter the levels of IsoLG and closely related dicarbonyl, they allow us to distinguish between the effects of IsoLG and other lipid aldehydes like 4-hydroxynonenal and acrolein, as well as non-reactive lipids like F2-isoprostanes and HETEs. Two of these aldehyde scavengers, salicylamine (alternatively named SAM, 2-hydroxylbenzylamine, or 2HOBA) and pentylpyridoxamine (PPM) have good DMPK characteristics and oral bioavailability so they can be used in animal models as well as in cultured cells. Excitingly, SAM protects against oxidant induced cytotoxicity, oxidant induce sodium channel inactivation, age-related neurodegeneration, angiotensin-induced hypertension, and rapid pacing induced amyloid oligmer formation.

Recently, we have begun studying the contribution of IsoLG and related dicarbonyls to HDL dysfunction, an important element to the development of atherosclerosis.


Exposure of vascular cells to these aldehydes results in endothelial dysfunction, secretion of inflammatory cytokines, and recruitment of of monocytes, key steps in the initiation of inflammation. The inflammatory effects of lipid aldehydes have often been presumed to arise from their modification of proteins or DNA. However, recent studies have shown that many of these aldehydes also modify phosphatidylethanolamines(PE) and that PE modification increases under conditions associated with oxidative stress. These led us to hypothesize that these aldehyde-modified PE may play a critical role in inflammatory diseases associated with oxidative stress. Our lab is examining the molecular mechanisms of aldehyde-modified PE generation, how they exert their proinflammatory effects, and how they are inactivated by catabolic enzymes.

Research Keywords
Lipid Mediators and Sustainable Therapeutic Interventions for Chronic Diseases
Sidorova TN, Yermalitskaya LV, Mace LC, Wells KS, Boutaud O, Prinsen JK, Davies SS, Roberts LJ, Dikalov SI, Glabe CG, Amarnath V, Barnett JV, Murray KT. Reactive ¿-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells. J. Mol. Cell. Cardiol [print-electronic]. 2015 Feb; 79: 295-302. PMID: 25463275, PMCID: PMC4302000, PII: S0022-2828(14)00373-3, DOI: 10.1016/j.yjmcc.2014.11.013, ISSN: 1095-8584.

Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J, Harrison DG. DC isoketal-modified proteins activate T cells and promote hypertension. J. Clin. Invest [print-electronic]. 2014 Oct; 124(10): 4642-56. PMID: 25244096, PMCID: PMC4220659, PII: 74084, DOI: 10.1172/JCI74084, ISSN: 1558-8238.

Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz RL, Morris LC, Matafonova E, Stien X, Kang L, Coulon D, McGuinness OP, Niswender KD, Davies SS. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J. Clin. Invest [print-electronic]. 2014 Aug; 124(8): 3391-406. PMID: 24960158, PMCID: PMC4109548, PII: 72517, DOI: 10.1172/JCI72517, ISSN: 1558-8238.

Davies SS, Guo L. Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids. Chem. Phys. Lipids [print-electronic]. 2014 Jul; 181: 1-33. PMID: 24704586, PMCID: PMC4075969, PII: S0009-3084(14)00040-1, DOI: 10.1016/j.chemphyslip.2014.03.002, ISSN: 1873-2941.

Guo L, Gragg SD, Chen Z, Zhang Y, Amarnath V, Davies SS. Isolevuglandin-modified phosphatidylethanolamine is metabolized by NAPE-hydrolyzing phospholipase D. J. Lipid Res [print-electronic]. 2013 Nov; 54(11): 3151-7. PMID: 24018423, PMCID: PMC3793619, PII: jlr.M042556, DOI: 10.1194/jlr.M042556, ISSN: 0022-2275.

Barrett CW, Singh K, Motley AK, Lintel MK, Matafonova E, Bradley AM, Ning W, Poindexter SV, Parang B, Reddy VK, Chaturvedi R, Fingleton BM, Washington MK, Wilson KT, Davies SS, Hill KE, Burk RF, Williams CS. Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS ONE [electronic-print]. 2013; 8(7): e67845. PMID: 23861820, PMCID: PMC3701622, PII: PONE-D-13-14817, DOI: 10.1371/journal.pone.0067845, ISSN: 1932-6203.

Guo L, Davies SS. Bioactive aldehyde-modified phosphatidylethanolamines. Biochimie [print-electronic]. 2013 Jan; 95(1): 74-8. PMID: 22819995, PII: S0300-9084(12)00292-1, DOI: 10.1016/j.biochi.2012.07.010, ISSN: 1638-6183.

Guo L, Chen Z, Amarnath V, Davies SS. Identification of novel bioactive aldehyde-modified phosphatidylethanolamines formed by lipid peroxidation. Free Radic. Biol. Med [print-electronic]. 2012 Sep 9/15/2012; 53(6): 1226-38. PMID: 22898174, PMCID: PMC3461964, PII: S0891-5849(12)00471-6, DOI: 10.1016/j.freeradbiomed.2012.07.077, ISSN: 1873-4596.

Kocalis HE, Turney MK, Printz RL, Laryea GN, Muglia LJ, Davies SS, Stanwood GD, McGuinness OP, Niswender KD. Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPARd) in mice leads to increased susceptibility to diet-induced obesity. PLoS ONE [print-electronic]. 2012; 7(8): e42981. PMID: 22916190, PMCID: PMC3423438, PII: PONE-D-12-05087, DOI: 10.1371/journal.pone.0042981, ISSN: 1932-6203.

Milne GL, Yin H, Hardy KD, Davies SS, Roberts LJ. Isoprostane generation and function. Chem. Rev [print-electronic]. 2011 Oct 10/12/2011; 111(10): 5973-96. PMID: 21848345, PMCID: PMC3192249, DOI: 10.1021/cr200160h, ISSN: 1520-6890.

Guo L, Chen Z, Cox BE, Amarnath V, Epand RF, Epand RM, Davies SS. Phosphatidylethanolamines modified by ¿-ketoaldehyde (¿KA) induce endoplasmic reticulum stress and endothelial activation. J. Biol. Chem [print-electronic]. 2011 May 5/20/2011; 286(20): 18170-80. PMID: 21454544, PMCID: PMC3093889, PII: M110.213470, DOI: 10.1074/jbc.M110.213470, ISSN: 1083-351X.

Davies SS, Roberts LJ. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic. Biol. Med [print-electronic]. 2011 Mar 3/1/2011; 50(5): 559-66. PMID: 21126576, PMCID: PMC3058898, PII: S0891-5849(10)01395-X, DOI: 10.1016/j.freeradbiomed.2010.11.023, ISSN: 1873-4596.

Davies SS, Bodine C, Matafonova E, Pantazides BG, Bernoud-Hubac N, Harrison FE, Olson SJ, Montine TJ, Amarnath V, Roberts LJ. Treatment with a ¿-ketoaldehyde scavenger prevents working memory deficits in hApoE4 mice. J. Alzheimers Dis. 2011; 27(1): 49-59. PMID: 21709376, PMCID: PMC3289064, PII: P6Q787755RMQ5530, DOI: 10.3233/JAD-2011-102118, ISSN: 1875-8908.

Guo L, Amarnath V, Davies SS. A liquid chromatography-tandem mass spectrometry method for measurement of N-modified phosphatidylethanolamines. Anal. Biochem [print-electronic]. 2010 Oct 10/15/2010; 405(2): 236-45. PMID: 20599652, PMCID: PMC2922460, PII: S0003-2697(10)00380-5, DOI: 10.1016/j.ab.2010.06.027, ISSN: 1096-0309.

Sullivan CB, Matafonova E, Roberts LJ, Amarnath V, Davies SS. Isoketals form cytotoxic phosphatidylethanolamine adducts in cells. J. Lipid Res [print-electronic]. 2010 May; 51(5): 999-1009. PMID: 19965577, PMCID: PMC2853468, PII: jlr.M001040, DOI: 10.1194/jlr.M001040, ISSN: 0022-2275.

Zagol-Ikapitte IA, Matafonova E, Amarnath V, Bodine CL, Boutaud O, Tirona RG, Oates JA, Roberts LJ, Davies SS. Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent ¿-Ketoaldehyde Scavenger, by LC/MS/MS. Pharmaceutics. 2010 Mar; 2(1): 18-29. PMID: 21822464, PMCID: PMC3150493, DOI: 10.3390/pharmaceutics2010018, ISSN: 1999-4923.

Nakajima T, Davies SS, Matafonova E, Potet F, Amarnath V, Tallman KA, Serwa RA, Porter NA, Balser JR, Kupershmidt S, Roberts LJ. Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation. J. Mol. Cell. Cardiol [print-electronic]. 2010 Feb; 48(2): 352-9. PMID: 19962379, PMCID: PMC2818591, PII: S0022-2828(09)00491-X, DOI: 10.1016/j.yjmcc.2009.11.016, ISSN: 1095-8584.

Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L, Mathews PM, Matsuoka Y, Ariga T, Yu RK, Thompson R, McDonald MP. Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol. Aging [print-electronic]. 2009 Nov; 30(11): 1777-91. PMID: 18258340, PII: S0197-4580(07)00498-8, DOI: 10.1016/j.neurobiolaging.2007.12.022, ISSN: 1558-1497.

Davies SS, Traustadóttir T, Stock AA, Ye F, Shyr Y, Harman SM, Roberts LJ. Ischemia/reperfusion unveils impaired capacity of older adults to restrain oxidative insult. Free Radic. Biol. Med [print-electronic]. 2009 Oct 10/1/2009; 47(7): 1014-8. PMID: 19596063, PMCID: PMC2748908, PII: S0891-5849(09)00409-2, DOI: 10.1016/j.freeradbiomed.2009.07.005, ISSN: 1873-4596.

Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat. Med [print-electronic]. 2009 Apr; 15(4): 380-3. PMID: 19330009, PMCID: PMC2904954, PII: nm.1942, DOI: 10.1038/nm.1942, ISSN: 1546-170X.

Chopra N, Laver D, Davies SS, Knollmann BC. Amitriptyline activates cardiac ryanodine channels and causes spontaneous sarcoplasmic reticulum calcium release. Mol. Pharmacol [print-electronic]. 2009 Jan; 75(1): 183-95. PMID: 18845675, PMCID: PMC2685059, PII: mol.108.051490, DOI: 10.1124/mol.108.051490, ISSN: 1521-0111.

Davies SS. Modulation of protein function by isoketals and levuglandins. Subcell. Biochem. 2008; 49: 49-70. PMID: 18751907, DOI: 10.1007/978-1-4020-8831-5_2, ISSN: 0306-0225.

Davies SS, Amarnath V, Brame CJ, Boutaud O, Roberts LJ. Measurement of chronic oxidative and inflammatory stress by quantification of isoketal/levuglandin gamma-ketoaldehyde protein adducts using liquid chromatography tandem mass spectrometry. Nat Protoc. 2007; 2(9): 2079-91. PMID: 17853863, PII: nprot.2007.298, DOI: 10.1038/nprot.2007.298, ISSN: 1750-2799.

Davies SS, Brantley EJ, Voziyan PA, Amarnath V, Zagol-Ikapitte I, Boutaud O, Hudson BG, Oates JA, Roberts LJ. Pyridoxamine analogues scavenge lipid-derived gamma-ketoaldehydes and protect against H2O2-mediated cytotoxicity. Biochemistry [print-electronic]. 2006 Dec 12/26/2006; 45(51): 15756-67. PMID: 17176098, PMCID: PMC2597444, DOI: 10.1021/bi061860g, ISSN: 1520-4995.

Talati M, Meyrick B, Peebles RS, Davies SS, Dworski R, Mernaugh R, Mitchell D, Boothby M, Roberts LJ, Sheller JR. Oxidant stress modulates murine allergic airway responses. Free Radic. Biol. Med [print-electronic]. 2006 Apr 4/1/2006; 40(7): 1210-9. PMID: 16545689, PII: S0891-5849(05)00710-0, DOI: 10.1016/j.freeradbiomed.2005.11.012, ISSN: 0891-5849.

Davies SS, Zackert W, Luo Y, Cunningham CC, Frisard M, Roberts LJ. Quantification of dinor, dihydro metabolites of F2-isoprostanes in urine by liquid chromatography/tandem mass spectrometry. Anal. Biochem [print-electronic]. 2006 Jan 1/15/2006; 348(2): 185-91. PMID: 16309621, PII: S0003-2697(05)00729-3, DOI: 10.1016/j.ab.2005.10.012, ISSN: 0003-2697.

Fukuda K, Davies SS, Nakajima T, Ong BH, Kupershmidt S, Fessel J, Amarnath V, Anderson ME, Boyden PA, Viswanathan PC, Roberts LJ, Balser JR. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circ. Res [print-electronic]. 2005 Dec 12/9/2005; 97(12): 1262-9. PMID: 16284182, PII: 01.RES.0000195844.31466.e9, DOI: 10.1161/01.RES.0000195844.31466.e9, ISSN: 1524-4571.

Roberts LJ, Fessel JP, Davies SS. The biochemistry of the isoprostane, neuroprostane, and isofuran Pathways of lipid peroxidation. Brain Pathol. 2005 Apr; 15(2): 143-8. PMID: 15912887, ISSN: 1015-6305.

Davies SS, Talati M, Wang X, Mernaugh RL, Amarnath V, Fessel J, Meyrick BO, Sheller J, Roberts LJ. Localization of isoketal adducts in vivo using a single-chain antibody. Free Radic. Biol. Med. 2004 May 5/1/2004; 36(9): 1163-74. PMID: 15082070, PII: S0891584904001315, DOI: 10.1016/j.freeradbiomed.2004.02.014, ISSN: 0891-5849.

Brame CJ, Boutaud O, Davies SS, Yang T, Oates JA, Roden D, Roberts LJ. Modification of proteins by isoketal-containing oxidized phospholipids. J. Biol. Chem [print-electronic]. 2004 Apr 4/2/2004; 279(14): 13447-51. PMID: 14715668, PII: M313349200, DOI: 10.1074/jbc.M313349200, ISSN: 0021-9258.

Davies SS, Amarnath V, Roberts LJ. Isoketals: highly reactive gamma-ketoaldehydes formed from the H2-isoprostane pathway. Chem. Phys. Lipids. 2004 Mar; 128(1-2): 85-99. PMID: 15037155, PII: S0009308403001567, DOI: 10.1016/j.chemphyslip.2003.10.007, ISSN: 0009-3084.

Boutaud O, Li J, Zagol I, Shipp EA, Davies SS, Roberts LJ, Oates JA. Levuglandinyl adducts of proteins are formed via a prostaglandin H2 synthase-dependent pathway after platelet activation. J. Biol. Chem [print-electronic]. 2003 May 5/9/2003; 278(19): 16926-8. PMID: 12637576, PII: M300940200, DOI: 10.1074/jbc.M300940200, ISSN: 0021-9258.

Davies SS, Ju WK, Neufeld AH, Abran D, Chemtob S, Roberts LJ. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther. 2003 Feb; 19(1): 45-54. PMID: 12648303, DOI: 10.1089/108076803762718105, ISSN: 1080-7683.

Davies SS, Amarnath V, Montine KS, Bernoud-Hubac N, Boutaud O, Montine TJ, Roberts LJ. Effects of reactive gamma-ketoaldehydes formed by the isoprostane pathway (isoketals) and cyclooxygenase pathway (levuglandins) on proteasome function. FASEB J [print-electronic]. 2002 May; 16(7): 715-7. PMID: 11978738, PII: 01-0696fje, DOI: 10.1096/fj.01-0696fje, ISSN: 1530-6860.

Bernoud-Hubac N, Davies SS, Boutaud O, Montine TJ, Roberts LJ. Formation of highly reactive gamma-ketoaldehydes (neuroketals) as products of the neuroprostane pathway. J. Biol. Chem [print-electronic]. 2001 Aug 8/17/2001; 276(33): 30964-70. PMID: 11413140, PII: M103768200, DOI: 10.1074/jbc.M103768200, ISSN: 0021-9258.

Davies SS, Pontsler AV, Marathe GK, Harrison KA, Murphy RC, Hinshaw JC, Prestwich GD, Hilaire AS, Prescott SM, Zimmerman GA, McIntyre TM. Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists. J. Biol. Chem [print-electronic]. 2001 May 5/11/2001; 276(19): 16015-23. PMID: 11279149, PII: M100878200, DOI: 10.1074/jbc.M100878200, ISSN: 0021-9258.

Harrison KA, Davies SS, Marathe GK, McIntyre T, Prescott S, Reddy KM, Falck JR, Murphy RC. Analysis of oxidized glycerophosphocholine lipids using electrospray ionization mass spectrometry and microderivatization techniques. J Mass Spectrom. 2000 Feb; 35(2): 224-36. PMID: 10679985, PII: 10.1002/(SICI)1096-9888(200002)35:2<224::AID-JMS933>3.0.CO;2-G, DOI: 10.1002/(SICI)1096-9888(200002)35:2<224::AID-JMS933>3.0.CO;2-G, ISSN: 1076-5174.

Marathe GK, Davies SS, Harrison KA, Silva AR, Murphy RC, Castro-Faria-Neto H, Prescott SM, Zimmerman GA, McIntyre TM. Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J. Biol. Chem. 1999 Oct 10/1/1999; 274(40): 28395-404. PMID: 10497200, ISSN: 0021-9258.

Available Postdoctoral Position Details
Posted: 1/5/2015