Vanderbilt University School of Medicine

Davies, Sean S. , Ph.D.
Assistant Professor of Pharmacology

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Phone Number: 322-5049


Davies, Sean's picture

Office Address   Mailing Address

506A RRB

506A RRB Clinical Pharmacology 6602

Research Keywords
Bioactive Lipids, Obesity, Oxidative Stress, Lipid Aldehydes, Protein Modification, Gut Microbiota, Therapeutics, Drug Delivery, Chronic Diseases, Atherosclerosis, HDL ,Bacteria,Biochemistry,Diabetes,Mass spectroscopy,Membrane,Microbiology,Mouse,Pharmacology,Physiology,Post-transcriptional modification,Receptor,Signal transduction,Toxicology

Research Specialty
Lipid Mediators and Sustainable Therapeutic Interventions for Chronic Diseases

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.

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, 124(8), 3391-406, 2014.

Davies, SS, Guo, L. Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids. Chem Phys Lipids, 181, 1-33, 2014.

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, 124(10), 4642-56, 2014.

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, 79C, 295-302, 2014.

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, 8(7), e67845, 2013.

Guo, L, Davies, SS. Bioactive aldehyde-modified phosphatidylethanolamines. Biochimie, 95(1), 74-8, 2013.

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, 54(11), 3151-7, 2013.

Guo, L, Chen, Z, Amarnath, V, Davies, SS. Identification of novel bioactive aldehyde-modified phosphatidylethanolamines formed by lipid peroxidation. Free Radic Biol Med, 53(6), 1226-38, 2012.

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 (PPAR??) in mice leads to increased susceptibility to diet-induced obesity. PLoS One, 7(8), e42981, 2012.

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, 27(1), 49-59, 2011.

Davies, SS, Roberts, LJ. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med, 50(5), 559-66, 2011.

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, 286(20), 18170-80, 2011.

Milne, GL, Yin, H, Hardy, KD, Davies, SS, Roberts, LJ. Isoprostane generation and function. Chem Rev, 111(10), 5973-96, 2011.

Guo, L, Amarnath, V, Davies, SS. A liquid chromatography-tandem mass spectrometry method for measurement of N-modified phosphatidylethanolamines. Anal Biochem, 405(2), 236-45, 2010.

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, 48(2), 352-9, 2010.

Sullivan, CB, Matafonova, E, Roberts, LJ, Amarnath, V, Davies, SS. Isoketals form cytotoxic phosphatidylethanolamine adducts in cells. J Lipid Res, 51(5), 999-1009, 2010.

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, 2(1), 18-29, 2010.

Chopra, N, Laver, D, Davies, SS, Knollmann, BC. Amitriptyline activates cardiac ryanodine channels and causes spontaneous sarcoplasmic reticulum calcium release. Mol Pharmacol, 75(1), 183-95, 2009. PMCID:2685059

Davies, SS, Traustad??ttir, 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, 47(7), 1014-8, 2009.

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, 15(4), 380-3, 2009.

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, , , 2008.

Davies, SS. Modulation of protein function by isoketals and levuglandins. Subcell Biochem, 49, 49-70, 2008.

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, 2(9), 2079-91, 2007.

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, 45(51), 15756-67, 2006. PMCID:2597444

Davies, SS, Zackert, W, Luo, Y, Cunningham, CC, Frisard, M, Roberts, LJ. Quantification of dinor,dihydro metabolites of F(2)-isoprostanes in urine by liquid chromatography/tandem mass spectrometry. Anal Biochem, 348(2), 185-91, 2006.

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, 40(7), 1210-9, 2006.

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, 97(12), 1262-9, 2005.

Roberts, LJ, Fessel, JP, Davies, SS. The biochemistry of the isoprostane, neuroprostane, and isofuran Pathways of lipid peroxidation. Brain Pathol, 15(2), 143-8, 2005.

Brame, Cynthia J., Boutaud, Olivier, Davies, Sean S., Yang, Tao, Oates, John A., Roden, Dan, Roberts, L. Jackson. Modifcation of proteins by isoketal-containing oxidized phospholipids. J Biol Chem, , , 2004.

Davies, SS, Amarnath, V, Roberts, LJ. Isoketals: highly reactive gamma-ketoaldehydes formed from the H2-isoprostane pathway. Chem Phys Lipids, 128(1-2), 85-99, 2004.

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, 36(9), 1163-74, 2004.

Boutaud, Olivier, Li, Junyu, Zagol, Irene, Shipp, Elizabeth A, Davies, Sean S, Roberts, L Jackson, Oates, John A. Levuglandinyl adducts of proteins are formed via a prostaglandin H2 synthase-dependent pathway after platelet activation. J Biol Chem, 278(19), 16926-8, 2003.

Davies, Sean S, Ju, Won-Kyu, Neufeld, Arthur H, Abran, Daniel, Chemtob, Sylvain, Roberts, L Jackson. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther, 19(1), 45-54, 2003.

Davies, Sean S, Amarnath, Ventkataraman, Montine, Kathleen S, Bernoud-Hubac, Nathalie, Boutaud, Olivier, Montine, Thomas J, Roberts, L Jackson. Effects of reactive gamma-ketoaldehydes formed by the isoprostane pathway (isoketals) and cyclooxygenase pathway (levuglandins) on proteasome function. FASEB J, 16(7), 715-7, 2002.

Bernoud-Hubac, N, Davies, S S, Boutaud, O, Montine, T J, Roberts, L J. Formation of highly reactive gamma-ketoaldehydes (neuroketals) as products of the neuroprostane pathway. J Biol Chem, 276(33), 30964-70, 2001.

Davies, S S, Pontsler, A V, Marathe, G K, Harrison, K A, Murphy, R C, Hinshaw, J C, Prestwich, G D, Hilaire, A S, Prescott, S M, Zimmerman, G A, McIntyre, T M. Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists. J Biol Chem, 276(19), 16015-23, 2001.

Harrison, K A, Davies, S S, Marathe, G K, McIntyre, T, Prescott, S, Reddy, K M, Falck, J R, Murphy, R C. Analysis of oxidized glycerophosphocholine lipids using electrospray ionization mass spectrometry and microderivatization techniques. J Mass Spectrom, 35(2), 224-36, 2000.

Marathe, G K, Davies, S S, Harrison, K A, Silva, A R, Murphy, R C, Castro-Faria-Neto, H, Prescott, S M, Zimmerman, G A, McIntyre, T M. Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J Biol Chem, 274(40), 28395-404, 1999.

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