Profile

Overview

My 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 (bioactive lipids) in modulating physiological and pathophysiological processes, and then using this knowledge to design novel interventions to modulate these processes.

Therapeutic Modification of Gut Bacteria

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 the proof of concept therapeutic compounds: N-acyl phosphatidylethanolamine (NAPE) and their bioactive metabolites, N-acyl-ethanolamides (NAEs). 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.

Reactive Lipid Aldehydes (Isolevuglandins/Isoketals)

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, 4-oxo-nonenal (ONE) and isolevuglandins (IsoLG, also given trivial name of isoketals). These lipid aldehydes react with proteins and phosphatidylethanolamine (PE) to exert their effects.

One difficulty in studying the contribution of reactive lipid aldehydes has been the lack of tools to isolate their effects from the myriad of other products formed by lipid peroxidation at the same time. Therefore, in order to determine the contribution of IsoLG to disease processes, we first had to develop the appropriate tools. These included mass spectrometric methods to measure the IsoLG-protein and IsoLG-PE adducts. We also developed a single-chain antibody that selectively recognized IsoLG-protein adducts that has been used by a number of our collaborators to localize sites of IsoLG-protein adduct formation in tissues and cultured cells. Perhaps most importantly, we 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 cytotoxicityoxidant induce sodium channel inactivationage-related neurodegenerationangiotensin-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.

Aldehyde-Modified Phosphatidylethanolamines

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 generationhow they exert their proinflammatory effects, and how they are inactivated by catabolic enzymes.

 

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment. Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS (2019) Appl Microbiol Biotechnol 103(16): 6711-6723
    › Primary publication · 31203417 (PubMed)
  2. Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor Mice Improves Indices of Cardiometabolic Disease. May-Zhang LS, Chen Z, Dosoky NS, Yancey PG, Boyd KL, Hasty AH, Linton MF, Davies SS (2019) Sci Rep 9(1): 420
    › Primary publication · 30674978 (PubMed) · PMC6344515 (PubMed Central)
  3. Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function. May-Zhang LS, Yermalitsky V, Huang J, Pleasent T, Borja MS, Oda MN, Jerome WG, Yancey PG, Linton MF, Davies SS (2018) J Biol Chem 293(24): 9176-9187
    › Primary publication · 29712723 (PubMed) · PMC6005447 (PubMed Central)
  4. Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D. Chen Z, Zhang Y, Guo L, Dosoky N, de Ferra L, Peters S, Niswender KD, Davies SS (2017) J Lipid Res 58(8): 1624-1635
    › Primary publication · 28596183 (PubMed) · PMC5538284 (PubMed Central)
  5. Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro. Longato L, Andreola F, Davies SS, Roberts JL, Fusai G, Pinzani M, Moore K, Rombouts K (2017) Free Radic Biol Med : 162-173
    › Primary publication · 27890721 (PubMed)
  6. Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. Mont S, Davies SS, Roberts Second LJ, Mernaugh RL, McDonald WH, Segal BH, Zackert W, Kropski JA, Blackwell TS, Sekhar KR, Galligan JJ, Massion PP, Marnett LJ, Travis EL, Freeman ML (2016) Sci Rep : 24919
    › Primary publication · 27118599 (PubMed) · PMC4847119 (PubMed Central)
  7. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Zhang LS, Davies SS (2016) Genome Med 8(1): 46
    › Primary publication · 27102537 (PubMed) · PMC4840492 (PubMed Central)
  8. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KR, Xiao L, Chen W, Mernaugh RL, Cai H, Bernstein KE, Goronzy JJ, Weyand CM, Curci JA, Barbaro NR, Moreno H, Davies SS, Roberts LJ, Madhur MS, Harrison DG (2016) J Clin Invest 126(4): 1607
    › Primary publication · 27035819 (PubMed) · PMC4811163 (PubMed Central)
  9. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KR, Xiao L, Chen W, Mernaugh RL, Cai H, Bernstein KE, Goronzy JJ, Weyand CM, Curci JA, Barbaro NR, Moreno H, Davies SS, Roberts LJ, Madhur MS, Harrison DG (2016) J Clin Invest 126(1): 50-67
    › Primary publication · 26595812 (PubMed) · PMC4701546 (PubMed Central)
  10. Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts. Guo L, Chen Z, Amarnath V, Yancey PG, Van Lenten BJ, Savage JR, Fazio S, Linton MF, Davies SS (2015) Antioxid Redox Signal 22(18): 1633-45
    › Primary publication · 25751734 (PubMed) · PMC4485367 (PubMed Central)
  11. DC isoketal-modified proteins activate T cells and promote hypertension. 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 (2014) J Clin Invest 124(10): 4642-56
    › Primary publication · 25244096 (PubMed) · PMC4220659 (PubMed Central)
  12. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. 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 (2014) J Clin Invest 124(8): 3391-406
    › Primary publication · 24960158 (PubMed) · PMC4109548 (PubMed Central)
  13. Identification of novel bioactive aldehyde-modified phosphatidylethanolamines formed by lipid peroxidation. Guo L, Chen Z, Amarnath V, Davies SS (2012) Free Radic Biol Med 53(6): 1226-38
    › Citation · 22898174 (PubMed) · PMC3461964 (PubMed Central)
  14. Bioactive aldehyde-modified phosphatidylethanolamines. Guo L, Davies SS (2013) Biochimie 95(1): 74-8
    › Citation · 22819995 (PubMed)
  15. Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent γ-Ketoaldehyde Scavenger, by LC/MS/MS. Zagol-Ikapitte IA, Matafonova E, Amarnath V, Bodine CL, Boutaud O, Tirona RG, Oates JA, Roberts LJ, Davies SS (2010) Pharmaceutics 2(1): 18-29
    › Citation · 21822464 (PubMed) · PMC3150493 (PubMed Central)
  16. Treatment with a γ-ketoaldehyde scavenger prevents working memory deficits in hApoE4 mice. Davies SS, Bodine C, Matafonova E, Pantazides BG, Bernoud-Hubac N, Harrison FE, Olson SJ, Montine TJ, Amarnath V, Roberts LJ (2011) J Alzheimers Dis 27(1): 49-59
    › Citation · 21709376 (PubMed) · PMC3289064 (PubMed Central)
  17. Oxidative stress in older adults: effects of physical fitness. Traustadóttir T, Davies SS, Su Y, Choi L, Brown-Borg HM, Roberts LJ, Harman SM (2012) Age (Dordr) 34(4): 969-82
    › Citation · 21671197 (PubMed) · PMC3682074 (PubMed Central)
  18. Phosphatidylethanolamines modified by γ-ketoaldehyde (γKA) induce endoplasmic reticulum stress and endothelial activation. Guo L, Chen Z, Cox BE, Amarnath V, Epand RF, Epand RM, Davies SS (2011) J Biol Chem 286(20): 18170-80
    › Citation · 21454544 (PubMed) · PMC3093889 (PubMed Central)
  19. A liquid chromatography-tandem mass spectrometry method for measurement of N-modified phosphatidylethanolamines. Guo L, Amarnath V, Davies SS (2010) Anal Biochem 405(2): 236-45
    › Citation · 20599652 (PubMed) · PMC2922460 (PubMed Central)
  20. Isoketals form cytotoxic phosphatidylethanolamine adducts in cells. Sullivan CB, Matafonova E, Roberts LJ, Amarnath V, Davies SS (2010) J Lipid Res 51(5): 999-1009
    › Citation · 19965577 (PubMed) · PMC2853468 (PubMed Central)
  21. Ischemia/reperfusion unveils impaired capacity of older adults to restrain oxidative insult. Davies SS, Traustadóttir T, Stock AA, Ye F, Shyr Y, Harman SM, Roberts LJ (2009) Free Radic Biol Med 47(7): 1014-8
    › Citation · 19596063 (PubMed) · PMC2748908 (PubMed Central)
  22. Potential role of isoketals formed via the isoprostane pathway of lipid peroxidation in ischemic arrhythmias. Boyden PA, Davies SS, Viswanathan PC, Amarnath V, Balser JR, Roberts LJ (2007) J Cardiovasc Pharmacol 50(5): 480-6
    › Citation · 18030056 (PubMed)
  23. Pyridoxamine analogues scavenge lipid-derived gamma-ketoaldehydes and protect against H2O2-mediated cytotoxicity. Davies SS, Brantley EJ, Voziyan PA, Amarnath V, Zagol-Ikapitte I, Boutaud O, Hudson BG, Oates JA, Roberts LJ (2006) Biochemistry 45(51): 15756-67
    › Citation · 17176098 (PubMed) · PMC2597444 (PubMed Central)
  24. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Fukuda K, Davies SS, Nakajima T, Ong BH, Kupershmidt S, Fessel J, Amarnath V, Anderson ME, Boyden PA, Viswanathan PC, Roberts LJ, Balser JR (2005) Circ Res 97(12): 1262-9
    › Citation · 16284182 (PubMed)
  25. Covalent binding of isoketals to ethanolamine phospholipids. Bernoud-Hubac N, Fay LB, Armarnath V, Guichardant M, Bacot S, Davies SS, Roberts LJ, Lagarde M (2004) Free Radic Biol Med 37(10): 1604-11
    › Citation · 15477011 (PubMed)
  26. Localization of isoketal adducts in vivo using a single-chain antibody. Davies SS, Talati M, Wang X, Mernaugh RL, Amarnath V, Fessel J, Meyrick BO, Sheller J, Roberts LJ (2004) Free Radic Biol Med 36(9): 1163-74
    › Citation · 15082070 (PubMed)