Pharmacology & Therapeutics 177 (2017) 44–55

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: B.J. Song

Advanced glycation end-products produced systemically and by

macrophages: A common contributor to inflammation and
degenerative diseases
Kyunghee Byun a,b,1, YongCheol Yoo c,1, Myeongjoo Son b, Jaesuk Lee a, Goo-Bo Jeong b, Young Mok Park c,⁎,1,
Ghasem Hosseini Salekdeh d,⁎⁎,1, Bonghee Lee a,b,⁎⁎⁎,1
a
Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea
b
Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon 406-799, Republic of Korea
c
Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 305-811, Republic of Korea
d
Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

a r t i c l e i n f o a b s t r a c t

Available online 13 February 2017 Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many in-
tractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degen-
Keywords: erative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated
Advanced glycation end products (AGEs) macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by
Receptor for AGEs (RAGE)
macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has
Macrophage
been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have result-
Inflammation
Degenerative diseases
ed in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs
have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases.
This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in as-
sociation with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition.
© 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: AD, Alzheimer's disease; ADMA, asymmetric dimethylarginine; AGEs, advanced glycation end products; AFLD, alcoholic fatty liver disease; ALI, acute lung injury; ALS,
amyotrophic lateral sclerosis; AMI, acute myocardial infarction; APP, acute phase protein; Aβ, amyloid beta; Bax, BCL2 associated X, apoptosis regulator; CaMKKβ, calcium/calmodulin-
dependent protein kinase kinase beta; CCL3, chemokine (C\ \C motif) ligand 3; CCL4, chemokine (C\ \C motif) ligand 4; CD36, cluster of differentiation 36; CKD, chronic kidney disease;
CMA, N(omega)-carboxymethylarginine; CML, N(6)-carboxymethyllysine; COPD, chronic obstructive pulmonary disease; CTGF, connective tissue growth factor; CVDs, cardiovascular
diseases; DAMPs, damage-associated molecular pattern molecules; DN, diabetic nephropathy; EGCG, epigallocatechin gallate; Egr-1, early growth response-1; ERK1/2, extracellular
signal-regulated kinase 1/2; FEEL-1, fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1; FEEL-2, fasciclin EGF-like, laminin-type EGF-like, and
link domain-containing scavenger receptor-2; HDL, high-density lipoprotein; HMGB1, high mobility group protein B1; HUVEC, human umbilical vein endothelial cell; IL-6, interleukin-
6; IL-10, interleukin-10; IL-1β, interleukin-1 beta; INF-γ, interferon gamma; IPF, idiopathic pulmonary fibrosis; JAK, janus kinase; JNK, c-Jun N-terminal kinase; Lox-1, lectin-like
oxidized low-density lipoprotein receptor 1; LPS, lipopolysaccharide; Mac-1, macrophage-1 antigen; MAPK, mitogen activated protein kinase; MCP-1, monocyte chemoattractant
protein-1; MMP, matrix metalloproteinase; MMP-13, matrix metalloproteinase 13; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; NO, nitric
oxide; NOS, nitric oxide synthases; OA, osteoarthritis; PAR, protease-activated receptor; PAR1, protease-activated receptor 1; PAR2, protease-activated receptor 2; PAR3, protease-
activated receptor 3; PAR4, protease-activated receptor 4; PD, Parkinson's disease; PDGF, platelet-derived growth factor; PG, prostaglandin; PGE2, prostaglandin E2; PPAR-α,
peroxisome proliferator activated receptor-alpha; PPAR-γ, peroxisome proliferator-activated receptor gamma; RA, rheumatoid arthritis; Rac2, ras-related C3 botulinum toxin substrate
2; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; S100A8, S100 calcium binding protein A8; S100A9, S100 calcium binding protein A9; S100A12,
S100 calcium binding protein A12; SAPK, stress-activated protein kinase; SCI, spinal cord injury; sRAGE, soluble RAGE; SR-BI, scavenger receptor class B type I; SR-BII, scavenger
receptor class B type II; STAT, signal transducer and activator of transcription; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of
transcription 3; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.
⁎ Correspondence to: Y.M. Park, Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34047, Republic of Korea.
⁎⁎ Correspondence to: G.H. Salekdeh, Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
⁎⁎⁎ Correspondence to: B. Lee, Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
E-mail addresses: ympark@kbsi.re.kr (Y.M. Park), Salekdeh@royaninstitute.org (G.H. Salekdeh), bhlee@gachon.ac.kr (B. Lee).
1
These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.pharmthera.2017.02.030
0163-7258/© 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55 45

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2. Advanced glycation end-products (AGEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3. Receptors for AGEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4. Mediators of macrophage activation and AGE formation . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
47
5. Development of therapeutics against AGEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
49
6. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
50
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
51
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

1. Introduction
Advanced glycation end products (AGEs) have long been considered
potent toxic molecules that promote host cell death and contributing to
organ damage in man. AGEs can induce the development or progression
of not only diabetic complications but the pathophysiologies of many
diseases, including cardiovascular diseases (CVDs) and neurodegenera-
tive diseases like Alzheimer's disease (AD), Parkinson's disease (PD),
and alcoholic brain damage (Bayarsaikhan et al., 2016; Byun et al.,
2012a, 2014; Simm et al., 2007; Srikanth et al., 2011; Yan et al., 2007).
AGEs bind with their receptor RAGE (receptor for advanced glycation
end products), which is highly expressed during host cell death through
reactive oxygen species (ROS) and strong activations of extracellular
signal-regulated kinase 1/2 (ERK1/2) ERK1/2 and nuclear factor kappa
B (NF-κB) pathways in many diseases. (Teismann et al., 2012; Wang
et al., 2013, 2014). Inhibition of AGEs from blood or activated macro-
phages had been well shown to decrease the pathogenesis of several
diseases and several agents have been developed to ameliorate their ad-
verse effects. Anti-inflammatory molecules that inhibit AGEs may be
good candidate treatments for diabetic complications and degenerative
diseases. In this review, we discuss the formation of AGEs and RAGE,
their association with the mononuclear phagocytic system in diseases,
the current therapeutic agents used and their adverse effects, and finally
we suggest a strategy for targeting macrophage AGEs and RAGE interac-
tion for possible drug target.
2. Advanced glycation end-products (AGEs)
AGEs are a heterogeneous group of irreversible products resulting
from nonenzymatic glycation and oxidation of proteins, nucleic acids,
and lipids (Goldin et al., 2006; Singh et al., 2001). Glycation produces
AGEs compounds with toxic properties associated with inflammation
and oxidative stress (Takeuchi & Yamagishi, 2004). AGEs accumulate
in the extra cellular matrix of various tissues and critically contribute
to chronic diseases (Bierhaus et al., 1998; Tessier et al., 1999). Further-
more, AGEs have been shown to become antigenic, and thus, to induce
immune responses (Ge et al., 2005; Kurien & Scofield, 2008). AGEs also
have adverse effects on cellular functions by cross-linking intracellular
and extracellular proteins, which trigger diverse diseases, such as arthri-
tis, neurological disorders, cancers, diabetes and cardiovascular disor-
ders, (Abe et al., 2004; Jono et al., 2002; Russo & Frangogiannis, 2016;
Ryan et al., 2014) (Fig. 1).
2.1. Intracellular formation and the toxic properties of AGEs
2.1.1. Formation of AGEs
AGEs are formed by glycation, which is a nonenzymatic reaction be-
tween ketones or aldehydes and the amino groups of various proteins
and contributes to protein aging (Gkogkolou & Böhm, 2012;
Ramasamy et al., 2012). Protein glycation occurs in both normal and hy-
perglycemic condition, and forms irreversible AGEs. This process begins
with the conversion of reversible Schiff base adducts to more stable, co-
valently-bound Amadori rearrangement products and finally the
Maillard reaction (Ansari & Dash, 2013; Ott et al., 2014). AGEs are also
formed in the absence of hyperglycemia by homeostatic imbalances,
such as redox imbalances (Limongi & Baldelli, 2016), aging
(Karumanchi et al., 2015), kidney disease (Arsov et al., 2014), or auto-
immune diseases (Nienhuis et al., 2009). In addition, AGEs are derived
from foods (e.g. milk, meat, coffee, cheese), especially those prepared
under high temperature conditions, stored for long periods, or with
food additives (Luevano-Contreras & Chapman-Novakofski, 2010).
2.1.2. Toxic properties of AGEs
Elevated levels of AGEs support the formations of reactive oxygen
and nitrogen species which in turn induce further AGEs formation.
AGEs induce oxidative stress by activating RAGE, which results in mito-
chondrial dysfunction (Lane et al., 2015; Ward et al., 2013). Under oxi-
dative stress, mitochondrial Ca2 + accumulation leads to a cell death
signal (Mahali et al., 2011), and AGEs excreted by activated macro-
phages also induce mitochondrial dysfunction and cell death. Extensive
studies have demonstrated that mitochondrial dysfunction is an impor-
tant factor in the pathogenesis of AD (Aliev et al., 2010), alcoholic fatty
liver disease (AFLD) (Song et al., 2014), diabetes (Rolo & Palmeira,
2006), and chondrocyte degeneration (Blanco et al., 2004) (Fig. 2).

3. Receptors for AGEs

Fig. 1. Association of advanced glycation end products (AGEs) and human diseases. AGEs
are related to disease incidence of several organs through common mechanism of
oxidative stress, neovascularization, inflammation or cross linking with extracellular
matrix (ECM).
AGEs can interact with two types of cell surface receptors. Scavenger
receptors are predominantly involved in AGEs capture, removal and
degradation. This group of receptors includes type I and type II macro-
phage scavenger receptors, cluster of differentiation 36 (CD36), fasciclin
EGF-like, laminin-type EGF-like, and link domain-containing scavenger
receptor-1 (FEEL-1) and fasciclin EGF-like, laminin-type EGF-like,
and link domain-containing scavenger receptor-2 (FEEL-2), scavenger
receptor class B type I (SR-BI) and scavenger receptor class B type II
46 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55

Fig. 2. AGEs from activated macrophage and its receptor mediated tissue injury via mitochondrial dysfunction. AGE is one of major five protein modification induced by ROS/RNS after
exposure to alcohol, high fat diet, tobacco, drugs or gene alterations. AGEs induce RAGE increase and mitochondrial dysfunction leading to tissue injury.

(SR-BII), and lectin-like oxidized low-density lipoprotein receptor 1
(Lox-1) (Miyazaki et al., 2002; Ott et al., 2014). The other type of AGEs
receptor, RAGE initiates specific cellular signaling events in response
to AGEs exposure. RAGE is a member of immunoglobulin (Ig) superfam-
ily, and binds multi-ligands like AGEs (Huttunen et al., 1999), high mo-
bility group protein B1 (HMGB1) (Dhumale et al., 2015), S100 (Donato,
2007), Aβ (Stern et al., 2002), amphoterin, and calgranulins, and then
activate several condition-dependent cellular pathways (Li et al.,
2004). RAGE is expressed in various tissues including brain, heart,
liver, lung, kidney, and cartilage and it plays an important role in disease
progression. Expression level of RAGE is minimal under normal condi-
tions but increases in disease states, such as AD, PD, alcoholic brain

Fig. 3. Cell specific ligands for Receptor for AGEs (RAGE) and their high-lighted signaling pathways in relevant diseases. AD; Alzheimer's disease, PD; Parkinson's disease, Alc; Alcoholic
brain damage, AMI; Acute myocardial infarction, LC; Liver cirrhosis, IPF; Idiopathic pulmonary fibrosis, DN; diabetic nephropathy, OA; osteoarthritis, F; fibrosis, I; inflammation, O;
oxidative stress, A; autophagy, D; degeneration, Cd; cell death.
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
damage, vascular disease, diabetes, acute myocardial infarction (AMI),
chronic kidney disease (CKD), hepatic fibrosis, chronic obstructive pul-
monary disease (COPD), and inflammatory disease, which may be the
result of cell damage caused by the overproductions of ROS, cytokines,
and pro-inflammatory molecules (Fig. 3, Supplementary Table 1).
3.1. Intracellular signaling pathway of RAGE in disease
AGEs dependent RAGE expression is well documented in many dis-
eases. The signaling pathways downstream of RAGE are similar and
eventually lead to mitochondrial dysfunction and cell death. The de-
tailed summary is provided below and in Fig. 3 and Supplementary
Table 1.
3.1.1. Relations between RAGE and neuronal death
RAGE is highly expressed on neurons during neurodegenerative pro-
cesses, such as AD, PD, stroke, alcoholic brain damage, and amyotrophic
lateral sclerosis (ALS). In the presence of inflammation, binding of AGEs
to RAGE strongly induces the activations of the NF-κB pathways
(Teismann et al., 2012; Wang et al., 2013, 2014). Furthermore, the inter-
action between AGE-albumin and RAGE induces neuronal cell death
through stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase
(JNK)/BCL2 associated X, apoptosis regulator (Bax) in AD (Byun et al.,
2012a) and the SAPK/JNK/p38 pathway in the alcoholic brain damage
(Byun et al., 2014). Furthermore, increased HMGB1 binding with
RAGE can cause neuronal cell death through NF-κB activation in stroke
and AD (Bortolotto & Grilli, 2016; Wang et al., 2010). S100 protein in-
duces neuronal cell death through the NF-κB/tumor necrosis factor
alpha (TNF-α) pathway in PD (Abdelsalam & Safar, 2015; Sathe et al.,
2012), and in AD, binding of Aβ to RAGE also leads to neurodegenera-
tion and neuronal cell death through p21ras, ERK1/2, p38, SAPK/JNK,
phosphoinositol-3 kinase, and the janus kinase (JAK)/signal transducer
and activator of transcription (STAT) pathway (Origlia et al., 2010; Son
et al., 2012).
3.1.2. Cardiomyocytes and RAGE
RAGE expression of cardiomyocytes is increased in acute myocardial
infarction by AGEs, HMGB1 and S100, and these proteins induce cell
death via activation of the MAPK pathway (Aleshin et al., 2008;
Andrassy et al., 2008; Tsoporis et al., 2010).
3.1.3. Hepatocytes and RAGE
Binding of AGEs to RAGE strongly induces the phosphorylation of
uncoupling protein-2 (UCP-2) and ATP synthesis (Kuhla et al., 2011).
HMGB1 released from damaged hepatocyte after injury interacts with
RAGE and leads to hepatic fibrosis by activating SMAD2 and phosphor-
ylating ERK1/2 (Kao et al., 2014) or JNK/ERK1/2 during early growth re-
sponse-1 (Egr-1) (Zeng et al., 2009).
3.1.4. Alveolar epithelial cells and RAGE
The RAGE binding with AGEs and HMGB1 has been well described in
idiopathic pulmonary fibrosis (IPF). Binding of AGEs and RAGE inhibits
TGF-β induced ERK1/2 and SMAD phosphorylation (Song et al., 2011)
and up-regulates Egr-1, which also activates RAGE transcription in
COPD (Reynolds et al., 2008b). In addition, the interaction between
HMGB1 and RAGE leads to alveolar disruption and fibrosis due to the ac-
tivation of TGF-β via the productions of platelet-derived growth factor
(PDGF) in IPF (He et al., 2007).
3.1.5. Renal tubular epithelial cells and RAGE
Interaction between AGEs and RAGE stimulates oxidative stress and
promotes diabetic nephropathy (DN) progression. Importantly, AGE-
RAGE acts to the mitogen activated protein kinase (MAPK)/NF-κB and
protein kinase C signaling pathway (Yamagishi & Matsui, 2010) or pro-
mote to connective tissue growth factor (CTGF) and TGF-β during in-
flammation and fibrotic process (Cheng et al., 2015a). Up-regulation
47
of HMGB1 binding to RAGE provokes inflammatory reactions via
ERK1/2-NF-kB signaling, which turn on transcription of TNF-α, interleu-
kin-6 (IL-6), chemokine (C\\C motif) ligand 3 (CCL3), chemokine (C\\C
motif) ligand 4 (CCL4) and C-X-C motif chemokine 12 (CXCL12) in DN
and enhances asymmetric dimethylarginine (ADMA) in CKD
(Nakamura et al., 2009).
3.1.6. Chondrocytes and RAGE
The binding AGEs to RAGE activate the JNK/p38, peroxisome
proliferator-activated receptors alpha (PPAR-α), and NF-κB signaling
pathway and these signaling pathways associated with inflammatory
and oxidative responses in osteoarthritis (OA). Furthermore, high levels
of HMGB1 have been reported in the synovial fluid of arthritis patients
(Kokkola et al., 2002), and the interaction between HMGB1 and RAGE
induces the expressions of TNF-α and interleukin 1 beta (IL-1β) on
chondrocytes (Terada et al., 2011). Furthermore, when the expression
of S100 calcium binding protein A12 (S100A12) and A4 (S100A4) is in-
creased and it stimulates inflammation and degeneration via the RAGE
mediated MAPK, NF-κB and MMP-13/vascular endothelial growth fac-
tor (VEGF)/p38 and NF-κB signaling pathway in OA (Nakashima et al.,
2012; Yammani et al., 2009).
4. Mediators of macrophage activation and AGE formation
The macrophages originate from bone marrow and then migrate and
circulate in different tissues, such as the brain, liver, heart, kidney, and
cartilage (Kraft & Harry, 2011; Varol et al., 2015). Activated macro-
phages often induce inflammatory degeneration of host cells or dys-
function in AD, PD, stroke, vascular disease, and inflammatory
diseases. Macrophages are activated by exposure to various stimuli,
such as cytokines, proteases, prostaglandins (PGs), nitric oxide (NO),
free radicals or RAGE ligands, including Aβ, AGEs, HMGB1 and lipopoly-
saccharide (LPS), under pro- and inflammatory conditions (Fig. 4).
4.1. Cytokines
Cytokines are involved in systemic inflammation and degenerative
diseases. They can be released by neurons, cardiomyocytes, hepato-
cytes, alveolar epithelial cells, neutrophils, eosinophils, or mast cells at
various levels when cells are stimulated or in the presence of disease
conditions. These cytokines such as α-synuclein (Kim & Joh, 2006),
Chromogranin A (Heneka et al., 2010, and Interferon gamma (INF-γ)
(Gensel & Zhang, 2015) were well reported as activating macrophages
under disease conditions.
4.2. Proteases
Serine proteases cleave their receptors to modulate important bio-
logical processes including host defense, chemotaxis, cytokine and
growth factor release, vascular function, tissue repair, apoptosis, inflam-
mation and immune response (Steinhoff et al., 2005). Protease-activat-
ed receptors (PARs) compose a subfamily of G protein-coupled
receptors with seven transmembrane receptors that couple to guano-
sine-nucleotide-binding proteins (Brass & Molino, 1997). The PAR fam-
ily has four members, namely, protease-activated receptor 1 (PAR1),
protease-activated receptor 2 (PAR2), protease-activated receptor 3
(PAR3), and protease-activated receptor 4 (PAR4), and of these, PAR2
can modulate the activities of various cells, including epithelial cells,
smooth muscle cells, endothelial cells, and macrophages in a variety of
tissues (Nystedt et al., 1996; Steinhoff et al., 2005).
4.3. Prostaglandins (PGs)
PGs act as critical regulators during the initiation of inflammatory
processes. PG expressions are significantly increased in infected tissues,
and contribute to the development of the principal signs of the acute
48 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55

Fig. 4. Activators of macrophages and secreted proteins from activated macrophages. RAGE ligands also induce activation of macrophages and they are secreted from activated
macrophages. AGEs; advanced glycation end products, HMGB1; high-mobility group protein B1, Mac-1; macrophage-1 antigen, LPS; lipopolysaccharide, Aβ; amyloid beta, IL-10;
interleukin-10, NO; nitric oxide, ROS; reactive oxygen species.

inflammatory phase (Ricciotti & FitzGerald, 2011). Prostaglandin E2 4.6. RAGE ligands
(PGE2) is one of the most abundant PGs and exhibits variable biological
activities, which include the regulations of blood pressure, gastrointes- RAGE ligands including Aβ, AGEs, HMGB1, LPS, macrophage-1 anti-
tinal integrity, and immune response (Legler et al., 2010). gen (Mac-1), phosphatidylserine and S100 also modulate important bi-
ological processes required for macrophage activation (Chavakis et al.,
2004; He et al., 2011; Hofmann et al., 1999; Schmidt et al., 2001). The
4.4. Acute phase proteins (APPs) various types of RAGE ligands that induce macrophage activation in de-
generative diseases are summarized in Table 1. Aβ is cleaved from am-
APPs response to inflammation may be an increase (positive acute- yloid precursor protein and is the main cause of AD, a major component
phase proteins, APPs) or decrease (negative APPs) in plasma concentra- of amyloid plaque (Fang et al., 2010). Nuclear HMGB1 regulates pro-in-
tion (Gruys, Toussaint, Niewold, & Koopmans, 2005). Positive APPs are flammatory factors, and HMGB1 can be released by neurons in the dam-
involved in different physiological functions in the immune system. aged brain (Fang et al., 2010). HMGB1 up-regulation leads to microglial
For example, haptoglobin acts to inhibit or prevent microbe growth activation in many diseases including alcoholic brain damage (Crews &
and alpha 2 macroglobulin and serpins provide negative feedback on Vetreno, 2014, 2016), stroke (Liesz et al., 2015; Xiong et al., 2016), spi-
the inflammatory processes (Jain, Gautam, & Naseem, 2011). nal cord injury (SCI) (Kikuchi et al., 2011), AMI (Herzog et al., 2014) and
Some of these proteins act to inhibit or prevent microbe growth, acute lung injury (ALI) (Deng et al., 2013). LPS can stimulate macro-
while others modulate negative feedback from inflammatory processes phages and monocytes to secrete various inflammatory mediators, in-
which include albumin, transferrin, transthyretin, transcortin, retinol- cluding IL-6 (Hirohashi & Morrison, 1996). LPS also induces
binding protein and anti-thrombin (Gruys et al., 2005; Ritchie et al., macrophage activation in SCI (Xie et al., 2004), hypertension (Hernanz
1999). et al., 2004), ALI (Zhu et al., 2013), liver cirrhosis (Jirillo et al., 2002),
IPF (Freeburn et al., 2005), and COPD (Miles et al., 1999). S100 members
4.5. Nitric oxide and free radicals also activate macrophages, and are also secreted by activated macro-
phages (Donato, 1999).
4.5.1. Nitric oxide (NO)
NO is a free radical and an important cellular signaling mediator re-
Table 1
lated to various pathological and physiological processes, including the
RAGE ligands that activate macrophages under inflammatory conditions and in degener-
modulation of blood pressure, neurotransmission, and of macrophage ative diseases.
cytotoxicity. NO is synthesized by nitric oxide synthase (NOS) from ox-
Cytokine Disease Reference
ygen and NADPH as cofactor of NOS (Mayer et al., 1990). NO is well
known as endogenous mediator during vasodilator inflammatory pro- HMGB1 Alcoholic brain damage Crews and Vetreno (2014)
cesses (Wallace, 2005). Crews and Vetreno (2016)
Spinal cord injury Kikuchi et al. (2011)
Stroke Liesz et al. (2015)
Xiong, Liu, and Yang (2016)
4.5.2. Oxidative stress Acute myocardial injury Herzog et al. (2014)
In oxidative stress, greater amounts of oxygen free radicals are found S100A8/9 Osteoarthritis van Lent et al. (2012)
under disease states or after exposure to toxic agents and are increased Aβ Alzheimer's disease Fang et al. (2010)
by environmental stresses such as UV or heat. Oxidative stress elevates LPS Spinal cord injury Xie, Smith, and Van Eldik (2004)
Hypertension Hernanz, Briones, Alonso, Vila, and
the expressions of inflammatory mediators, which induce macrophage
Salaices (2004)
activation in the presence of inflammation (Macdonald, Galley, & Liver cirrhosis Jirillo et al. (2002)
Webster, 2003), AMI (Di Filippo, Cuzzocrea, Rossi, Marfella, & Chronic obstructive Miles, Bowman, Rao, Baatz, and
D'Amico, 2006), COPD (Rahman, 2005), OA (Ziskoven et al., 2010) and pulmonary disease Huffman (1999)
neurodegenerative disease, such as AD (Zhu et al., 2004), and PD Idiopathic pulmonary fibrosis Freeburn, Armstrong, and Millar (2005)
Acute lung injury Zhu et al. (2013)
(Dias, Junn, & Mouradian, 2013).
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
4.7. Proteomic analysis of activated macrophages
To further understand the molecular mechanism responsible for
macrophage activation, proteomic studies have been recently conduct-
ed in a variety of disease models, including neurodegenerative disease
(Ma et al., 2013; Reynolds et al., 2008a; Yoo et al., 2015; Zhou et al.,
2005), acute lung injury/acute respiratory distress syndrome (Dong et
al., 2013), kidney stone disease (Singhto et al., 2013), metabolic diseases
(Freiwald et al., 2013; Kratz et al., 2014), cancer (Kobayashi et al., 2009;
Zhu et al., 2015), atherosclerosis (Burillo et al., 2009; Kang et al., 2006),
and virus infections (Lietzén et al., 2011; Miettinen et al., 2012). The
proteins secreted by activated macrophages are being actively investi-
gated in terms of their abilities to damage or protect tissues.
4.7.1. Secretome analysis of activated macrophages
The most dramatically inducible proteins secreted by activated mac-
rophages are inflammatory molecules, such as cytokines and
chemokines. Among cytokines, surprisingly, various types of RAGE li-
gands, such as AGEs (most abundantly in albumin), HMGB1 and S100
proteins, are secreted by activated macrophages. HMGB1 and S100 pro-
tein are damage-associated molecular pattern molecules (DAMPs) that
are released by damaged and stressed cells. DAMPs, which are also
called alarmins or danger signals, are host-derived endogenous mole-
cules that can trigger immune response, and are recognized by DAMP
receptors, which include RAGE (Saïd-Sadier & Ojcius, 2012).
HMGB1 can be released from necrotic or damaged cells or by activat-
ed immune cells, and regulates endothelial cell activation, cell migra-
tion, inflammation, proliferation, and differentiation (Bertheloot &
Latz, 2016; Saïd-Sadier & Ojcius, 2012). In post-ischemic brains,
HMGB1 was found to be induced in and secreted by activated microglia
(Kim et al., 2008; Kim et al., 2012; Shin et al., 2014). Interestingly, the
release and translocation of HMGB1 in macrophages were observed to
be inhibited by various molecules that can reduce inflammation and
mortality in sepsis models (Cheng et al., 2015b; Elfeky et al., 2016;
Hagiwara et al., 2009; Kim et al., 2015; Ye et al., 2012; Zhang et al.,
2014; Zhou et al., 2014). HMGB1 secretion was also significantly in-
creased by macrophages in the presence of chronic inflammation dis-
eases and in models of atherosclerosis (Kalinina et al., 2004), COPD
(Mortaz et al., 2015), rheumatoid arthritis (RA) (Zetterström et al.,
2008), and renal tubule-interstitial fibrosis (Tian et al., 2015). The
S100 protein family is composed of approximately 25 proteins (Gross
et al., 2014), and among them, S100A8 and S100 calcium binding pro-
tein A9 (S100A9) are often found abundantly in macrophages (Farris
et al., 2011; McCormick et al., 2005; Rammes et al., 1997; Xu & Geczy,
2000; Xu, Yen, & Geczy, 2001). These two proteins are also released by
activated macrophages in patients with inflammatory muscle diseases,
and induced myoblast apoptosis via caspase 3 activation (Seeliger et
al., 2003).
4.7.2. Albumin and AGE-albumin synthesis in macrophages
The liver is known as responsible for production of albumin in body,
however there are also reports of non-hepatic origins. These include
pancreas, kidney (Nahon et al., 1988), skeletal muscle (Kobayashi &
Tashima, 1990; Müller & Heizmann, 1982), thyroid gland (De Vijlder
et al., 1992). Activated macrophages are also known as alternate source
which include microglial cells in AD (Byun et al., 2012a; 2012b), Alco-
holic brain damages (Byun et al., 2014) and PD (Bayarsaikhan et al.,
2016).
Macrophage activation leads to the release RAGE ligands, including
AGEs, HMGB1, amyloid beta (Aβ) and pro-inflammatory cytokines,
which at elevated levels damage host cells. These ligands are released
during inflammation or injury and this leads to the up-regulation of
RAGE on host cells such as neurons (Borsi et al., 2012). Binding of
AGEs to RAGE releases IL-β and TNF-α in AD (Fang et al., 2010), and
in PD regulates the expressions of pro-inflammatory cytokines and acti-
vates of MAPK, NF-κB, and IFN-γ (Kim & Joh, 2006). Furthermore in AD,
49
Aβ interacts with AGEs and induces microglial activation and neuroin-
flammation via ERK1/2 and NF-κB activation (Lv et al., 2014). Several
authors have demonstrated AGEs accumulation in the brains of patients
with AD (Ahn et al., 2008) or alcoholic brain damage (Byun et al., 2014).
In addition, Aβ stimulated human microglial cells significantly synthe-
size and release more albumin (Ahn et al., 2008), and abundant quanti-
ties of AGE-albumin, a new RAGE ligand (Byun et al., 2012a). Aβ plaques
are co-localized with AGE-albumin in Aβ1-42 injected rat and human
AD brain (Byun et al., 2012b) and the AGE-albumin induces calcium in-
flux via up-regulation of RAGE, and this leads to neuronal death in AD
(Byun et al., 2012a). Furthermore, alcohol-stimulated microglial cells
also exhibit much increased synthesis and release of AGE-albumin and
induce neuronal cell death (Byun et al., 2014).
5. Development of therapeutics against AGEs
Developmental efforts have resulted in many agents that reduce the
damage induced by AGEs. These agents can be summarized as AGEs in-
hibitors and breakers, angiotensin II receptor antagonists and angioten-
sin converting enzyme inhibitors, antioxidants, natural substances, and
anti-inflammatory molecules (Table 2).
5.1. AGEs inhibitors & breakers
AGEs inhibitors that prevent AGEs formation and AGEs cross-link
breakers were identified as initial efforts. Aminoguanidine was the
first AGEs inhibitor found to inhibit the formation of AGEs, and was
also reported to effectively reduce the pathologic effects of the nephrop-
athy and vascular complications associated with AGEs in diabetes
(Bolton et al., 2004; Brownlee et al., 1986; Freedman et al., 1999). Sev-
eral AGEs cross-link breakers have also been reported to effectively re-
duce AGEs products and proposed as possible therapeutics for the
treatment of diabetic vascular complications. Alagebrium and related
compounds including ALT-711, ALT-462, ALT-486, and ALT-946 appar-
ently break some existing AGEs cross-links (Krautwald et al., 2011).
ALT 711 was initially reported to effectively reduce the severity of
AGE-induced pathological lesions (Vasan et al., 2001). Another AGEs-
breaker, TRC4186, was reported to inhibit AGEs formation or break
AGEs cross-links and to ameliorate diabetes-related cardiomyopathy
and nephropathy (Joshi et al., 2009).
5.2. Angiotensin II receptor antagonist and angiotensin converting enzyme
inhibitor
Telmisartan, an anti-hypertension drug and angiotensin II receptor
blocker, was found to decrease AGEs formation. For example, a clinical
study demonstrated that telmisartan decreased RAGE expression by ac-
tivating PPAR-γ in liver (Yoshida et al., 2006). In addition, pyridoxamine
has been reported as preventing the Amadori reaction leading to AGEs
formation (Adrover et al., 2008; Thomas et al., 2005).
5.3. Antioxidants
Antioxidants have been developed to inhibit AGEs. Statins, which
have antioxidant activity, are commonly used to lower blood cholester-
ol levels. The antioxidant effect of statins was found to inhibit reactive
protein C release effectively from toxic AGEs, and thus, to prevent diabe-
tes-associated vascular complications (Ajith et al., 2006, 2008; Takeuchi
et al., 2010). Atorvastatin was introduced as means of decreasing serum
AGEs levels in patients with type 2 diabetes in a soluble RAGE (sRAGE)
and a splice variant of sRAGE dependent manner (Jinnouchi et al., 2006;
Tam et al., 2010). Other study supported the notion that atorvastatin re-
stored reduced glutathione levels, inhibited RAGE up-regulation, and
down-regulated the expression of RAGE and MCP-1 (Feng et al.,
2011). Recently, a RAGE antagonist from the part of human serum albu-
min was found to reduce the increased NF-κB signaling by anti-
50 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55

inflammatory mechanism (Maltais et al., 2016). Ascorbic acid, alpha- peptide-1 receptor agonist exendin, and NF-κB inhibitor-pyrrolidine di-
lipoic acid, carnosine, and quercetin have been shown to inhibit AGEs thiocarbamate were also showed to provide strong in vitro protection
effectively (Abdul & Butterfield, 2007; Ashraf et al., 2015; Bierhaus et against AGEs-induced neuronal apoptosis by reducing the overexpres-
al., 1997; Guiotto et al., 2005; Zafar, 2012). Recently the glucagon-like sion of RAGE (Chen et al., 2016).

5.4. Natural substances

Table 2
Therapeutic agent for AGEs and RAGE related pathology in disease.
Category
AGEs inhibitor
AGEs cross link breaker
Angiotensin II receptor
antagonist and angiotensin
converting enzyme
inhibitor
Antioxidant
Natural substance
Anti-inflammatory molecules
Name Reference
Aminoguanidine Brownlee, Vlassara,
Kooney, Ulrich, and
Cerami (1986)
Freedman et al.
(1999)
Bolton et al. (2004)
Alagebrium and related Vasan, Foiles, and
compounds (ALT-711, Founds (2001)
ALT-462, ALT-486, ALT- Krautwald et al.
(2011)
TRC4186 Joshi et al. (2009)
Telmisartan Yoshida et al. (2006)
Pyridoxamine Thomas et al. (2005)
Adrover, Vilanova,
Frau, Muñoz, and
Donoso (2008)
Statins Ajith, Harikumar,
Thasna, Sabu, and
Babitha (2006)
Ajith, Riji, and Anu
(2008)
Takeuchi, Takino, and
Yamagishi (2010)
Atorvastatin Jinnouchi et al. (2006)
Tam et al. (2010)
Feng et al. (2011)
RAGE antagonist Maltais et al. (2016)
Ascorbic acid Zafar (2012)
Alpha-lipoic acid Bierhaus et al. (1997)
Abdul and Butterfield
(2007)
Carnosine Abdul and Butterfield
(2007)
Quercetin Ashraf et al. (2015)
Dhumale et al.
(2015)
Exendin Chen et al. (2016)
Pyrrolidine Chen et al. (2016)
dithiocarbamate
Resveratrol Mizutani, Ikeda, and
Yamori (2000)
Curcumin Tang (2014)
Prenylflavonoids Nakashima et al.
(2016)
p-Cymene Joglekar, Panaskar,
and Arvindekar
(2014)
Chebulic acid of Terminalia Lee, Oh, Kim, and Lee
chebula, (2014)
Sulphoraphene Matsui, Nakamura,
Ojima, Nishino, and
Yamagishi (2016)
Vitamin D Salum et al. (2013)
Gymnema Sugihara et al. (2000)
Metformin Matsuki et al. (2009)
Epigallocatechin Gallate Lee and Lee (2007)
S-allylcysteine Ahmad and Ahmed
(2006)
Ramipril Gosse and
Schumacher (2014)
LR-90 Figarola,
Shanmugam,
Natarajan, and
Rahbar (2007)
Bisphosphonates Takeuchi et al. (2010)
Minodronate Yamagishi,
Nakamura, Matsui,
and Takeuchi (2006)
Studies have shown that some natural substances, such as resvera-
trol and curcumin, can prevent AGEs-induced pathology (Mizutani et
al., 2000). Resveratrol inhibited the AGE-induced proliferation of colla-
gen in smooth muscle cells of blood vessels (Mizutani et al., 2000),
and curcumin blocked the effect of AGEs on the RAGE expression
(Tang, 2014). Recently, new prenylflavonoids were reported to inhibit
the formations of N(6)-carboxymethyllysine (CML) and N(omega)-
carboxymethylarginine (CMA) in the methanol extract of the aerial por-
tions of Epimedii Herba (Nakashima et al., 2016). Similarly, p-cymene, a
monoterpene was demonstrated to act as AGEs breakers for AGEs cross-
linking (Joglekar et al., 2014; Lee et al., 2014). Recently, sulphoraphene
was demonstrated to inhibit inflammation in AGEs-exposed human
umbilical vein endothelial cells (HUVECs) and AGEs-infused rat aorta
partly by suppressing RAGE expression (Matsui et al., 2016). Vitamin
D also reported as reducing the risk of CVDs. AGEs, such as CML, have
been implicated in diabetic vascular complications via oxidative
stress-mediated pathways (Salum et al., 2013). Gymnema also reported
to contribute to the anti-hyperglycemic effects (Sugihara et al., 2000),
and metformin has been reported to restore glycated high-density lipo-
protein (HDL)-mediated cholesterol efflux (Matsuki et al., 2009). Epi-
gallocatechin gallate (EGCG), a major component of green tea
polyphenols, showed protective effects against AGEs-induced dam-
age in neuron cells (Lee & Lee, 2007), and S-allyl cysteine from
aged garlic has been reported to act as a potent antioxidant and in-
hibit AGEs protein formation (Ahmad & Ahmed, 2006). Ramipril
has also been reported to be an efficient AGEs inhibitor as well
(Gosse & Schumacher, 2014).
5.5. Anti-inflammatory molecules and AGEs inhibitors that act on activated
macrophages
Anti-inflammatory molecules have also been found to reduce
the toxic effects of AGEs. In particular, LR-90 had been shown to in-
hibit the NF-κB activation, which stimulates the gene expressions of
proinflammatory molecules in human monocytes (Figarola et al.,
2007).
Bisphosphonates were found to inhibit toxic AGEs-mediated inflam-
mation and finally stopped ROS formation during the pathogeneses of
the vascular complications of diabetes (Takeuchi et al., 2010). Similarly,
another nitrogen-containing bisphosphonate, minodronate, inhibited
signaling pathways initiated by the interaction between AGEs and
RAGE in diabetic retinopathy (Yamagishi et al., 2006). It appears that in-
hibitors of AGEs with anti-inflammatory effects can deactivate macro-
phages and reduce tissue damage as well.
Because most known therapeutic reagents used to treat diabetes
target AGEs in blood, AGEs inhibition in activated macrophages lo-
cated in tissues has been investigated as a novel targeting strategy.
The sRAGE-based masking of secreted AGEs has shown strong potent
therapeutic effects in several diseases, such as AD, PD, alcoholic brain
damage, and AMI (Bayarsaikhan et al., 2016; Byun et al., 2012a;
2014) (Fig. 5). Since sRAGE is the extracellular part of RAGE, it can
bind to AGEs, and thus, prevent their adverse effects. Targeting
AGEs in activated macrophage probably could be one of the most
ideal strategies for AGEs related diseases.
6. Conclusion and future perspectives
The role played by the AGEs-RAGE interaction in the aggravation
of the chronic complications of diabetes, CVDs, and degenerative
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
Fig. 5. A proposed model of AGE albumin from activated macrophage and its relevancy to cell death in various tissues.
diseases has been well established. The interaction between AGEs
and RAGE on the plasma membrane triggers the downstream signal-
ing of inflammation, oxidative stress, and apoptosis in many cells, in-
cluding neurons, endothelial cells, lung cells and muscle cells.
Therapeutic agent development has focused mainly on suppressing
AGEs or RAGE formation or preventing the AGEs-RAGE interaction.
Although agents have been devised to prevent AGEs formation and
activity, most are under in the early phase of clinical studies. Similar-
ly, studies on natural substances like resveratrol and curcumin have
been described to inhibit RAGE-associated vascular damage and the
long-term complications of diabetes. Furthermore, sRAGE and its
variants can inhibit the interaction between AGEs and RAGE effec-
tively and have also been suggested to be promising therapeutic
agents.
Recently, it was found that activated macrophages are one of prima-
ry contributors to AGE-albumin accumulation in tissues, and suggested
that AGE-albumin is a potentially useful therapeutic and diagnostic bio-
marker with high sensitivity and resolution. In addition, labeling and vi-
sualizing accumulated AGE-albumin with proper antibodies may
provide a near ideal theragnostic means to combat AGEs/RAGE associat-
ed diseases.
In conclusion, more studies are required to determine how to pre-
vent, remove, and estimate the AGEs/RAGE interaction in relation to
macrophage activation and to elucidate its pathophysiologic mecha-
nism in many intractable diseases.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.pharmthera.2017.02.030.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
51
Acknowledgments
This work was supported by the Korean Health Technology R&D Pro-
ject through the Korean Health Industry Development Institute (KHIDI),
funded by the Ministry of Health & Welfare, Republic of Korea (Lee, B.,
grant no. HI13C2098), and by the National Research Foundation of Ko-
rea (Byun, K., grant no. 2015R1A2A2A01005212).
References
Abdelsalam, R. M., & Safar, M. M. (2015). Safar neuroprotective effects of vildagliptin in rat
rotenone Parkinson's disease model: Role of RAGE-NFκB and Nrf2-antioxidant signal-
ing pathways. Journal of Neurochemistry 133, 700–707.
Abdul, H. M., & Butterfield, D. A. (2007). Involvement of PI3K/PKG/ERK1/2 signaling path-
ways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine
and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Im-
plications for Alzheimer's disease. Free Radical Biology & Medicine 42, 371–384.
Abe, R., Shimizu, T., Sugawara, H., Watanabe, H., Nakamura, H., Choei, H., et al. (2004).
Regulation of human melanoma growth and metastasis by AGE-AGE receptor inter-
actions. The Journal of Investigative Dermatology 122, 461–467.
Adrover, M., Vilanova, B., Frau, J., Muñoz, F., & Donoso, J. (2008). The pyridoxamine action
on Amadori compounds: A reexamination of its scavenging capacity and chelating ef-
fect. Bioorganic & Medicinal Chemistry 16, 5557–5569.
Ahmad, M. S., & Ahmed, N. (2006). Antiglycation properties of aged garlic extract: Possi-
ble role in prevention of diabetic complications. The Journal of Nutrition 136,
796S–799S.
Ahn, S. M., Byun, K., Cho, K., Kim, J. Y., Yoo, J. S., Kim, D., et al. (2008). Human microglial
cells synthesize albumin in brain. PloS One 3, e2829.
Ajith, T. A., Harikumar, K. B., Thasna, H., Sabu, M. C., & Babitha, N. V. (2006). Proapoptotic
and antitumor activities of the HMG-CoA reductase inhibitor, lovastatin, against
Dalton's lymphoma ascites tumor in mice. Clinica Chimica Acta 366, 322–328.
Ajith, T. A., Riji, T., & Anu, V. (2008). In vitro anti-oxidant and DNA protective effects of the
novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin.
Clinical and Experimental Pharmacology & Physiology 35, 625–629.
Aleshin, A., Ananthakrishnan, R., Li, Q., Rosario, R., Lu, Y., Qu, W., et al. (2008). RAGE mod-
ulates myocardial injury consequent to LAD infarction via impact on JNK and STAT
signaling in a murine model. American Journal of Physiology. Heart and Circulatory
Physiology 294, H1823–H1832.
52 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
Aliev, G., Palacios, H. H., Gasimov, E., Obrenovich, M. E., Morales, L., Leszek, J., et al. (2010).
Oxidative stress induced mitochondrial failure and vascular hypoperfusion as a key
initiator for the development of Alzheimer disease. Pharmaceuticals (Basel) 3,
158–187.
Andrassy, M., Volz, H. C., Igwe, J. C., Funke, B., Eichberger, S. N., Kaya, Z., et al. (2008). High-
mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 117,
3216–3226.
Ansari, N. A., & Dash, D. (2013). Amadori glycated proteins: Role in production of autoan-
tibodies in diabetes mellitus and effect of inhibitors on non-enzymatic glycation.
Aging and Disease 4, 50–56.
Arsov, S., Graaff, R., van Oeveren, W., Stegmayr, B., Sikole, A., Rakhorst, G., et al. (2014).
Advanced glycation end-products and skin autofluorescence in end-stage renal dis-
ease: A review. Clinical Chemistry and Laboratory Medicine 52, 11–20.
Ashraf, J. M., Shahab, U., Tabrez, S., Lee, E. J., Choi, I., & Ahmad, S. (2015). Quercetin as a
finer substitute to aminoguanidine in the inhibition of glycation products.
International Journal of Biological Macromolecules 77, 188–192.
Bayarsaikhan, E., Bayarsaikhan, D., Lee, J., Son, M., Oh, S., Moon, J., et al. (2016). Microglial
AGE-albumin is critical for neuronal death in Parkinson's disease: A possible implica-
tion for theranostics. International Journal of Nanomedicine 23(Spec Iss), 281–292.
Bertheloot, D., & Latz, E. (2016). HMGB1, IL-1α, IL-33 and S100 proteins: Dual-function
alarmins. Cellular & Molecular Immunology 13, 1–22.
Bierhaus, A., Chevion, S., Chevion, M., Hofmann, M., Quehenberger, P., Illmer, T., et al.
(1997). Advanced glycation end product-induced activation of NF-κB is suppressed
by α-lipoic acid in cultured endothelial cells. Diabetes 46, 1481–1490.
Bierhaus, A., Hofmann, M. A., Ziegler, R., & Nawroth, P. P. (1998). AGEs and their interac-
tion with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept.
Cardiovascular Research 37, 586–600.
Blanco, F. J., López-Armada, M. J., & Maneiro, E. (2004). Mitochondrial dysfunction in os-
teoarthritis. Mitochondrion 4, 715–728.
Bolton, W. K., Cattran, D. C., Williams, M. E., Adler, S. G., Appel, G. B., Cartwright, K., et al.
(2004). Randomized trial of an inhibitor of formation of advanced glycation end
products in diabetic nephropathy. American Journal of Nephrology 24, 32–40.
Borsi, V., Cerofolini, L., Fragai, M., & Luchinat, C. (2012). NMR characterization of the C-ter-
minal tail of full-length RAGE in a membrane mimicking environment. Journal of
Biomolecular NMR 54, 285–290.
Bortolotto, V., & Grilli, M. (2016). Every cloud has a silver lining: Proneurogenic effects of
Aβ oligomers and HMGB-1 via activation of the RAGE-NF-κB axis. CNS & Neurological
Disorders Drug Targets 15, 1–14.
Brass, L. F., & Molino, M. (1997). Protease-activated G protein-coupled receptors on
human platelets and endothelial cells. Thrombosis and Haemostasis 78, 234–241.
Brownlee, M., Vlassara, H., Kooney, A., Ulrich, P., & Cerami, A. (1986). Aminoguanidine
prevents diabetes-induced arterial wall protein cross-linking. Science 232,
1629–1632.
Burillo, E., Recalde, D., Jarauta, E., Fiddyment, S., Garcia-Otin, A. L., Mateo-Gallego, R., et al.
(2009). Proteomic study of macrophages exposed to oxLDL identifies a CAPG poly-
morphism associated with carotid atherosclerosis. Atherosclerosis 207, 32–37.
Byun, K., Bayarsaikhan, E., Kim, D., Kim, C. Y., Mook-Jung, I., Paek, S. H., et al. (2012a). In-
duction of neuronal death by microglial AGE-albumin: Implications for Alzheimer's
disease. PloS One 7, e37917.
Byun, K., Bayarsaikhan, E., Kim, D., Son, M., Hong, J., Jeong, G. B., et al. (2012b). Activated
microglial cells synthesize and secrete AGE-albumin. Anatomy and Cell Biology 45,
47–52.
Byun, K., Bayarsaikhan, D., Bayarsaikhan, E., Son, M., Oh, S., Lee, J., et al. (2014). Microglial
AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and
humans. PloS One 9, e104699.
Chavakis, T., Bierhaus, A., & Nawroth, P. P. (2004). RAGE (receptor for advanced glycation
end products): A central player in the inflammatory response. Microbes and Infection
6, 1219–1225.
Chen, S., Yin, L., Xu, Z., An, F. M., Liu, A. R., Wang, Y., et al. (2016). Inhibiting receptor for
advanced glycation end product (AGE) and oxidative stress involved in the protective
effect mediated by glucagon-like peptide-1 receptor on AGE induced neuronal apo-
ptosis. Neuroscience Letters 612, 193–198.
Cheng, M., Liu, H., Zhang, D., Liu, Y., Wang, C., Liu, F., & Chen, J. (2015a). HMGB1 enhances
the AGE-induced expression of CTGF and TGF-β via RAGE-dependent signaling in
renal tubular epithelial cells. American Journal of Nephrology 41, 257–266.
Cheng, Y., Wang, H., Mao, M., Liang, C., Zhang, Y., Yang, D., et al. (2015b). Escin increases
the survival rate of LPS-induced septic mice through inhibition of HMGB1 release
from macrophages. Cellular Physiology and Biochemistry 36, 1577–1586.
Crews, F. T., & Vetreno, R. P. (2014). Neuroimmune basis of alcoholic brain damage.
International Review of Neurobiology 118, 315–357.
Crews, F. T., & Vetreno, R. P. (2016). Mechanisms of neuroimmune gene induction in al-
coholism. Psychopharmacology 233, 1543–1557.
De Vijlder, J. J., Veenboer, G. J., & van Dijk, J. E. (1992). Thyroid albumin originates from
blood. Endocrinology 131, 578–584.
Deng, Y., Yang, Z., Gao, Y., Xu, H., Zheng, B., Jiang, M., et al. (2013). Toll-like receptor 4 me-
diates acute lung injury induced by high mobility group box-1. PloS One 8, e64375.
Dhumale, S. S., Waghela, B. N., & Pathak, C. (2015). Quercetin protects necrotic insult and
promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in
human breast adenocarcinoma cells. IUBMB Life 67, 361–373.
Di Filippo, C., Cuzzocrea, S., Rossi, F., Marfella, R., & D'Amico, M. (2006). Oxidative stress as
the leading cause of acute myocardial infarction in diabetics. Cardiovascular Drug
Reviews 24, 77–87.
Dias, V., Junn, E., & Mouradian, M. M. (2013). The role of oxidative stress in Parkinson's
disease. Journal of Parkinson's Disease 3, 461–491.
Donato, R. (1999). Functional roles of S100 proteins, calcium-binding proteins of the EF-
hand type. Biochimica et Biophysica Acta 1450, 191–231.
Donato, R. (2007). RAGE: A single receptor for several ligands and different cellular re-
sponses: The case of certain S100 proteins. Current Molecular Medicine 7, 711–724.
Dong, H., Li, J., Lv, Y., Zhou, Y., Wang, G., Hu, S., et al. (2013). Comparative analysis of the
alveolar macrophage proteome in ALI/ARDS patients between the exudative phase
and recovery phase. BMC Immunology 17, 14–25.
Elfeky, M., Kaede, R., Okamatsu-Ogura, Y., & Kimura, K. (2016). Adiponectin inhibits LPS-
induced HMGB1 release through an AMP kinase and Heme oxygenase-1-dependent
pathway in RAW 264 macrophage cells. Mediators of Inflammation 2016, 5701959.
Fang, F., Lue, L. F., Yan, S., Xu, H., Luddy, J. S., Chen, D., et al. (2010). RAGE-dependent sig-
naling in microglia contributes to neuroinflammation, Aβ accumulation, and im-
paired learning/memory in a mouse model of Alzheimer's disease. The FASEB
Journal 24, 1043–1055.
Farris, S. D., Hu, J. H., Krishnan, R., Emery, I., Chu, T., Du, L., et al. (2011). Mechanisms of
urokinase plasminogen activator (uPA)-mediated atherosclerosis: Role of the uPA re-
ceptor and S100A8/A9 proteins. The Journal of Biological Chemistry 286, 22665–22677.
Feng, B., Xu, L., Wang, H., Yan, X., Xue, J., Liu, F., et al. (2011). Atorvastatin exerts its anti-
atherosclerotic effects by targeting the receptor for advanced glycation end products.
Biochimica et Biophysica Acta 1812, 1130–1137.
Figarola, J. L., Shanmugam, N., Natarajan, R., & Rahbar, S. (2007). Anti-inflammatory ef-
fects of the advanced glycation end product inhibitor LR-90 in human monocytes.
Diabetes 56, 647–655.
Freeburn, R. W., Armstrong, L., & Millar, A. B. (2005). Cultured alveolar macrophages from
patients with idiopathic pulmonary fibrosis (IPF) show dysregulation of lipopolysac-
charide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10)
inductions. European Cytokine Network 16, 5–16.
Freedman, B. I., Wuerth, J. P., Cartwright, K., Bain, R. P., Dippe, S., Hershon, K., et al. (1999).
Design and baseline characteristics for the aminoguanidine clinical trial in overt type
2 diabetic nephropathy (ACTION II). Controlled Clinical Trials 20, 493–510.
Freiwald, A., Weidner, C., Witzke, A., Huang, S. Y., Meierhofer, D., & Sauer, S. (2013). Com-
prehensive proteomic data sets for studying adipocyte-macrophage cell-cell commu-
nication. Proteomics 13, 3424–3428.
Ge, J., Jia, Q., Liang, C., Luo, Y., Huang, D., Sun, A., et al. (2005). Advanced glycosylation end
products might promote atherosclerosis through inducing the immune maturation of
dendritic cells. Arteriosclerosis, Thrombosis, and Vascular Biology 25, 2157–2163.
Gensel, J. C., & Zhang, B. (2015). Macrophage activation and its role in repair and pathol-
ogy after spinal cord injury. Brain Research 1619, 1–11.
Gkogkolou, P., & Böhm, M. (2012). Advanced glycation end products: Key players in skin
aging? Dermatoendocrinology 4, 259–270.
Goldin, A., Beckman, J. A., Schmidt, A. M., & Creager, M. A. (2006). Advanced glycation end
products: Sparking the development of diabetic vascular injury. Circulation 114,
597–605.
Gosse, P., & Schumacher, H. (2014). Effect of telmisartan vs. ramipril on ‘dipping’ status
and blood pressure variability: Pooled analysis of the PRISMA studies. Hypertension
Research 37, 151–157.
Gross, S. R., Sin, C. G., Barraclough, R., & Rudland, P. S. (2014). Joining S100 proteins and
migration: For better or for worse, in sickness and in health. Cellular and Molecular
Life Sciences 71, 1551–1579.
Gruys, E., Toussaint, M. J., Niewold, T. A., & Koopmans, S. J. (2005). Acute phase reaction
and acute phase proteins. Journal of Zhejiang University. Science. B 6, 1045–1056.
Guiotto, A., Calderan, A., Ruzza, P., & Borin, G. (2005). Carnosine and carnosine-related an-
tioxidants: A review. Current Medicinal Chemistry 12, 2293–2315.
Hagiwara, S., Iwasaka, H., Matumoto, S., Hidaka, S., & Noguchi, T. (2009). Effects of an an-
giotensin-converting enzyme inhibitor on the inflammatory response in in vivo and
in vitro models. Critical Care Medicine 37, 626–633.
He, M., Kubo, H., Ishizawa, K., Hegab, A. E., Yamamoto, Y., Yamamoto, H., et al. (2007). The
role of the receptor for advanced glycation end-products in lung fibrosis. American
Journal of Physiology. Lung Cellular and Molecular Physiology 293, L1427–L1436.
He, M., Kubo, H., Morimoto, K., Fujino, N., Suzuki, T., Takahasi, T., et al. (2011). Receptor for
advanced glycation end products binds to phosphatidylserine and assists in the clear-
ance of apoptotic cells. EMBO Reports 12, 358–364.
Heneka, M. T., O'Banion, M. K., Terwel, D., & Kummer, M. P. (2010). Neuroinflammatory
processes in Alzheimer's disease. Journal of Neural Transmission (Vienna) 117,
919–947.
Hernanz, R., Briones, A. M., Alonso, M. J., Vila, E., & Salaices, M. (2004). Hypertension alters
role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after
LPS in rat cerebral arteries. American Journal of Physiology. Heart and Circulatory
Physiology 287, H225–H234.
Herzog, C., Lorenz, A., Gillmann, H. J., Chowdhury, A., Larmann, J., Harendza, T., et al.
(2014). Thrombomodulin's lectin-like domain reduces myocardial damage by
interfering with HMGB1-mediated TLR2 signalling. Cardiovascular Research 101,
400–410.
Hirohashi, N., & Morrison, D. C. (1996). Low-dose lipopolysaccharide (LPS) pretreatment
of mouse macrophages modulates LPS-dependent interleukin-6 production in vitro.
Infection and Immunity 64, 1011–1015.
Hofmann, M. A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., et al. (1999). RAGE mediates a
novel proinflammatory axis: A central cell surface receptor for S100/calgranulin poly-
peptides. Cell 97, 889–901.
Huttunen, H. J., Fages, C., & Rauvala, H. (1999). Receptor for advanced glycation end prod-
ucts (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cyto-
plasmic domain of the receptor but different downstream signaling pathways. The
Journal of Biological Chemistry 274, 19919–19924.
Jain, S., Gautam, V., & Naseem, S. (2011). Acute-phase proteins: As diagnostic tool. Journal
of Pharmacy & Bioallied Sciences 3, 118–127.
Jinnouchi, Y., Yamagishi, S., Takeuchi, M., Ishida, S., Jinnouchi, Y., Jinnouchi, J., et al. (2006).
Atorvastatin decreases serum levels of advanced glycation end products (AGEs) in
patients with type 2 diabetes. Clinical and Experimental Medicine 6, 191–193.
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
Jirillo, E., Caccavo, D., Magrone, T., Piccigallo, E., Amati, L., Lembo, A., et al. (2002). The role
of the liver in the response to LPS: Experimental and clinical findings. Journal of
Endotoxin Research 8, 319–327.
Joglekar, M. M., Panaskar, S. N., & Arvindekar, A. U. (2014). Inhibition of advanced
glycation end product formation by cymene–A common food constituent. Journal of
Functional Foods 6, 107–115.
Jono, T., Kimura, T., Takamatsu, J., Nagai, R., Miyazaki, K., Yuzuriha, T., et al. (2002). Accu-
mulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl) lysine in hip-
pocampal CA4 pyramidal neurons of aged human brain. Pathology International 52,
563–571.
Joshi, D., Gupta, R., Dubey, A., Shiwalkar, A., Pathak, P., Gupta, R. C., et al. (2009).
TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephrop-
athy in Ob-ZSF1 model of type 2 diabetes. Journal of Cardiovascular Pharmacology
54, 72–81.
Kalinina, N., Agrotis, A., Antropova, Y., DiVitto, G., Kanellakis, P., Kostolias, G., et al. (2004).
Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic
lesions: Role of activated macrophages and cytokines. Arteriosclerosis, Thrombosis, and
Vascular Biology 24, 2320–2325.
Kang, J. H., Kim, H. T., Choi, M. S., Lee, W. H., Huh, T. L., Park, Y. B., et al. (2006). Proteome
analysis of human monocytic THP-1 cells primed with oxidized low-density lipopro-
teins. Proteomics 6, 1261–1273.
Kao, Y. H., Lin, Y. C., Tsai, M. S., Sun, C. K., Yuan, S. S., Chang, C. Y., et al. (2014). Involvement
of the nuclear high mobility group B1 peptides released from injured hepatocytes in
murine hepatic fibrogenesis. Biochimica et Biophysica Acta 1842, 1720–1732.
Karumanchi, D. K., Karunaratne, N., Lurio, L., Dillon, J. P., & Gaillard, E. R. (2015). Non-en-
zymatic glycation of α-crystallin as an in vitro model for aging, diabetes and degen-
erative diseases. Amino Acids 47, 2601–2608.
Kikuchi, K., Uchikado, H., Miura, N., Morimoto, Y., Ito, T., Tancharoen, S., et al. (2011).
HMGB1 as a therapeutic target in spinal cord injury: A hypothesis for novel therapy
development. Experimental and Therapeutic Medicine 2, 767–770.
Kim, Y. S., & Joh, T. H. (2006). Microglia, major player in the brain inflammation: Their roles in
the pathogenesis of Parkinson's disease. Experimental & Molecular Medicine 38, 333–347.
Kim, J. M., Han, H. J., Hur, Y. H., Quan, H., Kwak, S. H., Choi, J. I., et al. (2015). Stearoyl
lysophosphatidylcholine prevents lipopolysaccharide-induced extracellular release
of high mobility group box-1 through AMP-activated protein kinase activation.
International Immunopharmacology 28, 540–545.
Kim, S. W., Jin, Y., Shin, J. H., Kim, I. D., Lee, H. K., Park, S., et al. (2012). Glycyrrhizic acid
affords robust neuroprotection in the postischemic brain via anti-inflammatory effect
by inhibiting HMGB1 phosphorylation and secretion. Neurobiology of Disease 46,
147–156.
Kim, J. B., Lim, C. M., Yu, Y. M., & Lee, J. K. (2008). Induction and subcellular localization of
high-mobility group box-1 (HMGB1) in the postischemic rat brain. Journal of
Neuroscience Research 86, 1125–1131.
Kobayashi, R., & Tashima, Y. (1990). Purification, biological properties and partial se-
quence analysis of 67-kDa calcimedin and its 34-kDa fragment from chicken gizzard.
European Journal of Biochemistry 188, 447–453.
Kobayashi, R., Deavers, M., Patenia, R., Rice-Stitt, T., Halbe, J., Gallardo, S., et al. (2009). 14-
3-3 zeta protein secreted by tumor associated monocytes/macrophages from ascites
of epithelial ovarian cancer patients. Cancer Immunology, Immunotherapy 58, 247–258.
Kokkola, R., Sundberg, E., Ulfgren, A. K., Palmblad, K., Li, J., Wang, H., et al. (2002). High
mobility group box chromosomal protein 1: A novel proinflammatory mediator in
synovitis. Arthritis and Rheumatism 46, 2598–2603.
Kraft, A. D., & Harry, G. J. (2011). Features of microglia and neuroinflammation relevant to
environmental exposure and neurotoxicity. International Journal of Environmental
Research and Public Health 8, 2980–3018.
Kratz, M., Coats, B. R., Hisert, K. B., Hagman, D., Mutskov, V., Peris, E., et al. (2014). Meta-
bolic dysfunction drives a mechanistically distinct proinflammatory phenotype in ad-
ipose tissue macrophages. Cell Metabolism 20, 614–625.
Krautwald, M., Leech, D., Horne, S., Steele, M. L., Forbes, J., Rahmadi, A., et al. (2011). The
advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of
thiamine diphosphokinase. Rejuvenation Research 14, 383–391.
Kuhla, A., Trieglaff, C., & Vollmar, B. (2011). Role of age and uncoupling protein-2 in oxi-
dative stress, RAGE/AGE interaction and inflammatory liver injury. Experimental
Gerontology 46, 868–876.
Kurien, B. T., & Scofield, R. H. (2008). Autoimmunity and oxidatively modified
autoantigens. Autoimmunity Reviews 7, 567–573.
Lane, R. K., Hilsabeck, T., & Rea, S. L. (2015). The role of mitochondrial dysfunction in age-
related diseases. Biochimica et Biophysica Acta 1847, 1387–1400.
Lee, S. -J., & Lee, K. -W. (2007). Protective effect of (-)-epigallocatechin gallate against ad-
vanced glycation endproducts-induced injury in neuronal cells. Biol Pharm Bull 30(8),
1369–1373.
Lee, J. Y., Oh, J. G., Kim, J. S., & Lee, K. W. (2014). Effects of chebulic acid on advanced
glycation endproducts-induced collagen cross-links. Biological & Pharmaceutical
Bulletin 37, 1162–1167.
Legler, D. F., Bruckner, M., Uetz-von Allmen, E., & Krause, P. (2010). Prostaglandin E2 at
new glance: Novel insights in functional diversity offer therapeutic chances. The
International Journal of Biochemistry & Cell Biology 42, 198–201.
Li, Y., Takemura, G., Kosai, K. I., Takahashi, T., Okada, H., Miyata, S., et al. (2004). Critical
roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and
heart failure. Circulation Research 95, 627–636.
Liesz, A., Dalpke, A., Mracsko, E., Antoine, D. J., Roth, S., Zhou, W., et al. (2015). DAMP sig-
naling is a key pathway inducing immune modulation after brain injury. The Journal
of Neuroscience 35, 583–598.
Lietzén, N., Ohman, T., Rintahaka, J., Julkunen, I., Aittokallio, T., Matikainen, S., et al. (2011).
Quantitative subcellular proteome and secretome profiling of influenza A virus-in-
fected human primary macrophages. PLoS Pathogens 7, e1001340.
53
Limongi, D., & Baldelli, S. (2016). Redox imbalance and viral infections in neurodegener-
ative diseases. Oxidative Medicine and Cellular Longevity 2016, 6547248.
Luevano-Contreras, C., & Chapman-Novakofski, K. (2010). Dietary advanced glycation end
products and aging. Nutrients 2, 1247–1265.
Lv, C., Wang, L., Liu, X., Cong, X., Yan, S. S., Wang, Y., et al. (2014). Geniposide attenuates
oligomeric Aβ(1-42)-induced inflammatory response by targeting RAGE-dependent
signaling in BV2 cells. Current Alzheimer Research 11, 430–440.
Ma, Y., Bao, J., Zhao, X., Shen, H., Lv, J., Ma, S., et al. (2013). Activated cyclin-dependent ki-
nase 5 promotes microglial phagocytosis of fibrillar β-amyloid by up-regulating lipo-
protein lipase expression. Molecular & Cellular Proteomics 12, 2833–2844.
Macdonald, J., Galley, H. F., & Webster, N. R. (2003). Oxidative stress and gene expression
in sepsis. British Journal of Anaesthesia 90, 221–232.
Mahali, S., Raviprakash, N., Raghavendra, P. B., & Manna, S. K. (2011). Advanced glycation
end products (AGEs) induce apoptosis via a novel pathway: Involvement of Ca2+
mediated by interleukin-8 protein. The Journal of Biological Chemistry 286 (34903-
34013).
Maltais, J. S., Simard, E., Froehlich, U., Denault, J. B., Gendron, L., & Grandbois, M. (2016).
iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end
product-induced apoptosis and endoplasmic reticulum stress in vascular smooth
muscle cells. Pharmacological Research 104, 176–185.
Matsui, T., Nakamura, N., Ojima, A., Nishino, Y., & Yamagishi, S. I. (2016). Sulforaphane re-
duces advanced glycation end products (AGEs)-induced inflammation in endothelial
cells and rat aorta. Nutrition, Metabolism, and Cardiovascular Diseases 26, 797–807.
Matsuki, K., Tamasawa, N., Yamashita, M., Tanabe, J., Murakami, H., Matsui, J., et al. (2009).
Metformin restores impaired HDL-mediated cholesterol efflux due to glycation.
Atherosclerosis 206, 434–438.
Mayer, B., John, M., & Böhme, E. (1990). Purification of a Ca2+/calmodulin-dependent ni-
tric oxide synthase from porcine cerebellum. FEBS Letters 277, 215–219.
McCormick, M. M., Rahimi, F., Bobryshev, Y. V., Gaus, K., Zreiqat, H., Cai, H., et al. (2005).
S100A8 and S100A9 in human arterial wall. Implications for atherogenesis. Journal
of Biological Chemistry 280, 41521–41529.
Miettinen, J. J., Matikainen, S., & Nyman, T. A. (2012). Global secretome characterization of
herpes simplex virus 1-infected human primary macrophages. Journal of Virology 86,
12770–12778.
Miles, P. R., Bowman, L., Rao, K. M., Baatz, J. E., & Huffman, L. (1999). Pulmonary surfactant
inhibits LPS-induced nitric oxide production by alveolar macrophages. The American
Journal of Physiology 276, L186–L196.
Miyazaki, A., Nakayama, H., & Horiuchi, S. (2002). Scavenger receptors that recognize ad-
vanced glycation end products. Trends in Cardiovascular Medicine 12, 258–262.
Mizutani, K., Ikeda, K., & Yamori, Y. (2000). Resveratrol inhibits AGEs-induced prolifera-
tion and collagen synthesis activity in vascular smooth muscle cells from stroke-
prone spontaneously hypertensive rats. Biochemical and Biophysical Research
Communications 274, 61–67.
Mortaz, E., Adcock, I. M., Ricciardolo, F. L., Varahram, M., Jamaati, H., Velayati, A. A., et al.
(2015). Anti-inflammatory effects of Lactobacillus rahmnosus and Bifidobacterium
breve on cigarette smoke activated human macrophages. PloS One 10, e0136455.
Müller, G., & Heizmann, C. W. (1982). Albumin in chicken skeletal muscle. European
Journal of Biochemistry 123, 577–582.
Nahon, J. L., Tratner, I., Poliard, A., Presse, F., Poiret, M., Gal, A., et al. (1988). Albumin and
alpha-fetoprotein gene expression in various nonhepatic rat tissues. The Journal of
Biological Chemistry 263, 11436–11442.
Nakamura, T., Sato, E., Fujiwara, N., Kawagoe, Y., Ueda, Y., Suzuki, T., et al. (2009). Positive
association of serum levels of advanced glycation end products and high mobility
group box-1 with asymmetric dimethylarginine in nondiabetic chronic kidney dis-
ease patients. Metabolism 58, 1624–1628.
Nakashima, K., Miyashita, H., Yoshimitsu, H., Fujiwara, Y., Nagai, R., & Ikeda, T. (2016).
Two new prenylflavonoids from Epimedii herba and their inhibitory effects on ad-
vanced glycation end-products. Journal of Natural Medicines 70, 290–295.
Nakashima, M., Sakai, T., Hiraiwa, H., Hamada, T., Omachi, T., Ono, Y., et al. (2012). Role of
S100A12 in the pathogenesis of osteoarthritis. Biochemical and Biophysical Research
Communications 422, 508–514.
Nienhuis, H. L., Westra, J., Smit, A. J., Limburg, P. C., Kallenberg, C. G., & Bijl, M. (2009). AGE
and their receptor RAGE in systemic autoimmune diseases: An inflammation propa-
gating factor contributing to accelerated atherosclerosis. Autoimmunity 42, 302–304.
Nystedt, S., Ramakrishnan, V., & Sundelin, J. (1996). The proteinase-activated receptor 2 is
induced by inflammatory mediators in human endothelial cells comparison with the
thrombin receptor. The Journal of Biological Chemistry 271, 14910–14915.
Origlia, N., Bonadonna, C., Rosellini, A., Leznik, E., Arancio, O., Yan, S. S., et al. (2010).
Microglial receptor for advanced glycation end product-dependent signal pathway
drives β-amyloid-induced synaptic depression and long-term depression impair-
ment in entorhinal cortex. The Journal of Neuroscience 30, 11414–11425.
Ott, C., Jacobs, K., Haucke, E., Navarrete Santos, A., Grune, T., & Simm, A. (2014). Role of
advanced glycation end products in cellular signaling. Redox Biology 2, 411–429.
Rahman, I. (2005). The role of oxidative stress in the pathogenesis of COPD. Treatments in
Respiratory Medicine 4, 175–200.
Ramasamy, R., Yan, S. F., & Schmidt, A. M. (2012). Advanced glycation endproducts: From
precursors to RAGE: Round and round we go. Amino Acids 42, 1151–1161.
Rammes, A., Roth, J., Goebeler, M., Klempt, M., Hartmann, M., & Sorg, C. (1997).
Myeloidrelated protein (MRP) 8 and MRP14, calcium-binding proteins of the S100
family, are secreted by activated monocytes via a novel, tubulin-dependent pathway.
The Journal of Biological Chemistry 272, 9496–9502.
Reynolds, A. D., Glanzer, J. G., Kadiu, I., Ricardo-Dukelow, M., Chaudhuri, A., Ciborowski, P.,
et al. (2008a). Nitrated alpha-synuclein-activated microglial profiling for Parkinson's
disease. Journal of Neurochemistry 104, 1504–1525.
Reynolds, P. R., Kasteler, S. D., Cosio, M. G., Sturrock, A., Huecksteadt, T., & Hoidal, J. R.
(2008b). RAGE: Developmental expression and positive feedback regulation by Egr-
54 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
1 during cigarette smoke exposure in pulmonary epithelial cells. American Journal of
Physiology. Lung Cellular and Molecular Physiology 294, L1094–L1101.
Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis,
Thrombosis, and Vascular Biology 31, 986–1000.
Ritchie, R. F., Palomaki, G. E., Neveux, L. M., Navolotskaia, O., Ledue, T. B., & Craig, W. Y.
(1999). Reference distributions for the negative acute-phase serum proteins, albu-
min, transferrin and transthyretin: A practical, simple and clinically relevant ap-
proach in a large cohort. Journal of Clinical Laboratory Analysis 13, 273–279.
Rolo, A. P., & Palmeira, C. M. (2006). Diabetes and mitochondrial function: Role of hy-
perglycemia and oxidative stress. Toxicology and Applied Pharmacology 212,
167–178.
Russo, I., & Frangogiannis, N. G. (2016). Diabetes-associated cardiac fibrosis: Cellular ef-
fectors, molecular mechanisms and therapeutic opportunities. Journal of Molecular
and Cellular Cardiology 90, 84–93.
Ryan, B. J., Nissim, A., & Winyard, P. G. (2014). Oxidative post-translational modifications
and their involvement in the pathogenesis of autoimmune diseases. Redox Biology 28,
715–724.
Saïd-Sadier, N., & Ojcius, D. M. (2012). Alarmins, inflammasomes and immunity.
Biomedical Journal 35, 437–449.
Salum, E., Kals, J., Kampus, P., Salum, T., Zilmer, K., Aunapuu, M., et al. (2013). Vitamin D
reduces deposition of advanced glycation end-products in the aortic wall and system-
ic oxidative stress in diabetic rats. Diabetes Research and Clinical Practice 100,
243–249.
Sathe, K., Maetzler, W., Lang, J. D., Mounsey, R. B., Fleckenstein, C., Martin, H. L., et al.
(2012). S100B is increased in Parkinson's disease and ablation protects against
MPTP-induced toxicity through the RAGE and TNF-α pathway. Brain 135,
3336–3347.
Schmidt, A. M., Du Yan, S., Yan, S. F., & Stern, D. M. (2001). The multiligand receptor RAGE
as a progression factor amplifying immune and inflammatory responses. The Journal
of Clinical Investigation 108, 949–955.
Seeliger, S., Vogl, T., Engels, I. H., Schröder, J. M., Sorg, C., Sunderkötter, C., et al. (2003). Ex-
pression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle dis-
eases. The American Journal of Pathology 163, 947–956.
Shin, J. H., Lee, H. K., Lee, H. B., Jin, Y., & Lee, J. K. (2014). Ethyl pyruvate inhibits HMGB1
phosphorylation and secretion in activated microglia and in the postischemic brain.
Neuroscience Letters 558, 159–163.
Simm, A., Wagner, J., Gursinsky, T., Nass, N., Friedrich, I., Schinzel, R., et al. (2007). Ad-
vanced glycation endproducts: A biomarker for age as an outcome predictor after car-
diac surgery? Experimental Gerontology 42, 668–675.
Singh, R., Barden, A., Mori, T., & Beilin, L. (2001). Advanced glycation end-products: A re-
view. Diabetologia 44, 129–146.
Singhto, N., Sintiprungrat, K., & Thongboonkerd, V. (2013). Alterations in macrophage cel-
lular proteome induced by calcium oxalate crystals: The association of HSP90 and F-
actin is important for phagosome formation. Journal of Proteome Research 12,
3561–3572.
Son, S. M., Jung, E. S., Shin, H. J., Byun, J., & Mook-Jung, I. (2012). Aβ-induced formation of
autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling. Neurobiology of
Aging 33, 1006.e11–1006.e23.
Song, B. J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., et al. (2014). Mito-
chondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances
and pathological conditions through post-translational protein modifications. Redox
Biology 3, 109–123.
Song, J. S., Kang, C. M., Park, C. K., Yoon, H. K., Lee, S. Y., Ahn, J. H., et al. (2011). Inhibitory
effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced
alveolar epithelial to mesenchymal transition. Experimental & Molecular Medicine 43,
517–524.
Srikanth, V., Maczurda, A., Phan, T., Steele, M., Westcott, B., Juskiw, D., et al. (2011). Ad-
vanced glycation endproducts and their receptor RAGE in Alzheimer's disease.
Neurobiology of Aging 32, 763–777.
Steinhoff, M., Buddenkotte, J., Shpacovitch, V., Rattenholl, A., Moormann, C., Vergnolle, N.,
et al. (2005). Proteinase-activated receptors: Transducers of proteinase-mediated sig-
naling in inflammation and immune response. Endocrine Reviews 26, 1–43.
Stern, D., Yan, S. D., Yan, S. F., & Schmidt, A. M. (2002). Receptor for advanced glycation
endproducts: A multiligand receptor magnifying cell stress in diverse pathologic set-
tings. Advanced Drug Delivery Reviews 54, 1615–1625.
Sugihara, Y., Nojima, H., Matsuda, H., Murakami, T., Yoshikawa, M., & Kimura, I. (2000).
Antihyperglycemic effects of gymnemic acid IV, a compound derived from Gymnema
sylvestre leaves in streptozotocin-diabetic mice. Journal of Asian Natural Products
Research 2, 321–327.
Takeuchi, M., & Yamagishi, S. (2004). TAGE (toxic AGEs) hypothesis in various chronic
diseases. Medical Hypotheses 63, 449–452.
Takeuchi, M., Takino, J. I., & Yamagishi, S. I. (2010). Involvement of the toxic AGEs (TAGE)-
RAGE system in the pathogenesis of diabetic vascular complications: A novel thera-
peutic strategy. Current Drug Targets 11, 1468–1482.
Tam, H. L., Shiu, S. W., Wong, Y., Chow, W. S., Betteridge, D. J., & Tan, K. C. (2010). Effects of
atorvastatin on serum soluble receptors for advanced glycation end-products in type
2 diabetes. Atherosclerosis 209, 173–177.
Tang, Y. (2014). Curcumin eliminates the effect of advanced glycation endproducts
(AGEs) on the divergent regulation of gene expression of receptors of AGEs by
interrupting leptin signaling. Laboratory Investigation 94, 503–516.
Teismann, P., Sathe, K., Bierhaus, A., Leng, L., Martin, H. L., Bucala, R., et al. (2012). Receptor
for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxici-
ty. Neurobiology of Aging 33, 2478–2490.
Terada, C., Yoshida, A., Nasu, Y., Mori, S., Tomono, Y., Tanaka, M., et al. (2011). Gene ex-
pression and localization of high-mobility group box chromosomal protein-1
(HMGB-1) in human osteoarthritic cartilage. Acta Medica Okayama 65, 369–377.
Tessier, F., Obrenovich, M., & Monnier, V. M. (1999). Structure and mechanism of forma-
tion of human lens fluorophore LM-1. Relationship to vesperlysine A and the ad-
vanced Maillard reaction in aging, diabetes, and cataractogenesis. The Journal of
Biological Chemistry 274, 20796–20804.
Thomas, M. C., Tikellis, C., Burns, W. M., Bialkowski, K., Cao, Z., Coughlan, M. T., et al.
(2005). Interactions between renin angiotensin system and advanced glycation in
the kidney. Journal of the American Society of Nephrology 16, 2976–2984.
Tian, S., Zhang, L., Tang, J., Guo, X., Dong, K., & Chen, S. Y. (2015). HMGB1 exacerbates renal
tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early
stage of obstructive injury. American Journal of Physiology. Renal Physiology 308,
F69–F75.
Tsoporis, J. N., Izhar, S., Leong-Poi, H., Desjardins, J. F., Huttunen, H. J., & Parker, T. G.
(2010). S100B interaction with the receptor for advanced glycation end products
(RAGE): A novel receptor-mediated mechanism for myocyte apoptosis
postinfarction. Circulation Research 106, 93–101.
van Lent, P. L., Blom, A. B., Schelbergen, R. F., Slöetjes, A., Lafeber, F. P., Lems, W. F., et al.
(2012). Active involvement of alarmins S100A8 and S100A9 in the regulation of sy-
novial activation and joint destruction during mouse and human osteoarthritis.
Arthritis and Rheumatism 64, 1466–1476.
Varol, C., Mildner, A., & Jung, S. (2015). Macrophages: Development and tissue specializa-
tion. Annual Review of Immunology 33, 643–675.
Vasan, S., Foiles, P. G., & Founds, H. W. (2001). Therapeutic potential of AGE inhibitors and
breakers of AGE protein cross-links. Expert Opinion on Investigational Drugs 10,
1977–1987.
Wallace, J. L. (2005). Nitric oxide as a regulator of inflammatory processes. Memórias do
Instituto Oswaldo Cruz 100, 5–9.
Wang, C. Y., Xie, J. W., Xu, Y., Wang, T., Cai, J. H., Wang, X., et al. (2013). Trientine reduces
BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a
transgenic mouse model of Alzheimer's disease. Antioxidants & Redox Signaling 19,
2024–2039.
Wang, X., Yu, S., Hu, J. P., Wang, C. Y., Wang, Y., Liu, H. X., et al. (2014). Streptozotocin-in-
duced diabetes increases amyloid plaque deposition in AD transgenic mice through
modulating AGEs/RAGE/NF-κB pathway. The International Journal of Neuroscience
124, 601–608.
Wang, L., Zhang, X., Liu, L., Yang, R., Cui, L., & Li, M. (2010). Atorvastatin protects rat brains
against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors
(RAGE and TLR4), NF-kappaB expression. Neuroscience Letters 471, 152–156.
Ward, M. S., Fortheringham, A. K., Cooper, M. E., & Forbes, J. M. (2013). Targeting ad-
vanced glycation endproducts and mitochondrial dysfunction in cardiovascular dis-
ease. Current Opinion in Pharmacology 13, 654–661.
Xie, Z., Smith, C. J., & Van Eldik, L. J. (2004). Activated glia induce neuron death via MAP
kinase signaling pathways involving JNK and p38. Glia 45, 170–179.
Xiong, X. Y., Liu, L., & Yang, Q. W. (2016). Functions and mechanisms of microglia/macro-
phages in neuroinflammation and neurogenesis after stroke. Progress in Neurobiology
142, 23–44.
Xu, K., & Geczy, C. L. (2000). IFN-gamma and TNF regulate macrophage expression of the
chemotactic S100 protein S100A8. Journal of Immunology 164, 4916–4923.
Xu, K., Yen, T., & Geczy, C. L. (2001). IL-10 up-regulates macrophage expression of the
S100 protein S100A8. Journal of Immunology 166, 6358–6366.
Yamagishi, S., & Matsui, T. (2010). Advanced glycation end products, oxidative stress and
diabetic nephropathy. Oxidative Medicine and Cellular Longevity 3, 101–108.
Yamagishi, S., Nakamura, K., Matsui, T., & Takeuchi, M. (2006). Minodronate, a nitrogen-
containing bisphosphonate, is a promising remedy for treating patients with diabetic
retinopathy. Medical Hypotheses 66, 273–275.
Yammani, R. R., Long, D., & Loeser, R. F. (2009). Loeser interleukin-7 stimulates secretion
of S100A4 by activating the JAK-STAT signaling pathway in human articular
chondrocytes. Arthritis and Rheumatism 60, 792–800.
Yan, S. F., D'Agati, V., Schmidt, A. M., & Ramasamy, R. (2007). Receptor for advanced
glycation end products (RAGE): A formidable force in the pathogenesis of the cardio-
vascular complications of diabetes & aging. Current Molecular Medicine 7, 699–710.
Ye, C., Choi, J. G., Abraham, S., Wu, H., Diaz, D., Terreros, D., et al. (2012). Human macro-
phage and dendritic cell-specific silencing of high-mobility group protein B1 amelio-
rates sepsis in a humanized mouse model. Proceedings of the National Academy of
Sciences of the United States of America 109, 21052–21057.
Yoo, Y., Byun, K., Kang, T., Bayarsaikhan, D., Kim, J. Y., Oh, S., et al. (2015). Amyloid-beta-
activated human microglial cells through ER-resident proteins. Journal of Proteome
Research 14, 214–223.
Yoshida, T., Yamagishi, S., Nakamura, K., Matsui, T., Imaizumi, T., Takeuchi, M., et al.
(2006). Telmisartan inhibits AGE-induced C-reactive protein production through
downregulation of the receptor for AGE via peroxisome proliferator-activated recep-
tor-gamma activation. Diabetologia 49, 3094–3099.
Zafar, H. (2012). Inhibition of protein glycation and advanced glycation end products by
ascorbic acid. African Journal of Biotechnology 11, 51.
Zeng, S., Dun, H., Ippagunta, N., Rosario, R., Zhang, Q. Y., Lefkowitch, J., et al. (2009). Recep-
tor for advanced glycation end product (RAGE)-dependent modulation of early
growth response-1 in hepatic ischemia/reperfusion injury. Journal of Hepatology 50,
929–936.
Zetterström, C. K., Jiang, W., Wähämaa, H., Ostberg, T., Aveberger, A. C., Schierbeck, H.,
et al. (2008). Pivotal advance: Inhibition of HMGB1 nuclear translocation as a mech-
anism for the anti-rheumatic effects of gold sodium thiomalate. Journal of Leukocyte
Biology 83, 31–38.
Zhang, Z., Zhang, L., Zhou, C., & Wu, H. (2014). Ketamine inhibits LPS-induced HGMB1 re-
lease in vitro and in vivo. International Immunopharmacology 23, 14–26.
Zhou, H., Ji, X., Wu, Y., Xuan, J., Qi, Z., Shen, L., et al. (2014). A dual-role of Gu-4 in sup-
pressing HMGB1 secretion and blocking HMGB1 pro-inflammatory activity during in-
flammation. PloS One 9, e89634.
 K. Byun et al. / Pharmacology & Therapeutics 177 (2017) 44–55
Zhou, Y., Wang, Y., Kovacs, M., Jin, J., & Zhang, J. (2005). Microglial activation induced by
neurodegeneration: A proteomic analysis. Molecular & Cellular Proteomics 4,
1471–1479.
Zhu, Y., Chen, X., Pan, Q., Wang, Y., Su, S., Jiang, C., et al. (2015). A comprehensive prote-
omics analysis reveals a secretory path-and status-dependent signature of exosomes
released from tumor-associated macrophages. Journal of Proteome Research 14,
4319–4331.
Zhu, X., Raina, A. K., Lee, H. G., Casadesus, G., Smith, M. A., & Perry, G. (2004). Oxidative
stress signalling in Alzheimer's disease. Brain Research 1000, 32–39.
55
Zhu, T., Wang, D. X., Zhang, W., Liao, X. Q., Guan, X., Bo, H., et al. (2013). Andrographolide
protects against LPS-induced acute lung injury by inactivation of NF-κB. PloS One 8,
e56407.
Ziskoven, C., Jäger, M., Zilkens, C., Bloch, W., Brixius, K., & Krauspe, R. (2010). Oxidative
stress in secondary osteoarthritis: From cartilage destruction to clinical presentation?
Orthopedic Reviews (Pavia) 2, e23.