Aplicación de la propuesta y análisis de los resultados

In 1908, Arthur Robert Ling developed a process involving thermal drying of proteins with sugars, which produced a coloured and flavoured mixtures. He termed referred to the formation of browning pigments after heating the glucose with asparagine (Ling, 1908). These were the first documented adducts formed between amino acids and glucose. Louise Camille Maillard (1912) – considered the founder of glycation research - studied the reaction between glucose and glycine on heating. He suggested that brown pigments produced, melanoidins, were formed by an initial reaction between amines and saccharides that produced Schiff’s base adducts. The name given to this reaction and related parallel and sequential reaction is the “Maillard reaction”.

In 1913, the glyoxalase system was discovered. It is an important system catalysing MG to D-lactate in physiological systems (Dakin and Dudley, 1913, Neuberg, 1913).

Between 1925 and 1931, Mario Amadori discovered that the condensation of D-glucose with aromatic amines p-phentidine, p-anisidine or p-toluidine form two different structure of isomers which were not anomers (Amadori, 1929a). He found one of the isomers is more liable to hydrolysis and vulnerable to decomposition on standing in the solid state in air. He identified this as N-glycosylamine. Conversely, he incorrectly assumed that the Schiff’s base was the more stable isomer,

overlooking its resistance to hydrolysis by acid (Amadori, 1929b). Then, Kuhn and Dansi (1936) stated that the stable isomer was the product of a molecular

68 rearrangement instead of a Schiff’s base. They also confirmed Amadori finding about the labile isomer, the N-substituted glycosylamine (Kuhn R and Dansi A, 1936). In 1937 Kuhn and Wegand found the structure of the stable isomer. It is the unbranched N-substituted 1-amino-1-deoxy-2-ketose (Kuhn R, 1937). Later, the reaction was called the Amadori rearrangement, involving the reaction of aldoses with amines. In 1953, Hodge suggested that formation of a Schiff’s base followed by Amadori rearrangement is involved in the initial stages of the Maillard reaction. In addition, He suggested enolisation, oxidation and fragmentation reactions are contributed in fructosamine degradation to glucosone and other adducts (Hodge, 1953).

In 1958, Allan et al. described the first observation of glycation of a protein

in vivo. They found a glycated variant of haemoglobin, HbA1c, identifying it as a

negatively charged component of human blood cell haemoglobin (Allen et al., 1958). Bookchin and Gallop (1968) studied glycated haemoglobin and described its

elevation in diabetes (Bookchin and Gallop, 1968). Bunn et al (1975) described reactions which explain the creation of glycated haemoglobin (Bunn et al., 1975). In 1976, Anthony Cerami and his colleagues suggested the use of glycated haemoglobin HbA1c as an indicator for the glycaemic control in patients with diabetes (Peterson et

al., 1977). The value of HbA1c is now a common clinical diagnostic marker of

glycaemic control in diabetic patients (ADA, 2015).

Anet in 1960 described the degradation of a fructosamine (N,N-

difructosylglycine) to 3-deoxyglucosone (Anet, 1960). Kato successfully isolated 3DG and 3-deoxypentosone from the browning reactions of amine with glucose and ribose (Kato, 1960, Kato et al., 1988). In biological systems, the reactive α-

oxoaldehydes are essential precursors of formation of glycation adducts (Nass et al., 2014).

Bonsignore in 1973 reported the first indication of formation of MG by non- enzymatic degradation of triosephosphates to MG under physiological conditions and the degradation of glyceraldehyde-3-phosphate to MG (Bonsignore et al., 1973). In 1977, Takahashi described the reaction between amino-acids and glyoxal derivatives containing glyoxal and MG. Then, arginine was identified as the main amino acid altered and hydroimidazolone was one molecular structure suggested for adducts. However, no analytical data was presented to prove the suggestion (Takahashi, 1977). Later, the formation of hydroimidazolone adducts was confirmed. Then,

69 hydroimidazolones in the physiological systems and some foods found to be a

principal AGE (Thornalley et al., 2003b, Henle et al., 1994). The formation of α- oxoaldehydes by fragmentation of saccharide moiety early in the Maillard reaction, this evidence was provided by Hayashi and Namiki (1980). This is called the Namiki pathway of the Maillard reaction, involving the formation of glyoxal and MG by saccharide fragmentation (Hayashi and Namki, 1980, Rabbani et al., 2010).

Dicarbonyls are also formed by monosaccharide auto-oxidation as the slow oxidative degradation of monosaccharides under physiological conditions to form the

respective α-oxoaldehydes and hydrogen peroxide (Wolff et al., 1984). Nakayama et al (1980) defined the formation of 6-(2-formyl-5-

hydroxymethylpyrrol-1-yl)-L-norleucine from 3-DG and lysyl residues in proteins known as AGE – pyrraline (Nakayama et al., 1980).

A product formed by degradation of Amadori product, 2-(2-furoyl)-4(5)-(2- furanyl)-1H-imidazole (FFI), was reported in 1984, (Pongor et al., 1984). This was later found to be an artefact – formed in pre-analytic processing (Obayashi et al., 1996).

The phrase “advanced glycation endproducts” (AGEs) was first used in 1986 by Cerami to refer them as “brown fluorescent pigments which cross link proteins” (Cerami, 1986). Brownlee and his colleagues found elevated collagen cross-linking in the arterial walls of diabetic rats and related fluorescence features of AGE

compounds. The nucleophilic hydrazine derivative, aminoguanidine – later given the trademark name (PimagedineTM ) - was studied as a prototype AGE inhibitor and diabetes-induced protein cross-linking (Brownlee et al., 1986).

Baynes and co-workers described the formation of Nε(carboxymethyl)lysine

(CML) and erythronic acid from degradation of proteins glycated by glucose and later the presence of both compounds in human urinary metabolite was reported (Ahmed et al., 1986). CML is also formed by the reaction of lysine residues with ascorbate and glyoxal formed in lipid peroxidation (Thorpe and Baynes, 2002).

Thornalley (1988) presented evidence of link between hyperglycaemia in diabetes, elevated flux of formation and concentration of MG and its potential involvement as main pathway causing the appearance of diabetic vascular complications (Thornalley, 1988) and reported 3 – 5 fold increase in MG

concentration in blood samples of patients with T1DM and T2DM (McLellan et al., 1994a). In 2001 Brownlee included glycation by MG one of the major metabolic

70 pathways involved in the appearance of diabetic vascular complications (Brownlee, 2001). Between 1994 and 1998, clinical trials (ACTION I and ACTION II) for the avoidance of obvious nephropathy were conducted using the AGE inhibitor

PimagedineTM. However, due to safety reasons and obvious absence of efficacy these trials were later terminated (Thornalley, 2003c).

In 1989, Sell and Monnier discovered an acid stable fluorescent compound formed by the glycation of collagen and called it pentosidine (Sell and Monnier, 1989). Pentosidine is a crosslink formed by a pentose moiety with lysine and arginine residues (Sell and Monnier, 1989).

Horiuchi and Kurokawa (1991) discovered the enzymatic metabolism of fructosamine adduct. It was reported that the fructosyl-amino acid oxidase catalysed the transformation of fructosyl-amino acids to free amino acid, glucosone and hydrogen peroxide (Horiuchi and Kurokawa, 1991). Later, Delpierre et al. (2000) discovered an enzyme that catalysed the phosphorylation of fructosamine and fructosamine residues forming fructosamine-3-phosphate (F3P). This enzyme called fructosamine 3-kinase. F3P fragments spontaneously resulting in de-glycation and repair of early glycated proteins.

Schmidt et al (1992) identified a cell surface protein that bound proteins highly modified by AGEs prepared in vitro. This was called an AGE receptor and was initially found in bovine lung endothelial cells and had a sequence molecular mass of 42 kDa (Schmidt et al., 1992). This is the best recognised AGE receptor called the receptor for advanced glycosylation end products (RAGE).

In 1996, Cerami et al. proposed the concept of AGE breakers, which were defined as compounds that may cleave glycation-derived crosslinks and reverse one of the damaging of glycation associated with ageing and disease. N-

phenacylthiazolium bromide (PTB) was the prototype compound (Vasan et al., 1996). This and associated analogues had stability problems and the claimed complete breaking of crosslinks was rather slowing of the putative AGE breaker reaction by spontaneous degradation of PTB and acidification of incubations and cell cultures (Thornalley and Minhas, 1999, Price et al., 2001).

Shipanova and his colleagues (1997) identified argpyrimidine - a fluorescence AGE formed from MG (Shipanova et al., 1997). Vlassara and co- workers (1997) suggested the term “glycotoxins” to refer to highly reactive AGE

71 intermediates and created a series of current studies, assessing the physiological effects on AGEs in diet on health (Koschinsky et al., 1997).

Since 2000, there is a marked advances in glycation – particularly in relation to improved quantitation of glycation adducts and free adducts by stable isotopic dilution analysis LC-MS/MS (Thornalley et al., 2003b, Thornalley et al., 2010). Application of high resolution mass spectrometry proteomics was identified proteins susceptible to glycation by glucose and by MG (Rabbani and Thornalley, 2014a, Zhang et al., 2007, Schmidt et al., 2015). Pre-clinical models with genetically controlled increased exposure to glycation – F3K knockout mice and glyoxalase 1 (Glo1)-deficient mice (da-Cunha et al., 2006, El-Osta et al., 2008), and decreased glycation exposure – Glo1 transgenic mice (Inagi et al., 2002), have been developed and employed in studies of glycation in health and disease. The concept of

“dicarbonyl stress” has emerged defined as the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. This explains the involvement of dicarbonyl glycation in health decline in ageing and in disease – particularly diabetes and its vascular complications, CVD, renal failure, schizophrenia, Parkinson’s disease, carcinogenesis and mechanisms of action of anticancer drugs and Glo1 overexpression in multi-drug resistance – reviewed in (Rabbani and Thornalley, 2015)

The concept of AGE receptors has been well-investigated and role in health and disease has been best developed for RAGE. Even its involvement in responses to glycated porteins has been questioned and non-glycation ligands considered to be major phsyiological agonists. The link of RAGE to glycation was further

complicated by suggestion that activaion of RAGE is linked to downregulation of Glo1, increasing sensitivity to dicarbonyl stress (Thornalley, 2007).

Roles for glycation in ageing, obesity and chronic disease have been advanced – particularly for diabetic complications (Ahmed et al., 2005a), renal failure (Agalou, 2005, Miyata et al., 2001), cardiovascular diseases, Alzheimer’s, uremia, g (Ahmed et al., 2004, Chen et al., 2004, Rabbani et al., 2010), arthritis and cirrhosis (Ahmed et al., 2004), schizophrenia (Arai et al., 2010, Hambsch et al., 2010) Parkinson’s disease (Kurz et al., 2010), carcinogenesis (Zender et al., 2008) and multidrug resistance (Santarius et al., 2010, Thornalley et al., 2010).

72 Treatments emerging from glycation research are dicarbonyl scavengers and Glo1 inducers. Treatments under current investigation are pyridoxamine as a

dicarbonyl scavenger and small molecule Glo1 inducers (Lewis et al., 2012, Rabbani et al., 2014b) such as sulforaphane (Xue et al., 2012a) trans- resveratrol and

hesperetin (Xue et al., 2016).