Ramanakoppa H. Nagaraj's research while affiliated with City of Cleveland and other places

... Factors such as oxidant stress, molecular cross-linking, the sequelae of RAGE signaling and changes of DNA integrity extrapolate this process from the molecular to the biological (cellular and tissue) level (Huttunen et al. 1999(Huttunen et al. , 2000(Huttunen et al. , 2002. This pertains to ageing (Bjorksten 1977;Monnier et al. 1990) and AD (Heitner and Dickson 1997;Smith et al. 1994). ...

... Induction of cross-links is a well established procedure in polymer chemistry to increase the elastic modulus of materials (Eyre, 1984 ;Mark, 1988). Cross-linking in connective tissue may occur during aging (Albon et al., 1995 ;Balisky et al., 1996 ;Reiser, 1991 ;Yamauchi et al., 1996) and as a side-effect of diabetes (Hadley, Meek and Malik, 1996 ;Malik et al., 1992 ;Sady, Khosrof and Nagaraj, 1995 ;Zhao, Nagaraj and Abraham, 1997). Recently cross-linking has been used medically to increase the stability, and reduce the biodegradation of collagen-based biomaterials for bioprostheses such as porcine heart valves, blood vessel prostheses, dural substitute and meniscal allografts (Ersek and Derlerm, 1988 ;Nimni, 1988 ;Perkins and Bui, 1996 ;Pietrucha, 1991 ;Remacle, 1995 ;Wisnewski, Power and Kennedy, 1988). ...

... end-stage renal disease). 22 In end-stage renal disease, markedly elevated serum levels of AGEs have been established, 23,24 with no difference between patients with and without diabetes, 25 indicating a pivotal role of the kidney in AGEs metabolism. ...

... Next, the material was dialyzed against distilled water to remove the unreacted material and lyophilized. BSA modified by methylglyoxal was obtained by the incubation of BSA water solution (25 mg/mL) with methylglyoxal (3.6 mg/mL) at 37 °C for 7 days [19]. Two groups of low molecular mass products were also synthesized: one from D-melibiose and N-α-acetyl-Llysine (LM), and the second one from a mixture of D-melibiose, N-α-acetyl-L-lysine and N-α-acetyl-L-arginine (LMA). ...

... Pentosidine (PENT) crosslinks are one of the major AGE products formed by nonenzymatic glycation and oxidation of proteins [13]. Over the years, fluorescent crosslinks such as PENT were used as a biomarker for AGEs [14,15]. Even though only traces of PENT can be discovered in tissue proteins, they are extremely beneficial to analyze cumulative tissue proteins. ...

... [7][8][9] Cataract development in DM could be due to changes in lens proteins from hyperglycemia related glycation endproduct (AGE) accumulation [10][11] Hyperglycemia generates AGEs through non-enzymatic glycation, followed by oxidative reactions between reducing sugars and proteins, which can lead to osmotic stress and accumulation of fluid 12 It has been found that AGEs, including N-(carboxyethyl) lysine (CEL), pentosidine, N-(carboxymethyl)-L-lysine (CML), pyrraline, and fluorophore LM-1 are found at higher levels in cataractous lenses of diabetic patients when compared to the normal aging population. [13][14][15] The increased glucose levels in the aqueous humor induce glycation of lens proteins and therefore increase the level of free radicals. This process, also known as ''glucoxidation,'' further opacifies the lens as a result of increased oxidative stress especially given impaired antioxidant capacity in diabetic lenses. ...

... One of the well-studied AGEs is Pentosidine, a composition of glycosylation and cross-linking between arginine, lysine, and pentose. Its molecular weight is 378.48 da [7,8]. Another well-known AGEs is N-(carboxymethyl)lysine (CML), and its molecular weight is 204.20 da [9]. ...

... The genetic lesions include point mutations, translocations, chromosomal gains and losses, telomere shortening and gene disruption caused by the integration of viruses or transposons (Lopez-Otin et al. 2013). Causal evidence linking the lifelong increase in genomic damage and aging came from studies in mice and humans indicating that altered DNA repair mechanisms cause augmented aging in mice and trigger numerous human progeroid syndromes (Monnier et al. 1991, Fukada et al. 2014. Overall there is broad evidence that genomic damage occurs in aging and that its artifi cial induction can aggravate accelerated aging. ...

... The final step of AGE formation is very complex, but a possible process is displayed in Figure 2. Other AGEs that have been identified in the body are carboxymethyl arginine (CMA) [17], imidazolone [18], formyl threosyl pyrrole (FTP) [19], argpyrimidine [20], pentosidine [21], and crossline [22]. compound for AGE formation than glucose. ...

... In the modification of a single arginyl residue, the following are formed: glyoxal-derived hydroimidazolones (G-H) including isomers: glyoxal-derived hydroimidazolone 1 (G-H1), glyoxal-derived hydroimidazolone 2 (G-H2), glyoxal-derived hydroimidazolone 3 (G-H3) [23], glyoxal-derived dihydroimidazolones (G-DH): G-DH1 and G-DH2 [24], methylglyoxal-derived hydroimidazolone (MG-H): MG-H1, MG-H2 and MG-H3 [25], methylglyoxal-derived dihydroimidazolone (MG-DH): MG-DH1, MG-DH2 [26] and other arginyl-AGEs: 3-DG-imidazolone [27], argpyrimidine (RPYR) [28], N δ -(4-carboxy-4, 6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP) [24] and Nx-carboxymethyl-arginine (CMA) [28], as shown in Fig. 1. As a result of glycation of a single lysyl residue (Cε), there are formed: N ε -(1-Carboxymethyl)-L-lysine (CML) [29,30], N ε -(1-Carboxyethyl)-L-lysine (CEL) [31], Nε-glycoloyl lysine (GALA) [28], fructosyl-lysine (FL) [32], glycoaldehyde-pyridine [28], pyrraline [33], 1-alkyl-2-formyl-3,4-glycosyl-pyrrole (AFGP) [28] (Fig. 2). Glycation may occur on both amino acids residues: lysyl and arginyl, giving arginine-lysine AGE cross-links: N δ -(2-{[(4 S)-4-ammonio-5-oxido-5-oxopentyl]amino}-3,5-dihydro-4H-imidazole -4-ylidene)-L-lysine (GODIC) [24], 2-ammonio-6-({2-[4-ammonio-5-oxido-5-oxopently)amino]-4-methyl-4,5-dihydro-1H-imidazole-5-yli-dene}amino)hexanoate (MODIC) [28], 3-deoxyglucosone-derived imidazolium cross-link (DOGDIC) [28], pentosidine [34] and glucosepane [28]. ...