
==== Front
Rev Cardiovasc Med
Rev Cardiovasc Med
RCM
Reviews in Cardiovascular Medicine
1530-6550
2153-8174
IMR Press

10.31083/j.rcm2508295
S1530-6550(24)01495-9
Review
The Role of Natural Low Molecular Weight Dicarbonyls in Atherogenesis and Diabetogenesis
Lankin Vadim Z. 1 * lankin0309@mail.ru

Tikhaze Alla K. 1
Sharapov Mars G. 2
Konovalova Galina G. 1
Balistreri Carmela Rita Academic Editor
Kadoglou Nikolaos P. E. Academic Editor
1Department for Free Radical Biochemistry, E.I. Chazov' National Medical Research Center of Cardiology, Russian Ministry of Health, 121552 Moscow, Russia
2Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow, Russia
*Correspondence: lankin0309@mail.ru (Vadim Z. Lankin)
20 8 2024
8 2024
25 8 2953 3 2024
20 5 2024
18 6 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY 4.0 license.
This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not “oxidized” (lipoperoxide-containing) LDL, but dicarbonyl-modified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 (LOX-1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus.

reactive oxygen species (ROS)
free radical oxidation (FRO)
superoxide anion radical (O2•-)
lipoperoxides (LOOH)
oxidative stress
low molecular weight dicarbonyls
malondialdehyde (MDA)
glyoxal
methylglyoxal
reactive carbonyl species (RCS)
carbonyl stress
low density lipoproteins (LDL)
oxidized (LOOH contained) LDL (LOOH-LDL)
MDA-modified LDL (MDA-LDL)
lectin like oxidized low density lipoprotein receptor 1 (LOX-1)
NADPH oxidase 1 (NOX-1)
antioxidant enzymes
superoxide dismutase (SOD)
glutathione peroxidase (GSH-Px)
peroxiredoxines
endotheliocites
apoptosis
atherosclerosis
diabetes
==== Body
pmc1. Atherosclerosis as Free Radical Pathology

Denhem Harman was the first scientist to herald the hypothesis that the aging of an organism is caused by the accumulation of molecular lesions resulting froms buildup of the products of free radical reactions [1]. Consequently, he coined the term “free radical disease” in order to signify such age-related pathology as atherosclerosis [2]. However, the first experimental data on the content of free radical oxidation (FRO) products in the regions of atherosclerotic lesions in human aorta were rather contradictory [3, 4]. Not earlier than two decades later the adequate method such as high performance liquid chromatography (HPLC) detected pronounced elevation of the content of lipohydroperoxides (LOOH), which are the primary FRO products, in aortal autopsy samples of atherosclerotic patients [5, 6]. Importantly, HPLC employing the column with chiral phase detected equal amounts of S and R stereoisomers of LOOH in the regions of human aortal atherosclerotic damage attesting to their formation due to spontaneous (non-enzymatic) FRO of unsaturated lipids [6]. Simultaneously, diminished activity of the key antioxidant enzymes such as Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and Se-containing glutathione peroxidase (GSH-Px) was observed in the same areas of atherosclerotic lesions [7, 8]. These data assume that atherosclerosis is characterized by an imbalance between the generation and utilization of FRO products [5, 8, 9]. Based on these results, one could reliably consider atherosclerosis as “free radical pathology” [5].

Significant increases in the levels of primary and secondary products FRO of the lipids were observed in representative epidemiological studies in the blood plasma of probands with diagnosticated atherosclerosis [5, 8]. These data assumed that in atherogenesis, oxidisation of the nanoparticles of the lipid transport system in blood plasma, i.e., the low-density lipoproteins (LDL), which are easily subjected to FRO initiated by metal ions of variable valence and other oxidation inductors [10]. Chemical modification of LDL with acetaldehyde made them “more atherogenic” [11], i.e., capable of binding with the scavenger receptor of macrophages and build up in the vascular wall [11]. In numerous subsequent studies, it was found that oxidised LDL also became “atherogenic” [12, 13, 14, 15, 16, 17, 18].

2. Free Radical Peroxidation of Biomembranes and LDL. Malondialdehyde (MDA)-Modified LDL in Atherosclerosis

FRO of polyene lipids is performed in two stages: initially, the primary products are formed, which are unstable LOOH subjected to subsequent oxidative destruction with formation of the secondary products, i.e., the low molecular weight dicarbonyls [19]. Therefore, the oxidative stress in atherogenesis which is characterised by dramatic LOOH elevation in tissues must inevitably transform into the carbonyl stress accompanied with buildup of such reactive carbonyl species (RCS) as hydroxynonenals and malondialdehyde (MDA) [8, 19]. The aldehyde groups of dicarbonyls can rapidly react with the terminal amino groups of the proteins according to the Maillard reaction resulting in intra- and inter-molecular cross-links capable of modifying the proteins [19]. Although the implication of MDA in chemical modification of apoprotein B-100 in LDL was firmly established [20], the molecular mechanism of oxidative modification of LDL resulting in their ‘atherogenicity’ [10] is still not clear.

In strict terms, the oxidized LDL are those which contain LOOH-acyls in the phospholipids of the outer layer of the particles [10]. Importantly, accumulation of LOOH-acyls in the outer phospholipid monolayer of LDL can change the conformation of apoprotein B-100, the only protein in LDL. Actually, FRO of unsaturated “fluid” acyls of membrane phospholipids results in a dramatic rise of membrane microviscosity [5, 21] due to the displacement of the more polar LOOH acyls into aqueous phase and elevation of the content of saturated ‘solid’ fatty acid residues in the phospholipids resulting in increased membrane rigidity [5, 21]. Evidently, the pronounced changes of such fundamental properties of biomembranes as microviscosity and polarity can possibly modify conformation of peripheral and integral proteins incorporated into the phospholipid bilayer. Specifically, FRO of microsomes is characterized by divergent changes in activity of the membrane-bound enzymes: activity of the oxidation-sensitive enzymes decreases while that of oxidation-resistant enzymes increases [5, 8]. This phenomenon is explained by a physical change in the conformation of these protein molecules caused by a change in the physicochemical properties of membrane lipids. These data suggest that LOOH accumulation in LDL phospholipids may alter the conformation of apoprotein B-100, which may cause changes in the binding efficiency of oxidised LDL with scavenger receptor of macrophages.

After in vitro FRO initiation in LDL with diverse inducers such as azo-initiators, H2O2, superoxide anion radical (O2•-) generators, metal ions with variable valence, etc., elevation of concentration of primary (LOOH) and secondary (MDA) products of lipoperoxidation occurs virtually simultaneously [10].

At the same time, the formation of MDA-modified LDL occurs only after a significant accumulation of MDA in the incubation medium [10]. Thus, the medium in which LDL had been oxidized for a long time contains a mixture of LOOH-containing LDL (LOOH-LDL) and MDA-modified LDL (MDA-LDL) in unpredictable proportion [10]. Therefore, any study of physiological effects of such mixtures of oxidatively modified LDL cannot establish what kind of products of lipid FRO provoke ‘atherogenic’ modification of LDL particles. By employing the homogenous preparation C-15 of lipoxygenases of rabbit reticulocytes known to catalyze oxidation of polyene acyls of phospholipids in the lipid-protein supramolecular complexes (LDL included, [22]), we could obtain the LOOH-LDL without admixture of MDA-LDL [23]. Simultaneously, incubation of LDL with MDA yielded MDA-modified LDL without admixture of LOOH-LDL [23]. Examination of atherogenicity of modified LDL (i.e., efficacy of LDL captured by cultured human macrophages) unequivocally proved that not oxidized (LOOH-LDL), but exclusively MDA-LDL bind with the scavenger receptors of macrophages [23]. Thus, expressly LDL particles that are modified with natural dicarbonyls but not the oxidized LDL (i.e., LOOH-LDL) are effectively captured in vascular wall cells to be accumulated in the lipid vacuoles [23]. As a consequence of buildup of exogenous lipids, the macrophages and pleomorphic smooth muscle cells convert into so-called foam cells, which form the lipidosis regions, where the primary pre-atherosclerotic lesions to vascular wall develop [5, 8]. These facts do not merely refine the current terminology, but they principally renovate it due to substantiation of certain molecular mechanisms of atherogenic modification of LDL particles with implication of natural low molecular weight carbonyl compounds. The representative epidemiologic studies corroborated the view that atherogenic (cholesterol-rich) LDL particles also are and the MDA-modified ones [24]. Consequently, the carbonyl modification of LDL particles promotes effective delivery of cholesterol into the vascular wall [24]. Moreover, the novel data show that enhanced accumulation of MDA-modified LDL is typical of the patients with certain mutations of apoprotein B-100, which means that carbonyl modification of LDL can be genetically determined [25]. Endothelial dysfunction induced by oxidative stress also plays an important role in the development of cerebrovascular diseases, particularly in stroke [26]. An important role in the progression of these diseases is associated with the activation of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase generating O2•-, however, the role of LOX-1 and dicarbonyl-modified LDL in this process has not been studied to date [26].

3. Dicarbonil-Dependent Inhibition of Antioxidant Enzymes in Atherosclerosis

Similar to apoprotein B-100, the protein molecules Cu,Zn-SOD and GSH-Px are modified during the accumulation of MDA resulting in the inhibition of their activity [27, 28] because of conformational alterations in the structure of the active center [29]. Evidently, the dicarbonyl-dependent inhibition of activity of the antioxidant enzymes during atherogenesis should stimulate oxidative stress. Hence, the development of oxidative stress (hallmarked by LOOH buildup) and the following carbonyl stress (reported by MDA accumulation) in atherogenesis lead to the formation and accumulation of dicarbonyl-modified LDL, which are the key factors provoking the pre-atherogenic lesions to vascular wall [30].

4. The Role of Dicarbonil-Modified LDL in Diabetogenesis

It is common knowledge that diabetes mellitus is a risk factor for atherosclerosis, and diabetes promotes its rapid progress; however, the majority of diabetic patients die of vascular incidents [31, 32, 33]. Nevertheless, the available literature does not comprehensively explain the pathophysiological mechanisms associated with these phenomena. A rather long time ago, a hypothesis was advanced on the important role of FRO in the pathogenesis of diabetes mellitus [34]. Importantly, diabetes mellitus is characterized by the development of not oxidative but carbonyl stress [35] characterised by the accumulation of not MDA, but RCS, formed during oxidative transformation of glucose, such as glyoxal (MDA homolog) and methylglyoxal (MDA isomer) [35, 36, 37]. Glyoxal is formed in the process of glyoxylation during autoxidation of glucose and other six-carbon carbohydrates, whereas methylglyoxal is mainly produced by glycolysis during the enzymatic oxidation of glucose with the generation of triozophosphates [35, 36, 37]. In addition, glyoxal and methylglyoxal can be produced non-enzymatically when hydroperoxyl free radicals attack glucose [38, 39] or its derivatives [40]. During co-oxidation of LDL in the presence of glucose in concentrations characteristic of its level in the blood of patients with insulin-independent (type II) diabetes, a dramatic increase in the rate of FRO of LDL occurs in parallel with the augmented generation of O2•- [41]. During the Maillard reaction, i.e., the interaction of methylglyoxal with terminal amino groups of apoprotein B-100, generation of O2•- is also possible [42]. Therefore, in contrast to atherogenesis, diabetogenesis is characterized by the initial development of the carbonyl stress manifested by RCS accumulation, while oxidative stress is the secondary process, provoked at the later stages of the disease by reactive oxygen species (ROS) generated in the above reactions. Accordingly, in diabetogenesis, one should differentiate the stages of carbonyl stress development and the subsequent oxidative stress manifested by the accumulation of diverse oxidation products. Accumulation of glyoxal and methylglyoxal in the blood plasma of patients with diabetes mellitus was documented experimentally [36, 37]. In patients with insulin-independent (type II) diabetes, the carbonyl modification of LDL is essentially increased [41] in parallel with a pronounced decrease of activity of erythrocytic Cu,Zn-SOD and GSH-Px [28, 43], which are the typical hallmarks of carbonyl stress. At the same time, the oxidative stress in diabetic patients is manifested by a decrease in the length of telomeres in the nucleated blood cells [43] as well as by the rise of the blood and urine levels of 8-hydroxy-2′-deoxyguanosine (the final product of oxidative DNA destruction) in patients with insulin-independent (type II) diabetes [43]. It is worth noting that 8-hydroxy-2′-deoxyguanosine is a widely accepted biomarker of oxidative stress [44]. The enhanced level of LOOH-LDL [41] in the blood of patients with insulin-independent (type II) diabetes also attests to the possibility that the secondary induction of oxidative stress can occur in diabetogenesis. Pronounced elevation of blood concentrations of glyoxal and methylglyoxal in patients with type II diabetes [36, 37, 45] can provoke modification of LDL, which will be recognised by the scavenger receptors in macrophages with subsequent development of lipoidosic lesions in the vascular wall. Specifically, modification of LDL with glyoxal essentially augments the receptive capture of LDL by macrophages [35]. Based on the above data, we advanced a hypothesis on the similar molecular mechanism underlying lesions to vascular wall in atherosclerosis and diabetes mellitus, which assumes enhancement of chemical modification of apoprotein B-100 in LDL with dicarbonyls that are accumulating during FRO of the lipids in atherosclerosis or oxidative transformations of glucose molecules in diabetes mellitus [41, 46]. This hypothesis reliably explains the reasons for atherogenesis stimulation in diabetes and the fact that diabetes elevates the risk of atherosclerosis [41, 46].

5. Lectin-Like Oxidized LDL Receptor LOX-1 and Endothelial Dysfunction

Recent studies have shown that oxidized LDL plays an important role in the onset of endothelial dysfunction [30, 46, 47, 48, 49, 50, 51]. It is hypothesized that endothelial lectin-type oxidized LDL receptor 1 (LOX-1) binds with oxidized LDL thereby triggering expression of NADPH oxidase (NOX-1), which generates O2•- which is responsible for the damage to endotheliocytes [30, 46, 52]. It was established that powerful expression of LOX-1 and NOX-1 in human endotheliocytes is caused by culturing the cells with dicarbonyl-modified (MDA-, glyoxal-, and methylglyoxal-modified) LDL [53], the greatest expression of LOX-1 and NOX-1 being provoked by MDA-modified LDL. Simultaneously, a compensatory reaction was revealed in the endothelial cells based on the expression of the genes responsible for the biosynthesis of the antioxidant enzymes such as SOD, GSH-Px, and peroxiredoxins [53]. Despite these processes, the expression of genes relating to the key factors of apoptosis (BCL2-associated X protein (BAX), caspase 9, and caspase 3) elevates, which finally stimulates damage and apoptosis in endotheliocytes [53]. Thus, the initial stages in the development of endothelial dysfunction known to play the leading role in atherogenesis and diabetogenesis directly depend on the formation of non-oxidized (LOOH-containing) but dicarbonyl-modified LDL [53]. In the end, O2•--dependent lesions of endotheliocytes provokes stimulation of apoptosis and the death of these cells [30, 46, 52, 53], which in turn, alleviates invasion of dicarbonyl-modified LDL into the vascular wall.

6. Antioxidant Enzymes of Endotheliocytes. Their Inhibition by Natural Low Molecular Weight Dicarbonyls

The enzymatic antioxidant system in endotheliocytes is formed predominantly by a special class of enzymes, i.e., peroxiredoxins [54], which similar to Cu,Zn-SOD and GSH-Px [28] are rather sensitive to the inhibitory action of low molecular weight dicarbonyls accumulating during oxidative and carbonyl stresses [55]. It is beyond any doubt that suppression of activity of peroxiredoxins weakens the antiradical defense of endothelial cells thereby promoting their damage and endothelial dysfunction. The available data suggest that the generation of dicarbonyl-modified LDL is the key factor in the development of endothelial dysfunction, which is the leading process in atherogenesis and diabetogenesis.

7. Free Radicals as Promoters of Endothelial Glycocalyx Fragmentation

Clearly, a lesion to endothelial glycocalyx should precede the development of endothelial dysfunction. Glycocalyx is the protective layer composed of macromolecules such as proteoglycans and glycoproteins, which cover the luminal face of endotheliocytes [56, 57]. A lesion to glycocalyx is considered as the earliest stage in the damage to vascular wall in diverse pathologies [58, 59, 60, 61]. Now it is a common knowledge that glycocalyx controls vascular permeability [62] and adhesion of the blood formed elements on the outer face of endotheliocytes [63, 64]. Moreover, glycocalyx protects the endothelium against a moiety of damaging factors such as viruses, proinflammatory cytokines, and ROS [65, 66]. Presumably, namely, glycocalyx is the barrier that prevents penetration of atherogenic LDL into the subendothelial space of the vascular wall [67]. Importantly, thinning of glycocalyx due to its fragmentation was observed in the process of O2•- hyperproduction (“oxidative burst”) during ischemia and/or ischemia-reperfusion injury [68, 69, 70]. It is worthy to note that a lesion to glycocalyx was revealed when the blood plasma level of oxidized LDL increased [71, 72], which can be explained by the enhanced production of O2•- due to the expression of LOX-1 and NADPH oxidase [30, 46, 53]. These facts are evidence that oxidatively modified LDL (most probably, the dicarbonyl-modified ones) generated during oxidative and carbonyl stresses are the key factors in the outbreak and the progress of endothelial dysfunction. The integrity of glycocalyx should prevent the development of athero- and diabetogenesis, whereas damage to glycocalyx is probably the first stage in the atherosclerotic lesion to the vascular wall. The previously described (see review sections 2–7) processes leading to the development of endothelial dysfunction are presented in the following scheme (Fig. 1).

Fig. 1. Main stages of vascular wall damage under oxidative/carbonyl stress and development of endothelial dysfunction in the process of atherogenesis/diabetogenesis under the actions of dicarbonyl-modified LDLs according to the literature and our results. LDL, low-density lipoproteins; MDA, malondialdehyde; GL, glyoxal; MGL, methylglyoxal; LOOH-contained LDL, lipohydroperoxydes-contained LDL (see explanation in the text); LOX-1, lectin like oxidized low density lipoprotein receptor 1; NADPH, nicotinamide adenine dinucleotide phosphate.

8. Reasons for Failure in Using LDL Protection against FRO by Natural Antioxidants

Based on the above premise, it seems logical to employ antioxidants to inhibit lipoperoxidation of LDL. With this aim in mind, some clinical studies tested safe natural antioxidants such as vitamin E (α-tocopherol, α-TOH). In contrast to rather promising results obtained in the animals with experimental atherosclerosis, the clinical trials of the action of antioxidants (α-TOH predominantly) in cardiovascular diseases were not so unequivocal [30, 73, 74, 75, 76]. However, it should be noted that in most clinical studies, the use of vitamin E as an antioxidant was not reasonable. One should take into consideration that vitamin E is the dosage form, in which α-TOH is included as the ethers of organic acids (acetate or succinate), so it is not an antioxidant because of the blocked OH-group. In the intestine, the esterified α-TOH can be hydrolyzed, although there are no data on the effectiveness of this process in patients with ischemic heart disease or atherosclerosis. Thus, there is no firm evidence that α-TOH was available in the patients’s organisms in the phenolic form capable to exert its antioxidant effects. Moreover, similar to other phenolic antioxidants, α-TOH does not block FRO of the lipids completely, but it only decreases FRO intensity due reduction of the hyperactive lipid hydroxyperoxyl (LO2•) and alkoxy (LO•) radicals with production of low-activity radical inhibitor (tocoferoxyl radical – α-TO•) according to the following reaction:

LO2∙⁢(LO∙)+α⁢-TOH→LOOH⁢(LOH)+α⁢-TO∙.

Under pronounced accumulation of α-TO• radicals, which can occur when antioxidants are administered in high doses, these radicals can induce FRO. Therefore, the antioxidant effect can transform into the pro-oxidant one [77]. In other words, the concentration-dependent inversion of the antioxidant effect is possible, which was observed both in vitro [78] and in vivo [77]. Similar to other liposoluble vitamins, α-TOH is transported within the hydrophobic lipid core of LDL particles [79], although defense of circulating LDL against FRO is performed not by α-TOH, but by the reduced (phenolic) form of coenzyme Q10 [80, 81, 82, 83]. Remembering that one LDL particle contains no more than 1-2 molecules of coenzyme Q10 per about 800 molecules of FRO substrate, i.e., unsaturated phospholipids [84], effective inhibition of FRO in LDL by this antioxidant is possible only with its efficient reduction (biogeneration), which occurs, probably, with the participation of radical intermediates α-TOH and ascorbate [85, 86, 87, 88]. Administration of α-TOH in high doses produces no effect on LDL oxidability in patients [83], which means that the use of α-TOH to inhibit the oxidability of LDL in clinical trials is not sufficiently substantiated both theoretically and experimentally. At the same time, coenzyme Q10 effectively suppresses FRO of liver biomembranes in vitro [89] and LDL particles in vivo [83]. The data of clinical trials with high doses of α-TOH revealed no apparent positive clinical effects, although at the same time, there were no detrimental consequences of this antioxidant therapy [30, 46]. When analyzing these studies, some authors allege without sound reasons that the antioxidants exert negative clinical action [74, 75], although it is incorrect to consider the absence of an effect as the negative action. From our viewpoint, it is unacceptable to generalise seemingly “negative” data harvested with some antioxidants such as α-TOH [8, 30, 46] onto a rather diverse group of antioxidants that consists of compounds with different structures and mechanisms of action. Enhanced effectiveness in the protection of LDL against oxidation is typical not only for coenzyme Q10 [83] but other phenolic antioxidants such as non-toxic synthetic antioxidant probucol [90, 91, 92] which has been shown to effectively inhibit free radical peroxidation of LDL in vivo [41, 83, 92].

9. Perspectives of Pharmacotherapy Aimed at Enhancing the Utilisation of Low Molecular Weight Natural Dicarbonyls

The data summarized in this review suggest that to suppress atherogenesis and prevent endothelial dysfunction, it is necessary to inhibit not only accumulation of the primary products (LOOH) in LDL, but also to suppress the buildup of secondary FRO products, i.e., low molecular weight dicarbonyls. Theoretical substantiation and experimental confirmation of the leading role of secondary products of free radical peroxidation of lipids and products of oxidative transformation of six-atom carbohydrates in the development of endothelial dysfunction in atherosclerosis and diabetes mellitus dictates fundamentally new approaches to pharmacotherapy of these diseases. The main emphasis should be placed on the search for nontoxic compounds that can act as scavengers of natural dicarbonyls, such as MDA, glyoxal and methylglyoxal [93, 94]. Such investigations are already underway, with simple compounds such as glucosamine, taurine, histamine, pyridoxamine, etc. shown to be effective in model systems [95, 96, 97, 98]. Importantly, there are already examples of the successful use of natural dicarbonyl scavengers in clinical trials [99, 100]. Now positive examples are available, which demonstrate the effective inhibition of FRO intensity by the scavengers of dicarbonyls such as biguanides [41, 101] and imidazole-containing peptides [93, 102, 103]. There are also positive examples which demonstrate the effective inhibition of FRO intensity with dicarbonyl scavengers such as biguanides [41, 99, 100] and imidazole-containing peptides in clinical investigations [102, 103]. Specifically, the use of biguanides pronouncedly suppresses the symptoms of oxidative and carbonyl stresses in patients with diabetes mellitus, even without intake of any antioxidants (so-called “quasi-antioxidant effect”) [41]. There are data that hypolipidemic therapy with inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), which activates utilization of cholesterol-rich LDL in the liver, simultaneously lowering the level of MDA-modified LDL in blood plasma [104]. In such therapy, the kinetics of the reduction of LDL and MDA-modified LDL levels virtually coincide attesting to the predominant utilization of oxidatively modified LDLs, indicating why the use of PCSK9 in pharmacotherapy of atherosclerosis seems to be so promising [104]. Determination of the levels of soluble LOX-1, the fragments of glycocalyx, 8-hydroxy-2′-deoxyguanosine and other indices of oxidative and/or carbonyl stress is rather reasonable because they can be viewed as supplementary biomarkers to diagnose and control therapeutic effectiveness in atherosclerosis and diabetes mellitus. Preventive cardiology should aim to prevent the negative consequences of LDL oxidative modification, since dicarbonyl-modified LDL plays a key role in the molecular mechanisms of atherogenesis and diabetogenesis described in this review.

10. Conclusions

The review supports the authors’ experimentally proven idea that not “oxidized”, i.e., LOOH-containing LDL particles in phospholipids of the outer layer, but LDL particles chemically modified by low molecular weight natural dicarbonyls are atherogenic and capable of inducing endothelial dysfunction. The authors of numerous experimental studies obtaining “oxidized” LDL by multi-hour initiated FRO inevitably use a mixture of truly oxidised (LOOH-containing) LDL and MDA-modified LDL formed in the incubation medium. The atherogenic effect of these conditions, as well as stimulation of endothelial dysfunction, is caused exclusively by dicarbonyl-modified LDLs. The hypothesis put forward here allows a satisfactory explanation for the cause of the progression of atherosclerotic lesions in the vascular wall in the presence of diabetes mellitus, as well as proposing new approaches for the pharmacotherapy of atherosclerosis and diabetes.

Acknowledgment

Not applicable.

Author Contributions

The article is a review of the literature and the authors’ own research. VL, AT, MS and GK participated in the plan, design, and conception of the article; participated in the collection, analysis, and interpretation of the literature; and participated in the writing and final revision of the article. All authors read and approved the final manuscript. All authors participated sufficiently and agreed to be responsible for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Funding

This work was supported by the Russian Science Foundation grant № 22-15-00013.

Conflict of Interest

The authors declare no conflict of interest.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

[1] Нarman D The free radical theory of aging. Free Radicals in Biol. Academic Press NY, London, Paris etc. 1982 5 255 275
[2] Нarman D The free radical theory of aging: the “free radical” diseases Age 1984 7 111 131
[3] Glavind J Hartmann S Clemmesen J Jessen KE Dam H et al Studies on the role of lipoperoxides in human pathology. II. The presence of peroxidized lipids in the atherosclerotic aorta Acta Pathologica et Microbiologica Scandinavica. 1952 30 1 6 14933036
[4] Woodford FP Boettcher CJ Oette K Ahrens Eh Jr The Artifactual Nature of Lipid Peroxides Detected in Extracts of Human Aorta Journal of Atherosclerosis Research 1965 5 311 316 14292181
[5] Lankin VZ Tikhaze AK Atherosclerosis as a free radical pathology and antioxidative therapy of this disease. Free radicals, NO and inflammation. IOS Press Amsterdam 2003 218 231
[6] Kühn H Belkner J Wiesner R Schewe T Lankin VZ Tikhaze AK Structure elucidation of oxygenated lipids in human atherosclerotic lesions Eicosanoids 1992 5 17 22 1419075
[7] Lankin VZ Vikhert AM Kosykh VA Tikhaze AK Galakhov IE Orekhov AN et al Enzymatic detoxication of superoxide anion-radicals and lipoperoxides in intima and media of atherosclerotic aorta Biomedica Biochimica Acta 1984 43 797 802 6091625
[8] Lankin VZ Tikhaze AK Role of Oxidative Stress in the Genesis of Atherosclerosis and Diabetes Mellitus: A Personal Look Back on 50 Years of Research Current Aging Science 2017 10 18 25 27677837
[9] Lankin VZ Free radical lipoperoxidation during atherosclerosis Free Radical Biology and Medicine 1994 16 8
[10] Lankin VZ Tikhaze AK Konovalova GG Differences in Structural Changes and Pathophysiological Effects of Low-Density Lipoprotein Particles upon Accumulation of Acylhydroperoxy Derivatives in Their Outer Phospholipid Monolayer or upon Modification of Apoprotein B-100 by Natural Dicarbonyls Biochemistry. Biokhimiia 2023 88 1910 1919 38105208
[11] Goldstein JL Ho YK Basu SK Brown MS Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition Proceedings of the National Academy of Sciences of the United States of America 1979 76 333 337 218198
[12] Steinberg D Parthasarathy S Carew TE Khoo JC Witztum JL Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity The New England Journal of Medicine 1989 320 915 924 2648148
[13] Steinbrecher UP Lougheed M Kwan WC Dirks M Recognition of oxidized low density lipoprotein by the scavenger receptor of macrophages results from derivatization of apolipoprotein B by products of fatty acid peroxidation The Journal of Biological Chemistry 1989 264 15216 15223 2768257
[14] Kita T Ishii K Yokode M Kume N Nagano Y Arai H et al The role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis European Heart Journal 1990 11 Suppl E 122 127 2226520
[15] Witztum JL The oxidation hypothesis of atherosclerosis Lancet (London, England) 1994 344 793 795 7916078
[16] Ylä-Herttuala S Macrophages and oxidized low density lipoproteins in the pathogenesis of atherosclerosis Annals of Medicine 1991 23 561 567 1721825
[17] Yla-Herttuala S Role of lipid and lipoprotein oxidation in the pathogenesis of atherosclerosis Drugs Today 1994 30 507 514
[18] Steinberg D Role of oxidized LDL and antioxidants in atherosclerosis Advances in Experimental Medicine and Biology 1995 369 39 48 7598015
[19] Estévez M Padilla P Carvalho L Martín L Carrapiso A Delgado J Malondialdehyde interferes with the formation and detection of primary carbonyls in oxidized proteins Redox Biology 2019 26 101277 31352127
[20] Fogelman AM Shechter I Seager J Hokom M Child JS Edwards PA Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages Proceedings of the National Academy of Sciences of the United States of America 1980 77 2214 2218 6769124
[21] Lankin VZ Tikhaze AK Osis YG Modeling the cascade of enzymatic reactions in liposomes including successive free radical peroxidation, reduction, and hydrolysis of phospholipid polyenoic acyls for studying the effect of these processes on the structural-dynamic parameters of the membranes Biochemistry. Biokhimiia. 2002 67 566 574 12059777
[22] Schewe T Rapoport SM Kühn H Enzymology and physiology of reticulocyte lipoxygenase: comparison with other lipoxygenases Advances in Enzymology and Related Areas of Molecular Biology 1986 58 191 272 3087141
[23] Lankin VZ Tikhaze AK Kumskova EM Macrophages actively accumulate malonyldialdehyde-modified but not enzymatically oxidized low density lipoprotein Molecular and Cellular Biochemistry 2012 365 93 98 22307746
[24] Lankin V Viigimaa M Tikhaze A Kumskova E Konovalova G Abina J et al Cholesterol-rich low density lipoproteins are also more oxidized Molecular and Cellular Biochemistry 2011 355 187 191 21647615
[25] Khlebus E Kutsenko V Meshkov A Ershova A Kiseleva A Shevtsov A et al Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels PloS One 2019 14 e0217620 31150472
[26] Scicchitano P Cortese F Gesualdo M De Palo M Massari F Giordano P et al The role of endothelial dysfunction and oxidative stress in cerebrovascular diseases Free Radical Research 2019 53 579 595 31106620
[27] Tikhaze AK Kosach VY Lankin VZ Panferova AA Smirnova MD Indicator Characterizing Carbonyl-Dependent Modification of Erythrocytic Superoxy dismutase as a Biochemical Marker of Oxidative Stress in Coronary Heart Disease Kardiologiia 2020 60 1019 32515705
[28] Lankin VZ Konovalova GG Tikhaze AK Shumaev KB Belova Kumskova EM Grechnikova MA et al Aldehyde inhibition of antioxidant enzymes in the blood of diabetic patients Journal of Diabetes 2016 8 398 404 25990785
[29] Lankin VZ Shumaev KB Tikhaze AK Kurganov BI Influence of dicarbonyls on kinetic characteristics of glutathione peroxidase Doklady. Biochemistry and Biophysics 2017 475 287 290 28864892
[30] Lankin VZ Tikhaze AK Melkumyants AM Dicarbonyl-Dependent Modification of LDL as a Key Factor of Endothelial Dysfunction and Atherosclerotic Vascular Wall Damage Antioxidants (Basel, Switzerland) 2022 11 1565 36009284
[31] Nishizawa T Bornfeldt KE Diabetic vascular disease and the potential role of macrophage glucose metabolism Annals of Medicine 2012 44 555 563 21679104
[32] Bornfeldt KE Does Elevated Glucose Promote Atherosclerosis? Pros and Cons Circulation Research 2016 119 190 193 27390330
[33] Poznyak A Grechko AV Poggio P Myasoedova VA Alfieri V Orekhov AN The Diabetes Mellitus-Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation International Journal of Molecular Sciences 2020 21 1835 32155866
[34] Oberley LW Free radicals and diabetes Free Radical Biology & Medicine 1988 5 113 124 3075947
[35] Lankin VZ Tikhaze AK Kapel’ko VI Shepel’kova GS Shumaev KB Panasenko OM et al Mechanisms of oxidative modification of low density lipoproteins under conditions of oxidative and carbonyl stress Biochemistry. Biokhimiia 2007 72 1081 1090 18021066
[36] Thornalley PJ Langborg A Minhas HS Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose The Biochemical Journal 1999 344 109 116 10548540
[37] Wang XJ Ma SB Liu ZF Li H Gao WY Elevated levels of α-dicarbonyl compounds in the plasma of type II diabetics and their relevance with diabetic nephropathy Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2019 1106-1107 19 25 30639946
[38] Spiteller G The relation of lipid peroxidation processes with atherogenesis: a new theory on atherogenesis Molecular Nutrition & Food Research 2005 49 999 1013 16270286
[39] Spiteller G Peroxyl radicals are essential reagents in the oxidation steps of the Maillard reaction leading to generation of advanced glycation end products Annals of the New York Academy of Sciences 2008 1126 128 133 18448806
[40] Lankin VZ Shadyro OI Shumaev KB Tikhaze AK Sladkova AA Non-enzymatic methylglyoxal formation from glucose metabolites and generation of superoxide anion radical during methylglyoxal-dependend cross-links reaction Journal of Antioxidant Activity 2019 1 34 45
[41] Lankin V Konovalova G Tikhaze A Shumaev K Kumskova E Viigimaa M The initiation of free radical peroxidation of low-density lipoproteins by glucose and its metabolite methylglyoxal: a common molecular mechanism of vascular wall injure in atherosclerosis and diabetes Molecular and Cellular Biochemistry 2014 395 241 252 24997046
[42] Shumaev KB Gubkina SA Kumskova EM Shepelkova GS Ruuge EK Lankin VZ Superoxide formation as a result of interaction of L-lysine with dicarbonyl compounds and its possible mechanism Biochemistry. Biokhimiia 2009 74 461 466 19463101
[43] Lankin VZ Tikhaze AK Konovalova GG Odinokova OA Doroshchuk NA Chazova IE Oxidative and carbonyl stress as a factors of the modification of proteins and DNA destruction in diabetes Terapevticheskii Arkhiv 2018 90 46 50 30701795
[44] Graille M Wild P Sauvain JJ Hemmendinger M Guseva Canu I Hopf NB Urinary 8-OHdG as a Biomarker for Oxidative Stress: A Systematic Literature Review and Meta-Analysis International Journal of Molecular Sciences 2020 21 3743 32466448
[45] Knott HM Brown BE Davies MJ Dean RT Glycation and glycoxidation of low-density lipoproteins by glucose and low-molecular mass aldehydes. Formation of modified and oxidized particles European Journal of Biochemistry 2003 270 3572 3582 12919321
[46] Lankin VZ Tikhaze AK Melkumyants AM Malondialdehyde as an Important Key Factor of Molecular Mechanisms of Vascular Wall Damage under Heart Diseases Development International Journal of Molecular Sciences 2022 24 128 36613568
[47] Pirillo A Norata GD Catapano AL LOX-1, OxLDL, and atherosclerosis Mediators of Inflammation 2013 2013 152786 23935243
[48] Lubrano V Balzan S LOX-1 and ROS, inseparable factors in the process of endothelial damage Free Radical Research 2014 48 841 848 24886290
[49] Mitra S Goyal T Mehta JL Oxidized LDL, LOX-1 and atherosclerosis Cardiovascular Drugs and Therapy 2011 25 419 429 21947818
[50] Kattoor AJ Kanuri SH Mehta JL Role of Ox-LDL and LOX-1 in Atherogenesis Current Medicinal Chemistry 2019 26 1693 1700 29737246
[51] Akhmedov A Sawamura T Chen CH Kraler S Vdovenko D Lüscher TF Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease European Heart Journal 2021 42 1797 1807
[52] Galle J Schneider R Heinloth A Wanner C Galle PR Conzelmann E et al Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: role of oxidative stress Kidney International 1999 55 1450 1461 10201010
[53] Lankin VZ Sharapov MG Tikhaze AK Goncharov RG Antonova OA Konovalova GG et al Dicarbonyl-Modified Low-Density Lipoproteins Are Key Inducers of LOX-1 and NOX1 Gene Expression in the Cultured Human Umbilical Vein Endotheliocytes Biochemistry. Biokhimiia 2023 88 2125 2136 38462455
[54] Sharapov MG Goncharov RG Gordeeva AE Novoselov VI Antonova OA Tikhaze AK et al Enzymatic antioxidant system of endotheliocytes Doklady. Biochemistry and Biophysics 2016 471 410 412 28058676
[55] Lankin VZ Sharapov MG Goncharov RG Tikhaze AK Novoselov VI Natural Dicarbonyls Inhibit Peroxidase Activity of Peroxiredoxins Doklady. Biochemistry and Biophysics 2019 485 132 134 31201633
[56] Weinbaum S Tarbell JM Damiano ER The structure and function of the endothelial glycocalyx layer Annual Review of Biomedical Engineering 2007 9 121 167
[57] Reitsma S Slaaf DW Vink H van Zandvoort MAMJ oude Egbrink MGA The endothelial glycocalyx: composition, functions, and visualization Pflugers Archiv: European Journal of Physiology 2007 454 345 359 17256154
[58] Noble MIM Drake-Holland AJ Vink H Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process QJM: Monthly Journal of the Association of Physicians 2008 101 513 518 18319293
[59] Becker BF Jacob M Leipert S Salmon AHJ Chappell D Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases British Journal of Clinical Pharmacology 2015 80 389 402 25778676
[60] Pillinger NL Kam P Endothelial glycocalyx: basic science and clinical implications Anaesthesia and Intensive Care 2017 45 295 307 28486888
[61] Nieuwdorp M van Haeften TW Gouverneur MCLG Mooij HL van Lieshout MHP Levi M et al Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo Diabetes 2006 55 480 486 16443784
[62] Curry FE Adamson RH Endothelial glycocalyx: permeability barrier and mechanosensor Annals of Biomedical Engineering 2012 40 828 839 22009311
[63] Mulivor AW Lipowsky HH Role of glycocalyx in leukocyte-endothelial cell adhesion American Journal of Physiology. Heart and Circulatory Physiology 2002 283 H1282 H1291 12234777
[64] Reitsma S Oude Egbrink MGA Heijnen VVT Megens RTA Engels W Vink H et al Endothelial glycocalyx thickness and platelet-vessel wall interactions during atherogenesis Thrombosis and Haemostasis 2011 106 939 946 21901228
[65] Alphonsus CS Rodseth RN The endothelial glycocalyx: a review of the vascular barrier Anaesthesia 2014 69 777 784 24773303
[66] Henrich M Gruss M Weigand MA Sepsis-induced degradation of endothelial glycocalix TheScientificWorldJournal 2010 10 917 923
[67] van den Berg BM Spaan JAE Vink H Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice Pflugers Archiv: European Journal of Physiology 2009 457 1199 1206 18839207
[68] Rehm M Bruegger D Christ F Conzen P Thiel M Jacob M et al Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia Circulation 2007 116 1896 1906 17923576
[69] Chappell D Jacob M Hofmann-Kiefer K Rehm M Welsch U Conzen P et al Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion Cardiovascular Research 2009 83 388 396 19307232
[70] Rubio-Gayosso I Platts SH Duling BR Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury American Journal of Physiology. Heart and Circulatory Physiology 2006 290 H2247 H2256 16399871
[71] Vink H Constantinescu AA Spaan JA Oxidized lipoproteins degrade the endothelial surface layer: implications for platelet-endothelial cell adhesion Circulation 2000 101 1500 1502 10747340
[72] Constantinescu AA Vink H Spaan JA Elevated capillary tube hematocrit reflects degradation of endothelial cell glycocalyx by oxidized LDL American Journal of Physiology. Heart and Circulatory Physiology 2001 280 H1051 H1057 11179046
[73] Steinberg D Witztum JL Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 2002 105 2107 2111 11980692
[74] Jialal I Traber M Devaraj S Is there a vitamin E paradox? Current Opinion in Lipidology 2001 12 49 53 11176203
[75] Kuller LH A time to stop prescribing antioxidant vitamins to prevent and treat heart disease? Arteriosclerosis, Thrombosis, and Vascular Biology 2001 21 1253 11498446
[76] Steinberg D Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet (London, England) 1995 346 36 38 7603147
[77] Lankin VZ Tikhaze AK Konovalova GG Kozachenko AI Concentration inversion of the antioxidant and pro-oxidant effects of beta-carotene in tissues in vivo Biulleten’ Eksperimental’noi Biologii i Meditsiny 1999 128 314 316
[78] Bowry VW Ingold KU Stocker R Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant The Biochemical Journal 1992 288 341 344 1463440
[79] Traber MG Burton GW Ingold KU Kayden HJ RRR- and SRR-alpha-tocopherols are secreted without discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low density lipoproteins Journal of Lipid Research 1990 31 675 685 2351872
[80] Stocker R Bowry VW Frei B Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol Proceedings of the National Academy of Sciences of the United States of America 1991 88 1646 1650 2000375
[81] Mohr D Bowry VW Stocker R Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation Biochimica et Biophysica Acta 1992 1126 247 254
[82] Ahmadvand H Mabuchi H Nohara A Kobayahi J Kawashiri MA Effects of coenzyme Q(10) on LDL oxidation in vitro Acta Medica Iranica 2013 51 12 18 23456579
[83] Lankin VZ Tikhaze AK Kukharchuk VV Konovalova GG Pisarenko OI Kaminnyi AI et al Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins Molecular and Cellular Biochemistry 2003 249 129 140 12956408
[84] Stocker R Natural antioxidants and atherosclerosis Asia Pacific Journal of Clinical Nutrition 1993 2 15 20
[85] Frei B Kim MC Ames BN Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations Proceedings of the National Academy of Sciences of the United States of America 1990 87 4879 4883 2352956
[86] Beyer RE The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q Journal of Bioenergetics and Biomembranes 1994 26 349 358 7844109
[87] Packer JE Slater TF Willson RL Direct observation of a free radical interaction between vitamin E and vitamin C Nature 1979 278 737 738 431730
[88] Niki E Saito T Kawakami A Kamiya Y Inhibition of oxidation of methyl linoleate in solution by vitamin E and vitamin C The Journal of Biological Chemistry 1984 259 4177 4182 6706998
[89] Tikhaze AK Konovalova GG Lankin VZ Kaminnyi AI Kaminnaja VI Ruuge EK et al Effect of ubiquinone Q(10) and antioxidant vitamins on free radical oxidation of phospholipids in biological membranes of rat liver Bulletin of Experimental Biology and Medicine 2005 140 181 183 16282995
[90] Kagan VE Freisleben HJ Tsuchiya M Forte T Packer L Generation of probucol radicals and their reduction by ascorbate and dihydrolipoic acid in human low density lipoproteins Free Radical Research Communications 1991 15 265 276 1666624
[91] Shumaev KB Ruuge EK Dmitrovsky AA Bykhovsky VYa Kukharchuk VV Effect of lipid peroxidation products and antioxidants on the formation of probucol radical in low density lipoproteins Biochemistry. Biokhimiia 1997 62 657 660 9284547
[92] Tikhaze AK Lankin VZ Konovalova GG Shumaev KB Kaminnyi AI Kozachenko AI et al Antioxidant probucol as an effective scavenger of lipid radicals in low density lipoproteins in vivo and in vitro Bulletin of Experimental Biology and Medicine 1999 128 818 821
[93] Aldini G Dalle-Donne I Colombo R Maffei Facino R Milzani A Carini M Lipoxidation-derived reactive carbonyl species as potential drug targets in preventing protein carbonylation and related cellular dysfunction ChemMedChem 2006 1 1045 1058 16915603
[94] Aldini G Dalle-Donne I Facino RM Milzani A Carini M Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls Medicinal Research Reviews 2007 27 817 868 17044003
[95] Fang C Peng M Li G Tian J Yin D New functions of glucosamine as a scavenger of the lipid peroxidation product malondialdehyde Chemical Research in Toxicology 2007 20 947 953 17480103
[96] Li G Tang T Peng M He H Yin D Direct reaction of taurine with malondialdehyde: evidence for taurine as a scavenger of reactive carbonyl species Redox Report: Communications in Free Radical Research 2010 15 268 274 21208526
[97] Li L Li G Sheng S Yin D Substantial reaction between histamine and malondialdehyde: a new observation of carbonyl stress Neuro Endocrinology Letters 2005 26 799 805 16380691
[98] Kang Z Li H Li G Yin D Reaction of pyridoxamine with malondialdehyde: mechanism of inhibition of formation of advanced lipoxidation end-products Amino Acids 2006 30 55 61 15990947
[99] Ruggiero-Lopez D Lecomte M Moinet G Patereau G Lagarde M Wiernsperger N Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation Biochemical. Pharmacology. 1999 58 1765 1773 10571251
[100] Beisswenger P Ruggiero-Lopez D Metformin inhibition of glycation processes Diabetes & Metabolism 2003 29 6S95 6S103 14502106
[101] Wang G Wang Y Yang Q Xu C Zheng Y Wang L et al Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo Cell Death & Disease 2022 13 29 35013107
[102] Boldyrev AA Aldini G Derave W Physiology and pathophysiology of carnosine Physiological Reviews 2013 93 1803 1845 24137022
[103] Reddy VP Garrett MR Perry G Smith MA Carnosine: a versatile antioxidant and antiglycating agent Science of Aging Knowledge Environment: SAGE KE 2005 2005 pe12 15872311
[104] Lankin VZ Konovalova GG Domogatsky SP Tikhaze AK Klots IN Ezhov MV Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans International Journal of Molecular Sciences 2023 24 10471 37445648
