key: cord-0072017-6li0cswk authors: Belinskaia, D. A.; Voronina, P. A.; Goncharov, N. V. title: Integrative Role of Albumin: Evolutionary, Biochemical and Pathophysiological Aspects date: 2021-12-20 journal: J Evol Biochem Physiol DOI: 10.1134/s002209302106020x sha: 5323f923da826ffeb260f9948abbe7954f63fb8a doc_id: 72017 cord_uid: 6li0cswk Being one of the main proteins in the human body and many animal species, albumin plays a crucial role in the transport of various ions, electrically neutral molecules and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind almost all known drugs, many nutraceuticals and toxic substances, determining their pharmaco- and toxicokinetics. However, albumin is not only the passive but also the active participant of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. Due to the thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. The interaction of the protein with blood cells, blood vessels, and also with tissue cells outside the vascular bed is of great importance. The interaction of albumin with endothelial glycocalyx and vascular endothelial cells largely determines its integrative role. This review provides information of a historical nature, information on evolutionary changes, inflammatory and antioxidant properties of albumin, on its structural and functional modifications and their significance in the pathogenesis of some diseases. Albumin probably was the first protein that physicians of ancient civilizations paid attention to. Thus, Hippocrates in the V century BC associ ated kidney disease in his patients with the pres ence of foamy urine, which, as now is evident, becomes so due to the presence of albumin in it. The first recorded attempts to extract albumin from urine using vinegar were made in the 16th century by Paracelsus, but it was only in 1894 that Gurber first crystallized albumin from horse serum [1] . Since at first the object of the study and the source of albumin was blood serum, the defi nition of "serum albumin" was fixed for albumin, although modern technologies for the isolation of albumin deal with blood plasma [2] . At the same time, the initial reason for the frequent use of the phrase "serum albumin" is the need to emphasize its difference from egg, milky and plant albumins. Serum albumin belongs to the albuminoid superfamily, which also includes vitamin D bind ing protein (VDP), alpha fetoprotein and alpha albumin (afamin); accordingly, the gene family includes the genes of these four globular proteins [3] . This family is found only in vertebrates [4] , so serum albumin is available not only in mammals, but also in birds, some species of frogs, lampreys and salamanders (an exhaustive list is presented on the website albumin.org). Quantitatively, albu min is the dominant plasma or serum protein and, along with other representatives of the family, acts as a carrier of endogenous and exogenous sub stances, including thyroxine, fatty acids and drugs, while the main "cargo" of VDP is 25 hydroxyvita min D [3] . All albuminoids are evolutionarily related to serum albumin [5, 6] . This is one of the most evolutionarily variable proteins, thus, in dif ferent species, the differences between albumin domains are 70-80%. Clearly, this is due to the development in the course of evolution of its spe cial binding characteristics in relation to new ligands-hormones, metabolites, toxins. In con trast to albumin, the differences in the structure of retinol binding protein are on the average 40%, and in the structure of histones-less than 10% [7] . The study of albuminoid genes showed that the sites of binding of fatty acids and thyroxine, the contact surface with the neonatal Fc receptor, as well as the amino acid residues of albumin forming a pocket for binding prostaglandins were most affected by selection [3] . However, despite on the fact that albumin is a rapidly evolving pro tein, it has two conservative characteristics, one of them is a tertiary structure, which consists mainly of helical sections in the complete absence of any β sheet fragments, and other one is a pattern of disulfide bonds, there are seventeen ones in the albumin molecule [8] . Due to the presence of serum albumin in all vertebrates, it can be a kind of indicator of the time of evolution of the species [9] . Thus, as a result of the study of the phyloge netic tree of primate albumins, it was found that orangutans were the first to separate from pri mates, gorillas followed, later chimpanzees and, finally, humans [10] . The ancestral albumin gene underwent a tri pling in the process of evolution about 525 million years ago [11] , when vertebrates first appeared. The molecule of human serum albumin (HSA) consists of 585 amino acid residues forming one polypeptide chain with a molecular weight of 66439 Da, however, these figures may vary due to species differences, genetic and posttranslational modifications. The architecture of albumin is pre dominantly spiral and consists of three domains with very similar shapes, which together form the shape of a heart. However, in the lamprey, also they are called "living fossil", albumin consists of seven domains [12] . Four canonical representa tives of the human albuminoid family are located in tandem in the 4q13.3 region [13] . Gene alb of HSA consists of 16961 nucleotide pairs from the putative "cap site" to the first poly(A) attachment site. It is divided into 15 exons, which are sym metrically placed in three domains. The precursor of serum albumin (preproalbumin) has an N ter minal peptide that cleaves off before the protein leaves the rough endoplasmic reticulum. The product (proalbumin) is transported to the Golgi apparatus. Limited proteolysis occurs in secretory granules and mature non glycosylated albumin is secreted into the extracellular medium [1] . Pro tein synthesis occurs mainly in hepatocyte poly somes; a healthy adult produces 10-15 g of albumin per day, which is almost 10% of all pro tein synthesis in the liver [14] . About 1/3 of the synthesized albumin remains in the plasma, while most of it passes into the intercellular space of muscle tissue and skin. The synthesis of albumin in the liver largely depends on colloidal osmotic pressure, gene expression is regulated by the feed back principle [15] . Albumin is produced only by hepatocytes. To deliver the newly synthesized albumin to the basolateral side of the cells and the subsequent secretion of albumin into the bloodstream, the neonatal Fc receptor (FcRn) is needed. FcRn is localized mainly inside cells and, in addition to IgG, can bind albumin. The absence of FcRn expression in hepatocytes leads to an increase in the level of albumin in bile, its intracellular accu mulation and a decrease in the level of circulating albumin [16] . For example, during oncogenesis, cells may lose or suppress the expression of FcRn. In these cases, the cells will not be able to process albumin after its internalization, instead it decomposes, providing the tumor with nutrients and promoting its growth. Due to the peculiarities of the structure and the absence of a direct con nection with immune responses, FcRn was classi fied as a non classical FcγR [17] . IgG and albumin are the major serum proteins that have a relatively long half life in serum largely due to their interaction with FcRn, which saves them from intracellular degradation through the mech anism of cellular recycling. All members of the albumin family are water soluble and moderately soluble in concentrated salt solutions. The key physico chemical proper ties of serum albumin are that this protein is acidic, highly soluble and very stable and can withstand a temperature of 60°C for 10 h [1] . HSA has in total 83 positively charged amino acid resi dues (Arg + Lys) and 98 negatively charged resi dues (Asp + Glu) with a theoretical pI value of 5.12. The difference between albumin and other blood proteins is that normally it is non glyco sylated (non glycated, if we mean exclusively non enzymatic glycosylation), although even a small percentage of glycated albumin makes a sig nificant contribution to the pathogenesis of diabe tes and other diseases. Glycation by lysine residues has been most well studied. There are also known redox modifications of albumin such as cysteinylation, homocysteinylation and sulfi nylation of Cys34 [18] . The albumin molecule has 17 disulfide bonds and one free thiol group in Cys34, which determines the participation of albumin in redox reactions. According to the redox state of Cys34, there are three isoforms of HSA: mercaptalbumin (reduced albumin, HMA) and non mercaptalbumin 1 and 2 (variants of oxidized albumin HNA 1 and HNA 2) [19] . There are dozens of genetic variants of HSA (the full list is available on the website albu min.org). The possible effects of some point muta tions on the ligand binding ability of HSA were studied by the interaction of five structurally char acterized genetic variants of the protein with high affinity for albumin drugs such as warfarin, salicy late and diazepam [20] . Equilibrium dialysis data show a noticeable decrease in the high affinity binding of all three ligands to HSA Canterbury (313lys→Asn) and HSA Parklands (365asp→His). In the case of HSA Verona (570glu→Lys), change of affinity wasn't detected. Affinity to the modifi cation of HSA Niigata (269asp→Gly) was reduced only for salicylate; and affinity to the modification of HSA Roma (321glu→Lys) was reduced for salicylate and diazepam. In half of the cases, the decrease in the primary association constant reached one order of magnitude, which led to an increase in the unrelated fraction of pharmaceuti cals by at least 500% with therapeutically relevant molar ratios of the pharmaceutical and protein. The main reason for the decrease in ligand binding is conformational changes in the 313-365 region, while changes in the charge of the molecule play a secondary role [20] . Albumin can bind various endogenous and exogenous ligands such as water and metal cat ions, fatty acids, hormones, bilirubin, metallopor phyrins, nitric oxide, aspirin, warfarin, ibuprofen, phenylbutazone, etc. [21] . The binding of low molecular weight ligands occurs at two main sites Sudlow site I in subdomain IIA and Sudlow site II in subdomain IIIA and also in several secondary sites. When albumin interacts with various sub stances, cooperative and allosteric modulation effects occur, which are usually inherent in multi meric macromolecules [22, 23] . Albumin is not only passive, but also an active participant in pharmacokinetic and toxicokinetic processes. Numerous experiments have shown that albumin possesses the (pseudo)esterase, phosphatase, per oxidase and other types of enzymatic activities. The enzymatic activity of the protein is consid ered in more details in our previous reviews [24] [25] [26] . Previously, it was suggested that some simple reactions catalyzed by serum albumin with Michaelis-Menten kinetics include nonspecific substrate binding and catalysis by local functional groups [27] . Most enzymes are able to catalyze physiologically irrelevant (secondary, "promiscu ous") reactions in addition to those reactions that have become the main ones for them as a result of evolution; the number of "promiscuous" reac tions turned out to be quite large when consider ing the issue in detail [28, 29] , so it is more the rule than the exception. However, the catalytic "illegibility" of albumin, in our opinion, arose as a result of the loss (and not the acquisition) of some specialized activities, for example, such as the activity of esterases (hydrolases) with digestive functions. The so called Kemp elimination, a prototypical reaction of proton cleavage from car bon, plays a certain role in the mechanism of albumin "promiscuity". The reaction occurs in the Stern layer, at the interface between the micelle head or the protein surface and water, so that a significant acceleration of the reaction can be achieved independently of the spatial substrate location [30, 31] . The mechanism of Kemp elimi nation in protein molecules is associated with the presence of aromatic amino acid residues (Trp, Tyr, Phe) that provide stacking interaction with hydrogen bond donors (Lys, Arg, Ser, Tyr, His, water molecule) [32] . Previously, we proposed an explanation for the albumin mediated hydrolysis of some substrates by the existence of catalytic dyads (as opposed to catalytic triads in cholines terases) His-Tyr or Lys-Tyr, in which histidine or lysine residues function as acid residues and proton donors, and the tyrosine residue is a cata lytic base [24] . The redox status of the thiol group of Cys34 res idue ensures the heterogeneity of albumin iso forms: human mercaptalbumin (HMA) has a free thiol form; a mixed disulfide with Cys or cyste inylglycine (CysGly), to a lesser extent with homocysteine (HCys) or glutathione (GSH), is called nonmercaptalbumin 1 (HNA 1); albumin with a cysteine residue oxidized to sulfinic or sul fonic acid is called HNA 2. In healthy young peo ple, the content of HMA is 70-80%, HNA 1 is 20-30%, while HNA 2 is 2-5% of the total amount of albumin [33] . Oxidized forms of albu min differ in physical and chemical properties from the reduced form. Thus, an increase in the colloidal osmotic pressure of oxidized albumin was shown in in vitro experiments using hypo chlorite and was also found in patients with chronic kidney disease [34] . The affinity for the endogenous ligands bilirubin and tryptophan, as well as for the exogenous pharmaceuticals warfa rin and diazepam, decreases in proportion to the level of oxidized albumin (cysteinylation of Cys34) [35] . Affinity for lipids also differs: pro atherosclerotic lysophosphatidylcholine and lyso phosphatidic acid have a higher affinity for the oxidized isoform, while anti atherosclerotic derivatives of eicosapentaenoic and docosahexae noic acids have a higher affinity for the reduced isoform of albumin [36] . The residues HSA subject to oxidation are pri marily Cys34, but also tyrosine residues Tyr84, 138, 140, 161, 263, 319, 332, 334, 353 and 370, methionine residues Met87 and Met123, trypto phan residue Trp214 [37] . In the blood plasma of a healthy person, about 80% of all thiols are in the Cys34 residue of albumin [38] . It is able to stoi chiometrically inactivate hydrogen peroxide, per oxynitrite, superoxide anion and hypochlorous acid, while being oxidized to sulfenic acid (HSA SOH) [39, 40] . Under oxidative stress caused by reactive oxygen species (ROS), Cys34 forms a disulfide with free cysteine or glutathione; oxida tion changes the three dimensional structure of HSA and affects the binding of many xenobiotics (pharmaceuticals and toxic substances). Depend ing on the nature and state of oxidation of HSA, oxidized derivatives can be divided into reversible (HNA 1) and irreversible (HNA 2). It is assumed that both HNA 1 and HNA 2 cause the develop ment of inflammatory processes, which is associ ated with an increase in the level of pro inflammatory cytokines and markers of damage to certain tissues and organs [37] . Recent studies suggest that oxidized albumin isoforms are inde pendent pathogenetic factors of many common and socially significant diseases, and their level is closely related to human dietary habits [19] . How ever, it remains largely unclear what is the speci ficity of the response of different tissues to the action of different forms of modified albumin. The list of albumin activities associated with redox modulation of blood plasma and intercellu lar fluid includes the activity of thioesterase [41, 42] , glutathione peroxidase and cysteine peroxi dase, as well as the activity of peroxidase in rela tion to lipid hydroperoxides [43] [44] [45] . The important role of Cys392 and Cys438 of albumin should be noted. These residues form a redox sensitive disulfide in the complex of albumin with palmitoyl CoA [45] . Cys34 is the most important trap of ROS, although not the only one: six methionine residues also contribute to the antiox idant properties of albumin [39, 46] . Residues Met87 and Met123 are commonly oxidized to methionine sulfoxide, especially in renal failure and diabetes. Albumin is involved in the transport of copper [47] , which is a cofactor of many enzymes and a participant in redox reactions and signaling path ways in the body in health and disease [48] . The main binding site for Cu(II) cations is the N ter minal region of human albumin Asp Ala His Lys (N terminal site, NTS) [49] . It is assumed that the albumin structure contains a site for the bind ing of Cu(I). Using spectroscopic and computa tional methods, it was shown that the imidazole rings of two histidines play a key role in the bind ing of the Cu(I) cation [50] . The N terminal region of HSA in a complex with copper ions has superoxide dismutase activity [51] . In addition, the prooxidant properties of albumin should be noted: albumin bound Cu 2+ ions enhance the formation of an ascorbate radical, followed by oxidation of the formed Cu + ions with molecular oxygen and protons again to Cu 2+ [52] . The redox activity of albumin can be supple mented by the cyanide detoxification reaction with the formation of thiocyanate, which is cata lyzed by regions of the IIIA subdomain without the participation of Tyr411 [53] . The percentage of oxidized albumin serves as one of the biomarkers of oxidative stress accompanying various diseases: for example, the level of Cys34 cysteinylated albu min is significantly increased in patients with dia betes mellitus, liver and kidney diseases [35] . In kidney disease, excessive ROS production con tributes to oxidative damage, inflammation, endothelial dysfunction, and renal fibrosis [54] . Chronic kidney disease is common in diabetic patients, so glycated albumin is believed to be the main cause of kidney damage, although glycated and oxidized albumin has not been compared. The negative effects of albumin (both modified and unmodified) on tubular epithelial cells are not well understood. Albumin oxidation is thought to precede or occur in the early stages of chronic kidney disease. Albumin in healthy people par tially overcomes the glomerular filtration barrier, but is reabsorbed by receptor mediated endocyto sis in proximal (71%) and distal tubular cells (26%) [37] . Albumin binds to the megalin-cubu lin complex receptor and is directed to the clath rin coated vesicles, followed by endocytosis and endosome acidification, which causes albumin dissociation from the megalin-cubulin complex and albumin binding to FcRn. Albumin is then either transferred to the lysosomes or returned to the blood via the transcytosis route, while the receptors are subject to recycling. However, the level of oxidized plasma albumin correlates with a decrease in the glomerular filtration rate. Oxi dized albumin has a direct effect on neutrophils, increasing the levels of lipocalin associated with neutrophil gelatinase, which is a biomarker of renal damage. Moreover, oxidized albumin in patients with kidney disease independently cor relates with higher plasma levels of the pro inflammatory cytokines TGF β1, TNF α, IL 1β, and IL 6 [37] . Fatty acids appear to play an important role in regulating the antioxidant properties of albumin [52] . The binding of fatty acids by albumin changes the conformation of Sudlow sites I and II and increases the fluorescence quantum yield of dansylamide (Sudlow site I ligand) and dansylsar cosine (Sudlow site II ligand); in addition, the fatty acids increased the steric availability of the Cys34 thiol group and enhanced its reactivity with 5,5' dithiobis 2 nitrobenzoic acid (DTNB). Thus, the binding of fatty acids creates the prereq uisites for the simultaneous regulation of two important functions of the protein, transport and antioxidant [52] . In addition, albumin enhances the antioxidant status of the organism due to the binding of bilirubin (ligand of the Site III [55] ) and polyunsaturated fatty acids that interact with the residues Arg117, Lys351, and Lys475 [39] . Diabetes mellitus (DM) is like a global epi demic, which is growing at an alarming rate and is associated with an increase in the mortality rate of the population. In 2018, the number of diabetic patients in the USA was 34.2 million. Worldwide, their number is 425 million people, and it is expected that by 2045 this figure will grow to 629 million [56] . Gestational diabetes affects from 2 to 14% of pregnant women in the USA annually [57] . There is an increase in the process of non enzymatic condensation of sugars with nucleic acids, proteins and lipids in diabetic patients, and that ultimately forms advanced glycation end products (AGE), which lead to disruption of cell function and cytotoxic effects, so they are called glycotoxins. AGE can be formed as a result of physiological processes when they are not bal anced by detoxification mechanisms, or enter the body from external sources such as food, cigarette smoke and air pollution. Their accumulation leads to inflammation and oxidative stress, mainly through activation of specific AGE receptors (RAGE, AGER) [58] . RAGE was first described in 1992, later RAGE isoforms were identified: AGER 1, 2, 3, as well as CD36 scavenger receptor [59, 60] . AGER 2 are involved in the initiation of inflammatory processes, whereas AGER 1, 3 and CD36 receptors are responsible for detoxification of AGE [58, 61, 62] . RAGE is a receptor pertain ing to the immunoglobulin superfamily; its ligand binding domain recognizes, in addition to AGE, a large number of molecules, among which the most important are S100 proteins, high mobil ity group box 1 protein (HMGB1), β amyloid and antigenic macrophage complex 1 (Mac 1) [63] . That is, RAGE acts as a non specific pattern recognition receptor that can function as an extracellular sensor [58] . Glycated foods and RAGE activation are associated with the patho physiology of many metabolic diseases, such as type 2 DM, food allergies, asthma, chronic obstructive pulmonary disease, acute renal fail ure, Alzheimer's disease, polycystic ovary syn drome [64] [65] [66] . AGE promotes carcinogenesis in chronic local inflammation induced by Helico bacter pylori [67] . Signaling pathways during the activation of RAGE include p21ras, MAP kinases, Rho GTPases, N terminal kinase Jun (JNK) and JAK/STAT, which lead to the migration of tran scription factors into the nucleus and the expres sion of genes which regulate chemotaxis, cell activation and proliferation [58] . NF κB, NFAT, STAT, AP 1, ERK1/2 and the protein binding the cAMP sensitive element bind to their specific promoters for transcription of genes encoding pro inflammatory cytokines (for example, IL 1, IL 2 and IL 4), pro apoptotic proteins (for example, p53 Bax, which initiates the cascade of caspases) and surface proteins, such as endothe lial cell adhesion molecules [68] [69] [70] . RAGE is constitutively expressed in many tissues, whereas RAGE hyperactivation causes stimulation of the PI3K-PKB-IKK pathway, which leads to bind ing of NF κB on the RAGE promoter and auto amplification of expression [58] . Another self amplification loop is that AGE induces oxidative stress through RAGE activation followed by hyperactivation of NADPH oxidases, ROS gener ation, increased AGE and increased RAGE expression [71] . RAGE expression may increase not only due to the effects of AGE, but also due to the effects of proinflammatory cytokines [72] . AGE activated endothelial cells "attract" lym phocytes and delay monocyte apoptosis, increas ing the duration of inflammation [73] . Modifications of plasma proteins, structural proteins and other macromolecules are enhanced in diabetes not only due to increased glycation (secondary to increased glucose concentrations), but also due to oxidative stress that occurs during the course of the disease and may be a sign of non complicated DM. The combined effects of glyca tion and oxidation can accelerate the development of accompanying pathologies in DM. While glucose itself contains a carbonyl group that participates in the initial glycation reaction, the most important and reactive carbon yls are formed as a result of oxidation reactions that damage either carbohydrates (including glu cose itself) or lipids. The resulting intermediates containing carbonyl then modify the proteins, giving the products of "glycoxidation" and "lipo oxidation", respectively. This common pathway of glucose and lipid mediated stress is the foun dation of the carbonyl stress hypothesis [74] . AGE are formed endogenously even in a healthy body, but recent studies have shown that diet is an important exogenous source of AGE [75, 76] . Since glycation targets are free amino groups, potentially any protein can be modified, and each tissue can accumulate glycotoxins. In terms of the duration of AGE accumulation, long lived proteins are the most important to study: these are the components of the extracellu lar matrix (collagen, laminin and elastin), lens protein α crystallin, cartilage, hemoglobin [58, 68] . For example, currently, glucose and glycated hemoglobin A1c (HbA1c) are standard biomark ers for diabetes monitoring, but HbA1c is a repre sentative indicator for glycemic data for 2-3 previous months and is not adequate for moni toring therapy, whereas glucose levels can change significantly even during the day and can disorient the patient and even the doctor in gestational dia betes of mild and moderate severity [57] . More over, under certain conditions, the measurement of HbA1c is unreliable, in particular, for patients with modified erythrocytes or renal insufficiency [77, 78] . Thus, there is a need for an intermediate biomarker that can be effectively used to monitor the glycemic status of patients. Such a biomarker can be albumin, which has a relatively short half renewal period (20-21 days). Albumin, the amount of which significantly exceeds the amount of other plasma proteins, is subject to glycation in the first place and allows predicting the risk of dia betes even in the case of euglycemia [79] . One of the main reagents found in vivo in adducts with albumin is carboxymethyl lysine (CML). Also glyoxal (GO), methylglyoxal (MG) and 3 deoxy glucosone (3 DG) [58, 80] should be mentioned. As it has been already mentioned, albumin is synthesized and enters the bloodstream in the form of a non glycosylated protein, but over time, glycation of a certain part of albumin molecules occurs in the blood plasma of even a healthy per son, which can affect its structural and functional characteristics [81, 82] . According to some esti mates, from 10 to 18% of circulating proteins in normoglycemic blood are glycated in vivo, whereas in diabetics it reaches 40% [57, 83] . A comparative analysis of the ability of various sug ars to interact with bovine albumin (BSA) in vitro showed that d galactose is more reactive than d glucose or d lactose, whereas only conju gates of albumin with lactose were recognized by specific lectins [84] . To date, more than 60 human albumin glycation sites have been iden tified. Lys256 and Lys420 turned out to be the most accessible for conjugation, although Lys525 is considered the most reactive in HSA [85, 86] . In addition to lysine, arginine and histidine are the most reactive amino acid residues [58] . Oxi dized albumin is more easily glycated, even at a physiological glucose concentration (5 mM) [83] . The accumulation of AGE changes the structure and function of proteins, turning them into potential targets of the immune system, which can result in the production of autoantibodies against AGE. Albumin is not an exception, and it was shown that antibodies against albumin were found in the blood of patients with atherosclerotic vas cular damage and signs of DM [87] . Moreover, IgG and IgA autoantibodies to HSA may have diagnostic significance in autoimmune bullous dermatoses (AIBD), despite the fact that dermal autoantigens have not yet been identified [88] . The phospho p38 signaling pathway associated with DNA damage is a potential target for the treatment of patients with AIBD positive serum autoantibodies to HSA. Glycated albumin is used both for diagnostic purposes and for experimental study of systemic effects of AGE, many of which are mediated by NF κB, a universal transcription factor con trolling the expression of immune response, apop tosis and cell cycle genes [89] . As it was already mentioned, plasma glucose and HbA1c are pres ently recognized as markers of DM. An alterna tive to HbA1c as a marker of diabetes mellitus has become fructosamine, which plays an increas ingly important role in the diagnosis of this dis ease and is a measure of glycation of circulating proteins, among which albumin is the principal one, from the point of view of accessibility and assessment of the scale of observed changes [56] . Plasma albumin gradually displaces HbA1c during glycemic monitoring of patients with DM [77] . However, the accuracy of determining the degree of hyperglycemia by fructosamine is rela tively low, not only because different proteins interact differently with glucose and other sugars, but also because bilirubin, uric acid and a number of other low molecular compounds contribute to the error of the method. Other disadvantages of the test include the lack of a generally accepted standard and even its low availability [90] . It can not be said that various methods for determining glycated albumin are simple and accessible: we note here ion exchange high performance liquid chromatography, boronate affinity chromatography, immunoassays (radioimmunoanalysis and enzyme immunoassay), colorimetric method with thiobarbi turic acid, and enzymatic methods using proteinase and ketamine oxidase. In recent years, the most pop ular enzymatic method "Lucica GA LR" (Asahi Kasei Pharma Corporation, Japan), which has high reproducibility, accuracy and good correla tion with A1C [90] . A test system on an indicator strip has been developed to measure the propor tion of glycated albumin from total serum albu min. Aptamers with gold nanoparticles were used for colorimetric measurements. Both glycated and non glycated albumin can be measured in the corresponding physiological concentration ranges-from 50 to 300 microns with a detection limit (LoD) of 6.5 microns for glycated albumin and from 500 to 750 microns with a LoD of 21 microns for non glycated albumin [57] . The advantage of measuring of glycated albu min in clinical practice is its universality both as a mediator of inflammation and as a marker of hyperglycemia. A deeper understanding of the role of glycated albumin may lead to its accep tance as an independent marker of the inflamma tory process [91] . Glycated albumin makes it possible to predict the risk of death in dialysis patients with diabetes mellitus [77] , and in combi nation with hsCRP maximizes the accuracy of predicting cardiovascular diseases, especially those associated with left ventricular hypertrophy in patients with diabetic chronic kidney disease [78] . It should be particularly noted that glycated albumin can be transformed into amyloid fibrils that are rich in β sheets [92] . As in the case of the effect of Cys34 oxidation on the binding activity of Sudlow sites, data on the effect of glycation on the antioxidant properties of albumin are contradictory [39, [93] [94] [95] , which may be due to interspecies differences, the nature and concentration of carbohydrates involved in the reaction (glucose, methylglyoxal), incubation conditions with monosaccharides. Of particular interest are the differences between human and bovine albumin: glycation of HSA sharply reduces its antioxidant activity, while glycation of BSA slightly enhances its antioxidant properties. These data correlate with the results of computational experiments aimed at studying the effect of the redox status of HSA and BSA on their binding and esterase activity with respect to paraoxone [26, 96] . From the point of view of evolutionary and comparative biochemistry/physiology, the fol lowing fact seems to be important: the concentra tion of glucose in the blood plasma of birds is 1.5-2 times higher than in mammals of similar mass (this phenomenon is called benign hyperglyce mia), however, avian albumin (for example, Chicken Serum Albumin, CSA) is glycated to a lesser extent than BSA, even when in vitro experi ments albumins were exposed to increasing glu cose concentrations up to 500 mM [97] . Analysis of protein structures suggests that the relative resistance of CSA to glycation may be associated with fewer lysine residues and variations in pro tein stacking that protect lysine residues from interaction with plasma glucose. A comparative analysis of the reconstructed albumin sequences indicates that the ancestor of birds had 6-8 fewer lysine residues in the albumin molecule compared to mammalian albumin [97] . Benign hyperglyce mia is a common physiological feature of birds, and the development of mechanisms of resistance to albumin glycation seems to have been inextri cably linked with their evolution. It is believed that the development of benign hyperglycemia in birds corresponded with a radical rearrangement of the genome, in which the loss of important genes happened, including the gene encoding GLUT4-a carrier responsible for insulin depen dent glucose transport in insulin sensitive cells of other vertebrates. This loss apparently led to remodeling of the insulin dependent signaling pathway in avian tissues [98] . AGE causes multiple metabolic disorders in the vascular wall and can lead to endothelial dysfunc tion. Since a significant part of AGE is repre sented by glycated albumin, it is important to consider the features of the interaction of albumin with the vascular endothelium. Albumin interacts with endothelial cells (EC) through extracellular molecular agents, among which there are recep tors, but most of them are combined into glycoca lyx, which is a dynamic and heterogeneous "layer" between EC membranes, on the one hand, and blood components (plasma and blood cells), on the other hand. The endothelial glycoc alyx is a layer of glycoproteins associated with EC membranes, which holds from 700 to 1000 mL of practically non circulating plasma volume in the human body. This intravascular layer maintains its own colloidal osmotic (oncotic) pressure (COP) due to the plasma pro teins contained in it (primarily albumin), which are retained inside the endothelial glycocalyx layer (EGL). Consequently, it has a higher COP than circulating plasma [99] . According to some estimates, EGL provides approximately 60% of intravascular COP [100] . Structurally, EGL is a negatively charged gel like layer comprising oli gosaccharide and polysaccharide chains of gly cosaminoglycans (heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyal uronan), which are covalently bound to glycopro teins and proteoglycans, both transmembrane (antithrombin III, integrins, selectins, syndecans, glypicans) and soluble (perlecan, biglican, versi can, decorin, mimecan). EGL has a thickness from 0.1 to 4.5 microns, depending on the local ization and size of the vessel, and serves as a kind of reservoir of proteins and polysaccharides, such as antithrombin III and heparan sulfate [99] . The intact EGL maintains separation between the circulating plasma and the vascular endothe lium, creating an "exclusion zone" that prevents blood cells from contacting the EC surface. In the presence of intact EGL, water and electrolytes freely pass first through this layer, and then beyond the EC through the intercellular gaps. This "exclusion zone" also prevents contact with the endothelium of high molecular colloids weighing > 70 kDa. Albumin is practically the only plasma protein that easily moves between blood plasma and EGL due to the selective per meability of EGL for natural colloids with a molecular weight of < 70 kDa [101] . The molecular radius of albumin hinders its passage between neighboring cells of an intact endothelial monolayer, which limits paracellular diffusion to molecules smaller than 3-5 nm [102] [103] [104] . However, the detection of albumin in interstitial and lymphatic fluids (up to 40-60% of the plasma level) indicates that the protein is able to leave the lumen of microvessels even in the absence of inflammation [105, 106] . It was shown in the work of Palade et al. [107] that albumin which was injected into the bloodstream of ani mals was later detected in the intracellular vesicles of the capillary endothelium; in some cases, these vesicles got free the albumin into the interstitium, although there was never a rupture of interendo thelial contacts. Such vesicular transport is known as transcytosis and is mediated by caveoles; knockdown or deficiency of caveolin 1, without which caveoles cannot exist, averts transcytosis of albumin [108, 109] . Thus, albumin transcytosis is the main way of albumin transfer from the blood stream to the interstitium in physiological condi tions [107] . According to the important role of albumin as a vehicle for medicinal and toxic sub stances, the relevance of studying the kinetics and mechanisms of albumin transcytosis in blood ves sels can hardly be overestimated [110] . It is known little about the regulation of transendothelial albumin transport, which is partly due to techni cal difficulties in its study. Thus, when they mea sure the permeability of the endothelium by cultured cells, there were some difficulties with separation of the contribution of paracellular leakage from true transcytosis [111] . A more seri ous reason for the poor study of transcytosis of albumin by EC is associated with the uncertainty of the physiological significance of this process. Mice with caveolin 1 deficiency do not have caveols and demonstrate reduced endothelial internalization of albumin, but there is a compen satory increase in paracellular transport in these animals [112] . This model underlines the impor tance of transporting albumin outside the vascular bed, but does not give an answer about the physio logical function of transcytosis. Taking into account the numerous fatty acid binding sites [113] , it can be assumed that transcytosis of albu min is important for the regulated transfer of cir culating fatty acids to various tissues. In this regard, a long established phenomenon seems to be important: albumin deficiency correlates with an increased level of circulating cholesterol and phospholipids [114, 115] . Most of the work related to the study of trans cytosis was carried out on the lung endothelium, whose cells bind albumin through glycoprotein 60 (gp60) in caveoles and provide its transfer with the participation of tyrosine kinases [116, 117] . Tran scytosis of albumin in the lungs is stimulated by thrombin, this process is associated with an increase in the activity of acidic sphingomyelin ase, which promotes the synthesis of ceramide, caveolin 1 and its recruitment to the lipid rafts of the membrane; stimulation of albumin transcyto sis by proinflammatory mediators may contribute to the leakage of alveolar protein in lung injury [118] . However, another mechanism of transcy tosis is of great importance in the lungs, there is low affinity absorption of albumin in the liquid phase by the type of pinocytosis [119] . Pinocytosis is a process of nonselective absorption by the cell of the liquid phase from the environment contain ing soluble substances, due to the lacing inside of small bubbles (endosomes) that merge with lyso somes [120] . For a long time, practically nothing was known about the transcytosis of albumin in other tissues. Taking into account the notable heterogeneity of the vascular endothelium in different organs [121] , it could be assumed that there are different mechanisms of albumin transcytosis. This assumption was confirmed in a recent work by Raheel with co authors: according to their data, transcytosis of albumin in the skin, unlike in the lungs, has kinetics of saturation, which indicates a receptor mediated process [122] . It was found that for transcytosis of albumin through the endo thelium of the microvessels of the dermis, a nec essary and sufficient condition is the expression of CD36 glycoprotein, which is also known as a class 3B scavenger receptor (SR B3), platelet membrane glycoprotein IV (GPIV), glycoprotein IIIb (GPIIIB), thrombospondin receptor, colla gen receptor, fatty acid translocase (FAT) and even as the receptor of innate immunity [123] . When the ligand binds, CD36 triggers a signaling cascade that mediates a wide range of pro inflam matory responses. For example, amyloid β1 40 (Aβ), interacting with CD36, activates the gener ation of superoxide anions by NADPH oxidase [124] . In acute lung injury, an increased level of ROS and intracellular calcium play a key role in the dysfunction of the endothelial barrier: the H 2 O 2 induced increase in [Ca 2+ ] i in the EC of the microvessels of the lungs is associated with the activation of TRPV4 (type 4 cationic vanil loid channels with transient receptor potential) saturation, and CD36 plays an important role in H 2 O 2 mediated lung damage through CD36 depen dent fixation of Fyn kinase (from Src families) on the cell membrane to facilitate phosphorylation of TRPV4 [125] . CD36 glycoprotein is expressed on the surface of not only microvessels' EC, but also on the sur face of platelets, monocytes, smooth muscle cells, cardiomyocytes and a number of other cells, though it is absent in the lymphatic vessels of the dermis [126] . Despite its widespread distribution, CD36 remained a rather mysterious protein for a long time. It was gradually established that CD36 can influence cellular responses due to interaction with various ligands, in particular, with thrombos pondin 1, oxidized LDL and long chain fatty acids [127, 128] . Currently, CD36 is considered to be the main membrane protein involved in lipid homeostasis of the body. CD36 acts in agreement with membrane and cytoplasmic fatty acid bind ing proteins. The rate of absorption of fatty acids depends on the presence of CD36 on the cell sur face, which is regulated by subcellular vesicular recirculation of CD36 from endosomes to the plasma membrane [129] . However, non esterified fatty acids cannot circulate freely in plasma, they are bound to albumin [130] , which has seven fatty acid binding sites [131] . Interaction with CD36 is associated with activation of Src family kinases and mitogen activated protein kinases, as well as with the participation of Rho GTPases and tran scription factor NF κB [132] . Still to be found out does albumin binding and transcytosis require the involvement of these or other signaling pathways. In mice selectively deficient in endothelial CD36, a reduced level of subcutaneous fat was noted, despite the fact that the level of circulating lipids was comparable to that of control animals, and representatives of both groups had a similar body weight [122] . This is consistent with a defect in the transport or metabolism of lipids at the bor der between the endothelium and the skin. According to this hypothesis, analbuminemic rats exhibit intense hypercholesterolemia [133] , and patients with congenital albumin deficiency demonstrate elevated serum concentrations of cholesterol and phospholipids, which temporar ily return to normal after intravenous albumin infusions [114, 115] . Deficit of CD36 or muta tions in it have not previously been associated with the skin phenotype [134] , but this is due to the fact that previous studies have investigated the effect of CD36 deficiency throughout the body, and not in deletion specific to EC. After the dis covery of the role of CD36 in the skin, the ques tion arises about the role of CD36 in the endothelium of the microvessels of the lungs. Although it does not mediate albumin transcyto sis, there is evidence that the endothelial CD36 of the lungs is involved in the reaction to inhaled pollutants [135] or to infection [136] . However, CD36 is not an exclusive mediator of the effect of fatty acids on EC. In the absence or lack of albumin, inflammation may occur as a result of their interaction with Toll like receptors, and not as a consequence of absorption through CD36 [137] . Thus, palmitate, which is not associ ated with albumin, activates inflammatory path ways in microvessels, increases the generation and/or expression of IL 6, IL 8, TLR2 and ICAM 1 in them, disrupts insulin transport and promotes monocyte transmigration. Inhibition of CD36 does not affect palmitate induced expres sion of adhesion molecules; at the same time, sup pression of signaling through TLR4 to NF κB reduces palmitate induced expression of ICAM 1 [137] . Such signaling switching options are important for understanding the significance of albumin in both the prevention and development of diseases of the cardiovascular system. In diabetic patients, the level of glycated albu min is more than 70 μM; it is one of the initiators of EC apoptosis [138] . The likelihood of athero sclerotic plaque formation in the carotid artery in patients with type 2 DM correlates with an increased level of glycated albumin and a decreased level of endothelial progenitors (CD34+/133+/309+) [139] . Interestingly, as the plaques formed, the level of glycated albumin decreased, as did the ratio of glycated albumin to glycated hemoglobin. This is partly due to the fact that in diabetes, aortic EC switch to a biosynthetic phenotype with an increased number of caveolae and increased (by about 20%) transcytosis of glycated albumin. In EC culture, 25 mM glucose causes an approximately 2.6 fold increase in pSTAT 3 and pERK1 and an approximately 1.8 fold increase in pERK2; exposure to glycated albumin (5 μM) causes an approximately 4.3 fold increase in pERK1/2 compared to 5 mM glucose [140] . Glycated albumin induces the expression of procoagulant and inflammatory factors by EC [141, 142] . At the same time, there is evidence that the increased level of von Willebrand factor in dia betics is due not to glycated albumin, but to the effect of mannose specific lectins on the hydro carbon determinants of EC [143] . However, it should be noted that glycated albumin was tested at low concentrations in the culture of human umbilical vein EC (HUVEC) (25-100 μg/mL), while physiologically much more active lectins (concanavalin A, ConA, and wheat germ aggluti nin, WGA) were tested at not far lower concen trations (4-16 μg/mL). In diabetes mellitus, many morphofunctional abnormalities of cells are mediated by auto and paracrine TGF β, which is induced by high levels of glucose in the environment and glycosylated proteins. For most cell types, TGF β is an inducer of apoptosis, which is mediated by Alk5, the type I TGF β receptor. In contrast, early diabetic microangiopathy is characterized by increased proliferation of EC. EC are unique in that they express a second type I TGF β receptor, Alk1, as well as the endoglin coreceptor, which increases the ligand's affinity for Alk1. In differentiated EC of healthy subjects, Alk1 and endoglin are constitu tively expressed. However, incubation of EC with high glucose and glycated albumin in the medium induces Alk5 expression and increases TGF β secretion by a factor of 3, without affecting Alk1 or endoglin levels. The "diabetic" environment accelerates cell proliferation, at least in part, due to TGF β/Alk1 smad1/5 and, probably, with the participation of VEGF, as well as promigratory MMP2 below Alk1. In addition, the activity of caspase 3 is partially increased, which indicates an increase in apoptosis using the TGF β/Alk5 smad2/3 pathway. These data suggest pleiotropy of TGF β in EC, including proliferative effects (via Alk1 smad1/5) and pro apoptotic signals (via Alk5 smad2/3) [144] . Among other proinflam matory cytokines whose synthesis induces glyco sylated albumin, TNF α should be mentioned [145] . IL 6 expression by EC is also increased when exposed to glycated albumin, but this increase can be prevented by angiotensin 1-7, a product of ACE2 activity [146] . Glycated albumin enhances the expression of RAGE against the background of shear stress [147] and increases the expression of adhesion mole cules VCAM 1, ICAM 1, and E selectin [148] . The expression of EC adhesion proteins (in partic ular, E selectin, or CD62E) increases precisely when exposed to glycated albumin; this effect is not observed under the action of a heterogeneous mixture of AGE, which are formed as a result of non enzymatic glycation and oxidation of pro teins, lipids and nucleic acids [149] . Glycated albumin of patients with heart failure and high lev els of glycation also increased the expression of adhesion molecules in HUVEC and enhanced adhesion of peripheral blood mononuclear cells to the EC [150] . It is well known that mononuclear cells are powerful generators of ROS, but what is especially important, the increase in the expression of adhesion molecules is mediated by the genera tion of ROS by NADPH oxidases of EC and sig naling with the participation of kinases PKB-IKK and JNK, transcription factors NF κB and AP 1. It was found that the generation of ROS is maxi mally expressed 4 h after the onset of exposure to glycated albumin and is accompanied by an increase in the expression of Nox4 and p22phox mRNA [151] . Endothelial NOX2 activation also contributes to dysfunction of the glomerular appa ratus in insulin dependent mice, decreasing the expression of the glomerular glycocalyx and caus ing morphofunctional changes in podocytes and mesangial cells; ultimately, this contributes to the development of diabetic nephropathy, one of the signs of which is albuminuria [152] . In addition to NOX4, another source of ROS under the action of glycated albumin on EC is uncoupled eNOS [153] . Glycated albumin can both enhance and weaken the activity of NO synthase, and both response variants were noted during the develop ment of EC apoptosis under the action of glycated albumin [138, 154, 155] . This is consistent with the notion that oxidative stress plays a key role in endothelial damage in diabetes, and the degree of albumin glycation affects its intensity through a possible connection between NADPH oxidases, mitochondria, and other sources of ROS [156] . Recently, it has been shown that one of the important mediators of AGE induced diabetic endothelial dysfunction is peroxidasin (PXDN), a member of the peroxidase family, which catalyzes the conversion of hydrogen peroxide to hypo chlorous acid. It is believed that NOX2 is the main source of ROS upon exposure to AGE, while the action of HOCl leads to a weakening of eNOS phosphorylation at Ser1177 and a decrease in NO synthesis [157] . Another participant in the antioxi dant defense of EC and the target of glycated albu min is intracellular paraoxonase 2 (PON2). Glycated albumin, as well as N carboxymethyl lysine (CML, the most famous representative of AGE), suppresses the expression and activity of PON2 in EC [158] . In addition, the effect of gly cated albumin and CML on the endothelium leads to an increase in the level of endoplasmic reticu lum stress markers GRP78 and IRE1α, as well as to an increase in the expression of proinflamma tory cytokines MCP 1, IL 6, IL 8, adhesion pro teins ICAM1 and VCAM1. On the other hand, an increase in the expression of PON2 leads to a decrease in the level of ROS and facilitates endo thelial dysfunction caused by AGE [158] . Despite the availability of major proteins in gen eral and albumin in particular, information about the mechanisms of albumin modification and the mechanisms of the effect of modified albumin on cells, tissues, and human health is insufficient, and the available data are often contradictory. The specificity of the pathogenesis of a particular organ is due to the fact that when the endothelium is damaged, the release of albumin outside the vas cular bed goes out of control, that leads to a change in the biological activity of parenchyma cells. In addition, various blood cells can also serve as a target for AGE and glycated albumin, which, as a rule, aggravates the state of EC and causes dis ruption of the blood-tissue barriers. Thus, gly cated albumin enhances the thrombogenic potential of platelets due to an increase in the number and sensitivity of receptors [159] . The pathogenic role of AGE and glycated albu min is best studied in obesity, diabetic polyneu ropathy and nephropathy [58, 160, 161] . The SARS CoV 2 coronavirus, which caused the COVID 19 pandemic, has stimulated research on the relationship between susceptibility to infec tion and a history of other diseases, including those listed above, one of the pathogenic factors of which is glycated albumin. Visceral fat is one of the main sources of pro inflammatory cytokines due to activated macro phages, which are much more abundant in com parison with subcutaneous fat. This is primarily due to the accumulation of glycated albumin and increased expression of RAGE [160] . Among the cytokines, there are the molecules that interact with RAGE (S100β and HMGB 1), as well as the molecules whose level increases upon activation of RAGE (MCP 1, IL 6, TNFα, TGF β, and a number of others). Chronic inflammation is maintained by constant recruitment of macro phages through RAGE dependent expression of MCP 1 and further RAGE activation; this self amplification loop is called the RAGE/MCP 1 axis [162] . Increased levels of AGE, the main of which is glycated albumin, fuels both oxidative stress and the AGE/RAGE axis, which in turn can increase inflammation in already inflamed tissue, thereby accelerating the progression of obesity. In addition, the adaptive functions of adi pocytes are disrupted by other AGE receptors: for example, the capture and degradation of AGE by the CD36 scavenger leads to a decrease in the generation of leptin by adipocytes, which may contribute to the development of obesity [163] . It was found that diabetic polyneuropathy (DPN) develops in all patients with type 1 DM within 15 years and in 30% of patients with type 2 DM within 25 years [164] . A characteristic feature of DPN is EC hyperplasia and thickening of the basement membrane of endoneural capillaries and other microvessels. The mechanism of this phenomenon remains unclear. To what extent is it related to the polyol pathway of glucose metabo lism in EC or to the effect of glycated albumin on AGE receptors? One of the molecular pathoge netic factors of DPN is a decrease in the synthesis of claudin 5, which leads to disruption of the bar rier function of the endothelium and edema of the nerve fiber. AGE reduce the amount of claudin 5 indirectly, by increasing the autocrine secretion of endothelial growth factor (VEGF) by EC forming the blood-nerve barrier (BNB) [161] . In addi tion, pericytes play an important role in the for mation and maintenance of the basement membrane of the BNB. They produce fibronectin and type IV collagen, as well as a tissue inhibitor of metalloprotease 1 (TIMP 1), which prevents degradation of the basement membrane. It turned out that during hyperglycemia, AGE accumulate in pericytes, increasing the autocrine secretion of VEGF and TGF β. VEGF and TGF β signaling enhances the production of fibronectin and type IV collagen, which leads to a thickening of the basement membrane [161] . Interestingly, treatment of hyperglycemia reduces the incidence of DPN by 60-70% in patients with type 1 DM [165] and only by 5-7% in patients with type 2 DM [166] . Moreover, at least 40% of patients with type 2 DM develop DPN even with glucose control [167] . The data on the role of modified (glycated and/or oxidized) albumin in the pathogenesis of DPN are insuffi cient to seriously discuss the prospects for the development of effective therapy. Each kidney contains approximately 1 million nephrons. Each nephron consists of a glomerulus and tubules. Glomeruli are composed of four types of cells: parietal epithelium, glomerular endothe lial cells (GEC), podocytes (visceral epithelial cells), and mesangial cells. Endothelium and podocytes share a common extracellular matrix called glomerular basement membrane (GBM). GEC and their openings are covered with endo thelial glycocalyx. Podocytes have processes with slit diaphragms that surround the outer part of the capillaries. GEC with endothelial glycocalyx, GBM and podocytes constitute the renal filtration barrier, or glomerular filtration barrier. In diabe tes, the exchange of signals between cells is dis turbed in the filtration barrier, while the primary increase in the synthesis of vascular endothelial growth factor A (VEGFA) by podocytes, observed in the early stages, is replaced by a decrease in VEGF synthesis during the progression of the dis ease. There is also a loss of interaction between angiopoietin 1 (Angpt1) and the tyrosine protein kinase receptor (Tie2), and the production of acti vated protein C (APC) in the glomeruli is reduced due to suppression of thrombomodulin expression. A decrease in the functional activity of APC affects the permeability of the glomerular capillary wall and enhances apoptosis of glomerular EC and podocytes. Metabolic changes associated with DM, along with the activation of the renin-angio tensin-aldosterone system (RAAS), cause the generation of ROS and RNS (nitric oxide, nitro gen dioxide, and peroxynitrite) in glomerular EC. The activity of endothelin 1 (Edn1) in DM increases oxidative stress, causes depletion of endothelial nitric oxide (NO) and degradation of endothelial glycocalyx [168] . However, glomerular endothelial dysfunction is characterized not only by damage of the endothe lial glycocalyx and oxidative stress in the EC, but also by the endothelial-mesenchymal transition (EndMT) [169] . EndMT is the process by which EC lose their endothelial phenotype (for example, a reduced expression of endothelial cell markers CD31 and CD144) and endothelial specific func tional characteristics (athrombogenicity, barrier functions, etc.). The decrease in the expression of endothelial markers is accompanied by an increase in the expression of mesenchymal mark ers such as α smooth muscle actin (αSMA) and fibroblast specific protein 1 (FSP 1); in addition, the synthesis of extracellular matrix proteins (ECM) increases [170] . EndMT promotes the development of fibrosis and is observed in diseases of a wide variety of organs, including cancer [171] [172] [173] . EndMT is also observed in the glom eruli of patients with diabetic nephropathy, as evi denced by the co expression of endothelial and mesenchymal markers [174] . Hyperglycemia, AGE, glycated albumin, hypoxia and a number of other factors cause glomerular endothelial dys function, which is characterized by damage to the endothelial glycocalyx, oxidative stress, inflam matory phenotype of EC and EndMT; this leads to proteinuria, damage or loss of podocytes, acti vation of mesangial cells, and ultimately glomeru losclerosis. An additional pathway of kidney damage in DM is the transdifferentiation of renal tubular cells into myofibloblasts. This occurs when RAGE is activated, which induces the expression of TGF β and other cytokines that mediate this transdifferentiation [175] . Activation of NF κB, along with RAGE amplification and cytokine expression, causes the activation of gene ZEB2 encoding the ZEB2 protein. Transcription factors of the ZEB family lead to EndMT, impair ment of podocyte adhesion, detachment of the basement membrane and the loss of podocytes in the glomeruli [68] . Activation of PKC, TGF β and gene expression in mesangial cells, along with a similar effect on the EC of the glomerular appa ratus, is also a cause of diabetic nephropathy, especially in type 1 DM [176, 177] . It should be noted that EndMT is not an irreversible process; the possibility of reverse reprogramming of trans formed ECs has been shown [170] , and EndMT is also controlled by autophagy [178, 179] . In addition to numerous observations indicat ing albumin modifications and decrease in its level in various diseases accompanied by inflam matory processes, including in many patients with coronavirus infection [180] , the cytokine storm observed in patients with COVID 19 occurs par tially due to an increased level of oxidized albu min [181] . At the same time, RAGE plays an important role in the pathogenesis of lung diseases such as fibrosis, pneumonia and acute respiratory distress syndrome (ARDS). Overexpression or hyperactivation of RAGE enhances the negative effect of renin-angiotensin system (RAS) media tors on chronic diseases, which are the main risk factors for coronavirus infection: diabetes, kidney and cardiovascular diseases [182] . After recogni tion and binding of the spike protein of the coro navirus by the angiotensin converting enzyme type 2 (ACE2), SARS CoV 2 enters the cell, which leads to suppression of ACE2 regulation and an increase in angiotensin II (AngII). Infected cells undergo pyroptosis and release of damage associated molecular patterns (DAMP), including HMGB1. DAMP, cytokines and RAGE ligands lead to increased expression of RAGE by NF κB. Under these conditions, RAGE induces further downregulation of ACE2, upregulates the expression of AT1R (type 1 recep tor of AngII), and transactivates with AT1R, enhancing the pathogenetic effects of the ACE/ AngII/AT1R axis. At the same time, the interac tion of AngII with AT1R induces the activation of NF κB and the release of RAGE ligands; a vicious circle is formed. Connection of RAGE with RAS effectors promotes cytokine storm development in macrophages and splenocytes; causes endothelial dysfunction by increasing cap illary permeability and release of components of DAMP; enhances the production of ROS and the formation of atherosclerotic plaques; increases the risk of thrombosis by inducing the formation and release of extracellular traps by neutrophils (NET), followed by platelet aggregation; cause muscle wasting, stimulating apoptosis, increasing protein degradation and decreasing protein syn thesis. The combined effect of RAGE and AT1R occurs in the vessels and parenchyma of the lungs, brain, heart and kidneys, in the cells of the immune system, causing irreversible damage to many organs [183] . In this case, the question of what is primary (cause) and what is secondary (consequence) not only has the right to exist, but deserves the most serious attitude on the part of scientists and physicians. Recent findings strongly suggest that AGE are the main contributors to brain microvascular damage and disruption of the blood-brain barrier (BBB) [184] . Interactions between the BBB, cerebral blood vessels, neurons, astrocytes, microglia and pericytes form a dynamic func tional neurovascular unit. Damage to the cerebral cortex as a result of trauma, intoxication, isch emia or infection can lead to the development of post traumatic epilepsy (PTE), one of the most common neurological disorders, the pathogene sis of which is closely related to the violation of the BBB integrity [123, 185] . In turn, it leads to leakage of plasma components into the brain parenchyma and increased excitability of neu rons. First, the levels of K + and glutamate rise, then coupled mechanisms are triggered: extrava sated albumin is absorbed by astrocytes through TGF βR and leads to Smad2 mediated suppres sion of the Kir4.1 potassium channel, while astro cytic TNF α initiates a decrease in the expression of glutamate transporter EAAT 2. Both mecha nisms exacerbate primary neuronal overactivity due to impaired buffering of K + and glutamate by astrocytes, resulting in extracellular potassium accumulation, relief of NMDA mediated hyper excitability and, ultimately, epileptiform activity [186] [187] [188] . It should be noted that the same sig naling pathway is activated in aging people with BBB dysfunction [189] . Nowadays there are no funds to identify patients at risk of developing PTE or to prevent its development. Seizures can occur months or years after stroke, do not respond to anticonvulsants in more than a third of patients, and are often associated with significant neuropsychiatric illness [190] . An increased con centration of albumin causes an increase of [Ca 2+ ] due to activation of inositol 1,4,5 triphos phate (IP3) signaling pathway; in addition, albu min induces DNA synthesis. These processes are partially blocked by heparin and TGF β antago nists [191] . Thus, the use of SJN2511, a specific inhibitor of the ALK5/TGF β astrocytic path way, prevents excitatory synaptogenesis and albu min induced epilepsy [190] . At the same time, the use of nonspecific drugs, such as losartan (AT1 antagonist), also prevents BBB impairment and the development of epileptogenesis [185] . However, the question of the differences in the affinity of unmodified and modified albumin for cytokine receptors of the brain parenchyma remains unexplored. The development of specific and nonspecific drugs for PTE therapy taking into account the pathogenetic role of albumin is one of the most pressing problems of modern pharma cology. Plasma or serum albumin has been a classic marker of nutritional status for many years, espe cially for protein foods. Albumin level less than 35 g/L defined as hypoalbuminemia. Recently, low albumin level is increasingly considered as a risk factor and predictor of morbidity/mortality, regardless of gender, age, comorbidities and all kinds of gene polymorphisms [192] [193] [194] . From the point of view of diagnostics, the level of albu min in blood plasma and in urine characterizes not just the level of one of the proteins, but, in fact, its integrative characteristics in terms of assessing the state of the whole organism, since it reflects the protein synthesizing function of the liver (hence its role as negative acute phase pro tein [195] ) and the functional state of the vascular endothelium, which determines the integrity of the blood-tissue barriers. The relationship between the integrity of the endothelium and the level of albumin in urine is the most studied phe nomenon in medical practice, indicating primar ily kidney pathology, but also the state of other components of the blood and cardiovascular sys tem [196] [197] [198] . Among these components, the cerebral vascular endothelium is the most inter esting, because there is the brain parenchyma on the other side of the barrier, whose functional units have proven to be extremely vulnerable to the action of albumin due to the presence on astrocytes of a receptor, until recently thought to be specific to TGF β, one of the minor cytokine proteins that regulate cell differentiation and apoptosis [190, 191] . At the time when cytokine regulation research began or even flourished, this was hard even to imagine: a common receptor to proteins whose concentration difference in blood serum is more than 9 (!) orders of magnitude. The difference in affinity to the receptor is more than offset by the potential superiority in the number of albumin molecules that can access astrocyte receptors when the integrity of the BBB is com promised. In this regard, of great interest are the cytotoxic characteristics of redox modified and glycated albumin not only in relation to the EC of blood vessels, but also in relation to the cytokine receptors of astrocytes. A large scale search for new diagnostic indica tors using modern metabolomics technologies has made it possible to single out from a huge list of only four simple indicators of blood plasma, which allow to accurately assess the state of human health and predict the likelihood of death for patients, regardless of their age, gender and the nature of existing or past diseases; among these four indicators, the level of albumin in terms of the degree of contribution to the integral assess ment was in second place after orosomucoid (alpha 1 acid glycoprotein) [193] . A similar result was obtained in the study of patients in intensive care units: the use of a simple ratio of positive (C reactive protein) and negative (albu min) acute phase proteins can significantly increase the accuracy of assessing the risk of death [199] . A structurally similar ratio, but with mark ers of muscle fiber damage in the numerator (cre atine kinase or myoglobin), significantly increases the correlation of biochemical indicators with functional and physiological (instrumental) indi cators [200] . The urine albumin/creatinine ratio is one of the most sensitive indicators of glomerular renal dysfunction and hypertension in patients with high risk neuroblastoma treated with mye loablative regimens [201] . And already during the pandemic of coronavirus infection, it was found that there was an inverse correlation between mortality from COVID 19 and blood albumin concentration [202] . The authors of the study sug gested that this association might be related to the anticoagulant and antioxidant properties of albu min. Competent application of regression analysis methods makes it possible to increase the sensitiv ity and specificity of diagnosing diabetic compli cations through the use of "internal" indicators of albumin, such as the ratio of its reduced and oxi dized forms [203] . The ratio of oxidized albumin to total albumin can increase in liver diseases, dia betes, cardiovascular diseases, which leads to bac terial or viral infections. And again, during the pandemic, it was found that, due to the induction of a cytokine storm, the level of oxidized albumin in the blood of patients with COVID 19 can be a positive predictor of mortality [181] . However, albumin can serve not only as a bio marker of the severity of various pathologies, but also as a means of therapy. Due to its critical physiological role, human albumin is in the great est demand among other biopharmaceuticals. Currently, the annual demand for HSA world wide is estimated at about 500 tons [204] . Injec tions of a 5% albumin solution (isooncotic solution) are prescribed if necessary to increase the intravascular volume, injections of a 20-25% albumin solution (hyperoncotic solution) are pre scribed to restore the colloid osmotic (oncotic) pressure and maintain the fluid balance between the intravascular and extravascular compartments [205] . Clinical indications for the use of a 4-5% albumin solution are hypovolemic shock, acute liver failure, cardiopulmonary bypass [206] . Indi cations for use of a 20-25% solution are not so evident [207] . It should be borne in mind that routine correction of hypoalbuminemia in seri ously ill patients is not recommended, and its use in sepsis and septic shock remains controversial. Continuous infusion of 4% albumin solution to ICU patients reduces the risk of nosocomial infections [208] . According to the data obtained, albumin reduces the oxidized form of vasostatin 1 and thereby restores its antimicrobial properties. Albumin can be used to deliver organosulfur com pounds to melanoma cells to inhibit melanin syn thesis [209] . The ability of albumin to bind water can be used in the treatment of organophosphate poisoning. A decrease in glycocalyx leads to a decrease in oncotic pressure and hypovolemia, so that appropriate compensation could become one of the therapeutic factors in acute organophos phate poisoning in order to reduce the risk of death and prevent delayed pathology. Indeed, cases of successful use of fresh frozen plasma in the treatment of the intermediate syndrome, which is one of the possible consequences of poi soning with organophosphates, have been described [210] . At the same time, the introduction of albumin in some situations can be dangerous. Conditions in which the use of albumin is contraindicated due to the risk of acute circulatory overload are cardiac and renal failure, acute or chronic pancreatitis, pulmonary edema, or severe anemia. Also, the use of albumin is not recommended for the conditions such as ascites responsive to diuretics, non hem orrhagic shock, hypoalbuminemia without edema or acute hypotension, malnutrition, open wounds, acute normovolemic hemodilution in surgery, protein loss due to enteropathy or malabsorption. In addition, the use of albumin can be life threat ening for patients with cerebral ischemia and trau matic brain injury [205, 211] . From a physiological point of view, the simplest and most natural way of influencing the level and properties of albumin is the so called "functional nutrition", i.e. the use of such products in food and the use of such methods of processing them, which would maximally preserve the amount and useful qualities of the nutraceuticals contained in them. These nutraceuticals, in turn, would have a positive effect on the intestinal microflora and on the functional state of the liver, where partial metabolism of nutraceuticals and albumin synthe sis occurs, as well as on the state of albumin in the blood plasma, because many polyphenols and other nutraceuticals are bound and transported in the systemic circulation mainly by albumin [212] , changing its conformation and competing with other ligands, including fatty acids and AGE. The relationship between glycated albumin and other dietary AGE, on the one hand, and gut microbi ota, on the other, has recently become the subject of research [213] . The need for the development of standardized methods for determining the rate of consumption of AGE is rightly indicated. Numer ous studies have shown that polyphenols largely determine the number, composition and condi tion of intestinal bacteria, which, in turn, modu late neurological diseases [214] . Polyphenols have not only antioxidant properties, but also the ability to protect proteins from glycation (antiglycating ability). The consumption of polyphenols with food causes an increase in the peripheral blood concentration of phenolic acids, of which the major (dominant) is 3 hydroxyphenylacetic acid (up to 338 μM), while the concentrations of other phenolic acids are in the range from 13 nM to 200 μM. In an in vitro experiment, it was shown that pre incubation of BSA with various phenolic acids and subsequent glycoxidation of albumin (5-10 mM glucose in combination with 10 nM H 2 O 2 ) significantly reduces the concentration of fructosamine [215] . Common polyphenols that can reduce albumin glycation include chrysin and luteolin, structurally related flavone aglycones found in broccoli, chili peppers, celery, rosemary, and honey [80] . The anticarcinogenic and cardio protective properties of luteolin and chrysin are known, in particular, due to their ability to neu tralize ROS, suppress the expression of cyclooxy genase 2 and the formation of prostaglandin E2 [216] . The polyphenol rich extract of the medici nal plant Doratoxylon apetalum proved to be an effective antioxidant for protecting EC by reduc ing the level of ROS-hydrogen peroxide and superoxide [215] . In addition to polyphenols, gar lic extract also inhibits the formation of AGE, including glycated albumin [217] . It is believed that aging related conjugation of oxidative and carbonyl stress (gluco oxidative stress) with the formation of AGE generates neo epitopes on blood proteins, promoting the pro duction of autoantibodies in the elderly, especially in smokers. The use of natural products with antioxidant nutraceuticals reduces the mani festation of age related pathophysiological changes. The mechanism of the protective action of polyphenols is not fully understood, but it is assumed that polyphenols interact non covalently with aromatic amino acid residues of albumin; this hydrophobic interaction promotes the remodeling of mature AGE modified amyloid fibrils and transforms the secondary structure into a helical or disordered helical conformation [92] . Chrysin and luteolin inhibit the formation of albumin fibrils. The docking results showed that both flavonoids non covalently interact with vari ous amino acid residues of the IIA subdomain, including lysines and arginines prone to glycation, and additionally stabilize the HSA structure, which explains the mechanism of their action as antiglycating and antifibrillating agents [80] . It is assumed that polyphenolic compounds have a pleiotropic effect and prevent glycation at differ ent levels: by regulating glucose metabolism, che lating metals, trapping intermediate dicarbonyl compounds, influencing cell insulin resistance, and finally, by activating the signaling pathway of the insulin like growth factor receptor [218] . Thus, the characteristics of albumin revealed in recent years indicate that this major blood plasma protein, which until recently was assigned the "modest" role of an osmotically active compo nent, is in fact a molecular "core", a link between various tissues and organs, indicating health of the whole organism and in many respects determines this health. Modern diagnostics, the pathogenesis of various diseases and the development of thera peutic agents are currently unthinkable without a comprehensive account of the physicochemical, evolutionary genetic, and physiological bio chemical characteristics of albumin. These studies were supported by the State assignment AAAA А18 118012290142 9. 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