Influence of certain d-metals on formation of advanced glycation end products, aggregation and amyloid transformation of albumin in glycation reaction

Cover Page

Cite item

Full Text

Abstract

The aim of the research is to investigate the influence of the factor of the glycation behavior of bovine serum albumin (BSA) by glucose, and the factor of d-metal cations (nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II)) presence, on the process of aggregation and the amyloid transformation of BSA and, therefore, to establish the effect of these cations on the rate of the formation of advanced glycation end products (AGEs), and the intensity of fluorescence of the amino acids tyrosine and tryptophan.

Materials and methods. Reagents in the glycation are: glucose (at the final concentration of 0.36 M), BSA (at the final concentration of 1 mg/ml), deionized water, one of the d-metal cations, i. e. nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II) (in the form of chloride, sulfate or nitrate salts, at the final concentration of 40 μM). The conditions for the glycation reaction are the incubation for 24 hours at the temperature of 60°C. The influence of two factors (the factor of the glycation reaction and the factor of a d-metal ion presence in the reaction medium) on the concentration of glycation end products (AGEs) formed during the glycation reaction, on the fluorescence intensity of the amino acids tryptophan and tyrosine, on the aggregation of BSA, and on the ability of BSA to the amyloid transformation under the described conditions, have been studied.

Results. It was found out that the studied factors have a statistically significant effect on the considered parameters. The highest activity was found for the copper ion (II), which intensifies the formation of the AGEs in the samples where glycation occurs, reduces the fluorescence intensity of the amino acids’ tryptophan and tyrosine (independently and increasing the effect against the background of glycation). Besides, it independently causes the aggregation of BSA hereby intensifying the effect against the background of glycation, it independently causes the amyloid transformation of BSA enhancing the effect against the background of glycation. The above-listed effects were the least pronounced in the reaction media with the addition of nickel (II) or cobalt (II). These cations reduce the rate of the AGEs formation, do not cause the formation of protein aggregates. In the presence of glucose, nickel (II) weakly suppresses the fluorescence intensity of tryptophan and tyrosine, and slightly enhances the amyloid transformation of BSA. Cobalt (II) slightly inhibits the amyloid transformation of BSA. In terms of the severity and nature of the effects, the iron (II), iron (III) and zinc (II) cations occupy an intermediate position between copper (II), on the one hand, and nickel (II) and cobalt (II), on the other hand, combining the influence on the AGEs formation, the intensity of fluorescence of tryptophan and tyrosine, the aggregation and amyloid transformation of BSA. In the absence of glucose, the ability of zinc (II) to induce the formation of protein aggregates turned out to be the highest, and its ability to stimulate the amyloid transformation of BSA corresponded to that of copper (II).

Conclusion. The presence of d-metal cations affects the rate of the AGEs formation in the glycation reaction, affects the rate of the BSA amyloid transformation and the protein aggregates formation. Among such ions as nickel (II), cobalt (II), iron (II), iron (III), copper (II) and zinc (II), copper (II) ions turned out to be the most active in their ability to accelerate the AGEs formation, suppress the fluorescence of tryptophan and tyrosine, enhance the aggregation and amyloid transformation of BSA in the glycation reaction. The least manifestation of these properties is observed for nickel (II) and cobalt (II) ions.

Full Text

Abbreviations: AGEs – advanced glycation end products; BSA – bovine serum albumin; RAGEs – Receptor for advanced glycation end products; ThT – thioflavine Т

 

INTRODUCTION

Non-enzymatic glycation is the source of toxic advanced glycation end products (AGEs). AGEs are a group of more than 20 molecules [1, 2], differing in their properties, including the ability to autofluorescence and the crosslinks formation. AGEs are important pathogenetic factors in the development of cognitive impairments (diabetic encephalopathy, conformational brain diseases) [3–6]. The structures of some AGEs are shown in Fig. 1.

 

Figure 1 – Structures of various advanced glycation end products

 

AGEs are involved in the pathogenesis of cognitive impairment through various mechanisms. In the culture of hippocampal neurons, AGEs induced apoptosis, increased the production of pro-apoptotic Bax protein and acetylcholinesterase, decreased the level of antiapoptotic protein Bcl-2, glutathione peroxidase, superoxide dismutase and choline acetyltransferase, increased the concentration of malondialdehyde, etc. [7] AGEs are able of activating the AGEs receptor (RAGEs). It is assumed that the RAGEs links the pathogenesis of diabetes mellitus and Alzheimer’s disease [8]. The RAGEs can be activated by Aβ protein [9] and is involved in its intraneuronal transport from the blood [10]. The RAGEs activation can lead to the development of the neuronal oxidative stress [11]. Under these conditions, if amyloid peptides are glycated, their RAGEs-mediated action can be enhanced [12]. For these reasons, it is advisable to consider the amyloid transformation and protein glycation as pathogenetically related processes.

In addition to the receptor-mediated relationship, AGEs are able to directly influence the amyloid transformation of proteins. By modifying the lateral chains of amino acids and the N-terminal residue of some proteins, AGEs can cause a change in the surface charge of the protein, a change in its hydrophobic properties and, as a consequence, lead to the amyloid transformation [13]. It is assumed that glycation contributes to the stabilization of protofibrillar structures, and the ability of AGEs to cross-link proteins to make the formation of larger conglomerates from amyloid aggregates possible [13, 14]. Under certain conditions, glycation slows down the formation of mature amyloid fibrils; however, this is associated with an extension of the life span of cytotoxic oligomeric forms [15, 16]. Amyloid oligomeric forms are able of destroying cell membranes, leading to a calcium imbalance, causing a mitochondrial dysfunction, and directly interacting with membrane proteins, leading to a change in their native state [14]. Thus, against the background of glycation, both acceleration and deceleration of the amyloid transformation have negative consequences, which makes the task of studying the effect of glycation on this process urgent.

The glycation reaction depends on many factors, in particular, on the presence of d-metal ions in trace concentrations (including transition metals and those close to them in properties), the presence of reactive oxygen intermediates, etc. [17, 18]. Transition metals include chemical elements the atoms of which have a partially filled d-sublevel or are able of forming cations with an incompletely filled d-sublevel (IUPAC1). The zinc subgroup and zinc itself belong to the metals close in properties to the transitional ones (some of them are called post-transition at times). Many properties of zinc are identical to those of transition metals, but its d-orbitals are filled2. To a great extent, a biological role of transition metals is due to the presence of an incomplete d-sublevel and how this sublevel is filled with electrons, since this, in turn, determines the tendency of a particular transition metal to form certain chemical bonds and their stability. In addition, the electronic configuration of the d-sublevel determines the presence of specific stable oxidation states and, as a consequence, the redox properties of the metal itself and its ions [19]. It was found out that the ability to change the oxidation state is an important property due to which some transition metals are able to stimulate glycation [20, 21]. Thus, in glycation reactions, copper (II) is reduced to copper (I), and oxygen is converted into superoxide anion with the participation of hydrogen peroxide, the source of which is some stages of glycation. After that, copper (I) ions are oxidized to copper (II), catalyzing the decomposition of hydrogen peroxide to a hydroxyl radical [20]. It should be noted that d-metals (zinc, iron, copper, etc.) are involved in the pathogenesis of cerebral conformational diseases by the mechanisms independent of glycation, associated with both the direct action of the ion on the protein (cross-linking of tyrosine residues, etc.) and indirectly, through the influence on the activity of enzymes (secretase, etc.) [22–25, 10]. Thus, the glycation reaction, the amyloid transformation of proteins, and the activity of d-metal ions, which can influence both of these processes, are pathogenetically related.

The amyloid protein transformation can be modeled using bovine serum albumin (BSA) [26, 27]. BSA is prone to the enhanced formation of β-sheets and the amyloid transformation under the physicochemical action (eg, heating), which causes its frequent use as a model protein in the study of amyloid transformation processes [28]. At the temperature that is borderline for the initiation of BSA amyloid aggregation, it becomes possible to assess the ability of the studied factor to accelerate or slow down the course of aggregation and amyloid transformation.

A comparative study of the d-metal ions ability to influence the rate of the AGEs formation in the glycation reaction, as well as their ability to stimulate or suppress the formation of amyloid and non-amyloid protein aggregates against the background of the glycation reaction and independently of it, are of interest.

THE AIM of the research is to evaluate the combined and independent influence of the factor of the BSA glycation reaction and the factor of the presence of d-metal cations (nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II)) in the reaction medium, on the process of the BSA transformation into aggregates of the amyloid and non-amyloid nature. Besides, the influence of these factors on the fluorescence intensity of the amino acids’ tryptophan and tyrosine and the ability of the indicated cations of d-metals to influence the intensity of the AGEs formation in the glycation reaction, are to be assessed.

MATERIALS AND METHODS

Modeling of glycation reaction

Glycation substrate is BSA (fraction V, 1 mg/ml, Himmed, Russia); glycating agent – glucose (0.36 M, Vekton, Russia); the reaction medium was deionized water (pH 6.2, deionizer Milli-Q, Germany) with the addition of one of the transition metal cations, i.e. nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II) at the final concentration of 40 μM in the form of salts NiSO4•7H2O, Co(NO3)2•6H2O, FeSO4, FeCl3•6H2O, CuSO4•5H2O or ZnSO4•7H2O, respectively (or without them). The studied concentration of metal salts was selected on the basis of the previously adjusted model of BSA glyoxidation by glucose in the presence of CuSO4•5H2O, with modifications [29, 30]. The interest in a comparative study of the activities of d-metals, determines the need to research them in equal concentrations. In the body, the concentrations of the studied metals are variable. Thus, the physiological concentrations of copper and zinc in the serum of healthy people are ~1 mg/L (~15.7 μM and ~15.3 μM, respectively) [31, 32]. At the same time, in Alzheimer’s disease, a significantly higher concentration of copper in amyloid plaques (~400 μM) has been reported [10, 25]. During the neuronal activity, zinc is released into the synaptic cleft and can reach the concentration of 300 μM [25]. For these reasons, the selected concentration (40 μM) is a compromise with respect to a wide range of d-metal concentrations in the body under normal and pathological conditions, and is more related to the previously established activity of the copper (II) cation.

The reaction conditions are: the temperature is 60°C, the incubation duration is 24 hours. These conditions were selected on the basis of the literature data [33], indicating that the effect of the selected temperature on BSA (the author used a Tris buffer containing NaCl) is favorable for the transformation of protein α-helices into β-sheets (which may not occur at lower temperatures), while the transformation process is intensified at higher temperatures. In another study it was shown that the BSA aggregation does not occur when exposed to the given temperature (for BSA in a Na-phosphate buffer solution) [34].

Determination of glycation end products and fluorescence intensity of amino acids tryptophan and tyrosine

After the incubation, the aliquots of the samples (200 μL) were added to a 96-well flat-bottom black plate, the fluorescence intensity samples was determined at the excitation/emission wavelengths specific for the following AGEs: pentosidine (335/385 nm), vesperlysine C (345/405 nm), vesperlysines A and B (366/442 nm), crossline (379/463 nm) [35]. The fluorescence intensity at the excitation wavelengths exceeding 400 nm (440/520 nm), was also measured [36]. There is evidence that the product (or products) fluorescent at the excitation/emission wavelengths of 440/520 nm, belongs to the AGEs and is/are able of forming protein cross-links [37]. In addition to AGEs, the fluorescence intensity of the amino acids tryptophan and tyrosine was determined at the excitation/emission wavelengths of 295/335 nm. These wavelenghts are more specific for tryptophan, and 270/330 nm are characteristic of both amino acids (Infinite М200 Pro spectrofluorimeter, TECAN, Austria) [38–40]. The evaluation of the glycation effect and the d-metal ions action on the fluorescence of these amino acids is informative in view of the sensitivity of their fluorescence intensity to changes in the protein conformation and glycation of their amino acid environment [41, 42]. In addition, copper (II) cations promote the formation of dityrosine crosslinks, which is important for the pathogenesis of Alzheimer’s disease [43], and, as a result, the fluorescent characteristics of tyrosine change. The possibility of a change in fluorescence upon oxidation of tryptophan and/or tyrosine, as well as an activation of tyrosine and its direct interaction with the reaction products upon glycation of its environment, cannot be ruled out [44, 42]. This makes the determination of the fluorescence of these amino acids relevant for the present study, and makes it possible to indirectly note changes in the course of both glycation and protein aggregation.

Investigation of aggregation and amyloid transformation of proteins

In the study using spectrophotometry, the intensity of the protein aggregates formation was assessed, and the spectrofluorimetric determination of their amyloid affiliation in the reaction with thioflavin T (ThT) was carried out. A spectrophotometric detection of BSA aggregates was carried out by the increase in the optical density at the wavelength of 405 nm [45] in aliquots of 200 μL in a 96-well flat-bottom transparent plate (Infinite M200 Pro spectrofluorimeter, TECAN, Austria). The study [45] showed that the optical density at the given wavelength is directly proportional to the aggregation degree. The confirmation of the amyloid belonging of the aggregates, was carried out in the reaction with ThT (Sigma Aldrich, USA), at the final ThT concentration of 20 μM [46], by determining the fluorescence intensity of the samples at the excitation/emission wavelength’s of 450/482 nm (Infinite М200 Pro spectrofluorimeter, TECAN, Austria).

Statistical data analysis

In order to determine the contribution of each factor (both the factor of the glycation reaction and the factor of a metal ion presence), statistical data processing was carried out using a two-way analysis of variance, followed by a multiple comparison of data groups “all with all” according to Tukey test, at the significance level of p≤0,05 (GraphPad Prism 9). The correlation analysis was carried out using the Spearman rank correlation method (GraphPad Prism 9). The results are presented as mean with a standard error (M ± SEM).

RESULTS

Analysis of fluorescence intensity of tryptophan and tyrosine

As a result of the influence analysis of the investigated factors on the intensity of tryptophan and tyrosine fluorescence, it was found out that metal cations make a more significant contribution to the change in this parameter. For the cations of copper (II), iron (II), iron (III) and zinc (II), the ability to exert an effect was noted regardless of the glucose presence (a decrease in the fluorescence intensity of the amino acids tryptophan and tyrosine was noted not only in glycated, but also in glucose-free samples) (Table 1). At the same time, no differences were revealed when comparing the fluorescence intensity of tryptophan and tyrosine in the glycated samples that do not contain metals with the fluorescence intensity of the corresponding non-glyca- ted samples (in which only BSA is present). Despite the absence of an intrinsic effect of the glycation reaction on the fluorescence intensity of amino acids, for some metals it was found out that they enhance their ability to suppress the fluorescence of amino acids in the presence of glucose, which indicates the importance of the glycation factor. Thus, a statistically significant decrease in the fluorescence intensity of tryptophan and tyrosine in glucose-containing samples (in comparison with the corresponding samples without glucose) was observed for the cases of glycation in the presence of copper (II) cations (at the excitation/emission wavelengths of 270/330 nm and 295/335 nm), iron (II) (at the excitation/emission wavelengths of 270/330 nm) and zinc (II) (at the excitation/emission wavelengths of 270/330 nm). Thus, these cations were able to enhance their action in the presence of glucose. With respect to cobalt (II), the effect of reducing the fluorescence of tyrosine and tryptophan in the presence of glucose was not observed when compared with the glucose-free samples. In the presence of nickel (II), this effect was weak (there were differences in the fluorescence intensity of the glycated samples containing nickel (II) and the glycated samples without metals, but there were no statistically significant differences in signals from the glycated and glucose-free samples containing nickel (II)).

Influence of d-metals on the rate of AGEs formation in glycation reactions

The intensity of fluorescence at the wavelength’s characteristic of various AGEs, reflects the intensity of the glycation reaction. As expected, in all cases, glucose-containing samples showed an increase in the intensity of AGEs fluorescence in comparison with the corresponding glucose-free samples (Table 1). However, the attention is drawn to the differences in the nature and degree of d-metal cations influence on the glycation reaction. When comparing the AGEs fluorescence intensities of the metal-containing samples in which glycation occurred, with the indices of the corresponding samples without metals, the following was found out. Only copper (II) cations (at all the excitation/emission wavelengths except 335/385 nm) and zinc (II) (the excitation/emission wavelengths of 440/520 nm) had the ability to enhance the formation of AGEs. The rest of the metals, on the contrary, or with statistical significance, prevented an increase in fluorescence at the wavelength’s characteristic of AGEs, or did not change the values of the indicator. At the wavelengths characteristic of pentosidine (335/385 nm), no metal was able to intensify the formation of AGEs in comparison with the samples without metals. At the same time, nickel (II), cobalt (II), iron (II), and iron (III) were able to reduce the intensity of the signal detected at these wavelengths. The established activity makes it possible to isolate copper (II) and zinc (II) into the category of d-metals capable of accelerating the glycation under the described conditions. The cumulative results are shown in Table 1.

 

Table 1 – Influence of investigated factors on the intensity of fluorescence emission characteristic of various AGEs, as well as amino acids tryptophan and tyrosine; absolute values of fluorescence (M ± SEM)

Glucose factor

Fluorescence parameters (λexc/λtest), nm and corresponding product

Metal cation factor

None

Nickel (II)

Cobalt (II)

Iron (II)

Copper (II)

Iron (III)

Zinc (II)

Glucose

270/

330

Tryptophan and tyrosine

83147.2±1561.7

75475.8±1415.6

**

78131.2±1441.9

68838.8±1290.9

****##

30211.8±1680.2

****####

63999.6±1399.6

****

70210.8±1417.6

****#

Glucose-free

83063.0±1000.5

80763.0±664.4

78733.8±926.2

76121.0±279.1

*

56691.4±1055.4

****

62589.2±1609.8

****

76616.8±837.1

*

Glucose

295/

335

Tryptophan (predominantly)

41994.3±1290.6

37012.8±1205.5

*

39814.8±1459.9

34861.6±1056.5

***

14637.2±587.9

****####

31014.8±845.1

****

33909.6±707.4

****

Glucose-free

43126.5±303.6

40918.8±757.4

38680.0±881.2

*

36587.8±813.1

**

27971.5±785.8

****

30535.0±1180.7

****

37617.0±456.1

**

Glucose

335/

385

Pentosidine

752.8±13.4

####

538.6±15.8

****####

580.6±17.2

****####

490.2±15.0

****####

757.0±29.5

####

395.0±11.9

****####

748.8±17.7

####

Glucose-free

284.5±6.9

278.0±4.0

268.5±3.1

244.3±4.2

250.5±6.5

202.8±6.3

**

302.5±12.7

Glucose

345/

405

Argpyrimidine

812.4±14.6

####

578.8±15.3

****####

609.4±14.5

****####

594.0±10.2

****####

1058.2±19.1

****####

452.4±7.3

****####

861.8±8.6

####

Glucose-free

313.0±14.1

291.3±6.8

313.0±12.1

273.3±4.5

302.3±11.1

229.0±11.1

**

391.3±30.2

**

Glucose

366/

442

Vesperlysines A and B

921.0±22.8

####

744.0±17.0

**####

728.2±13.6

**#

874.0±61.5

####

2009.8±37.0

****####

666.0±13.2

****####

977.0±5.6

####

Glucose-free

491.0±11.0

477.2±9.2

561.2±33.9

504.8±49.4

594.8±21.5

390.0±27.6

661.4±40.8

*

Glucose

379/

463

Crossline

826.6±21.7

####

675.4±18.7

**####

644.2±10.9

****##

786.6±47.2

####

1917.8±34.9

****####

618.8±12.1

****####

828.6±7.6

####

Glucose-free

477.8±11.2

471.6±9.8

500.0±23.9

439.3±5.9

594.4±22.9

*

365.2±20.7

*

603.6±32.9

*

Glucose

440/

520

Cross-links

451.6±8.1

####

355.4±9.2

****####

348.8±9.3

****####

416.2±9.9

####

727.4±9.3

****####

372.4±8.2

****####

496.0±8.0

*####

Glucose-free

323.4±4.9

282.6±6.3

300.0±4.7

291.2±6.3

310.0±4.9

233.8±6.7

****

375.0±15.0

**

Note: significance level p when compared with the corresponding metal-free samples (**** corresponds to p˂0.0001; *** corresponds to p˂0.001; ** corresponds to p˂0.01; * corresponds to p˂0.05). Significance level p when compared with corresponding glucose-free samples (#### corresponds to p˂0.0001; ### corresponds to p˂0.001; ## corresponds to p˂0.01; # corresponds to p˂0.05 (two-way ANOVA, Tukey’s post-test).

 

In the absence of glucose, a slight increase in fluorescence was observed under the action of copper (II) cations (at all the excitation/emission wavelengths of 379/463 nm) and zinc (II) (at all the excitation/emission wavelengths of 345/405 nm, 366/442 nm, 379/463 nm and 440/520 nm, respectively). A partially similar effect, as well as the ability of iron (III) to reduce the fluorescence intensity at the excitation/emission wavelength’s characteristic of AGEs, can be associated with the effect on residual amounts of glucose, the presence of which is probably explained by the technology of albumin production. At the same time, it was shown that, in the identical test system, the presence of zinc cations also leads to the appearance of fluorescence at the wavelengths of 320/438 nm, due to the coordination (or complexation) of zinc cations with amino acid residues at different sites of albumin [47]. In this case it can suggest the formation of coordination structures similar to those previously described by Wu F.-Y. et al. [47]. In the case of copper, the possibility of its interaction with the lysine residue resulting in the formation of a product, fluorescent at the wavelengths of 370/440 nm, was considered in the work by Zhang M. et al. [48]. The above-mentioned information does not exclude the possibility of the formation of other products associated with the specific effect of the metal ion on the protein, and significant for the pathogenesis analized in the article.

Effect of d-metals on BSA aggregation and amyloid transformation

It is known from the literature data that cations of transition metals (copper (II), iron (III)) are able to stimulate the amyloid transformation of proteins [10, 49]. The research of the glycation reaction influence on this metal’s property is of great interest. Studying the optical density of the reaction medium at the wavelength of 405 nm is used to assess the kinetics of the protein aggregates formation in the process of the amyloid transformation [45]. The result obtained in the course of this study (during the glycation reaction and/or independently), confirms the ability of some of the studied d-metals to stimulate the BSA aggregation. The results are shown in Table 2.

Considering the intrinsic (independent of glycation) ability of the studied d-metals to cause the BSA aggregation, it should be noted that the activity of metals can be arranged in the ascending order: nickel (II) (inactive) = cobalt (II) (inactive) = iron (II) (inactive) ˂ copper (II) ˂ iron (III) ˂ zinc (II) (Table 2).

 

Table 2 – Influence of investigated factors on formation of BSA aggregates, optical density of samples at wavelength of 405 nm; absolute values (M ± SEM)

Glucose factor

Metal cation factor

None

Nickel (II)

Cobalt (II)

Iron (II)

Copper (II)

Iron (III)

Zinc (II)

Glucose

0.06±0.0004

0.06±0.0006

0.06±0.0020

0.19±0.0021

****####

1.08±0.0122

****####

0.37±0.0188

****

0.65±0.0236

****####

Glucose- free

0.05±0.0004

0.06±0.0007

0.05±0.0007

0.06±0.0007

0.18±0.0036

****

0.4±0.0090

****

1.02±0.0180

****

Note: significance level p when compared with corresponding metal-free samples (**** corresponds to p˂0.0001; *** corresponds to p˂0.001; ** corresponds to p˂0.01; * corresponds to p˂0.05). Significance level p when compared with corresponding glucose-free samples: #### corresponds to p˂0.0001; ### matches p˂0.001; ## matches p˂0.01; # corresponds to p˂0.05 (two-way ANOVA, Tukey’s post-test

 

The glycation reaction in a metals-free medium did not lead to any statistically significant aggregation of BSA. In this case, glycation affected the ability of some cations to induce the BSA aggregation. Nickel (II) and cobalt (II) cations did not cause any BSA aggregation either independently or in the presence of glucose.

The ability to enhance the BSA aggregation only in the presence of glucose and not without it, has been established for iron (II) cations. For copper (II), iron (III), and zinc (II), the BSA aggregation was observed both in the absence of glucose (due to its own activity) and under the action of cations against the background of the glycation reaction. In case of copper (II), the intensity of the aggregation was higher in the samples with glucose, for iron (III), the result is the same for glucose-containing and glucose-free samples, and in case of zinc (II), the intensity of the aggregation was higher in the glucose-free samples.

For the studied metal cations, there is a mismatch between the ability to influence the formation of AGEs in the glycation reaction and the ability to stimulate the BSA aggregation. Thus, in the presence of glucose, iron (II) and iron (III), causing the aggregation (Table 2), do not stimulate the AGEs formation (Table 1). The ability of these cations to aggregate BSA does not depend on the AGEs formation, and in case of iron (II), it does not depend on the AGEs formation, but is obviously associated with the presence of glucose. At the same time, when conducting a correlation analysis according to Spearman, a statistically significant inverse correlation between the ability of metal ions to aggregate BSA in the glycated samples and the fluorescence intensity of the amino acids tyrosine and tryptophan at the wavelengths of 270/330 nm specific for both amino acids (r = –0, 85, p = 0.03), and 295/335 nm, more specific for tryptophan (r = –0.93, p = 0.01), has been established.

Alongside with the study of the BSA aggregation, the samples were examined for the amyloid belonging of the aggregates in the reaction with thioflavin T (ThT), an amyloid-specific agent. A more pronounced amyloid BSA transformation in the glucose-free samples compared with the glucose-containing samples in all cases, except for the reaction in the presence of copper (II), is noteworthy.

In the presence of glucose, copper (II) stimulates the amyloid BSA transformation more intensively than without it (Table 3). Regarding the other metals and the reaction medium without the ones, the equally increased intensity of ThT fluorescence in the glucose-free samples in comparison with the corresponding glucose-containing samples, indicates that under the described experimental conditions, glycation prevents the amyloid BSA transformation. At the same time, in the samples glycated in the presence of copper (II) cations, a statistically significant higher intensity of ThT fluorescence indicates a mutual reinforcing effect of glucose and copper factors on the intensity of the amyloid transformation (Table 3). It follows from the result that copper showed both the ability to stimulate the amyloid BSA transformation, independent of glycation, and leveled the ability of the ongoing glycation reaction to slow it down.

 

Table 3 – Influence of the studied factors on amyloid BSA transformation, intensity of fluorescent ThT emission at excitation/emission wavelengths of 450/482 nm; absolute values (M ± SEM)

Glucose factor

Metal cation factor

None

Nickel (II)

Cobalt (II)

Iron (II)

Copper (II)

Iron (III)

Zinc (II)

Glucose

6051.0±320.2

####

7954.2±391.5

*####

5740.8±283.3

####

6083.4±241.7

####

18277.3±792.1

****#

2704.8±190.4

****####

13415.2±238.7

****####

Glucose- free

11693.8±280.2

13841.6±109.3

**

9695.4±132.0

**

10887.6±157.8

16304.8±335.2

****

7266.0±257.3

****

17900.0±672.5

****

Note: significance level p when compared with the corresponding metal-free samples (**** corresponds to p˂0.0001; *** corresponds to p˂0.001; ** corresponds to p˂0.01; * corresponds to p˂0.05). Significance level p when compared with corresponding glucose-free samples (#### corresponds to p˂0.0001; ### corresponds to p˂0.001; ## corresponds to p˂0.01; # corresponds to p˂0.05 (two-way ANOVA, Tukey’s post-test)

 

When assessing the influence of the factor of each cation presence on the amyloid BSA transformation, it was found out that in both glucose and glucose-free samples, this process is enhanced by the cations of copper (II) and zinc (II) (to the maximum extent) as well as nickel (II) (least of all). Cobalt (II) cations slightly suppress the reaction (statistically significant only in the absence of glucose), while iron (II) cations were found to be inactive. Iron (III) was found out to be able to reduce ThT fluorescence in both glucose-containing and glucose-free samples. The ability of copper and zinc to transform proteins into the amyloid form has been previously described more than once. The authors’ unexpected results regarding a weak activity of nickel, are consistent with the recently established role of nickel in the formation of human β-amyloid [24].

DISCUSSION

As a result of the study, it was found out that in the absence of metals, the glycation reaction does not affect the fluorescence intensity of tyrosine and tryptophan (the fluorescence intensity of glycated and non-glycated samples is the same). However, glycation can enhance the ability of metals to suppress the fluorescence of these amino acids. In the case of tyrosine, a possible mechanism for decreasing its fluorescence has been described for the reaction of collagen with ribose-5-phosphate [41]. It may be associated with such events as glycation of amino acids located in the spatial proximity to tyrosine (which leads to quenching of its fluorescence); a change in the spatial organization of the protein (which leads to quenching of the fluorescence of tyrosine), the reaction of tyrosine itself. Herewith tyrosine is not expected to directly interact with the glycating agent, but the participation of nearby lysine or arginine residues in the reaction can lead to the activation of tyrosine and its subsequent glycation, or oxidation.

At the same time, as for tryptophan, its residue can be oxidized during glycation [44], and this process can be enhanced in the presence of copper (II) [42]. Thus, a decrease in the intensity of tryptophan fluorescence during the glycation reaction in the presence of copper (II) is due to both the oxidation of the amino acid residue and a change in the protein conformation [42]. Summing up what has been said, it can be assumed that d-metals, which are able of suppressing the fluorescence of tyrosine and/or tryptophan during glycation more intensely, are active, influencing these mechanisms.

It is known that the ability of some d-metals to accelerate the AGEs formation in the glycation reaction is associated with their stimulation of oxidative reactions. This property is characteristic of metals such as copper, and the reaction that occurs with their participation is called the glyoxidation reaction [20]. Thus, the role of copper (II) in the course of glyoxidation is presumably in the catalysis of the electron transfer from enediols formed from reduced monosaccharides or during the fragmentation of Schiff bases and Amadori products. That leads to the formation of reactive oxygen species and dicarbonyl compounds. In these reactions, copper (II) is probably reduced to copper (I), and oxygen is converted to superoxide anion with the participation of hydrogen peroxide. Its source of some glycation stages. Then copper (I) ions are oxidized to copper (II), catalyzing the decomposition of hydrogen peroxide to a hydroxyl radical. Considering this, it can be concluded that the intensification of the glycation reaction in the presence of some transition metals under study can occur according to the described mechanism of glyoxidation.

The analysis of the zinc activity as a non-transition but d-metal, is of particular interest. According to the concept of the glyoxidation mechanism with the participation of copper (II), for the reaction to proceed, it is necessary for the metal ion to be able of changing the oxidation degree. A zinc ion has a constant oxidation degree, but it was able to slightly increase the fluorescence intensity at some excitation/emission wavelengths characteristic of AGEs. According to the literature data [50], zinc can exhibit antiglycating, antioxidant, and antiapoptotic properties, and its deficiency can contribute to the accelerated AGEs formation. However, according to the studies conducted by Zhuang X. et al. [51], in the in vitro glycation reaction, zinc (II) is able to enhance the formation of fluorescent AGEs, which is consistent with the results of the research. According to the same study [51], the transition metal manganese exhibits the ability to suppress the AGEs formation in the manner similar to that described for nickel, cobalt and iron, which are also transition metals. All these data indicate that belonging of the metal to transitional ones and the ability of its ion to change the oxidation degree is probably not a necessary and sufficient condition for accelerating a glycation reaction. This also indicates the uniqueness of the zinc properties among the studied metals.

Summarizing the investigation results of the d-metals effect on the fluorescence of the amino acids tyrosine and tryptophan, and the effect of the d-metals on the glycation reaction, it can be assumed that the mechanisms of the metals influence on both processes differ (at least, there are activity components associated with the effect on only one process). The results make it possible to assume the following: there is an additional mechanism of damage to tyrosine and/or tryptophan caused by the glycation factor (not limited by the intrinsic action of the metal ion), which manifests itself during the course of the reaction in the presence of copper (II), iron (II), zinc (II) cations, and, possibly nickel (II). Herewith, an increase in the fluorescence intensity at the wavelengths characteristic of AGEs, regarded as an intensification of the glycation reaction, was noted only when glycation proceeded in the presence of copper (II) cations (to a greater extent) and zinc (II) (to a lesser extent).

As for the results of albumin aggregation studies, it should be noted that, according to the literature data [43], one of the factors of the pathogenetic action of copper (II) cations in Alzheimer’s disease, is its participation in the formation of amyloid dimers linked by dityrosine cross-links. This is consistent with the intense suppression of amino acid fluorescence observed in this study in the presence of copper, as well as with the presence of a statistically significant inverse correlation between the fluorescence intensity of these amino acids and the degree of BSA aggregation for the studied cations. Thus, a decrease in the fluorescence intensity of the amino acids tryptophan and tyrosine in the presence of d-metal ions, obviously accompanies the BSA aggregation process. The most intense aggregation of BSA proceeded in the presence of ions that showed the ability to enhance the formation of AGEs (copper, zinc).

As mentioned above, the amyloid transformation of a protein during glycation, depends on many factors, and in particular on the type of protein. Thus, according to the literature data, an increase in the amyloid transformation is observed in the process of albumin glycation (bovine and human), Aβ-protein, β2 microglobulin, etc. In contrast, the ability of α-synuclein to form amyloid fibrils after the glycation by methylglyoxal was reduced, and the resulting aggregates had the character of a molten glo

bule [52]. According to the results obtained, glycation under the described experimental conditions prevents the formation of ThT-sensitive amyloid forms. A similar result is observed when glycation occurs in the presence of nickel (II), cobalt (II), iron (II), iron (III), and zinc (II), but not copper (II), which has shown the ability to enhance the amyloid transformation and the BSA aggregation. Banerjee S. describes a decrease in the intensity of the amyloid transformation of chicken lysozyme after the exposure to the protein with methylglyoxal. Based on this result, the author puts forward a controversial assumption that carbonyl compounds can be used for pharmacological purposes [53]. Despite the doubtfulness of the therapeutic use of carbonyl compounds, this study and the similar ones confirm the fact that glycation can not only potentiate the amyloid transformation [13], but also prevent it [13, 53]. At the same time, it is known that the retardation of the amyloid transformation under the glycation action can be associated with the prolongation of the amyloid residence time in the oligomeric form – the form with the highest cytotoxicity. The latter negates the potential utility of glycation-induced slowing down of the amyloid transformation. According to the literature data [54, 55], ThT, in contrast to other forms (monomers, fibrils), may not detect the formation of amyloid oligomeric forms. It can be suggested that a comparatively lower intensity of ThT fluorescence in the samples glycated in the presence of all d-metal ions with the exception of copper (II), is related to the possibility of slowing down the reaction at the stage of the oligomer formation. However, that will be the subject of a further research. This property has not been found for the glycation in the presence of copper (II).

When evaluating the results obtained, one should obviously take into account all the conditions of the experiment (not only the factors of glycation and the presence of metal, but also heating, the content and pH of the reaction medium, etc.). It can be assumed that unaccounted for factors, can also affect the ability of albumin to undergo the amyloid transformation during glycation, and under other conditions, the course of the reaction can lead to a different result. Thus, for a comprehensive assessment of the glycation ability to influence the amyloid transformation, one should take into account the ability of a protein to transform into an amyloid form under various experimental conditions (different pH values, temperatures, ionic strength of the buffer solution, etc.), including conducting studies under the conditions close to physiological ones.

CONCLUSION

As a result of the research, it was shown that the course of the glycation reaction affects the amyloid transformation of BSA, and in the presence of d-metal ions it affects the ability of some of them to cause aggregation and the amyloid transformation. Under the described experimental conditions, copper (II) cations were the only ones able of enhancing the formation of AGEs, reducing the fluorescence intensity of the amino acids tryptophan and tyrosine in the glucose-mediated and glucose-independent ways, causing aggregation and the amyloid transformation of BSA. Ions of other metals showed these effects only partially, in various combinations. This makes it possible to suggest that in the series of d-metal ions such as nickel (II), cobalt (II), iron (II), iron (III), copper (II) and zinc (II), only copper ions (II) are probably the most significant factors in enhancing the amyloid transformation and BSA aggregation, and are the most active catalysts for the formation of AGEs in the glycation reaction. Thus, we believe that this element is a promising target for the development of methods for a pharmacological control of pathological conditions associated with all the processes considered – glycation, aggregation, and amyloid transformation of proteins (long term complications of diabetes mellitus, including diabetic encephalopathy; conformational brain diseases, etc.).

FUNDING

This work was supported by a grant from the President of the Russian Federation to support young scientists – candidates of sciences MK-1887.2020.7.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHORS’ CONTRIBUTION

Roman A. Litvinov – development of the research idea, planning, preparation and writing of the publication text, organization and control of the research at all its stages; Arina V. Gontareva – setting up and carrying out the glycation reaction, preparation of reagents, obtaining primary data; Lyudmila E. Usmiyanova – setting and carrying out the glycation reaction, preparation of reagents, obtaining primary data; Daria R. Klimenko – preparation of reagents, statistical processing of primary data, correction of the publication text at the stage of its preparation, work with literature sources.

 

1 IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A.D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-9-8. DOI: 10.1351/goldbook.

2 General Properties of Transition Metals. (2020, December 7). Retrieved: June 28, 2021. Available from: https://chem.libretexts.org/@go/page/24341.

×

About the authors

Roman A. Litvinov

Volgograd State Medical University ; Volgograd Medical Research Center

Author for correspondence.
Email: litvinov.volggmu@mail.ru
ORCID iD: 0000-0002-0162-0653

Candidate of Sciences (Medicine), Senior Researcher, Laboratory of Metabotropic Medicines, Department of Pharmacology and Bioinformatics, Scientific Center for Innovative Medicines with Pilot Production; Researcher, Laboratory of Experimental Pharmacology

Russian Federation, Pavshikh Bortsov Sq., Volgograd, Russia, 400131; Pavshikh Bortsov Sq., Volgograd, Russia, 400131

Arina V. Gontareva

Volgograd State Medical University

Email: arinaarinag@gmail.com

6th year student, specialty “Medical Biochemistry”; co-executor of the grant of the President of the Russian Federation to support young scientists, candidates of sciences 

Russian Federation, Pavshikh Bortsov Sq., Volgograd, Russia, 400131

Lyudmila E. Usmiyanova

Volgograd State Medical University

Email: mila.getmanets@gmail.com

6th year student, specialty “Medical Biochemistry”;co-executor of the grant of the President of the Russian Federation to support young scientists, candidates of sciences

Russian Federation, Pavshikh Bortsov Sq., Volgograd, Russia, 400131

Daria R. Klimenko

Volgograd State Medical University

Email: vip.klimenko.darya@mail.ru

4th year student, specialty “Pharmacy”

Russian Federation, Pavshikh Bortsov Sq., Volgograd, Russia, 400131

References

  1. Perrone A, Giovino A, Benny J, Martinelli F. Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Oxid Med Cell Longev. 2020 Mar 18;2020:3818196. doi: 10.1155/2020/3818196.
  2. Chaudhuri J, Bains Y, Guha S, Kahn A, Hall D, Bose N, Gugliucci A, Kapahi P. The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality. Cell Metab. 2018 Sep 4;28(3):337–52. doi: 10.1016/j.cmet.2018.08.014.
  3. Yu L, Chen Y, Xu Y, He T, Wei Y, He R. D-ribose is elevated in T1DM patients and can be involved in the onset of encephalopathy. Aging (Albany NY). 2019 Jul 15;11(14):4943–69. doi: 10.18632/aging.102089.
  4. Akhter F, Chen D, Akhter A, Sosunov AA, Chen A, McKhann GM, Yan SF, Yan SS. High Dietary Advanced Glycation End Products Impair Mitochondrial and Cognitive Function. J Alzheimers Dis. 2020;76(1):165–78. doi: 10.3233/JAD-191236.
  5. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA. 1994 May 24;91(11):4766–70. doi: 10.1073/pnas.91.11.4766.
  6. König A, Vicente Miranda H, Outeiro TF. Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson’s Disease. J Parkinsons Dis. 2018;8(1):33–43. doi: 10.3233/JPD-171285.
  7. Gan WJ, Gao CL, Zhang WQ, Gu JL, Zhao TT, Guo HL, Zhou H, Xu Y, Yu LL, Li LF, Gui DK, Xu YH. Kuwanon G protects HT22 cells from advanced glycation end product-induced damage. Exp Ther Med. 2021 May;21(5):425. doi: 10.3892/etm.2021.9869.
  8. Kong Y, Wang F, Wang J, Liu C, Zhou Y, Xu Z, Zhang C, Sun B, Guan Y. Pathological Mechanisms Linking Diabetes Mellitus and Alzheimer’s Disease: the Receptor for Advanced Glycation End Products (RAGE). Front Aging Neurosci. 2020 Jul 22;12:217. doi: 10.3389/fnagi.2020.00217.
  9. Yan SS, Chen D, Yan S, Guo L, Du H, Chen JX. RAGE is a key cellular target for Abeta-induced perturbation in Alzheimer’s disease. Front Biosci (Schol Ed). 2012 Jan 1;4:240-50. doi: 10.2741/265.
  10. Kim, DK., Song, JW., Park, JD. Choi BS. Copper induces the accumulation of amyloid-beta in the brain. Mol. Cell. Toxicol. 2013;9:57–66. doi: 10.1007/s13273-013-0009-0.
  11. Piras S, Furfaro AL, Domenicotti C, Traverso N, Marinari UM, Pronzato MA, Nitti M. RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage. Oxid Med Cell Longev. 2016;2016:9348651. doi: 10.1155/2016/9348651.
  12. Li XH, Du LL, Cheng XS, Jiang X, Zhang Y, Lv BL, Liu R, Wang JZ, Zhou XW. Glycation exacerbates the neuronal toxicity of β-amyloid. Cell Death Dis. 2013 Jun 13;4(6):e673. doi: 10.1038/cddis.2013.180.
  13. Iannuzzi C, Irace G, Sirangelo I. Role of glycation in amyloid: Effect on the aggregation process and cytotoxicity. IntechOpen 2016:165. doi: 10.5772/62995.
  14. Sirangelo I, Iannuzzi C. Understanding the Role of Protein Glycation in the Amyloid Aggregation Process. International Journal of Molecular Sciences. 2021; 22(12):6609. doi: 10.3390/ijms22126609.
  15. Milordini G, Zacco E, Percival M, Puglisi R, Dal Piaz F, Temussi P, Pastore A. The Role of Glycation on the Aggregation Properties of IAPP. Front Mol Biosci. 2020 Jun 3;7:104. doi: 10.3389/fmolb.2020.00104.
  16. Emendato A, Milordini G, Zacco E, Sicorello A, Dal Piaz F, Guerrini R, Thorogate R, Picone D, Pastore A. Glycation affects fibril formation of Aβ peptides. J Biol Chem. 2018 Aug 24;293(34):13100–11. doi: 10.1074/jbc.RA118.002275.
  17. Bhuiyan MN, Mitsuhashi S, Sigetomi K, Ubukata M. Quercetin inhibits advanced glycation end product formation via chelating metal ions, trapping methylglyoxal, and trapping reactive oxygen species. Biosci Biotechnol Biochem. 2017 May;81(5):882–90. doi: 10.1080/09168451.2017.1282805.
  18. Wu Q, Li SY, Yang T, Xiao J, Chua QM, Li T, Xie BJ, Sun ZD. Inhibitory effect of lotus seedpod oligomeric procyanidins on advanced glycation end product formation in a lactose-lysine model system. Electronic Journal of Biotechnology. 2015;18(2):68–76. doi: 10.1016/j.ejbt.2014.10.005.
  19. Clayton PT. Inherited disorders of transition metal metabolism: an update. J Inherit Metab Dis. 2017 Jul;40(4):519–29. doi: 10.1007/s10545-017-0030-x.
  20. Serban AI, Condac E, Costache M, Dinischiotu A. The relationship between ages, Cu2+ and crosslinking of collagen. Revue Roumaine de Chimie. 2009;54 (1):93–101.
  21. Bavkar LN, Patil RS, Rooge SB, Nalawade ML, Arvindekar AU. Acceleration of protein glycation by oxidative stress and comparative role of antioxidant and protein glycation inhibitor. Mol Cell Biochem. 2019 Sep;459(1-2):61–71. doi: 10.1007/s11010-019-03550-7.
  22. Sadakane Y, Kawahara M. Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation. Int J Mol Sci. 2018 Aug 19;19(8):2449. doi: 10.3390/ijms19082449.
  23. Xu Y, Xiao G, Liu L, Lang M. Zinc transporters in Alzheimer’s disease. Mol Brain. 2019 Dec 9;12(1):106. doi: 10.1186/s13041-019-0528-2.
  24. Benoit SL, Maier RJ. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation. Sci Rep. 2021 Mar 23;11(1):6622. doi: 10.1038/s41598-021-86060-1.
  25. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci. 1998 Jun 11;158(1):47–52. doi: 10.1016/s0022-510x(98)00092-6.
  26. de la Arada I, Seiler C, Mäntele W. Amyloid fibril formation from human and bovine serum albumin followed by quasi-simultaneous Fourier-transform infrared (FT-IR) spectroscopy and static light scattering (SLS). Eur Biophys J. 2012 Nov;41(11):931–8. doi: 10.1007/s00249-012-0845-1.
  27. Holm NK, Jespersen SK, Thomassen LV, Wolff TY, Sehgal P, Thomsen LA, Christiansen G, Andersen CB, Knudsen AD, Otzen DE. Aggregation and fibrillation of bovine serum albumin. Biochim Biophys Acta. 2007 Sep;1774(9):1128-38. doi: 10.1016/j.bbapap.2007.06.008.
  28. Ma XJ, Zhang YJ, Zeng CM. Inhibition of Amyloid Aggregation of Bovine Serum Albumin by Sodium Dodecyl Sulfate at Submicellar Concentrations. Biochemistry (Mosc). 2018 Jan;83(1):60–68. doi: 10.1134/S000629791801008X.
  29. Litvinov RA, Kosolapov VA, Muravyova EA, Skachko IV, Shamshin DD. Modificirovannyj metod izucheniya reakcii glikoksidacii [A modified method for studying the glycoxidation reaction]. Vestnik Volgogradskogo gosudarstvennogo medicinskogo universiteta = Journal of VolgSMU. 2020;2(74):61–66. Russian
  30. Litvinov RA, Usmiyanova LE, Klimenko DR, Gontareva AV. Paradoksal’naya aktivnost’ aminoguanidina v modeli glikoksidacii v prisutstvii kationov cu(II) [Paradoxal activity of aminoguanidine in the model of glycoxidation with copper cations]. Vestnik Volgogradskogo gosudarstvennogo medicinskogo universiteta = Journal of VolgSMU. 2020;3(75):159–165. Russian
  31. Ramirez Segovia A.S., Wrobel K., Acevedo Aguilar F.J., Corrales Escobosa A.R., Wrobel K. Effect of Cu(II) on in vitro glycation of human serum albumin by methylglyoxal: a LC-MS-based proteomic approach. Metallomics. 2017;9(2):132–40. doi: 10.1039/c6mt00235h.
  32. Michalska-Mosiej M, Socha K, Soroczyńska J, Karpińska E, Łazarczyk B, Borawska MH. Selenium, Zinc, Copper, and Total Antioxidant Status in the Serum of Patients with Chronic Tonsillitis. Biol Trace Elem Res. 2016 Sep;173(1):30–4. doi: 10.1007/s12011-016-0634-2.
  33. Shanmugam G, Polavarapu PL. Vibrational circular dichroism spectra of protein films: thermal denaturation of bovine serum albumin. Biophys Chem. 2004 Sep 1;111(1):73–7. doi: 10.1016/j.bpc.2004.04.005.
  34. Chebotareva NA, Roman SG, Borzova VA, Eronina TB, Mikhaylova VV, Kurganov BI. Chaperone-Like Activity of HSPB5: The Effects of Quaternary Structure Dynamics and Crowding. Int J Mol Sci. 2020 Jul 13;21(14):4940. doi: 10.3390/ijms21144940.
  35. Séro L, Sanguinet L, Blanchard P, Dang BT, Morel S, Richomme P, Séraphin D, Derbré S. Tuning a 96-well microtiter plate fluorescence-based assay to identify AGE inhibitors in crude plant extracts. Molecules. 2013 Nov 19;18(11):14320–39. doi: 10.3390/molecules181114320.
  36. Beisswenger PJ, Howell S, Mackenzie T, Corstjens H, Muizzuddin N, Matsui MS. Two fluorescent wavelengths, 440(ex)/520(em) nm and 370(ex)/440(em) nm, reflect advanced glycation and oxidation end products in human skin without diabetes. Diabetes Technol Ther. 2012 Mar;14(3):285–92. doi: 10.1089/dia.2011.0108.
  37. Zhang Y, Baloglu FK, Ziemer LEH, Liu Z, Lyu B, Arendt LM, Georgakoudi I. Factors associated with obesity alter matrix remodeling in breast cancer tissues. J Biomed Opt. 2020 Jan;25(1):1–14. doi: 10.1117/1.JBO.25.1.014513.
  38. Oto N, Oshita S, Makino Y, Kawagoe Y, Sugiyama J, Yoshimura M. Non-destructive evaluation of ATP content and plate count on pork meat surface by fluorescence spectroscopy. Meat Sci. 2013 Mar;93(3):579–85. doi: 10.1016/j.meatsci.2012.11.010.
  39. Yang H, Xiao X, Zhao X, Wu Y.”Intrinsic fluorescence spectra of tryptophan, tyrosine and phenyloalanine”, Proc. SPIE 10255, Selected Papers of the Chinese Society for Optical Engineering Conferences held October and November 2016, 102554M (8 March 2017). doi: 10.1117/12.2268397.
  40. Lakowicz JR. Protein Fluorescence. Principles of Fluorescence Spectroscopy. Springer, Boston, MA. (2006). doi: 10.1007/978-0-387-46312-4_16.
  41. Bansode S, Bashtanova U, Li R, Clark J, Müller KH, Puszkarska A, Goldberga I, Chetwood HH, Reid DG, Colwell LJ, Skepper JN, Shanahan CM, Schitter G, Mesquida P, Duer MJ. Glycation changes molecular organization and charge distribution in type I collagen fibrils. Sci Rep. 2020 Feb 25;10(1):3397. doi: 10.1038/s41598-020-60250-9.
  42. Hunt JV, Wolff SP. Oxidative glycation and free radical production: a causal mechanism of diabetic complications. Free Radic Res Commun. 1991;12–13:115–23. doi: 10.3109/10715769109145775.
  43. Ejaz HW, Wang W, Lang M. Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches. Int J Mol Sci. 2020 Oct 16;21(20):7660. doi: 10.3390/ijms21207660.
  44. Chetyrkin SV, Mathis ME, Ham AJ, Hachey DL, Hudson BG, Voziyan PA. Propagation of protein glycation damage involves modification of tryptophan residues via reactive oxygen species: inhibition by pyridoxamine. Free Radic Biol Med. 2008 Apr 1;44(7):1276–85. doi: 10.1016/j.freeradbiomed.2007.09.016.
  45. Wang SS, Chen YT, Chou SW. Inhibition of amyloid fibril formation of beta-amyloid peptides via the amphiphilic surfactants. Biochim Biophys Acta. 2005 Sep 25;1741(3):307–13. doi: 10.1016/j.bbadis.2005.05.004.
  46. Khurana R, Coleman C, Ionescu-Zanetti C, Carter SA, Krishna V, Grover RK, Roy R, Singh S. Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol. 2005 Sep;151(3):229–38. doi: 10.1016/j.jsb.2005.06.006.
  47. Wu FY, Zhang LN, Ji ZJ, Wan XF. Spectroscopic investigation of the interaction between thiourea-zinc complex and serum albumin // Journal of Luminescence. 2010;130:1280–1284.
  48. Zhang M, Qiao J, Zhang S, Qi L. Copper nanoclusters as probes for turn-on fluorescence sensing of L-lysine. Talanta. 2018 May 15;182:595-599. doi: 10.1016/j.talanta.2018.02.035.
  49. Tahmasebinia F, Emadi S. Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron. Biometals. 2017 Apr;30(2):285–293. doi: 10.1007/s10534-017-0005-2.
  50. Kheirouri S, Alizadeh M, Maleki V. Zinc against advanced glycation end products. Clin Exp Pharmacol Physiol. 2018 Jun;45(6):491–498. doi: 10.1111/1440-1681.12904.
  51. Zhuang X, Pang X, Zhang W, Wu W, Zhao J, Yang H, Qu W. Effects of zinc and manganese on advanced glycation end products (AGEs) formation and AGEs-mediated endothelial cell dysfunction. Life Sci. 2012 Jan 16;90(3–4):131–9. doi: 10.1016/j.lfs.2011.10.025.
  52. Iannuzzi C, Irace G, Sirangelo I. Differential effects of glycation on protein aggregation and amyloid formation. Front Mol Biosci. 2014 Sep 2;1:9. doi: 10.3389/fmolb.2014.00009.
  53. Banerjee S. Effect of glyoxal and 1-methylisatin on stress-induced fibrillation of Hen Egg White Lysozyme: Insight into the anti-amyloidogenic property of the compounds with possible therapeutic implications. Int J Biol Macromol. 2020 Dec 15;165(Pt A):1552–61. doi: 10.1016/j.ijbiomac.2020.10.017.
  54. Persichilli C, Hill SE, Mast J, Muschol M. Does Thioflavin-T Detect Oligomers Formed During Amyloid Fibril Assembly. Biophysical Journal. 2011;100(3). Suppl 1:538A. doi: 10.1016/j.bpj.2010.12.3140.
  55. Hanczyc P, Fita P. Laser Emission of Thioflavin T Uncovers Protein Aggregation in Amyloid Nucleation Phase. ACS Photonics. 2021. doi: 10.1021/acsphotonics.1c00082.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Figure 1 – Structures of various advanced glycation end products

Download (149KB)
Indexing metadata

Copyright (c) 2021 Litvinov R.A., Gontareva A.V., Usmiyanova L.E., Klimenko D.R.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 67428 от 13.10.2016. 

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies