Correction of the state of oxidative modification of proteins in patients with cancer undergoing surgery involving multiple organs

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Correction of the state of oxidative modification of proteins in patients with cancer undergoing surgery involving multiple organs

Shulga Yevheniia Viktorivna

Shulga Yevheniia Viktorivna assistant of the Department of General and Clinical Pathology of the School of Medicine, V.N. Karazin Kharkiv National University, Kharkiv

ABSTRACT

Introduction. Very important for us is the question of restoring indicators of oxidative modification of proteins in cancer patients with surgical interventions for vital requirements with surgery involving multiple organs.

Purpose. Correction of redox metabolism on the basis data of oxidative modification of proteins and the degree of catabolic reaction in cancer patients with surgery involving multiple organs in conditions of perioperative intensive therapy in different age groups.

Materials and Methods. 78 oncological patients with surgery involving multiple organs (at the age of 67.6 ± 3.7 g.) The oxidative modification of proteins was studied both in the degree of fragmentation of their products in spontaneous and iron-induced reactions and in the level of protein molecules of medium mass. Control groups were also used in conditions of intensive therapy by arginine glutamate and Corvitin. Groups of up to 65 years and 65 years and older were singled out separately.

Results and discussion. In the study of patients there were increase the indicators of oxidative modification of proteins both among middle-weight molecules and among protein degradation products in spontaneous and induced reactions. During our therapy, these indicators improved.

Conclusions. In the group of patients aged 65 years and older performing perioperative intensive therapy, it is possible to reliably restore the indicators of oxidative modification products of proteins in both spontaneous and iron-induced reactions and aldehyde and ketones metabolites of proteins (on day 4 and 2 week, p <0.05). This gives us a basis for recommending these groups of cancer patients determine these parameters and conduct metabolic intensive therapy.

Keywords: oxidative modification of proteins, redox metabolism, perioperative intensive therapy, antioxidant system, surgery involving multiple organs.

Шульга Євгенія Вікторівна, асистент кафедри загальної та клінічної патології медичного факультету, Харківський національний університет імені В.Н.Каразіна, м. Харків

КОРЕКЦІЯ СТАНУ ОКИСНОЇ МОДИФІКАЦІЇ БІЛКІВ У ОНКОХВОРИХ З МУЛЬТИОРГАННИМИ ОПЕРАТИВНИМИМ ВТРУЧАННЯМИ

Анотація

Вступ. Дуже важливим є для нас питання відновлення показників окисної модифікації білків у онкохворих з хірургічними втручаннями за життєвими вимогами з мультиорганними хірургічними втручаннями. Звичайно, цікавим є дослідження покращення цих показників за умов проведення описаної нами інтенсивної терапії як оцінки надалі зменшення частоти ускладнень і летальності.

Мета дослідження. Корекція окисно-відновного метаболізму на основі даних окисної модифікації білків та ступеня катаболічної реакції в онкохворих з мультиорганними оперативними втручаннями за умов проведення періопераційної інтенсивної терапії у різних вікових групах.

Матеріали та методи дослідження. 78 онкохворих з мультиорганними оперативними втручаннями (віком 67,6±3,7 р.) проведені дослідження окисної модифікації білків як за ступенем фрагментації їх продуктів в спонтанних та індукованих залізом реакціях, так і за рівнем білкових молекул середньої маси. Використовувалися групи контролю та заумов проведення інтенсивної терапії аргініном глутаматом та корвітином. Окремо виділяли групи до 65 років та 65 років і більше.

Результати досліджень та їх обговорення. При дослідженні хворих відмічається підвищення показників окисної модифікації білків як серед молекул середньої маси, так і серед продуктів деградації білків в спонтанних та індукованих реакціях. При проведенні нашої терапії ці показники покращувалися.

Висновки. В групі пацієнтів віком 65 років і більше проведення періопераційної інтенсивної терапії дає можливість достовірно відновити показники продуктів окисної модифікації білків як в спонтанних та індукованих залізом реакціях, так і альдегідних та кетонових метаболітів білків(на 4 день та 2 тиждень, р<0,05). Це дає нам підставу до рекомендації проведення у даної групи онкохворих визначень цих показників та проведення метаболічної інтенсивної терапії.

Ключові слова: окисна модифікація білків, окисно-відновний метаболізм, періопераційна інтенсивна терапія, антиоксидантна система, мультиорганні оперативні втручання.

Introduction

Oncological pathologies have one of the first places in the lethality in the whole world. Unfortunately, the incidence of cancer does not decrease, but only increases. The study of the oxidative modification of proteins in oncology has been carried out in many clinics around the world for several decades, which gives us an advantage in determining the correlation between disturbances of the redox balance and further promotion of its progression in cancer pathology.

The activity of the redox process can be a triggering mechanism for triggering the cascade process in other cells and lead to a sharp violation of the biochemical regulation of homeostasis by active oxygen ions and, subsequently, to the depletion of the antioxidant system and the reparative potential of the cell. This leads to complications after surgery or further special treatment and even to subsequent malignant transformations at the level of the whole organism.

The processes of peroxidation in the primary damage of protein molecules by active forms of oxygen lead to cell death and are important at the present time, since proteins in the human body have different functions. Their destruction during the oxidative modification of proteins in proteosomes leads to cell death, which initiates secondary damage (lipids, DNA, etc.), which also indicates the presence of a link between oncoprocess and oxidative modification of proteins (OMP) [1]. Therefore, there is the advisability of laboratory monitoring of oxidative modification of proteins in all conditions, accompanied by intoxication and development of stress in the body.

The most researched for the restoration of redox homeostasis are the use of exogenous glutathione [2] vitamins A, E, C and Q [3].

But the problem of studying the oxidative modification of proteins in the conditions with surgery involving multiple organs in oncological patients is still topical at present. Bowel obstruction occurs when a cancerous growth or adhesions block intestinal flow; the resulting pain, nausea, vomiting, bloating and not passing gas and dehydration usually require inpatient hospitalization. Untreated bowel obstruction can be fatal, most patients receive treatment because onset is typically progressive rather than acute, and symptoms are too severe to be ignored. It is very important to investigate the correction of disturbances of this link in the redox homeostasis in conditions of carrying out various variants of perioperative correction of these disorders [4]. In our study, the most interesting was the use of the arginine glutamate and corvitin.

A modern approach to solving this problem is the possibility of improving these protein disorders against the background of the correction of protein oxidation by a complex effect on all links of the repair process [5, 6, 7, 8]. Interesting enough for further study and restoration of disturbances of redox mechanisms is the study of changes in the early postoperative period. Of course, it is interesting to study the improvement in the indices of oxidative modification of proteins (namely, the study of the accumulation of aldehyde and carbonyl products in induced and spontaneous reactions [4, 9], under the condition of the intensive therapy described by us, as an assessment of the subsequent decrease in the incidence of complications and mortality (whichwe estimated on a scale SOFA), the biological meaning of which is to rupture the mechanism of harmful effects of protein metabolites, improve reparative processes and inhibit the triggering of apoptogenesis light [10, 11].

Purpose. Correction of redox metabolism on the basis data of oxidative modification of proteins and the degree of catabolic reaction in cancer patients with surgery involving multiple organs in conditions of perioperative intensive therapy in different age groups.

Materials and methods

oncoprocess redox metabolism biochemical

The study examined 78 patients with oncological diseases with surgery involving multiple organs (aged 67.6 ± 3.7). All patients were divided into four groups: I - control group under the age of 65 years (n1 = 27 people), in which antioxidant agents were not previously used; II - group aged up to 65 years (n2 = 29 people), who underwent antioxidant protection of arginine glutamate (40.0% 5 ml twice daily intravenously drip in 200 ml of saline) and corvitin (lyophilizate solution for 0.5 g twice daily, intravenously drip in 100 ml of physiological solution); III - control group at the age of 65 years and older (n3 = 28 people), in which antioxidant agents were not previously used; IV - group at the age of 65 years and over (n4 = 33 people), who underwent antioxidant protection of arginine glutamate (40.0% 5 ml twice daily intravenously drip in 200 ml of physiological solution) and corvitin (lyophilizate solution 0.5 g twice daily intravenously drip in 100 ml of physiological solution). Intensive therapy was performed in the form of antioxidant therapy for two days before surgery, intraoperatively and three days postoperatively.

Studies were conducted before surgery, on the 4th day after surgery and at the 2nd week after surgery. All patients were clinically comparable, all standards in the study were met in accordance with the standards of biomedical research and according to international ethical standards in science.

Biochemical measurements were performed with blood serum. To evaluate the oxidative modification of proteins was used. A.Z. Reznick and L. Parker method in the modification of E.E. Dubinina, based on the interaction of the derivatives of amino-acid residues with 2, 4-dinitrophenylhydrazine and the formation of dinitrophenylhydrazones [6].

The method for determining oxidative modification of proteins products is based on the fact that the final products of free radical oxidation of proteins can be quantitatively reacted with 2,4-dinitrophenylhydrazine to form 2,4-dinitrophenylhydrazones. The products also determined the products of spontaneous and metal- catalyzed (iron-induced) oxidative degradation of proteins.

To assess the degree of fragmentation of plasma proteins, a supernatant was used, which was obtained after protein precipitation. To 0.05 ml of plasma diluted with physiological saline in the ratio 1:10, 0.1 M phosphate buffer was added to conduct spontaneous oxidative modification of proteins reactions. Due to the use of the Fenton medium (0.1 molar phosphate buffer pH = 7.4, containing mmol of FeSO4 and 40.3 mmol of H2O2),induced OMP was performed. After a 15-minute incubation at 25 ° C, the oxidized proteins were precipitated and centrifuged. The acid-soluble peptides in the ultraviolet region were determined to evaluate fragmentation spectrophotometrically in the ultraviolet region at wavelengths of 254 nm (small), 270 nm (average) and 280 nm (large) in spontaneous (respectively, S254, S270, S280) and induced (respectively, I254, I270, I280) reactions. The degree of OMP was expressed in units of optical density per mg (OD / mg) of protein.

The method of estimating oxidative modification of proteins in combination with the level of mediummass molecules can be realized, respectively, through a reaction with 2,4-dinitrophenylhydrazine to form aldehyde and carbonyl derivatives of proteins (2,4- dinitrophenylhydrazones). The registration of oxidative modification of proteins levels was carried out on a SF- 46 spectrophotometer at four wavelengths, which made it possible to reveal the level of 2,4 dinitrophenylhydrazones of various nature: at 356 nm - neutral aliphatic aldehyde-dinitrophenylhydrazones, at 370 nm - neutral aliphatic ketone dinitrophenylhydrazones, at 430 and 530 - aliphatic aldehyddinitrophenylhydrazones and ketone dinitrophenylhydrazones of basic character [5,6,12].

Research was also conducted with an assessment of early and distant (3 years) SOFA scores as an assessment of organ failure and mortality.

A preliminary evaluation of the distribution of the indicators was carried out by a visual method and using the Shapiro-Wilkie criterion. The statistical processing of the results was carried out using the Statistika 10 software package, using the Wilcoxon-Mann-Whitney test. For each sample, the median (Me), the upper and lower quartiles [Q1; Q3]. The statistical significance of differences in the indices of the experimental group from the comparison group was estimated by the Mann- Whitney U test. The results obtained are given in the form of an arithmetic mean-standard deviation. Differences were considered statistically significant at p <0.05 or tended to be reliable at 0.1> p> 0.05.

Results and discussion

According to the researchers, in the conditions of oxidative stress, the active forms of oxygen of all human cells are damaged. This leads to denaturation and defragmentation of proteins in the case of excessive oxidative modification of proteins. The formed ionized amino acid fragments react with a number of amino acids present. This leads to violations of protein metabolism, as well as reparative processes [13]. According to the literature, oxidative modification of proteins is an early indicator of damage to tissues and organs, gives us all grounds to talk about the need for continuous laboratory monitoring of its processes in routine practice [14, 15]. The study of oxidative modification of proteins at the stages of perioperative intensive therapy in patients under 65 years of age with surgery involving multiple organs showed that the parameters in the control group significantly decreased in the preoperative period, compared with the values on day 4, and further decrease for the 2nd week (Table 1).

In the pool for neutral aldehyde products (absorption maximum at 356 nm), respectively, from 0.119 ± 0.004 to 0.037 ± 0.001 and 0.032 ± 0.001, p <0.05, for neutral ketone products (absorption maximum at 370 nm) from 0.044 ± 0.003 to 0.036 ± 0.002 and 0.030 ± 0.003, p <0.05, for the main aldehyde products (absorbance maximum at 430 nm), respectively, from 0.025 ± 0.003 to 0.019 ± 0.003 and 0.017 ± 0.003, p <0.05, for the basic ketone products absorption at 530 nm) from 0.011 ± 0.001 to 0.009 ± 0.003 and 0.006 ± 0.002, p <0.05.

In the pool for neutral aldehyde products (absorbance maximum at 356 nm), respectively, from 0.119 ± 0.004 to 0.037 ± 0.001 and 0.032 ± 0.001, p <0.05, for neutral ketone products (absorption maximum at 370 nm) from 0.044 ± 0.003 to 0.036 ± 0.002 and 0.030 ± 0.003, p <0.05, for the main aldehyde products (absorbance maximum at 430 nm), respectively, from 0.025 ± 0.003 to 0.019 ± 0.003 and 0.017 ± 0.003, p <0.05, for the basic ketone products (maximum absorption at 530 nm) from 0.011 ± 0.001 to 0.009 ± 0.003 and 0.006 ± 0.002, p <0.05.

Table 1. Level of products of oxidative modification of proteins in the intensive care stages of patients at the age of up to 65 with surgery involving multiple organs

Notes: OMP - oxidative modification of plasma proteins; AD - aldehyde derivatives; CD - carbonyl derivatives; І - in induced reactions; S - in spontaneous reactions; Ta - before surgery; Tb - on the 4th day after surgery; Tc - at the 2nd week after surgery; n - control group under the age of 65 years (n1 = 27 people), in which antioxidant agents were not previously used; m - group aged up to 65 years (n2 = 29 people), who underwent antioxidant protection of arginine glutamate (40.0% 5 ml twice daily intravenously drip in 200 ml of saline) and corvitin (lyophilizate solution for 0.5 g twice daily, intravenously drip in 100 ml of physiological solution); * - compared with n group at the same time point, p <0.05; + - compared Ta in the same group, p <0.05.

For oxidative modification of proteins products in spontaneous reactions for S254 (at a wavelength of 254 nm), respectively, from 1.834 ± 0.021 to 1.755 ± 0.017 and 1.711 ± 0.031, p <0.05, for S270 (at a wavelength of 270 nm), respectively, from 0.225 ± 0.014 to 0.232 ± 0.005 and 0.243 ± 0.004, p <0.05, for S280 (at a wavelength of 280 nm), respectively, from 0.119 ± 0.004 to 0.109 ± 0.001 and 0.098 ± 0.003, p <0.05. In the iron- induced reactions for I254 (at a wavelength of 254 nm), respectively, from 2.231 ± 0.016 to 2.112 ± 0.012 and 2.110 ± 0.011, p <0.05, for I270 (at a wavelength of 270 nm), respectively, from 0.409 ± 0.017 to 0.384 ± 0.012 and 0,357 ± 0,007, p <0.05, for I280 (at a wavelength of 280 nm), respectively, from 0,311 ± 0,012 to 0,297 ± 0,007 and 0,315 ± 0,004, p <0.05.

In the group undergoing antioxidant protection of arginine glutamate and corvitin, the indices decreased more confidently reliably on day 4, and further in 2 weeks.

Thus, for neutral aldehyde products (at a wavelength of 356 nm), respectively, from 0.046 ± 0.002 to 0.035 ± 0.002 and 0.030 ± 0.003, p <0.05, for neutral ketone products (absorption maximum at 370 nm) from 0.045 ± 0.003 to 0,0432 ± 0.003 and 0.021 ± 0.001, p <0.05, for the main aldehyde products (absorption maximum at 430 nm), respectively, from 0.027 ± 0.002 to 0.016 ± 0.003 and 0.013 ± 0.002, p <0.05, for the basic ketone products (at a wavelength of 530 nm) from 0.009 ± 0.003 to 0.006 ± 0.003 and 0.005 ± 0.003, p <0.05.

For oxidative modification of proteins products in spontaneous reactions for S254 (at a wavelength of 254 nm), respectively, from 1.854 ± 0.022 to 1.729 ± 0.020 and 1.682 ± 0.022, p <0.05, for S270 (at a wavelength of 270 nm), respectively, from 0.230 ± 0.014 to 0.191 ± 0.009 and 0.195 ± 0.010, p <0.05, for S280 (at a wavelength of 280 nm), respectively, with 0.111 ± 0.003 to 0.094 ± 0.002 and 0.092 ± 0.001, p <0.05.

Table 2. Level of products of oxidative modification of proteins in the intensive care stages of patients at the age of 65 years and older with surgery involving multiple organs

Notes: OMP - oxidative modification of plasma proteins; AD - aldehyde derivatives; CD - carbonyl derivatives; І - in induced reactions; S - in spontaneous reactions; Ta - before surgery; Tb - on the 4th day after surgery; Tc - at the 2nd week after surgery; пз - control group at the age of 65 years and older (n3 = 28 people), in which antioxidant agents were not previously used; ид - group at the age of 65 years and over (n4 = 33 people), who underwent antioxidant protection of arginine glutamate (40.0% 5 ml twice daily intravenously drip in 200 ml of physiological solution) and corvitin (lyophilizate solution 0.5 g twice daily intravenously drip in 100 ml of physiological solution); * - compared with пз group at the same time point, p <0.05; + - compared Ta in the same group, p <0.05.

In the iron-induced reactions for I254 (at a wavelength of 254 nm), respectively, from 2.211 ± 0.032 to 1.988 ± 0.018 and 1.876 ± 0.022, p <0.05, for the U270 (at a wavelength of 270 nm), respectively, from 0.389 ± 0.013 to 0.298 ± 0.017 and 0.278 ± 0.009, p <0.05, for I280 (at a wavelength of 280 nm), respectively, from 0.319 ± 0.003 to 0.257 ± 0.004 and 0.248 ± 0.011, p <0.05.

In the study of patients aged 65 years and over, the same changes in the OMP indices was observed among both middle-weight molecules and products of oxidative modification of proteins in spontaneous and induced reactions, but with more pronounced differences (Table 2).

We also see that under the influence of our intensive therapy, there was a more significant decrease in the number of modified proteins. Especially significant decrease in comparison with the control we see in patients aged 65 years and older. At the same time, the changes in the control groups had a reliably insignificant decrease with the temporal nature of the changes.

Conclusions

In patients with surgery involving multiple organs, significant disturbances in protein metabolism were revealed with an increase in prooxidant processes, manifested by an increase in the products of oxidative modification of proteins in the preoperative period, followed by a decrease on day 4 and at the 2 weeks in the postoperative period, both in spontaneous and induced reactions (for example, for patients up to 65 years for S254, respectively, these indicators decrease from 1,834 ± 0,021 to 1,755 ± 0,017 and 1,711 ± 0,031, p <0,05, for I254 from 2,231 ± 0,016 to 2,122 ± 0,012 and 2,110 ± 0,011, р<0,05 and for the patient 65 years and older for S254 from 1.885 ± 0.019 to 1.881 ± 0.013 and 1.711 ± 0.031, p <0.05, and for I254 from 2.224 ± 0.016 to 2.239 ± 0.012 and 2.216 ± 0.015, p <0.05) and aldehyde and ketone derivatives of the basic and neutral nature (for example, for patients under 65 years for AD430, respectively, these values decrease from 0.025 ± 0.003 to 0.019 ± 0.003 0.017 ± 0.003, p <0.05, for CD530 from 0.011 ± 0.001 to 0.009 ± 0.003 and 0.006 ± 0.002, p <0.05 and forpatients 65 years and older for AD430 with 0.032 ± 0.002 to 0.027 ± 0.003 and 0.021 ± 0.003, p <0.05, and for CD530 with 0.032 ± 0.001 to 0.017 ± 0.001 and 0.015 ± 0.002, p <0.05).

In the group of patients aged 6 5 years and older there is a greater weakening of antioxidant protection, which is confirmed by the presence in this group compared with patients under 65 years (for example, compared with preoperative, on day 4 and at the 2 weeks in the postoperative period in 62 group to 65 years for S254, these values are less (1,834 ± 0,021 to 1,755 ± 0,017 and 1,711 ± 0,031, р<0,05) than in the group of 65 years and older for S254 (1,885 ± 0,019 to 1,881 ± 0,013 and 1,711 ± 0,031, р <0, 05)) significantly higher amounts of products of oxidative modification of proteins. Therefore, for this group of patients, there is a need for routine measurement of oxidative modification of proteins.

In the presence of perioperative intensive care, we had a significant decrease in the postoperative period of all oxidative modification of proteins units, which indicates an increase in antioxidant protection against the background of using these agents (for example, on day 4 and at the weeks (in the rank sequence), for patients under

65 years for S254 decrease to 1,729 ± 0,020 and further to 1,682 ± 0,022, р<0,05, for I254 to 1,988 ± 0,018 and further 1,876 ± 0,022, р <0,05 and for patients 65 years and older for S254 to 1,765 ± 0,020 and further up to 1, 727 ± 0.030, p <0.05, and for I254 to 1.123 ± 0.015 and further 1.103 ± 0.021, р <0.05, and for aldehyde x and ketone derivatives of the basic and neutral character for patients under 65 years for AD430, respectively, these indicators are reduced to 0.016 ± 0.003 and further to 0.013 ± 0.002, p <0.05, for CD530 to 0.006 ± 0.003 and further to 0.005 ± 0.003, p <0.05 and for patients 65 years and older for AD430 to 0.021 ± 0.003 and further to 0.017 ± 0.003, p <0.05, and for CD530 to 0.014 ± 0.003 and further to 0.012 ± 0.003, p <0.05).

We see that in the group of patients aged 65 years and over, the intensive therapy makes it possible to reliably restore the indices of oxidative modification products of proteins both in spontaneous and induced reactions (as compared to values on day 4 and at the 2 weeks for patients 65 years and older for S254 to 1.765 ± 0.020 andfurther 1.727 ± 0.030, p <0.05, and for I254 to 1.123 ± 0.015 and further to 1.103 ± 0.021, p <0.05) and aldehyde and ketone metabolites of proteins on day 4 and at the 2 weeks for patients 65 years and older for AD430 to 0.021 ± 0.003 and further up to 0.017 ± 0.003, p <0.05, and for CD530 to 0.014 ± 0.003 and further to 0.012 ± 0.003, p <0.05), which gives us grounds for conducting this therapy in all patients with surgery involving multiple organs.

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16. Information about the conflict of interests. The research is a fragment of the research work "Development of an algorithm for individualizing the tactics of intensive care in cancer patients after multiple organ procedures" (№ of state registration 0117U001049) SI «Grigoriev Institute for Medical Radiology of National Academy of Medical Sciences of Ukraine» (director - prof. M. V. Krasnoselskiy). Clinical and laboratory studies were conducted on the basis of this institution.

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