USING OF INFORMATIONAL PARAMETERS AS A CRITERION FOR DETERMINING THE EFFECTIVENESS OF BIOSTIMULATION WITH USE OF TISSUE PREPARATIONSHTML Full Text
USING OF INFORMATIONAL PARAMETERS AS A CRITERION FOR DETERMINING THE EFFECTIVENESS OF BIOSTIMULATION WITH USE OF TISSUE PREPARATIONS
D. A. Areshidze *, M. A. Kozlova, L. A. Makartseva, A. A. Gritsyunayte, K. A. Sakhnova and E. A. Shmigelskiy
Researching Laboratory of Experimental Biology and Biotechnology, Moscow State Regional University, 10A Radio st., Moscow, Russian Federation.
ABSTRACT: Possibility of use of the informational parameters, which characterize adaptational and regenerative opportunities of organ, as potential criteria for the assessment of biological activity of tissue preparations, is investigated in this research. The influence of tissue preparation «STEMB» on the morphofunctional condition of a liver of rats at experimental toxic damage of organs was studied. The assessment of a morphofunctional condition of a liver under the influence of preparation was carried out as with use of traditional morphological, biochemical and histologic parameters, and also by means of informational parameters. A correlation analysis was conducted between the used biochemical, morphological and morphometric parameters and informational criteria. As a result of research it is established that hepatoprotective activity of preparation «STEMB» is confirmed both with results of traditional techniques of an assessment and with informational parameters, that allows drawing a conclusion on possibility of use of informational parameters as criterion of an estimation of biological activity of tissue preparations.
Liver, Tissue preparation, Biological activity, Entropy
INTRODUCTION: Now the increasing number of researches is devoted to the potential biological activity of preparations made of tissues of plants or animals. This fact is due to a very wide range of biological effects of substances contained in the preparations of tissue origin, which ensures their applicability in various fields of biology, medicine and veterinary 1-5. The high development of modern biotechnological and pharmaceutical technologies improves the process of extracting biologically active agents from natural raw materials, allow to specify the active components of preparations and to definite mechanisms and targets of their actions 6, 7.
Particularly, biologically active remedies are now produced from tissues of a wide range of species of eukaryotes. Extractions from different parts of the organism of invertebrates and vertebrates and vegetative and generative organs of plants possess significant biological activity 8-11. The entire organism, or separately taken organs, like skin, muscles, liver, immunocompetent organs, blood serum, and whole blood, antlers, placenta and chorion, fragments of tissue of an embryo of various species or whole embryo completely can be raw materials for producing of biologically active agents 12-14. In particular, an embryonic tissue should be highlighted as one of the most promising sources of bio stimulating preparations, and the most convenient for use for this purpose is the chicken embryo 15-18.
The effect of bioactive preparations of natural origin is caused by the contents of the natural composites similar to constructs of living cells or tissue in them. These composites carry out stimulation in process of functional inquiry of an organism. They may serve as an additional source of the major nutrients, bioactive peptides, growth factors, and the vitamins and mineral nutrition for an organism. Natural bioactive preparations contain so-called biogenous stimulators that have impact on the main parts of metabolism. This impact is expressed in changes of metabolic conversion and energy processes of an organism 19-21. Biogenous stimulators and adaptogens are one of bases of efficiency of preparations of natural origin 22-23.
Experiments show that remedies made of living tissues demonstrate considerable effectiveness at application at smoldering pathological processes like inflammation, degeneration, atrophy, tumorigenesis, etc., as they activate immune and regenerative functions of an organism at diseases and injuries of various genesis. Tissue preparations also show the properties making them applicable as adaptogens at high physical activities at sportsmen and manual workers and at persons having strong cognitive and emotional load 24-29.
Derivatives of living tissues are widely applied also in veterinary science where their application is expedient because of the necessity of large volumes and high efficiency of the using substances and also their potential safety for the end-user of food and other products of farm animal origin 30-33. In this regard, the matter of criteria of determination of efficiency of action of tissue biological preparations is important now.
For determination of efficiency of use of biologically active substances and biological products (which are in essence the highly active catalyst of biological processes, including their ability for essential change and violation in the existing tissue homeostasis through changing of both adaptive and regenerative specifics of tissue), the wide range of methods and techniques is now applied. Traditionally, tests of stimulators are carried out on laboratory animals 34. Speaking about the influence of one or another biostimulator on the studied organ or system, we estimate the level of adaptational and regenerative opportunities of this system, but the uniform integrative criteria of an assessment of these opportunities are not present.
At all wide range of approaches to a question of determination of level of adaptational and regenerative processes in norm, at pathologies and as a result of biostimulation 35-48, 50, it isn't possible to mark out an adequate criterion of an assessment of intensity of these processes which wouldn't demand confirmation by any other methods and reflect unity of a structure and functions of the studied systems.
One of the methods applied to an assessment of adaptational and regenerative processes is use of informational parameters. In particular, this method finds application in medicine. So, entropy was used for the definition of violations of cardiac activity at fetuses at the last stages of prenatal ontogenesis 51. Also, entropy was applied to the description of regularities of secretion of hormones 52. Very widely informational parameters are used at research of cardiovascular system 53, 54, in neurophysiology 55, 56, and also in various areas of science studying cellular, tissue, and organ structures 57-63.
Research of the possibility of an assessment of informational parameters as the criterion displaying an effect of application of a tissue biostimulator seemed to us actual. For this purpose, the assessment of influence of the tissue preparation «STEMB» on a morphofunctional condition of a liver of rats at experimental toxic hepatitis was carried out. Thus, the assessment was performed with use of traditional morphological, physiological, histochemical and histologic techniques, and also by an assessment of informational condition of organ. The choice of the preparation «STEMB» is caused by that its biostimulating influence on a liver, which is shown by earlier conducted researches. Besides, it is revealed that the informational parameters applied by us reflect the level of adaptational and regenerative resources of organ 64.
MATERIALS AND METHODS:
Animals: Male Wistar Albino rats of body weights ranging from 170 g to 200 g were used in the study. The animals were fed with standard pellet diet and water ad libitum. They were maintained in a controlled environment (12:12 h light/dark cycle) and temperature (30 ± 2 °C). All the animal experiments were performed according to the compliance with the EC Directive 86/609/EEC and with the Russian law regulating experiments on animals.
Each animal was assigned with an individual number, in accordance with which the animal was marked by coloring with stains according to the developed schemes. On the cage label of a certain color the group, animal number, type of mark and research code were indicated.
Treatment Design: 150 animals (Male Wistar Albino rats) were randomized and divided into three groups of fifty animals in each group. One of the groups served as intact control. Animals in Group I was inhaled with carbon tetrachloride for 2 min per day for 6 days (control group). Rats in Group II were inhaled with carbon tetrachloride for 2 min per day for 6 days, but at the same time received hypodermic injections of «STEMB» in a dosage of 3 mg/kg.bw at 1-5th days of research. The use of carbon tetrachloride (CCl4) as an agent acting on the liver is caused by the fact that this substance is a direct liver poison, widely used in experimental medicine and biology. Selecting the liver-toxic and exposure method is determined by the fact that the use of carbon tetrachloride under this scheme provides the appearance and development of reversible changes in liver at tissue and organ level.
On the 7th day of research, animals were sacrificed in carbon dioxide chamber.
Weight Measurements: All rats were weighed in grams. The weighing was made at the beginning and at the end of research in each group. At the end of experiment, it was measured absolute (in grams) and relative mass of a liver of rats.
Biochemical Analyses: Levels of uric acid, creatinine, total bilirubin, of an alanine amino-transferase (ALT) and aspartate aminotransferase (AST) in blood serum were investigated by means of the biochemical StatFax3300 analyzer (USA) by means of sets of Spinreact firm (Spain); then the De Ritis ratio was calculated.
Histochemical Analysis: Small fragments of liver were taken and fixed in 10% formaldehyde. After several treatments for dehydration in alcohol, sections of 5 mm thickness were cut. Sections were subjected to stain with hematoxylin and eosin, and then the histopathological analysis was carried, including determination of mitotic, apoptotic and necrotic indexes in the liver. A hematoxylin and eosin-stained sections we determined quantity of mitotic and necrotic cells. At sections stained by methylene blue-azure II with after staining by fuchsine we determined a quantity of apoptotic cells. Visualization was performed using a microscope Nikon Eclipse 80i at 900x magnification. All studies were made for 10 fields of view on each section.
Apoptotic index was calculated by the formula:
AI = Na/N×100%
Where Na - the number of apoptotic cells; N - total number of cells in the test population.
Mitotic index was calculated by the formula:
MI = Nm/N×100%
Where Nm - number of mitotic cells; N - total number of cells in the test population.
Necrotic index was calculated by the formula:
Where Nn- number of necrotic cells; N - total number of cells in the test population
Morphometric Studies: All measurements were taken with use of image analyzer "Video test" at hematoxylin and eosin-stained sections. The study was made for 10 fields of view on each section.
Studies of the Informational Condition of the System of the Organs: To determine the informational status at focal lesions of the liver, pieces of tissue were taken from the least altered areas on the border of macroscopically visible lesions. In case of visual homogeneity of the organ the material for research was taken from random part of it.
Based on the concept of information in a tissue system as the displaying of the diversity of morphology and function of the process for assessing the informational status of organs and tissues such parameters have been proposed and tested: informational morphological capacity (Hmax), informational morphological entropy (H), informational morphological organization (S), the relative morphological entropy (h) and redundancy (R) 65-68. The baseline characteristics, which are used to calculate these parameters, can vary widely (the linear dimensions of the structures, their quantity, etc). In our study we defined the volume of the nuclei of hepatocytes. Informational morphological capacity Hmax, which means the maximum structural diversity, was calculated by formula:
Hmax = log2n
Where n - number of classes.
Next, we made the calculation of the real structural diversity Н. Real structural diversity (informational morphological entropy) is the parameter that clearly illustrates the degree of the determinism of morphofunctional system in time and space 65-68. The calculation was made using the formula:
Where ΣPi is the sum of probabilities of staying of the measured parameter of cells in one of the existing classes; log2Pi - logarithm of the probability of staying in one of the possible classes. In this case, the value of Pi is defined as the classical probability.
Knowing the maximum and real structural diversity, we can calculate the organization of the system (S), the difference between the maximum possible and the real structural diversity (implemented structural diversity). This parameter, in our opinion, displays the state of the system adaptability to date. To determine the value of this parameter we used the formula:
S = Hmax-H
It is necessary to consider that when H = Hmax, the system is deterministic, but such relation to the vast majority of permissible is possible only in theory.
Then we determined the coefficient of relative entropy of the system (or the coefficient of compression of information) h by the formula:
h = H/Hmax
High levels of relative morphological entropy provide evidence of the disorder of the system and of significant reduction of its structural integrity.
The coefficient of the relative organization of the system (redundancy factor) R is given by formula:
R = (S/Hmax)×100%
With this data, the researcher has the opportunity to calculate the equivocation of the system(the value of reliability) e:
e = (Hp-Hn)
Where Hn - real structural diversity in the norm, Hp - real structural diversity in pathology.
Statistical Analysis: The obtained data, analyzed using Graph Pad Prism 6.0, were expressed as Mean ± SD. The difference between the control and experimental groups was analyzed using Mann-Whitney U test. P<0.05 was considered statistically significant. Using the same program, the correlation analysis was performed.
RESULTS AND DISCUSSION:
Effect on Body and Liver Mass: By results of research it is established that at experimental toxic hepatitis (I group) there is a decrease in body weight of animals and also in an absolute and relative mass of a liver. At the same time, similar parameters of animals of the second experimental group are reliably higher, than in the first, and don't differ significantly from control parameters Table 1.
Effect on Blood Serum Parameters: Results of biochemical researches testify that at experimental toxic hepatitis, there is an essential deviation of all studied parameters of blood serum, except for the total protein, in comparison with norm.
In the second group, there is insignificant change of the studied parameters in comparison with control, except for the level of AST, but also the level of a total protein is constant in Table 2.
TABLE 1: SOME MORPHOLOGICAL PARAMETERS OF A LIVER OF RATS AT AN ASSESSMENT OF BIOLOGICAL ACTIVITY OF THE TISSUE PREPARATION «STEMB»
|Group||Bodyweight, g||Absolute mass of liver, g||Relative mass of liver, %|
|Control group (n=50)||209.30±5.61||7.60±0.37||3.62±0.30|
|I group (n=50)||181.40±9.14*||9.10±0.44*||5.02±0.37*|
|II group (n=50)||201.80±12.51▲||7.69±0.91▲||3.81±0.31▲|
Hereinafter: control group – intact animals; I group – the animals inhaled by CCl4; II group – the animals inhaled by CCl4 and at the same time treated with tissue preparation «STEMB». *P≤0,0 5 - in comparison with control group, ▲P≤0,05- the II group in comparison with the I group
TABLE 2: SOME BIOCHEMICAL PARAMETERS OF BLOOD SERUM OFRATSAT AN ASSESSMENT OF BIOLOGICAL ACTIVITY OF THE TISSUE PREPARATION «STEMB»
|Group||AST, u/l||ALT, u/l||De Ritis ratio||Total bilirubin, g/l||Total protein, g/l||Glucose, µmol/l|
|Control group (n=50)||141.5±3.72||84.2±2.78||1.68||9.82±0.38||75.24±5.23||6.58±0.52|
|I group (n=50)||168.8±22.14*||303.1±33.74*||0.55||23.88±1.42*||76.52±4.48||11.84±1.1*|
|II group (n=50)||148.51±25.98*||190.11±37.18▲||0.78||10.74±1.40▲||74.59±4.16||7.61±1.14▲|
Effect on Mitotic, Apoptotic and Necrotic Activity: In a liver of animals of Group I there is an essential decrease in mitotic and apoptotic activity at simultaneous increase in number of necroses. Under the influence of «STEMB» the quantity of cells in a condition of mitosis and necrosis reaches control level, but thus the level of apoptotic activity is higher, than in a liver of intact rats and animals of the first group Table 3.
TABLE 3: MITOTIC, APOPTOTIC AND NECROTIC INDEXES OF RAT LIVER AT AN ASSESSMENT OF BIO-LOGICAL ACTIVITY OF THE TISSUE PREPARATION «STEMB»
|Group||Mitotic index, %||Apoptotic index, %||Necrotic index, %|
|Control group (n=50)||6.41±0.37||1.87±0.22||0.70±0.09|
|I group (n=50)||2.41±0.36*||0.71±0.20*||14.14±2.56*|
|II group (n=50)||6.91±0.48▲||3.12±0.30*▲||1.21±0.25▲|
Histopathologic Findings: The histopathologic feature of a liver of intact rats complied with norm Fig. 1, 2.
At the pathomorphological examination of the liver of rats exposed to carbon tetrachloride, it was found that the organs had a red color, sometimes with yellow or gray tint. About 20% of rat liver were spotty. The organs were loose and easily tearing, with blood oozing on the cut. The histological study revealed a pronounced attenuation of hepatic beams. Hepatocytes were swollen, with turbid cytoplasm; the edges of the cells were not clearly discernible; the nuclei were also swollen, bright, with blurred edges. In hepatocytes the clear vacuoles were distinctly observed. Detached hepatocytes were in state of granular dystrophy. The vessels of the liver in different parts of the cut were irregularly expanded and filled with blood, in the field of triads the signs of mild perivascular mesenchymal reaction were observed.
FIG. 1: LIVER OF INTACT RAT ×400, H & E
FIG. 2: LIVER OF INTACT RAT × 200, H & E
In a number of cases the layers of connective tissue, thickened and infiltrated by small cells, primarily in the fields of triads, are observed. Blood vessels (central vein capillaries) of the liver are dilated (hyperemia of blood vessels), the permeability of the walls of vessels for the blood cells is increased, the focal hemorrhages are observed. Among the cells, a large number of white blood cells, the macrophages, are observed. Some single cells are very large and are in fact a continuous vacuole.
In 80% of cases, the multiple foci of necrosis of different sizes are observed, in which the structural elements of the individual cells are not rendered, and the tissue of liver is a homogeneous structureless mass. In 47% of cases the extensive necroses are noted. The observed changes indicate the development of typical toxic damage of liver at animal groups. However, at some rats the characteristic signs of the micro-focal alterative inflammation were established. A significant part of animals had typical signs of acute toxic hepatitis with high intensity of tissue damage (alterative hepatitis). Some animals had severe hepatic steatosis with necrotic component Fig. 3, 4.
FIG. 3: LIVER OF RAT FROM GROUP I ×200, H & E
FIG. 4: LIVER OF RAT FROM GROUP I ×100, H & E
At inhalation by CCl4 with the simultaneous use of the «STEMB» the pathological changes in the liver are much less severe. In particular, hepatic beams and lobular structure in the liver of all animals stay intact. A few fields of malnutrition alternate with areas represented with binuclear and intact hepatocytes (signs of recovery) or hepato-cytes in a condition of the initial stage of granular dystrophy, fatty degeneration occurs in 21%.
Also, there are substantially less hepatocytes in a state of necrosis. It is noted the absence of focal hemorrhages, capillaries are moderately bloodshot, and there are no signs of swelling.
The permeability of vessels is also considerably less. Vessels in the triads are moderately dilated. Over 29% of hepatocytes have small vacuoles Fig. 5, 6.
FIG. 5: LIVER OF RAT FROM GROUP II. ×400, H&E
FIG. 6: LIVER OF RAT FROM GROUP II. ×400, H&E
TABLE 4: INFORMATIONAL PARAMETERS OF LIVER OF RATS AT AN ASSESSMENT OF BIOLOGICAL ACTIVITY OF THE TISSUE PREPARATION «STEMB»
|Group||Нмах(bit)||H (bit)||S (bit)|
|Control group (n=50)||3.32±0.002||2.518±0.023||0.8018±0.023|
|I group (n=50)||3.32±0.002||2.719±0.024*||0.6013±0.024*|
|II group (n=50)||3.32±0.002||2.569±0.029*▲||0.7508±0.029*▲|
|Group||h (bit)||R (%)||e (bit)|
|Control group (n=50)||0.7585±0.007||24.15±0.71||-|
|I group (n=50)||0.8189±0.007*||18.11±0.73*||0.201±0.010|
|II group (n=50)||0.7739±0.009*▲||22.61±0.89▲||0.051±0.006▲|
Effect on Informational Condition: At comparing with control in a liver of both studied groups it is observed an increase in level of parameters H and h, decrease of level of parameters S and R. At the same time, changes of the studied informational parameters in the group II are reliably differed than parameters of the first group I Table 4.
TABLE 5: CORRELATIONS BETWEEN VALUE OF PARAMETER Н AND VALUES OF OTHER STUDIED PARAMETERS
|Bodyweight, g||Absolute mass of liver, g||Relative mass of liver, %||AST,
|De Ritis ratio|
|H, Control group (n=50)||r=0,77*||r=0,77*||r=0,74*||r=0,81**||r=0,80*||r=-0,81**|
|Н, I group (n=50)||r=0,78**||r=0,84*||r=0,73*||r=0,84*||r=0,92*||r=-0,83**|
|Н, II group (n=50)||r=0,71*||r=0,88*||r=0,74*||r=0,77**||r=0,90*||r=-0,80**|
|Total bilirubin, g/l||Total protein, g/l||Glucose, µmol/l||Mitotic
|H, Control group (n=50)||r0=0,73*||r=0,69*||r=0,58*||r=-0,92**||r=-0,71*||r=0,80**|
|Н, I group (n=50)||r=0,74*||r=0,77*||r=0,64*||r=-0,94*||r=-0,80**||r=0,82 **|
|Н, II group (n=50)||r=0,70*||r=0,78**||r=0,66*||r=-0,84**||r=-0,84**||r=0,80**|
Results of Correlation Analysis: The conducted correlation analysis showed significant correlations between informational parameters and all other studied criteria. In particular, in all the studied groups, the negative correlations between the value of H and values of MI and AI were found, while at the same time there was a positive correlation between the values of this parameter and other studied parameters Table 5.
CONCLUSION: The conducted research shows that the tissue preparation «STEMB» has a hepatoprotective effect on experimental toxic hepatitis at rats. It is shown in the expressed normalization of most of studied biochemical parameters, preservation of morphological integrity of a liver, maintenance of tissue homeostasis of organ. It is remarkable that the leading mechanism of cellular death at toxic hepatitis and simultaneous application of the preparation «STEMB» is not the necrosis, but apoptosis, which intensity increases in a liver of animals of the second experimental group even in comparison with control.
By results of the analysis of informational condition, we noted an increase in parameter H in both groups, which testifies that there is an increase in degree of disorder of tissue system of organ. Also, in both groups the level of structural integrity of system decreases, which is confirmed by increase in value of parameter h. At the same time, the decrease in the values of parameters S and R testifies about decrease of adaptational opportunities of organs and about decrease in quantity of the structural elements capable to provide the necessary level of adaptation and the necessary level of structural and functional integrity of organ. At comparing of values of the studied parameters, the intergroup distinctions are clearly evident.
Values of parameters H and h are increased in the group treated with the preparation to 2.02% and 2.03% respectively (that is no more than for 5% of norm) in comparison with control, but in group without application of preparation these parameters increased for 7.98% and 7.96% respectively. These data testify to success of biostimulation at use the preparation «STEMB». Besides, values of parameters S and R decrease in the range up to 10% from norm, to 6.36% and 6.38% respectively, whereas in group without application of preparation these parameters decreased to 25.0% and 25.01%. The increase of parameter e to level of 0.051 bits (which isn't exceeding 0.1 bits), is also revealed in group treated with «STEMB», whereas in group without application of tissue preparation it made up more than 0.2 bits.
Correlation analysis testifies about a close interrelation of the dynamics of the values of informational parameters with the dynamics of other studied parameters. Thus, the decrease in morphological and functional integrity of a liver, as it is shown by results of the analysis of informational condition of organ, is more expressed at animals of the first group. At the same time, the studied informational parameters characterizing the liver of rats of the second experimental group, despite the identification of certain changes in structure and function of organ, confirm the hepatoprotective effect of preparation «STEMB» to the same extent as the earlier described results of biochemical, morphological and histologic researches. These facts allow claiming that the informational investigations used in research can be applied as the criteria characterizing biological activity of tissue preparations.
ACKNOWLEDGEMENT: Financial support of research was carried out by Moscow State Regional University.
CONFLICTS OF INTEREST: The authors declared that there is no conflict of interest.
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How to cite this article:
Areshidze DA, Kozlova MA, Makartseva LA, Gritsyunayte AA, Sakhnova KA and Shmigelskiy EA: Using of informational parameters as a criterion for determining the effectiveness of biostimulation with use of tissue preparations. Int J Pharm Sci & Res 2020; 11(4): 1592-01. doi: 10.13040/IJPSR.0975-8232.11(4).1592-01.
All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
D. A. Areshidze *, M. A. Kozlova, L. A. Makartseva, A. A. Gritsyunayte, K. A. Sakhnova and E. A. Shmigelskiy
Researching Laboratory of Experimental Biology and Biotechnology, Moscow State Regional University, Moscow, Russian Federation.
04 June 2019
18 October 2019
30 November 2019
01 April 2020