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DOI 10.11603/ijmmr.2413-6077.2021.1.12100

INFLUENCE OF THICK EXTRACT FROM MAITAKE MUSHROOMS  
ON SIGNS OF INFLAMMATORY PROCESS IN EXPERIMENTAL TOXIC 
HEPATITIS

*I.I. Herasymets, L.S. Fira, I.I. Medvid 
I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE

Background. The priority of the contemporary pharmaceutical industry is to create effective, safe and 
inexpensive drugs to ensure the highest quality of care and optimal use of available raw materials.

Objective. The aim of our study was to investigate anti-inflammatory properties of the Maitake mushrooms 
thick extract in the experiment on rats with paracetamol(acetaminophen)-induced hepatitis.

Methods. 60 white male rats, weighing 180-210 g, randomized into 10 groups of 6 animals in each, were 
used for the experiment. Paracetamol hepatitis was simulated by acetaminophen intragastric administering in 
a dose of 1250 mg/kg 1 time per day (for 2 days) as a suspension in 2% starch gel solution. Maitake mushrooms 
thick extract, which was administered intragastrically 2 hours before the administration of acetaminophen and 
daily after the lesion in a dose of 150 mg/kg of the animal’s body weight, was used for the toxic lesion correction. 
“Silibor” was selected as the comparison drug, which was administered according to the same scheme as the 
investigated extract in a dose of 20 mg/kg of the animal’s body weight. Euthanasia was conducted on the 3rd, 7th 
and 10th day of the experiment with sodium barbamyl. Liver homogenate and animal serum were used for the 
studies. The development of inflammatory processes was studied by the content of pro-inflammatory and anti-
inflammatory cytokines, as well as C-reactive protein in the serum of rats with toxic hepatitis and after the 
application of Maitake mushroom extract and the comparison drug.

Results. It was found that the introduction of acetaminophen to animals for the acute hepatitis simulation 
is accompanied by changes in the cytokine profile, i.e. an increase in the level of IL-6 and a decrease in the level 
of IL-4 in the serum of rats. Inflammatory development is evidenced by the content of C-reactive protein increase 
in the blood of the affected animals. The application of Maitake mushroom extract facilitated bringing the studied 
indicators almost to the level of intact control.

Conclusions. Reduction of inflammation signs in rats with the simulated paracetamol hepatitis under the 
influence of Maitake mushrooms thick extract confirms its anti-inflammatory properties.

KEYWORDS: maitake mushrooms, paracetamol, acute hepatitis, inflammation.

*Corresponding author: Iryna Herasymets, Associate Professor, 
I. Horbachevsky Ternopil National Medical University, Ternopil, 
46002, Ukraine. E-mail: irunaherasymets@gmail.com

International Journal of Medicine and Medical Research 
2021, Volume 7, Issue 1, p. 81-86
copyright © 2021, TNMU, All Rights Reserved

Introduction
Due to the serious consequences of he-

patitis, there is a need for its earliest diagnosis 
and appropriate pharmacotherapy. The search 
for effective hepatoprotectors, which can 
influence the initial stages of initiation and 
development of inflammatory processes in the 
liver without side effects, is an important task 
of contemporary medicine [1, 2]

Maitake mushroom has properties for 
which the Japanese have valued it for centuries: 
the ability to lose weight, to reduce discomfort 
and problems associated with menopause in 
women, to gently eliminate the unpleasant 
sensations of premenstrual syndrome, to lower 
blood sugar level, to reduce the effects of 
inflammation, to increase immunity due to B 

polysaccharides, available in the composition 
of the fungus [3, 4, 5, 6, 7, 8, 9].

The aim of our study was to investigate the 
anti-inflammatory properties of the Maitake 
mushrooms thick extract in the experiment on 
rats with acute hepatitis induced by paracetamol 
(acetaminophen).

Methods
The material for the experimental work was 

a thick extract of Maitake mushrooms (TEOMM), 
obtained by scientists from the Department of 
Chemistry of Natural Compounds of the 
National University of Pharmacy.

The experiments were performed on white 
outbred male rats, weighing 180-210 g, kept on 
the standard diet of the vivarium of I. Hor-
bachevsky Ternopil National Medical University. 
All studies were conducted in compliance with 
the rules of bioethics in accordance with the 

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“European Convention for the protection of 
vertebrate animals, which are used for expe-
rimental and other scientific purposes” [10]. 

Intoxication with acetaminophen, which 
was administered intragastrically in a dose of 
1250 mg/kg 1 time per day for 2 days as a 
suspension in 2% starch gel solution, was a 
model of toxic lesions in rats [11, 12]. TEOMM 
was administered intragastrically 2 hours 
before administration of the toxic agent and 
daily after the lesion in a dose of 150 mg/kg of 
the animal’s body weight, which, in our previous 
studies, was found to be conditionally thera-
peutic for this extract [5]. “Silibor” (the active 
basis is silymarin) was chosen as the comparison 
drug. It was administered according to the 
same scheme as the investigated extract in a 
dose of 20 mg/kg (in terms of silymarin) of the 
animal’s body weight. The value of the dose of 
the comparison drug was chosen according to 
the instructions for its application and using 
the coefficients of species sensitivity by 
Rybolovlev Yu. R. and his method of converting 
the dose for humans to the dose for rats [12, 
13]. The animals were randomized into 10 
groups, 6 rats each: the 1st group – the animals 
of intact control; the 2nd, 3rd and 4th – the animals 
affected by acetaminophen on the 3rd, 7th and 
10th days of the study, respectively; the 5th, 6th 
and 7th groups – the rats, which were injected 
with an extract of Maitake mushrooms in a dose 
of 150 mg/kg of body weight on the 3rd, 7th and 
10th days of the experiment, respectively; the 
8th, 9th and 10th groups of animals that were 
intragastrally administered with the drug silibor 
on the 3rd, 7th and 10th days of the study, 
respectively. The rats were removed from the 
experiment by euthanasia under sodium bar-
bamyl anesthesia. Euthanasia was conducted 
on the 3rd, 7th and 10th days of the experiment. 
The study was subjected to liver homogenate 
and animal serum. Blood was taken from the 
heart of the animals. 

The concentration of pro-inflammatory and 
anti-inflammatory interleukins in the serum of 
rats was determined by enzyme-linked im-
muno sorbent assay using commercial kits 
(GEHealth care: Amersham, UK) [14]. The 
content of C-reactive protein (CRP) was 
determined by immunoturbidimetric method 
[15, 16].

The obtained data were statistically pro-
cessed by the program STATISTICA 12. The 
significance of intergroup differences was 
determined using the criterion of rank sums of 
the Wilcoxon and the Mann-Whitney tests. p 

values lower than 0.05 were considered to be 
statistically significant [17, 18].

Results
C-reactive protein is a non-glycosylated 

protein with a pentameric structure, which 
belongs to β-globulins. Due to its affinity to 
phosphorylcholine, which is a component of 
the cell walls of some bacteria and unicellular 
fungi, CRP is able to bind the relevant microbial 
cells and opsonize them for phagocytosis or 
lysis with complement [16, 19]. CRP acts as a 
pro-inflammatory “trigger” that stimulates mo-
nocytic synthesis of cytokines such as tumour 
necrosis factor-α, interleukin-1 and interleukin-6. 
Thus, CRP performs an immunoregulatory func-
tion: it stimulates protective reactions and 
activates immunity [14].

CRP is determined in almost all pathological 
processes and diseases regarding tissue da-
mage. The increased levels of C-reactive protein 
are one of the earliest laboratory signs of 
inflammation or tissue damage. Increased pro-
tein production by the liver begins 6 hours after 
the onset of inflammation [20].

We found out that in rats with acute hepa-
titis induced by acetaminophen, the serum CRP 
increased in 1.9, 2.4 and 2.7 times on the 3rd, 7th 
and 10th days of the study, respectively, accor-
ding to the group of intact control. After cor-
rection with TEOMM there was a probable 
decrease in the content of CRP in the serum of 
rats in 1.2, 1.5 and 2.1 times on the 3rd, 7th and 
10th days of the experiment, respectively, in the 
animals of control pathology. When using 
silibor, the studied indicator probably (p≤0.05) 
decreased in 1.4 and 1.9 times on the 7th and 
10th days of the experiment, respectively, for 
the animals with toxic hepatitis (Tab. 1).

The obtained results are a confirmation of 
the inflammatory processes development in 
the body of rats with acute hepatitis, which is 
caused by the action of acetaminophen.

Cytokines, a group of hormone-like proteins, 
peptides and mediators of inflammation, play 
a significant role in the pathogenesis of deve-
lopment and course of inflammatory processes. 
Imbalance in the cytokine system can have a 
significant effect on the course of inflammatory 
reaction [21].

Hepatocytes are very sensitive to the action 
of cytokines, as they contain a number of spe-
cific receptors on their surface, through which 
the regulation of protein synthesis, proliferation, 
differentiation, specialized functioning and 
apoptosis of liver cells is carried out. Pro-

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inflammatory cytokines: IL-1, IL-6, IL-8, IL-12, 
TNF-, IFN-γ are involved in the specific immune 
response triggering, while anti-inflammatory 
cytokines: IL-4, IL-10, IL-13, TGF are involved in 
the development of reactions of the anti-inflam-
matory process and inhibit the synthesis of 
pro-inflammatory interleukins [14, 15, 20, 21].

Our further research was to study the con-
tent of pro-inflammatory and anti-inflammatory 
cytokines, IL-4 and IL-6, in the blood serum of 
rats with simulated acetaminophen hepatitis, 
as well as to study the corrective effect of 
TEOMM and silibor on them.

Numerous studies confirm that violation of 
normal proportions of pro-inflammatory and 
anti-inflammatory cytokines synthesis can lead 
to disruption of regulation and development of 
vital immune reactions and, above all, inflam-
matory reactions. In the case of violations of 
lo cal protective reactions, inflammation spreads, 
cytokine synthesis increases, then they enter 
the bloodstream and have their effect on the 
systemic level, i.e. have their effect on almost 
all organs and systems of the body [19, 20, 22].

It was experimentally established that 
during the formation of acute hepatitis in rats 
on the 3rd day of the study, the content of IL-6 
increased by 82% compare to the intact animals. 
On the 7th and 10th days of the experiment, the 
content of the studied indicator increased by 
126% and 150%, respectively, compare to the 
intact control animals (Tab. 2).

TEOMM application for correction the de-
tected disorders in toxic hepatitis led to a 

probable decrease in the content of IL-6 on the 
7th day of the study compare to control. The 
comparison drug Silibor had a positive effect 
on this indicator, although slightly inferior to 
our studied extract.

Local inflammatory process, after intro-
duction of a pro-inflammatory agent, is impor-
tant for healing and protection of the body from 
infection. However, excessive accumulation of 
pro-inflammatory cytokines in the blood leads 
to generalized sepsis and multiorgan failure. It 
is anti-inflammatory interleukins, which include 
IL-4 and IL-10, are able to reduce inflammation 
and cause a cessation of the inflammatory 
response [14, 15].

Hence, it was advisable to study the content 
of anti-inflammatory cytokines, in particular 
IL-4, in the serum of rats with toxic lesion.

After affection of animals with aceta mi-
nophen in the serum, the IL-4 content decrease 
in 1.4, 1.5 and 1.6 times was observed on the 
3rd, 7th and 10th days of the experiment, res-
pectively, compare to the group of intact control 
animals (Tab. 3).

TEOMM caused a probable increase in the 
IL-4 content by 30% and 46% on the 7th and 10th 
days of the study, respectively, in the animals 
with toxic hepatitis. When using the comparison 
drug, a probable (p≤0.05) increase in the 
cytokine content on the 7th day in 1.3 times and 
in 1.4 times on the 10th day of the study compare 
to the control pathology group was noted.

The obtained results suggest that the use 
of TEOMM in rats at a dose of 150 mg/kg for 10 

Table 1. The content of C-reactive protein in the serum (mg/l) of the rats affected  
by acetaminophen, and after application of the Maitake mushrooms extract (M±m; n=60)

Groups of animals
Indicators

3rd day 7th day 10th day
ІC 3.51±0.28 3.51±0.28 3.51±0.28
CP 6.83±0.23* 8.47±0.24* 9.54±0.32*
CP+silibor 6.10±0.20 5.93±0.29** 5.08±0.23**
CP+TEOMM 5.71±0.18** 5.63±0.28** 4.49±0.3**

Notes. Here and in the following tables * – probable changes between the rate of the control and paracetamol-affected animals, 
** – probable changes between the rates of the paracetamol-affected and treated animals.

Table 2. The content of IL-6 in the serum (pg/l) of the rats affected by paracetamol,  
and after application of the Maitake mushrooms extract (M±m; n=60)

Groups of animals
Indicators

3rd day 7th day 10th day
ІC 2.96±0.22 2.96±0.22 2.96±0.22
CP 5.38±0.30* 6.69±0.34* 7.39±0.27*
CP+silibor 4.93±0.21 4.51±0.26** 4.35±0.29**
CP+TEOMM 4.85±0.16 4.22±0.22** 3.98±0.26**

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days has a positive effect on the initial stages 
of the inflammatory reaction.

Discussion
The inflammatory process caused by im-

mune mechanisms is significant in the patho-
genesis of diseases. CRP is a marker of systemic 
inflammation. Therefore, the experimentally 
revealed increase in its level in the serum of 
animals with toxic lesion indicates an inflam-
matory process in the body. CRP is one of the 
activators of the complement system – a 
compound of complex proteins involved in the 
formation of the body’s immune response [16].

Cytokines are a major factor in the interac-
tion between immune cells and somatic cells. 
Determination of their concentration in the 
blood provides information about the functional 
activity of different types of immunocompetent 
cells, severity of the inflammatory process, its 
transition to the systemic level, prognosis of 
the disease. Excessive production of cytokines 
and other mediators of inflammation disrupts 
regulatory function of the immune system, their 
uncontrolled release takes place, as well as the 
imbalance between pro-inflammatory and anti-
inflammatory cytokines with a predominance 
of pro-inflammatory. As a result, the mediators 
of inflammation from the factors that protect 
the body become damaging for it [15].

The study of the content of the pro-inflam-
matory cytokine IL-6 showed a probable 
increase throughout the experiment. At the 
same time, the serum content of the anti-in-
flammatory cytokine IL-4 decreased. This indi-
cates an imbalance of pro-inflammatory and 
anti-inflammatory cytokines caused by toxic 
liver damage by acetaminophen.

We established an anti-inflammatory effect 
of the studied extract, which consists in 
changing the cytokine profile, in particular in 
reducing the dynamics of the pro-inflammatory 
IL-6 content and increase in the anti-inflam-
matory cytokine IL-4 content compare to the 
group of intact control rats.

Conclusions 
It was established that in cases of acute 

hepatitis in the rats induced by acetaminophen, 
the concentration of CRP increased in the blood 
serum, the content of pro-inflammatory IL-6 
probably increased and the content of anti-
inflammatory cytokine IL-4 decreased, which 
indicated the development of inflammatory 
processes in the affected animals.

The application of a Maitake mushrooms 
thick extract had a positive effect on the content 
of C-reactive protein and cytokines in the serum 
of the animals with acute hepatitis, which 
indicated its anti-inflammatory properties and 
the relevance of further study to creation of 
effective drugs.

Funding
This research received no external funding.
Conflict of interest
The authors declare no conflict of interests 

in this study.
Author Contributions
Herasymets I.I. – conceptualization, data 

curation, formal analysis, investigation, visua-
lization, article writing; Fira L.S. – con cep tua-
lization, supervision, validation, methodology; 
Medvid I.I. – formal analysis, investigation, 
software.

Table 3. The content of IL-4 in the serum (pg/l) of the rats affected by paracetamol,  
and after application of the Maitake mushrooms extract (M±m; n=60)

Groups of animals
Indicators

3rd day 7th day 10th day
ІC 1.57±0.08 1.57±0.08 1.57±0.08
CP 1.14±0.05* 1.03±0.07* 0.96±0.09*
CP+silibor 1.22±0.07 1.29±0.08** 1.34±0.06**
CP+TEOMM 1.29±0.05 1.34±0.06** 1.40±0.08**

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ВПЛИВ ГУСТОГО ЕКСТРАКТУ З ГРИБІВ МАйТАКЕ НА ОЗНАКИ ЗАПАЛЬНОГО 
ПРОЦЕСУ ЗА ЕКСПЕРИМЕНТАЛЬНОГО ТОКСИЧНОГО ГЕПАТИТУ

І.І. Герасимець, Л.С. Фіра, І.І. Медвідь
ТЕРНОПІЛЬСЬКИЙ НАЦІОНАЛЬНИЙ МЕДИЧНИЙ УНІВЕРСИТЕТ ІМЕНІ І.Я. ГОРБАЧЕВСЬКОГО,  

ТЕРНОПІЛЬ, УКРАЇНА

Вступ. Пріоритетним завданням сучасної фармацевтичної галузі є створення ефективних, 
безпечних та доступних лікарських засобів, щоб забезпечити максимально високу якість надання 
медичної допомоги та оптимального використання наявних сировинних ресурсів.

Мета роботи. Метою нашого дослідження було вивчити протизапальні властивості густого 
екстракту з грибів майтаке в експерименті на щурах із гепатитом, індукованим парацетамолом 
(ацетамінофеном).

Методи. Для проведення експерименту було використано 60 білих щурів-самців, масою 180-210 г, 
рандомізованих на 10 груп по 6 тварин у кожній. Парацетамоловий гепатит моделювали шляхом 
введення ацетамінофену інтрагастрально у дозі 1250 мг/кг 1 раз на добу у вигляді суспензії в 2 % розчині 
крохмального гелю протягом 2 діб. Для корекції токсичного ураження використовували густий екстракт 
грибів майтаке, який вводили інтрагастрально за 2 години до введення ацетамінофену та щоденно 
після ураження в дозі 150 мг/кг маси тіла тварини. Як препарат порівняння обрали “Силібор” (виробник 
– ТОВ «Фармацевтична компанія «Здоров’я»), який вводили за тією ж схемою, що і екстракт майтаке 
в дозі 20 мг/кг маси тіла тварини. На 3-тю, 7-му та 10-ту добу експерименту здійснювали евтаназію 
щурів із використанням барбамілу натрію. Для досліджень брали гомогенат печінки та сироватку 
крові. Розвиток запальних процесів вивчали за вмістом про- та протизапальних цитокінів, а також 
С-реактивного протеїну у сироватці крові щурів із токсичним гепатитом та після застосування 
екстракту грибів майтаке та препарату порівняння.

Результати. Встановлено, що введення тваринам ацетамінофену для моделювання гострого 
гепатиту супроводжується змінами цитокінового профілю, а саме, зростанням рівня IL-6 та 
зменшенням рівня IL-4 у сироватці крові щурів. Про розвиток запального процесу свідчить підвищення 
вмісту С-реактивного протеїну в крові уражених тварин.Застосування екстракту грибів майтаке 
сприяло наближенню досліджуваних показників до рівня інтактного контролю.

Висновки. Зменшення ознак запального процесу у щурів при модельованому парацетамоловому 
гепатиті під впливом густого екстракту грибів майтаке підтверджує його протизапальні властивості.

КЛЮЧОВІ СЛОВА: гриби майтаке, парацетамол, гострий гепатит, запалення.

Information about the authors
Herasymets I.I. – PhD in Pharmacy, Associate Professor, Department of Pharmacology and Clinical 

Pharmacology, I. Horbachevsky Ternopil National Medical University.
ORCID0000-0001-7108-3251, e-mail: irunaherasymets@gmail.com
Fira L.S. – Doctor of Biological Sciences, Professor, Head of the Department of Pharmacy of the Institute 

of Postgraduate Education, I. Horbachevsky Ternopil National Medical University.
ORCID 0000-0002-5325-0973, e-mail: ludafira@ukr.net
Medvid I.I. – PhD in Medicine, Assistant Professor, Department of Microbiology, Virology and 

Immunology, I. Horbachevsky Ternopil National Medical University.
ORCID 0000-0003-4703-4438, e-mail: medvid_ii@meta.ua

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Received 17 May 2021; revised 28 May 2021; 
accepted 3 Jun 2021.

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