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The Effects of AHCC®, a Standardized Extract of Cultured Lentinura edodes Mycelia, on Natural Killer and T Cells in Health and Disease: Reviews on Human and Animal Studies

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Abstract

Mushrooms have been used for various health conditions for many years by traditional medicines practiced in different regions of the world although the exact effects of mushroom extracts on the immune system are not fully understood. AHCC® is a standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC® is reported to modulate the numbers and functions of immune cells including natural killer (NK) and T cells which play important roles in host defense, suggesting the possible implication of its supplementation in defending the host against infections and malignancies via modulating the immune system. Here, we review in vivo and in vitro effects of AHCC® on NK and T cells of humans and animals in health and disease, providing a platform for the better understanding of immune-mediated mechanisms and clinical implications of AHCC®.
Review Article
The Effects of AHCC®, a Standardized Extract of Cultured
Lentinura edodes Mycelia, on Natural Killer and T Cells in Health
and Disease: Reviews on Human and Animal Studies
Min Sun Shin,
1
Hong-Jai Park,
1
Takahiro Maeda,
2
Hiroshi Nishioka,
2
Hajime Fujii,
2
and Insoo Kang
1
1
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
2
Research and Development Division, Amino Up Co., Ltd., 004-0839 Sapporo, Japan
Correspondence should be addressed to Insoo Kang; insoo.kang@yale.edu
Received 7 October 2018; Accepted 20 November 2019; Published 20 December 2019
Academic Editor: Paola Nistico
Copyright © 2019 Min Sun Shin et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Mushrooms have been used for various health conditions for many years by traditional medicines practiced in dierent regions of
the world although the exact eects of mushroom extracts on the immune system are not fully understood. AHCC® is a
standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including
oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC® is reported to modulate the numbers and
functions of immune cells including natural killer (NK) and T cells which play important roles in host defense, suggesting the
possible implication of its supplementation in defending the host against infections and malignancies via modulating the
immune system. Here, we review in vivo and in vitro eects of AHCC® on NK and T cells of humans and animals in health and
disease, providing a platform for the better understanding of immune-mediated mechanisms and clinical implications of AHCC®.
1. Introduction
Mushrooms have been considered to have possible benecial
eects in health and disease for many years by traditional
medicines practiced in dierent regions of the world [1].
Although the exact biological mechanisms underlying such
eects are yet to be elucidated, extracts from a group of
mushrooms are now used as dietary supplements and func-
tional foods in health conditions possibly associated with
immune dysregulations that include infections, inamma-
tory diseases, and malignancies [1]. The eects of mush-
rooms on the immune system could stem from bioactive
polysaccharides such as beta- (β-) glucans or polysaccharide
complexes in mushrooms in that these molecules appear to
aect innate and adaptive immune responses [2, 3]. Also,
studies reported the activation of natural killer (NK) and T
cells by alpha- (α-) glucans extracted from edible mushrooms
like Tricholoma matsutake and maitake (Grifola frondosa)
[4, 5], supporting the implication of α-glucans in regulat-
ing the immune system.
AHCC® is a standardized extract of cultured shiitake or
Lentinula edodes mycelia (AHCC®) which contains a mix-
ture of nutrients including oligosaccharides, amino acids,
and minerals obtained through the liquid culture process of
shiitake mycelia [6, 7]. It is produced by Amino Up Co.,
Ltd. (Sapporo, Japan) under the trademark AHCC®.Here-
inafter, AHCC® and ECLM are used interchangeably in the
manuscript. The shiitake mycelia used for AHCC® are cul-
tured in a liquid medium where the mycelia proliferate and
form globular fungal bodies but not fruiting bodies [8].
AHCC® is produced through the unique manufacturing
process of culturing the mycelia followed by separation,
sterilization, and freeze-drying [8]. The most abundant
component of AHCC® is oligosaccharides which comprise
about 74% of the dry weight of AHCC® [6, 7]. Of the oli-
gosaccharides in AHCC®, about 20% are α-1,4-glucans, of
Hindawi
Journal of Immunology Research
Volume 2019, Article ID 3758576, 7 pages
https://doi.org/10.1155/2019/3758576
which a proportion is partially acylated, with a mean
molecular weight around 5000 Daltons [6, 7]. The eects of
AHCC® on immune cells of humans and animals were
reported in in vitro and in vivo studies, suggesting the possi-
ble help of its supplementation in defending the host against
infections and malignancies via modulating the immune sys-
tem [6, 928]. This review focuses on the reported eects of
AHCC® on natural killer (NK) and T cells given their roles
in host defense and inammation [2934], providing a plat-
form for the better understanding of immune-mediated
mechanisms and clinical implications of AHCC® and possi-
bly other medical mushrooms in health and disease.
2. Effects of AHCC® on Natural Killer (NK)
Cells in Infections and Malignancies
NK cells are large granular lymphocytes considered as the
rst line of defense against viral infections and possibly
malignancies via secreting cytokines and expressing cyto-
toxic molecules [30, 34, 35]. Indeed, NK cells are armed with
receptors that sense signals from target cells such as infected
or tumorous cells, leading to killing [31, 34]. Impaired func-
tion or deciency of NK cells has been associated with
increased risk of infections and malignancies in humans
and animals [34, 35]. Mushroom products have been sug-
gested to modulate NK cell activity against infected or tumor-
ous cells [36]. A recent study showed that water and ethanol
extracts of cultured mycelium from various species could
have distinct eects on NK cell-mediated cytotoxity against
tumor cells [37]. Water extracts of cultured mycelium from
medicinal mushrooms including Agaricus blazei and Gano-
derma lucidum enhanced cytotoxic activity in human NK cell
lines by upregulating the cytotoxic molecules perforin and
granulysin as well as the NK cell receptors natural killer
group 2D (NKG2D) and natural cytotoxicity receptors
(NCR) [37]. However, ethanol extracts of the mycelium from
the same mushrooms inhibited the expression of these mol-
ecules by the same NK cells [37]. These ndings support the
notion that the mode of extraction of medicinal mushrooms
may inuence the immunomodulatory eects of the mush-
rooms on NK cells [37]. The possible eects of AHCC® on
NK cells of humans and mice were reported in dierent
clinical settings including infections and malignancies. In
human studies, AHCC® was orally administered at 3 g a
day while most mouse studies used oral AHCC® in a range
of 0.1-0.48 g/kg/day, except two studies where the doses
were 1 and 3 g/kg/day, respectively. In the latter study,
AHCC® was evaluated for colitis in mice. It is noticeable
that 0.1-0.48 g/kg/day of AHCC® in mice is equivalent to
0.0081-0.039 g/kg/day of AHCC® in humans based on the
guidance of the US FDA [38, 39]. These doses are similar
to the recommended AHCC® doses of 1-3 g a day (0.017-
0.05 g/kg/day based on weight 60 kg) for humans. The nd-
ings from these studies are summarized in the following
sections (see also Table 1).
2.1. Infections. Inuenza virus is one of the most signicant
viral infections that causes substantial mortality and morbidity
Table 1: The eects of AHCC® on natural killer (NK) cells in health and disease.
Host Condition AHCC®
supplementation dose Eects Reference
Mice Inuenza viral
infection (H1N1)
Oral, 1 g/kg/day
∗∗(25 mg/day)
Increased NK cell percentage and activity
Improved survival, lung integrity, and viral titers [24]
Mice Inuenza viral
infection (H1N1)
Oral, 0.1 g/kg/day
∗∗(2.5 mg/day)
Increased NK cell lytic eciency
Improved survival with enhanced
viral clearance
[22]
Mice Melanoma
Oral, 12 mg/day
∗∗(0.48 g/kg/day)
Increased NK cell number
Increased γδT cell number
Increased tumor antigen-specic CD8
+
T cells producing IFN-γ
Delayed melanoma development
[16]
Mice Melanoma
Oral, 10 mg/day with or
without i.p. CpG ODN
∗∗(0.40 gm/kg/day)
Decreased melanoma development (size)
in mice treated with AHCC® alone or
AHCC® and CpG ODN
No immune cells analyzed
[18]
Mice Hepatoma
Oral, 0.36 g/kg/day
With 5-FU
∗∗(9 mg/day)
Increased NK cell percentage
Increased CD4
+
T cell percentage
Potentiate the eect of 5-FU on tumor
weight, size, and by AHCC®
[13]
Humans Cancers (open
label observational) Oral, 3 g/day Enhanced NK cell activity [17]
Humans
Healthy volunteers:
a double-blind,
placebo-controlled
Oral, 3 g/day or placebo No dierence in NK cell activity between
AHCC® and placebo groups [26]
Dose used in each study. ∗∗Dose in g/kg/day was converted to dose in mg/day or vice-versa based on mouse weight of 25 g.
2 Journal of Immunology Research
in older adults, children, and immune-compromised hosts
[40]. The eect of AHCC® on inuenza viral infection has
been studied, showing the possible benecial eect, especially
through aecting NK cells [24]. Supplementing mice orally
with AHCC® (1 g/kg/day) improved survival and lung integ-
rity upon intranasal challenge with inuenza virus (H1N1)
[24]. The mice that received AHCC® had increased NK cell
percentages and activity as measured against YAC-1 target
cells, along with decreased viral titers in the lungs [24]. The
former nding could be a potential mechanism responsible
for the benecial eect of AHCC® in this mouse model in that
NK cells were suggested to have a role in controlling inuenza
viral infection by secreting cytokines and expressing cytotoxic
molecules [30]. The improvement of survival with enhanced
viral clearance and NK cell lytic eciency was also found in
inuenza virus-infected mice which were supplemented with
a low-dose AHCC® (0.1g/kg/day) [22]. Of note, a transient
deciency of NK and T cells was found in patients with severe
H1N1 inuenza [41]. Given the increased NK cells in mice
treated with AHCC® [24], it would be intriguing to test
whether AHCC® could increase NK cells in patients with
H1N1 inuenza. The eect of AHCC® can be beyond H1NI
inuenza. The survival benet by AHCC® supplementation
was observed in mice infected with avian (bird) inuenza virus
H5N1 which could infect humans and poultry although its
mechanism is yet to be demonstrated [15]. In fact, the mortal-
ity rate of H5N1 avian inuenza is much higher than that of
past inuenza pandemics, reaching up to 60% [42]. The avail-
able data support the implication of NK cells in controlling
inuenza virus via promoting the number and function of
NK cells, raising the possible consideration of exploring the
clinical utility of AHCC® for inuenza viral infections, includ-
ing avian inuenza infection, in humans.
2.2. Malignancies. The immune system, which plays an
essential role in the development and control of malignan-
cies, can become tolerant to tumor cells by multiple mecha-
nisms [36]. Dierent modalities such as cytokines and food
supplements have been considered to boost NK cell immu-
nity in treating cancers [3, 36]. Indeed, studies reported the
possible benecial eects of AHCC® supplementation in
controlling cancers, especially in a combination with other
anticancer therapies like chemotherapy [23]. NK cells appear
to be involved in providing such eects. In an observational
study without a placebo control, AHCC® supplementation
(3 g/day) enhanced NK cell activity in a small number of
patients with various cancers including the prostate [17].
Also, the possible role of AHCC® in suppressing the develop-
ment of melanoma and immune mechanisms involved in
this process was studied. In fact, antitumor immunity is crit-
ical in controlling melanoma as evidenced by the recent
introduction of immunotherapies specically enhancing T
cell function through blocking inhibitory check point mol-
ecules expressed on T cells [43, 44]. In a mouse model of
melanoma, AHCC® signicantly delayed tumor develop-
ment after B16-F0 melanoma inoculation [16]. This phe-
nomenon was accompanied by an increase in the number
of NK cells, tumor antigen-specic CD8
+
T cells producing
IFN-γand gamma delta T cells [16]. The benecial eect of
AHCC® on murine B16 melanoma is further supported
by a recent study reporting decreased melanoma sizes in
mice supplemented with AHCC® with or without CpG-
oligodeoxynucleotide (ODN), which is known to activate
innate immunity and serve as an immunologic adjuvant
[18]. The antitumor eects of low-dose 5-uorouracil (5-FU)
were potentiated by AHCC® in hepatoma 22 tumor-bearing
mice through modulation of immune function, including
increased percentages of NK cells [13]. However, no signi-
cant dierence in NK cell activity was found between healthy
human volunteers who took AHCC® (3 g/day × 4 weeks)and
placebo, which could be related to small sample sizes
(n=10and 11 for AHCC® and placebo groups, respectively)
[26]. Given the potential eects of AHCC® on the number
and function of NK cells that play an essential role in
immune surveillance against malignancies, further human
and animal studies on NK cell-mediated anticancer eects
of AHCC® are warranted.
3. Effects of AHCC® on T Cell Immunity in
Infections, Inflammations, and Malignancies
3.1. T Cell Immune Responses. T cells, a component of the
adaptive immunity, play a critical role in defending hosts
against microorganisms and malignancy [29]. CD4
+
T cells
are T helper (Th) cells with the capacity to promote the func-
tion of other immune cells such as B cells and macrophages
by secreting cytokines and expressing costimulatory mole-
cules [45, 46]. CD8
+
T cells, which are cytotoxic T cells armed
with the cytotoxic molecules perforin and granzymes, can kill
infected or tumor cells [47]. Mushroom extracts, especially
polysaccharides, are reported to promote immune responses
to tumor by aecting the functions of T cells and other
immune cells [3]. Oligosaccharides are the most abundant
component of AHCC® accounting for about 74% of its dry
weight [6] [7]. Indeed, the eects of AHCC® on T cell immu-
nity are observed in humans and animals (see Table 2 for
summaries). In human studies, AHCC® was orally adminis-
tered at 3 g a day (0.05 g/kg/day based on 60 kg weight), while
most mouse studies used oral AHCC® in a range of 0.36-
1 g/kg/day, which is equivalent to 0.029-0.081 g/kg/day of
AHCC® for humans based on the guidance of the US FDA
[38, 39]. In an observational study of healthy adults aged 50
or older, AHCC® supplementation (3 g/day for 60 days)
increased the frequency of peripheral CD4
+
and CD8
+
T cells
producing IFN-γand/or TNF-αat 30 and 60 days of ELCM
supplementation compared to the baseline [28]. Such a nd-
ing was still noticed at 30 days after discontinuing AHCC®.
However, additional studies are necessary to determine the
eect of AHCC® on other T cell functions. The eects of
AHCC® on T cells could be mediated by aecting innate
immune cells since oligosaccharides including α-glucans
and β-glucans are known to stimulate innate immune cells
such as monocytes, macrophages, and dendritic cells that
can modulate the activation and dierentiation of T cells
[5, 4851]. We recently reported the promotion of Th 1
and 17 cells, which predominantly produced IFN-γand IL-
17, respectively, by AHCC® through inducing IL-1βproduc-
tion from monocytes in humans [20]. In accordance with this
3Journal of Immunology Research
nding, the culture supernatants of AHCC®-treated murine
monocytic J744.2 cells promoted the production of TNF-α
from splenic T cells of mice [12] while AHCC® induced
IL-8 production from human myelocytic THP-1 cells via
activating mitogen-activated protein kinases (MAPKs) and
NF-κB pathways [14]. In a mouse study, AHCC® administra-
tion increased cytokine production in the intestine uid
dependently of TLR2 and TLR4, suggesting the implication
of these molecules in AHCC®-mediated immune modulation
[52]. Also, an increase in the number of circulating dendritic
cells (DCs) was found in healthy adults after receiving
AHCC® (3 g/day × 4 weeks), suggesting the possible implica-
tion of AHCC® in promoting immune responses via modu-
lating DCs [26]. Overall, the data support that AHCC® can
modify T cell immunity in part by activating innate immune
cells with the capacity to promote T cell activation.
3.2. Infections, Inammations, and Malignancies. The possi-
ble eects of AHCC® on T cell immunity may have biological
signicance in developing immune responses to antigens.
This is evidenced by a study reporting increased NKT cells
and CD8
+
T cells along with increased protective antibody
titers to inuenza B in healthy people who received inuenza
vaccine and AHCC® supplementation (3 g/day × 3 weeks)
[25]. Also, in a mouse model of West Nile encephalitis, mice
supplemented with AHCC® (600 mg/kg every other day) had
the expansion of γδT cells, which had an important role in
controlling West Nile virus infection, along with decreased
viremia [27]. The potential benecial eects of AHCC® on
the immune system and bacterial infection were previously
reported in the hindlimb unloading mouse model of space
ight conditions which could adversely aect the immune
system [9, 10, 53]. Indeed, a recent study using the same
mouse model showed a trend towards increased T cell prolif-
eration in mice supplemented with AHCC® compared to
control mice [54].
The eect of AHCC® on CD4
+
T cells was found in hep-
atoma 22 tumor-bearing mice [13]. Compared to mice
treated with 5-FU, mice treated with 5-FU and AHCC® had
an increase in the percentage of CD4
+
T cells and levels of
Table 2: The eects of AHCC® on T cells in health and disease.
Host or origin
of cells Condition AHCC®
supplementation dose Eects Reference
Mice In vitro 100 μg/mL
Promoted the production of TNF-αby splenic
T cells by inducing IL-1 from murine monocytic
J744.2 cells
[12]
Mice
West Nile virus
infection in young
and old mice
Oral, 0.6 g/kg
every other day
∗∗(15 mg every
other day)
Increased γδT cells
Decreased viremia
Decreased mortality in young but not old mice
[27]
Mice Hepatoma
Oral, 0.36 g/kg/day
With 5-FU
∗∗(9 mg/day)
Increased CD4
+
T cell percentage and circulatory
IL-2 levels
Potentiate the eect of 5-FU on tumor weight,
size, and by AHCC®
[13]
Mice
A hindlimb unloading
mouse model of
space ight conditions
Oral, 1 g/kg/day
∗∗(25 mg/day)
Trend towards increased T cell
proliferation not reaching the level
of statistical signicance
[54]
Mice Lymphocyte-driven
colitis model
Oral, 75 mg/day
∗∗(3 g/kg/day)
Decreased STAT4 phosphorylation in splenic CD4
+
T cells
Decreased colitis
[21]
Humans Healthy volunteers
age 50 or older Oral, 3 g/day Increased frequency of CD4
+
and CD8
+
T cells
producing IFN-γand/or TNF-α[28]
Humans In vitro 500 μg/ml
Promoted the production of IFN-γand IL-17 by
CD4
+
T cells by inducing IL-1βproduction
from monocytes
[20]
Humans
Healthy adults
receiving inuenza
vaccination
Oral, 3 g/day
Increased CD8
+
T cells
Increased NKT cells
Increased protective antibody titers to inuenza
B strain after inuenza vaccination
[25]
Humans In vitro 250-500 μg/ml
Decreased IL-10, IL-17, and IFN-γproduction
from puried CD4
+
T cells stimulated with
anti-CD3 and CD28 antibodies
No eect on proliferation and survival
No change in FOXP3 expression
Kang et al.,
unpublished
observations
Dose used in each study. ∗∗Dose in g/kg/day was converted to dose in mg/day or vice-versa based on mouse weight of 25 g.
4 Journal of Immunology Research
IL-2, the T cell growth factor, in peripheral blood [13]. This
observation raises the possibility that the antitumor eect
of AHCC® can be mediated in part by modulating T cell
function. The immune system, including T cells, can
become tolerant to tumor cells by multiple mechanisms
[36]. Probably, the best-known mechanism is suppressing
T cell activation and eector function by triggering inhibi-
tory checkpoint molecules, including CTLA-4 (cytotoxic T
lymphocyte-associated antigen 4) and PD-1 (programmed
cell death protein 1), expressed on T cells [43, 44]. Immu-
notherapy targeting these molecules has made substantial
impacts in oncology by improving the survival of patients
with cancers such as non-small cell lung cancer, bladder
cancer, and melanoma [32, 44]. However, the eects of
mushroom extracts on inhibitory checkpoint molecules in
T cells are largely unknown.
Although the exact mechanism of how AHCC® aects T
cells is yet to be demonstrated, AHCC® can promote T cell
function through activating innate immune cells especially
with oligosaccharides like other mushroom extracts [3, 12,
14, 20, 26]. A recent study reported that AHCC® supplemen-
tation (75 mg/day) improved lymphocyte-driven colitis in
recombination activating gene 1- (RAG-1-) decient mice
transferred with CD4
+
CD62L
+
T cells [21]. In this study,
the production of IL-6, IL-17, and IL-10 by mesenteric lymph
node cells as well as STAT4 phosphorylation in splenic CD4
+
T cells were decreased in colitis mice supplemented with
AHCC®. Of note, we noticed the suppression of cytokine
production from human CD4
+
T cells activated with anti-
CD3 and CD28 antibodies in vitro in the presence of AHCC®
(Kang et al., unpublished data). This suppressive eect of
AHCC® appeared to be greater on IL-10, IL-17, and IFN-γ.
However, AHCC® did not aect the proliferation and sur-
vival of human CD4
+
T cells activated with anti-CD3 and
CD28 antibodies. We also determined the eect of AHCC®
on the transcription factor FOXP3 that is highly upregulated
in T cells with regulatory function [29]. No eect of AHCC®
on FOXP3 expression in human CD4
+
T cells was noticed
(Kang et al., unpublished data). As aforementioned, since
AHCC® can promote T cell function by activating innate
immune cells, it is possible that the eects of AHCC® on T
cells could depend on the context of immune activation.
For instance, AHCC® could directly suppress cytokine pro-
duction from activated T cells while the function of T cells
may be promoted by innate immune cells in the presence
of AHCC®.
4. Conclusions
AHCC®, which is an extract from the culture of shiitake
(Lentinula edodes) mycelia, has a broad range of eects on
the immune system including NK and T cells. Such eects
could be executed by directly modulating the numbers and
functions of these cells as well as by aecting the function
of monocytes, macrophages, and DCs with the capacity to
promote T cell function. Plus, the eects of AHCC® on NK
and T cells appear to have biological implications as sug-
gested by the results of clinical studies and in vivo animal
studies on infections, inammations, and tumors. Studies
exploring additional immunologic eects of AHCC® and
mechanisms underlying these eects in health and disease
are warranted. Of note, the intestinal microbiome has been
a subject of intensive investigations in the eld of food sup-
plements and medicinal foods including extracts of mush-
rooms. However, the eects of AHCC® on the intestinal
microbiome is unknown. The results of such studies explor-
ing the eects of AHCC® on the immune system and/or
microbiome would lead to advancing our understanding in
the utility of medical mushrooms including AHCC®, espe-
cially in the context of recently introduced immunotherapies
targeting inhibitory checkpoint molecules including CTLA-4
and PD-1.
Conflicts of Interest
Insoo Kang received unrestricted research funding from
Amino Up Co., Ltd., Sapporo, Japan, the manufacturer of
AHCC® that was discussed in this work, and is a consultant
of Amino Up Co., Ltd. Takahiro Maeda, Hiroshi Nishioka,
and Fujii Hajime are employees of Amino Up Co., Ltd.
Acknowledgments
This work was supported in part by an unrestricted research
fund from Amino Up Co., Ltd., Sapporo, Japan.
References
[1] S. P. Wasser, Medicinal mushroom science: current perspec-
tives, advances, evidences, and challenges,Biomedical Jour-
nal, vol. 37, no. 6, pp. 345356, 2014.
[2] Y. K. Mohanta, S. K. Singdevsachan, U. K. Parida, H. Bae, T. K.
Mohanta, and S. K. Panda, Green synthesis and antimicrobial
activity of silver nanoparticles using wild medicinal mush-
room Ganoderma applanatum (Pers.) pat. from Similipal bio-
sphere reserve, Odisha, India,IET Nanobiotechnology, vol. 10,
no. 4, pp. 184189, 2016.
[3] X. Meng, H. Liang, and L. Luo, Antitumor polysaccharides
from mushrooms: a review on the structural characteristics,
antitumor mechanisms and immunomodulating activities,
Carbohydrate Research, vol. 424, pp. 3041, 2016.
[4] Y. Masuda, Y. Nakayama, A. Tanaka, K. Naito, and
M. Konishi, Antitumor activity of orally administered mai-
take α-glucan by stimulating antitumor immune response in
murine tumor,PLoS One, vol. 12, no. 3, p. e0173621, 2017.
[5] H. Hoshi, Y. Yagi, H. Iijima, K. Matsunaga, Y. Ishihara, and
T. Yasuhara, Isolation and characterization of a novel immu-
nomodulatory alpha-glucan-protein complex from the myce-
lium of Tricholoma matsutake in basidiomycetes,Journal of
Agricultural and Food Chemistry, vol. 53, no. 23, pp. 8948
8956, 2005.
[6] B. W. Ritz, Supplementation with active hexose correlated
compound increases survival following infectious challenge
in mice,Nutrition Reviews, vol. 66, no. 9, pp. 526531, 2008.
[7] K. Sato and M. Kashimoto, Prole summary of AHCC: com-
position,in Clinician's Guide to AHCC, A. D. Kulkarni, P. C.
Calder, and T. Ito, Eds., pp. 2433, International Congress on
Nutrition and Integrative Medicine, 2017.
[8] N. Fujii and S. Kudo, Prole summary of AHCC:
manufacturing progress,in Clinician's Guide to AHCC:
5Journal of Immunology Research
Internationl Congress on Nutrition and Integrative Medicine,
A. D. Kulkarni, P. C. Calder, and T. Ito, Eds., pp. 2123, Inter-
national Congress on Nutrition and Integrative Medicine,
2017.
[9] H. Aviles, T. Belay, K. Fountain, M. Vance, B. Sun, and
G. Sonnenfeld, Active hexose correlated compound enhances
resistance toKlebsiella pneumoniaeinfection in mice in the
hindlimb-unloading model of spaceight conditions,Journal
of Applied Physiology, vol. 95, no. 2, pp. 491496, 2003.
[10] H. Aviles, T. Belay, M. Vance, B. Sun, and G. Sonnenfeld,
Active hexose correlated compound enhances the immune
function of mice in the hindlimb-unloading model of space-
ight conditions,Journal of Applied Physiology, vol. 97,
no. 4, pp. 14371444, 2004.
[11] H. Aviles, P. O'Donnell, J. Orshal, H. Fujii, B. Sun, and
G. Sonnenfeld, Active hexose correlated compound activates
immune function to decrease bacterial load in a murine model
of intramuscular infection,American Journal of Surgery,
vol. 195, no. 4, pp. 537545, 2008.
[12] T. Belay, C. L. Fu, and A. Woart, Active hexose correlated
compound activates immune function to decrease Chlamydia
trachomatis shedding in a murine stress model,Journal of
Nutritional Medicine and Diet Care, vol. 1, no. 1, 2015.
[13] Z. Cao, X. Chen, L. Lan, Z. Zhang, J. Du, and L. Liao, Active
hexose correlated compound potentiates the antitumor eects
of low-dose 5-uorouracil through modulation of immune
function in hepatoma 22 tumor-bearing mice,Nutrition
Research and Practice, vol. 9, no. 2, pp. 129136, 2015.
[14] A. Daddaoua, E. Martínez-Plata, M. Ortega-González et al.,
The nutritional supplement active hexose correlated com-
pound (AHCC) has direct immunomodulatory actions on
intestinal epithelial cells and macrophages involving
TLR/MyD88 and NF-κB/MAPK activation,Food Chemistry,
vol. 136, no. 3-4, pp. 12881295, 2013.
[15] H. Fujii, H. Nishioka, K. Wakame, and B. Sun, Nutritional
food active hexose correlated compound (AHCC) enhances
resistance against bird u,Japanese Journal of Complemen-
tary and Alternative Medicine, vol. 4, no. 1, pp. 3740,
2007.
[16] Y. Gao, D. Zhang, B. Sun, H. Fujii, K. Kosuna, and Z. Yin,
Active hexose correlated compound enhances tumor surveil-
lance through regulating both innate and adaptive immune
responses,Cancer Immunology, Immunotherapy, vol. 55,
no. 10, pp. 12581266, 2006.
[17] M. Ghoneum, M. Wimbley, F. Salem, A. McKlain, N. Attallah,
and G. Gill, Immunomodulatory and anticancer eects of
active hemicellulose compound (AHCC),International Jour-
nal of Immunotherapy, vol. 11, no. 1, pp. 2328, 1995.
[18] R. M. Ignacio, C. S. Kim, Y. D. Kim, H. M. Lee, X. F. Qi, and
S. K. Kim, Therapeutic eect of active hexose-correlated com-
pound (AHCC) combined with CpG-ODN (oligodeoxynu-
cleotide) in B16 melanoma murine model,Cytokine, vol. 76,
no. 2, pp. 131137, 2015.
[19] H. ISHIBASHI, T. IKEDA, S. TANSHO et al., Prophylactic
ecacy of a basidiomycetes preparation AHCC against lethal
opportunistic infections in mice,Yakugaku Zasshi, vol. 120,
no. 8, pp. 715719, 2000.
[20] W. W. Lee, N. Lee, H. Fujii, and I. Kang, Active Hexose
Correlated Compound promotes T helper (Th) 17 and 1
cell responses via inducing IL-1βproduction from mono-
cytes in humans,Cellular Immunology, vol. 275, no. 1-2,
pp. 1923, 2012.
[21] C. Mascaraque, M. D. Suárez, A. Zarzuelo, F. S. de Medina, and
O. Martínez-Augustin, Active hexose correlated compound
exerts therapeutic eects in lymphocyte driven colitis,Molec-
ular Nutrition & Food Research, vol. 58, no. 12, pp. 23792382,
2014.
[22] S. Nogusa, J. Gerbino, and B. W. Ritz, Low-dose supple-
mentation with active hexose correlated compound improves
the immune response to acute inuenza infection in C57BL/6
mice,Nutrition Research, vol. 29, no. 2, pp. 139143, 2009.
[23] B. Ritz, Active hexose correlated compound (AHCC) and
immune outcomes in humans: a review,Natural Medicine
Journal, vol. 3, no. 1, pp. 37, 2011.
[24] B. W. Ritz, S. Nogusa, E. A. Ackerman, and E. M. Gardner,
Supplementation with active hexose correlated compound
increases the innate immune response of young mice to pri-
mary inuenza infection,The Journal of Nutrition, vol. 136,
no. 11, pp. 28682873, 2006.
[25] B. E. Roman, E. Beli, D. M. Duriancik, and E. M. Gardner,
Short-term supplementation with active hexose correlated
compound improves the antibody response to inuenza B
vaccine,Nutrition Research, vol. 33, no. 1, pp. 1217,
2013.
[26] N. Terakawa, Y. Matsui, S. Satoi et al., Immunological eect
of active hexose correlated compound (AHCC) in healthy vol-
unteers: a double-blind, placebo-controlled trial,Nutrition
and Cancer, vol. 60, no. 5, pp. 643651, 2008.
[27] S. Wang, T. Welte, H. Fang et al., Oral administration of
active hexose correlated compound enhances host resistance
to West Nile encephalitis in mice,The Journal of Nutrition,
vol. 139, no. 3, pp. 598602, 2009.
[28] Z. Yin, H. Fujii, and T. Walshe, Eects of active hexose corre-
lated compound on frequency of CD4+ and CD8+ T cells pro-
ducing interferon-γand/or tumor necrosis factor-αin healthy
adults,Human Immunology, vol. 71, no. 12, pp. 11871190,
2010.
[29] N. Lee, M. S. Shin, and I. Kang, T-cell biology in aging, with a
focus on lung disease,The Journals of Gerontology. Series A,
Biological Sciences and Medical Sciences, vol. 67A, no. 3,
pp. 254263, 2012.
[30] S. Schultz-Cherry, Role of NK cells in inuenza infection,
Current Topics in Microbiology and Immunology, vol. 386,
pp. 109120, 2015.
[31] M. G. Morvan and L. L. Lanier, NK cells and cancer: you can
teach innate cells new tricks,Nature Reviews. Cancer, vol. 16,
no. 1, pp. 719, 2016.
[32] P. Sharma and J. P. Allison, Immune checkpoint targeting in
cancer therapy: toward combination strategies with curative
potential,Cell, vol. 161, no. 2, pp. 205214, 2015.
[33] J. E. Craft, Follicular helper T cells in immunity and systemic
autoimmunity,Nature Reviews Rheumatology, vol. 8, no. 6,
pp. 337347, 2012.
[34] A. Cerwenka and L. L. Lanier, Natural killer cell memory in
infection, inammation and cancer,Nature Reviews. Immu-
nology, vol. 16, no. 2, pp. 112123, 2016.
[35] J. S. Orange, Natural killer cell deciency,The Journal of
Allergy and Clinical Immunology, vol. 132, no. 3, pp. 515
525, 2013, quiz 526.
[36] D. S. Vinay, E. P. Ryan, G. Pawelec et al., Immune evasion
in cancer: mechanistic basis and therapeutic strategies,
Seminars in Cancer Biology, vol. 35, Suppl, pp. S185S198,
2015.
6 Journal of Immunology Research
[37] C. C. Lu, Y. J. Hsu, C. J. Chang et al., Immunomodulatory
properties of medicinal mushrooms: dierential eects of
water and ethanol extracts on NK cell-mediated cytotoxicity,
Innate Immunity, vol. 22, no. 7, pp. 522533, 2016.
[38] A. B. Nair and S. Jacob, A simple practice guide for dose con-
version between animals and human,Journal of Basic and
Clinical Pharmacy, vol. 7, no. 2, pp. 2731, 2016.
[39] Guidance for Industry, Estimating the maximum safe starting
dose in initial clinical trials for therapeutics in adult healthy
volunteers,in Administration USDoHaHSFaD, M. D. Rock-
ville, Ed., p. 7, U.S. Department of Health and Human Services
Food and Drug Administration, 2005.
[40] S. Ghebrehewet, P. Mac Pherson, and A. Ho, Inuenza,BMJ,
vol. 355, p. i6258, 2016.
[41] A. Fox, L. N. M. Hoa, P. Horby et al., Severe pandemic H1N1
2009 infection is associated with transient NK and T deciency
and aberrant CD8 responses,PLoS One, vol. 7, no. 2,
p. e31535, 2012.
[42] F. C. Li, B. C. Choi, T. Sly, and A. W. Pak, Finding the real
case-fatality rate of H5N1 avian inuenza,Journal of Epide-
miology and Community Health, vol. 62, no. 6, pp. 555559,
2008.
[43] D. M. Pardoll, The blockade of immune checkpoints in can-
cer immunotherapy,Nature Reviews Cancer, vol. 12, no. 4,
pp. 252264, 2012.
[44] S. Farkona, E. P. Diamandis, and I. M. Blasutig, Cancer
immunotherapy: the beginning of the end of cancer?,BMC
Medicine, vol. 14, no. 1, 2016.
[45] K. M. Murphy and B. Stockinger, Eector T cell plasticity:
exibility in the face of changing circumstances,Nature
Immunology, vol. 11, no. 8, pp. 674680, 2010.
[46] S. L. Reiner, Development in motion: helper T cells at work,
Cell,vol. 129, no. 1, pp. 3336, 2007.
[47] W. Cui and S. M. Kaech, Generation of eector CD8+ T cells
and their conversion to memory T cells,Immunological
Reviews, vol. 236, pp. 151166, 2010.
[48] F. Gerosa, B. Baldani-Guerra, L. A. Lyakh et al., Dierential
regulation of interleukin 12 and interleukin 23 production in
human dendritic cells,The Journal of Experimental Medicine,
vol. 205, no. 6, pp. 14471461, 2008.
[49] V. C. B. Bittencourt, R. T. Figueiredo, R. B. da Silva et al., An
alpha-glucan of Pseudallescheria boydii is involved in fungal
phagocytosis and toll-like receptor activation,The Journal of
Biological Chemistry, vol. 281, no. 32, pp. 2261422623, 2006.
[50] A. Estrada, C. H. Yun, A. Van Kessel, B. Li, S. Hauta, and
B. Laarveld, Immunomodulatory activities of oat beta-
glucan in vitro and in vivo,Microbiology and Immunology,
vol. 41, no. 12, pp. 991998, 1997.
[51] R. Nisini, A. Torosantucci, G. Romagnoli et al., Beta-glucan of
Candida albicans cell wall causes the subversion of human
monocyte dierentiation into dendritic cells,Journal of Leu-
kocyte Biology, vol. 82, no. 5, pp. 11361142, 2007.
[52] J. F. Mallet, E. Graham, B. W. Ritz, K. Homma, and C. Matar,
Active hexose correlated compound (AHCC) promotes an
intestinal immune response in BALB/c mice and in primary
intestinal epithelial cell culture involving toll-like receptors
TLR-2 and TLR-4,European Journal of Nutrition, vol. 55,
no. 1, pp. 139146, 2016.
[53] G. Sonnenfeld, The immune system in space, including earth-
based benets of space-based research,Current Pharmaceuti-
cal Biotechnology, vol. 6, no. 4, pp. 343349, 2005.
[54] M. Kogiso, K. Wakame, T. Sakai, S. Yamamoto,
A. Sundaresan, and A. D. Kulkarni, Active hexose correlated
compound and T cell response in hind-limb-unloaded BALB/c
mice,International Journal of Surgery and Research, vol. 2,
no. 5, pp. 3238, 2015.
7Journal of Immunology Research
... Medicinal plants traditionally are a source of active compounds that could be employed as supplements for conventional chemotherapies [6,7]. Among these compounds, AHCC ® , a standardized extract of cultured Lentinula edodes mycelia, is currently being assessed for its innate properties as a potential adjuvant to conventional therapies [8]. AHCC is composed of various small molecular weight oligosaccharides, polysaccharides, amino acids, lipids, and minerals [8][9][10]. ...
... Among these compounds, AHCC ® , a standardized extract of cultured Lentinula edodes mycelia, is currently being assessed for its innate properties as a potential adjuvant to conventional therapies [8]. AHCC is composed of various small molecular weight oligosaccharides, polysaccharides, amino acids, lipids, and minerals [8][9][10]. The principal component is α-glucan, well known for its immunomodulatory effects [8][9][10]. ...
... AHCC is composed of various small molecular weight oligosaccharides, polysaccharides, amino acids, lipids, and minerals [8][9][10]. The principal component is α-glucan, well known for its immunomodulatory effects [8][9][10]. For this reason, AHCC has been widely used as supplement in immunocompromised people, including cancer patients, and several studies reported the beneficial effects of AHCC in cancer treatment. ...
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The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with immunomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.
... 12 AHCC contains various nutrients including oligosaccharides, amino acids, and minerals. The effect of AHCC on the immune system for malignancy by natural killer (NK) and T cell, its usefulness in clinical cancer therapy [13][14][15] and its anti-inflammatory and anti-oxidant effects [16][17][18] have been reported. Only 1 study reported that the intake of AHCC improved the prognosis for patients with HCC who underwent curative hepatectomy. ...
... AHCC has been reported to exert immune-protective effects against many types of cancer and the effect of AHCC on the components of the immune system, such as NK cells, dendritic cells (DCs), and T cells, including CD4 and CD8 positive T cells. 15 After AHCC treatment, NK cell activity, which was depressed by an anticancer drug, was reportedly restored and peritoneal macrophage cytotoxicity, nitric oxide production, and cytokine production were stimulated. 12 In patients with breast cancer, who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, administration of L. edodes mycelia extract maintained patients' quality of life and immune function by inhibiting the increase in the proportion of regulatory T cells to peripheral CD4+ cells. ...
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Purpose Active hexose-correlated compound (AHCC), a standardized extract of cultured Lentinula edodes mycelia, exerts antitumor effects through anti-inflammatory and immune-modulatory functions. Adjuvant therapy for patients with hepatocellular carcinoma (HCC) who have undergone curative hepatectomy has not been established. The purpose of this study was to evaluate the efficacy and safety of AHCC as adjuvant therapy in patients with advanced HCC after curative hepatectomy. Patients and methods The study design was single-armed, non-randomized, open (no one was blinded), and uncontrolled. Patients with HCC who underwent curative hepatectomy were treated with AHCC (1 g) 3 times daily orally for 2 years. The inclusion criteria were HCC diagnosed preoperatively as stages A and B of the Barcelona clinic liver cancer (BCLC) classification and alpha-fetoprotein × protein induced by vitamin K absence or antagonist II (PIVKA-II) ≥ 10 ⁵ for stage A. Results A total of 29 patients were treated with AHCC, of which 25 (4 patients discontinued) were followed up. The 2-year recurrence-free survival rate after resection was 48% for those without discontinuations and 55.2% for all patients with a history of treatment. Serum albumin levels decreased to a minimum in the first postoperative month and gradually recovered to the preoperative level at 6 months. Almost no change in lymphocyte percentage was observed during follow-up. Inflammation-based prognostic scores were maintained at favorable levels after hepatectomy. Toxicity and adverse events were not observed in any patient. Conclusion AHCC may be safe and effective in preventing HCC recurrence after curative hepatectomy, and further randomized trials of AHCC for its use in this setting are warranted. This clinical trial was registered in UMIN Clinical Trials Registry (ID UMIN000024396).
... The most abundant component of AHCC ® is oligosaccharides which comprise about 74% of the dry weight of AHCC ® (6). Previous human and animal studies showed the possible effects of AHCC ® on the frequency and function of T cells (8). Also, the suppression of tumor growth by AHCC ® was reported in murine models of melanoma and hepatoma (9,10). ...
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Full-text available
Treatment strategies combining immune checkpoint blockade (ICB) with other agents have emerged as a promising approach in the treatment of cancers. AHCC®, a standardized extract of cultured Lentinula edodes mycelia, has been reported to inhibit tumor growth and enhance immune cell function. Here we investigated whether AHCC® promotes the therapeutic effect of immunotherapy in cancers. A combination of oral AHCC® and dual immune checkpoint blockade (DICB), including PD-1/CTLA-4 blockade, had reduced tumor growth and increased granzyme B and Ki-67 expression by tumor-infiltrating CD8+ T cells in MC38 colon cancer bearing mice compared to a combination of water and DICB. In the same tumor bearing mice, AHCC® and DICB treatment also altered the composition of the gut microbiome with the increased abundance of the species of Ruminococcaceae family which is associated with increased therapeutic efficacy of immunotherapy. The anti-tumor effect of AHCC® and DICB was not found in MC38 tumor-bearing mice treated with antibiotics. These data suggest that AHCC® increases the anti-tumor effect of DICB by enhancing T cell function and affecting the gut microbiome.
... This product was developed by Amino Up Chemical Co. Ltd. (Sapporo, Japan) in Japan in 1992. Several articles describe its therapeutic effects in both in vitro assays and in human and animal studies, including modulation of the immune response, antioxidant and anticancer activity, and prevention of infectious processes [179][180][181][182][183][184][185][186][187]. Leishmaniasis patients could benefit from some of these reported positive effects, such as increased Th1 cell responses [179][180][181], increased production of IL-17 and IFN-γ by CD4+ T cells [180], and modulation of the immune response in intestinal epithelial cells and macrophages [183]. ...
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Leishmaniasis is an emerging, uncontrolled, and neglected zoonotic disease. Climate change is contributing to its ongoing global expansion. The dog is the main reservoir; hence the importance of implementing effective treatment, prevention, and control measures in this animal species to protect public health. However, although the standard treatment for canine leishmaniosis (CanL) is effective, it does not provide full parasitological clearance, and side effects and drug resistance have been described. The host’s immune system plays a key role in the establishment and evolution of leishmaniasis. Dietary nucleotides modulate the immune response and, given their reported efficacy and safety in sick and clinically healthy Leishmania-infected dogs and because they represent a sustainable option with no associated side effects or resistance, they could be included within the prevention, treatment, and control strategies for leishmaniasis. This article briefly summarizes the scientific literature on CanL management, including unresolved issues, and reviews the scientific evidence on immunomodulatory effects of dietary nucleotides in different animal species. It also proposes a CanL management algorithm, including nucleotides. It is concluded that nutritional modulation of the immune response with nucleotides can contribute to better management of leishmaniasis following a One Health approach, especially in the COVID-19 era.
... Active hexose correlated compound (AHCC) is a Basidiomycotina polysaccharide extract derived from the hybridization of mushrooms [206]. AHCC has been shown to play a role in immune cell function and cell number; such immune cells include natural killer (NK) cells and T cells, which can possibly defend the host from infections and malignancies [207]. When administered with a high dose of 9 g of liquid AHCC per day, no significant abnormalities in laboratory parameters in healthy subjects was reported [208]. ...
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Full-text available
Hepatocellular carcinoma (HCC) is the most abundant form of liver cancer. It accounts for 75–85% of liver cancer cases and, though it ranks globally as the sixth most common cancer, it ranks second in cancer-related mortality. Deaths from HCC are usually due to metastatic spread of the cancer. Unfortunately, there are many challenges and limitations with the latest HCC therapies and medications, making it difficult for patients to receive life-prolonging care. As there is clearly a high demand for alternative therapy options for HCC, it is prudent to turn to plants for the solution, as their phytochemicals have long been used and revered for their many medicinal purposes. This review explores the promising phytochemical compounds identified from pre-clinical and clinical trials being used either independently or in conjunction with already existing cancer therapy treatments. The phytochemicals discussed in this review were classified into several categories: lipids, polyphenols, alkaloids, polysaccharides, whole extracts, and phytochemical combinations. Almost 80% of the compounds failed to progress into clinical studies due to lack of information regarding the toxicity to normal cells and bioavailability. Although large obstacles remain, phytochemicals can be used either as an alternative or integrative therapy in conjunction with existing HCC chemotherapies. In conclusion, phytochemicals have great potential as treatment options for hepatocellular carcinoma.
... In addition, other studies have reported the activation of NK and/or T cells by a different type of high molecular weight polysaccharides, named a-glucans, effective in human and animal immunity, therefore suggesting a theoretical role in defending the host against respiratory infections (40). The most investigated and well-documented a-glucan formulation, active hexose correlated compound (AHCC), has been shown to be effective against different types of infectious diseases caused by viruses such as West Nile virus, influenza virus, avian influenza virus, hepatitis C virus, and human papillomavirus (41)(42)(43)(44)(45)(46)(47). In those studies, it was shown that NK cells, natural killer T (NKT) cells, and gamma delta T (gd T) cells are modulated and activated by AHCC intake. ...
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Full-text available
IntroductionSeveral months ago, Chinese authorities identified an atypical pneumonia in Wuhan city, province of Hubei (China) caused by a novel coronavirus (2019-nCoV or SARS-CoV-2). The WHO announced this new disease was to be known as “COVID-19”.Evidence AcquisitionSeveral approaches are currently underway for the treatment of this disease, but a specific cure remains to be established.Evidence SynthesisThis review will describe how the use of selected nutraceuticals could be helpful, in addition to pharmacological therapy, in preventing some COVID-19-related complications in infected patients.Conclusions Even if a specific and effective cure for COVID-19 still has some way to go, selected nutraceuticals could be helpful, in addition to pharmacological therapy, in preventing some COVID-19-related complications in infected patients.
... The АНСС ® has been used in more than 45 countries for over 30 years. More than 100 studies have been published on the results of its application in various fields of medicine [10,11]. Considering the isolated studies on the use of АНСС® in thyroidology, it seems relevant to assess its effect on the course of NG and MEG. ...
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Aim: of the study is to evaluate the effectiveness of Аctive Hexose Correlated Compound (АНСС®) use in monotherapy and its impact on the echographic characteristics of the thyroid gland during (multi) nodular goiter. Methods: The study involved 27 people with (multi) nodular euthyroid goiter. The main treatment group consisted of 13 patients who received АНСС®. The placebo control group consisted of 14 participants. The duration of the drug intake lasted for 100 days. Three visiting schedules were arranged including initial, intermediate and final visits. Research methods included clinical examinations, laboratory tests, a thyroid ultrasound (classification by K-TIRADS) and completing a questionnaire. Results: The laboratory tests confirmed the euthyroid status of patients in both groups at baseline and at the end of the study. A decrease in the total volume of the right and left lobes of the thyroid gland was noted among the main treatment group. In addition, a decrease in the volume of all types of nodules was seen in this group. A decrease in the volume of the type 2 colloid node was statistically significant. On the contrary, a statistically significant increase in the average volume of the same type of node among the control group was seen. Overall, the average volume of the node decreased by 37.2% in the main group and increased by 4.9% in the control group by the end of the study. Conclusion: The results of this double-blind, placebo-controlled study make it possible to assess the efficiency of АНСС® in (multi) nodular goiter affecting primarily the volume of nodes (mainly of the 2nd and 3rd types). This is especially important when a potential surgery or radioiodine therapy may carry a high risk of complications among patients.
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Background: The anticancer effects of phytohormones of cytokinin nature are similar to those of medicinal mushrooms, which are able to synthesize cytokinins in large amounts. Aim: To determine the antiproliferative effect of crude extracts and cytokinin fractions from the mycelial biomass of seven fungi species on colon cancer cells in vitro. Materials and methods: Cytokinin content in mycelial biomass of Ganoderma lucidum, Lentinula edodes, Trametes versicolor, Pleurotus ostreatus, Morchella esculenta, Hericium coralloides, and Fomitopsis officinalis was determined by high performance liquid chromatography mass spectrometry. The antiproliferative effect of the mushroom extracts on the human colon adenocarcinoma Colo 205 cells was assessed by MTT-test. Results: The content of cytokinins (trans-zeatin, zeatin riboside, isopentenyladenosine, isopentenyladenine and zeatin-O-glucoside) was determined in the mycelial biomass of the medicinal macromycetes. Zeatin-type hormones prevailed in all species, though trans-zeatin was the most abundant in H. coralloides and M. esculenta. In P. ostreatus, only zeatin-O-glucoside was detected. The lowest IC50 was found for both the cytokinin fraction (0.21 μg/ml) and the crude extract (0.17 μg/ml) from mycelial biomass of H. coralloides. F. officinalis also demonstrated high antiproliferative effect against Colo 205 cells: IC50 was 0.9 μg/ml for the crude extract and almost twice lower for the cytokinin fraction. In the studied concentration range (0.016-2 μg/ml), the crude extracts from G. lucidum and M. esculenta and the cytokinin fraction from L. edodes did not reach IC50 values. Conclusions: The present study showed that crude extracts and/or cytokinin fractions of several medicinal Basidiomycetes species are capable to inhibit proliferation of colon cancer cells in vitro. Crude extract cytotoxicity of H. coralloides, P. ostreatus and T. versicolor was higher than that of cytokinin fraction while antiproliferative effect of cytokinin fraction from F. officinalis was higher than that in its crude extract.
Chapter
Mushrooms are among the few natural products that have been relied upon for prophylactic and therapeutic applications in human diseases. They have been referred to as forest gems since they can be picked in the wild or better domesticated for appropriate use. Several scientific studies have been conducted to establish claimed potentials or further probe new areas into which mushrooms can find application. Many disciplines, including mycology, microbiology, physiology, chemistry, genetics, and medicine, among others, conduct research on mushrooms. These enable broad and in-depth studies of mushrooms, to include in vitro and in vivo demonstrations of their bioactivity, structural characterization, and isolation of bioactive components. This chapter highlights the bioactive composition of mushrooms by relating structure to bioactivity and demonstrating therapeutic effects on some human diseases using existing literature. The potentials of mushrooms or their products for the treatment or management of diseases, such as tropical illnesses and COVID-19 pandemic, among other issues, have been discussed. Chemistry of bioactive compounds, structure–activity relationships, patents, and analyses of data obtained have been reported and studied for interpretation of results.
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Chlamydia trachomatis genital infection is the most common bacterial sexually transmitted disease worldwide. Previously we reported that cold-induced stress results in immune suppression of mice that subsequently leads to increased intensity of Chlamydia muridarum genital infection. Furthermore, we demonstrated that stressed mice orally fed with active hexose correlated compound (AHCC) have reduced shedding of C. muridarum from the genital tract. However, the mechanism of AHCC on reducing the organ load and changes in the immune response in the stress model is not well known. This study evaluated infection and changes in immunological parameters of stressed AHCC-fed mice with or without C. muridarum genital infection. We hypothesized that AHCC feeding to stressed mice restores the protective immune function and reduces susceptibility to C. muridarum genital infection. Results show that oral feeding of stressed mice with AHCC resulted in decreased shedding of C. muridarum from the genital tract, reduced production of plasma catecholamines, increased expression of T-bet and reduced GATA-3 in CD4+ T cells, increased production of IL-12 and IFN-γ, and reduced production of IL-4 in CD4+ T cells, and enhanced expression of surface markers and co-stimulatory molecules of CD4+ T cells, bone marrow-derived dendritic cells (BMDCs), and natural killer cells. Co-culturing of mature BMDCs with splenic CD4+ T cells led to the increased and decreased production of T-helper 1 and T-helper2 cytokines, respectively. Overall, our results show that AHCC fosters the restoration of Th1 cytokine production while reducing Th2 cytokine production, which would promote C. muridarum clearance in the murine stress model.
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Maitake α-glucan, YM-2A, isolated from Grifola frondosa, has been characterized as a highly α-1,6-branched α-1,4 glucan. YM-2A has been shown to possess an anti-virus effect in mice; however, it does not directly inhibit growth of the virus in vitro, indicating that the anti-virus effect of YM-2A might be associated with modulation of the host immune system. In this study, we found that oral administration of YM-2A could inhibit tumor growth and improve survival rate in two distinct mouse models of colon-26 carcinoma and B16 melanoma. Orally administered YM-2A enhanced antitumor immune response by increasing INF-γ-expressing CD4⁺ and CD8⁺ cells in the spleen and INF-γ-expressing CD8⁺ cells in tumor-draining lymph nodes. In vitro study showed that YM-2A directly activated splenic CD11b⁺ myeloid cells, peritoneal macrophages and bone marrow-derived dendritic cells, but did not affect splenic CD11b⁻ lymphocytes or colon-26 tumor cells. YM-2A is more slowly digested by pancreatic α-amylase than are amylopectin and rabbit liver glycogen, and orally administered YM-2A enhanced the expression of MHC class II and CD86 on dendritic cells and the expression of MHC class II on macrophages in Peyer’s patches. Furthermore, in vitro stimulation of YM-2A increased the expression of pro-inflammatory cytokines in Peyer’s patch CD11c⁺ cells. These results suggest that orally administered YM-2A can activate dendritic cells and macrophages in Peyer’s patches, inducing systemic antitumor T-cell response. Thus, YM-2A might be a candidate for an oral therapeutic agent in cancer immunotherapy.
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A cold-induced stress mouse model for investigating chlamydia genital infection and immune response analysis was established in our laboratory. Previous results showed that cold-induced stress results in suppression of the immune response and increased intensity of chlamydia genital infection in the mouse model. The purpose of the present study was to evaluate the potential therapeutic value of active hexose correlated compound (AHCC) against chlamydia genital infection in mice. AHCC is an extract of mushroom commonly used as a dietary supplement is known to boost the immune system. Mice were infected intravaginally with Chlamydia trachomatis after a 24-day cold-stress application. Oral administration of AHCC to stressed or non-stressed mice was carried out seven days before infection and during the course of infection along with cervicovaginal swabbing. Cytokine production by peritoneal and splenic T cells isolated from AHCC-fed stressed mice and non-stressed mice was measured ELISA. Splenic T cells from both animal groups were co-cultured with mouse monocyte J774.2 cell line or cultured by addition of supernatants of AHCC-treated J774.2 cell line for 24 hours. Infection studies showed that AHCC-feeding compared to phosphate buffered saline (PBS)-feeding to stressed mice resulted in reduced Chlamydia trachomatis shedding from the genital tract. Levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) were significantly increased in stressed mice receiving AHCC compared to stressed mice receiving PBS. Production of interferon gamma (IFN-γ) and interleukin 2 (IL-2) in the AHCC group was significantly high compared to production in PBS-fed group. Splenic T cells from stressed and non-stressed cultured with supernatants of AHCC-treated J774.2 cell line resulted in significantly increased TNF-α or IFN-γ production. Results obtained in this study show that AHCC improves the function of immune cells as indicated by the restoration of levels of cytokines production that were suppressed under cold induced-stress conditions. This is the first report showing that oral administration of AHCC enhances the function of the immune system, which could result in increased resistance of the host to chlamydia genital infection.
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