Third Party Articles Describing AHCC Research

Active Hexose Correlated Compound (AHCC®) is a fermented mushroom extract which has been the subject of over 60 published studies in peer-reviewed medical journals.

“AHCC” is a registered trademark of the Amino-Up Chemical Company of Sapporo, Japan.

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1. Human2. Review3. In Vivo (animal)4. In Vitro


Kenner, D. Chronic Fatigue Syndrome And Natural Killer Cells.
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Pescatore, F. Reversing Immunosenescence: The Key to Anti-Aging? Winter 2000. International Journal of Anti-Aging Medicine.
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Kenner, D. Treatment for Immune Dysfunction from Post-Traumatic Stress Disorder and Chronic Disease with AHCC. Dec 2001. Townsend Letter For Doctors.
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Pescatore, F. Immune System Enhancer Helps Fight Cancer. May 2001. Whole Foods.
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Sosin, A. Winning the Battle Against Cancer Therapy Side Effects. May 2001. Whole Foods.
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AHCC Research Publications: Listing of publications describing human clinical trials, in vitro and in vivo research with AHCC as of May 2016 – in publication date order by category.

 


I. Human Studies – 19

A. Yanagimoto H, Satoi S, Yamamoto T, Hirooka S, Yamaki S, Kotsuka M, Ryota H, Michiura T, Inoue K, Matsui Y, Tsuta K, Kon M. Alleviating Effect of Active Hexose Correlated Compound (AHCC) on Chemotherapy-Related Adverse Events in Patients with Unresectable Pancreatic Ductal Adenocarcinoma. Nutr Cancer. 2016;68(2):234-40.
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The present study was conducted to determine whether active hexose correlated compound (AHCC), a functional food extracted from cultured basidiomycetes, possesses the potential to attenuate adverse events in unresectable pancreas ductal adenocarcinoma (PDAC) patients receiving chemotherapy. Unresectable PDAC patients receiving gemcitabine treatment (GEM) as the first-line chemotherapy were prospectively divided into 2 groups according to AHCC intake (AHCC group, n = 35) or not (control group, n = 40). The patients in the AHCC group ingested 6.0 g of AHCC for 2 mo. Hematological and nonhematological toxicity was compared between the AHCC and control groups. The C-reactive protein (CRP) elevation and albumin decline of the AHCC group were significantly suppressed as compared to the control group during the GEM administration (P = 0.0012, P = 0.0007). Patients in the AHCC group had less frequency of taste disorder caused by GEM (17% vs. 56%, P = 0.0007). Frequency of grade 3 in the modified Glasgow Prognostic Score (mGPS) during chemotherapy was found significantly less in the AHCC group (14%) than the control group (53%, P = 0.0005). AHCC intake can be effective in reducing the adverse events associated with chemotherapy and may contribute to maintaining the QOL of patients with PDAC during GEM administration.

B. Takanari J, Hirayama Y, Homma K, Miura T, Nishioka H, Maeda T. Effects of Active Hexose Correlated Compound on the Seasonal Variations of Immune Competence in Healthy Subjects. J Evid Based Compl Altern Med. 2014;4:1-7.
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The aim of this study was to evaluate the effects of active hexose correlated compound intake on the immune competence in healthy volunteers. Thirty-four subjects were randomized to receive placebo or active hexose correlated compound at 1.0 g/d for 4 weeks in early winter. Natural killer cell activity was significantly increased in both groups during the study period, the natural killer cell number, however, was not altered in the active hexose correlated compound group while placebo group showed remarkable decline. In addition, the score of immunological vigor, an index of total immune competence, was maintained in the active hexose correlated compound group although that of placebo group lowered during the test period. These results suggested that the continuous active hexose correlated compound intake maintained the immune competence against the seasonal change.

C. Ito T, Urushima H, Sakaue M, Yukawa S, Honda H, Hirai K, Igura T, Hayashi N, Maeda K, Kitagawa T, Kondo K. Reduction of adverse effects by a mushroom product, active hexose correlated compound (AHCC) in patients with advanced cancer during chemotherapy–the significance of the levels of HHV-6 DNA in saliva as a surrogate biomarker during chemotherapy. Nutr Cancer. 2014;66(3):377-82.
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Chemotherapy improves the outcome of cancer treatment, but patients are sometimes forced to discontinue chemotherapy or drop out of a clinical trial due to adverse effects, such as gastrointestinal disturbances and suppression of bone marrow function. The objective of this study was to evaluate the safety and effectiveness of a mushroom product, active hexose correlated compound (AHCC), on chemotherapy-induced adverse effects and quality of life (QOL) in patients with cancer. Twenty-four patients with cancer received their first cycle of chemotherapy without AHCC and then received their second cycle with AHCC. During chemotherapy, we weekly evaluated adverse effects and QOL via a blood test, EORTC QLQ-C30 questionnaire, and DNA levels of herpes virus type 6 (HHV-6) in saliva. The DNA levels of HHV-6 were significantly increased after chemotherapy. Interestingly, administration of AHCC significantly decreased the levels of HHV-6 in saliva during chemotherapy and improved not only QOL scores in the EORTC QLQ-C30 questionnaire but also hematotoxicity and hepatotoxicity. These findings suggest that salivary HHV-6 levels may be a good biomarker of QOL in patients during chemotherapy, and that AHCC may have a beneficial effect on chemotherapy-associated adverse effects and QOL in patients with cancer undergoing chemotherapy.

D. Kim H, Kim JH, Im JA. Effect of Active Hexose Correlated Compound (AHCC) in alcohol-induced liver enzyme elevation. J Nutr Sci Vitaminol (Tokyo). 2014;60(5):348-56.
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To investigate the effects of Active Hexose Correlated Compound (AHCC) supplementation and the mechanism of action of AHCC in patients with alcohol-induced mildly elevated liver enzyme levels, participants were randomly allocated to the placebo, 1 g AHCC, or 3 g AHCC group and took the supplement for 12 wk. Subjects visited the hospital for clinical and biochemical measurements, for examination of adverse events, to return unused supplements, and to obtain their next supplements. Biochemical tests including liver enzymes, a questionnaire survey, and anthropometric measurements were collected at baseline and every 4 wk thereafter. Adherence and adverse events were evaluated. After 12 wk of supplementation, the percentage change in alanine aminotransferase (ALT) level was significantly different between the placebo (4.02±59.07%) and both AHCC groups (1 g AHCC: 223.89±20.59%, 3 g AHCC: 224.09±30.73%) (p=0.04). Serum levels of tumor necrosis factor-α (p<0.05) and interleukin-1β (p<0.01) were significantly lower, while those of adiponectin were higher in both AHCC groups than in the placebo group (p<0.01). AHCC supplementation for 12 wk may improve the levels of liver enzymes and circulating pro-inflammatory and anti-inflammatory cytokines in patients with alcohol-induced liver enzyme elevation with mildly elevated liver enzyme levels.

E. Hangai S, Iwase S, Kawaguchi T, Kogure Y, Miyaji T, Matsunaga T, Nagumo Y, Yamaguchi T. Effect of active hexose-correlated compound in women receiving adjuvant chemotherapy for breast cancer: a retrospective study. J Altern Complement Med. 2013;19(11):905-10.
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OBJECTIVES: Anthracyclines and taxanes are often used as first-line chemotherapy treatments in patients with breast cancer. There are, however, significant toxicity and side effects associated with these therapies. Previous studies have demonstrated that active hexose-correlated compound (AHCC) reduces such side effects. The present study explored the beneficial effects of AHCC on adverse events in patients receiving adjuvant chemotherapy for breast cancer. SUBJECTS: Forty-one women who were treated with anthracyclines and taxanes at Nagumo Clinic in Tokyo from October 2004 to March 2011 were selected for this study. OUTCOME MEASURES: We compared the occurrence of adverse events in patients who received AHCC with those who did not receive AHCC. Using Fisher’s exact tests, we also compared the worst-grade adverse events in each treatment cycle. Generalized estimating equations were employed to compare longitudinal changes, and the use of granulocyte colony-stimulating factor, in the two groups was analyzed using Student’s t-test. RESULTS: We found that, compared to the control group, the AHCC group had significantly fewer neutrophil-related events (odds ratio, 0.30; p=0.016), significantly lower use of granulocyte colony-stimulating factor, and a higher (although not significant) rate of adverse events associated with γ-glutamyl transpeptidase. CONCLUSIONS: AHCC has the potential to reduce the severity of neutropenia induced by breast cancer chemotherapy and the use of G-CSF during chemotherapy.

F. Roman BE, Beli E, Duriancik DM, Gardner EM. Short-term supplementation with active hexose correlated compound improves the antibody response to influenza B vaccine. Nutr Res. 2013;33(1):12-7.
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Administration of bioactive nutritional supplements near or at the time of immunization has been a recent approach to stimulate human immune response to vaccination. Active hexose correlated compound (AHCC), a mushroom extract, has been shown to protect mice against lethal primary influenza infection. Moreover, when AHCC was administered pre-vaccination in mice, they showed improved protection from lethal avian flu infection when compared to mice vaccinated alone. In this study, we hypothesized that AHCC will also improve the immune responses of healthy individuals to influenza vaccine. A randomized controlled study was performed with 30 healthy adults to evaluate the effects of AHCC supplementation on the immune response to the 2009-2010 seasonal influenza vaccine. Blood was drawn pre-vaccination and 3 wk post-vaccination. Immediately post-vaccination, the AHCC group began supplementation with AHCC (3 g/d). Flow cytometric analysis of lymphocyte subpopulations revealed that AHCC supplementation increased NKT cells (P < .1), and CD8 T cells (P < .05) post-vaccination compared to controls. Analysis of antibody production 3 weeks post-vaccination revealed that AHCC supplementation significantly improved protective antibody titers to influenza B, while the improvement was not significant in the control group. Overall, our study showed that AHCC supplementation improved some lymphocyte percentages and influenza B antibody titers over the control. Future studies are required to determine the kinetics of AHCC supplementation to improve the overall response to influenza vaccination.

G. Parida D, Wakame K, Nomura T. Integrating Complementary and Alternative Medicine in Form of Active Hexose Correlated Compound (AHCC) in the Management of Head & Neck Cancer Patients. Int J of Clin Med. 2011;2:588-592.
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Objectives: The Active Hexose Correlated Compound (AHCC), produced from mushroom mycelium and rich in alpha-glucans, was administered to the cancer patients along with chemotherapy to see if it is having any beneficial effects on the final outcome in terms of reducing side effects of chemotherapy, maintaining the general condition and having effect on tumor control. Methods: Twenty-five patients were administered AHCC along with conventional palliative chemotherapy regimen out of which sixteen patients received paclitaxel and cisplatinum/carboplatin, and nine patients received combination of cisplatin and 5-Fluorouracil. All the patients were having advance stage (T3/T4) head and neck cancers. Thirteen patients were cancer of cheek, followed by cancer of tongue (4), oro-pharyngeal cancer (6) and cancer of naso-pharynx (2). Results: All the patients tolerated AHCC well with no added symptoms. Twenty patients reported that they are feeling stronger than before at the time of initiation of chemotherapy cycles. Almost all the patients reported to have better appetite after they started taking AHCC. Twelve patients who required blood transfusion before chemotherapy cycles, decrease in the rate of fall in hemoglobin was observed in these patients and only three patients required blood transfusion before subsequent chemotherapy cycles. In 22 patients definite reduction of chemotherapy side effects like nausea, vomiting, drop in total leukocyte count, loose motion/constipation etc. were observed, which reduced the hospital stay of these patients. Tumor regressed in 11 patients, 8 patients had stable disease and in rest of the patients, the disease progressed. Conclusions: AHCC up to 3 g is safe to administer and definitely helps cancer patients in reducing side effects of chemotherapeutic drugs, getting a sense of well-being and improved intake maintains general condition as well as prepare them to continue and tolerate further cycles in a better way.

H. Yin Z, Fujii H, Walshe T. Effects of active hexose correlated compound on frequency of CD4+ and CD8+ T cells producing interferon-γ and/or tumor necrosis factor-α in healthy adults. Hum Immunol. 2010;71(12):1187-90.
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Active hexose correlated compound (AHCC) is a natural compound with the potential to be used as an immuno-enhancer in cases in which the immune system is compromised. The purpose of this study was to evaluate the effects of this compound on the immune function of healthy adults aged 50 years or more. The production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α by CD4(+) and CD8(+) T cells was measured by flow cytometry in peripheral blood obtained from subjects at different time points after AHCC intake. The frequency of CD4(+) and CD8(+) T cells producing IFN-γ alone, TNF-α alone, or both increased during AHCC intake compared with baseline values. Furthermore, the frequency of such cells remained high even 30 days after discontinuing AHCC. Overall, these findings suggest that AHCC enhances CD4(+) and CD8(+) T cell immune responses in healthy elderly persons taking at least 30 days to obtain such effect, which remained up to 30 days after discontinuing treatment with this compound.

I. Sumiyoshi Y, Hashine K, Kakehi Y, Yoshimura K, Satou T, Kuruma H, Namiki S, Shinohara N. Dietary administration of mushroom mycelium extracts in patients with early stage prostate cancers managed expectantly: a phase II study. Jpn J Clin Oncol. 2010;40(10):967-72.
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OBJECTIVE: To assess the efficacy and safety of dietary supplements in patients with early stage prostate cancers who are managed expectantly. METHODS: Seventy-four patients with early prostate cancer, who were treated with expectant management, enrolled in the study. A mushroom mycelium extract was given at a dose of 4.5 g/day for 6 months. The primary endpoint was the proportion of patients in which the prostate specific antigen level decreased by 50% or more following treatment. The adverse events, change of prostate specific antigen value and quality of life were also evaluated. RESULTS: In only one of 74 patients (1.4%), the prostate specific antigen value decreased more than 50%. Grade 2 diarrhea and grade 1 itching were observed in one patient, and patient ingestion compliance was maintained near 100%. The alternation of prostate specific antigen values was stable before and after treatment. In subjects with strong anxiety prior to supplement ingestion, these feelings were significantly alleviated (state anxiety, P = 0.0018; trait anxiety, P = 0.0099). CONCLUSIONS: In this phase II study of early prostate cancer patients who were managed expectantly, a mushroom mycelium extract was an ineffective treatment for reducing 50% or more the patient prostate specific antigen values.

J. Kawaguchi, Yusai. Improved Survival of Patients with Gastric Cancer or Colon Cancer when treated with Active Hexose Correlated Compound (AHCC): Effect of AHCC on digestive system cancer. Nat Med J. 2009;1(1):1-6.
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Background/Aim: Active hexose correlated compound (AHCC) is a functional food extracted from Basidiomycete mushrooms. AHCC has demonstrated immune stimulating activity in vitro and in vivo and may be a potent biological response modifier in cancer therapy. AHCC has been shown to improve the prognosis of patients with hepatocellular carcinoma. We investigated the effect of AHCC on the survival rate of patients with gastric cancer or colon cancer. Study Design: From April 1995 to April 2002 we conducted a prospective cohort study. Methods: 245 patients with a histopathological diagnosis of gastric or colon cancer were recruited to receive oral AHCC as a postoperative adjunctive therapy in conjunction with standard chemotherapy. Patients diagnosed with Stage I, II or III gastric or colon cancer received 3.0 g/day oral AHCC in divided doses (1 g AHCC three times per day). Patients diagnosed with Stage IV gastric or colon cancer received 6.0 g/day oral AHCC in divided doses (2 g AHCC three times per day). The cumulative survival rates for gastric and colon cancer patients were analyzed by Kaplan-Meier method. Results: AHCC as a functional food improved the cumulative five-year survival rates of Stage IA to Stage IIIA gastric cancer (n = 83) and Stage II to Stage III colon cancer (n = 52) patients compared to other institutions. Conclusion: AHCC may improve survival in patients with early stage gastric cancer or colon cancer.

K. Matsui Y, Kamiyama Y. Retrospective study in breast cancer patients supplemented with AHCC. Int J Integr Oncol. 2009;3(2):12-16.
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OBJECTIVE This retrospective study was conducted in terms of the prognosis of advanced breast cancer patients supplemented with Active Hexose Correlated Compound (AHCC). METHODS Out of 47 enrolled subjects, Stage I, II, III and IV were 5, 13, 10 and 19 cases respectively. Study period was six years from 1996 to 2002, and all subjects received AHCC administration in our department. RESULTS The prognosis of AHCC group was worse in comparison to that of the national counting in Stage I, II and III although a statistical work was impossible. AHCC supplementation improved the prognosis in Stage IV as compared to the national counting. CONCLUSION The results suggested that AHCC might contribute to improving the prognosis in Stage IV breast cancer patients although the improvement remains to be further elucidated in Stage I, II and III.

L. Turner J, Chaudhary U. Dramatic prostate-specific antigen response with activated hemicellulose compound in metastatic castration-resistant prostate cancer. Anticancer Drugs. 2009;20(3):215-6.
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Castration-resistant prostate cancer (CRPC) is an incurable disease with limited treatment options. Herbal supplements are unconventional treatments for a variety of diseases. Active hemicellulose compound (AHCC) is a Japanese supplement discovered by hybridizing several mushrooms used in traditional healing for the purpose of maintaining ‘super immunity’. We report on a 66-year-old gentleman with CRPC with an excellent serologic response to AHCC. This case hypothesizes that AHCC may have potential activity against CRPC.

M. Terakawa N, Matsui Y, Satoi S, Yanagimoto H, Takahashi K, Yamamoto T, Yamao J, Takai S, Kwon AH, Kamiyama Y. Immunological effect of active hexose correlated compound (AHCC) in healthy volunteers: a double-blind, placebo-controlled trial. Nutr Cancer. 2008;60(5):643-51.
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The aim of this study was to evaluate the effects of active hexose correlated compound (AHCC) intake on immune responses by investigating the number and function of circulating dendritic cells (DCs) in healthy volunteers. Twenty-one healthy volunteers were randomized to receive placebo or AHCC at 3.0 g/day for 4 wk. The number of circulating cluster of differentiation (CD)11c(+) DCs (DC1) and CD11c(-) DCs (DC2) were measured. Allogeneic mixed-leukocyte reaction (MLR) was performed. Natural killer (NK) cell activity and the proliferative response of T lymphocytes toward mitogen (phytohemagglutinin [PHA]) were measured. We also measured cytokine production stimulated by lipopolysaccharide [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-gamma, tumor necrosis factor-alpha). The AHCC group (n = 10) after AHCC intake had a significantly higher number of total DCs compared to that at baseline and values from control subjects (n = 11). The number of DC1s in the AHCC group after intake was significantly higher than at baseline. DC2s in the AHCC group were significantly increased in comparison with controls. The MLR in the AHCC group was significantly increased compared to controls. No significant differences in PHA, NK cell activity, and cytokine production were found between groups. AHCC intake resulted in the increased number of DCs and function of DC1s, which have a role in specific immunity.

N. Spierings EL, Fujii H, Sun B, Walshe T. A Phase I study of the safety of the nutritional supplement, active hexose correlated compound, AHCC, in healthy volunteers. J Nutr Sci Vitaminol (Tokyo). 2007;53(6):536-9.
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Active Hexose Correlated Compound (AHCC) is an extract of Lentinula edodes of the basidiomycete family of fungi rich in alpha-glucans. AHCC has been used for many years as a dietary supplement to enhance the immune system and in clinical trials as an adjunctive treatment in Hepatocellular cancer. This multiple dose, Phase I trial, using FDA guidelines, directly investigates the clinical safety and tolerability of AHCC in healthy subjects. Its safety has been based previously on anecdotal reports and its use in clinical practice. Twenty-six healthy male or female subjects between the ages of 18 and 61 were recruited from the community and gave their consent to participate in the trial. The subjects were given 9 g of AHCC (150 mL of the currently available liquid AHCC) PO daily for 14 d. Laboratory data was obtained at baseline and after 14 d of exposure to AHCC and adverse events were monitored by a non-directed review of systems questionnaire three times during the trial. At each visit the vital signs and adverse events were recorded. Two subjects (7%) dropped out because of nausea and intolerance of the liquid. Adverse effects of nausea, diarrhea, bloating, headache, fatigue, and foot cramps occurred in a total of 6 subjects (20%) but were mild and transient. There were no laboratory abnormalities. When used in high dose in healthy subjects, AHCC causes no significant abnormality in laboratory parameters. The adverse effects of 9 g of liquid AHCC per day, a higher dose than used in routine clinical applications, are minimal and the dose was tolerated by 85% of the subjects.

O. Cowawintaweewat S, Manoromana S, Sriplung H, Khuhaprema T, Tongtawe P, Tapchaisri P, Chaicumpa W. Prognostic improvement of patients with advanced liver cancer after active hexose correlated compound (AHCC) treatment. Asian Pac J Allergy Immunol. 2006;24(1):33-45.
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Most patients with liver cancer are diagnosed when they are not suitable for resection. Although some palliative approaches can be applied to these patients, the overall survival rate remains unsatisfactory. Active hexose correlated compound (AHCC), a newly developed functional food, has been shown to act as a potent biological response modifier in in vitro experiments. Recently, AHCC was found to improve the prognosis of hepatocellular carcinoma patients following surgical treatment. We investigated whether AHCC could prolong survival and improve the prognosis of patients with advanced liver cancer. A prospective cohort study was performed with 44 patients with histologically confirmed liver cancer. All of the patients underwent supportive care. Survival time, quality of life, clinical and immunological parameters related to liver function, cellular immunity, and patient status were determined. Of the 44 patients, 34 and 10 received AHCC and placebo (control) orally, respectively. Patients in the AHCC treated-group had a significantly prolonged survival when compared to the control group by Mann-Whitney test (95% CI, p = 0.000). Quality of life in terms of mental stability, general physical health status, and ability to have normal activities were significantly improved after 3 months of AHCC treatment when tested using the Wilcoxon signed-rank test (on one-sided test, p = 0.028, 0.037, and 0.040, respectively). The apparent different clinical parameters between the two groups were the levels of albumin and percentage of lymphocytes with p-values of 0.000 and 0.026 at 1 and 2 months after treatment, respectively. Unlike the control patients, AHCC treated-patients with longer survival time had the tendency of better outcomes since the levels of AST and ALT had not increased rapidly from their baselines at follow-up. In addition, the levels of total IL-12 and neopterin were slightly increased in AHCC treated-patients. This study suggests that AHCC intake could prolong the survival and improve the prognosis of patients with advanced liver cancer and delay the gradual decline of their physiological status.

P. Jang S. The Hematoimmunologic Effect of AHCC for Korean Patients with Various Cancers. Biotherapy. 2002;16(6):560-564.
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Active hexose correlated compound (AHCC) is an extract obtained from several kinds of mushroom (basidiomycetes) which are cultured in a liquid medium. This study attempted to assess the hematologic change and the cellular immunity effect of AHCC in 12 different cancer patients. The dosage of AHCC was 3 to 6 g per day orally. Peripheral blood examination, including total leukocytes, peripheral lymphocytes, hemoglobin, and hematocrit, was performed before initiation of AHCC administration and then every 3 months for a total of 3 times. Multiplying the lymphocyte % in the leukocyte count yielded the number of lymphocytes. Assessment of immune parameters, such as CD4, CD8, CD4:CD8 ratio, and natural killer cells, was done before intake of AHCC and then every 3 months for 2 times after intake. The chemotherapy protocol was conducted as usual, and it was not related to the administration of AHCC. There was no clear change in white blood cells (WBC), hemoglobin, hematocrit, or thrombocyte number after taking AHCC, even though the patients were undergoing chemotherapy or radiotherapy. The ratio of natural killer cells to total lymphocytes, which was 21.67% before taking AHCC, increased to 26.21% and 26.0% 3 and 6 months after taking AHCC, respectively. However, the ratio of natural killer cells to total lymphocytes was in the normal range in some patients, so more large-scale randomized studies are required. This study suggests that AHCC can be used for the prevention of bone marrow depression from chemotherapy. Also, from the hematoimmunologic point of view, AHCC treatment seems to be safe and good for Korean cancer patients, acting as a biological response modifier.

Q. Matsui Y, Uhara J, Satoi S, Kaibori M, Yamada H, Kitade H, Imamura A, Takai S, Kawaguchi Y, Kwon AH, Kamiyama Y. Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study. J Hepatol. 2002;37(1):78-86.
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BACKGROUND/AIMS: Active hexose correlated compound (AHCC) is a newly developed functional food. In vitro experiments have shown that AHCC enhances natural killer cell activity, and may be considered a potent biological response modifier in the treatment of cancer patients. However, the effects of AHCC in a clinical setting have not been reported. We seek to determine whether AHCC can improve the prognosis of hepatocellular carcinoma (HCC) patients following surgical treatment. METHODS: A prospective cohort study was performed from February 1, 1992 to December 31, 2001. A total of 269 consecutive patients with histologically confirmed HCC were studied. All of the patients underwent resection of a liver tumor. Time to treatment failure (disease recurrence or death) and ten parameters related to liver function after surgery were examined. RESULTS: Of the 269 patients, 113 received AHCC orally after undergoing curative surgery (AHCC group). The AHCC group had a significantly longer no recurrence period [hazard ratio (HR), 0.639; 95% confidence interval (CI), 0.429-0.952; P=0.0277] and an increased overall survival rate (HR, 0.421; 95% CI, 0.253-0.701; P=0.0009) when compared to the control group by Cox’s multivariate analysis. CONCLUSIONS: This study suggests that AHCC intake can improve the prognosis of postoperative HCC patients.

R. Ghoneum M, Wimbly M, Salem F, McKlain A, Aitallah N, Gill.G. Immunomodulatory and Anticancer Effects of Active Hemicellulose Compound (AHCC). Int J Immunother. 1995;XI(1):23-28.
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Summary: The effects of therapy with active hemicellulose compound (AHCC) were examined in 11 cancer patients. AHCC is a myecelic extract of basidiomycota originating from hybrid mushrooms. Significant anticancer activity by AHCC was observed with advanced malignancies in patients given 3 g of AHCC daily. The percentages of patients with complete remission were as follows: i) prostatic, 2/3 (66%), PSA level <02; ii) ovarian, 2/3, CA-125 <35; iii) multiple myeloma, 1/2 (50%), BJP <5; (iv) breast, 1/3 complete remission and 2 partial. Two mechanisms by which AHCC exerts Its effect were investigated. The first was natural killer (NK) immunomodulation. Patients demonstrated a low base level of NK activity (18.8%), which was significantly enhanced by AHCC at 2 weeks (2.5 fold), and was maintained at a high level. The second was direct anticancer properties. In vitro studies showed that AHCC possesses suppressive effects on tumour cell growth. AHCC (1 mg/ml) cultured with K562 and Raji tumour cells caused 21% and 43% decrease in cell counts, respectively, as compared to control untreated cells. It is concluded that the high augmentory effect of AHCC and the absence of notable side effects make AHCC a promising immunotherapeutic agent for the treatment of cancer patients.

S. Ghoneum M. Immunomodulation by Active Hemicellulose Compound (AHCC) in 17 Cancer Patients. 2nd Meeting of the Society for Natural Immunity, Taormina, Italy May 1994. Drew Univ of Med and Sci, Dept of Otolaryngology, Head and Neck Surgery, Los Angeles, CA USA.

The present study was designed to examine the immunomodulatory function of active hemicellulose compound (AHCC). AHCC is an extract of Mycelia basidiomycota which was originated by hybridization of several types of mushrooms. Seventeen cancer patients with different advanced malignancies participated in the study: ovarian carcinoma (3), multiple myeloma (2), stomach (2), breast (5), lung (2), rhabdomyosarcoma (1) and prostate (2). Patients received AHCC 3g/day orally for 2-6 months. NK cell activity was examined by 4-hour Cr release assay against sensitive K562 and resistant Raji tumor cells. Results showed significant enhancement of NK activity against K562 as early as 2 weeks (2 to 3 fold of baseline). Activity was further increased at subsequent time periods up to 6 months post treatment with AHCC. NK activation was also detected against Raji cells, but at later stages, i.e. 1-2 months (2 to 10 fold). AHCC appears to activate NK cells by increasing their binding capacity to tumor cell targets (2 fold), and also by increasing NK cell granularity as examined microscopically, in cytospin preparation and biochemically. On the other hand, flow cytometry analysis showed no significant change in the percentage of NK cells (CD3-, CD16+/CD56+). We conclude that AHCC is a potent immunomodulator and may be useful in immunotherapy of cancer.


II. Review Articles – 6

A. Ulbricht C, Brigham A, Bryan JK, Catapang M, Chowdary D, Costa D, Culwell S, D’Auria D, Giese N, Iovin R, Isaac R, Juturu V, Liu A, Mintzer M, Rusie E, Shaffer M, Windsor RC. An evidence-based systematic review of active hexose correlated compound (AHCC) by the Natural Standard Research Collaboration. J Diet Suppl. 2013;10(3):264-308.

An evidence-based systematic review of active hexose correlated compound (AHCC) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

B. Shah SK, Walker PA, Moore-Olufemi SD, Sundaresan A, Kulkarni AD, Andrassy RJ. An evidence-based review of a Lentinula edodes mushroom extract as complementary therapy in the surgical oncology patient. J Parenter Enteral Nutr. 2011;35(4):449-58.
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The purpose of this review is to present the currently published evidence regarding the use, efficacy, potential mechanisms of action, and results of published clinical trials regarding the use of a Lentinula edodes mushroom-derived extract (active hexose correlated compound) as complementary therapy in patients with cancer. The authors explore the current pre-clinical and clinical evidence as it relates to this topic and its potential use in the surgical oncology patient. There has been a growing interest in stimulation of the immune system in trauma, cancer, and surgical patients in general. Little, however, has been written about some of the supplements widely used in Japan and China, but relatively unheard of in the United States.

C. Ritz B. Active Hexose Correlated Compound (AHCC) and Immune Outcomes in Humans: A Review. Nat Med J. 2011;3(1):3-7.
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Active hexose correlated compound (AHCC) is a fermented mushroom extract that is commercially available and promoted for immune support. This review focuses on safety and efficacy results from human clinical trials that have included subjects with a variety of cancers, as well as healthy populations. Animal data are also briefly discussed in the context of recent human data, with an emphasis on the possible applications of AHCC in promoting resistance to influenza virus infection. Available data suggest that AHCC supplementation clearly affects immune outcomes and immune cell populations—especially natural killer cell activity. Additional human studies are needed, as well as studies to explore the mechanistic rationale for these reported effects.

D. Ritz BW. Supplementation with active hexose correlated compound increases survival following infectious challenge in mice. Nutr Rev. 2008;66(9):526-31.
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Active hexose correlated compound (AHCC) is a fermented mushroom extract that is promoted for immune support. This review focuses on results from in vivo studies evaluating the effects of AHCC supplementation on survival and the immune response to a variety of infectious agents, including influenza virus, avian influenza virus, Klebsiella pneumoniae, Candida albicans, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. Supplementation with AHCC appears to modulate immunity and increase survival in response to acute infection and warrants further investigation.

E. Sonnenfeld G. Use of animal models for space flight physiology studies, with special focus on the immune system. Gravit Space Biol Bull. 2005;18(2):31-5.
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Animal models have been used to study the effects of space flight on physiological systems. The animal models have been used because of the limited availability of human subjects for studies to be carried out in space as well as because of the need to carry out experiments requiring samples and experimental conditions that cannot be performed using humans. Experiments have been carried out in space using a variety of species, and included developmental biology studies. These species included rats, mice, non-human primates, fish, invertebrates, amphibians and insects. The species were chosen because they best fit the experimental conditions required for the experiments. Experiments with animals have also been carried out utilizing ground-based models that simulate some of the effects of exposure to space flight conditions. Most of the animal studies have generated results that parallel the effects of space flight on human physiological systems. Systems studied have included the neurovestibular system, the musculoskeletal system, the immune system, the neurological system, the hematological system, and the cardiovascular system. Hindlimb unloading, a ground-based model of some of the effects of space flight on the immune system, has been used to study the effects of space flight conditions on physiological parameters. For the immune system, exposure to hindlimb unloading has been shown to result in alterations of the immune system similar to those observed after space flight. This has permitted the development of experiments that demonstrated compromised resistance to infection in rodents maintained in the hindlimb unloading model as well as the beginning of studies to develop countermeasures to ameliorate or prevent such occurrences. Although there are limitations to the use of animal models for the effects of space flight on physiological systems, the animal models should prove very valuable in designing countermeasures for exploration class missions of the future.

F. Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5(1):4-27.
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Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor – PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide – have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens.


III. Animal Studies – 31

A. Mallet JF, Graham É, Ritz BW, Homma K, Matar C. 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. Eur J Nutr. 2016;55(1):139-46.
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PURPOSE: Active Hexose Correlated Compound (AHCC®) is a cultured mushroom extract that is commercially available and promoted for immune support. Available data suggest that AHCC supplementation affects immune cell populations and immune outcomes, including natural killer cell response to infection. The mechanism by which AHCC exerts its effects is not well understood. The present work aimed to characterize the immunomodulatory activity of AHCC in the gut and to study the effects of AHCC on toll-like receptor (TLR) signaling in intestinal epithelial cells (IECs). METHODS: BALB/c mice were fed AHCC by gavage. In vivo activities were assessed by immunohistochemistry and cytokine production. The effects of AHCC on ex vivo primary cell culture from IECs were examined after challenge with LPS or E. coli alone or in the presence of anti-TLR-2 and TLR-4 blocking antibodies. RESULTS: Feeding AHCC resulted in increased IgA+ cells in the intestine and increased sIgA, IL-10, and IFN-γ in the intestinal fluid. In IECs, contact with AHCC increased IL-6 production but not to the pro-inflammatory level of positive controls, LPS and E. coli. Blocking TLR-2 and TLR-4 reduced the induction of IL-6 by AHCC, suggesting that these innate receptors are involved in generating the immune response of IECs to AHCC. CONCLUSIONS: AHCC may play a role in the orchestration of immune response and the maintenance of immune homeostasis in part by priming the TLR-2 and TLR-4 gate at the intestinal epithelium. Such a response is likely due to the recognition of non-pathogenic food-associated molecular patterns (FAMPs) such as those found associated with other mushroom or yeast-derived compounds.

B. Ignacio RM, Kim CS, Kim YD, Lee HM, Qi XF, Kim SK. Therapeutic effect of Active Hexose-Correlated Compound (AHCC) combined with CpG-ODN (oligodeoxynucleotide) in B16 melanoma murine model. Cytokine. 2015;76(2):131–137.
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While Active Hexose Correlated Compound (AHCC) and CpG oligodeoxynucleotide (ODN) are separately known to modulate oxidative stress and immune responses in cancer patients, the combined effect of these two compounds is unknown. To clarify this, we investigated whether AHCC plus KSK-CpG ODN would be therapeutic in B16 melanoma mouse model, if so, and how in reduction-oxidation (redox) balance and cytokines network. We found that treatment groups (AHCC only, KSK-CpG ODN only and AHCC/KSK-CpG ODN) markedly reduced (p<0.001) tumor size when compared to the positive control (PC) group. The total white blood cell (WBC) of AHCC only and KSK-CpG ODN only-treated groups showed significant lower counts than that of PC group. Next, the production of nitric oxide (NO) was significantly increased (p<0.01) in AHCC/KSK-CpG ODN group compared to the PC group. Further, the redox balance was improved in AHCC/KSK-CpG ODN group through significantly low (p<0.001) reactive oxygen species (ROS) production and significantly high (p<0.05) glutathione peroxidase (GPx) activity compared to the PC group. Finally, AHCC/KSK-CpG ODN (p<0.01) and KSK-CpG ODN (p<0.001)-treated groups augmented tumor immune surveillance as shown by significantly increased level of anti-inflammatory cytokine (IL-10) and significantly decreased (p<0.05) level of pro-tumorigenic IL-6 of AHCC/KSK-CpG ODN treated group as compared to the PC group. Collectively, our study indicates therapeutic effect of Active Hexose-Correlated Compound (AHCC) combined with KSK-CpG ODN in B16 melanoma murine model via balancing redox and cytokines network.

C. Cao Z, Chen X, Lan L, Zhang Z, Du J, Liao L. Active hexose correlated compound potentiates the antitumor effects of low-dose 5-fluorouracil through modulation of immune function in hepatoma 22 tumor-bearing mice. Nutr Res Pract. 2015;9(2):129-36.
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BACKGROUND/OBJECTIVES: A variety of immunomodulators can improve the efficacy of low-dose chemotherapeutics. Active hexose correlated compound (AHCC), a mushroom mycelia extract, has been shown to be a strong immunomodulator. Whether AHCC could enhance the antitumor effect of low-dose 5-fluorouracil (5-FU) via regulation of host immunity is unknown. MATERIALS/METHODS: In the current study Hepatoma 22 (H22) tumor-bearing mice were treated with PBS, 5-FU (10 mg·kg(-1)·d(-1), i.p), or AHCC (360 mg·kg(-1)·d(-1), i.g) plus 5-FU, respectively, for 5 d. CD3(+), CD4(+), CD8(+), and NK in peripheral blood were detected by flow cytometry. ALT, AST, BUN, and Cr levels were measured by biochemical assay. IL-2 and TNFα in serum were measured using the RIA kit and apoptosis of tumor was detected by TUNEL staining. Bax, Bcl-2, and TS protein levels were measured by immunohistochemical staining and mRNA level was evaluated by RT-PCR. RESULTS: Diet consumption and body weight showed that AHCC had no apparent toxicity. AHCC could reverse liver injury and myelosuppression induced by 5-FU (P < 0.05). Compared to mice treated with 5-FU, mice treated with AHCC plus 5-FU had higher thymus index, percentages of CD3(+), CD4(+), and NK cells (P < 0.01), and ratio of CD4(+)/CD8(+) (P < 0.01) in peripheral blood. Radioimmunoassay showed that mice treated with AHCC plus 5-FU had the highest serum levels of IL-2 and TNFα compared with the vehicle group and 5-FU group. More importantly, the combination of AHCC and 5-FU produced a more potent antitumor effect (P < 0.05) and caused more severe apoptosis in tumor tissue (P < 0.05) compared with the 5-FU group. In addition, the combination of AHCC and 5-FU further up-regulated the expression of Bcl-2 associated X protein (Bax) (P < 0.01), while it down-regulated the expression of B cell lymphoma 2 (Bcl-2) (P < 0.01). CONCLUSIONS: These results support the claim that AHCC might be beneficial for cancer patients receiving chemotherapy. KEYWORDS: 5-fluorouracil; Mushroom; hepatocarcinoma; immune; toxicity

D. Mascaraque C, Suárez MD, Zarzuelo A, de Medina FS, Martínez-Augustin O. Active hexose correlated compound exerts therapeutic effects in lymphocyte driven colitis. Mol Nutr Food Res. 2014;58(12):2379-82.
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Active hexose correlated compound (AHCC) is a commercial extract of Basidiomycetes fungi enriched in oligosaccharides that is used as a human nutritional supplement for various purposes in humans. Our aim was to study the anti-inflammatory effect of AHCC in the CD4+ CD62L+ T cell transfer model of colitis, considered one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to recombination activating gene 1-/- mice. AHCC (75 mg/d) was administered by gavage as a post-treatment. Three groups were established: noncolitic, colitic (CD4+ CD62L+ transferred mice treated with vehicle), and AHCC (colitic treated with AHCC). AHCC improved colitis, as evidenced by a 24% lower colonic myeloperoxidase and a 21% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory genes assessed by RT-qPCR was observed, particularly TNF-α and IL-1β. Ex vivo mesenteric lymph node cells obtained from AHCC treated mice exhibited a fully normalized production of IL-6, IL-17, and IL-10 (p < 0.05). Also, AHCC treated mice exhibited decreased STAT4 and IκB-α phosphorylation in splenic CD4+ cells. Our data provide validation of AHCC colonic anti-inflammatory activity in a chronic, T cell driven model of inflammatory bowel disease.

E. Vetvicka V, Vetvickova J. Immune-enhancing effects of Maitake (Grifola frondosa) and Shiitake (Lentinula edodes) extracts. Ann Transl Med. 2014;2(2):14.
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BACKGROUND: The role of glucan in stimulation of immune reactions has been studied for several decades. In this report, we focused on the effects of orally administered glucan Maitake and Shiitake on immune reactions. MATERIALS AND METHODS: We measured phagocytosis, NK cell activity, and secretion of IL-6, IL-12, IFN-γ as well as C-reactive protein (CRP) after 14 days of oral application of tested glucans. For comparison, active hexose correlated compound (AHCC) was used in all reactions. RESULTS: We found significant stimulation of defense reaction. In all cases, the most active was the Maitake-Shiitake combination, with Maitake alone being the second strongest, followed by Shiitake on its own and AHCC. CONCLUSIONS: Short-term oral application of natural immunomodulating glucans from Maitake and Shiitake mushrooms strongly stimulated both the cellular and humoral branch of immune reactions. These activities were significantly higher than those of AHCC.

F. Love KM, Barnett RE, Holbrook I, Sonnenfeld G, Fujii H, Sun B, Peyton JC, Cheadle WG. A natural immune modulator attenuates stress hormone and catecholamine concentrations in polymicrobial peritonitis. J Trauma Acute Care Surg. 2013;74(6):1411-8.
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BACKGROUND: Activated hexose correlated compound (AHCC), derived from shiitake mushrooms, increases resistance to infection in immunocompromised hosts with positive effects on dendritic cells, natural killer cell function and interleukin 12 production. It may also be attenuating the systemic inflammatory response by regulating the secretion of cortisol and norepinephrine (NE). METHODS: Female Swiss-Weber mice were pre-treated with AHCC (Amino Up Chemical Co., Sapporo, Japan) or water by gavage for 10 days before undergoing cecal ligation and puncture (CLP). Peritoneal exudate cells and blood samples were harvested at 4 hours and 24 hours following CLP. Plasma and peritoneal concentrations of cortisol and NE were obtained using enzyme-linked immunosorbent assay. Peritoneal bacteria were quantified by colony counts after 4 hours and 24 hours. Significance was denoted by a p < 0.05. RESULTS: Plasma and peritoneal cortisol concentrations were increased 4 hours after CLP compared with normal controls, with no difference between the pre-treated groups. Concentrations of cortisol decreased from 4 hours to 24 hours after CLP with AHCC (plasma, p = 0.009; peritoneal, p < 0.001), and peritoneal cortisol at 24 hours was lower with AHCC as compared with water (p = 0.028). There was no change in plasma or peritoneal NE concentrations at 4 hours. At 24 hours, higher concentrations of NE were detected in both plasma and peritoneal fluid, with lower plasma concentrations in those gavaged with AHCC (p = 0.015). There was no significant difference in peritoneal bacteria counts. CONCLUSION: Enhanced immune function observed with AHCC could be caused by attenuated concentrations of stress hormones and catecholamines.

G. Ocón B, Anzola A, Ortega-González M, Zarzuelo A, Suárez MD, Sánchez de Medina F, Martínez-Augustin O. Active hexose-correlated compound and Bifidobacterium longum BB536 exert symbiotic effects in experimental colitis. Eur J Nutr. 2013;52(2):457-66.
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PURPOSE: Active hexose-correlated compound (AHCC) is a commercial extract obtained from Basidiomycetes under controlled conditions, yielding a 74 % content in oligosaccharides, especially α-glucans. AHCC has a number of therapeutic effects, including intestinal anti-inflammatory activity. Bifidobacterium longum BB536 is a probiotic with potential health-promoting effect at the gut level. The purpose of the present study was to evaluate the possibility of synergism between AHCC, which is believed to act as a prebiotic, and B. longum BB536. METHODS: We used the trinitrobenzene sulfonic acid model (TNBS) of colitis in rats. AHCC (100 or 500 mg kg(-1)) and B. longum BB536 (5 × 10(6) CFU rat(-1) day(-1)) were administered together or separately for 7 days prior to colitis induction and then for another 7 days and compared with control (noncolitic) and TNBS rats. RESULTS: The results show that both treatments had intestinal anti-inflammatory activity separately, which was enhanced when used in combination, as shown by changes in body weight gain, colonic weight to length ratio, myeloperoxidase activity and iNOS expression. Interestingly, the association of AHCC 100 mg kg(-1) + B. longum BB536 showed the highest anti-inflammatory activity. CONCLUSIONS: Our data provide a preclinical experimental basis for the synergistic effect of AHCC and B. longum BB536 on inflammatory bowel disease.

H. Nakamoto D, Shigama K, Nishioka H, Fujii H. Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced Hematological Toxicity in Non-Tumor-Bearing Mice. Inter J of Clin Med. 2012;3:361-367.
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Active hexose correlated compound (AHCC) is known as a dietary supplement derived from an extract of a basidiomycete mushroom. The present study was conducted to evaluate the role of AHCC in alleviating the side effects, particularly hematological toxicity, in non-tumor-bearing mice receiving monotherapy with gemcitabine (GEM). The results from the GEM treatment groups with and without AHCC administration were compared to control group that received vehicle alone. The GEM alone treatment reduced peripheral leukocytes and hemoglobin, and bone marrow cell viability in spite of no influence on body weight, food consumption, and renal and hepatic parameters. Supplementation with AHCC significantly alleviated these side effects. The colony forming assay of bone marrow cells revealed that AHCC improved reduction of colony forming unit-granulocyte macrophage (CFU-GM) and burst forming unit-erythroid (BFU-E) related to GEM administration. However, when mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) was examined using a quantitative reverse transcription polymerase chain reaction (RT-PCR), AHCC showed no effect for the mRNA levels of their hematopoietic growth factors. These results support the concept that AHCC can be beneficial for cancer patients with GEM treatment through alleviating the hematotoxicity.

I. Fujii H, Nishioka N, Simon RR, Kaur R, Lynch B, Roberts A. Genotoxicity and subchronic toxicity evaluation of Active Hexose Correlated Compound (AHCC). Regul Toxicol Pharmacol. 2011;59(2):237-50.
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Active Hexose Correlated Compound (AHCC), a mushroom extract rich in α-1,4 linked glucans, is associated with immunostimulatory effects. AHCC is used in Japan as a dietary supplement to boost immune function and it also is purported to improve the symptoms of cancer and liver disease patients. A series of toxicological studies were conducted on a freeze dried preparation of AHCC (AHCC-FD) to further develop the body of evidence supporting the safety of this ingredient. AHCC-FD was not mutagenic to Salmonella typhimurium and did not exhibit clastogenicity in a mouse micronucleus assay. In a 90-day study, Sprague-Dawley rats were administered 1000, 3000, or 6000 mg/kg body weight/day by gavage. No changes attributable to AHCC-FD treatment were observed in overall condition, body weight, food consumption, ophthalmology findings, hematology and clinical chemistry parameters, and absolute and relative organ weights. Changes in urinary pH values observed in high-dose animals and mid-dose females were considered physiological rather than adverse effects given the acidic nature of AHCC-FD. Urinary protein also was increased in the same dose groups. As this finding was associated with decreased urinary pH and no evidence of kidney dysfunction was observed, it was considered of no toxicological significance. Histopathological changes related to AHCC-FD administration were observed in the limiting ridge of the stomach and in the liver of the high-dose group. The NOAEL was considered to be 3000 mg/kg body weight/day.

J. Sun B, Wakame K, Sato E, Nishioka H, Aruoma OI, Fujii H. The effect of active hexose correlated compound in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine- and methotrexate-induced liver injury in rodents. Cancer Epidemiol. 2009;33(3-4):293-9.
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BACKGROUND: Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). METHODS: Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). RESULTS: Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. CONCLUSION: Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.

K. Shigama K, Nakaya A, Wakame K, Nishioka H, Fujii H. Alleviating effect of active hexose correlated compound (AHCC) for anticancer drug-induced side effects in non-tumor-bearing mice. J Exp Ther Oncol. 2009;8(1):43-51.
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Active hexose correlated compound (AHCC) is an extract of a basidiomycete mushroom that is used as a supplement by some cancer patients undergoing chemotherapy; it is thought to enhance the therapeutic effects and reduce the side effects of select anti-carcinogenic agents. AHCC has been reported to strengthen the anticancer effects of cisplatin (CDDP) and ameliorate its side effects in female BALB/cA mice inoculated with Colon-26 tumor cells. In this study, the role of AHCC in alleviating the side effects induced by several other anticancer drugs was explored in non-tumor-bearing mice receiving monotherapy with paclitaxel (TAX), or multi-drug chemotherapy with TAX plus CDDP, 5-fluorouracil (5FU) plus irinotecan, CDDP plus 5FU, or doxorubicin plus cyclophosphamide. Outcomes from the drug treatment groups with and without AHCC supplementation were compared to controls that received vehicle alone. The multi-drug treatments significantly reduced bone marrow cell viability in all groups and leukocyte count in all groups except for TAX+CDDP; these myelosuppressive effects were generally alleviated by AHCC. Hepatotoxicity and nephrotoxicity caused by the treatments that included TAX and CDDP were also significantly improved by AHCC. The death rate was 20 to 30 percent in all treatment groups except TAX+CDDP, and supplementation with AHCC greatly reduced or eliminated mortality. These results support the concept that AHCC can be beneficial for cancer patients receiving chemotherapy.

L. Wang S, Welte T, Fang H, Chang GJ, Born WK, O’Brien RL, Sun B, Fujii H, Kosuna K, Wang T. Oral administration of active hexose correlated compound enhances host resistance to West Nile encephalitis in mice. J Nutr. 2009;139(3):598-602.
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West Nile virus (WNV) poses a serious threat to public health, especially to the elderly and the immuno-compromised. Neither vaccines nor treatments are available for humans. Active hexose correlated compound (AHCC) is an extract of Lentinula edodes of the Basidiomycete family of fungi rich in alpha-glucans. In this study, we evaluated the effect of AHCC on host susceptibility in the murine model of WNV infection. Mice orally administered with AHCC (600 mg/kg) every other day for 1 wk before and at d 1 and 3 postinfection were assessed using viremia levels, survival rate, and protective immunity. AHCC administration in young (6- to 8-wk-old) mice attenuated viremia and mortality following lethal WNV infection. WNV-specific IgM and IgG production and gammadelta T cell expansion were also enhanced in these mice. Aged (21- to 22-mo-old) mice were more susceptible to WNV infection than young mice, partially due to the dysfunction of gammadelta T cell subsets. AHCC administration in aged mice enhanced the protective Vgamma1(+) T cell response as well as WNV-specific IgG but not IgM antibodies production. AHCC administration in aged mice attenuated viremia levels but led to no difference in mortality rate. Overall, our data suggests that AHCC enhances protective host immune responses against WNV infection in young and aged mice. Dietary supplementation with AHCC may be potentially immunotherapeutic for WNV-susceptible populations.

M. Nogusa S, Gerbino J, Ritz BW. Low-dose supplementation with active hexose correlated compound improves the immune response to acute influenza infection in C57BL/6 mice. Nutr Res. 2009;29(2):139-43.
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Supplementation with mushroom-derived active hexose correlated compound (AHCC) modulates immunity and increases survival in response to a broad spectrum of acute infections, including influenza virus infection. However, dose-response data are nonexistent. Therefore, the aims of this study were to evaluate AHCC supplementation at various doses and determine the effects of low-dose supplementation on the immune response in a mouse model of influenza virus infection. We hypothesized that AHCC supplementation would influence the immune response to influenza infection in a dose-dependent manner. Male C57BL/6 mice were supplemented with AHCC at daily doses of 0.05, 0.1, 0.5, and 1 g/kg and infected intranasally with influenza A virus (H1N1, PR8). Supplemented mice demonstrated a dose-dependent increase in survival and reduction in the loss of body weight. To further evaluate the effects of low-dose AHCC supplementation on the immune response to influenza infection, mice were supplemented with 0.1 g/kg per day and infected with a sublethal dose of influenza virus. Supplemented mice exhibited enhanced virus clearance and decreased weight loss compared to controls. Low-dose supplementation did not influence total natural killer (NK) cell cytotoxicity, although lytic efficiency was increased in the spleens of AHCC-supplemented mice, indicating enhanced NK cell function per cell. In conclusion, these data suggest that the effects of AHCC on the immune response to influenza infection are dose dependent and that low-dose AHCC supplementation improves the response to influenza infection despite no effect on total NK cell cytotoxicity.

N. Aviles H, O’Donnell P, Orshal J, Fujii H, Sun B, Sonnenfeld G. Active hexose correlated compound activates immune function to decrease bacterial load in a murine model of intramuscular infection. Am J Surg. 2008;195(4):537-45.
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BACKGROUND: Infection is a serious, costly, and common complication of surgery and constitutes the principal cause of late death in patients undergoing surgery. The objective of this study was to clarify the mechanisms by which active hexose correlated compound (AHCC) increases survival in a murine model of intramuscular infection. METHODS: Food-deprived mice receiving either AHCC or excipient were infected with bacteria. Kinetics of bacterial load, white blood cell counts, cytokine levels, and antibody levels were compared between groups. RESULTS: AHCC-treated mice had reduced bacterial load at day 5 and cleared bacteria entirely at day 6. Levels of interleukin-12, tumor necrosis factor-alpha, and interleukin-6 peaked earlier in this group (day 3) compared with controls (day 5). Increased percentages of peripheral lymphocytes and monocytes and decreased numbers of polymorphonuclear cells were detected in the AHCC group. CONCLUSIONS: AHCC appears to induce an early activation of the immune response, leading to an effective clearance of bacteria and rapid recovery.

O. Hirose A, Sato E, Fujii H, Sun B, Nishioka H, Aruoma OI. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice. Toxicol Appl Pharmacol. 2007;222:152-8.
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Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p<0.05) and weight (p<0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with cisplatin.

P. Daddaoua A, Martínez-Plata E, López-Posadas R, Vieites JM, González M, Requena P, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O. Active hexose correlated compound acts as a prebiotic and is anti-inflammatory in rats with hapten-induced colitis. J Nutr. 2007;137(5):1222-8.
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Active hexose correlated compound (AHCC) is a product prepared from the mycelium of edible Basidiomycete fungi that contains oligosaccharides. Here we have studied the anti-inflammatory effect of AHCC in the trinitrobenzene sulfonic acid (TNBS) model of colitis in rats. Rats received AHCC (100 or 500 mg/kg) daily starting 2 d before (pretreatment) colitis induction and were killed 6 d after the TNBS challenge. The status of the rats was assessed by morphological and biochemical methods. The effect of AHCC on the colonic microflora was also assessed by studying the bacteria profile in feces by standard culture techniques. AHCC administration attenuated colonic inflammation, improving rat weight, food intake, damage score, extension of necrosis, colonic weight, colonic weight-to-length ratio, myeloperoxidase and alkaline phosphatase activities, glutathione concentration, and the expression of proinflammatory cytokines and chemokines (IL-1beta, IL-1 receptor antagonist, TNF, and monocyte chemoattractant protein-1) and of mucins 2-4 and trefoil factor 3. The magnitude of the anti-inflammatory effect of AHCC was similar to that of sulfasalazine (200 mg/kg). The study of colonic microflora indicated that rats treated with AHCC had higher aerobic and lactic acid bacteria counts as well as higher bifidobacteria counts, whereas clostridia were reduced when compared with the TNBS group. Therefore, our results indicate that AHCC is anti-inflammatory and could be useful as a prebiotic to design functional foods for inflammatory bowel disease patients.

Q. Fujii H, Nishioka H, Wakame K, Sun B. Nutritional Food Active Hexose Correlated Compound (AHCC) Enhances Resistance against Bird Flu. Jap J Compl Alt Med. 2007;2:37-40.
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AHCC is a nutritional food that has been broadly adopted in Japan as well as other countries. Several laboratories have demonstrated that AHCC has immune modulating effect. Increasing immunity against bird flu virus, H5N1, may help to prevent the next pandemic. We hypothesize that uptaking AHCC improves immunity against infection with this virus. Administration of AHCC for 7 days effectively improved survival rate by 30% and this effect can last for 3 to 4 weeks. Our results indicate a potential role of AHCC in helping to build up immunity for preventing the pandemic of bird flu.

R. Aviles H, O’Donnell P, Sun B, Sonnenfeld G. Active hexose correlated compound (AHCC) enhances resistance to infection in a mouse model of surgical wound infection. Surg Infect (Larchmt). 2006;7(6):527-35.
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BACKGROUND: Infection is the most common postoperative complication within the surgical wound and during severe trauma. In spite of the use of modern sterile techniques and prophylaxis, infection continues to be a leading cause of death in these patients. Therefore, it has become crucial to develop new alternatives to prevent the effects of trauma and other complications on the immune system and improve resistance to infection. The objective of this study was to test the prophylactic effects of oral administration of active hexose correlated compound (AHCC), a natural immunoenhancer, on survival in a mouse model of surgical soft tissue infection. METHODS: The model involves the intramuscular administration of a 50% lethal dose (LD50) of K. pneumoniae to mice that have restricted food intake for 24 hours prior to and six hours after infection and simulates local infection and food deprivation that often occur during trauma or surgical procedures. In the present study, AHCC was administrated orally to Swiss Webster mice for eight days prior to and during the infection period. Survival, time of death, LD50, and clearance of bacteria of this group were compared with those control mice receiving the excipient alone. RESULTS: Survival and mean time to death were increased significantly in the AHCC-treated group; the LD50 was greater in mice receiving AHCC than in mice receiving the excipient. Mice receiving AHCC were better able to clear bacteria from their systems than were control animals. CONCLUSIONS: The results suggest that AHCC protects mice in this model by restoring the immune and other systems negatively affected by trauma, infection, and food deprivation. More studies are necessary to determine the intrinsic mechanisms involved in this model and whether AHCC can prevent infection or improve survival in human beings with severe trauma or undergoing surgical procedures.

S. Ritz BW, Nogusa S, Ackerman EA, Gardner EM. Supplementation with active hexose correlated compound increases the innate immune response of young mice to primary influenza infection. J Nutr. 2006;136(11):2868-73.
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The emergence of H5N1 avian influenza and the threat of new or adapted viruses in bioterrorism have created an urgent interest in identifying agents to enhance the immune response to primary virus infection. Active hexose correlated compound (AHCC) is a natural mushroom extract reported to increase natural killer (NK) cell activity, survival, and bacterial clearance in young mice. However, the effects of AHCC on the response to viral infections have not been studied. In this study, young C57BL/6 mice were supplemented with 1 g AHCC/(kg body weight x d) for 1 wk prior to and throughout infection with influenza A (H1N1, PR8). Supplementation increased survival, decreased the severity of infection, and shortened recovery time following intranasal infection with flu, as determined by the recovery of body weight and epithelial integrity in the lungs. AHCC increased NK activity in lungs at d 1 (P < 0.05) and d 4 (P < 0.01) and in the spleen at d 2 postinfection (P < 0.01). Supplementation increased the percentage (P < 0.05) and number (P < 0.01) of NK1.1+ cells in the lung and reduced the infiltration of lymphocytes and macrophages compared with controls (P < 0.01). These data suggest that AHCC supplementation boosts NK activity, improves survival, and reduces the severity of influenza infection in young mice. Bolstering innate immunity with dietary bioactives may be one avenue for improving the immune response to primary flu infection.

T. Gao Y, Zhang D, Sun B, Fujii H, Kosuna K, Yin Z. Active hexose correlated compound enhances tumor surveillance through regulating both innate and adaptive immune responses. Cancer Immunol Immunother. 2006;55(10):1258-66.
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Active hexose correlated compound (AHCC) is a mixture of polysaccharides, amino acids, lipids and minerals derived from cocultured mycelia of several species of Basidiomycete mushrooms. AHCC has been implicated to modulate immune functions and plays a protective role against infection. However, the potential role of AHCC in tumor immune surveillance is unknown. In this study, C57BL/6 mice were orally administered AHCC or water, followed by tumor cell inoculation. We showed that compared to pure water-treated mice, AHCC treatment significantly delayed tumor development after inoculation of either melanoma cell line B16F0 or lymphoma cell line EL4. Treatment with AHCC enhanced both Ag-specific activation and proliferation of CD4(+) and CD8(+) T cells, increased the number of tumor Ag-specific CD8(+) T cells, and more importantly, increased the frequency of tumor Ag-specific IFN-gamma producing CD8(+) T cells. Interestingly, AHCC treatment also showed increased cell number of NK and gammadelta T cells, indicating the role of AHCC in activating these innate-like lymphocytes. In summary, our results demonstrate that AHCC can enhance tumor immune surveillance through regulating both innate and adaptive immune responses.

U. Aviles H, Belay T, Vance M, Sun B, Sonnenfeld G. Active hexose correlated compound enhances the immune function of mice in the hindlimb-unloading model of spaceflight conditions. J Appl Physiol (1985). 2004;97(4):1437-44.
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Hindlimb unloading is a ground-based model that simulates some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. It has been shown that treatment with active hexose correlated compound (AHCC) restores resistance to infection in mice maintained under hindlimb-unloading conditions. The present study was designed to clarify the mechanisms by which AHCC enhances resistance to infection in this model. We hypothesized that oral administration of AHCC will enhance the function of the immune system, which could lead to the increased resistance to infection observed in this model. AHCC or the excipient was orally administered to mice, and the function of the immune system was assessed in spleen and peritoneal cells isolated from those groups. The results of the present study showed that administration of AHCC for 1 wk before and throughout the second day of the hindlimb-unloading period enhanced the function of the immune system assessed by spleen cell proliferation and cytokine production in spleens and nitric oxide and cytokine production in peritoneal cells. These findings suggest that AHCC can be used as a potent immunoenhancer, especially in cases in which the immune system is suppressed by any condition, including diseases such as human immunodeficiency virus infection and cancer.

V. Ye SF, Wakame K, Ichimura K, Matsuzaki S. Amelioration by active hexose correlated compound of endocrine disturbances induced by oxidative stress in the rat. Endocr Regul. 2004;38(1):7-13.
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OBJECTIVE: Active hexose correlated compound (AHCC), an extract derived from fungi of Basidiomycetes family, has been found to be a potent antioxidant. Since the secretion of some hormones can be affected by reactive oxygen species, the objective of this study was to examine how ferric nitrilotriacetate (FeNTA), which generates hydroxyl radicals in vivo, modulates the hormone secretion and the effects of AHCC. METHODS: AHCC at 3 % in drinking water was given to male rats for one week, and the animals were decapitated at different time intervals after the treatment with FeNTA intraperitoneally. Serum levels of hormones (corticosterone, testosterone, thyroxine and triiodothyronine), adrenal ascorbic acid as well as changes in hepatic oxidative status were evaluated by immunoassay and spectrometry. RESULTS: Serum corticosterone levels increased significantly following FeNTA treatment, while AHCC reduced the increased levels to normal. Adrenal ascorbic acid levels that reflect ACTH secretion, were decreased by FeNTA and restored to normal by AHCC. Serum levels of testosterone and thyroxine (T4) decreased rapidly after FeNTA treatment, while AHCC pretreatment prevented this fall. Serum triiodothyroxine (T3) levels remained unchanged either by FeNTA or AHCC treatment. The hepatic oxidized glutathione, glutathione-related enzymes and also serum lipid peroxide were greatly enhanced after FeNTA treatment. All of these changes were restored to normal by AHCC pretreatment. CONCLUSION: FeNTA induces various endocrine disorders and AHCC ameliorates these effects by acting as an antioxidant.

W. Ye SF, Ichimura K, Wakame K, Ohe M. Suppressive effects of Active Hexose Correlated Compound on the increased activity of hepatic and renal ornithine decarboxylase induced by oxidative stress. Life Sci. 2003;74(5):593-602.
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Active Hexose Correlated Compound (AHCC), an extract derived from fungi of Basidiomycetes family has been shown to act as a biological response modifier in various disorders. In our present study, ferric nitrilotriacetate (Fe-NTA), which generates hydroxyl radicals in vivo, was given intraperitoneally to rats and AHCC was tested for its ability to suppress oxidative stress and the activity of ornithine decarboxylase (ODC) in the liver and kidney. Substantial increments in glutathione-related enzymes including glutathione reductase, glutathione peroxidase activity as well as oxidized glutathione contents were shown in the liver at 12 h after treatment with Fe-NTA (7.5 mg Fe/kg body weight). Effects of oxidative stress induced by Fe-NTA were also demonstrated by the increase in serum lipid peroxidation, aminotransferases and urinary 8-hydroxy-2′-deoxyguanosine. However, the increases in these parameters were restored to normal in AHCC-pretreated rats. The ODC activity in the liver and kidney was significantly increased by Fe-NTA, while the increased ODC activity induced by Fe-NTA was normalized in AHCC-pretreated rats. These results suggest AHCC acts as a potent antioxidant and protects against disorders induced by oxidative stresses.

X. Aviles H, Belay T, Fountain K, Vance M, Sun B, Sonnenfeld G. Active hexose correlated compound enhances resistance to Klebsiella pneumoniae infection in mice in the hindlimb-unloading model of spaceflight conditions. J Appl Physiol (1985). 2003;95(2):491-6.
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Previous studies have demonstrated that resistance to infection is decreased in Swiss Webster female mice maintained in the hindlimb-unloading model (Aviles H, Belay T, Fountain K, Vance M, and Sonnenfeld G. J Appl Physiol 95: 73-80, 2003; Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 110: 262-268, 2002). This is a model of some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. Active hexose correlated compound (AHCC), extracted from Basidiomycete mushrooms, has been shown to induce enhancement of immune responses, including enhanced natural killer activity. In the present study, AHCC was orally administered to mice to determine whether the treatment could decrease immunosuppression and mortality of mice maintained in the hindlimb-unloaded model and infected with Klebsiella pneumoniae. The results of the present study showed that administration of AHCC by gavage for 1 wk (1 g/kg body wt) before suspension and throughout the 10-day suspension period yielded significant beneficial effects for the hindlimb-unloaded group, including 1). decreased mortality, 2). increased time to death, and 3). increased ability to clear bacteria. The results suggest that AHCC can decrease the deleterious effects of the hindlimb-unloading model on immunity and resistance to infection.

Y. Yagita A, Maruyama S, Wakasugi S, Sukegawa Y. H-2 haplotype-dependent serum IL-12 production in tumor-bearing mice treated with various mycelial extracts. In Vivo. 2002;16(1):49-54.
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IL-12 is considered to be one of the most important cytokines in anti-cancer therapy. We have demonstrated that substances derived from Basidiomycetes, such as active hexose-correlated compound (AHCC) and PSK induce the production of IL-12. In this study, the MHC dependency of IL-12 production induced by various mycelial extracts, PSK, AHCC and IL-X, was examined. During tumor-bearing, higher serum IL-12 levels were observed in H-2a and H-2b mice as compared to H-2d mice. Concerning the effect of genetic background of mice on response to mycelial extracts, AHCC administration enhanced the serum IL-12 level in H-2b mice but not in H-2d mice, while PSK administration increased the serum IL-12 level in H-2d mice but not in H-2b mice. IL-X, components derived from the same Basidiomycetes, also enhanced the serum IL-12 level in H-2b mice in the early stage of tumor like AHCC, and maintained serum IL-12 at a level higher than the normal value accompanying tumor growth, whereas AHCC did not restore the lowered serum IL-12 level accompanying tumor growth. These results showed that AHCC or IL-X is effective in a genetically Th1-dominant individual whereas PSK is effective in a genetically Th2-dominant individual or Th2-dominant status in advanced cancer patients. So we propose that the suitable combinations of various mycelial extracts may be effective methods of endogenous IL-12 induction for cancer patients of all stages, which is important as a cancer therapy that is relatively free from adverse reactions and which emphasizes the QOL in individual patients.

Z. Wang S, lchimwa K, Wakame K. Preventive Effects of Active Hexose Correlated Compound (AHCC) on Oxidative Stress Induced by Ferric Nitrilotriacetate in the Rat. Dokkyo J Med Sci 2001;28(2-3):745-752.
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Ferric nitrilotriacetate (Fe -NTA) is a strong oxidant, which generates highly active hydroxyl radical and causes injuries of various organs including the kidney and liver. The formation of 8-hydroxy-2′ deoxyguanosine (8-OHdG) adducts in the renal DNA is one of the earliest events after treatment with Fe-NTA. Since Active Hexose Correlated Compound (AHCC), an extract of fungi, has been shown to act as an antioxidant, its protective effect on the oxidative stress induced by Fe-NTA was examined in the present study. AHCC at 3% in drinking water was given to male Wister rats for 1 week, then Fe-NTA was injected intraperitoneally. At 3 h after the treatment with Fe-NTA, levels of 8-OHdG in the bladder urine, creatinine in the serum, thymic apoptosis, serum levels of aspartate and alanine aminotransferases were significantly increased. All of these increases were restored to normal by the AHCC pretreatment. These results suggest that AHCC is potent in restoring the disorders of various organs induced by oxidative stress.

AA. Wang S, Wakame K, Igarashi Y, Kosuna K, Matsuzaki S. Beneficial Effects of Active Hexose Correlated Compound (AHCC) on Immobilization Stress in the Rat. Dokkyo J Med Sci. 2001;28(I):559-565.
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Active Hexose Correlated Compound (AHCC™), an extract from several basidiomycetes, has been known as a biological response modifier (BRM) in humans as well as in animals. In the present study, AHCC was tested for its ability to modulate the hormonal responses to immobilization stress in the rat. AHCC at 3% in drinking water was given to male Wistar rats for one week, then rats were exposed to immobilization for 1 h. At 1 h after immobilization, the serum levels of corticosterone, norepinephrine, epinephrine, dopamine and glucose were increased significantly. Except for the corticosterone levels, all of these changes were restored to control levels by the AHCC pretreatment These results suggest that AHCC can protect various effects induced by immobilization by attenuating the sympathetic nerve activity.

BB. Burikhanov RB, Wakame K, Igarashi Y, Wang S, Matsuzaki S. Suppressive effect of active hexose correlated compound (AHCC) on thymic apoptosis induced by dexamethasone in the rat. Endocr Regul. 2000;34(4):181-8.
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OBJECTIVE: Mushroom extracts are known to have immunomodulating and antitumor effects in humans as well as in animals. In the present study Active Hexose Correlated Compound (AHCC), an extract obtained from several kinds of basidiomycetes was examined for its suppressive effect on thymocyte apoptosis induced by dexamethasone. METHOD: Thymic apoptosis was evaluated by gel electrophoresis and by flow cytometry at 3 h after injection of dexamethasone to rats. RESULTS: When given to rats at 4 % concentration in drinking water for more than 4 days, AHCC suppressed the internucleosomal DNA fragmentation in the thymus induced by dexamethasone. Flow cytometry also revealed that thymic apoptosis induced by dexamethasone was prevented by pretreatment with AHCC. Dexamethasone increased the caspase 3-like activity within 3 h after its treatment and AHCC pretreatment suppressed the increased enzyme activity only slightly. No apparent increase in serum levels of melatonin and interleukin 1beta was observed after AHCC treatment. CONCLUSIONS: These results suggest that AHCC exhibits immuno-modulating effects at least partially by regulating thymic apoptosis.

CC. Wakame K. Protective Effects of Active Hexose Correlated Compound (AHCC) on the Onset of Diabetes Induced by Streptozotocin in the Rat. Biomedical Research. 1999;20(3):145-152.
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Effects of Active Hexose Correlated Compound (AHCC) on the onset of diabetes were studied in rats treated with streptozotocin (STZ). AHCC was given to male rats at 4% in drinking water. A single i.v. injection of STZ (40 mg/kg body weight) to rats resulted in an increase in blood glucose levels, a decrease in serum insulin levels, suppression of body weight gain. and an increase in serum GOT and OPT activities and serum levels of lipid peroxides. Treatment of AHCC restored these parameters to normal. Insulin immunoreactive β-cells in Langerhans islets reduced in number after treatment with STZ, while insulin immunoreactivity in the islets was normalized when AHCC was administered to STZ-treated rats. These results show that AHCC treatment is effective on the prevention of diabetes onset induced by STZ.

DD. Matsushita K, Kuramitsu Y, Ohiro Y, Obara M, Kobayashi M, Li YQ, Hosokawa M. Combination therapy of active hexose correlated compound plus UFT significantly reduces the metastasis of rat mammary adenocarcinoma. Anticancer Drugs. 1998;9(4):343-50.
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Synergistic effects of active hexose correlated compound (AHCC) extracted from mushroom on the treatment with UFT against mammary adenocarcinoma, SST-2 cells, in congenitally T cell-depressed spontaneously hypertensive rats (SHR) were observed. AHCC plus UFT had slight but significant effects on the growth of primary tumors. Pulmonary metastases were not inhibited by the treatment with AHCC plus UFT, whereas metastases to axillary lymph nodes (LN) were obviously inhibited. Combination of AHCC plus UFT showed similar synergistic anti-metastatic effects in SHR rats with accelerated pulmonary metastases following the surgical removal of the primary tumors. In vitro studies demonstrated that AHCC plus UFT enhanced the NK cell activity in tumor-bearing rats, whereas UFT alone depressed the NK cell activity. AHCC plus UFT also enhanced the NO production and cytotoxicity of peritoneal macrophages. In addition, AHCC restored the suppressed mRNA expression of interleukin-1alpha and tumor necrosis factor-alpha induced by the chemotherapy. Taken together, the combination of AHCC plus UFT brought about good therapeutic effects not only on primary tumor growth but also on reducing metastasis and these effects were mediated by host immunity which was restored or activated by AHCC. AHCC may be a good candidate for a biological response modifier.

EE. Sun B, Wakame K. Mukoda T, Toyoshima A, Kanazawa T, Kosuna K. Preventive Effects of AHCC on Carbon Tetrachloride Induced Liver Injury in Mice. Nat Med. 1997;51(4):310-315.
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In the natural world, it is said that approximately 5,900 genera, 6,400 kinds of mycelia inhabit [the earth]. Lingzhi (Ganoderma lucidum, reishi), zhuling (Polyporus umbellatus, chorei) are popular Chinese traditional medicine derived from fungi of basidiomycetes family. Those mycelia are identified to contain various physiologically active substances, such as polysaccharide with b-1, 3-glucan structure. It has been reported its activities; anti-tumor activity, accommodation activity on immune system, hypoglycemic activity, etc. Recent advance of culturing techniques has enabled artificial culture of basidiomycetes. Active Hexose Correlated Compounds (AHCC; from Amino Up Chemical Co., Ltd.) is a mixture containing polysaccharide obtained by culturing in a liquid culture tank followed by enzyme reactions and hot water extraction. AHCC has been observed and reported its bioactivity as Biological Response Modifiers (BRM) or nonspecific immunoreactive activator. Especially in clinical studies, the effects of AHCC have been reported; improvement of adult diseases such as diabetes or hepatic disease, cancer cell atrophy and inhibition of metastases in tumor patients, the survival time prolongation, reducing side effects caused by chemotherapy, etc. Although there are many clinical studies reported, actual pharmacological mechanism is known only a little. To investigate its pharmacological mechanism as the first step, we prepared an acute carbon tetrachloride hepatitis model in mice-which symptom is said to be similar to drug liver injury in human. This is the report of the investigation of the effect of AHCC administered per os (p.o.) on liver function change and drug metabolizing enzymes in liver.


IV. In Vitro Studies – 12

A. Tokunaga M, Baron B, Kitagawa T, Tokuda K, Kuramitsu Y. Active Hexose-correlated Compound Down-regulates Heat Shock Factor 1, a Transcription Factor for HSP27, in Gemcitabine-resistant Human Pancreatic Cancer Cells. Anticancer Res. 2015;35(11):6063-7.
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BACKGROUND: Active hexose-correlated compound (AHCC) is an extract of a basidiomycete mushroom that enhances the therapeutic effects and reduces the side-effects of chemotherapy. Our previous studies demonstrated that heat-shock protein 27 (HSP27) was involved in gemcitabine-resistance of pancreatic cancer cells and it was down-regulated by AHCC-treatment. However, how AHCC down-regulated HSP27 is unknown. In the present study, we focused on two transcription factors reported to induce HSP27, heat shock factor 1 (HSF1) and high-mobility group box 1 (HMGB1) and investigated the effect of AHCC on their expression. MATERIALS AND METHODS: KLM1-R cells were treated with AHCC and the protein expression of HSF1 and HMGB1 were analyzed by western blotting. RESULTS: The protein expression of HSF1 in KLM1-R was down-regulated by AHCC treatment. On the other hand, the protein expression of HMGB1 was not reduced in KLM1-R cells after AHCC treatment. CONCLUSION: The possibility that AHCC down-regulated HSP27 through down-regulation of the HSF1, was herein shown.

B. Olamigoke L, Mansoor E, Mann V, Ellis I, Okoro E, Wakame K, Fuji H, Kulkarni A, Francoise Doursout M, Sundaresan A. AHCC Activation and Selection of Human Lymphocytes via Genotypic and Phenotypic Changes to an Adherent Cell Type: A Possible Novel Mechanism of T Cell Activation. Evid Based Complement Alternat Med. 2015;508746:9pp.
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Active Hexose Correlated Compound (AHCC) is a fermented mushroom extract and immune supplement that has been used to treat a wide range of health conditions. It helps in augmentation of the natural immune response and affects immune cell activation and outcomes. The goal of this project was to study and understand the role and mechanisms of AHCC supplementation in the prevention of immunosuppression through T cell activation. The method described here involves “in vitro” culturing of lymphocytes, exposing them to different concentrations of AHCC (0 μg/mL, 50 μg/mL, 100 μg/mL, 250 μg/mL, and 500 μg/mL) at 0 hours. Interestingly, clumping and aggregation of the cells were seen between 24 and 72 hours of incubation. The cells lay down extracellular matrix, which become adherent, and phenotypical changes from small rounded lymphocytes to large macrophage-like, spindle shaped, elongated, fibroblast-like cells even beyond 360 hours were observed. These are probably translated from genotypic changes in the cells since the cells propagate for at least 3 to 6 generations (present observations). RNA isolated was subjected to gene array analysis. We hypothesize that cell adhesion is an activation and survival pathway in lymphocytes and this could be the mechanism of AHCC activation in human lymphocytes.

C. Nawata J, Kuramitsu Y, Wang Y, Kitagawa T, Tokuda K, Baron B, Akada J, Suenaga S, Kaino S, Maehara S, Maehara Y, Sakaida I, Nakamura K. Active hexose-correlated compound down-regulates sex-determining region Y-box 2 of pancreatic cancer cells. Anticancer Res. 2014;34(9):4807-11.
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BACKGROUND/AIM: Active hexose-correlated compound (AHCC) is an extract of basidiomycete mushroom. It has been used as health food due to its efficacy of enhancing antitumor effects and reducing adverse effects of chemotherapy. Our previous research showed that AHCC down-regulated heat-shock protein (HSP)-27 and exhibited cytotoxic effects against gemcitabine-resistant pancreatic cancer cells. Sex-determining region Y-box 2 (SOX2) is reported to be up-regulated in other kinds of cancer cells and involved in carcinogenesis and malignancy. The aim of this study was to investigate the effects of AHCC on protein expression of SOX2 in the gemcitabine-resistant pancreatic cancer cell line KLM1-R. MATERIALS AND METHODS: AHCC was applied to KLM1-R cells and expression of SOX2 was analyzed by western blotting. RESULTS: AHCC down-regulated SOX2 in KLM1-R cells. Nanog and Oct4, co-workers of SOX2 in maintaining pluripotency, did not exhibit any significant change in protein expression. CONCLUSION: We showed the potential of AHCC to be a candidate for combinatorial therapy in anticancer drug regimens. This result suggests that the target of AHCC in expressing therapeutic efficacy was not the pluripotent cells such as cancer stem cells (CSCs) but SOX2-specific.

D. Tanaka Y, Ohashi S, Ohtsuki A, Kiyono T, Park EY, Nakamura Y, Sato K, Oishi M, Miki H, Tokuhara K, Matsui K, Kaibori M, Nishizawa M, Okumura T, Kwon AH. Adenosine, a hepato-protective component in active hexose correlated compound: its identification and iNOS suppression mechanism. Nitric Oxide. 2014;31(40):75-86.
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Supplementation of active hexose correlated compound (AHCC) improved the prognosis of postoperative hepatocellular carcinoma patients. Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) is an inflammatory biomarker in liver injury. AHCC suppressed iNOS induction in hepatocytes, suggesting that AHCC has a potential liver-protective effect. However, the active component in AHCC responsible for NO suppressive activities has not been identified. The objective of this study was to identify this NO suppressive component and to investigate its mechanisms of action. AHCC was subjected to fractionation by cation exchanger, size exclusion chromatography, and normal- and reversed-phase HPLC. Aliquots of the fractions were added to primary cultured rat hepatocytes stimulated with interleukin (IL)-1β, and NO production was assayed. By activity-guided fractionation and electron spray ionization mass spectrometry analysis, adenosine was identified as one of the NO suppressive components in AHCC. Adenosine inhibited NO production, and reduced the expression of iNOS protein and mRNA. It had no effects on IκB degradation, but it inhibited NF-κB activation. Adenosine also inhibited the upregulation of type I IL-1 receptor (IL-1RI). Experiments with iNOS promoter-luciferase constructs revealed that adenosine decreased the levels of iNOS mRNA at the promoter transactivation and mRNA stabilization steps. Adenosine decreased the expression of the iNOS gene antisense transcript, which is involved in iNOS mRNA stability. Adenosine in AHCC suppressed iNOS induction by blocking NF-κB activation and the upregulation of the IL-1RI pathways, resulting in the inhibition of NO production.

E. Suenaga S, Kuramitsu Y, Kaino S, Maehara S, Maehara Y, Sakaida I, Nakamura K. Active hexose-correlated compound down-regulates HSP27 of pancreatic cancer cells, and helps the cytotoxic effect of gemcitabine. Anticancer Res. 2014;34(1):141-6.
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BACKGROUND/AIM: Active hexose-correlated compound (AHCC), an extract of basidiomycete mushroom, is used as health food to enhance the therapeutic effects and reduce the adverse effects of chemotherapy. Our previous proteomic analysis revealed that up-regulation of heat-shock protein 27 (HSP27) was responsible for gemcitabine resistance of pancreatic cancer cells. The aim of the present study was to investigate the effect of AHCC on the expression of HSP27 and the effect of combinatorial treatment of AHCC and gemcitabine on the gemcitabine-resistant pancreatic cancer cell line KLM1-R. MATERIALS AND METHODS: KLM1-R cells were treated with AHCC, and the expression of HSP27 as well as the cytotoxic effects of combinatorial treatment of AHCC and gemcitabine were investigated with western blotting and MTS assay, respectively. RESULTS: AHCC down-regulated HSP27 and exhibited a cytotoxic effect on KLM1-R cells. Furthermore, the cytotoxic effect of the combinatorial treatment of AHCC and gemcitabine was synergistic. CONCLUSION: This study supports the potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer.

F. Haidari M, Zhang W, Wakame K. Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC. Life Sci. 2013;18;93(25-26):994-1003.
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AIMS: The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ). The molecular mechanism underlying the anti-metastatic effects of mushroom-derived active hexode correlated compound (AHCC) remains elusive. MAIN METHODS: Several cellular and biochemical techniques were used to determine the contribution of oxidative stress in the disruption of EAJ and to test this hypothesis that AHCC inhibits the breast cancer cell-induced disruption of EAJ. KEY FINDINGS: Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells. Induction of VE-cadherin tyrosine phosphorylation by PMA or by interaction of MDA-MB-231 cells with HUVECs was mediated by HRas and protein kinase C-α signaling pathways. Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDA-MB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs. SIGNIFICANCE: Our studies suggest that ROS contributes to disruption of EAJ induced by interaction of MDA-MB-231 cells with HUVECs and AHCC attenuates this alteration.

G. Daddaoua A, Martínez-Plata E, Ortega-González M, Ocón B, Aranda CJ, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O. The nutritional supplement Active Hexose Correlated Compound (AHCC) has direct immunomodulatory actions on intestinal epithelial cells and macrophages involving TLR/MyD88 and NF-κB/MAPK activation. Food Chem. 2013;15;136(3-4):1288-95.
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Active Hexose Correlated Compound (AHCC) is an immunostimulatory nutritional supplement. AHCC effects and mechanism of action on intestinal epithelial cells or monocytes are poorly described. AHCC was added to the culture medium of intestinal epithelial cells (IEC18 and HT29 cells) and monocytes (THP-1 cells) and assessed the secretion of proinflammatory cytokines by ELISA. Inhibitors of NFκB and MAPKs were used to study signal transduction pathways while TLR4 and MyD88 were silenced in IEC18 cells using shRNA. It was found that AHCC induced GROα and MCP1 secretion in IEC18 and IL-8 in HT29 cells. These effects depended on NFκB activation, and partly on MAPKs activation and on the presence of MyD88 and TLR4. In THP-1 cells AHCC evoked IL-8, IL-1β and TNF-α secretion. The induction of IL-8 depended on JNK and NFκB activation. Therefore, AHCC exerts immunostimulatory effects on intestinal epithelial cells and monocytes involving TLR4/MyD88 and NFκB/MAPK signal transduction pathways.

H. Lee WW, Lee N, Fujii H, Kang I. Active Hexose Correlated Compound promotes T helper (Th) 17 and 1 cell responses via inducing IL-1β production from monocytes in humans. Cell Immunol. 2012;275(1-2):19-23.
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The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL-1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Oligosaccharides from microorganisms, crops and mushrooms can stimulate innate immune cells. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus. This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4(+) T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.

I. Hunter RJ, Fujii H, Wakame K, Gaikwad A, Wolf JK, Smith JA. Evaluation of active hexose correlated compound (AHCC) in combination with pegylated liposomal doxorubicin for treatment of ovarian cancer. Inter J of Appl Res in Nat Prod. 2011;4(3):6-14.
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Summary: The objective was to define the mechanism of the growth inhibition of active hexose correlated compound (AHCC) alone and evaluate its activity in combination with pegylated liposomal doxorubicin (PLD). Scientific Methods: In vitro growth inhibition assays were completed with AHCC alone and in combination with PLD in panel of human cancer cell lines and findings confirmed in vivo in an ovarian cancer xenograft mouse model. AHCC mechanism of action was evaluated with immunoblotting and flow cytometry studies. Major Findings: The in vitro growth inhibition assays demonstrated additive activity when AHCC is co-administered with PLD. The combination of AHCC with PLD demonstrated a 64.1% reduction in tumor growth compared to the untreated group (p value = 0.03) and a 31.2% improvement in tumor response with combination regimen compared to PLD alone. No difference in toxicity was observed in the control or treatment groups. An increased expression of Bcl-2 was observed and induction of apoptosis confirmed in presence of AHCC. Conclusions: There is potential improvement in PLD activity when co-administered with AHCC and decrease side effects of PLD. A clinical study to evaluate of the combination of AHCC plus PLD in the treatment of ovarian cancer is being pursued. Industrial Relevance: This study presents an example of the successful integration of a well-known herbal supplement, AHCC, with traditional western medicine cytotoxic agent, pegylated liposomal doxorubicin, for the treatment of recurrent ovarian cancer. In addition to providing evidence of the efficacy of AHCC, the mechanism of improved activity was also investigated. Using a traditional approach this study provides pre-clinical data to support the benefits previously observed and reported in the clinical setting and supports future endeavors to integrate AHCC into standard of care to be given with chemotherapy. These finding are particularly beneficial in the treatment of recurrent cancer when maintaining a good quality of life during chemotherapy is a priority and allows patients to have a natural, nutritional approach to preventing and managing chemotherapy adverse effects.

J. Matsui K, Ozaki T, Oishi M, Tanaka Y, Kaibori M, Nishizawa M, Okumura T, Kwon AH. Active hexose correlated compound inhibits the expression of proinflammatory biomarker iNOS in hepatocytes. Eur Surg Res. 2011;47(4):274-83.
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BACKGROUND/AIMS: Excess production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as proinflammatory biomarker in liver injury. The application of active hexose correlated compound (AHCC) as a functional food in complementary and alternative medicine has increased. The possibility that AHCC might inhibit iNOS induction was investigated as a potential liver-protective effect. METHODS: Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured hepatocytes were treated with interleukin-1β in the presence or absence of AHCC-sugar fraction (AHCC-SF). RESULTS AND CONCLUSION: AHCC-SF inhibited the production of NO and reduced expressions of iNOS mRNA and its protein. AHCC-SF had no effects on either IκB degradation or nuclear factor-κB (NF-κB) activation. In contrast, AHCC-SF inhibited the upregulation of type I interleukin-1 receptor (IL-1RI) through the inhibition of Akt phosphorylation. Transfection experiments with iNOS promoter-luciferase constructs revealed that AHCC-SF reduced the levels of iNOS mRNA at both promoter transactivation and mRNA stabilization steps. AHCC-SF inhibited the expression of iNOS gene antisense transcript, which is involved in iNOS mRNA stabilization. These findings demonstrate that AHCC-SF suppresses iNOS gene expression through a IκB/NF-κB-independent but Akt/IL-1RI-dependent pathway, resulting in the reduction of NO production. AHCC-SF may have therapeutic potential for various liver injuries.

K. Mach CM, Fugii H, Wakame K, Smith J. Evaluation of active hexose correlated compound hepatic metabolism and potential for drug interactions with chemotherapy agents. J Soc Integr Oncol. 2008;6(3):105-9.
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Active hexose correlated compound (AHCC), a Basidiomycotina extract, is a well-tolerated nutritional supplement with no reported adverse effects. It has demonstrated potential antitumor activity and immune modulator activity. However, there is no current information regarding its metabolism and the potential for drug-drug interactions for AHCC in combination with chemotherapy. The objective of this study was to characterize AHCC hepatic metabolism, specifically involving the potential for drug interactions with selected chemotherapy agents. High-throughput cytochrome P-450 (CYP450) metabolism inhibition experiments were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6 followed by an evaluation of AHCC as a substrate of these same isoenzymes. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of AHCC for CYP450 3A4, 2C8/2C9, and 2D6. No inhibition of CYP450 activity was observed in presence of AHCC; however, AHCC was a substrate of CYP450 2D6. The CYP450 induction metabolism assays indicate that AHCC is an inducer of CYP450 2D6. AHCC does have the potential for drug-drug interactions involving CYP450 2D6, such as doxorubicin or ondansetron; however, the overall data suggest that AHCC would be safe to administer with most other chemotherapy agents that are not metabolized via the CYP450 2D6 pathway.

L. Matsui K, Kawaguchi Y, Ozaki T, Tokuhara K, Tanaka H, Kaibori M, Matsui Y, Kamiyama Y, Wakame K, Miura T, Nishizawa M, Okumura T. Effect of active hexose correlated compound on the production of nitric oxide in hepatocytes. J Parenter Enteral Nutr. 2007;31(5):373-80; discussion 380-1.
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BACKGROUND: Active hexose correlated compound (AHCC) is a “complex compound” containing polysaccharides. AHCC has been reported to improve the prognosis of postoperative hepatocellular carcinoma patients. However, the molecular mechanism of this improvement is not fully understood. In the diseased liver, nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) is considered to be a causal factor for various hepatopathies. In this study, the possibility of AHCC regulation of NO production by iNOS was pursued as a potential liver-protecting mechanism. METHODS: Primary cultured rat hepatocytes were treated with interleukin-1beta (IL-1beta) in the presence or absence of AHCC. NO production, iNOS induction, and iNOS signal were analyzed. RESULTS: IL-1beta stimulated iNOS induction through the activation of nuclear factor kappaB (NFkappaB), leading to NO production. The addition of AHCC inhibited NO production, showing >80% inhibition at 8 mg/mL. AHCC also decreased the levels of iNOS protein and mRNA. However, AHCC influenced neither the degradation of inhibitory protein kappaB (IkappaB) nor the activation of NFkappaB stimulated by IL-1beta. Transfection experiments with an iNOS promoter-luciferase construct (iNOS-Luc) revealed that AHCC had no effect on the transactivation activity of the iNOS promoter. By contrast, AHCC inhibited the activity of iNOS-Luc containing a 3’untranslated region (UTR) with adenosine and uridine (AU)-rich elements, which shows the stabilizing activity of iNOS mRNA. CONCLUSIONS: Results indicated that AHCC inhibits the induction of iNOS at the level of transcription, causing a decrease in NO production in hepatocytes. AHCC seems to decrease the levels of iNOS mRNA by reducing mRNA stabilization rather than inhibiting its synthesis.