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Scientific Studies on the Effectiveness andMechanism of Biobran MGN-3Comprehensive Scientific Overview of Biobran MGN-3 Arabinoxylan by Hiroaki Maeda(Edited by Chris Gutch PhD) Sept 2003

1. INTRODUCTION

Fibers and other indigestible components in foods are valued as substancesdeeply involved in human health which have the effect of maintaininghomeostasis and perform a therapeutic role through actions different fromessential nutrients. Their main actions are improvement of lipid metabolism,improvement of sugar metabolism, improvement of intestinal environment andinhibition of the toxicity of hazardous substances in the diet.

Dietary fibers derive mainly from plants, algae and microorganisms, and manyare sugar polymers, i.e. polysaccharides. There have been a number of reportsconcerning the immunostimulatory action of polysaccharides in foods andmicroorganisms for fermentation, leading to their description as BiologicalResponse Modifiers (BRM). Such polysaccharides include zymozan (β-1-3-glucan), a cell wall component of beer yeast, chitin and a cell wall componentof baker's yeast (α-1-6-mannan), and cell wall components of mushrooms suchas shiitake mushroom, suehirotake mushroom and kawaratake mushroom (β-1-3-glucan), etc. Some of these are used in cancer treatments asimmunostimulators, administered mainly intravenously. These components arecharacterized by the fact that they generally have high molecular weight (0.5-1million dalton) and their effects are only slight if given orally.

Based on such research background concerning polysaccharides andimmunoenhancement, Biobran MGN-3 (Biobran) has been developed as a foodwith immunostimulatory action designed to work by oral intake.

2. DEVELOPMENT OF RICE BRAN ARABINOXYLANDERIVATIVE (Biobran MGN-3)

Dietary fiber components of rice bran are cellulose, lignin and hemicellulose.Hemicellulose is further categorized into high molecular weight insolublehemicellulose A and low molecular weight soluble hemicellulose B.Hemicellulose is a heteroglycan with a highly branched and complicated sugarcomposition of mainly arabinose and xylose, and, as other components,rhamnose, galactose, mannose, glucose and uronic acid, etc. Hemicellulose Bcontains a relatively small amount of a molecule with a polymerization degreeof approximately 200, which can be absorbed through the intestinal wall afteroral intake.

Partial decomposition of hemicellulose B was accomplished by using enzymesable to break down carbohydrates and derivatives were obtained with strongimmunostimulatory action, especially on natural killer cells (NK cells), toproduce the chemical structure in Figure 1 below.

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Figure 1

In industrial production, the enzymes used to make the derivatives are acarbohydrase complex that contains α, β-glucosidase, α, β-galactosidase, β-1-4-glucosidase and β-1-3-glucosidase produced outside the fungus body ofshitake fungus.

3.PHYSIOLOGICAL ACTIVITY OF RICE BRANARABINOXYLAN DERIVATIVE (Biobran)

1. Immuno Regulation

(a) Enhancement of human NK cell activity by modifiedarabinoxylan from Rice Bran (Biobran MGN-3)

1. In vitro test

Rat-derived NK cells were incubated with K-562 tumor cells, which werethe target cells, in the presence of Biobran MGN-3, and the amount of theK-562 cells dissolved was measured by 51Cr-release assay. The dissolvedamount increased concentration-dependently between Biobran MGN-3concentrations of 25 μg/ml and 100 μg/ml, which confirmed that theincrease of NK activity was due to Biobran MGN-3.

2. In vivo test (rat)

Biobran MGN-3 was given orally to Sprague-Dawly rats and after twoweeks the change of NK cell activity was measured. Rats were divided intothree groups with doses of 0.5 mg, 5 mg and 50 mg/kg/day, with five ratsper group. NK cell activities increased dose-dependently with theadministration of Biobran MGN-3. Compared with the control group, theactivities increased by 119%, 130% and 142% for the 0.5 mg, 5 mg and50 mg dose groups, respectively. In the 50 mg dose group, the activityincreased by 132% compared with the control group within three days ofthe dose initiation. The increase of NK cell activities by Biobran MGN-3could be attributed to the increased dissolving power of NK cells but alsodepended on the number of NK cells. Some difference in effect wasobserved between male and female rats, and the manifestation of theeffect was more remarkable in female rats (Figure 3).

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3. Actions on humans

A 60-day continuous intake test of Biobran MGN-3 was conducted on 24healthy subjects (15 women and 9 men, average 34 years old) and thechange in NK cell activities was observed. The subjects were divided intothree groups with intake amounts of 15 mg/kg/day, 30 mg/kg/day and 45mg/kg/day, with 8 subjects per group. Twenty cc of blood was collectedfrom each participant: prior to the intake of Biobran MGN-3, after oneweek, after one month, after two months (at the termination of the test)and one month after the termination and NK activities were measured. Inthe 30 mg and 45 mg intake groups, NK activities increased approximatelytwo-fold one week after initiation of intake and reached three-fold in twomonths. In the 15 mg intake group, the activity rapidly increased from onemonth after initiation and reached almost the same level as in the 30 mgand 45 mg groups in two months. One month after the termination of theintake NK activities returned to the level before the intake (Figure 4).These results suggested that the intake of 15-45 mg/kg/day of BiobranMGN-3 influences NK activities in human.

Figure 4: Time and dosage dependence of natural killer (NK) cell activation by Biobran MGN-3 againstK562 tumour cells…_.._.._.._ = 45mg/kg/day; …………=30mg/kg/day; _______=15mg/kg/day

4. Mechanism of Biobran MGN-3 action on NK cells

Both in vitro and in vivo tests confirmed that the number of cytotoxicgranules increases in NK cells stimulated by Biobran MGN-3. The increaseof binding ability to target cells was also investigated. NK cells of ahuman who took 45 mg/kg/day of Biobran MGN-3 for 30 days wereincubated with K-562, which were the target cells, and the increase of thebinding ability was measured. After NK cells and K-562 tumor cells wereincubated at 4ºC for one hour, 200 NK cells were measured and thebinding rate with K-562 was calculated. The binding rate of NK cells to thetarget cells (K-562) in a subject who took Biobran MGN-3 significantlyincreased to 38.5% compared with 9.4% before intake (Figure 5). Thetypical photograph that indicates binding is shown in Figure 6.

Figure 5: Percentage of conjugate formation between natural killer (NK) cells and K562 target cells.

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Figure 6: Natural killer (NK) effector-tumour targets conjugate formation.

Ghoneum M. (Drew Univ., USA):INT. IMMUNO THERAPY XIV (2) PP.89-99,1998

(b) In vitro effect of Biobran MGN-3 on macrophage group cellactivity

The effect of Biobran MGN-3 on macrophage group cells in inducing theproduction of pharmacological mediators has been investigated. TNF-a, IL-6 and NO were assayed as mediators. Macrophage cells were incubatedwith various concentrations of Biobran MGN-3 (1-100µg/ml) andsupernatants were collected for assay of mediators. TNF-a was assayed bycytotoxicity on L929, IL-6 by cytosis on B13.19 and NO colorimetrically byreaction with Griess reagant. LPS was used as a positive control.

i. Using Murine macrophage cell line RAW264.7, Biobran MGN-3 showedstrong activity on the three mediators at concentrations greater than10µg/ml, as did LPS.

ii. Murine peritoneal macrophages(C3H/He). The effect of Biobran MGN-3against the macrophage originating from peritoneal cavity of normalmouse is showed in Figure 7. Again Biobran MGN-3 showed strongactivity at concentrations above 10µg/ml.

iii. Human macrophage cell line U937. Biobran MGN-3 induced strongactivity as measured by production of cytokines TNF-a and IL-6,equivalent to LPS at 100µg/ml.

The results show that Biobran MGN-3 is a potent substance for activatingeither normal mouse or human macrophage. The studies suggested activeconcentrations of over 10µg/ml.

Figure 7: Murine peritoneal macrophages (C3H/He mice)

Matsuura M. (Jichi Medical School, JAPAN) : Report of Jichi Medical school

(c) Immunostimulation and cancer prevention

Several studies have established the excessive cancer risk for workersexposed to various chemicals common in the workplace. A study wasdesigned to examine the immune alteration associated with exposure totoxic chemicals and the possibility of counteracting chemical toxicity usingBiobran MGN-3.

Eleven individuals who had been exposed to chemicals in the workplaceparticipated in the study. The participants demonstrated immunedysfunction as indicated by: low levels of natural killer (NK) cell activity(10.2±4.2 LUs), lymphocyte blastogenic responses to T-cell mitogens(PHA, 39060±12517cpm and COMA, 36224±11922cpm) and B-cell mitogen(PWM, 16550±6330cpm), compared to control responses. Subjects

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received Biobran MGN-3 at a dose of 15mg/kg/day for four months.Treatment with Biobran MGN-3 increased NK cell activity 4 and 7 fold attwo and four months respectively, while T and B-cell functions were 130-150% higher than base line values.

Ghoneum M. (Drew Univ., USA) : The abstract of the 7th InternationalCongress on Anti-Aging & Biomedical Technolgies Conference ProceedingsManual, 1999

(d) Production of TNF-α and IF-γ from Human PBL by BiobranMGN-3 Modified Arabinoxylan from Rice Bran.

The mechanism by which Biobran MGN-3 elevates NK cytotoxic activity hasbeen investigated. This was done by testing the action of Biobran MGN-3on the levels of both tumor necrosis factor-α, (TNF-α) and interferon-γ(IFN-γ) secretions and on the expression of key cell surface receptors.

Peripheral blood lymphocytes were treated with Biobran MGN-3 atconcentrations of 0.1 mg/ml and 1 mg/ml, and supernatants weresubjected to enzyme-linked immunosorbent assay. Results showed thatBiobran MGN-3 is a potent TNF-α inducer and the effect was dose-dependent. Biobran MGN-3 concentration at 0.1mg/ml and 1 mg/mlincreased TNF-α production by 22.8- and 47.1-fold, respectively. BiobranMGN-3 also increased production of IFN-γ but at lower levels as comparedto TNF-α. W ith respect to key cell surface receptors, Biobran MGN-3increased the expression of CD69, an early activation antigen at 16 hoursafter treatment. Furthermore, the interleukin-2 receptor CD25 and theadhesion molecule ICAM-1 (CD54) were up-regulated after treatment withBiobran MGN-3. Treating highly purified NK cells with Biobran MGN-3 alsoresulted in increased levels of TNF-α and IFN-γ secretion in conjunctionwith augmentation of NK cell cytotoxic function. Furthermore, addition ofBiobran MGN-3 to interleukin-2-activated NK cells resulted in a synergisticinduction of TNF-α and IFN-γ secretion.

Ghoneum M. (Drew Univ., USA), Jewett A. (UCLA, USA) : Cancer Detectionand Prevention Vol.24/Issue 4, 2000

(e) The effect of modified rice-bran arabinoxylan on NK activityof human peripheral blood lymphocytes.

The effects of Biobran MGN-3 and its molecular fractionates on NK activityhave been investigated High molecular weight fraction (M.W. 10-50 kDa)obtained by gel filtration technique using Sephadex G-25 and G-75 wasadded to human peripheral blood lymphocytes. After 3-days incubation, NKactivity was determined. Fluorescence-labeled K-562 cell line was used asthe target cells and the activity was determined gy fluorescence methodusing Tere Scan. The same experiment was conducted in the presence ofIL-2.

In these experiments no significant differences were found in theactivation of NK cells either by BioBan Biobran MGN-3 or by the highmolecular weight fraction. However, when IL-2 was added at the sametime and incubated, increased NK activity was observed compared to theaddition of IL-2 by itself. This indicates that Biobran MGN-3 activates NKcells in the presence of IL-2 and that such activity is also present in thehigh molecular weight fraction.

Ueda Y., Shimomura C. (Chiba Univ., JAPAN) : The abstract of the 2002Annual Meeting of the Japan Society for Bioscience, Biotechnology andAgrochemistry

2. Anti-Viral Effect

Anti-HIV activity in Vitro of Biobran MGN-3

Anti-HIV activity of Biobran MGN-3 has been evaluated in vitro. First, theinhibitory action against the production of the HIV-1 p24 antigen wasevaluated. Mononuclear cells collected from three healthy subjects wereincubated with the HIV-1 SF strain at 37ºC for one hour in the presence ofBiobran MGN-3. The Biobran MGN-3 concentrations were 0-100 μg/ml.Biobran MGN-3 concentration-dependently inhibited the production of theHIV-1 p24 antigen (Figure 8).

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Next, the inhibitory action against syncytia formation was evaluated.Mononuclear cells from five AIDS patients were incubated with PHA in thepresence of Biobran MGN-3 at 37ºC for seven days. Biobran MGN-3concentrations were 0-100 μg/ml. Biobran MGN-3 concentration-dependently inhibited syncytia formation, and the maximum inhibitory ratewas 75% with 100 μg/ml 7) (Table 1).

Table 1

Inhibition of Syncytia Formation by Biobran

Biobran dosage(μg/ml)

Syncytia formation (SF)

No. of SF %Inhibition

012.52550100

42.0±825.8±721.5±515.8±410.5±3

00.038.550.062.575.0

Figure 8 __ Ghoneum M. (Drew Univ., USA):Biochemical and Biophysical ResearchCommunications 243, (1998)

3. Anti-Tumor Effect

(a) Study on the growth inhibiting component of cancerous cellsin culture cell lines derived from modified rice-branarabinoxylan

In this study, the growth inhibiting effect of Biobran MGN-3 modified rice-bran arabinoxylan on various cancerous cell lines such as HL60, K562, HLEwas investigated, and the potential differentiation-induction of HL60 andK562. Biobran MGN-3 was added to the culture cell lines. After 3-daysincubation, the rate of live cells decreased in all cells lines as the amountof Biobran MGN-3 added increased.

After precipitation with ethanol, the precipitate was mixed with distilledwater and the supernatant was fractionated using Sephadex G-25 column.It was fractionated into 3 fractions (A,B,C) which were added to theculture cell lines. Growth inhibiting effects were observed with C fractionfor HL60 and K562 and with B and C fractions for HLE. In addition, fromGiemsa stain and nonspecific esterase stain, potential differentiation-induction was indicated for HL60 and K562. These results indicate thatBiobran MGN-3 has components which show growth inhibition of cancerouscells and the potential differentiation-induction for HL60 and K562.

Masada M. (Chiba Univ., JAPAN) : The abstract of the 2002 AnnualMeeting of the Japan Society for Bioscience, Biotechnology andAgrochemistry

(b) Effectiveness of Biobran MGN-3 against Tumor cell Growth

The direct effect of Biobran MGN-3 on skin cancer cell growth and cytokineproduction has been evaluated. Incubation of a squamous cell carcinoma[SCC13] cell line with Biobran MGN-3 arrested tumor cell growth (30%decrease in cell number after 48 hours and 50% at 72 hours of culture) ascompared to control SCC13 cells grown in a MEM media alone, whichcontinued to increase in cell number.

Employing flow cytometry procedures, analyses showed that after 16 hoursof treatment of SCC13 cells with Biobran MGN-3, there was a five-foldincrease in intracellular levels of interleukin 10 [ IL-10], but no apparentchange in content of interferon-γ [INF-γ]. ELISA analyses showed 8-foldhigher levels of IL-10 and a 3-fold increase in IL-12 in the culture media ofSCC13 cells. However, little change in INF-γ concentration was detected.The effect of Biobran MGN-3 on other cell lines, such as normal and tumorbreast cells and prostate cancer cells, was also evaluated.

These findings indicate that Biobran MGN-3 acts by not only enhancing thehost immune function but also through a direct alteration of tumor cellgrowth and production of cytokines. These findings may offer a mechanismof action which could explain the high clinical success and impressivebenefits of Biobran MGN-3 treatment observed by the author over a period

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of 4 years.

Ghoneum M. (Drew Univ., USA) : The abstract of the 8th InternationalCongress on Anti-Aging & Biomedical Technolgies Conference ProceedingsManual, 2000

4. Complementary Effect in Cancer Therapy

(a) Evaluation of NK cell Activity and survival rates in multi-immuno therapies for various cancer patients

A study has been reported which was designed to determine whether ornot the administration of Biobran MGN-3 could have an apothanasia effectand improve the Quality of Life (QOL) for 205 progressive and partiallymetastasized cancer patients in stages late III-IV, after surgery.Participants in the clinical study were hospitalized patients in the SanoSurgical Clinic, Japan. They were treated with complementary alternativemedicines and conventional anticancer medicines with low side effects.

The 205 patients hospitalized for 6 months were grouped into two groups,viz. 109 patients (control group) treated with the clinic's standardcomplementary alternative medicines, and 96 patients who were inaddition given Biobran MGN-3 (Biobran MGN-3 group) for one year and ahalf.

All the patients were measured for natural killer activity as an indicationfor the variation of immunoparameter. Simultaneously, the QOL of thepatients were also checked. The NK cell activities of the patients aftersurgery were low on average, however by the administration of BiobranMGN-3, NK activity was observed to increase and the apothanasia ratioalso increased; the higher the NK activity of patient, the higher theapothanasia ratio that was observed. (Table 2) The findings indicated thatNK activity can be used as a pathological index of progressive cancers.QOL improvement was also observed on administration of Biobran MGN-3.

Table 2: Relation between total survival rate, NK activity and survivalrates in 2 groups

Group Biobran Group Control GroupTotal survival rate 52/96 (54.2%) 19/63 (33.9%NK activity categoryLess than 19.9%20%-40%More than 40%

17/40 (42.5%)**18/35 (51.4%)*17/21 (81.0%)

2/16 (12.5%)7/25 (28.0%)10/15 (66.7%)

% significant to the control group **p<0.01 *p<0.05

Takahara K. (Sano Surgical Clinic, JAPAN) : The Abstract of the 3rd AnnualMeeting of the Japanese Society for Complementary & AlternativeMedicine & treatment, 2000

(b) Immunomodulatory and Anti-Cancer Properties of BiobranMGN-3 in 5 Patients with Breast Cancer

Five patients with breast cancer were given Biobran MGN-3 at 3g/day, andtheir NK cell activities were measured by 4-hr 51Cr-release assay usingK562 tumor cells as targets. The Results showed:

i. Patients having a low level of basal NK activity (12.7-58.3%) ateffector : to target (E:T) ratios of 12 and 100:1, had their NK activitysignificantly enhanced by Biobran MGN-3 treatment (41.8-89.5%) atthe same E:T ratios.

ii. The augmentation in NK activity was detected as early as 1-2 weekspost treatment and was further increased with continuation ofadministering Biobran MGN-3.

iii. Two patients who participated early in the study (6-8 months) wentinto complete remission.

Ghoneum M. (Drew Univ., USA) : The abstract of An American Associationfor Cancer Research Special Conference, 1995

(c) NK immunomodulatory function in 27 cancer patients byBiobran MGN-3, a modified arabinoxylan from rice bran

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Biobran MGN-3 immunomodulatory function was examined in 27 cancerpatients. The patients had different types of advanced malignancies: 7patients had breast CA, 7 prostate, 8 multiple myeloma (MM), 3 leukemiaand 2 cervical CA. All patients were under treatment with conventionaltherapy and were also given 3g of Biobran MGN-3 daily, then NK activitywas examined at 2 weeks, 3 months and 6 months. Activity of NK cellswas examined by 51Cr-release assay using K562 tumor cells as targets, ateffector : taget ratios from 12:1-100:1. The results showed that:

i. Patients had a low level of basal NK activity.ii. Treatment with Biobran MGN-3 caused a remarkable increase in NK

activity after 2 weeks. The percentage of induction were as follows:breast CA 154-332%, prostatic 174-385%, leukemia 100-240%, MM100-537%, and cervical CA 100-275%.

iii. Enhancement of NK activity continue to rise at 3 months and 6months after treatment.

Ghoneum M. (Drew Univ., USA): The abstract of 87th Annual Meeting ofthe American Association for Cancer Research, 1996

(d) A case in which Biobran MGN-3 was used as a supplementaltreatment when curing metastasis from lung cancer

A case in which a favourable outcome was obtained as a result of usingBiobran MGN-3 as a supplement in treatment of a lung cancer which hadspread from the lungs to a wide area of bones is presented in this report.

The patient was a 67 year old male. In August, 1996, he had consulted adoctor because of a drastic decrease in body weight and complained ofsevere coughing and expectoration. The diagnosis was a complication oflung cancer (squamous cell carcinoma) and tuberculosis (M. tuberculosis).After preferentially treating the tuberculosis with antibiotics, treatment ofthe lung cancer by irradiation was initiated in October in parallel with thetuberculosis treatment. In December of the same year, the lower half ofhis right lung was excised, removing the tumor. After irradiationtreatment, he left hospital in January, 1997.

In June of the same year, he consulted the doctor again, complaining ofpain in the right breast. After diagnosis by bone scintigram, multipleosteo-metastasis was confirmed. The tumor had spread mainly to the ribsof the right chest, but there was also a wide dispersion to the bones ofthe entire body. From July, sustained-release morphine morphine wasadministered as analgesic. Meanwhile, administration of Biobran MGN-3was started at 3g per day from the end of May. From January, 1998, hispain decreased. While Biobran MGN-3 was continually administered, theslow-release morphine was gradually reduced and in June, the morphinewas stopped altogether. The tumor marker ICPP was 16.8ng/ml when therecurrence was confirmed and gradually reduced to 7.6ng/ml in December1997 and 6.7ng/ml in June 1998. A remarkable improvement was shown inthe bone scintigram and an obvious retraction of the tumor spread to thebones was confirmed. NK cell activity was as low as 9.0% when thedisease recurred but it gradually increased and is now maintained at ahigh level.

Sobajima T. (Hoshigaoka Kosei Nenkin Hospital, JAPAN) : The Abstract ofthe 2nd Annual Meeting of the Japanese Society for Complementary &Alternative Medicine & Treatment, 1999

(e) Applications of Biobran MGN-3 in Post Conventional Therapy

The concept of Tumor Dormancy therapy is becoming a major concept ofcancer therapy in Japan. The basic therapeutic policy is to prolong thepatient's life while maintaining a high quality of life. Dr Tunekawaperforms the therapy when this is the patient's wish and he regardsimprovement of quality of life an important therapeutic objective. Hereported that he has thirty-four cancer patients receiving a combination ofdormant chemotherapy and complementary and alternative medicine(CAM), and described the therapeutic course for three of these:

i. Patients (primary disease): Gastric cancer in 3, pulmonary cancer in3, malignant lymphoma in 2, colon (rectal) cancer in 6, breast cancerin 3 and others in 17

ii. Treatment period: 6-18 monthsiii. Case studiesiv. T.S. (60), F, gastric cancer (stage IV), cancerous peritonitis: The

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patient was operated on for scirrhous gastric cancer in January 2000.In February 2000, she developed cancerous peritonitis and underwentgastrectomy at stage IV. CA19-9 was 108. In August 2000, shevisited our clinic with complaints of abdominal pain, constipation,anemia and anorexia. CA19-9 was 390 and NK activity was 25.6. Shereceived a combination of TS1 and holistic therapy. Biobran MGN-3 3g/day was given for immune enhancement. She responded 1 monthlater with CA19-9 being 63. She showed a steady decrease in tumormarkers and increase in NK activity. In August 2001, 11 months later,CA19-9 became 25 and NK activity was 51.5. Almost no subjectivesymptoms persist and she is now well nourished.

v. F.A. (46), F, breast cancer, metastases to the lumbar vertebra anduterine body: The patient was operated on for breast cancer in July1998 and was treated with hormones and anticancer agents. She wasfound to have metastases of the lumbar vertebra in March 2001 anduterine body in April 2001, and underwent hysterectomy in May 2001.She was discharged home on Taxol and Paraplatin. In July 2001, shevisited Dr. Tunekawa with a complaint of bone pain. At that time, CAwas 153, NCC-ST was 439 and NK activity was 9.3. Paraplatin wascontinued and holistic therapy was started. Biobran MGN-3 3 g/daywas given for immune enhancement. Two months later, CA became18, NCC-ST was 28.9, NK activity was 22.0 and pain was resolved.Subsequently, she showed a steady decrease in tumor markers andincrease in NK activity. In July 2002, CA was 14, NCC-ST was 3.2, NKactivity was 59, there was no pain and bone scintigraphic findingswere less remarkable. Now she is well nourished and is enjoyingplaying the drums.

Tunekawa H. (Tokai Society for Promotion of Holistic Medicine, JAPAN):Abstract from Biobran Workshop in Berlin, 2002

(f) Assessment of Biobran MGN-3 in Treatment of ProgressiveCancer

Dr Mizukami has experience of giving Biobran MGN-3 to 97 advancedcancer patients. The kinds of cancer were stomach cancer, large intestinecancer, breast cancer, lung cancer, pancreatic cancer, liver cancer, bile ductcancer, pharyngeal cancer, ovarian cancer, glandulae cervicales uterinecancer, corpus uterine cancer, renal cancer, thyroid cancer, prostatic cancer,cancer of the oral cavity, multiple myeloma, etc. Although the patients hadalready received operations, chemotherapy, radiotherapy, etc. in largehospitals, the progress of most patients was poor. They had sufferedmetastasis and recurrences, and requested immunotherapy and visited DrMizukami's hospital. In almost all examples of Biobran MGN-3 use, neitherchemotherapy nor radiation were used at the same time. Clinicalobservation and inquiry were carried out in detail regarding the Quality ofLife (QOL) of patients taking Biobran MGN-3. Note was taken ofphenomena common to patients taking Biobran MGN-3.

There were some cases in which the QOL clearly improved after takingBiobran MGN-3. Generally, although the QOL of advanced cancer patientstends to fall in a straight line with progress of time, patients takingBiobran MGN-3 showed this tendency to a reduced extent, and had atendency to live longer with good QOL. Examples of long-term survivalwere also seen.

The following concrete observations were made concerning QOL:

i. Although control of sharp pain is not easy and morphine is used inmany cases for advanced cancer patients, some of those who tookBiobran MGN-3 did not need to use morphine. Even when morphinewas used, a tendency to use smaller quantities of morphine wasobserved.

ii. Overall a decreased tendency to feel languid was observed.iii. A decreased tendency for loss of appetite was observed.iv. A tendency to be able to stay at home and to feel good just before

death was observed.v. Retention of clear consciousness even just before death, and a

tendency to be able to talk to their family was observed.

Dr Mizukami concluded that for advanced cancer patients, the fact thatQOL does not decrease so readily when Biobran MGN-3 is taken, isimportant for future cancer medical treatment.

Mizukami O. (Health Promotion Research Institute New Life Layman

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Foundation, JAPAN) : Abstract from Biobran Workshop in Berlin, 2002

5. Effect of Apoptosis

Biobran MGN-3 sensitizes Human T cell leukemia cells to DeathReceptor (C95)-induced Apoptosis

In this study, the effect of Biobran MGN-3 on death receptor-inducedapoptosis in human leukemic HUT 78 cell line was investigated. HUT 78cells were pretreated with Biobran MGN-3 and then were incubated withagonistic antibody against death receptor (Fas, CD95). Apoptosis wasdetermined by propidium iodide technique using FACScan. Activation ofcaspase 3, caspase 8 and caspase 9 was determined by flow cytometry.Mitochonodrial membrane potential was measured with DIOC6 dye usingFACScan. Expression of CD95 and BCl-2 were measured by flow cytometry.

Biobran MGN-3 was found to enhance anti-CD95 –induced apoptosis in adose-dependent manner. Increased cell death was correlated withincreased depolarization of mitochondrial membrane potential andincreased activation of caspase 3, caspase 8 and caspase 9. Biobran MGN-3 treatment had no effect on the level of expression CD95 but it causeddown regulation of BCl-2 expression. These results suggest that BiobranMGN-3 increases the susceptibility of cancer to undergo apoptosismediated by death ligands, which may be relevant to anti-cancer activity.

Ghoneum M. (Drew Univ., USA) : Cancer Letter, 2003

6. Activation of Vital Defence

(a) Active oxygen radical scavenging by Biobran MGN-3

Investigations on scavenging of oxygen radicals by Biobran MGN-3 and itsfractionates have been reported. Biobran MGN-3 was fractionated intocomponents using a Sephadex G-25 column. Each component was namedin descending order as L (L > 10,000 molecular weight), M (10,000 > M >3,000 molecular weight), and S (3,000 molecular weight> S).

Active enzyme scavenging activity was evaluated by measuring thesuperoxide anion radical (•O2) scavenging activity, hydroxyl radicalscavenging activity of the Fenton reaction (•OH), and the scavengingactivity of the hydroxyl radical generated by ultraviolet irradiation.

The results of the measurements are shown in Table. The S (low molecularweight) fraction excelled all others in the inhibition of •OH generationcaused by •O2 and ultraviolet irradiation. High scavenging activity wasobserved in all fractions for the scavenging activity of •OH generated inthe Fenton reaction . (Table 3 )

Table 3

Scavenging Activity of Biobran MGN-3 on Active Oxygen radicals(•O2 and •OH and UV induced •OH)

Kind ofActiveOxygenandSODactivity

Scavenging ratio ofSuperoxide anionradical (%)

SOD activity (U/ml) Scavenging ratio of UVinduced Hydroxylradical (%)

20 2.0(mg/ml)

0.2 20 2.0(mg/ml)

0.2 20 2.0(mg/ml)

0.2

BioB

BioB-L

BioB-M

BioB-S

64.6

39.9

49.5

90.4

23.0

10.4

15.6

68.1

4.4

0

0

26.4

7.6

5.0

7.2

70.5

0.9

0.8

1.4

15.7

0

0

0

2.6

94.9(72.6)97.2

(41.8)97.0

(45.4)96.5(71.0

78.9(35.9)34.4

(16.5)68.4(9.9)55.1

(54.9)

3.3(11.5)

3.3(1.0)8.7

(3.9)4.2

(19.6)·O2:HPX-XOD reaction,·OH:Fenton reaction·OH by UV light reaction:365nm,4×103J/m2/min×5

Tazawa K. (Toyama Medical and Pharmaceutical Univ., JAPAN) :Biotherapy Vol.14, 2000

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(b) A basic study of arabinoxlan compound (Biobran MGN-3) onthe activation of vital defenses.

In this study, through an animal experiment, the influence of BiobranMGN-3 as regards its biophylactic activation on survival rate in thelipopolysaccharide (LPS)-induced lethal sepsis model was observed.

In the experiment, BALB/c mice (male, 5-7 weeks old) were used.20mg/kg and 200 mg/kg of Biobran MGN-3 were dissolved in 0.5ml of PBS,and via an oral zonde, administered every other day for two weeks, intotal seven times. 0.5 ml of PBS was administered orally in the sameinterval for the control group. 200μg/mouse of LPS was administeredintraperitoneally 12 hours after the final oral administration, and theconditions of the mice were observed over time. In another experiment,100 μg/mouse of LPS was administered intraperitoneally in the BiobranMGN-3 group and control group, the mice were euthanized 0, 2, 4, 8 hrafter the LPS administrations, and peripheral blood was collected from theheart. Serum was separated, and IL-6 and TNF were measured. IL-6activity was measured using the B9 cell line and TNF activity wasmeasured by bioassay in the WEHI164-13 cell line.

As shown in Figure 9, when 200 μg/mouse of LPS was administered, thesurvival rate significantly improved in groups where 20 mg/kg or 200mg/kg of Biobran MGN-3 was administered everyday, compared with thatin the control group (20 mg/kg Biobran MGN-3 group vs. control group, p =0.0456; 200 mg/kg Biobran MGN-3 group vs. control group, p = 0.0232, byMantel-Cox test). When 100 μg/mouse of LPS was administered, all themice survived in groups where 20 mg/kg or 200 mg/kg of Biobran MGN-3was administered everyday, while 3 out of 10 mice died in the controlgroup.

To establish the mechanism for improvement of the survival rate byBiobran MGN-3, blood concentrations of IL-6 and TNF were measured. Inthe experimental group where Biobran MGN-3 was administered, comparedwith the control group, the blood IL-6 level was significantly lower twohours after the administration of LPS (control group 702.9 ± 24.7 ng/ml,Biobran MGN-3 group 403.1 ± 59.6 ng/ml; p < 0.01); however, 8 hr afterthe administration, it significantly increased (control group 88.5 ± 50.0ng/ml, Biobran MGN-3 group 441.0 ± 115.0 ng/ml; p < 0.05). Meanwhile, 4hr after LPS administration, the blood TNF level significantly increased inthe Biobran MGN-3 group compared with those in the control group(control group 492 ± 187, Biobran MGN-3 group 1816 ± 307 pg/ml; p <0.01).

In the LPS-induced lethal sepsis model, multiple organ failure wasassumed to be induced by a large amount of inflammatory cytokines (IL-1,6, TNF-α) released from the reticuloendothelial system cells of the wholebody, which leads to death. In this study, significant improvement of thesurvival rate by the administration of Biobran MGN-3 was observed.Possible causes were that Biobran MGN-3 intake inhibits the production ofhistotoxic cytokines generated from macrophages or Biobran MGN-3 blocksthe route to histotoxicity at the target cell level.

Sudo N., Kubo C. (Kyushu Univ., JAPAN) : The Japanese Journal of Clinicaland Experimental Medicine, Vol.78, 1, 2001

(c) Reduction in weight loss of mice treated with Cisplatin dueto Biobran MGN-3.

In treatment of cancers platinum based drugs frequently cause substantialside effects, such as nausea, vomiting, nephropathy and hypomagesemiadue to damage of renal tubules (Lajer & Dangaard 1999). Futhermore, inaddition to hearing loss and peripheral neuropathy, myelosuppression isone of the most devastating suppressive side effects (Prestayko et al.1979) leading to immunocomopromised states. Therefore, any reducutionof the side effects of cisplatin would be worthy of achieving. To do this,the effect of Biobran MGN-3 was studied on amelioration of weight loss ofmice under tolerable maximal dose of cisplatin.

One week before cisplatin administration, Biobran MGN-3 was started tobe administered to two groups of mice at a concentration of 10mg/ml ofBiobran MGN-3 (dry weight) in water or by intraperitoneal injection in avolume of 0.1 ml at the same concentration of Biobran MGN-3 in PBS. Thedose of 1 mg of Biobran MGN-3 per mouse was calculated from that

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recommended for human usage (50mg/kg). One shot of cisplatin wasadministered intraperitoneally in a volume of 0.1 ml at the concentrationof 15mg/kg of cisplatin in PBS containing 0.5% DMSO as a vehicle. Twogroups of mice received a gavage of water or intraperitonealadministration of PBS and one week later cisplatin was administered tothe both groups.

Weight loss after intraperitoneal injection of cisplatin occurred the nextday in both groups with and without administration of Biobran MGN-3. Thegreatest weight loss was observed in both groups at the 5th day aftercisplatin treatment, with or without Biobran MGN-3 orally as well asintraperitoneally. The greatest weight loss occurred in mice given cisplatinwithout Biobran MGN-3 administration. Although loss of body weight inmice given Biobran MGN-3 appeared to be close to the 20% shown for inthe groups of cisplatin treatment without Biobran MGN-3, no mice died,nor did any show diarrhea or rectal bleeding, frequent side effects ofcisplatin. In the recovery phase, earlier weight gain took place in thegroups of mice given Biobran MGN-3 than those without it.

Figure 10

Figure 11

Endo Y., Kanbayashi H. (Mac Master Univ., CANADA) : Pharmacology andToxicology, 2003

(d) The Effect of Biobran MGN-3 on Cisplatin and AdriamycinInduced Toxicity in the Rat

Biobran MGN-3 is derived from rice bran and is produced by the partialhydrolysis of the water soluble hemicellulose fraction of rice bran bycarbohydrases derived from Lentius edodes mycelia [US Pat. 5560914].Biobran MGN-3 has been shown to be a biological response modifierproducing an increase in natural killer cell activity in immunocompromisedpatients [Int. J. Immunother. 14 (1) 1998].

Aim: To prevent gross pathological changes and weight loss produced by asingle dose of cisplatin (CIS) or adriamycin (ADR) by daily oral dosing of 5or 50mg/kg Biobran MGN-3. Following an acclimation period of 13 days,male Spraque-Dawley rats were selected for test based on body weightsand assigned (10 rats/group) to each of the following (dose stated asmg/ml):

1. Biobran 5 gm PO+Veh IP2. Biobran 50 gm PO+Veh IP3. Biobran control PO+CIS 8mg IP4. Biobran 5 gm PO+ CIS 8mg IP5. Biobran 50 gm PO+ CIS 8mg IP6. Biobran Control PO+ADR 10mg IP7. Biobran 5 gm PO+ ADR 10mg IP8. Biobran 50 gm PO+ ADR 10mg IP

Rats received oral (PO) Biobran MGN-3 (suspended in distilled water) or

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vehicle (veh) daily for 11days. The chemotherapeutic agents or veh wereadministreted to each rat by a single IP injection on Day 3. Rats wereobserved for clinical sings daily for 11 days. Body weights were recordedevery other day. On Day 11, all animals were euthanized by CO2inhalation and necropsied. Gross appearance of major organs wasevaluated and the presence of gastrointestinal damage noted.

Results: Five rats from Group 3, 3 from Group 5, and 1 from Group 4 diedbetween D7 and 11. Rats receiving Biobran MGN-3 at 5 or 50 mg/kg POshowed a statistically significant increase in body weight (+72%). Ratsreceiving CIS or ADR alone showed a smaller increase in body weight (-1.5%, CIS; +30%, ADR). Rats receiving Biobran MGN-3 at 5 or 50 mg plusCIS or ADR had a significantly greater weight gain than that observed withthe chemotherapeutic agent alone (Biobran MGN-3 5 mg in CIS treatedrats, +11% and +46% in ADR treated rats). Biobran MGN-3 50 mg in CIStreated rats, +44% and +43% in ADR treated rats.Surviving rats receivingBiobran MGN-3 appeared healthier, gained weight and had a lowerincidence of gross intestinal pathology than those taking CIS or ADRwithout Biobran MGN-3.

Table 4: Effect of Biobran on Body Weight Loss Induced by Cisplatin andDoxorubicin

Treatment (all intraperitoneal) Day 0 Day 3 Day 5 Day 7 Day 9 Day 115mg/kg PO+Vehicle50mg/kg PO+VehicleControl PO+Cp8mg/kg5mg/kg PO+Cp8mg/kg50mg/kg PO+Cp8mg/kgControl PO+Dx10mg/kg5mgn/kg PO+Dx10mg/kg50mg/kg PO+Dx10mg/kg

10010010399101103101101

100981019999100100101

100100828592889292

10097697690828987

10097556885778685

10097576584768583

PO-oral, Dx-Doxorubicin, Cp-Cisplatin

Jacoby H. I . (USA) : Journal of Nuturaceuticals, Function & Medical Foods,Vol.3 (4) 2001

(e) The effect of Biobran MGN-3 on radiation therapy inducedtoxicity in the mouse

This study, investigates the modifying effect of Biobran MGN-3 onradiosensitivity as expressed in bone-marrow death caused by total bodyirradiation. First, with possible clinical application in mind, the authorsstudied each effect quantitatively across a wide range of radiation dosagebetween 4.5 Gy and 8.5 Gy.

Four or 5-week-old SPF male BALB/c mice (F2) were the subject of theseexperiments. In the Biobran MGN-3 groups Biobran MGN-3 was added tothe food of F2 mice at 50 mg/kg body weight. There were 10-50 mice pergroup. Starting at two days after caging, the food was changed in the F2group to Biobran MGN-3 added food. Four and 5-week-old mice wereirradiated after feeding with Biobran MGN-3 for 15 days and 8 days.. Bodyweight was measured 3 times a week and the number of deaths waschecked every day. In some cases mice used in the experiment had beengiven Biobran MGN-3 for two weeks before irradiation in other casesadministration of Biobran MGN-3 was only started after irradiation.

Although in the F2 group, mortality of mice due to bone-marrow death wasobserved from the seventh day after irradiation, mice tended to die a littlelater in the Biobran MGN-3 groups. In the F2 group, LD50 wasapproximately 5.15 Gy and the dose reduction factor (DRF) wasapproximately 1.14. As for body weights, a tendency towards a heavierbody weight was maintained in the Biobran MGN-3 groups. The effect ofstarting Biobran MGN-3 administration earlier, suggested that it waspreferable for Biobran MGN-3 to be given prior to irradiation.

The irradiation dose of mice was calculated as being 1.21-fold of theabove dosages at their body center, meaning that LD50 in the controlgroup was equivalent to 6.23 Gy. Though the radioprotective effect ofBiobran was DRF = 1.14, which was not a large effect, no side effectswere observed in the present study.

Nakatugawa S. (Nagoya Univ., JAPAN) : The Report of Nagoya Univ., 2003

(f) Effect of Biobran MGN-3 on Experimental Liver Dysfunction in

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Rats

This study investigated the effect of Biobran MGN-3 on liver dysfuncution.The effect of Biobran MGN-3 on the development of experimental liverdysfunction in rats induced by galactosamine (GalN) and acetaminophen(AAP) was investigated. To develop experimental liver dysfunction, GalNwas administered in Experiments 1-3 and AAP in Experiments 4 and 5.

In Experiment 1, Biobran MGN-3 of different concentrations wasadministered intraperitoneally to the rats and after 1 hour GalN wasadministered at the rate of 800 mg/kg.

In Experiment 2, Biobran MGN-3 was administered orally, and fractionatedBiobran MGN-3 of high molecular weight and low molecular weight wasadministered intraperitoneally. After 1 hour, GalN was administered at therate of 800 mg/kg.

In Experiment 3, after being heated, hydrolysed and processed with ionexchange resin, Biobran MGN-3 was administered intraperitoneally. After1hour, GalN was administered at the rate of 800 mg/kg.

In Experiment 4, Biobran MGN-3 was administered intraperitoneally ororally, and after 1 hour, AAP was administered at the rate of 700 mg/kg.

In Experiment 5, after being heated, hydrolysed and processed with ionexchange resin, Biobran MGN-3 was administered intraperitoneally, andafter 1 hour, AAP was administered at the rate of 500 mg/kg.

In all experiments, rats were dissected 24 hours after administration ofGalN or AAP and their serum transaminase (GOT, GPT) levels weredetermined.

Results

Experiment 1: In all groups where Biobran MGN-3 was administered, theincreases of serum GOT and GPT activities due to GalN-induced liverdysfunction were significantly suppressed, compared with those in thecontrol group. The suppressing effect of Biobran MGN-3 on GalN-inducedliver dysfunction peaked at 20 mg/kg and no further change was observedwith higher concentration of Biobran MGN-3 in the suppressing effect onGalN-induced liver dysfunction.

Experiment 2: In all groups where Biobran MGN-3 or high/low molecularweight fractions of Biobran MGN-3 was administered intraperitoneally, theincreases of serum GPT activities due to GalN-induced liver dysfunctionwere significantly suppressed, compared with those in the control group.The suppressing effects was similar to those observed with Biobran MGN-3itself.

Experiment 3: In groups where hydrolyzed Biobran MGN-3 wasadministered, the increases of serum GOT activities due to GalN-inducedliver dysfunction were significantly suppressed, compared with those inthe control group.

Experiment 4: In groups of where Biobran MGN-3 was administeredintraperitoneally or orally, the increases of serum GOT activities due toAAP-induced liver dysfunction were significantly suppressed, comparedwith those in the control group.

Experiment 5: Corresponding to the results of Experiment 3, the effect ofhydrolyzed Biobran MGN-3 on AAP was assessed. In groups wherehydrolyzed Biobran MGN-3 was administered, the increase of serum GOTactivities were significantly suppressed, compared with those in thecontrol group.

Thus, Biobran MGN-3 was confirmed to have a suppressive effect on GalN-induced or AAP-induced liver dysfunction. The active constituent appearsnot to be hydrolyzed by HCl.

Yamada T. (Chiba Univ., JAPAN): The abstract of the 6th Annual Meetingof Japanese Association for Dietary Fiber Research, 2002

(g) Oral administration of Biobran MGN-3 alleviates commoncold syndrome in elderly people

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For high-risk groups such as the elderly or children, preventive measuresagainst infections, such as influenza vaccination, and drastic precautionsagainst secondary bacterial infection are important. When community-acquired pneumonias that may have developed through exacerbation ofthe common cold were investigated by age, the risk of secondary infectionby bacteria became higher in elderly people over 75 years old. The risk ofacquiring concomitant pneumonia is also high in elderly patients withneurological disorders who are at high risk of aspiration. In the elderlywhose immunocompetence declines due to various factors, the clinicalusefulness of Biobran MGN-3 against the development of the common coldwas therefore evaluated.

Elderly subjects were selected from those under the care of "AtreyuUozaki" a health care facility for the elderly in Kobe, Hyogo, betweenJanuary and March in 2002, who were not seriously ill, and who consentedto the present study. A Biobran MGN-3 fraction (HRB) was used as the testfood and rice bran containing mainly the water soluble component, wasused as the control (RB).

For the symptoms of common cold (fever, headache, fatigue, chill, cough,sputum, nasal discharge, nasal obstruction, sore throat, chest pain), thenumber of days when even a single symptom of common cold wasmanifest was counted. Each symptom was converted to scores dependingon its level (no symptom = "0", mild = "1", moderate = "2", severe = "3")and the "common cold symptom score" was calculated by dividing theaccumulated score of each subject by the number of intake days.

Results: Among individual symptoms, manifestation frequencies of"cough," "fatigue," "fever" and "sore throat" were high on starting intakeof both foods. The number of days when symptoms were manifest wasfewer in the HRB group than in the RB group. Looking at the common coldsymptom score, the RB group showed a high score in total. Although thescore for "nasal symptoms" was lower in RB group, the scores for commonsymptoms such as "cough," "fatigue" and "fever" were higher. Hence it wasconcluded that common cold symptoms were less prevalent in the HRBgroup.

This study demonstrated that when HRB was taken orally by elderlypatients with the common cold, the period of symptom manifestation wasshortened, aggravation of symptoms was halted, and the necessity forsymptomatic treatment was reduced through the extract'simmunostimulatory action.

Tazawa K. (Toyama Medical and Pharmaceutical Univ., JAPAN) : Joural ofTraditional Medicines, 20 (3), 2003

7. Anti-Allergology Effect

(a) Evaluation of the effects of asthma prevention and symptomreduction Biobran MGN-3 in model asthmatic mice

The effect of asthma prevention and symptom reduction by Biobran MGN-3has been evaluated using TDI-induced asthma model mice.

First, 2 g/litre of Biobran MGN-3 was diluted with drinking water and givendaily to the above model mice (BALB/c, female), which were divided into 4groups (A-D) as follows:

Group A: One month pre-administration of Biobran MGN-3 andadministration during TDI sensitization period and challenging period.

Group B: One month pre-administration of Biobran MGN-3 andadministration until the end of TDI sensitization period.

Group C: Administration of Biobran MGN-3 only during TDI challengingperiod.

Group D: control group.

Group B was for the assessment of preventive effect and Group C was forthe assessment of symptom reduction effect. The effect of Biobran MGN-3was evaluated by blood histamine concentrations, the number ofeosinophils in BALF, TDI earlobe application test, and blood IgG1, IgG2a,IgE-type specific antibody values at sensitization.

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Biobran and MGN-3 are both registered trademarks of Daiwa Pharmaceutical, Tokyo, Japan MGN-3 is also the generic/research name for Daiwa Pharmaceutical's arabinoxylan complex

The peak blood histamine concentrations at 7 minutes after TDI challengewere, Group A: 2.5±0.53, Group B: 4.2±0.75, Group C: 4.3±7.8, Group D:6.4±0.87 (ng/ml), and Biobran MGN-3 administration groups showedsignificantly lower values compared with the control group. In thesensitization test with various concentrations (0.01-10%) of TDI, theBiobran MGN-3 administration groups showed a reduction of sensitivity of10-100 fold compared with the control group. In addition, the BiobranMGN-3 administration groups showed a significantly lower number ofeosinophils in BALF and lower value in TDI application test. In contrast,there were no significant differences among blood antibody values.

In conclusion, the administration of Biobran MGN-3 showed obviouspreventive and symptom reducing effect of asthma in TDI-inducedasthmatic model mice. This suggests that Biobran MGN-3 does not affectthe production of IgG1 or IgE-type antibody induced by Th2 and thatBiobran MGN-3 works as a suppressive factor against mast cells.

Kobayashi H., Endo Y. (Mc Master Univ., CANADA) : The abstract of the52th Annual Meeting of Japanese Society of Allergology, 2002

(b) Inhibitory Effect of Biobran MGN-3 on the progress of AtopicDermatitis in NC mice

The immunoreglatory effects of Biobran MGN-3 on NC mice, whichnaturally develop increased serum IgE and atopic dermatitis-like skinlesions in response to sensitisation with OVA, have been investigated.Biobran MGN-3 was given orally to five NC mice with were compared to acontrol group without Biobran MGN-3. The mice were then sensitised usingOVA. Blood samples were collected biweekly before and after thesensitisation. Amounts of total IgE, as well as OVA specific IgE, in thesera measured by specific ELISA were significantly decreased in theBiobran MGN-3 treated NC mice compared to the control group.Furthermore, atopic dermatis-like skin lesions was not developed in fiveout of five Biobran MGN-3 treated NC mice, while all the NC mice notreceiving Biobran MGN-3 developed skin lesions. It was concluded thatBiobran MGN-3 has an inhibitory effect on the progression of atopicdermatitis in NC mice.

Nonoyama S. (Tokyo Medical and Dental Univ., JAPAN) : The abstract ofthe 11th Annual Meeting of International Congress of Immunology, 2001

© Copyright 2003 by Hiroaki Maeda / Daiwa Pharmaceutical(Thank you for permission to reprint this article on Biobran.org.)

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