Biobran MGN-3 - An Overview

Biobran MGN-3 was first developed in Japan in 1992 by Hiroaki Maeda, Director of Research and Development of Daiwa Pharmaceutical Co., Ltd, in Tokyo. Maeda's area of interest is in finding natural phytonutrient solutions for both human health and agriculture, and in the late 1980s, he turned his attention to polysaccharides, which have been known to have been known to strengthen immune response, and developed the immune system supplement, AHCC®.

After moving to Daiwa Pharmaceutical, headed by Yasuo Ninomiya, Maeda developed a new complex of short chain polysaccharides (primarily arabinoxylan and other hemicelluloses) which he gave the generic name MGN-3 after the initials of its developers — M-Maeda, G-Ghoneum, N-Ninomiya and "3" because it was a third generation product. (Mamdooh Ghoneum, Professor of Immunology at Drew University of Medicine and Science in Los Angeles, did much of the immunological research with the product.) Daiwa subsequently marketed this MGN-3 complex under the brand name Biobran.

General non-technical overview of Biobran MGN-3
Overview for practitioners

Q: What is Biobran MGN-3 arabinoxylan compound?

It has been well documented, for many years, that certain large polysaccharide molecules — complex carbohydrates such as plant fibre — can stimulate the immune system. Fibre in general has also been linked in research to the lowering of cholesterol, improved sugar metabolism and the reduction of intestinal toxicity; rice bran has anti-viral properties whereas certain mushroom fibre has been shown to enhance immune response. Unfortunately, plant fibres are mostly indigestible, and so these immune enhancing benefits remain mostly unrealized as the fibre passes through and out the body. However, if these very long polysaccharide molecules (specifically from rice bran) are broken up into much smaller components, called hemicelluloses — of which the most powerful are the arabinoxylan compounds — these benefits were not only greatly magnified, but they could be directly affect the body's immune system because the fibre now had a small enough molecular weight to be absorbed undigested through the small intestine into the blood system.

The leading manufacturer of this type of hemicellulose food supplement is Daiwa Pharmaceutical in Japan, which has a unique and patented process in which rice bran is broken down (partially hydrolyzed) using Shitake mushroom enzymes (lentius edodes mycelia extract) to make a unique and natural blend of hemicelluloses, the principal ingredient of which is the arabinoxylan compound or b-1, 4 xylophyronase hemicellulose. (Although Shitake mushroom enzymes are used in the manufacture, there is no measurable mushroom content in the end product and so most of those with mushroom intolerances have no reaction to it.) The diagram below shows how the basic unit or segment of the fibre has been broken down or "pruned" to produce, in this case, the hemicellulose called arabinoxylan.

The resulting blend of hemicellulose compounds from this process was generically called Biobran MGN-3 — or just Biobran for short. (Much of the research refers to it as MGN-3 which is the generic manufacturers name, although another generic name used is Modified Rice Bran - MRB). It is also referred to as Biobran arabinoxylan compound because the arabinoxylan is one of its main components. As a blend of natural compounds (hemicelluloses), Biobran consists of an array of short chain polysaccharides, which makes it much easier for the body to assimilate than single component substances (such as conventional drugs). This natural array of ingredients is also thought to be a reason for its non-toxicity and lack of unwanted side effects.

The Immune System

The immune system is the collective army of a trillion white blood cells, the bone marrow, antibodies, cytokines and the thymus gland that help to identify and destroy the millions of microbes (bacteria, viruses, parasites, fungi) that penetrate our bodies every day, and the thousands of our own cells that have become genetically abnormal or cancerous. In fact, the immune system is considered every bit as complex as our nervous system, and is not only able to produce a matching antibody for every one of the millions of different infective agents, but is able to remember how to produce these decades later.

Q: What is its effect on the body?

Biobran MGN-3 arabinoxylan compound can stimulate a weak immune system (see right) more powerfully and safely than any other agent, natural or synthetic. In fact, Mamdooh Ghoneum, Professor of Immunology at the Charles R. Drew University of Medicine and Science, has stated that Biobran is the most powerful immunomodulator he has ever tested. Although nobody yet knows the exact mechanism, it appears to be able to do this by increasing the body's production of natural cytokynes — substances such as interferons, interleukins and tumour necrosis factors, which not only help destroy rogue cells and viruses directly, but kick-start the immune system by increase the activity of the lymphocytes — B cells, T cells and especially NK (natural killer) cells. B cells focus on producing antibodies whilst the T and NK cells wander through the body directly destroying virally or bacterially infected cells, and cells that have turned cancerous. (In its lifetime, a single NK cell can kill as many as 27 cancer cells, sticking to them and then injecting lethal chemical granules that can destroy the abnormal cell in less than 5 minutes.)

When the body is stressed or in a diseased state, the immune system can become overloaded and the activity of these protector cells becomes sluggish. This is often compounded by medical treatment - such as chemotherapy in the case of cancer - which further depresses the immune system. A weak immune system is less able to prevent cancer cells and infections from taking hold and spreading in the body.

It is extremely important to both disease prevention and disease treatment, therefore, to optimize the immune system, and especially NK cell activity, as these cells, which comprise 15% of the white blood cells, are considered the "elite troops" of the immune system, and any rise in their activity can increase the chance and speed of recovery. This is why research into immunomodulators often focus on this single parameter of NK cell activity: it is easy to measure in a laboratory with a 51Cr-release assay test and it gives a good indication or "snap shot" of overall immune system strength. Most of the research papers done on Biobran, therefore, involve extensive NK cell activity testing, and it has been shown that Biobran MGN-3 can stimulate sluggish NK cell activity by as much as 300% or more.

Biobran can also increase depressed T cell and B cell activity by 250% and 200% respectively, as well as other factors of the immune system such as TNF. And it can do this without any toxicity or other adverse side effects (unlike synthetic cytokines currently used by oncologists, such as interleukin-2, which can be extremely toxic).

Below is a graph showing the increase in activity of NK cells with just two weeks on Biobran supplementation. This activity can be scientifically measured by placing blood from a patient into a vial of live cancer cells, and then using a radioactive marker to measure, after a four hour period, the percentage of these cells destroyed by the bloods NK cells. Although intake was stopped after this two week period for this experiment, you can see from the graph that the NK activity is still well above the control level a few weeks later.

In VIVO tests on human NK cell activity

Research has also shown that, provided Biobran MGN-3 is regularly included in the diet, this stimulation of the immune system need not decrease over time. This lack of a tail-off (or hyporesponsiveness) with prolonged use is extremely unusual for immunomodulatory substances and means that Biobran is always effective, even with prolonged use. NK activity usually peaks around 1 or 2 months after being on a high dose, after which it can be maintained with a smaller maintenance does (see dosages below). The speed at which this peak is reached depends on the amount taken each day.

Biobran has also recently been shown to have an anti-inflammatory effect in the body. Indeed, the head of the research department at Daiwa Pharmaceutical, Dr. Endo, first took Biobran himself for a painful rheumatoid arthritic condition in his hands, which subsequently cleared up. Apart from obvious inflammation (itis) problems in the body such as arthritis and allergies, inflammation is believed to increase the rate of cell mutation, and therefore reducing it could be helpful in minimising cancer risk.

This ability to enhance the immune system and reduce inflammation means that Biobran is an important food supplement for a variety of situations. (Please note that the majority of research has been conducted in relation to cancer, and that more research needs to be done on viral infections, bacterial infections and diabetes.)

General health maintenance — Even in healthy people, Biobran MGN-3 helps to strengthen the immune system by increasing the activity of the white blood cells. This, in turn, increases immunity by enhancing the body's ability to destroy infections and abnormal cells before they have a chance to spread. For those that are unwell, Biobran can help speed up recovery by increasing immune function.

Cancer — When used in conjuction with a good treatment program, Biobran can help the body increase its own survival chances by boosting white blood cell activity and promoting the rejection of abnormal cells. Also, it can improve the quality of life for those who are on chemotherapy and hormone therapy due to it ability to alleviate the side effects of the drugs used in these treatments. (Nausea and hair loss, for example, are often reduced.) Cancers of the blood, such as leukaemia and multiple myeloma show the greatest benefit, whilst good results have been seen in other cancers like lymphoma, ovarian, prostate and breast cancer (see clinical research for more detailed research results). It is important to note that Biobran itself is NOT a cancer treatment, but a useful adjuct or addition to a cancer treatment program supervised by a qualified practitioner. Proper treatments can dramatically reduce the load of cancer cells in the body (a process called debulking) whilst the Biobran MGN-3 can help the immune system manage the remainder. (Most of the research into the benefits of Biobran arabinoxylan on cancers have been carried out in conjunction with conventional cancer treatments.)

Viral infections such as HIV, AIDS and hepatitis B & C — Biobran has the ability to improve immunological parameters in patients with these conditions (such as Interferon-Gamma production, GOT, GPT and Gamma GPT). In vitro research shows that it can inhibit the replication of the HIV virus without toxicity. Once again, Biobran is not a treatment in itself, but a useful adjuct to a treatment program supervised by a qualified practitioner. (Biobran has had very limited success with Chronic Fatigue Syndrome, indicating that this condition is likely to be much more complex than a straightforward viral infection.)

Bacterial infections such a colds, fevers and food poisoning — Biobran can help speed recovery alongside conventional treatments by strengthening the immune system. (Most of the evidence that Biobran can help with bacterial infections is anecdotal, although it is consistent with the activity of a stimulated immune system.)

Diabetes — Biobran has the ability to improve glucose tolerance — although it is NOT a substitute for insulin or for glucose monitoring. This is definitely an area that needs further research.

Inflammatory Conditions — Biobran reduces the inflammatory response in the body, helping to bring symptomatic relief for a variety of inflammatory conditions including arthritis. It does this by suppressing the infiltration of leukocytes, especially neutrophiles, into inflamed tissue. So far, there have been no human clinical trials on this ability of Biobran. Recent research has also indicated that there is a strong link between an excessive inflammation response in the body and abnormal cell growth.

Allergies — Similar to the above, by reducing the inflammatory response, Biobran has the ability to reduce the symptoms of allergies. It does this by suppressing the degranulation of mast cells, the storehouses of histamine which causes the symptoms of allergy.

Q: Is any of this backed up by clinical research?

Unlike with most natural supplements, there has been very encouraging clinical research (see clinical research), including many human trials, carried out on Biobran MGN-3 arabinoxylan, much of which have been published in peer-reviewed medical journals. This research has taken place at UCLA/DREW University in the United States, at some clinics and hospitals in Europe, and various universities and medical research institutions in Japan, including Chiba University, Kobe Women's College, Jichi Medical School, Nippon University, Kyushu University, Nagoya University, Kyoto University, Toyama Medical University and Kawasaki Medical University.

Dr.Mamdooh Ghoneum The main researcher on Biobran has been Dr. Mamdooh Ghoneum, a professor at the Department of Immunology at Drew University of Medicine and Science in the United States. Dr. Ghoneum, now an internationally recognized authority on cancer immune therapy, received his Ph.D. at the University of Tokyo in radioimmunology and did his postdoctoral work at UCLA in immunology. Over the last 20 years he has been researching various substances that can enhance the immune system, but says that "Biobran MGN-3 is the most powerful immune complex I have ever tested!" So impressed was he with the results that he has now devoted his entire research efforts to treatments with this compound.

Although the research on the immunological response to Biobran arabinoxylan compound has been very positive for a variety of diseases, ranging from cancer and diabetes to viral infections such as AIDS and hepatitis B & C, there is a clear need for larger clinical in vivo research, including double-blind trials, to determine exactly how increases in immune response (especially NK cell activity) translate into actual recovery and survival statistics for the various disease states mentioned.

Q: Does Biobran have any toxicity or side effects?

No. Biobran arabinoxylan compound is a natural product that has no adverse or toxic side-effects, confirmed by blood tests and examinations of liver and kidney function of people who have taken high amounts of the compound over several months. The only obvious contraindication is that, as an immunomodulator, able to boost weak immune systems, it should not be taken in conjunction with any medication specifically for suppressing the immune system.

And, although mushroom enzymes are used in Biobran's manufacture, there is no mushroom content in the final product, which means that nearly all those with mushroom intolerances have been able to take it without an allergic reaction. This compound has also been authorized by the Japan Health Food and Nutrition Food Association, and has passed strict evaluation standards set under the guidance of the Ministry of Health and Welfare.

Q: How much Biobran should I take and when?

As the body does not build up a resistance to Biobran over time, this food supplement can safely and effectively be taken over an extended period of time, and without the necessity of slowly increasing the dosage as with other immunomodulators.

Most research into Biobran has been conducted using 30 to 45mg/kg/day in a divided dose with meals, with maintenance doses down to 15mg/kg/day. A dosage of at least 500mg a day should be taken for general health maintenance (unless potentised with yeast); for more serious immune support (such as in the case of arthritis, diabetes, hepatitis B, hepatitis C and other infections) the recommended dosage should be 1000mg a day; and for serious conditions where the immune system is severely compromised (such as with cancer or AIDS) 3g per day is recommended for 1 month and then 1g per day thereafter.

Biobran should always be taken after food (ideally, 30 minutes after) and larger daily intakes should be divided into three portions and taken with breakfast, lunch and dinner. If the person taking the compound is very ill, they can stay on the 3g per day intake for an extended period.

Apart from the case of general health maintenance, we always recommend that your doctor be informed that you are taking this supplement, so that he or she can integrate it into your treatment program. intake for an extended period.

Scientific Studies on the Effectiveness and Mechanism of Biobran MGN-3

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

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BioBran - Rice Bran Arabinoxylan Compound

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1. INTRODUCTION

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

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

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

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

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

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

Chemical structure of BioBran MGN-3 Arabinoxylan

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

3.PHYSIOLOGICAL ACTIVITY OF RICE BRAN ARABINOXYLAN DERIVATIVE (Biobran)

3.1 Immuno Regulation

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

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

Concentration of MGN-3 in vitro

2. In vivo test (rat)
Biobran MGN-3 was given orally to Sprague-Dawly rats and after two weeks the change of NK cell activity was measured. Rats were divided into three groups with doses of 0.5 mg, 5 mg and 50 mg/kg/day, with five rats per group. NK cell activities increased dose-dependently with the administration of Biobran MGN-3. Compared with the control group, the activities increased by 119%, 130% and 142% for the 0.5 mg, 5 mg and 50 mg dose groups, respectively. In the 50 mg dose group, the activity increased by 132% compared with the control group within three days of the dose initiation. The increase of NK cell activities by Biobran MGN-3 could be attributed to the increased dissolving power of NK cells but also depended on the number of NK cells. Some difference in effect was observed between male and female rats, and the manifestation of the effect was more remarkable in female rats (Figure 3).

Concentration of MGN-3 in vivo

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

Figure 4: Time and dosage dependence of natural killer (NK) cell activation by Biobran MGN-3 against K562 tumour cells

<Figure 4: Time and dosage dependence of natural killer (NK) cell activation by Biobran MGN-3 against K562 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 cytotoxic granules increases in NK cells stimulated by Biobran MGN-3. The increase of binding ability to target cells was also investigated. NK cells of a human who took 45 mg/kg/day of Biobran MGN-3 for 30 days were incubated with K-562, which were the target cells, and the increase of the binding ability was measured. After NK cells and K-562 tumor cells were incubated at 4ºC for one hour, 200 NK cells were measured and the binding rate with K-562 was calculated. The binding rate of NK cells to the target cells (K-562) in a subject who took Biobran MGN-3 significantly increased to 38.5% compared with 9.4% before intake (Figure 5). The typical photograph that indicates binding is shown in Figure 6.

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

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 cell activity

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

Using Murine macrophage cell line RAW264.7, Biobran MGN-3 showed strong activity on the three mediators at concentrations greater than 10µg/ml, as did LPS.
Murine peritoneal macrophages(C3H/He). The effect of Biobran MGN-3 against the macrophage originating from peritoneal cavity of normal mouse is showed in Figure 7. Again Biobran MGN-3 showed strong activity at concentrations above 10µg/ml.
Human macrophage cell line U937. Biobran MGN-3 induced strong activity 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 activating either normal mouse or human macrophage. The studies suggested active concentrations 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 workers exposed to various chemicals common in the workplace. A study was designed to examine the immune alteration associated with exposure to toxic chemicals and the possibility of counteracting chemical toxicity using Biobran MGN-3.

Eleven individuals who had been exposed to chemicals in the workplace participated in the study. The participants demonstrated immune dysfunction 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 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 at two 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 International Congress on Anti-Aging & Biomedical Technolgies Conference Proceedings Manual, 1999

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

The mechanism by which Biobran MGN-3 elevates NK cytotoxic activity has been investigated. This was done by testing the action of Biobran MGN-3 on 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 at concentrations of 0.1 mg/ml and 1 mg/ml, and supernatants were subjected to enzyme-linked immunosorbent assay. Results showed that Biobran 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/ml increased TNF-α production by 22.8- and 47.1-fold, respectively. Biobran MGN-3 also increased production of IFN-γ but at lower levels as compared to TNF-α. With respect to key cell surface receptors, Biobran MGN-3 increased the expression of CD69, an early activation antigen at 16 hours after treatment. Furthermore, the interleukin-2 receptor CD25 and the adhesion molecule ICAM-1 (CD54) were up-regulated after treatment with Biobran MGN-3. Treating highly purified NK cells with Biobran MGN-3 also resulted in increased levels of TNF-α and IFN-γ secretion in conjunction with augmentation of NK cell cytotoxic function. Furthermore, addition of Biobran MGN-3 to interleukin-2-activated NK cells resulted in a synergistic induction of TNF-α and IFN-γ secretion.

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

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

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

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

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

3.2. 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, the inhibitory action against the production of the HIV-1 p24 antigen was evaluated. Mononuclear cells collected from three healthy subjects were incubated with the HIV-1 SF strain at 37ºC for one hour in the presence of Biobran MGN-3. The Biobran MGN-3 concentrations were 0-100 μg/ml. Biobran MGN-3 concentration-dependently inhibited the production of the HIV-1 p24 antigen (Figure 8).

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

Figure 8: BioBran MGN-3 Concentration (mcg/ml)

Table 1

Inhibition of Syncytia Formation by Biobran
Biobran dosage (μg/ml)	Syncytia formation (SF)
	No. of SF	% Inhibition
0 12.5 25 50 100	42.0±8 25.8±7 21.5±5 15.8±4 10.5±3	00.0 38.5 50.0 62.5 75.0

Figure 8

Ghoneum M. (Drew Univ., USA):Biochemical and Biophysical Research Communications 243, (1998)

3.3. Anti-Tumor Effect

(a) Study on the growth inhibiting component of cancerous cells in culture cell lines derived from modified rice-bran arabinoxylan

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

After precipitation with ethanol, the precipitate was mixed with distilled water and the supernatant was fractionated using Sephadex G-25 column. It was fractionated into 3 fractions (A,B,C) which were added to the culture cell lines. Growth inhibiting effects were observed with C fraction for HL60 and K562 and with B and C fractions for HLE. In addition, from Giemsa stain and nonspecific esterase stain, potential differentiation-induction was indicated for HL60 and K562. These results indicate that Biobran MGN-3 has components which show growth inhibition of cancerous cells and the potential differentiation-induction for HL60 and K562.

Masada M. (Chiba Univ., JAPAN) : The abstract of the 2002 Annual Meeting of the Japan Society for Bioscience, Biotechnology and Agrochemistry

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

The direct effect of Biobran MGN-3 on skin cancer cell growth and cytokine production 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) as compared to control SCC13 cells grown in a MEM media alone, which continued to increase in cell number.

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

These findings indicate that Biobran MGN-3 acts by not only enhancing the host immune function but also through a direct alteration of tumor cell growth and production of cytokines. These findings may offer a mechanism of action which could explain the high clinical success and impressive benefits of Biobran MGN-3 treatment observed by the author over a period of 4 years.

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

3.4. 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 or not the administration of Biobran MGN-3 could have an apothanasia effect and improve the Quality of Life (QOL) for 205 progressive and partially metastasized cancer patients in stages late III-IV, after surgery. Participants in the clinical study were hospitalized patients in the Sano Surgical Clinic, Japan. They were treated with complementary alternative medicines 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 standard complementary alternative medicines, and 96 patients who were in addition given Biobran MGN-3 (Biobran MGN-3 group) for one year and a half.

All the patients were measured for natural killer activity as an indication for the variation of immunoparameter. Simultaneously, the QOL of the patients were also checked. The NK cell activities of the patients after surgery were low on average, however by the administration of Biobran MGN-3, NK activity was observed to increase and the apothanasia ratio also increased; the higher the NK activity of patient, the higher the apothanasia ratio that was observed. (Table 2) The findings indicated that NK 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 survival rates in 2 groups

Group	Biobran Group	Control Group
Total survival rate	52/96 (54.2%)	19/63 (33.9%)
NK activity category Less 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 Annual Meeting of the Japanese Society for Complementary & Alternative Medicine & treatment, 2000

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

Five patients with breast cancer were given Biobran MGN-3 at 3g/day, and their NK cell activities were measured by 4-hr 51Cr-release assay using K562 tumor cells as targets. The Results showed:

Patients having a low level of basal NK activity (12.7-58.3%) at effector : to target (E:T) ratios of 12 and 100:1, had their NK activity significantly enhanced by Biobran MGN-3 treatment (41.8-89.5%) at the same E:T ratios.
The augmentation in NK activity was detected as early as 1-2 weeks post treatment and was further increased with continuation of administering Biobran MGN-3.
Two patients who participated early in the study (6-8 months) went into complete remission.

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

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

A case in which a favourable outcome was obtained as a result of using Biobran MGN-3 as a supplement in treatment of a lung cancer which had spread 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 a doctor because of a drastic decrease in body weight and complained of severe coughing and expectoration. The diagnosis was a complication of lung cancer (squamous cell carcinoma) and tuberculosis (M. tuberculosis). After preferentially treating the tuberculosis with antibiotics, treatment of the lung cancer by irradiation was initiated in October in parallel with the tuberculosis treatment. In December of the same year, the lower half of his right lung was excised, removing the tumor. After irradiation treatment, he left hospital in January, 1997.

In June of the same year, he consulted the doctor again, complaining of pain in the right breast. After diagnosis by bone scintigram, multiple osteo-metastasis was confirmed. The tumor had spread mainly to the ribs of the right chest, but there was also a wide dispersion to the bones of the entire body. From July, sustained-release morphine morphine was administered as analgesic. Meanwhile, administration of Biobran MGN-3 was started at 3g per day from the end of May. From January, 1998, his pain decreased. While Biobran MGN-3 was continually administered, the slow-release morphine was gradually reduced and in June, the morphine was stopped altogether. The tumor marker ICPP was 16.8ng/ml when the recurrence was confirmed and gradually reduced to 7.6ng/ml in December 1997 and 6.7ng/ml in June 1998. A remarkable improvement was shown in the bone scintigram and an obvious retraction of the tumor spread to the bones was confirmed. NK cell activity was as low as 9.0% when the disease recurred but it gradually increased and is now maintained at a high level.

Sobajima T. (Hoshigaoka Kosei Nenkin Hospital, JAPAN) : The Abstract of the 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 of cancer therapy in Japan. The basic therapeutic policy is to prolong the patient's life while maintaining a high quality of life. Dr Tunekawa performs the therapy when this is the patient's wish and he regards improvement of quality of life an important therapeutic objective. He reported that he has thirty-four cancer patients receiving a combination of dormant chemotherapy and complementary and alternative medicine (CAM), and described the therapeutic course for three of these:

Patients (primary disease): Gastric cancer in 3, pulmonary cancer in 3, malignant lymphoma in 2, colon (rectal) cancer in 6, breast cancer in 3 and others in 17
Treatment period: 6-18 months
Case studies
T.S. (60), F, gastric cancer (stage IV), cancerous peritonitis: The patient was operated on for scirrhous gastric cancer in January 2000. In February 2000, she developed cancerous peritonitis and underwent gastrectomy at stage IV. CA19-9 was 108. In August 2000, she visited our clinic with complaints of abdominal pain, constipation, anemia and anorexia. CA19-9 was 390 and NK activity was 25.6. She received a combination of TS1 and holistic therapy. Biobran MGN-3 3 g/day was given for immune enhancement. She responded 1 month later with CA19-9 being 63. She showed a steady decrease in tumor markers and increase in NK activity. In August 2001, 11 months later, CA19-9 became 25 and NK activity was 51.5. Almost no subjective symptoms persist and she is now well nourished.
F.A. (46), F, breast cancer, metastases to the lumbar vertebra and uterine body: The patient was operated on for breast cancer in July 1998 and was treated with hormones and anticancer agents. She was found to have metastases of the lumbar vertebra in March 2001 and uterine body in April 2001, and underwent hysterectomy in May 2001. She was discharged home on Taxol and Paraplatin. In July 2001, she visited Dr. Tunekawa with a complaint of bone pain. At that time, CA was 153, NCC-ST was 439 and NK activity was 9.3. Paraplatin was continued and holistic therapy was started. Biobran MGN-3 3 g/day was given for immune enhancement. Two months later, CA became 18, NCC-ST was 28.9, NK activity was 22.0 and pain was resolved. Subsequently, she showed a steady decrease in tumor markers and increase in NK activity. In July 2002, CA was 14, NCC-ST was 3.2, NK activity was 59, there was no pain and bone scintigraphic findings were less remarkable. Now she is well nourished and is enjoying playing 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 Progressive Cancer

Dr Mizukami has experience of giving Biobran MGN-3 to 97 advanced cancer patients. The kinds of cancer were stomach cancer, large intestine cancer, breast cancer, lung cancer, pancreatic cancer, liver cancer, bile duct cancer, pharyngeal cancer, ovarian cancer, glandulae cervicales uterine cancer, corpus uterine cancer, renal cancer, thyroid cancer, prostatic cancer, cancer of the oral cavity, multiple myeloma, etc. Although the patients had already received operations, chemotherapy, radiotherapy, etc. in large hospitals, the progress of most patients was poor. They had suffered metastasis and recurrences, and requested immunotherapy and visited Dr Mizukami's hospital. In almost all examples of Biobran MGN-3 use, neither chemotherapy nor radiation were used at the same time. Clinical observation and inquiry were carried out in detail regarding the Quality of Life (QOL) of patients taking Biobran MGN-3. Note was taken of phenomena common to patients taking Biobran MGN-3.

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

The following concrete observations were made concerning QOL:

Although control of sharp pain is not easy and morphine is used in many cases for advanced cancer patients, some of those who took Biobran MGN-3 did not need to use morphine. Even when morphine was used, a tendency to use smaller quantities of morphine was observed.
Overall a decreased tendency to feel languid was observed.
A decreased tendency for loss of appetite was observed.
A tendency to be able to stay at home and to feel good just before death was observed.
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 that QOL does not decrease so readily when Biobran MGN-3 is taken, is important for future cancer medical treatment.

Mizukami O. (Health Promotion Research Institute New Life Layman Foundation, JAPAN) : Abstract from Biobran Workshop in Berlin, 2002

3.5. Effect of Apoptosis

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

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

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

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

3.6. Activation of Vital Defence

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

Investigations on scavenging of oxygen radicals by Biobran MGN-3 and its fractionates have been reported. Biobran MGN-3 was fractionated into components using a Sephadex G-25 column. Each component was named in 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 the superoxide anion radical (•O2) scavenging activity, hydroxyl radical scavenging activity of the Fenton reaction (•OH), and the scavenging activity of the hydroxyl radical generated by ultraviolet irradiation.

The results of the measurements are shown in Table. The S (low molecular weight) fraction excelled all others in the inhibition of •OH generation caused by •O2 and ultraviolet irradiation. High scavenging activity was observed in all fractions for the scavenging activity of •OH generated in the Fenton reaction . (Table 3 )

Table 3

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

Kind of Active Oxygen and SOD activity	Scavenging ratio of Superoxide anion radical (%)			SOD activity (U/ml)			Scavenging ratio of UV induced Hydroxyl radical (%)
Kind of Active Oxygen and SOD activity	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

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

In this study, through an animal experiment, the influence of Biobran MGN-3 as regards its biophylactic activation on survival rate in the lipopolysaccharide (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, in total seven times. 0.5 ml of PBS was administered orally in the same interval for the control group. 200μg/mouse of LPS was administered intraperitoneally 12 hours after the final oral administration, and the conditions of the mice were observed over time. In another experiment, 100 μg/mouse of LPS was administered intraperitoneally in the Biobran MGN-3 group and control group, the mice were euthanized 0, 2, 4, 8 hr after the LPS administrations, and peripheral blood was collected from the heart. Serum was separated, and IL-6 and TNF were measured. IL-6 activity was measured using the B9 cell line and TNF activity was measured by bioassay in the WEHI164-13 cell line.

As shown in Figure 9, when 200 μg/mouse of LPS was administered, the survival rate significantly improved in groups where 20 mg/kg or 200 mg/kg of Biobran MGN-3 was administered everyday, compared with that in 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, by Mantel-Cox test). When 100 μg/mouse of LPS was administered, all the mice survived in groups where 20 mg/kg or 200 mg/kg of Biobran MGN-3 was administered everyday, while 3 out of 10 mice died in the control group.

To establish the mechanism for improvement of the survival rate by Biobran MGN-3, blood concentrations of IL-6 and TNF were measured. In the experimental group where Biobran MGN-3 was administered, compared with the control group, the blood IL-6 level was significantly lower two hours 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 after the administration, it significantly increased (control group 88.5 ± 50.0 ng/ml, Biobran MGN-3 group 441.0 ± 115.0 ng/ml; p < 0.05). Meanwhile, 4 hr after LPS administration, the blood TNF level significantly increased in the 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 was assumed to be induced by a large amount of inflammatory cytokines (IL-1, 6, TNF-α) released from the reticuloendothelial system cells of the whole body, which leads to death. In this study, significant improvement of the survival rate by the administration of Biobran MGN-3 was observed. Possible causes were that Biobran MGN-3 intake inhibits the production of histotoxic cytokines generated from macrophages or Biobran MGN-3 blocks the route to histotoxicity at the target cell level.

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

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

In treatment of cancers platinum based drugs frequently cause substantial side effects, such as nausea, vomiting, nephropathy and hypomagesemia due to damage of renal tubules (Lajer & Dangaard 1999). Futhermore, in addition to hearing loss and peripheral neuropathy, myelosuppression is one of the most devastating suppressive side effects (Prestayko et al. 1979) leading to immunocomopromised states. Therefore, any reducution of 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 of mice under tolerable maximal dose of cisplatin.

One week before cisplatin administration, Biobran MGN-3 was started to be administered to two groups of mice at a concentration of 10mg/ml of Biobran MGN-3 (dry weight) in water or by intraperitoneal injection in a volume of 0.1 ml at the same concentration of Biobran MGN-3 in PBS. The dose of 1 mg of Biobran MGN-3 per mouse was calculated from that recommended for human usage (50mg/kg). One shot of cisplatin was administered intraperitoneally in a volume of 0.1 ml at the concentration of 15mg/kg of cisplatin in PBS containing 0.5% DMSO as a vehicle. Two groups of mice received a gavage of water or intraperitoneal administration of PBS and one week later cisplatin was administered to the both groups.

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

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

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

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

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

Biobran 5 gm PO+Veh IP
Biobran 50 gm PO+Veh IP
Biobran control PO+CIS 8mg IP
Biobran 5 gm PO+ CIS 8mg IP
Biobran 50 gm PO+ CIS 8mg IP
Biobran Control PO+ADR 10mg IP
Biobran 5 gm PO+ ADR 10mg IP
Biobran 50 gm PO+ ADR 10mg IP

Rats received oral (PO) Biobran MGN-3 (suspended in distilled water) or vehicle (veh) daily for 11days. The chemotherapeutic agents or veh were administreted to each rat by a single IP injection on Day 3. Rats were observed for clinical sings daily for 11 days. Body weights were recorded every other day. On Day 11, all animals were euthanized by CO2 inhalation and necropsied. Gross appearance of major organs was evaluated and the presence of gastrointestinal damage noted.

Results: Five rats from Group 3, 3 from Group 5, and 1 from Group 4 died between D7 and 11. Rats receiving Biobran MGN-3 at 5 or 50 mg/kg PO showed a statistically significant increase in body weight (+72%). Rats receiving 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 plus CIS or ADR had a significantly greater weight gain than that observed with the chemotherapeutic agent alone (Biobran MGN-3 5 mg in CIS treated rats, +11% and +46% in ADR treated rats). Biobran MGN-3 50 mg in CIS treated rats, +44% and +43% in ADR treated rats.Surviving rats receiving Biobran MGN-3 appeared healthier, gained weight and had a lower incidence of gross intestinal pathology than those taking CIS or ADR without Biobran MGN-3.

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

Treatment (all intraperitoneal)	Day 0	Day 3	Day 5	Day 7	Day 9	Day 11
5mg/kg PO+Vehicle 50mg/kg PO+Vehicle Control PO+Cp8mg/kg 5mg/kg PO+Cp8mg/kg 50mg/kg PO+Cp8mg/kg Control PO+Dx10mg/kg 5mgn/kg PO+Dx10mg/kg 50mg/kg PO+Dx10mg/kg	100 100 103 99 101 103 101 101	100 98 101 99 99 100 100 101	100 100 82 85 92 88 92 92	100 97 69 76 90 82 89 87	100 97 55 68 85 77 86 85	100 97 57 65 84 76 85 83

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 induced toxicity in the mouse

This study, investigates the modifying effect of Biobran MGN-3 on radiosensitivity as expressed in bone-marrow death caused by total body irradiation. First, with possible clinical application in mind, the authors studied each effect quantitatively across a wide range of radiation dosage between 4.5 Gy and 8.5 Gy.

Four or 5-week-old SPF male BALB/c mice (F2) were the subject of these experiments. In the Biobran MGN-3 groups Biobran MGN-3 was added to the food of F2 mice at 50 mg/kg body weight. There were 10-50 mice per group. Starting at two days after caging, the food was changed in the F2 group to Biobran MGN-3 added food. Four and 5-week-old mice were irradiated after feeding with Biobran MGN-3 for 15 days and 8 days.. Body weight was measured 3 times a week and the number of deaths was checked every day. In some cases mice used in the experiment had been given Biobran MGN-3 for two weeks before irradiation in other cases administration of Biobran MGN-3 was only started after irradiation.

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

The irradiation dose of mice was calculated as being 1.21-fold of the above dosages at their body center, meaning that LD50 in the control group was equivalent to 6.23 Gy. Though the radioprotective effect of Biobran was DRF = 1.14, which was not a large effect, no side effects were 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 Rats

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

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

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

In Experiment 3, after being heated, hydrolysed and processed with ion exchange resin, Biobran MGN-3 was administered intraperitoneally. After 1hour, GalN was administered at the rate of 800 mg/kg.

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

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

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

Results

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

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

Experiment 3: In groups where hydrolyzed Biobran MGN-3 was administered, the increases of serum GOT activities due to GalN-induced liver dysfunction were significantly suppressed, compared with those in the control group.

Experiment 4: In groups of where Biobran MGN-3 was administered intraperitoneally or orally, the increases of serum GOT activities due to AAP-induced liver dysfunction were significantly suppressed, compared with those in the control group.

Experiment 5: Corresponding to the results of Experiment 3, the effect of hydrolyzed Biobran MGN-3 on AAP was assessed. In groups where hydrolyzed Biobran MGN-3 was administered, the increase of serum GOT activities were significantly suppressed, compared with those in the control group.

Thus, Biobran MGN-3 was confirmed to have a suppressive effect on GalN-induced or AAP-induced liver dysfunction. The active constituent appears not to be hydrolyzed by HCl.

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

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

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

Elderly subjects were selected from those under the care of "Atreyu Uozaki" a health care facility for the elderly in Kobe, Hyogo, between January and March in 2002, who were not seriously ill, and who consented to the present study. A Biobran MGN-3 fraction (HRB) was used as the test food and rice bran containing mainly the water soluble component, was used as the control (RB).

For the symptoms of common cold (fever, headache, fatigue, chill, cough, sputum, nasal discharge, nasal obstruction, sore throat, chest pain), the number of days when even a single symptom of common cold was manifest was counted. Each symptom was converted to scores depending on its level (no symptom = "0", mild = "1", moderate = "2", severe = "3") and the "common cold symptom score" was calculated by dividing the accumulated 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 intake of both foods. The number of days when symptoms were manifest was fewer in the HRB group than in the RB group. Looking at the common cold symptom score, the RB group showed a high score in total. Although the score for "nasal symptoms" was lower in RB group, the scores for common symptoms such as "cough," "fatigue" and "fever" were higher. Hence it was concluded that common cold symptoms were less prevalent in the HRB group.

This study demonstrated that when HRB was taken orally by elderly patients with the common cold, the period of symptom manifestation was shortened, aggravation of symptoms was halted, and the necessity for symptomatic treatment was reduced through the extract's immunostimulatory action.

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

3.7. Anti-Allergology Effect

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

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

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

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

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

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

Group D: control group.

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

The peak blood histamine concentrations at 7 minutes after TDI challenge were, 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 showed significantly lower values compared with the control group. In the sensitization test with various concentrations (0.01-10%) of TDI, the Biobran MGN-3 administration groups showed a reduction of sensitivity of 10-100 fold compared with the control group. In addition, the Biobran MGN-3 administration groups showed a significantly lower number of eosinophils 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 obvious preventive and symptom reducing effect of asthma in TDI-induced asthmatic model mice. This suggests that Biobran MGN-3 does not affect the production of IgG1 or IgE-type antibody induced by Th2 and that Biobran MGN-3 works as a suppressive factor against mast cells.

Kobayashi H., Endo Y. (Mc Master Univ., CANADA) : The abstract of the 52th Annual Meeting of Japanese Society of Allergology, 2002

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

The immunoreglatory effects of Biobran MGN-3 on NC mice, which naturally develop increased serum IgE and atopic dermatitis-like skin lesions in response to sensitisation with OVA, have been investigated. Biobran MGN-3 was given orally to five NC mice with were compared to a control group without Biobran MGN-3. The mice were then sensitised using OVA. Blood samples were collected biweekly before and after the sensitisation. Amounts of total IgE, as well as OVA specific IgE, in the sera measured by specific ELISA were significantly decreased in the Biobran MGN-3 treated NC mice compared to the control group. Furthermore, atopic dermatis-like skin lesions was not developed in five out of five Biobran MGN-3 treated NC mice, while all the NC mice not receiving Biobran MGN-3 developed skin lesions. It was concluded that Biobran MGN-3 has an inhibitory effect on the progression of atopic dermatitis in NC mice.

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

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