Immune System of Human Body

The condition of the body is maintained at a constant level by modulating body temperature and blood pressure, to cope with changes in the environment inside and outside the body. This mechanism is called homeostasis. In homeostasis, the innate immune system plays an important role: it eliminates foreign substances (non-self) such as pathogens, viruses and cancer cells. However, it is known that immune function deteriorates with aging, and is impaired or stimulated by a poor lifestyle such as smoking, insufficient physical exertion or an unbalanced diet, and by adverse environmental changes and pollution. Deterioration of immune function causes or aggravates infection and malignant tumors, while excessive elevation of the immune system may cause things such as hay fever, atopic dermatitis or chronic inflammation. Studies in recent years have clarified that fiber and indigestive components in food are deeply involved in the maintenance of homeostasis and immune responsiveness.



BioBran is a functional food manufactured using a water-soluble rice bran dietary fiber component (hemicellulose B). Collaborative research with Prof. Mamdooh Ghoneum Ph.D. at the University of California, Los Angeles, USA (UCLA/Drew University of Medicine) on rice bran dietary fiber components has led to the discovery and establishment of processing and manufacturing methods of a food that optimally modulates the innate immune function of the body. It was subsequently demonstrated that BioBran has not only an immunostimulatory effect but also an immunomodulating effect. Extensive efforts to maximize its stability and taste have resulted in BioBran rice bran arabinoxylan. Currently, BioBran is widely used not only in Japan but also in more than 50 countries worldwide, and has an excellent reputation.
Patent No.5358219.

Daiwa Pharmaceutical Co., Ltd. has focused on a dietary fiber thought to have the potential to impact the immune response and developed a multifunctional food closely related to the Japanese foodstuff of ancient times, named BioBran (Rice Bran Arabinoxylan Compound).


Manufacturing Process




Characteristics

BioBran is a functional food produced by water-soluble dietary fiber (hemicellulose B) with an enzyme derived from shiitake mushrooms.

Suggested daily dose
1-3g/day

Property
Easy soluble in water and heat-stable

Mechanism of Action

Starch, dietary fiber, and BioBran are classified as polysaccharides. 
Starch is digested by saliva, pancreatic juice, and intestinal juice, and is absorbed in the small intestine as glucose. Dietary fiber is not digested, and is excreted unchanged. BioBran is known to be partly absorbed directly in the digestive tract, entering the blood stream.It activates the Natural Killer Cells, T cells, B cells, and macrophages, either directly in the blood, or indirectly via the Peyer's patch of the ileum, BioBran plays an important role in immunomodulation (immunostimulation, anti-inflammation, anti-allergy, antioxidation processes). Overall, it is considered to enhance the body's natural healing abilities, alleviate the adverse drug reactions of chemotherapeutic agents, and improve quality of life.







Usefulness as a functional food

1. Immunomodulatory action

(1) Immunostimulating action

▶Response of human NK cell activation to dose of BioBran
▶NK cell activation in cancer patients following BioBran intake
▶Stimulation of lymphocyte transformation
▶Promotion of differentiation of dendritic cells
▶Anticancer effect of BioBran

(2) Anti-inflammatory action

▶Influence on liver damage

2. Combination therapy with a chemotherapeutic agent

▶BioBran in combination with a chemotherapeutic agent

3. Improvement of quality of life

▶Effect of BioBran on survival and quality of life improvement in patients with progressive cancer

Safety

Single dose ~ LD50>36g/kg.
Repeated dose ~ NOAEL>200mg/kg/day.
Mutagenicity (Ames test) ~ Negative.

▶Response of human NK cell activation to dose of BioBran

Twenty-four healthy human volunteers were divided into three groups of 8, and assigned to ingest BioBran at 15mg/kg body weight (approximately equal to 1g), 30mg/kg body weight (approximately equal to 2g), and 45mg/kg body weight (approximately equal to 3g) every day for a period of two months to measure the effects on NK cell activity.

The activity in the 15mg/kg group was almost unchanged after 1 week but increased to twice the baseline activity after 1 month. The activity in the 30mg/kg group increased to about 3 times the baseline value after 1 week and then gradually increased to 5 times the baseline value by 2 months. The 45mg/kg group showed a pattern of increase similar to that in the 30mg/kg group, but the rate and degree of increase were greater than that of the 30mg/kg group. Following cessation of treatment, the NK cell activity levels gradually returned to baseline in each group.



Response of human NK cell activation to dose of BioBran :

Ghoneum M.,“Enhancement of human natural killer cell activity by modified Arabinoxylan from rice bran (MGN-3)”, INT. J. IMMUNOTHERAPY XIV (2) 89-99 (1998)

▶NK cell activation in cancer patients following BioBran intake

NK cell activity was compared before and after 6 months of BioBran intake in 25 cancer patients with progressive disease, who received chemotherapy, surgery, and/or hormone therapy. Although a large difference in the baseline activity was observed between patients, all patients demonstrated an increase in NK cell activity after BioBran intake.



NK cell activation in cancer patients following BioBran intake :

Ghoneum M. and G. Namatalla, 87th Annual Meeting of the American Association for Cancer Research, 1996.

▶Stimulation of lymphocyte transformation

The proliferation of T-cell and B-cell lymphocytes was compared before and after BioBran intake. The proliferation of both T-cells and B-cells increased in the 3 patients following BioBran intake.



Stimulation of lymphocyte transformation:

Ghoneum M., 11th International AIDS Conference in Vancouver, 1996.

▶Promotion of differentiation of dendritic cells

Monocytes were isolated from the peripheral blood of healthy subjects and cultured in the presence of GM-CSF and IL-4 for 6 days, to prepare immature dendritic cells (iDC). On the 7th day, BioBran was added at various concentrations to the immature dendritic cells. The immature dendritic cells were incubated for 2 days and their maturation to dendritic cells was observed. The same operation was performed using two kinds of culture medium which have the effect of promoting the development of iDC to mature dendritic cells, designated mat DC1, and matDC2, respectively. In the immature dendritic cells (iDC), BioBran suppressed the expression of the monocyte marker CD14 and increased the expression of the dendritic cell marker CD83, both in a dose dependent manner. This result appears to show that BIoBran promotes the differentiation of dendritic cells.



Promotion of differentiation of dendritic cells :

Cholujova D., et al, “BioBran-augmented maturation of human monocyte-derived dendritic cells”, NEOPLASMA, 56, 2, 2009.

▶Anticancer effect of BioBran

Female Swiss albino mice were inoculated with 2.5 x 106 Ehrlich ascites carcinoma (EAC) cells into the right femoral region, and the tumor size determined on consecutive days, starting on the 8th day after inoculation until the 35th day. The control group received phosphate buffered saline (PBS), and the BioBran group received 40 mg/kg body weight of BioBran intraperitoneally three times a week for a period of 3 weeks, starting on the 8th day after the inoculation of EAC. After treatment, the tumor size was determined. The results showed a significantly greater suppression of tumor growth in the BioBran group compared to the control (PBS) group, starting on the 14th day after inoculation of EAC. The photographs of tumor on the 35th day also showed a tumor regression in the BioBran group.



バイオブランのin vivoにおける抗腫瘍効果
Anticancer effect of BioBran :

Ghoneum M., et al, “In vivo Tumor Inhibitory Effects of Nutritional Rice Bran Supplement MGN-3/Biobran on Ehrlich Carcinoma-Bearing Mice”, Nutrition and Cancer, 2008.

▶Influence on liver damage

Male Wistar rats (5 rats/group) were given intraperitoneal administration of 800 mg/kg D-galactosamine to induce liver disorder. Serum GOT and GPT were determined 24 hours after the administration of D-galactosamine, as induces of liver damage. One hour before administration of D-galactosamine, 20, 40, or 80 mg/kg of BioBran was administered intraperitoneally. The serum GOT and GPT in the control group without BioBran at 24 hours after the administration of D-galactosamine were 1410 IU/L and 445 IU/L, respectively. Compared to these values, serum GOT and GPT in the groups treated with BioBran were significantly lower at all doses.



Influence on liver damage :

Sanada H. and Y. Egashira, 7th meeting of the Japanese Association for Dietary Fiber Research, Tokyo, 2002.


▶BioBran in combination with a chemotherapeutic agent

Human breast cancer cells (MCF-7) (1 x 104 cells) were seeded into the wells of a plate and incubated for 3 days in the presence of differing concentrations of BioBran, and the chemotherapeutic agent daunorubicin (DNR). Viable cells were counted by the MTT method, and the concentration of DNR which reduced the number of viable cancer cells by 50% (IC50) was determined. DNR inhibited the survival of MCF-7 cells in a concentration-dependent manner, with the IC50 being 1μM. When MCF-7 cells were cultured in the presence of BioBran and DNR, the IC50 of DNR for MCF-7 was reduced significantly (IC50: 0.2μM).



BioBran in combination with a chemotherapeutic agent :
Ghoneum M. and S. Gollapudi, “MGN-3/Biobran, modified arabinoxylan from rice bran, sensitizes human breast cancer cells to chemotherapeutic agent, daunorubicin”, Cancer Detection and Prevention, 2008.

▶Effect of BioBran on survival and quality of life improvement in patients with progressive cancer

Two hundred and five patients with malignant tumors who were receiving treatment with alternative therapy and chemotherapy with mild adverse drug reactions were allocated into two groups. One of the groups (the control group) received conventional alternative therapy and chemotherapy, and the other group (BioBran group) was given 1 g of BioBran three times a day after each meal for 18 months, in addition to receiving the same therapy as the control group. The correlation between natural killer (NK) cell activity determined during the observation period and survival rate was studied.
The patients’ quality of life was assessed on a scale of 0 to 4 with regard to “pain”, “fatigue”, and “nausea” and 0 to 3 with regard to “appetite” at the start of, and during, the observation period. Of the 205 patients participating in the study, 53 patients of the control group could not continue the conventional alternative therapy and dropped out, and therefore 152 patients (56 patients in the control group and 96 in the BioBran group) were included in the analysis. The survival rates at the end of the observation period in the control group and the BioBran group were 35.8% and 54.2%, respectively. This represents a 50% higher survival rate in the BioBran group compared to the control group. It was also shown that higher NK cell activity was associated with a higher survival rate (Table 1). It was confirmed that the patients’ quality of life after the study had improved compared to the quality of life at the start of the study in both the control group and BioBran group; a notable improvement in appetite was observed in the BioBran group (Table 2).



Effect of BioBran on survival and quality of life improvement in patients with progressive cancer :

Takahara K., et al, “The Life Prolongation and QOL Improvement Effect of Rice Bran Arabinoxylan Derivative (MGN-3, BioBran) for Progressive Cancer”, Clinical Pharmacology and Therapy, 2004

Cell Biology

A cell is chemical system that is able to
maintain its structure and reproduce.
Cells are the fundamental unit of life. All
living things are cells or composed of cells.





The interior contents of cells is the
cytoplasm. The cytoplasm is isolated from
the surrounding environment by the
plasma membrane g y p. 
There are two fundamentally different
forms of cells.


 Prokaryotic cells - relatively simple cells -
lack nuclear membrane and many 
organelles -bacteria and their relatives are
all prokaryotic



Eukaryotic cells - more complex cells - have a nucleus and many organelles - all cells of plants, animals, fungi, and protists.




Most cells are small
Prokaryotic: 1-10 µm
Eukaryotic: 10 - 100 µm
(1 µm = .001 mm)




What are the types of cells?
Blood and immune system cells
Erythrocyte (red blood cell)
Megakaryocyte (platelet precursor)
Monocyte (white blood cell )
Connective tissue macrophage (various types)
Epidermal Langerhans cell.
Osteoclast (in bone)
Dendritic cell (in lymphoid tissues)
Microglial cell (in central nervous system)

Cells and organelles.

Organelles, Macromolecules, & Atoms .

Why are cells small?
As cell size increases the volume increases much faster than the surface area. 

Cells obtain nutrients, gain information
and rid waste through their plasma 
membrane. 

As cell size increases, a cell’s ability to
exchange with its environment becomes
limited by the amount of membrane
area that is available for exchange.

Robert Hooke - 1665 - using an early
microscope viewed cork and saw many 
repeating box-like structures and called
them “cells.”

What he saw were spaces surrounded by walls that once contained living cells. Since Hooke’s first observations what is known about cells has increased greatly.

Cell Theory
• Cells are the fundamental unit of life -
nothing less than a cell is alive.
• All organisms are constructed of and by cells.
• All cells arise from preexisting cells.
Cells contain the information necessary
for their own reproduction. No new cells
are originating spontaneously on earth today.
• Cells are the functional units of life. All
biochemical processes are carried out by cells.
• Groups of cells can be organized and
function as multicellular organisms
• Cells of multicellular organisms can
become specialized in form and function
to carry out sub-processes of the multicellular
organism.

Prokaryotic cell structure
small, with a plasma membrane surrounded by a rigid cell wall
- in many the cell wall is made of _____________ - a carbohydrate
cross-linked with polypeptides cell wall may be covered with a capsule made of polysaccharides few or no membrane enclosed spaces within the cytoplasm no nucleus - DNA is in a region called the nucleoid.
DNA is circular and naked (has no protein associated with it)

Bacteria often have flagella with a single protein core (flagellin)
that they can use to move in a rotary corkscrew like fashion.

The rotary motor of prokaryotic flagella is powered by proton flow
through the cell membrane.

Rotating structures are rare in nature.

Membrane enclosed spaces allow cell
functions to be compartmentalized
and isolated from other functions.
Prokaryotes lack membrane enclosed
spaces in their cytoplasm.

Some prokaryotes are photosynthetic.
The biochemical machinery for
trapping light energy is contained
within a highly folded plasma membrane.

Eukaryotic cell structure larger, with a typical plasma membrane - some with a cell wall.
Many _________________________ and
other interior spaces enclosed by membranes:
Nucleus, Endoplasmic reticulum, Golgi apparatus,
Mitochondria, Chloroplasts, Lysosomes,Vacuoles, Vesicles.
Cytoplasm with a cytoskeleton - protein tubules and fibers
cell wall found in plants (cellulose), fungi (chitin), some protists.

Cellular Organelles
Nucleus - the largest and most obvious
membrane bound compartment -
controls cell activities contains the
nucleolus - a darkened region where
ribosomal RNA is synthesized contains
chromosomes - consist of DNA
wrapped around proteins.

Nucleus is surrounded by the nuclear
envelope - a double membrane.
Nuclear membrane has nuclear pores
that control entry and exit of materials.

Chromosome - “colored body” consists of
both DNA and protein - seen as
chromosomes when highly condensed in
preparation for cell division. At other
times the DNA and protein are threadlike
and called __________.

The most common proteins are histones.
DNA is coiled around histones in a
regular pattern that produces structures
called nucleosomes.

Endoplasmic reticulum (ER) - a web-like
series of membranes within the cytoplasm
in the form of flattened sheets, sacs, tubes,
creates many membrane enclosed spaces -
spreads throughout the cytoplasm - has
connections with the outer membrane of
the nucleus and the plasma membrane 
interior space is called the ______

Functions:
-circulation and transport
-storage of proteins and minerals
-synthesis of lipids, carbohydrates, and proteins
-A large surface area for enzyme action.

Two types of ER - rough and smooth:

rough ER - studded with ribosomes site of synthesis of many proteins all ribosomes on rER are actively involved in protein synthesis -

smooth ER - site for synthesis of steroids
and other lipids Ca++ storage in muscles 
detoxification of drugs, toxins, alcohol
(especially in liver).

The highly convoluted surface provides a
large surface area for enzymatic activities.
Many enzymes are imbedded in the
membranes.

Ribosomes - protein synthetic machinery 
• two subunits - large and small - each made of protein and ribosomal RNA (rRNA)
• subunits associate when they are synthesizing proteins
• protein synthesis occurs on ribosomes that are free-floating in the
cytoplasm and on ribosomes attached to ER
• rRNA is synthesized in the nucleolus 

Golgi Apparatus -
a collection of membranes associated with
the ER composed of flatten sacs called ___
______concentrates and packages proteins
 synthesized on the ER

The Golgi is functionally associated with the ER.

Proteins synthesized on the ER are concentrated internally and transport vesicles are budded off.

Transport vesicles fuse with the Golgi, dump their contents into the Golgi.

Golgi packages proteins in vesicles so that they may be excreted from the cell, or used within the cell.

Secretory vesicles - used for excretion - leave the Golgi and move to plasma membrane where they fuse and dump their contents outside - seen in many glands.

The Golgi Apparatus also forms lysosomes.
Lysosomes - vesicles filled with digestive
enzymes - used for intracellular digestion.

Particles can be taken into cell by phagocytosis and vesicle fused
with lysosome.

The components of organelles can be
recycled after digestion by lysosomes.

Microbodies: Peroxisomes and
Glyoxisomes vesicles that form through
growth and division within the cytoplasm
Glyoxisomes are found in plants - contain
enzymes that convert fats into carbohydrates.
Peroxisomes - used for removing reactive compounds from the
cytoplasm - create H2O2 as a byproduct and degrade it with the enzyme catalase.

Mitochondria - cellular powerhouses - the site of much of the
energy harvest by cells have double membrane structure inner membrane folded into inward projections called cristae two spaces within the mitochondrion - the matrix and the intermembrane space.

Mitochondria -
• The site of oxygen consumption within cells
• Have their own DNA that is similar to prokaryotic DNA
• Have their own ribosomes that are
similar in construction to prokaryotic ribosomes
• Synthesize many, but not all, of their own proteins
• Mitochondria replicate by binary fission - similar to prokaryotic cell division

Chloroplasts - sites of photosynthesis - in
nearly all plants and some protists trap
light energy and convert it into chemical
energy have double membrane structure -
inner space is the stroma.

Within the stroma have a series of stacks
of flattened membrane structures called 
thylakoids - the stacks are called grana.
 The light energy trapping molecules of 
photosynthesis are found in the membranes of
the thylakoids.

Chloroplasts have their own DNA, similar to prokaryotic DNA.
Can synthesize many of their own proteins using prokaryote-like ribosomes'
Synthesize many, but not all, of their own proteins.
Replicate through division similar to prokaryotic cell division.
Chloroplasts can take on other functions.

____________ synthesize and store starch in roots and tubers.

____________ have pigments and give fruits ripened color.

Centrioles - are part of specialized region
of the cell called the centrosome (cell
center) found in animals and most protists.
The centrioles are involved in the 
production of microtubules.
Microtubules have many functions 
including moving chromosomes during
cell division centriole structure - 9 triplets
of microtubules surrounding a hollow core -________________similar to the basal
body of flagella

Cytoskeleton - scaffolding of proteins that
transport materials, position and move
organelles, maintain and change cell shape,
and organize enzymes into functional associations 3 components - actin filaments, microtubules, and intermediate filaments.

All are polymers of smaller protein subunits - lengthen through addition of polymer subunits, shorten through
actin filaments - involved in cell movements and in membrane
deformations - smallest components of the cytoskeleton.

microtubules - hollow tubes made of
proteins called tubulins responsible for cell
movements and movements of organelles
within the cytoplasm, movement of
chromosomes during cell division -
largest components of the cytoskeleton.

intermediate filaments- 8 stranded protein fibers - play a role in
cell structure, anchoring organelles and in transport of materials within the cytoplasm anchor neighboring cells to each other in tissues.

Flagella and Cilia - cellular appendages can propel cells or propel materials over the cell surface cells that have flagella have few (usually 1 or 2) cells that have cilia have many - covering the surface flagella move with whip-like movements to propel the cell
cilia have a more regular stroke and groups of cilia appear to
move in unison, resulting in a wave-like motion flagella 5 to 20x longer than cilia

Structure has basal body with 9 + 0 structure of microtubules
flagellum is membrane bound with pairs of microtubules in a 9+2
pattern.

Each pair of tubules has short arms of another protein - dynein -
that extend to neighboring tubules movement of the flagellum is produced by sliding of the microtubule pairs 

Plant Cells have, in addition to the collection of organelles found
in other groups, a central vacuole for storage and for producing
________ pressure inside the the cell.

The central vacuole is usually filled with water and solutes. A high solute concentration draws water into the vacuole, expanding the vacuole and the cell.

Because plant cells are enclosed by a cell
wall, the expansion of the vacuole can 
exert pressure on the cell without causing
the cell to burst.

Plants have cell walls made of cellulose.

During cell division plant cells build
dividing walls between the two new
cells called the cell plate. An adhesive
layer - the middle lamella - is laid down
between the new cell walls.

Cell walls can be thickened through the
addition of materials to the inside of the
primary cell wall.

Where did Eukaryotic Cells come from?
The oldest rocks with evidence of fossil
cells date to 3.5 billion years. The oldest
rocks with cells large and complex enough
to be eukaryotic date to 1.0 billion years.
For 2.5 billion years only prokaryotic cells
existed on earth.
The best hypothesis for the origin of
eukaryotic cells was proposed by Lynn
Margulis in the early 1970s. This
hypothes is now called the ___________
 ___________. 

Eukaryotic cells appear to be the product
of a collaboration among different types
of prokaryotic cells. Some prokaryotic
cells became the host for other prokaryotic
cells that lived inside them. Some of the 
complex organelles of eukaryotes provide
evidence for this theory.

Mitochondria and chloroplasts appear to
be the direct descendants of energy
producing bacteria. Mitochondria are the
descendants of bacteria that were capable
of oxidative respiration.

Chloroplasts are the descendants of
photosynthetic bacteria.

Evidence:
Both have their own DNA and ribosomes
that are similar to those found in
prokaryotes. Both make many of their
own proteins and both multiply in a
fashion similar to prokaryotic cell division.
Both are double membrane organelles -
the inner membrane descended from the
ancestral guest cell, and the outer
membrane descended from the vacuole
membrane that was formed around the
guest.
Other organelles may also be the product
of endosymbiosis.
Some centrioles and basal bodies have
naked DNA as part of their structure.
There are many modern examples of
endosymbiosis involving organisms that
can live together or live independently.
The same was probably true of the
ancestors of endosymbiotic organelles
in the distant past.