Dietary supplement and related method

BACKGROUND OF THE INVENTION

The present invention relates to a composition and method for correcting a dietary deficiency, including an inadequacy of phytochemicals, vitamins and minerals.

Many people fail to practice healthy eating habits, such as consuming an adequate quantity and variety of food to meet U.S. Recommended Dietary Allowances. Only 22% of the subjects of a National Cancer Institute Study consumed the recommended daily number of dietary servings of fruits and vegetables—despite the fact that the recommended dietary intake of fruits and vegetables is well-known. For example. The California Daily Food Guide; Dietary Guidelines for California, California Department of Health Services (1990) recommends that each person consume at least five to nine servings of fruit and vegetables per day, including one serving of a vitamin A-rich deep green or dark orange fruit or vegetable, and at least one serving of a vitamin C-rich fruit or vegetable. Additionally, it is well reported that each person should consume at least 3 servings per week of vegetable protein in the form of legumes, nuts, or seeds. Some researchers suggest that a target of 400 grams (13 ounces) of fruits and vegetables is a sensible goal for the optimal quantity to be consumed daily. In terms of variety, it is recommended that persons should eat at least three different colors of fruits and vegetables daily.

The benefits of consuming a sufficient amount and variety of fruits and vegetables are many. For example, consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases. In a prospective cohort study of 41,837 postmenopausal women, the association of fruit and vegetable consumption with lung cancer risk was investigated. The researchers found that the risk of lung cancer was approximately halved when the consumption of fruits and vegetables increased from 24 or less servings to an excess of 48 servings per week. Similarly, the risk of lung cancer was approximately halved when the consumption of green leafy vegetables, including spinach and parsley sources, increased from one or fewer servings to six or more servings per week. Steinmetz, K. et al., “Vegetables, Fruit, and Lung Cancer in the Iowa Women's Health Study,” Cancer Res. 53:536-43 (1993). Another study found that an increased intake of fresh tomatoes (a major source of lycopene) was associated with a pattern of protection for all sites of digestive tract cancer. Stahl, W. et al., “Lycopene: A Biologically Important Carotenoid for Humans?” Arc. Biochem. Biophys. 336:1-9 (1996).

In addition to fruits and vegetables, herbs also provide health benefits. For example, the herb, rosemary, contains antioxidants such as carnosol, which may play a preventive role in cholesterol oxidation. Likewise, the herb, basil is known for its antioxidant activity. Like fruits and vegetables, however, the dietary intake of beneficial herbs is unsatisfactory.

Further research has shown that the typical U.S. diet is lacking in phytochemicals. Phytochemicals generally refer to plant-derived compounds which, when taken daily in combination with vitamins and minerals, provide improved cardiovascular and bone health, an improved antioxidant profile, decreased free radical damage, and overall enhancement of the body's natural defense system.

The typical diet, especially the U.S. diet, includes an inadequate amount and variety of fruits, vegetables and herbs, as well as the phytochemicals and associated antioxidants present in these materials. A typical diet is similarly deficient in necessary vitamins and minerals associated with fruits and vegetables. Although conventional multivitamins can supplement western diets with needed vitamins and minerals, many of these multivitamins fail to provide phytochemicals that target free radicals in the body and thereby improve the antioxidant profile of the supplement.

SUMMARY OF THE INVENTION

The present invention provides a composition including a unique combination of fruit vegetable, and herb dehydrates, concentrates, or extracts; and optionally vitamins, minerals and specialty ingredients to correct a dietary deficiency of those materials.

The composition of the present invention provides substantial health benefits. For example, in one embodiment, it can support the health of people who consume a nutritionally deficient diet; improve antioxidant and nutrient status; replenish serum nutrient and phytochemical levels as a result of inadequate diets to levels associated with decreased risk of certain degenerative disease states; minimize free radical damage that occurs as a result of normal aging processes and exposure to environmental stresses; and/or improve the status of specific biomarkers indicative of optimal health, namely homocysteine, lipid byproducts, mineral status and glutathione peroxidase.

In a more specific embodiment, the composition of the present invention can provide β-carotene, α-lipoic acid, selenium, and vitamins C and E, which improve the antioxidant profile of a person. Increased levels of folic acid and vitamins E target and improve cardiovascular health. Calcium, magnesium, and vitamin D targets and improves bone health. B vitamins improve energy metabolism. The compositions according to the invention can provide 100% of the U.S. Recommended Daily Intake of all vitamins and most minerals. The composition also can provide a variety of phytochemicals to produce a diverse antioxidant profile.

In an even more specific embodiment, the composition can include a combination of fruit, vegetable and herbal ingredients, wherein the fruit ingredients are selected from acerola, apple, blueberry, citrus bioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein the vegetable ingredients are selected from asparagus, alfalfa, brassica, kale, lutein, lycopene, and watercress; and wherein the herbal ingredients are selected from basil, oregano, parsley, sage and rosemary. These ingredients can be concentrated, for example they may be extracted from raw ingredients. Optionally, the fruit ingredients, vegetable ingredients and herbal ingredients can be present in the composition in a ratio of about 3.5:1:1 by weight. Specialty ingredients, such as alpha lipoic acid and inositol can be added to the composition.

In yet another embodiment, the composition can include at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, plum and raspberry; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

In another embodiment, a method is provided for enhancing the immune system, as well as treating and/or reducing die risk of DMA damage of the human body comprising administering an effective amount of a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

These and other objects, advantages and features of the invention will be more readily understood and appreciated by reference to the detailed description of the invention and the drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect the composition has on Vitamin C levels.

FIG. 2 is a graph depicting the effect the composition has on beta carotene levels.

FIG. 3 is a graph depicting the effect the composition has on Vitamin B₆levels.

FIG. 4 is a graph depicting the effect the composition has on Vitamin B₁₂levels.

FIG. 5 is a graph depicting the effect the composition has on Folate levels.

FIG. 6 is a graph depicting the effect the composition has on homocysteine levels.

FIG. 7 is a graph depicting the numbers of genes related to DNA or chromatin maintenance or repair that were modulated by consumption of the composition.

FIGS. 8A and 8B which are a diagram (FIG. 8A) and a graph (FIG. 8B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 2-hydroxybutarate.

FIGS. 9A and 9B are a diagram (FIG. 9A) and a graph (FIG. 9B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 5-oxoproline.

FIG. 10 is a graph depicting the change in plasma beta-carotene concentration after treatment.

FIG. 11 is a graph depicting the change in plasma folate concentration after treatment.

FIG. 12 is a graph depicting the change in plasma vitamin B6 concentration after treatment.

FIG. 13 is a graph depicting the change in plasma vitamin B12 concentration after treatment.

FIG. 14 is a graph depicting the change in plasma homocysteine concentration after treatment.

FIG. 15 is a graph depicting the change in DNA damage after treatment.

FIG. 16 is a graph depicting the change in baseline expression activity of genes associated with DNA maintenance genes after treatment.

DETAILED DESCRIPTION OF THE INVENTION

I. Overview

In general, the invention relates to a composition comprising fruits, vegetables and herbs. In one embodiment, the composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can also be combined with a known therapy that can impact chromatin stability thereby limiting the detrimental effects of such therapy.

The following fruit ingredients also can be present in the composition: acerola, apple, blueberry, cranberry, grape skin, and plum. Further, the following vegetable ingredients also can be present in the composition: alfalfa, brassica, and kale. Finally, the following herbal ingredients also can be present in the composition: sage and parsley.

The composition has a synergistic effect in the treatments discussed herein. Thus, the components of the composition together are more effective that individually. Additionally, the composition modulates, and more specifically as discussed herein up-regulates, genes associated with chromatin stability, examples of which are discussed in the figures and examples.

Example of genes involved in telomere maintenance include, but are not limited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and three other genes, EST1, EST3, EST4/CDC13, MRE11, RAD50, XRS2 (yeast)/NBS1, p53, hTERT, ATM, TRF2, the TERF family of genes.

The composition of the present invention can either treat or reduce the occurrences/risks of chromatin damage, and thus support genome stability, by increasing the expression of genes involved in identifying and correcting damage to DNA as well as associated protein structures (i.e., chromatin). The reduction in the occurrence/risk of chromatin damage includes any statistically significant reduction that correlates to a biological response or outcome. These genes control activities including, but not limited to, repair of base pair mismatches, repair of double strand breaks, or other maintenance, repair or supervisory roles. Most damage is caused by oxidation, nutrient deficiency, radiation or toxins. There are four main types of damage to DNA due to endogenous cellular processes or exogenous insult such as ultraviolet radiation: oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine hydrolysis of bases, such as deamination, depurination and depyrimidination, mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted. There are four major DNA-repair pathways in human cells: mismatch repair, nucleotide-excision repair (NER), base-excision repair (BER), and double-strand-break (DSB) repair. The NER pathway mainly removes bulky DNA adducts. The BER pathway is responsible for removal of oxidized DNA bases that may arise endogenously or from exogenous agents. The DSB pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation, free radicals, and telomere dysfunction. Examples of such genes include, but are not limited to ERCC, RAD2, RAD6, RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAG1, PHR1, DIN1, DDR48, RNR1, RNR2, RNR3, UB14, repB, repD and APE. These genes are impacted by the composition of the present invention can modulate any of the types of damage disclosed above.

The composition can thus be used to treat diseases associated with DNA repair problems including, but not limited to, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom's syndrome and ataxia telangiectasia. All of which are associated with improper repair of DNA.

The composition can also be used to affect/modulate the function of mitochondria function-specific genes, examples of such genes are provided in Table 8 below. These genes generally fall into four categories. First, genes for mitochondrial transcription/translation, examples of which include, but are not limited to, MTRF1L, which is involved in mitochondrial translational machinery, GFM2, which is a protein involved in protein elongation, MRPL3, which is a mitochondrial ribosomal protein, TOMM20, which is a central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins and together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore. COX15, which is predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicated accurately by DNA polymerase gamma, and MRPS10, which is part of mitochondrial 28S Ribosomal protein. Second, genes for mitochondrial structure examples of such genes include, but are not limited to, DNMIL, which is critical for maintenance of mitochondrial morphology, OPA1, which is a major organizer of the mitochondria); inner membrane and is required for the maintenance of cristae integrity, MFN1, which is an essential transmembrane GTPase, which mediates mitochondrial fusion (MFN1 acts independently of the cytoskeleton.), BNIP3, which provides regulation of mitochondrial permeability, COX18, which is required for the insertion of integral membrane proteins into the mitochondrial inner membrane and is essential for the activity and assembly of cytochrome c oxidase and plays a central role in the translocation and export of the C-terminal part of the COX2 protein into the mitochondrial intermembrane space, and DNM1L, which functions in mitochondrial and peroxisomal division probably by regulating membrane fission and enzyme hydrolyzing GTP that oligomerizes to form ring-like structures and is able to remodel membranes. Third, miscellaneous mitochondrial proteins examples of such genes include, but are not limited to, WWOX, a tumor suppressor gene, PPIF, for protein folding, CoQ9, 10GB, which is involved in the final steps in the synthesis of CoQ, SLC25A37, which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis, ABCB7, which is involved in the transport of heme from the mitochondria to the cytosol, and SLC25A36, which is a transporter for mitochondria. Fourth, genes for mitochondrial enzymes examples of such genes include, but are not limited to, SDHD, which is part of the respiratory chain, ATPAF1 enzymes which are critical for generation of ATP, NARS2, IARS2, EARS2, LARS2, HARS2, which are enzymes involved in the production of amino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which is an enzyme providing succinyl coA for TCA cycle, ACADSB, which is an enzyme catalyzing one of the steps in fatty acid beta oxidation, MIB1, which is a E3 ligase necessary for protein ubiquitnation (deletion lethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA, AFG3L2, which is a AAA protease protecting against oxiative stress, PEO1, which is a DNA helicase, critical for lifetime maintenance of mtDNA integrity and to maintain mtDNA copy number, HK2 (Hexokinase 2), and HADHB, which is involved in fatty acid beta-oxidation.

The composition can also be combined with a known therapy to create a combinatorial therapy. This can primarily be used in instances where the known therapy has known detrimental side effects that impact DNA stability, such as chemotherapeutics and radiotherapeutics. Other compounds can also be used that negatively impact DNA repair and stability.

The invention also relates to a method for correcting a diet-induced deficiency of fruits, vegetables and herbs, and the nutrients present in such materials. The composition of the present invention additionally can contain phytochemicals, vitamins, and minerals known to improve the body's natural defenses against oxidants, free radicals, and diseases.

II. Composition and Method of Manufacture

The composition can include a combination of fruit, vegetable, herbal and other ingredients that provide significant health benefits. The following tables illustrate representative daily amounts of suitable fruits, vegetables, herbs, vitamins, and minerals which can be included in the composition. The dosages and methods of administration can be varied as desired from application to application. For example, Dosage A represents a range of dosages of the respective ingredients that is suitable for purposes of the present, invention. Dosage B represents a dosage of a particular embodiment. The unit “mg” in Tables 1-5 means that that the amount recited is given in the number of, e.g., milligrams, provided in a two-tablets per day dosage, unless otherwise noted, e.g., “JU” is recited. Thus, to determine the amount of a specific ingredient per single tablet, the amount recited in the respective tables must be halved.

TABLE 1

Fruit Ingredient
Dosage A, mg/day
Dosage B, mg/day

Acerola Powder
50-500
300

Apple extract
25-1000
50

Citrus Bioflavanoids
25-1000
100

Grape skin extract
25-1000
50

Plum extract
25-1000
50

Cranberry extract
25-1000
50

Pomagranate
5-500
25

Blueberry extract
25-1000
50

The citrus bioflavonoids are commercially available from Access Business Group International LLC of Ada, Mich. This ingredient can be in a concentrate form, and can include, but are not limited to, naringen, hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin, neohesperidin, nobiletin, and quercetin.

TABLE 2

Vegetable Ingredient
Dosage A, mg/day
Dosage B, mg/day

Asparagus
25-1000
50

Alfalfa
25-1000
70

Brassica

25-1000
50

Kale
20-1000
75

Lycopene
0.1-100
2

Lutein esters
0.1-100
2

NUTRILITE Watercress
5-500
28

NUTRILITE watercress is available from Access Business Group International LLC. The Brassica and/or kale can be in dehydrated, powdered form. As used herein the Brassica ingredient may include any material derived from plants in the Brassicae family, for example, broccoli. The lutein esters used in the composition can be of the type sold under the name Xangold 10% beadlets, which is available from Cognis Nutrition & Health of Cincinnati, Ohio. The lycopene used in the composition can be of the type sold under the name Lycobeads 5%, which is available from H. Reisman Corp. of Orange, N.J.

TABLE 3

Vegetable Ingredient
Dosage A, mg/day
Dosage B, mg/day

Basil extract
25-1000
50

Rosemary extract
25-1000
50

Sage
5-500
25

Oregano extract
25-1000
50

NUTRILITE Parsley
5-500
25

NUTRILITE parsley is available from Access Business Group International LLC. The composition can also include ingredients in addition to the fruit, vegetable and herbal ingredients noted above. For example, suitable vitamins for use in the compositions and methods of the present invention can include, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E. Table 4 below includes a suitable vitamin profile.

TABLE 4

Vitamin Profile

Dosage B,

Ingredient
Dosage A, mg/day
mg/day

Vitamin C from Acerola
20-100
60

Powder

Ascorbic Acid (C)
100-700
440

Vitamin A from Beta Carotene
1000-10,000 IU
7500 IU

Biotin
0.01-4
0.300

Pantothenic Acid from Cal
5-300
50

Pan Gran

Choline
10-400
50

Folic Acid
0.01-10
0.8

Inositol
5-100
25

Vitamin E
10-5000 IU
150 IU

Mixed Tocopherols
5-300
50

Niacin/Niacinamide
5-300
40

Pyridoxine (B6)
10-100
15

Riboflavin (B2)
1-100
12.75

Thiamine (B1)
1-100
11.25

Vitamin A from Acetate
100-10,000 IU
2500 IU

Vitamin B12
0.01-50
0.045

Vitamin D3
10-2000 IU
400 IU

Yeast, Standardized@
5-350
60

(source of 100% RDA Bs)

In addition to the vitamins listed above, minerals for use in the compositions and methods of the present invention include, for example, boron, calcium, chromium, copper, iodine, magnesium, manganese, molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins and minerals may also be used. Table 5 below includes a mineral profile suitable for the composition of the present invention.

TABLE 5

Mineral Profile

Ingredient
Dosage A, mg/day
Dosage B, mg/day

Calcium
100-2000
750

Chromium
0.01-5
0.120

Copper
0.01-5
2

Iodine
0.001-5
0.15

Magnesium
10-1000
300

Manganese
1-20
5

Molybdenum
0.001-75
0.075

Potassium
5-300
80

Selenium
0.001-5
0.100

Zinc
1-50
15

With the ingredients of Tables 1-3, and optionally the ingredients of Tables 4-5, the composition of the present invention can provide a significant portion of, and in many cases exceed, the recommended daily requirement for a variety of vitamins and minerals. Tables 6 and 7 below illustrate the potency of the composition, when taken in the above daily amounts, in terms of percentages of the daily requirements for the listed vitamins and minerals.

TABLE 6

Vitamin
Amount/Day
% Daily Value

Vitamin A (75% as β-
10,000
200%

Carotene), IU

Vitamin C, mg
500
833%

Vitamin D, IU
400
100%

Vitamin E, IU
150
500%

Niacin/Niacinamide, mg
40
200%

Vitamin B₆, mg
15
750%

Vitamin B₁₂, mcg
45
750%

Folic Acid, mcg
800
200%

Biotin, mcg
300
100%

Pantothenic Acid, mg
50
500%

TABLE 7

Minerals
Amount/Day
% Daily Value

Calcium, mg
750
75%

Magnesium, mg
300
75%

Iodine, mcg
150
100%

Potassium, mg
80
2%

Copper, mg
2
100%

Zinc, mg
15
100%

Manganese, mg
5
100%

Chromium, mcg
120
100%

Selenium, mcg
100
143%

Molybdenum, mcg
75
100%

Additional specialty ingredients which can be used in the composition include, for example, methyl sulfonyl methane (MSM), α-lipoic acid (10 mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast, inositol, and para-aminobenzoic acid (PABA).

The composition of the present invention can be formulated using any pharmaceutically acceptable form of respective fruit concentrates, vegetable concentrates, herb concentrates, phytochemicals, vitamins, minerals, and other nutrients, including their salts. The compositions can be formulated into tablets, powders, gels, or liquids (a tablet, for the purposes of the present invention and as used throughout the application disclosure, refers to any form of a solid oral dosage, including but not limited to tablets, caplets, capsules, powders, etc.). The compositions can be formulated as powders, for example, for mixing with consumable liquids such as milk, juice, water, or consumable gels or syrups for mixing into other liquids or foods. The compositions can also be formulated with other foods or liquids to provide pre-measured compositional foods, for example, single-serving bars. Flavorings, binders, protein, complex carbohydrates, and the like can be added as needed.

According to one aspect of the invention, the composition is administered as three separate tablets, all three of which are administered twice a day; however, the composition may be administered in other forms and unit dosages as desired.

The composition of the present invention will be illustrated by, but is not intended to be limited to, the following examples.

EXAMPLE 1

Three tablets may be prepared to provide a) fruit, vegetable and herbal ingredients, b) vitamins and c) minerals. The first tablet includes the fruit, vegetable and herbal ingredients of Tables 1-3. The amount of each ingredient in this first tablet is half of the amount listed in the Dosage B of the Tables, as the table-listed amount is the amount present in two such tablets. The first tablet may also include carriers and other tableting aids such as silicon dioxide, magnesium oxide, calcium carbonate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate in amounts that may be varied for purposes well known to those of skill in the art.

The second tablet includes vitamins of Table 4. The amount of each ingredient in this second tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The second tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The third tablet includes minerals of Table 5. The amount of each ingredient in this third tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The third tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The three tablets, when administered twice a day, complete the gap in phytochemicals that is present in the typical diet.

EXAMPLE 2

The following examples relate to methods of preparing the above three tablets. The ingredients are the same as those referred to above in Tables 1-5. For purposes of the following examples, however, tablets including the fruit, vegetable and herbal ingredients from Tables 1-3 are referred to as “Tablet 1”; tablets including the vitamin ingredients from Table 4 are referred to as “Tablet 2”; and tablets including the mineral ingredients from Table 5 are referred to as “Tablet 3.” It is noted that other methods for preparing the tablets and other suitable delivery vehicles can be used as desired.

Tablet 1

Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes Magnesium oxide (D.C. heavy), Acerola concentrate, citrus bioflavonoids complex, plum extract, apple extract, rosemary extract, basil extract, grape skin extract, cranberry extract, kale powder, asparagus extract, blueberry extract, parsley dehydrate, oregano extract, sage extract, pomegranate extract, and inositol are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calcium carbonate (granular), croscarmellose sodium and microcrystalline cellulose (silicified) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The mixture is blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 2

Acerola concentrate, microcrystalline cellulose (silicified) and alpha lipoic acid are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot P.K. blender. The ingredients are blended for ten minutes. Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin, niacinamide, biotin trituration (1%), vitamin B12 (1.1%), calcium pantothenate granular, folic acid, pyridoxine HCl (95%), and choline bitartrate. The ingredients are blended for ten minutes. Next, the following items are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender; beta carotene (beadlets), vitamin D3 (beadlets), yeast (standardized) and vitamin A (acetate). The mixture is blended for an additional ten minutes.

Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 1.00 cubic foot PK blender: ascorbic acid (97%), calcium carbonate (granular), croscarmellose sodium, d-alpha-tocopherol succinate, silicon dioxide (NF fine powder). The mixture is blended for an additional ten minutes.

Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 3

Zinc amino acid chelate, mixed tocopherols and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Co-processed alfalfa concentrate/microcrystalline cellulose/calcium carbonate, selenium yeast, microcrystalline cellulose, copper amino acid chelate, manganese amino acid chelate, potassium iodide trituration, chromium amino acid chelate, molybdenum amino acid chelate, brassica dehydrate, watercress dehydrate and croscarmellose sodium are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Potassium chloride, magnesium oxide (D.C. heavy) and calcium carbonate (granulation) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional live minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

EXAMPLE 3

The clinical study was an independent Review Board-approved, double-blind, placebo-controlled, parallel-groups study.

Subjects

Subjects were 120 healthy adult Japanese-Americans in California and Hawaii Subjects were ethnically Japanese (both parents and four grandparents ethnically Japanese) and ate a mostly Japanese diet

Treatment

Subjects took either composition or placebo as directed (12 tablets a day) for 8 weeks. The composition is the same formula as is currently marketed in Japan under the Alticor name of Triple X™. All products were coated and provided in coded foil packs to preserve double-blindedness.

Outcome Measures

There were four main categories of outcome measures; (1) plasma concentrations of a representative water-soluble antioxidant nutrient [vitamin c], and a representative fat-soluble antioxidant nutrient [beta carotene], (2) plasma concentrations of the “anti-homocysteine triad” vitamin B6, vitamin B12, and folate, as well as plasma concentrations of homocysteine, (3) nutrigenomic mechanisms of genomic stability, and (4) plasma metabolomic profile changes.

Analyses for plasma nutrient and homocysteine concentrations were based on blood samples obtained from 120 subjects (60 treated with Triple X, and 60 treated with Placebo), at baseline, Week 4, and Week 8.

Nutrigenomic analyses were based on blood samples obtained from 14 subjects (7 treated with Triple X, and 7 treated with Placebo) at baseline and Week 2.

Statistics

Plasma nutrient and homocysteine change score results were assessed with independent-groups t-test for between-groups comparisons. A P value smaller than 0.05 was considered significant.

Nutrigenomic data were first analyzed with paired t-tests within the composition-treated group only to identify which from among 44,000 genes measured showed a significant change in expression level following treatment. A P value smaller than 0.05 was considered significant. A Q value (false discovery rate) of 0.4 was used to control for false positive findings. This analysis identified about 2,000 genes, which were then examined for biologically relevant patterns of change.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking composition showed increased levels of folate, vitamin B6, vitamin B12, and vitamin C, as well as decreased levels of homocysteine, all within 4 weeks of treatment, with results maintained at 8 weeks. Metabolomic analyses indicate decreased oxidative stress. Nutrigenomic analyses indicate increased genomic integrity and tumor suppressor mechanisms, homocysteine metabolism, resistance to oxidative stress and lipid peroxidation.

Clinical interpretation of nutrigenomic data revealed the unexpected finding that about 150 genes, each known to function to support genomic stability (via chromatin maintenance, damage detection, and repair), were significantly increased in the Triple X group compared to the placebo group. Subsequent analysis of these genes in the Placebo-treated group showed no change following Placebo treatment. Compared to baseline, consumption of the composition of the present invention led to statistically significant increases in the expression of genes related to DNA maintenance, replication, or repair (FIG. 7).

Clinical interpretation of metabolomic data revealed the unexpected findings that consumption of Triple X led to significant decrease increases in 2-hydroxy bury rate, a metabolite related to oxidative stress (FIG. 9), as well as a trend towards a decrease in 5-oxoproline, also a metabolite related to oxidative stress (FIG. 10). This shows that the consumption of the composition can lead to increased plasma concentration of antioxidant nutrients, increased expression of chromatin maintenance and repair genes, decreased homocysteine, and decreased metabolomic indicators of oxidative stress.

EXAMPLE 4

Clinical testing was conducted to confirm the efficacy of the composition of the present invention. It was expected that consumption of the composition would: correct dietary deficiencies of phytochemicals; improve the amount of antioxidants in the body; decrease free radical damage; increase plasma vitamin, mineral and phytochemical concentrations; and improve plasma and systemic antioxidant capacity, among other things.

Inclusion criteria for this study were healthy men and women, from 18 to 80 years of age, who consume fewer than 12 items found on the Recommended Foods Checklist per week. These subjects are selected after administration of a food frequency questionnaire and application of the Recommended Foods Score (RFS). The RFS consists of 23 foods, 14 of which are fruits and vegetables, that when consumed on a weekly basis have been associated with reduced mortality. This was demonstrated in a cohort study of 42,254 women. Those with a mean RFS of 16.0 (highest quartile) had an all-cause mortality relative risk of 0.69 compared to those with a mean RFS of 6.4 (lowest quartile) who have an all-cause mortality relative risk. It was noted that those in the highest quartile consumed significantly more calories (131%), fiber (200%), Vitamin C (230%), folate (181%), and pro-Vitamin A carotenoids (253%) compared to those in the lowest quartile.

The clinical study encompassed a double-blind (i.e. to subjects and investigators) study of 120 subjects over a six-week period. During the six-week trial, subjects were told to consume three tablets, either the composition, or a placebo, twice a day, such as morning and evening. The subjects were tested by taking blood and urine samples and performing the following assays: total polyphenols, plasma ORAC (Oxygen Radical Absorption Capacity), CP450 enzyme induction, cytokinesis block micronucleus assay, comet assay, bioenergetics assay, urinary bile acids, B6, B12, folate, Vitamin C, homocysteine, alpha and gama tocopherols, beta-carotene, C-reactive protein and urinary 8-epi prostaglandins F2α, which were tested at baseline, two weeks, four weeks and six weeks into the study. Improvement, and thus, efficacy of the composition, was measured based on: plasma concentrations of vitamins, minerals and phytochemicals; plasma and systemic antioxidant capacity; detoxification capacity; cellular energy dynamics; genomic stability; other risk factors and subjective effects.

It was expected that the results of the study would show that following six weeks of composition consumption, subjects would have significantly increased plasma levels of alpha tocopherols, B12, B6, folate, Vitamin C, and other antioxidants, which indicates an improvement in the amount of antioxidants in the body and which is associated with a correction of dietary deficiencies in vitamins, nutrients and phytochemicals, and/or a decrease in free radical damage, as well as increased genomic stability (i.e., decreased DNA damage) among other things.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking the composition showed increased plasma concentrations of Beta Carotene, Alpha-Tocopherol, Folate, and Vitamins B6 and B12. Subjects taking composition also showed significantly reduced homocysteine, as well as decreased DNA damage as indicated by the cytokinesis micronucleus block assay. This shows that the consumption of the composition can increase plasma concentrations of antioxidant nutrients, decrease homocysteine, and decrease DNA damage.

The above descriptions are those of the preferred embodiments of the invention. Various alterations and changes can be made without departing from the spirit and broader aspects of the invention as defined in the appended claims, which are to be interpreted in accordance with the principles of patent law including the doctrine of equivalents. Any references to claim elements in the singular, for example, using the articles “a,” “an,” “the,” or “said,” is not to be construed as limiting the element to the singular.

TABLE 8

ADH5
\alcohol
Removal of S-nitrosoglutathione and
Anti-

dehydrogenase
thus controls its levels as well as levels
Nitrosative

5 (class III),
of nitrosylated proteins. Protects against
stress activity

chi
nitrosative stress. Low amounts of this
gene

polypeptide\“”
enzyme or absence can increase whole

cell nitrosylation and tissue damage and

susceptibility to bacteria.

TXNL1
thioredoxin-
TXNL1 acts as an effector of oxidants or
Anti-oxidant

like 1
a redox sensor
activity gene

TXNRD3
thioredoxin
Thioredoxin reductases (EC 1.6.4.5),
Anti-oxidant

reductase 3
such as TXNRD3, are selenocysteine
activity gene

(sec)-containing flavoenzymes that

maintain thioredoxins, small proteins

that catalyze redox reactions, in the

reduced state using the reducing power

of NADPH, sec residue of TXNRD1

serves as a sensor of reactive oxygen

species.

UHRF2
\ubiquitin-like,
Absence of this gene makes cells more
Anti-oxidant

containing
sensitive to X rays, UV light and
activity gene

PHD and
hydroxyurea

RING finger

domains, 2\“”

VPS8
vacuolar
VPS3, VPS8 and PEP7 genes to rescue
Anti-oxidant

protein sorting
lethal effects of oxidative damage
activity gene

8 homolog (S. cerevisiae)
resulted from the overexpression of

these genes.

PAFAH2
\platelet-
Membrane phospholipids are
Anti-oxidant
Detoxification

activating
susceptible to oxidation, which is
activity gene
activity

factor
involved in various pathological

gene

acetylhydrolase
processes such as inflammation,

2, 40 kDa\“”
atherogenesis, neurodegeneration, and

aging. One enzyme that may help to

remove oxidized phospholipids from

cells is intracellular type II platelet-

activating factor acetylhydrolase (PAF-

AH (II)), which hydrolyzes oxidatively

fragmented fatty acyl chains attached to

phospholipids. Overexpression of PAF-

AH (II) in cells or tissues was previously

shown to suppress oxidative stress-

induced cell death.

ME2
\malic enzyme
The primary role of malic enzyme,
Anti-oxidant

2, NAD(+)-
however, may be to generate reduced
activity gene

dependent,
NADP+ for biosynthesis rather than to

mitochondrial\
form an intermediate of carbohydrate

“”
catabolism. NADPH provides the

reducing equivalents for biosynthetic

reactions and for oxidation-reduction

involved in protection against the toxicity

of ROS

PON2
paraoxonase 2
The encoded protein is ubiquitously
Anti-oxidant

expressed in human tissues, membrane-
activity gene

bound, and may act as a cellular

antioxidant, protecting cells from

oxidative stress. Hydrolytic activity

against acylhomoserine lactones,

important bacterial quorum-sensing

mediators, suggests the encoded protein

may also play a role in defense

responses to pathogenic bacteria.

IVNS1ABP
influenza virus
Protects cells from cell death induced by
Anti-viral

NS1A binding
actin destabilization; Protects neurons

protein
from dendritic spines and actin filaments

damage induced by the actin-

destabilizing cytochalasin B when

overexpressed. May be a component of

the cellular splicing machinery with a

role in pre-mRNA splicing; may mediate

the inhibition of splicing by NS/influenza

virus NS1A protein. Highly present in

neutrophil

ILF3
\interleukin
Nuclear factor of activated T-cells
Anti-viral

enhancer
(NFAT) is a transcription factor required
activity gene

binding factor
for T-cell expression of interleukin 2.

3, 90 kDa\“”
NFAT binds to a sequence in the IL2

enhancer known as the antigen receptor

response element 2. In addition, NFAT

can bind RNA and is an essential

component for encapsidation and

protein priming of hepatitis B viral

polymerase. NFAT is a heterodimer of

45 kDa and 90 kDa proteins, the larger

of which is the product of this gene. The

encoded protein, which is primarily

localized to ribosomes, probably

regulates transcription at the level of

mRNA elongation, required for IL2

mRNA stabilization. Anti-viral activity

SRPK2
SFRS protein
SRPK1 and SRPK2 in HBV replication
Anti-viral

kinase 2
and found that both of them could
activity gene

suppress HBV replication by reducing

the packaging efficiency of the pgRNA

without affecting the formation of the

viral core particles.

PTX3
\pentraxin-
anti-viral activity
Anti-viral

related gene,

activity gene

rapidly

induced by IL-

1 beta\“”

RIPK2
receptor-
Anti-viral response
Anti-viral

interacting

activity gene

serine-

threonine

kinase 2

SMARCE1
\SWI/SNF
Suppression of hepatitis B virus (HBV)
Anti-viral

related, matrix
replication, a causative agent for chronic
activity gene

associated,
hepatitis, is an effective approach to

actin
controlling disease progression. Host

dependent
factors have a significant effect on viral

regulator of
replication efficiency and need to be

chromatin,
better characterized.. Cellular

subfamily e,
transcription modulator SMARCE1 binds

member 1\“”
to HBV core promoter containing

naturally occurring deletions and

represses viral replication.

Transcriptional coactivator cooperating

with nuclear hormone receptors to

potentiate transcriptional activation, he

SWI/SNF chromatin remodeling

complexes are evolutionarily conserved

multimeric enzymatic machines that alter

the nucleosomal structure using energy

derived from ATP hydrolysis (34). Ample

experimental evidence suggests that the

SWI/SNF complexes play important

roles in fundamental cellular processes

such as transcription, replication, and

the repair of chromatin

TLR7
toll-like
TLR7-specific agonists activate
Anti-viral

receptor 7
plasmacytoid DCs (pDCs) and B cells
activity gene

and induce mainly IFN-a and IFN-

regulated cytokines, the natural ligands

of TLR7 and TLR8 were identified as

single-stranded RNA (ssRNA), single

stranded (ss)RNA viruses [either

vesicular stomatitis virus (VSV; a

rhabdovirus) or influenza virus (an

orthomyxovirus)] stimulate type I IFN

responses through TLR7.

ZNF175
zinc finger
OTK18 was copiously expressed in
Anti-viral

protein 175
macrophages following HIV type I
activity gene

infection and diminished progeny virion

production. A mechanism for this

antiretroviral activity was by suppression

of HIV type 1 Tat-induced viral long

terminal repeat promoter activity.

BNIP2
BCL2/adenovirus
Adenovirus E1B 19-kD protein protects
Anti-viral

E1B
against cell death induced by viral
activity gene

19 kDa
infection and certain external stimuli.

interacting

protein 2

CDKN1A
\cyclin-
is an endogenous cellular component in
Anti-viral

dependent
stem cells that provides a molecular
activity gene

kinase
barrier to HIV-1 infection., anti-viral

inhibitor 1A

(p21, Cip1)\“”

CREBZF
CREB/ATF
The neuronal host cell factor-binding
Anti-viral

bZIP
protein Zhangfei inhibits herpes simplex
activity gene

transcription
virus replication.

factor

ELF1
E74-like factor
ELF-1 belongs to a subset of Ets factors
Blood vessel

1 (ets domain
that regulate vascular-specific gene
development

transcription
expression during blood vessel
gene

factor)
development.

NUS1
nuclear
Acts as a specific receptor for the N-
Blood vessel

undecaprenyl
terminus of Nogo-B, a neural and
development

pyrophosphate
cardiovascular regulator. Able to
gene

synthase 1
regulate vascular remodeling and

homolog (S. cerevisiae)
angiogenesis. Its similarity with UPP

synthetase proteins suggests that it may

act as a scaffold for the binding of

isoprenyl lipids and/or prenylated

proteins. Nogo-B receptor localizes with

the ligand Nogo-B during VEGF and

wound healing angiogenesis in vivo,

mediates chemotaxis in a heterologous

expression system and chemotaxis, and

3D tube formation in native endothelial

cells. Thus, identification of this receptor

may lead to the discovery of agonists or

antagonists of this pathway to regulate

vascular remodeling and angiogenesis.

CLIC4
chloride
CLIC4 is involved in formation of the
Blood vessel

intracellular
blood vessel lumen. Blood vessel
development

channel 4
formation. Chloride channel or a
gene

regulator or accessory subunit of other

proteins that could provide the pore-

forming function.

SGPP1
sphingosine-
Sphingosine-1-phosphate (S1P) is a highly
Blood vessel

1-phosphate
bioactive lipid that exerts numerous biological
development

phosphatase 1
effects both intracellularly as a second messenger
gene

and extracellularly by binding to its G-protein-

coupled receptors of the endothelial differentiation

gene family (S1P receptors-(1-5)). Intracellularly,

at least two enzymes, sphingosine kinase and S1P

phosphatase, regulate the activity of S1P by

governing the phosphorylation status of S1P. It is

now well established that S1P is the natural ligand

for specific G protein-coupled receptors (GPCRs),

hereafter referred to as S1PRs. To date, five

members, EDG-1/S1P1, vascular smooth muscle

cells and pericytes to migrate around arteries and

capillaries and properly reinforce

them.angiogenesis.

DMTF1
cyclin D
DMP1 is a pivotal tumor suppressor for
Bone health

binding myb-
both human and murine lung cancers.

like
DMP1 is essential for normal postnatal

transcription
chondrogenesis and subsequent

factor 1
osteogenesis-bone

LEMD3
LEM domain
LEMD3 is involved in both BMP (see
Bone Health

containing 3
112264) and TGF-beta (190180)
Activity Gene

signaling. an integral protein of the inner

nuclear membrane, binds Smad2 and

Smad3 and antagonizes transforming

growth factor-beta signaling. Involved in

multiple bone disorders.

MBTPS1
\membrane-
Site-1 protease (S1P) has an essential
Bone Health

bound
function in the conversion of latent,
Activity Gene

transcription
membrane-bound transcription factors to

factor
their free, active form. In mammals,

peptidase,
abundant expression of S1P in

site 1\“”
chondrocytes suggests an involvement

in chondrocyte function. Catalyzes the

first step in the proteolytic activation of

the sterol regulatory element-binding

proteins (SREBPs). Other known

substrates are BDNF and ATF6.

RPS6KA3
\ribosomal
Rsk2 plays an important role in neuronal
Bone Health

protein S6
plasticity. RSK2 is required for
Activity Gene

kinase,
osteoblast differentiation and function.

90 kDa,
Rsk2-null mice develop progressive

polypeptide
osteopenia due to impaired osteoblast

3\“”
function and normal osteoclast

differentiation.

BCAT1
\branched
This gene encodes the cytosolic form of
Cell health

chain
the enzyme branched-chain amino acid
Maintenance

aminotransferase
transaminase. This enzyme catalyzes
Gene

1,
the reversible transamination of

cytosolic\“”
branched-chain alpha-keto acids to

branched-chain L-amino acids essential

for cell growth.

CEPT1
choline/ethanolamine
Cholinephosphotransferase catalyses
Cell health

phosphotransferase 1
the final step in the synthesis of
Maintenance

phosphatidylcholine by the transfer of
Gene

phosphocholine from CDP-choline to

diacylglycerol. The synthesis of

phosphatidylethanolamine by

ethanolaminephosphotransferase occurs

using an analogous reaction. This gene

codes for a

choline/ethanolaminephosphotransferase.

The protein can synthesize either

choline- or ethanolamine-containing

phospholipids. Phosphatidylcholine is a

class of phospholipids called “essential

phospholipids

DSCR1
Down
The DSCR1 (Adapt78) gene is
Cell health

syndrome
transiently induced by stresses to
Maintenance

critical region
temporarily protect cells against further
Gene

gene 1
potentially lethal challenges.

PAPOLA
poly(A)
Polymerase that creates the 3′ poly(A)
Cell health

polymerase
tail of mRNA's. Also required for the
Maintenance

alpha
endoribonucleolytic cleavage reaction at
Gene

some polyadenylation sites.

HSBP1
heat shock
exert cytoprotection and anti-apoptotic
Cell health

factor binding
effects
Maintenance

protein 1

Gene

METAP1
methionyl
Protein synthesis is initiated with a
Cell health

aminopeptidase 1
methionine residue in eukaryotic cells or
Maintenance

a formylated methionine in prokaryotes,
Gene

mitochondria, and chloroplasts. For a

large subset of proteins, the initiator

methionine is cotranslationally removed

before further posttranslational

modification. The proteolytic removal of

N-terminal methionine is catalyzed by a

family of enzymes known as methionine

aminopeptidases (MetAPs).

SGMS1
sphingomyelin
Suppresses BAX-mediated apoptosis
Cell health

synthase 1
and also prevents cell death in response
Maintenance

to stimuli such as hydrogen peroxide,
Gene

osmotic stress, elevated temperature

and exogenously supplied sphingolipids.

May protect against cell death by

reversing the stress-inducible increase in

levels of proapoptotic ceramide.

Required for cell growth

STK39
\serine
STE20 kinases involved in the regulation
Cell health

threonine
of ion homoeostasis and volume control
Maintenance

kinase 39
in mammalian cells
Gene

(STE20/SPS1

homolog,

yeast)\“”

VCL
vinculin
Involved in cell adhesion. May be
Cell health

involved in the attachment of the actin-
Maintenance

based microfilaments to the plasma
Gene

membrane. May also play important

roles in cell morphology and locomotion.

XPNPEP1
\X-prolyl
prolyl aminopeptidase (EC 3.4.11.9) is a
Cell health

aminopeptidase
proline-specific metalloaminopeptidase
Maintenance

(aminopeptidase
that specifically catalyzes the removal of
Gene

P) 1,
any unsubstituted N-terminal amino acid

soluble\“”
that is adjacent to a penultimate proline

residue. Because of its specificity toward

proline, it has been suggested that X-

prolyl aminopeptidase is important in the

maturation and degradation of peptide

hormones, neuropeptides, and

tachykinins, as well as in the digestion of

otherwise resistant dietary protein

fragments, thereby complementing the

pancreatic peptidases. Deficiency of X-

prolyl aminopeptidase results in

excretion of large amounts of imino-

oligopeptides in urine

NCAPD3
\non-SMC
Regulatory subunit of the condensin II
Chomatin

condensin II
complex, a complex which establishes
stability

complex,
mitotic chromosome architecture and is

subunit D3\“”
involved in physical rigidity of the

chromatid axis.

AOF2
amine
a family of multiprotein corepressor
Chromatin

oxidase (flavin
complexes that function through
modification

containing)
modifying chromatin structure to keep

domain 2
genes silent. The polypeptide

composition of these complexes

includes a common core of 2 subunits,

HDAC1 (601241)/HDAC2 (605164) and

the FAD-binding protein AOF2.

functions as a histone demethylase and

transcriptional corepressor, histone

lysine-specific demethylase LSD1

interacts with p53 (191170) to repress

p53-mediated transcriptional activation,

and to inhibit the role of p53 in

promoting apoptosis.

HMGN1
high-mobility
HMGN1 enhances the rate of heat
Chromatin

group
shock-induced chromatin remodeling in
modification

nucleosome
the HSP70 promoter, thereby leading to

binding
an increase in the levels of HSP70

domain 1
transcripts during the early stages of

heat shock induction.

INOC1
INO80
INOC1 defines a subfamily of
Chromatin

complex
SWI2/SNF2 chromatin remodeling
modification

homolog 1 (S. cerevisiae)
proteins. INOC1 displayed ATPase

activity specific to double-stranded DNA

and exhibited activity on isolated human

mononucleosomes. ATP hydrolysis of

double-stranded DNA occurred in a

linear time course with a calculated Km

of 167 microM, similar to that of other

ATPases of the SNF2/SWI2 family.

PCAF
p300/CBP-
Histone acetyltransferase; Functions as
Chromatin

associated
a histone acetyltransferase (HAT) to
modification

factor
promote transcriptional activation. Has

significant histone acetyltransferase

activity with core histones (H3 and H4),

and also with nucleosome core particles.

RBBP4
retinoblastoma
Core histone-binding subunit that may
Chromatin

binding
target chromatin remodeling factors,
modification

protein 4
histone acetyltransferases and histone

deacetylases to their histone substrates

in a manner that is regulated by

nucleosomal DNA. Component of

several complexes which regulate

chromatin metabolism.

RCBTB1
regulator of
May be involved in cell cycle regulation
Chromatin

chromosome
by chromatin remodeling.
modification

condensation

(RCC1) and

BTB (POZ)

domain

containing

protein 1

TOP2B
topoisomerase
essential for mammalian neural
Chromatin

(DNA) II
development; catalyses topological
modification

beta 180 kDa
genomic changes essential for

chromosome segregation, chromatin

reorganization,

TSN
translin
Translin and TRAX have been proposed
Chromatin

to be involved in DNA recombination,
modification

chromosomal translocation and mRNA

transport and translation.

TSNAX
translin-
Translin and TRAX have been proposed
Chromatin

associated
to be involved in DNA recombination,
modification

factor X
chromosomal translocation and mRNA

transport and translation.

TSPYL1
TSPY-like 1
chromatin remodeling factor
Chromatin

modification

UTX
\ubiquitously
Histone H3 methylation at Lys27 (H3K27
Chromatin

transcribed
methylation) is a hallmark of silent
modification

tetratricopeptide
chromatin, dUTX, specifically

repeat, X
demethylates di- and trimethylated but

chromosome\“”
not monomethylated H3K27, dUTX is

intimately associated with actively

transcribed genes

WAPAL
wings apart-
regulates heterochromatin organization;
Chromatin

like homolog
Wapl is a new regulator of sister
modification

(Drosophila)
chromatid resolution

PHC3
polyhomeotic
Component of the Polycomb group
Chromatin

homolog 3
(PcG) multiprotein PRC1 complex, a
modification

(Drosophila)
complex required to maintain the

transcriptionally repressive state of many

genes, including Hox genes, throughout

development. PcG PRC1 complex acts

via chromatin remodeling and

modification of histones;

CDYL
\chromodomain
Proteins encoded by this gene
Chromatin

protein, Y-
superfamily possess a chromodomain, a
modification

like\“”
motif implicated in chromatin binding

and gene suppression, and a catalytic

domain believed to be involved in

histone acetylation.

CENPJ
centromere
structural role for CPAP to maintain
Chromatin

protein J
centrosome integrity and normal spindle
modification

morphology during cell division.

TPK1
thiamin

Cofactor

pyrophosphokinase 1

biosynthesis

gene

RFK
riboflavin

Cofactor

kinase

biosynthesis

gene

VNN1
vanin 1
VNN1 gene product is involved in the
Cofactor

thymus homing of bone marrow cells
biosynthesis

and in late adhesion steps of thymus
gene

homing under physiologic,

noninflammatory conditions.

Recently VNN1 gene upregulation has

been linked to increased HDL level

The product of CD1c gene is expressed

on cortical thymocytes, immature

myeloid dendritic cells, subset of normal

peripheral B cells and activated T cells

P4HA1
\procollagen-
When expressed intracellularly or
Collagen
Tumor

proline, 2-
exogenously delivered, P4HA1
formation
suppressor

oxoglutarate
significantly inhibited tumor growth in
activity gene
activity

4-
mice. Prolyl 4-hydroxylase (EC

gene

dioxygenase
1.14.11.2) plays a central role in

(proline 4-
collagen synthesis. It catalyzes the

hydroxylase),
formation of 4-hydroxyproline in

alpha
collagens by hydroxylation of proline

polypeptide
residues in peptide linkages. The 4-

I\“”
hydroxyproline residues are essential for

the folding of the newly synthesized

procollagen polypeptide chain into triple

helical molecules.

CHST2
carbohydrate
CHST1 and CHST2 contribute to the
Control of

(N-
generation of optimal L-selectin ligands
inflammation

acetylglucosamine-
in vascular endothelial cells at sites of
activity gene

6-O)
inflammation and thus control

sulfotransferase 2
inflammation.

PAPSS1
3′-
3′-phosphoadenosine 5′-phosphosulfate
Detoxification

phosphoadenosine
(PAPS) synthase (PAPSS) catalyzes the
Activity Gene

5′-
biosynthesis of PAPS which serves as

phosphosulfate
the universal sulfonate donor compound

synthase 1
for all sulfotransferase reactions. PAPSS

forms PAPS in two sequential steps.

First inorganic sulfate combines with

ATP to form adenosine 5′-

phosphosulfate (APS) and

pyrophosphate catalyzed by ATP

sulfurylase domain and in the second

step, APS combines with another

molecule of ATP to form PAPS and ADP

catalyzed by APS kinase domain. The

bifunctional PAPSS1 is comprised of

NH2-terminal APS kinase domain

(approximately 1-260 aa), and a COOH-

terminal ATP sulfurylase domain

(approximately 220-623 aa).. Many

different endogenous and xenobiotic

molecules are substrates for the

sulfotransferases; sulfation affects many

different physiological processes,

including: 1) deactivation and

bioactivation of xenobiotics, 2)

inactivation of hormones and

catecholamines, 3) structure and

function of macromolecules, and 4)

elimination of end products of

catabolism. PAPS is the obligate

cosubstrate that is synthesized in

tissues to make available an “activated

form” of sulfate for the sulfation reaction.

PPA2
pyrophosphatase
Inorganic pyrophosphates are generated
Detoxification

(inorganic) 2
as byproducts of many biosynthetic
Activity Gene

reactions, including DNA and RNA

synthesis, fatty acid and amino acid

activation, and cyclic nucleotide

synthesis. Inorganic pyrophosphatases

(EC 3.6.1.1), such as PPA2, maintain

the thermodynamic favorability of these

reactions by catalyzing the hydrolysis of

pyrophosphates into organic

phosphates, which are then exported

across the cell membrane (Curbo et al.,

2006)

RTN1
reticulon 1
In the presence of high RTN-1C levels,
Detoxification

genotoxic drugs become ineffective as a
Activity Gene

consequence of the cytoplasm

translocation of p53 protein, while the

silencing of endogenous RTN-1C results

in the potentiation of the genotoxic drugs

action. Highly present in CNS. CNS

stem cells?

ATRN
attractin
in its natural serum form, it mediates the
Detoxification
mitochondrial

spreading of monocytes that becomes
Activity Gene,
function

the focus for the clustering of

maintenance

nonproliferating T lymphocytes.

activity

Necessary for proper mitochondrial

gene

function and suppress oxidative stress.

Atrn may play a protective role against

environmental toxins

PGK1
phosphoglycerate
Glycolysis enzyme generating 1
Energy

kinase 1
molecule of ATP
Generation

GLS
glutaminase
human platelets. It is the major enzyme
Energy

yielding glutamate from glutamine.
generation

Significance of the enzyme derives from

its possible implication in behavior

disturbances in which glutamate acts as

a neurotransmitter. platelet

glutaminase activity is entirely

represented by the phosphate

dependent glutaminase or glutaminase I,

most probably localized in the

mitochondrial platelet fraction and

classified by kinetic analysis as a kidney-

type form. The following step of the

glutamine metabolizing pathway,

allowing the entrance of the amino acid

skeleton carbons in the Krebs cycle,

might be catalyzed by both glutamate

dehydrogenase and aspartate

transaminase

GLUD2
glutamate
The following step of the glutamine
Energy

dehydrogenase 2
metabolizing pathway, allowing the
generation

entrance of the amino acid skeleton

carbons in the Krebs cycle, might be

catalyzed by both glutamate

dehydrogenase and aspartate

transaminase

MUT
methylmalonyl
In mammalian cells only two enzymes
Energy

Coenzyme A
are known to require cobalamin (vitamin
generation

mutase
B12) as a cofactor: methionine

synthase, which uses methylcobalamin,

and methylmalonyl-coenzyme A (CoA)

mutase, which uses 5′-deoxyadenosyl-

cobalamin (AdoCbl) Methylmalonyl-CoA

mutase (MUT) (EC 5.4.99.2) is a

mitochondrial enzyme that catalyzes the

isomerization of methylmalonyl-CoA to

succinyl-CoA. Methylmalonyl-CoA

mutase occupies a key position in the

pathway converting propionyl-CoA to

succinyl-CoA, with the catabolism of

isoleucine, methionine, threonine, and

valine, as well as of cholesterol, odd

chain fatty acids, thymine, and uracil

leading to propionyl-CoA production.

The enzyme is, therefore, part of a

gluconeogenic pathway for converting

amino acids, lipids, and pyrimidines to

carbohydrates

PPAT
phosphoribosyl
Phosphopantetheine
Energy

pyrophosphate
adenylyltransferase (PPAT) is an
generation

amidotransferase
essential enzyme in Coenzyme A

biosynthesis. Biosynthesis of coenzyme

A (CoA) from pantothenic acid (vitamin

B5) is an essential universal pathway in

prokaryotes and eukaryotes. COASY is

a bifunctional enzyme that catalyzes the

2 last steps in CoA synthesis.

MTHFR
\5,10-
Methylenetetrahydrofolate reductase
Homocysteine

methylenetetrahydrofolate
(EC 1.5.1.20) catalyzes the conversion
metabolism

reductase
of 5,10-methylenetetrahydrofolate to 5-

(NADPH)\“”
methyltetrahydrofolate, a cosubstrate for

homocysteine remethylation to

methionine.

MTR
5-
The remethylation of homocysteine to
Homocysteine

methyltetrahydrofolate-
form methionine is catalyzed by the
metabolism

homocysteine
cytoplasmic enzyme 5-

methyltransferase
methyltetrahydrofolate-homocysteine S-

methyltransferase (EC 2.1.1.13), which

is also called methionine synthase. This

enzyme requires methylcobalamin

(MeCbl), a derivative of cobalamin, or

vitamin B12, for activity.

MTRR
5-
Methionine is an essential amino acid
Homocysteine

methyltetrahydrofolate-
required for protein synthesis and one
metabolism

homocysteine
carbon metabolism. Its synthesis is

methyltransferase
catalyzed by the enzyme methionine

reductase
synthase. Methionine synthase

eventually becomes inactive due to the

oxidation of its cob(l)alamin cofactor.

The protein encoded by this gene

regenerates a functional methionine

synthase via reductive methylation. It is

a member of the ferredoxin-NADP(+)

reductase (FNR) family of electron

transferases.

ADCY7
adenylate
Necessary for proper Eucaryotic signal
Immune health

cyclase 7
transduction in platelets and other blood

associated cells including natural killer

cells, monocytes, and neutrophils

NCKAP1L
NCK-
Expressed only in cells of hematopoietic
Immune

associated
origin.
Health

protein 1-like

ABCB7
\ATP-binding
essential for hematopoiesis
Immune

cassette, sub-

Health

family B

(MDR/TAP),

member 7\“”

AHI1
Abelson
expression of mouse and human AHI1
Immune

helper
was highest in the most primitive types
Health

integration
of normal hematopoietic cells and was

site 1
downregulated during early

differentiation. This indicates that early

precursors of blood cells are likely

present in the peripheral blood.

CD164
\CD164
myeloid cells, T cells, epithelial cells,
Immune

molecule,
bone marrow stroma cells; adhesion
Health

sialomucin\“”
molecule haem progenitor cells to

stroma

CD200
CD200
Normal brain and B-cell lines
Immune

molecule

Health

CD74
\CD74
B cells, macrophages, monocytes, MHC
Immune health

molecule,
class II positive cells

major

histocompatibility

complex,

class II

invariant

chain\“”

CD83
CD83
Activated B cells, activated T cells,
Immune health

molecule
circulating dendritic cells;

CD8A
CD8a
The CD8 antigen is a cell surface
Immune health

molecule
glycoprotein found on most cytotoxic T

lymphocytes that mediates efficient cell-

cell interactions within the immune

system. The CD8 antigen, acting as a

coreceptor, and the T-cell receptor on

the T lymphocyte recognize antigen

displayed by an antigen presenting cell

(APC) in the context of class I MHC

molecules. Cytotoxic T cells (TC cells, or

CTLs) destroy virally infected cells and

tumor cells, and are also implicated in

transplant rejection. These cells are also

known as CD8+ T cells, since they

express the CD8 glycoprotein at their

surface. Through interaction with helper

T cells, these cells can be transformed

into regulatory T cells, which prevent

autoimmune diseases such as

experimental autoimmune

encephalomyelitis

CERK
ceramide
Catalyzes specifically the
Immune

kinase
phosphorylation of ceramide to form
Health

ceramide 1-phosphate. Ceramide 1-

Phosphate, a Mediator of Phagocytosis,

might function as components of a

‘rheostat’ that regulates immune cell

functions, including mast cell

responsiveness, neutrophil and

macrophage priming, chemotaxis, and

survival of many types of immune cells.

CIAPIN1
cytokine
CIAPIN1, a necessary molecule for
Immune

induced
hematopoiesis that mediates
Health

apoptosis
antiapoptotic effects of various

inhibitor 1
cytokines.

CIITA
\class II,
Highly present in B-lymphocytes. This
Immune health

major
gene encodes a protein with an acidic

histocompatibility
transcriptional activation domain, 4

complex,
LRRs (leucine-rich repeats) and a GTP

transactivator\
binding domain. The protein is located in

“”
the nucleus and acts as a positive

regulator of class II major

histocompatibility complex gene

transcription, and is referred to as the

“master control factor” for the expression

of these genes. Mutations (lack of

fuction) in this gene have been

associated with bare lymphocyte

syndrome type II (also known as

hereditary MHC class II deficiency or

HLA class II-deficient combined

immunodeficiency), increased

susceptibility to rheumatoid arthritis,

multiple sclerosis, and possibly

myocardial infarction.

CLEC10A
\C-type lectin
Probable role in regulating adaptive and
Immune

domain family
innate immune responses. Binds in a
Health

10, member
calcium-dependent manner to terminal

A\“”
galactose and N-acetylgalactosamine

units, linked to serine or threonine.

CPNE3
copine III
copine III were expressed in the more
Immune

immature neutrophil precursors
Health

CPVL
\carboxypeptidase,
CPVL protein expression was induced
Immune

vitellogenic-
during maturation of monocytes into
Health

like\“”
macrophages.

CTNNB1
\catenin
Hematopoietic stem cells (HSCs) have
Immune

(cadherin-
the ability to renew themselves and to
Health

associated
give rise to all lineages of the blood.

protein), beta
Reya et al. (2003) showed that the WNT

1, 88 kDa\“”
signaling pathway has an important role

in this process. Overexpression of

activated beta-catenin expands the pool

of HSCs in long-term cultures by both

phenotype and function, beta-catenin is

essential for fate decisions of skin stem

cells: in the absence of beta-catenin,

stem cells failed to differentiate into

follicular keratinocytes and instead

adopted an epidermal fate

CTSC
cathepasin C
Needed for activity and stability of
Immune

neutrophil-derived serine proteases.
Health

CYFIP2
cytoplasmic
Necessary for T-cell adhesion function
Immune

FMR1

Health

interacting

protein 2

DPP8
dipeptidyl-
involve in immune functions
Immune

peptidase 8

Health

DPP9
dipeptidyl-
involve in immune functions
Immune

peptidase 9

Health

DPYSL2
dihydropyrimidinase-
involved in T-cell polarization and
Immune

like 2
migration.
Health

DUSP5
dual
Mkp5-deficient cells produced greatly
Immune

specificity
enhanced levels of proinflammatory
Health

phosphatase 5
cytokines during innate immune

responses and exhibited greater T-cell

activation than their wildtype

counterparts. However, Mkp5-deficient T

cells proliferated poorly upon activation,

which resulted in increased resistance to

experimental autoimmune

encephalomyelitis. By contrast, Mkp5-

deficient CD4+ (186940) and CD8+

(186910) effector T cells produced

significantly increased levels of

cytokines compared with wildtype cells,

which led to much more robust and

rapidly fatal immune responses to

secondary infection with lymphocytic

choriomeningitis virus. Zhang et al.

(2004) concluded that MKP5 has a

principal function in both innate and

adaptive immune responses.

EDG1
\endothelial
Adaptive immunity depends on T-cell
Immune

differentiation,
exit from the thymus and T and B cells
Health

sphingolipid
travelling between secondary lymphoid

G-protein-
organs to survey for antigens. After

coupled
activation in lymphoid organs, T cells

receptor, 1\“”
must again return to circulation to reach

sites of infection; however, the

mechanisms regulating lymphoid organ

exit are unknown. S1P1-dependent

chemotactic responsiveness is strongly

upregulated in T-cell development

before exit from the thymus, whereas

S1P1 is downregulated during peripheral

lymphocyte activation, and this is

associated with retention in lymphoid

organs.

FCRL5
Fc receptor-
May be involved in B-cell development
Immune

like 5
and differentiation in peripheral lymphoid
Health

organs and may be useful markers of B-

cell stages. May have an

immunoregulatory role in marginal zone

B-cells.

FER
fer (fps/fes
Fps/Fes modulates the innate immune
Immune

related)
response of macrophages to LPS, in
Health

tyrosine
part, by regulating internalization and

kinase
down-regulation of the TLR4 receptor

(phosphoprotein
complex. Fps/Fes and Fer are members

NCP94)
of a distinct subfamily of cytoplasmic

protein tyrosine kinases that have

recently been implicated in the

regulation of innate immunity, evidence

for functional redundancy between Fps

and Fer kinases in regulating

hematopoiesis.

FLT3
fms-related
CD135 is a cytokine receptor expressed
Immune

tyrosine
on the surface of hematopoietic
Health

kinase 3
progenitor cells. Signaling through

CD135 plays a role in cell survival,

proliferation, and differentiation. CD135

is important for lymphocyte (B cell and T

cell) development, but not for the

development of other blood cells

(myeloid development).

NKTR
natural killer-
The natural killer triggering receptor
Immune

tumor
(NKTR) is involved in the recognition of
Health

recognition
tumor cells by large granular

sequence
lymphocytes (LGLs) (Frey et al., 1991;

Anderson et al., 1993). LGLs are a

subpopulation of white blood cells that

have the ability to kill target tumor cells

by an MHC-independent mechanism.

The protein product of the NKTR gene is

present on the surface of LGLs and

facilitates their binding to tumor targets.

The gene codes for a protein of 150,000

Da, with a unique amino acid structure

consisting of a 58-amino acid

hydrophobic amino terminus followed by

a cyclophilin-related domain.

PABPC4
\poly(A)
might be necessary for regulation of
Immune

binding
stability of labile mRNA species in
Health

protein,
activated T cells.

cytoplasmic 4

(inducible

form)\“”

PAG1
phosphoprotein
Absence of external stimuli, the PAG-
Immune health

associated
Csk complex transmits negative

with
regulatory signals and thus may help to

glycosphingolipid
keep resting T cells in a quiescent state.

microdomains 1
PAG-CSK complex increases the

signaling threshold required for initiating

an immune response, thus helping to

keep lymphocytes in a resting state.

ADRBK2
\adrenergic,
Specifically phosphorylates the agonist-
Immune health

beta, receptor
occupied form of the beta-adrenergic

kinase 2\“”
and closely related receptors, in

leukocytes from patients with active

relapsing-remitting multiple sclerosis

(MS) or with secondary progressive MS,

GRK2 levels are significantly reduced,

probable role in immune Maintenance

and health

GFI1
growth factor
Gfi1 maintained hematopoietic stem cell
Immune health

independent 1
self-renewal, multilineage differentiation,

and efficient reconstitution of

hematopoiesis in transplanted hosts by

restricting stem cell proliferation

GPR34
G protein-
GPR34 is the functional mast cell lysoPS
Immune health

coupled
receptor. Lysophosphatidyl-L-serine

receptor 34
(lysoPS) is thought to be an

immunological regulator

GPR44
G protein-
This receptor also called, CRTH2 is a
Immune health

coupled
receptor for PGD2, PGD2 functions as a

receptor 44
neuromodulator as well as a trophic

factor in the central nervous system.

PGD2 is also involved in smooth muscle

contraction/relaxation and is a potent

inhibitor of platelet aggregation,

receptor for prostaglandin (PG) D(2),

which is a major mast cell product

released during the allergic response.

CRTH2 mediates the chemotaxis of

eosinophils, basophils, and Th2

lymphocytes

HHEX
hematopoietically
Transcriptional repressor. May play a
Immune health

expressed
role in hematopoietic differentiation.

homeobox

ID2
\inhibitor of
Id2 has an essential role in the
Immune health

DNA binding
generation of peripheral lymphoid

2, dominant
organs and NK cells. D (inhibitor of DNA

negative
binding) HLH proteins lack a basic DNA-

helix-loop-
binding domain but are able to form

helix protein\“”
heterodimers with other HLH proteins,

thereby inhibiting DNA binding,

importance of Id2 in regulating gene

expression by CD8(+) T cells and the

magnitude of effector responses,

suggesting a mechanism involving Id

protein- and E protein-mediated survival

and differentiation of mature T cells,

helix-loop-helix (HLH) transcription factor

Id2 (inhibitor of DNA

binding/differentiation 2) acts as a

molecular switch in development of

Langerhans cells (LCs), the cutaneous

contingent of dendritic cells (DCs), and

of specific DC subsets and B cells.

IL10RA
\interleukin 10
The protein encoded by this gene is a
Immune health

receptor,
receptor for interleukin 10. This protein is

alpha\“”
structurally related to interferon

receptors. It has been shown to mediate

the immunosuppressive signal of

interleukin 10, and thus inhibits the

synthesis of proinflammatory cytokines.

This receptor is reported to promote

survival of progenitor myeloid cells

through the insulin receptor substrate-

2/PI 3-kinase/AKT pathway. Activation of

this receptor leads to tyrosine

phosphorylation of JAK1 and TYK2

kinases.

IL7R
interleukin 7
This protein has been shown to play a
Immune health

receptor
critical role in the V(D)J recombination

during lymphocyte development. This

protein is also found to control the

accessibility of the TCR gamma locus by

STAT5 and histone acetylation.

Knockout studies in mice suggested that

blocking apoptosis is an essential

function of this protein during

differentiation and activation of T

lymphocytes. The functional defects in

this protein may be associated with the

pathogenesis of the severe combined

immunodeficiency (SCID). Receptor for

interleukin-7. Also acts as a receptor for

thymic stromal lymphopoietin

IRF8
interferon
ICSBP in regulating the proliferation
Immune health

regulatory
and differentiation of hematopoietic

factor 8
progenitor cells, antiviral responses

associated with impaired production of

IFN-gamma

ITK
IL2-inducible
Tec kinases Itk and Rlk provide
Immune health

T-cell kinase
important signals for terminal maturation,

efficient cytokine production, and

peripheral survival of NKT cells. This

gene encodes an intracellular tyrosine

kinase expressed in T-cells. The protein

contains both SH2 and SH3 domains

which are often found in intracellular

kinases. It is thought to play a role in T-

cell proliferation and differentiation.

JAK1
Janus kinase
Tyrosine kinase of the non-receptor
Immune health

1 (a protein
type, involved in the IFN-

tyrosine
alpha/beta/gamma signal pathway.

kinase)
Kinase partner for the interleukin (IL)-2

receptor. The Janus kinase-signal

transducer and activator of transcription

(Jak-Stat) pathway stands as a

paradigm of how diverse extracellular

signals can elicit rapid changes in gene

expression in specific target cells. This

pathway is widely used by members of

the cytokine receptor superfamily,

including those for the clinically

important cytokines granulocyte colony-

stimulating factor (G-CSF),

erythropoietin, thrombopoietin, the

interferons, and numerous interleukins,

which makes it central to hematopoietic

cell biology and hematologic therapy

alike. Impaired lymphoid development

in the absensce of JAK1

JMJD1A
jumonji
Jmjd1a and Jmjd2c histone H3 Lys 9
Immune health

domain
demethylases regulate self-renewal in

containing 1A
embryonic stem cells.

JMJD2C
jumonji
Jmjd1a and Jmjd2c histone H3 Lys 9
Immune health

domain
demethylases regulate self-renewal in

containing 2C
embryonic stem cells.

KIR2DS2
\killer cell
Killer-cell immunoglobulin-like receptors
Immune health

immunoglobulin-
(KIRs), are a family of cell surface

like
proteins found on important cells of the

receptor, two
immune system called natural killer (NK)

domains,
cells. They regulate the killing function of

short
these cells by interacting with MHC class

cytoplasmic
I molecules, which are expressed on all

tail, 2\“”
cell types. This interaction allows them

to detect virally infected cells or tumor

cells that have a characteristic low level

of Class I MHC on their surface. Most

KIRs are inhibitory, meaning that their

recognition of MHC suppresses the

cytotoxic activity of their NK cell. Only a

limited number of KIRs have the ability

to activate cells. This gene is an

activating receptor.

KLRC1
\killer cell
Natural killer (NK) cells are lymphocytes
Immune health

lectin-like
that can mediate lysis of certain tumor

receptor
cells and virus-infected cells without

subfamily C,
previous activation. They can also

member 1\“”
regulate specific humoral and cell-

mediated immunity. NK cells

preferentially express several calcium-

dependent (C-type) lectins, which have

been implicated in the regulation of NK

cell function.

L3MBTL3
l(3)mbt-like 3
H-L(3)MBT protein, whose deletion is
Immune health

(Drosophila)
predicted to be responsible for myeloid

hematopoietic malignancies, tumor

suppressor gene.

MEMO1
mediator of
Highly present in NK cells and other
Immune health

cell motility 1
hematopoeitic cells

NAGA
\N-
Highly present in monocytes (Ascenta)
Immune health

acetylgalactos
what are the implications? lysosomal

aminidase,
glycohydrolase that cleaves alpha-N-

alpha-\“”
acetylgalactosaminyl moieties from

glycoconjugates.

NDFIP1
Nedd4 family
Ndfip1 protein promotes the function of
Immune health

interacting
itch ubiquitin ligase to prevent T cell

protein 1
activation and T helper 2 cell-mediated

inflammation.

NR1D2
\nuclear
Heme as the ligand
Immune health

receptor

subfamily 1,

group D,

member 2\“”

PRNP
\prion protein
PrPc is expressed on hematopoietic
Immune health
Red blood

(p27-30)
cells, including erythroid precursors.

cell health

(Creutzfeldt-
Prion protein is expressed on long-term

Jakob
repopulating hematopoietic stem cells

disease,
and is important for their self-renewal.

Gerstmann-
PrP is a marker for long-term

Strausler-
hematopoietic stem cells. Prion protein

Scheinker
expression may be involved in both the

syndrome,
metabolism of copper and resistance to

fatal familial
oxidative stress, neuroprotective role of

insomnia)\“”
cellular prion protein (PrPC) rion protein

interferes with divalent metal Mn uptake

and protects against Mn-induced

oxidative stress

PSCD1
\pleckstrin
Members of this family appear to
Immune health

homology,
mediate the regulation of protein sorting

Sec7 and
and membrane trafficking. The PSCD1

coiled-coil
is highly expressed in natural killer and

domains
peripheral T cells, and regulates the

1(cytohesin
adhesiveness of integrins at the plasma

1)\“”
membrane of lymphocytes.

PTGER4
prostaglandin
This receptor can activate T-cell factor
Immune health

E receptor 4
signaling. It has been shown to mediate

(subtype EP4)
PGE2 induced expression of early

growth response 1 (EGR1), regulate the

level and stability of cyclooxygenase-2

mRNA, and lead to the phosphorylation

of glycogen synthase kinase-3.

Knockout studies in mice suggest that

this receptor may be involved in the

neonatal adaptation of circulatory

system, osteoporosis, as well as

initiation of skin immune responses.

Receptor for prostaglandin E2 (PGE2).

The activity of this receptor is mediated

by G(s) proteins that stimulate adenylate

cyclase. Has a relaxing effect on smooth

muscle. May play an important role in

regulating renal hemodynamics,

intestinal epithelial transport, adrenal

aldosterone secretion, and uterine

function.

PTPN11
\protein
Shp-2 is a widely expressed nonreceptor
Immune health

tyrosine
protein tyrosine phosphatase that

phosphatase,
participates early in hematopoietic

non-receptor
development.

type 11

(Noonan

syndrome

1)\“”

PTPN22
\protein
This gene encodes a protein tyrosine
Immune health

tyrosine
phosphatase which is expressed

phosphatase,
primarily in lymphoid tissues. This

non-receptor
enzyme associates with the molecular

type 22
adapter protein CBL and may be

(lymphoid)\“”
involved in regulating CBL function in

the T-cell receptor signaling pathway.

PTPRC
\protein
This gene is specifically expressed in
Immune health

tyrosine
hematopoietic cells. This PTP has been

phosphatase,
shown to be an essential regulator of T-

receptor type,
and B-cell antigen receptor signaling. It

C\“”
functions through either direct interaction

with components of the antigen receptor

complexes, or by activating various Src

family kinases required for the antigen

receptor signaling. This PTP also

suppresses JAK kinases, and thus

functions as a regulator of cytokine

receptor signaling.

RASSF5
Ras
Potential tumor suppressor. Seems to
Immune health

association
be involved in lymphocyte adhesion by

(RalGDS/AF-
linking RAP1A activation upon T cell

6) domain
receptor or chemokine stimulation to

family 5
integrin activation. Isoform 2 stimulates

lymphocyte polarization and the patch-

like distribution of ITGAL/LFA-1,

resulting in an enhanced adhesion to

ICAM1. Together with RAP1A may

participate in regulation of microtubule

growth. The association of isoform 2 with

activated RAP1A is required for

directional movement of endothelial cells

during wound healing

RFX5
\regulatory
MHC class II molecules play a key role
Immune health

factor X, 5
in the immune system. They present

(influences
exogenous antigenic peptides to the

HLA class II
receptor of CD4+ T-helper lymphocytes,

expression)\“”
thereby triggering the antigen-specific T-

cell activation events required for the

initiation and sustenance of immune

responses.. Activates transcription from

class II MHC promoters. Differentiation

of hematopoietic stem and progenitors

cells is an intricate process controlled in

large part at the level of transcription.

new transcriptional regulators of

megakaryopoiesis.

SENP6
SUMO1/sentrin
important in adult hematopoietic self-
Immune health

specific
renewal

peptidase 6

SERPINB9
\serpin
The intracellular granzyme B inhibitor,
Immune health

peptidase
proteinase inhibitor 9, is up-regulated

inhibitor,
during accessory cell maturation and

clade B
effector cell degranulation, and its

(ovalbumin),
overexpression enhances CTL (cytotoxic

member 9\“”
lymphocyte) potency, the presence and

subcellular localization of PI-9 in

leukocytes and DCs are consistent with

a protective role against ectopic or

misdirected grB during an immune

response.

SOX4
SRY (sex
Sox4 contribute to the survival and
Immune health

determining
proliferation of pro-B cells in response to

region Y)-box 4
extracellular signals.

SPEN
\spen
The ability of Ott1 to affect
Immune health

homolog,
hematopoietic cell fate and expansion in

transcriptional
multiple lineages is a novel attribute for

regulator
a spen family member and delineates

(Drosophila)\“”
Ott1 from other known effectors of

hematopoietic development.

SYBL1
synaptobrevin-
VAMP-7 is a crucial component of
Immune health

like 1
granzyme B release and target cell

killing in the NK cell

TMPO
thymopoietin
It is possible that TCERG1 interacts with
Immune health

the nascent transcript (or RNP) and

directly alters splicing decisions. This

could be consistent with independent

effects on transcription elongation and

alternative processing. Alternatively,

TCERG1 could work at

VNN1
vanin 1
VNN1 gene product is involved in the
Immune health

thymus homing of bone marrow cells

and in late adhesion steps of thymus

homing under physiologic,

noninflammatory conditions.

Recently VNN1 gene upregulation has

been linked to increased HDL level

The product of CD1c gene is expressed

on cortical thymocytes, immature

myeloid dendritic cells, subset of normal

peripheral B cells and activated T cells

ZFX
\zinc finger
Zfx controls the self-renewal of
Immune health

protein, X-
embryonic and hematopoietic stem cells.

linked\“”
Zfx as a shared transcriptional regulator

of ESC and HSC, suggesting a common

genetic basis of self-renewal in

embryonic and adult SC.

ZNF317
zinc finger
ZNF317 may play an important role in
Immune health
Red blood

protein 317
erythroid maturation and lymphoid

cell health

proliferation

ZNF589
zinc finger
Characterization of SZF1 implicates its
Immune health

protein 589
role in hematopoiesis.

OGT
O-linked N-
The regulation of topoisomerase I (topo
Immune

acetylglucosamine
I) activity is of prime importance for gene
Health

(GlcNAc)
expression. It participates in DNA

transferase
replication, transcription, recombination,

(UDP-N-
and DNA repair, and serves as a target

acetylglucosamine:
for anticancer drugs. Many proteins and

polypeptide-
enzymes are modified by O-linked beta-

N-
N-acetylglucosamine (O-GlcNAc), which

acetylglucosaminyl
exerts profound effects on their function.

transferase)
OGT is a central factor for T- and B-

lymphocytes activation.. OGT

participation in intracellular glycosylation

is essential for embryonic stem cell

viability

PIK3R1
\phosphoinositide-
Important in adult hematopoietic self-
Immune

3-kinase,
renewal
Health

regulatory

subunit 1 (p85

alpha)\“”

NKRF
NF-kappaB
Interacts with a specific negative
Inflammation

repressing
regulatory element (NRE) 5′-
control

factor
AATTCCTCTGA-3′ to mediate

transcriptional repression of certain NK-

kappa-B responsive genes. NF-κB-

repressing factor (NRF) is a

constitutively expressed nuclear

transcription factor that binds to beta

interferon (IFN-β), interleukin-8 (IL-8),

and inducible nitric oxide synthase

(iNOS) promoters and represses the

basal transcription of these genes

NR3C1
\nuclear
The glucocorticoid receptor (GR) is a
Inflammation

receptor
ligand-dependent transcription factor
control

subfamily 3,
belonging to the nuclear hormone

group C,
receptor superfamily. Due to its almost

member 1
ubiquitous expression, GR plays an

(glucocorticoid
important role in many physiological and

receptor)\“”
pathological processes. These include

regulation of homeostasis, adaptation to

stress, and modulation of central

nervous system. In addition, GR is a

major modulator of the immune system

due to its proficient anti-inflammatory

and immunosuppressive activity; and its

function is important for proper

regulation of many physiological

processes.

ZCCHC11
\zinc finger,
ZCCHC11 is a unique TLR signal
Inflammation

CCHC
regulator, which interacts with TIFA after
control

domain
LPS treatment and suppresses the

containing
TRAF6-dependent activation of NF-

11\“”
kappaB.

SIRT1
sirtuin (silent
Longevity gene
Longevity

mating type

gene

information

regulation 2

homolog) 1

(S. cerevisiae)

YTHDF2
\YTH domain
A polymorphism of the YTHDF2 gene
Longevity

family,
(1p35) located in an Alu-rich genomic
gene

member 2\“”
domain is associated with human

longevity.

AP15
apoptosis
Survival gene or anti-apoptotic gene
Longevity

inhibitor 5

gene

ARNT
aryl
Bmal1-null mice lose circadian
Longevity

hydrocarbon
rhythmicity but also display tendon
gene

receptor
calcification and decreased activity,

nuclear
body weight, and longevity

translocator

FRAP1
FK506
a gene expression signature associated
Longevity

binding
with mammalian target of rapamycin
gene

protein 12-
(mTOR) activity that was down-regulated

rapamycin
with age but preserved by CR in both

associated
WAT and heart, mammalian cells the

protein 1
mammalian TOR (mTOR) pathway plays

a significant role in determining both

resting oxygen consumption and

oxidative capacity, mTOR activity may

play an important role in determining the

relative balance between mitochondrial

and non-mitochondrial sources of ATP

generation.

HSPA9
heat shock
this member of the hsp70 family governs
Longevity

70 kDa protein
the longevity of worms and thus there
gene

9 (mortalin)
are common pathways that determine

mammalian and worm longevity

POLG2
\polymerase
Mitochondrial polymerase processivity
Mitochondrial

(DNA
subunit. Stimulates the polymerase and
DNA Health

directed),
exonuclease activities, and increases

gamma 2,
the processivity of the enzyme. Binds to

accessory
sc-DNA.

subunit\“”

OPA1
optic atrophy
Mitochondrial health is defined by
Mitochondrial

1 (autosomal
various parameters including fusion and
Health

dominant)
fission events. In older cells, giant

mitochondria accumulates. This is

because of insufficient autophagy.

These giants don't fuse with each other

or with normal mitochondria and it was

noticed that OPA1 is reduced in these

giant mitochondria, mitochondria fuse

and divide to change their morphology in

response to a multitude of signals.

During the past decade, work using

yeast and mammalian cells has

identified much of the machinery

required for fusion and division,

including the dynamin-related GTPases--

mitofusins (Fzo1p in yeast) and OPA1

(Mgm1p in yeast) for fusion and Drp1

(Dnm1p) for division. Mitochondrial fusion

requires coordinated fusion of the outer

and inner membranes. This process

leads to exchange of contents, controls

the shape of mitochondria, and is

important for mitochondrial function.

OPA1 is a major organizer of the

mitochondrial inner membrane and is

required for the maintenance of cristae

integrity. As the loss of OPA1 committed

cells to apoptosis without any other

stimulus. Olichon et al. (2003) proposed

that OPA1 is involved in the

sequestration of cytochrome c, and that

OPA1 may be a target for mitochondrial

apoptotic effectors.

PDSS2
\prenyl
PDSS2 gene, which encodes a subunit
Mitochondrial

(decaprenyl)
of decaprenyl diphosphate synthase, the
Health

diphosphate
first enzyme of the CoQ(10) biosynthetic

synthase,
pathway.

subunit 2\“”

MFN1
mitofusin 1
The regulated equilibrium between
Mitochondrial

mitochondrial fusion and fission is
Health

essential to maintain integrity of the

organelle. Mechanisms of mitochondrial

fusion are largely uncharacterized in

mammalian cells. It is unclear whether

OPA1, a dynamin-related protein of the

inner membrane mutated in autosomal

dominant optic atrophy, participates in

fusion or fission. OPA1 promoted the

formation of a branched network of

elongated mitochondria, requiring the

integrity of both its GTPase and C-

terminal coiled-coil domain. Stable

reduction of OPA1 levels by RNA

interference resulted in small,

fragmented, and scattered mitochondria.

Levels of OPA1 did not affect

mitochondrial docking, but they

correlated with the extent of fusion as

measured by polyethylene glycol

mitochondrial fusion assays. A genetic

analysis proved that OPA1 was unable

to tubulate and fuse mitochondria

lacking the outer membrane mitofusin 1

but not mitofusin 2. Our data show that

OPA1 functionally requires mitofusin 1 to

regulate mitochondrial fusion and reveal

a specific functional difference between

mitofusin 1 and 2.

MTRF1L
mitochondrial

Mitochondrial

translational

Health

release factor

1-like

NDUFC2
\NADH
Accessory subunit of the mitochondrial
Mitochondrial

dehydrogenase
membrane respiratory chain NADH
Health

(ubiquinone)
dehydrogenase (Complex I), that is

1,
believed to be not involved in catalysis.

subcomplex
Complex I functions in the transfer of

unknown, 2,
electrons from NADH to the respiratory

14.5 kDa\“”
chain. The immediate electron acceptor

for the enzyme is believed to be

ubiquinone.

NDUFS1
\NADH
Core subunit of the mitochondrial
Mitochondrial

dehydrogenase
membrane respiratory chain NADH
Health

(ubiquinone)
dehydrogenase (Complex I) that is

Fe—S protein
believed to belong to the minimal

1.75 kDa
assembly required for catalysis.

(NADH-
Complex I functions in the transfer of

coenzyme Q
electrons from NADH to the respiratory

reductase)\“”
chain. The immediate electron acceptor

for the enzyme is believed to be

ubiquinone (By similarity). This is the

largest subunit of complex I and it is a

component of the iron-sulfur (IP)

fragment of the enzyme. It may form part

of the active site crevice where NADH is

oxidized.

SDHD
\succinate
Complex II of the respiratory chain,
Mitochondrial

dehydrogenase
which is specifically involved in the
Health

complex,
oxidation of succinate, carries electrons

subunit D,
from FADH to CoQ. The complex is

integral
composed of four nuclear-encoded

membrane
subunits and is localized in the

protein\“”
mitochondrial inner membrane.

ENC1
ectodermal-
Highly present in neuronal cells (and
Nervous

neural cortex
brain tissues from Ascenta-almost
System Health

(with BTB-like
absent in other tissues) and involved in

domain)
neuronal differentiation. Likely a Redox

controlling protein

ADNP
activity-
Involved in proper lipid metabolism,
Nervous

dependent
coagulation as well as in neurogenesis.
System Health

neuroprotector
Multiple Roles in Neuronal

Differentiation and Maintenance,

neuroprotective protein

AGTPBP1
ATP/GTP
zinc carboxypeptidase that contains
Nervous

binding
nuclear localization signals and an
System Health

protein 1
ATP/GTP-binding motif that was initially

cloned from regenerating spinal cord

neurons of the mouse. Role in

preventing neurodegeneration.

OAT
ornithine
OAT encodes the mitochondrial enzyme
Nervous

aminotransferase
ornithine aminotransferase, which is a
system health

(gyrate
key enzyme is the pathway that converts

atrophy)
arginine and ornithine into the major

excitatory and inhibitory

neurotransmitters glutamate and GABA.

Vitamin B6 dependent enzyme.

PTDSS1
Phosphatidylserine
Phosphatidylserine (PS or PtdSer) is a
Nervous

synthase 1
phospholipid nutrient found in fish, green
system health

leafy vegetables, soybeans, and rice,

and is essential for the normal

functioning of neuronal cell membranes,

activating protein kinase C (PKC), which

has been shown to be involved in

memory function. PS has been

investigated in a small number of

double-blind placebo trials and has been

shown to increase memory performance

in the elderly. Because of the potential

cognitive benefits of phosphatidylserine,

the substance is sold as a dietary

supplement to people that believe they

can benefit from an increased intake.

SPOCK2
\sparc/osteonectin,
May participate in diverse steps of
Nervous

cwcv
neurogenesis
system health

and kazal-like

domains

proteoglycan

(testican) 2\“”

ADSS
adenylosuccinate
carries out the first of a 2-step sequence
Nucleotide

synthase
in the biosynthesis of AMP from IMP.
Biosynthesis

Plays an important role in the de novo

pathway of purine nucleotide

biosynthesis. AMP, is a nucleotide that

is found in RNA.

DCTD
dCMP
Supplies the nucleotide substrate for
Nucleotide

deaminase
thymidylate synthetase which is the
Biosynthesis

enzyme used to generate thymidine

monophosphate (dTMP), which is

subsequently phosphorylated to

thymidine triphosphate for use in DNA

synthesis and repair.

HPRT1
hypoxanthine
HPRT1 has a central role in the
Nucleotide

phosphoribosyltransferase
generation of purine nucleotides through
biosynthesis

1 (Lesch-
the purine salvage pathway. HPRT1

Nyhan
catalyzes conversion of hypoxanthine to

syndrome)
inosine monophosphate and guanine to

guanosine monophosphate via transfer

of the 5-phosphoribosyl group from 5-

phosphoribosyl 1-pyrophosphate

PRPS1
phosphoribosyl
Phosphoribosylpyrophosphate
Nucleotide

pyrophosphate
synthetase (PRPS; EC 2.7.6.1)
biosynthesis

synthetase 1
catalyzes the phosphoribosylation of

ribose 5-phosphate to 5-phosphoribosyl-

1-pyrophosphate, which is necessary for

the de novo and salvage pathways of

purine and pyrimidine biosynthesis

CMPK
cytidylate
Uridine monophosphate (UMP)/cytidine
Nucleotide
Mitochondrial

kinase
monophosphate (CMP) kinase (EC
Biosynthesis
Health

2.7.4.4) catalyzes the phosphoryl

transfer from ATP to UMP, CMP, and

deoxy-CMP (dCMP), resulting in the

formation of ADP and the corresponding

nucleoside diphosphate. These

nucleoside diphosphates are required

for cellular nucleic acid synthesis.

Enzyme deficiency in the salvage

pathway of deoxyribonucleotide

synthesis in mitochondria can cause

mtDNA depletion syndromes.

Maintenance of mitochondrial health.

ABCD3
\ATP-binding
Peroxisome biogenesis
Peroxisome

cassette, sub-

Health

family D

(ALD),

member 3\“”

ABCD4
\ATP-binding
Peroxisome biogenesis
Peroxisome

cassette, sub-

Health

family D

(ALD),

member 4\“”

PEX12
peroxisomal

Peroxisome

biogenesis

Health

factor 12

PEX3
peroxisomal

Peroxisome

biogenesis

Health

factor 3

RABGAP1L
RAB GTPase
Lower levles in platelet dysfunction
Platelet health

activating

protein 1-like

CANX
calnexin
Calcium-binding protein that interacts
Protein quality

with newly synthesized glycoproteins in
control

the endoplasmic reticulum. It may act in

assisting protein assembly and/or in the

retention within the ER of unassembled

protein subunits. It seems to play a

major role in the quality control

apparatus of the ER by the retention of

incorrectly folded proteins.

CLPX
ClpX
Clp ATPases are protein machines
Protein quality

caseinolytic
involved in protein degradation. The
control

peptidase X
ClpXP ATPase-protease complex is a

homolog (E. coli)
major component of the protein quality

control machinery in the cell.

DERL1
\Der1-like
Derlin-1 is an important factor for the
Protein quality

domain
extraction of certain aberrantly folded
control

family,
proteins from the mammalian ER.

member 1\“”
Functional component of endoplasmic

reticulum-associated degradation

(ERAD) for misfolded lumenal proteins.

May act by forming a chann

DNAJA1
\DnaJ
Human DnaJ 2 (Hdj-2) is a co-
Protein quality

(Hsp40)
chaperone of heat shock cognate 70
control

homolog,
(Hsc70) which is localized to the

subfamily A,
cytosolic face of the ER. Necessary for

member 1\“”
proper folding of proteins and therefore

proper functions of various proteins.

EDEM3
\ER
enhances glycoprotein endoplasmic
Protein quality

degradation
reticulum-associated degradation and
control

enhancer,
mannose trimming, accelerates ERAD of

mannosidase
misfolded glycoproteins.

alpha-like 3\“”

OMA1
\OMA1
The integrity of the inner membrane of
Protein quality

homolog, zinc
mitochondria is maintained by a
control

metallopeptidase
membrane-embedded quality control

S. cerevisiae)\
system that ensures the removal of

“”
misfolded membrane proteins. Two

ATP-dependent AAA proteases with

catalytic sites at opposite membrane

surfaces are key components of this

proteolytic system, identify Oma1 as a

novel component of the quality control

system in the inner membrane of

mitochondria. Mitochondrial protease

CTSO
cathepsin O
normal cellular protein degradation and
Protein quality

tumover
control

HSP90AB1
\heat shock
HSP90's function in the regulation and
Protein quality

protein 90 kDa
correct folding of at least 100
control

alpha
proteins[26] allows it to refold and/or

(cytosolic),
degrade these products before they

class B
trigger cell death. They participate in the

member 1\“”
regulation of the stress response [2, 3]

and, when associated with other co-

chaperones, function in correctly folding

newly synthesized proteins, stabilizing

and refolding denatured proteins after

stress, preventing misfolding and

aggregation of unfolded or partially

folded proteins, and assisting in protein

transport across the endoplasmic

reticulum (ER) and organellar

membranes [4-8]. HSP90 members

have key roles in the maturation of

signal transduction proteins, like

hormone receptors, various kinases,

nitric oxide synthase and calcineurin

HSPBAP1
HSPB (heat

Protein quality

shock 27 kDa)

control

associated

protein 1

NGLY1
N-glycanase 1
N-glycanase is a highly conserved
Protein quality

enzyme that catalyzes deglycosylation
control

of misfolded N-linked glycoproteins by

cleaving the glycan chain before the

proteins are degraded by the

proteasome

SACS
spastic ataxia
The presence of heat-shock domains
Protein quality

of Charlevoix-
suggested a function for sacsin in
control

Saguenay
chaperone-mediated protein folding.

(sacsin)

SELS
selenoprotein S
SEPS1 gene helps in ridding the cell of
Protein quality

misfolded proteins, preventing it from
control

accumulating and subsequently resulting

to inflammation. SEPS1 as a type of

“garbage truck” that helps clear faulty

proteins that accumulate in cells when

they are placed under stress, causing

inflammation to develop.

ST13
suppression
Hip facilitates may facilitate the
Protein quality

of
chaperone function of Hsc/Hsp70 in
control

tumorigenicity
protein folding and repair, and in

13 (colon
controlling the activity of regulatory

carcinoma)
proteins such as steroid receptors and

(Hsp70
regulators of proliferation or apoptosis.

interacting

protein)

PDIA6
\protein
Formation and rearrangement of
Protein quality

disulfide
disulfide bonds during the correct folding
control

isomerase
of nascent proteins is modulated by a

family A,
family of enzymes known as thiol

member 6\“”
isomerases, which include protein

disulfide isomerase (PDI),

PDCL
phosducin-like
most members of the phosducin family
Protein quality

act as co-chaperones with the cytosolic
control

chaperonin complex (CCT) to assist in

the folding of a variety of proteins from

their nascent polypeptides

PDCL3
phosducin-like 3
most members of the phosducin family
Protein quality

act as co-chaperones with the cytosolic
control

chaperonin complex (CCT) to assist in

the folding of a variety of proteins from

their nascent polypeptides

AGA
aspartylglucos
key enzyme in the catabolism of N-
Protein quality;

aminidase
linked oligosaccharides of glycoproteins.
Nervous

It cleaves the asparagine from the
system health

residual N-acetylglucosamines as one of

the final steps in the lysosomal

breakdown of glycoproteins. Needed for

proper folding of proteins, particularly in

the nervous system

ABCB10
\ATP-binding
a mitochondrial inner membrane
Red blood cell

cassette, sub-
erythroid transporter involved in heme
health

family B
biosynthesis

(MDR/TAP),

member 10\“”

CAPRIN2
caprin family
Involved in regulation of growth as
Red blood cell

member 2
erythroblasts shift from a highly
health

proliferative state towards their terminal

phase of differentiation.

CYBRD1
cytochrome b
Cybrd1 (duodenal cytochrome b) is not
Red blood cell

reductase 1
necessary for dietary iron absorption in
health

mice. Likely participates in enhanced

iron demand due to erythropoesis, ay

be involved in extracellular ascorbate

recycling in erythrocyte membranes.

EDRF1
Erythroid
Transcription factor involved in erythroid
Red blood cell

differentiation-
differentiation. Involved in transcriptional
health

related
activation of the globin gene.

factor 1

ERMAP
erythroblast
Human Ermap is highly expressed in
Red blood cell

membrane-
erythroid tissues and the protein
health

associated
localizes to the plasma membrane,

protein
particularly in sites of cell contact, and

(Scianna
“cytoplasmic bodies.” Ermap expression

blood group)
was restricted to fetal and adult erythroid

tissues

ETS1
v-ets
ETS is responsible for erythroblast and
Red blood cell
Immune

erythroblastos
fibroblast transformation. Critical for
health
Health

is virus E26
maturation of the T Cells. Tumor

oncogene
suppressor.

homolog 1

(avian)

FLVCR1
feline
Exports cytoplasmic heme. May be
Red blood cell

leukemia virus
required to protect developing erythroid
health

subgroup C
cells from heme toxicity.

cellular

receptor 1

ADD3
adducin 3
ADD3 may have a role in erythroblasts
Red blood cell

(gamma)
and play an earlier role in erythropoiesis,
health

hypertension.

IKZF1
IKAROS
structure of a chromatin remodeling
Red blood cell

family zinc
complex (PYR complex) with Ikaros as
health

finger 1
its DNA binding subunit that is

(Ikaros)
specifically present in adult murine and

human hematopoietic cells. Ikaros is

involved in human adult or fetal erythroid

differentiation as well as in the

commitment between erythroid and

myeloid cells.

MAEA
macrophage
The association of erythroblasts with
Red blood cell

erythroblast
macrophages plays a central role in the
health

attacher
terminal maturation and enucleation of

erythroblasts. MAEA mediates

attachment of erythroblasts to

macrophages.

MYB
v-myb
c-Myb is strictly required for expression
Red blood cell

myeloblastosis
of the c-Kit receptor in erythroid cells.
health

viral
The transcription factor c-Myb is

oncogene
expressed at high levels in immature

homolog
progenitors of all hematopoietic lineages

(avian)
and is involved in the regulation of

proliferation, differentiation, and survival,

role for c-Myb as a factor promoting

commitment to erythropoiesis and

progression from early to late stages of

differentiation (FIG. 6). We have

shown that this function of c-Myb is

probably not related to the cell cycle but

rather to the control of a network of

hematopoietic regulators. The

expression of c-Kit in erythroid

progenitors was tightly dependent on c-

Myb levels. Finally, we demonstrated

that c-Myb acts as a coordinator at the

CFU-E stage by promoting further

progression while supporting terminal

cell divisions.

NFE2L3
nuclear factor
Activates erythroid-specific, globin gene
Red blood cell

(erythroid-
expression
health

derived 2)-like 3

SMAP1
stromal
SMAP-1 may have a stimulatory effect
Red blood cell

membrane-
on stroma-supported erythropoiesis.
health

associated

protein 1

ZNF266
zinc finger
HZF1 play important roles in erythroid
Red blood cell

protein 266
and megakaryocytic differentiation.
health

Increased HZF1 mRNA expression was

observed following erythroid

differentiation of K562 cells induced by

hemin or megakaryocytic differentiation

of K562 cells induced by phorbol

myristate acetate (PMA). Both of the

antisense method and RNA interference

assay revealed that

RNPS1
\RNA binding
Formation of transcription-induced R-
RNA Quality

protein S1,
loops poses a critical threat to genomic
Control

serine-rich
integrity throughout evolution., RNA

domain\“”
binding protein RNPS1 alleviates

ASF/SF2 depletion-induced genomic

instability. RNPS1, that when

overexpressed strongly suppresses the

high molecular weight (HMW) DNA

fragmentation, hypermutation, and G2

cell cycle arrest phenotypes of ASF/SF2-

depleted cells. Involved in RENT2-

dependent nonsense-mediated decay

(NMD) of mRNAs containing premature

stop codons. Also mediates increase of

mRNA abundance and translational

efficiency. Binds spliced mRNA 20-25 nt

upstream of exon-exon junctions, low

NMD efficiency is shown to be

functionally related to the reduced

abundance of the exon junction

component RNPS1

PAPOLG
poly(A)
This gene encodes a member of the
RNA Quality

polymerase
poly(A) polymerase family which
Control

gamma
catalyzes template-independent

extension of the 3′ end of a DNA/RNA

strand. This enzyme is exclusively

localized in the nucleus and exhibits

both nonspecific and CPSF (cleavage

and polyadenylation specificity

factor)/AAUAAA-dependent

polyadenylation activity.

DCP2
DCP2
Necessary for the degradation of
RNA Quality

decapping
mRNAs, both in normal mRNA tumover
Control

enzyme
and in nonsense-mediated mRNA

homolog (S. cerevisiae)
decay.

DDX5
DEAD (Asp-
Nonsense mediated RNA degradation
RNA Quality

Glu-Ala-Asp)

Control

box

polypeptide 5

ERLIN2
ER lipid raft
key ERAD pathway component that may
RNA Quality

associated 2
act as a substrate recognition factor.
Control

PARN
pol(A)-
3′-exoribonuclease that has a preference
RNA quality

specific
for poly(A) tails of mRNAs, thereby
control

ribonuclease
efficiently degrading poly(A) tails.

(deadenylation
Exonucleolytic degradation of the

nuclease)
poly(A) tail is often the first step in the

decay of eukaryotic mRNAs and is also

used to silence certain maternal mRNAs

translationally during oocyte maturation

and early embryonic development.

Interacts with both the 3′-end poly(A) tail

and the 5′-end cap structure during

degradation, the interaction with the cap

structure being required for an efficient

degradation of poly(A) tails. Involved in

nonsense-mediated mRNA decay, a

critical process of selective degradation

of mRNAs that contain premature stop

codons.

UPF2
UPF2
Nonsense-mediated mRNA decay
RNA quality

regulator of
(NMD) represents a key mechanism to
control

nonsense
control the expression of wild-type and

transcripts
aberrant mRNAs. Phosphorylation of the

homolog
protein UPF1 in the context of

(yeast)
translation termination contributes to

committing mRNAs to NMD.

UPF3A
UPF3
They promote nonsense-mediated
RNA quality

regulator of
mRNA decay (NMD), and they also
control

nonsense
regulate translation efficiency.

transcripts

homolog A

(yeast)

TRNT1
\tRNA
Adds and repairs the conserved 3′-CCA
RNA quality

nucleotidyl
sequence necessary for the attachment
control

transferase,
of amino acids to the 3′ terminus of

CCA-adding,
tRNA molecules, using CTP and ATP as

1\“”
substrates.

MAT2B
\methionine
Methionine adenosyltransferase (MAT;
SAM

adenosyltransferase
S-adenosyl-L-methionine synthetase,
Biosynthetic

II,
EC 2.5.1.6)1 is an essential enzyme that
machinary

beta\“”
catalyzes the synthesis of S-

adenosylmethionine (AdoMet) from L-

methionine (L-Met) and ATP (1, 2).

AdoMet is the major methyl group donor,

participating in the methylation of

proteins, DNA, RNA, phospholipids, and

other small molecules (reviewed in Refs.

3-5). In addition, AdoMet is the ultimate

source of the propylamine moiety used

in polyamine biosynthesis, and it serves

as co-factor for other key enzymes in the

one-carbon metabolism pathway.

Methionine adenosyltransferase (MAT;

EC 2.5.1.6) catalyzes the biosynthesis of

S-adenosylmethionine (AdoMet) from

methionine and ATP. MAT II is a broadly

expressed MAT consisting of catalytic

alpha and noncatalytic beta subunits

encoded by MAT2A (601468) and

MAT2B, respectively. Methionine

adenosyltransferase (MAT) catalyzes

the biosynthesis of S-

adenosylmethionine (AdoMet), a key

molecule in transmethylation reactions

and polyamine biosynthesis. The MAT II

isozyme consists of a catalytic alpha2

and a regulatory beta subunit. Down-

regulation of the MAT II beta subunit

expression causes a 6-10-fold increase

in intracellular AdoMet levels.

SKIV2L2
superkiller
mutation in skiv2l2 causes defects in cell
Skin Health

viralicidic
proliferation, suggesting that skiv2l2

activity 2-like
plays a role in regulating melanoblast

2 (S. cerevisiae)
proliferation during early stages of

melanocyte regeneration. Skin

ALDH18A1
\aldehyde
Defects in this enzyme plays a role in
Skin health,
Nervous

dehydrogenase
neurodegeneration, joint laxity, skin

system

18 family,
hyperelasticity. Role in L-Proline

health

member A1\“”
biosynthesis

KIT
Mast/stem cell
mobilization of hematopoetic stem cells
Stem cell

growth factor
into peripheral blood; marker for HSCs
health

receptor
and MSCs

precursor

FLT3
FMS-like
restricted to CD34+ (high proportion of
Stem cell

tyrosine
stem/progenitor cells)
health

kinase 3)

ITK
IL2-inducible
play a role in T cell proliferation and
Stem cell

T-cell kinase
differentiation
health

CD74
Cluster of
Hematopoietic Stem Cell survival
Stem cell

Differentiation
pathway
health

74

HOXB2
Homeobox
Expressed in erythromegakaryocytic
Stem cell

B2,
cells and Hematopoietic Stem Cells
health

CIAPIN1
Cytokine
Necessary for hematopoiesis
Stem cell

induced

health

apoptosis

inhibitor 1

NOTCH4

hematopoietic stem/progenitor cells
Stem cell

health

NCOR1
nuclear
NCOR, a repressor or transcription, is a
Stem cell

receptor co-
principal regulator in neural stem cells
health

repressor 1

PUM2
pumilio
Sequence-specific RNA-binding protein
Stem cell

homolog 2
that regulates translation and mRNA
health

(Drosophila)
stability by binding the 3′-UTR of mRNA

targets. Its interactions and tissue

specificity suggest that it may be

required to support proliferation and self-

renewal of stem cells by regulating the

translation of key transcripts.

SLAIN2
\SLAIN motif
Slain1 was expressed at the stem cell
Stem cell

family,
and epiblast stages of ESC
health

member 2\“”
differentiation

ACVR1
\activin A
Necessary for proper skeletal/bone
Stem cell

receptor, type
formation; regulate the fate of
health

I\“”
hematopoietic progenitor and stem cells

during development

PDCD4
programmed
The translation inhibitor programmed cell
Tumor

cell death 4
death 4 (Pdcd4) suppresses
suppresor

(neoplastic
tumorigenesis and invasion.

transformation

inhibitor)

AXIN2
\axin 2
The Axin-related protein, Axin2,
Tumor

(conductin,
presumably plays an important role in
suppressor

axil)\“”
the regulation of the stability of beta-
function

catenin in the Wnt signaling pathway,

like its rodent homologs, mouse

conductin/rat axil. In mouse, conductin

organizes a multiprotein complex of APC

(adenomatous polyposis of the colon),

beta-catenin, glycogen synthase kinase

3-beta, and conductin, which leads to

the degradation of beta-catenin.

Apparently, the deregulation of beta-

catenin is an important event in the

genesis of a number of malignancies.

The AXIN2 gene has been mapped to

17q23-q24, a region that shows frequent

loss of heterozygosity in breast cancer,

neuroblastoma, and other tumors.

Mutations in this gene have been

associated with colorectal cancer with

defective mismatch repair.

AZIN1
antizyme
It has been shown to regulate DNA
Tumor

inhibitor 1
methylation and has tumor suppressor
suppressor

activity, enhances the nonhomologous
function

end-joining repair of DNA double-strand

breaks in human oral cancer cells.

BECN1
\beclin 1
UVRAG interacts with Beclin 1, leading
Tumor

(coiled-coil,
to activation of autophagy and thereof
suppressor

myosin-like
inhibition of tumorigenesis.
function

BCL2

interacting

protein)\“”

CREBBP
CREB binding
CBP has tumor suppressing activity. CBP
Tumor

protein
may function as a ‘master-switch’
suppressor

(Rubinstein-
between energy storage and
function

Taybi
expenditure, long term memory.

syndrome)

CREBL2
cAMP
potential tumor suppressor
Tumor

responsive

suppressor

element

function

binding

protein-like 2

DIDO1
death inducer-
Putative transcription factor, weakly pro-
Tumor

obliterator 1
apoptotic when overexpressed (By
suppressor

similarity). Tumor suppressor.
function

ING2
\inhibitor of
Tumor suppressor
Tumor

growth family,

suppressor

member 2\“”

function

KRAS
v-Ki-ras2
Pfeifer (2001) noted an interesting
Tumor

Kirsten rat
parallel to the p53 (191170) tumor
suppressor

sarcoma viral
suppressor, which was initially described
function

oncogene
as an oncogene, carrying point

homolog
mutations in tumors. Later it was

discovered that it is, in fact, the wildtype

copy of the gene that functions as a

tumor suppressor gene and is capable

of reducing cell proliferation

MTSS1
metastasis
putative metastasis suppressor gene
Tumor

suppressor 1

suppressor

function

RB1
retinoblastoma
Key regulator of entry into cell division
Tumor

1 (including
that acts as a tumor suppressor. Directly
suppressor

osteosarcoma)
involved in heterochromatin formation by
function

maintaining overall chromatin structure

and, in particular, that of constitutive

heterochromatin by stabilizing histone

methylation.

SDCCAG1
serologically
can function as a tumor suppressor in
Tumor

defined colon
human lung cancer cells.
suppressor

cancer

function

antigen 1

SMAD4
SMAD family
Common mediator of signal transduction
Tumor

member 4
by TGF-beta (transforming growth
suppressor

factor) superfamily; SMAD4 is the
function

common SMAD (co-SMAD). Promotes

binding of the SMAD2/SMAD4/FAST-1

complex to DNA and provides an

activation function required for SMAD1

or SMAD2 to stimulate transcription.

May act as a tumor suppressor.

STK3
\serine/threonine
Novel tumor suppressor function.
Tumor

kinase 3
Stress-activated, pro-apoptotic kinase
suppressor

(STE20
which, following caspase-cleavage,
function

homolog,
enters the nucleus and induces

yeast)\“”
chromatin condensation followed by

internucleosomal DNA fragmentation.

UVRAG
UV radiation
UVRAG interacts with Beclin 1, leading
Tumor

resistance
to activation of autophagy and thereof
suppressor

associated
inhibition of tumorigenesis.
function

gene

WWOX
WW domain
critical tumor suppressor gene
Tumor

containing

suppressor

oxidoreductase

function

FOXO1
forkhead box
Tumor suppressor and essential role in
Tumor
Immune

O1
the Maintenance of hematopoetic stem
suppressor
Health

cells
function

TFRC
\transferrin

receptor (p90,

CD71)\“”

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Number	Date	Country
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2001-095529	Apr 2001	JP
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	Number	Date	Country
Parent	10915784	Aug 2004	US
Child	12059868		US
Parent	10360789	May 2002	US
Child	10915784		US
Parent	09878377	Jun 2001	US
Child	10360789		US

Dietary supplement and related method

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Term Extension

Abstract

Description

Claims

Parent Case Info

US Referenced Citations (47)

Foreign Referenced Citations (7)

Related Publications (1)

Provisional Applications (1)

Continuation in Parts (3)