# Patent

## Title
Dietary supplement and related method

## Abstract

A composition including a unique combination of fruits, vegetables, herbs, and optionally vitamins, minerals and specialty ingredients. 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 be administered to subjects to correct a dietary deficiency of phytochemicals and other nutrients, improve plasma concentrations of antioxidant nutrients, and increase the activity of genetic mechanisms for DNA repair and stability.

## Background
This is a continuation-in-part application of U.S. application Ser. No. 10/915,784, filed Aug. 11, 2004, which is a continuation-in-part application of U.S. application Ser. No. 10/360,789, filed May 7, 2002 (now U.S. Pat. No. 6,989,161), which is a continuation-in-part application of U.S. application Ser. No. 09/878,377, filed Jun. 12, 2001 (now U.S. Pat. No. 6,511,675), which claims benefit of U.S. Provisional Application No. 60/210,746, filed Jun. 12, 2000, all of which are hereby incorporated by reference.


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 B6 levels.
FIG. 4 is a graph depicting the effect the composition has on Vitamin B12 levels.
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 XTM. 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)\“”

## Claims

1. A method for modulating the expression of genes related to chromatin stability in a subject in need thereof, the method comprising:
administering to the subject an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is pomegranate, present in a dosage range of about 5 mg/day to about 500 mg/day, and citrus bioflavonoids, present in a dosage range of about 25 mg/day to about 1000 mg/day, wherein the vegetable ingredient is asparagus, present in a dosage range of 25 mg/day to about 1000 mg/day, and watercress, present in a dosage range of about 5 mg/day to about 500 mg/day, and wherein the herbal ingredient is oregano, present in a dosage range of 25 mg/day to about 1000 mg/day, and rosemary, present in a dosage range of 25 mg/day to about 1000 mg/day; whereby the expression of genes related to chromatin stability is modulated.

2. The method of claim 1, wherein said administering step includes administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

3. The method of claim 1, wherein said modulating step includes up-regulating the expression of chromatin stability-related genes.

4. A method of modulating the expression of DNA repair-related genes in a subject in need thereof, the method comprising:
administering to the subject an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is pomegranate, present in a dosage range of about 5 mg/day to about 500 mg/day, and citrus bioflavonoids, present in a dosage range of about 25 mg/day to about 1000 mg/day, wherein the vegetable ingredient is asparagus, present in a dosage range of 25 mg/day to about 1000 mg/day, and watercress, present in a dosage range of about 5 mg/day to about 500 mg/day, and wherein the herbal ingredient is oregano, present in a dosage range of 25 mg/day to about 1000 mg/day, and rosemary present in a dosage range of 25 mg/day to about 1000 mg/day; whereby the expression of genes related to DNA repair is modulated.

5. The method of claim 4, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

6. The method of claim 4, wherein said modulating step includes up-regulating the expression of DNA repair-related genes.

7. A method for reducing the risk of chromatin damage, the method comprising:
administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is pomegranate, present in a dosage range of about 5 mg/day to about 500 mg/day, and citrus bioflavonoids, present in a dosage range of about 25 mg/day to about 1000 mg/day, wherein the vegetable ingredient is asparagus, present in a dosage range of 25 mg/day to about 1000 mg/day, and watercress, present in a dosage range of about 5 mg/day to about 500 mg/day, and wherein the herbal ingredient is oregano, present in a dosage range of 25 mg/day to about 1000 mg/day, and rosemary present in a dosage range of 25 mg/day to about 1000 mg/day; and
modulating the expression of genes to reduce the risk of chromatin damage with the administered effective amount of the composition.

8. The method of claim 7, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

9. The method of claim 7, wherein said modulating step includes up-regulating the expression of chromatin stability-related genes.