Zymes llc. Published Research

Science

Published Research

Published research on Ubisol-Aqua™ describes the discovery, solubilization capabilities, and preclinical studies in animal and cell models that demonstrate the efficacy of this new technology for solubilizing lipophillic compounds for potential use in various applications. The Ubisol-Aqua™ technology has been tested with two water-insoluble model compounds, coenzyme Q₁₀ (CoQ10) and amphotericin B, to demonstrate its broad applicability. These studies demonstrate that Ubisol-Aqua™ can be used to:

1. Enhance solubility of water-insoluble compounds
2. Improve bioavailability
3. Reformulate drugs to reduce toxicity
4. Act as a pro-drug

Zymes has also begun making significant contributions to research in the area of green chemistry. Zymes’ proprietary PTS, a nanomicelle-forming amphiphile, can be used to promote chemical reactions in water at room temperature by cost-effectively achieving solubilization of both reactants and catalysts. This can obviate the need for organic solvents and heat, both of which are potentially either costly, or detrimental to the environment. This approach highlights micellar catalysis, a reaction variable that has been relatively underdeveloped in the synthetic community, particularly among those working in transition metal based cross-couplings. These studies demonstrate the use of PTS as a new enabling technology in micellar catalysis for transition metal-mediated processes.

Published Papers:

Borowy-Borowski H, Sodia C, Docherty J, Walker PR, Sikorska M. Unique technology for solubilization and delivery of highly lipophilic bioactive molecules. Journal of Drug Targeting 2003;12(7):415-424.

The Ubisol-Aqua™ family of compounds was expanded to produce an assortment of novel carriers capable of solubilizing water-insoluble compounds. The new carriers included polyoxyethanyl-cholesteryl sebacate (PCS™) and polyoxyethanyl-β-sitosteryl sebacate (PSS™). The compounds were synthesized, purified and evaluated for safety. In vivo and in vitro safety studies demonstrated that the compounds were non-toxic and efficacious. Acute cardiotoxicity studies performed in rats further demonstrated the safety of the compounds. PTS™, PCS™, and PSS™ formed stable, water-soluble nano-sized complexes with a variety of water-insoluble molecules including vitamins, carotenoids, ubiquinones, poly-unsaturated fatty acids, and polyene macrolide antibiotics.

In vivo bioavailability experiments with PCS™: Coenzyme Q₁₀ showed increased blood levels of coenzyme Q₁₀ relative to control rats given an oil-based coenzyme Q₁₀ formulation. In addition, when rats were given PTS™ alone, plasma vitamin E levels increased, demonstrating the ability of PTS™ to act as a pro-drug. When amphotericin B was solubilized with PSS™, it was effective against a systemic c. neoformans infection in mice and was as effective as the antifungal drug, FUNGIZONE. In vitro toxicity studies showed it to be similar to AMBISOME, a commercially available liposomal preparation of amphotericin B. These exciting new formulations represent a major advance in the delivery of water-insoluble molecules with wide application for delivery of ingredients for the nutritional, cosmeceutical and pharmaceutical industries. These studies further demonstrate the vast potential of the technology including the reformulation of drugs with near term patent expiry or those that have failed clinical trials due to low solubility.

Sikorska M, Borowy-Borowski H, Zurakowski B, Walker PR. Derivatised alpha-tocopherol as a CoQ₁₀ carrier in a novel water-soluble formulation. Biofactors 2003;18(1-4):173-83.

This study describes the synthesis of polyoxyethanyl-α-tocopheryl sebacate (PTS™) and its use to successfully solubilize coenzyme Q₁₀. PTS™ and coenzyme Q₁₀ form a non-covalent complex (PTS™: Coenzyme Q₁₀) that is water-soluble and stable in solution for extended periods of time. Following oral administration of this formulation to rats, blood levels of both vitamin E and coenzyme Q₁₀ were measured. Blood levels of coenzyme Q₁₀ were elevated within 1 hour, peaked at 3 hours and remained elevated at 20 hours post administration. Vitamin E concentrations were 3 to 4 times higher than baseline levels observed 3-9 hours after ingestion and remained elevated at 24 hours. These results demonstrate that the active ingredients in PTS™ are absorbed rapidly through the gastrointestinal tract and are bioavailable.

The newly formulated, water-soluble coenzyme Q₁₀ was also tested in a rat model of ishemic brain damage induced by disruption of blood flow to the brain. Rats received PTS: Coenzyme Q₁₀ by intraperitoneal injections given immediately and 3 hours after ischemia was induced. Brain damage was assessed by histological evaluation. Rats treated with PTS™: Coenzyme Q₁₀ experienced significant neuroprotection relative to untreated rats. This study demonstrates the potential therapeutic value of water-soluble coenzyme Q₁₀ in treating acute ischemic conditions such as stroke and heart attack.

Sandhu JK, Pandey S, Ribecco-Lutkiewicz M, Monette R, Borowy-Borowski H, Walker PR, Sikorska M. Molecular mechanisms of glutamate neurotoxicity in mixed cultures of NT2 derived neurons and astrocytes: protective effects of Coenzyme Q₁₀. J. of Neuroscience Research 2003;72:691-703.

In the central nervous system, glutamate acts as a neurotransmitter but, at high concentrations, can also act as a neurotoxin through a process called excitotoxicity. Excitotoxicity contributes to nerve damage in neurologic disorders such as stroke, epilepsy, hypoglycemia, Alzheimer’s, Parkinson’s, Huntington’s disease and amyotrophic lateral sclerosis (ALS). Excitotoxicity causes nerve damage through the formation of reactive nitrogen and reactive oxygen species (RNOS, ROS), which cause neuronal cell death by decreasing energy (ATP) production in the mitochondria. Astrocytes are non-nerve cells in the brain which help to rapidly clear glutamate, preventing excitotoxic injury to nerve cells. In an experimental model where nerve cells are exposed to glutamate and low oxygen, astrocytes will no longer clear glutamate and accordingly, nerve cell death occurs. However, a number of antioxidants including coenzyme Q₁₀ and vitamin E are able to scavenge RNOS and protect nerve cells from the damaging effects induced by glutamate.

This study demonstrated that pretreatment of cultured nerve cells with Ubisol-Aqua™: Coenzyme Q₁₀ increased mitochondrial coenzyme Q₁₀ and ATP levels. Ubisol-Aqua™: Coenzyme Q₁₀ also effectively decreased RNOS production, decreased indicators of cell damage and death, and improved astrocyte function, significantly increasing nerve cell survival.

Chuang Y, Chan JYH, Chang, AYW, Sikorska M, Borowy-Borowski H, Liou C, Cha SHH, Neuroprotective effects of coenzyme Q₁₀ at rostral ventrolateral medulla against fatality during experimental endotoxemia in the rat. Shock 2003;19(5):427-432.

Sepsis is a systemic inflammatory response to infection or injury which continues to have high morbidity and mortality despite aggressive treatment. In this animal study, sepsis-induced death was usually preceded by a dramatic reduction in the low frequency components of blood pressure signals. The presence of these signals reflects the functional integrity of a specific area of the brain stem, the rostral ventrolateral medulla (RVLM). It was further observed that mitochondrial dysfunction in cells from the RVLM was associated with sepsis-induced death.

Since coenzyme Q₁₀ inhibits oxidative damage to lipids, proteins and DNA, it has potential to act as a neuroprotective agent in both acute and chronic brain damage. The efficacy of Ubisol-Aqua™: Coenzyme Q₁₀ to act as a neuroprotective agent in sepsis was therefore assessed. In this study, sepsis was induced in animals leading to progressive hypotension and death. However, pre-treatment by microinjection of Ubisol-Aqua™: Coenzyme Q₁₀ into the RVLM significantly prolonged survival time. This was associated with improvement in the blood pressure signal as well as blunting of the increased production of oxidants. These results support the potential efficacy of Ubisol-Aqua™: Coenzyme Q₁₀ for disorders associated with an immunoinflammatory response, such as sepsis.

McCarthy S, Somayajulu M , Sikorska M, Borowy-Borowski H, Pandey S. Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-insoluble Coenzyme Q₁₀. Toxicology and Applied Pharmocology 2004;201:21-31.

Paraquat is an extremely toxic herbicide, once widely used in North America. A strong association between paraquat exposure and Parkinson’s disease has been suggested. In this study performed in a cell model of human nerve cells, paraquat treatment induced mitochondrial dysfunction and ROS production leading to nerve cell death (apoptosis) similar to that seen in Parkinson’s disease. Pre-treatment of these cells with Ubisol-Aqua™: Coenzyme Q₁₀ prior to paraquat exposure inhibited ROS generation and significantly reduced the number of dead cells. Treatment also increased energy (ATP) production and maintained normal cell biochemical function. These results provide evidence supporting the protective effects of coenzyme Q₁₀ in nerve cell damage induced by environmental toxins.

Somayajulu M, McCarthy S, Hung M, Sikorska M, Borowy-Borowski H, and Pandey S. Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by coenzyme Q₁₀. Neurobiology of Disease 2005;18:618-827.

Nerve cells depend heavily on mitochondrial production of ATP due to their high energy expenditure. They are also at risk for oxidative damage caused by the potentially toxic by-products of energy metabolism. Such oxidative stress can ultimately lead to cell death. It is believed that this mechanism plays a role in contributing to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In this study, two types of human nerve cells were grown in culture and exposed to hydrogen peroxide, which causes mitochondrial dysfunction. Mitochondrial dysfunction leads to an increase in reactive oxygen species (ROS) which cause oxidative damage to cell membranes, DNA, and ultimately cell death. When the cells were pretreated with Ubisol-Aqua™: Coenzyme Q₁₀ and then exposed to hydrogen peroxide, total cellular ROS was decreased, the mitochondrial membrane remained intact and the nerve cells remained healthy. These studies suggest that water-soluble coenzyme Q₁₀ has the potential to be used therapeutically for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.

Naderi J, Somayajulu-Nitu M, Mukerji A, Sharda P, Sikorska M, Borowy-Borowski H, Antonsson B, Pandey S. Water-insoluble formulation of Coenzyme Q₁₀ inhibits Bax-induced destabilization of mitochondria in mammalian cells. Apoptosis 2006;8:1359-69.

This paper elucidates the mechanism by which coenzyme Q₁₀ acts to prevent programmed cell death (apoptosis). Cultured human fibroblasts and embryonic kidney cells were pre-treated with Ubisol-Aqua™: Coenzyme Q₁₀ and then subjected to hydrogen peroxide, a potent oxidant. The pre-treated cells showed a decrease in mitochondrial dysfunction and cell death compared to untreated cells. The mechanism by which this occurred involved the inhibition of a pro-apoptotic protein, Bax. These data further support the role of water-soluble coenzyme Q₁₀ to prevent oxidative damage.

Mobarol M, Cherry CL, Wesselingh SL, Fain R and Hooker DJ. International AIDS Society Meeting, Sydney Australia 2007, Ubisol-Aqua™: Coenzyme Q10 prevents antiretroviral toxic neuropathy in an in vitro model.

Cultured fetal rat dorsal root ganglia (DRGs) have been established as an in vitro model of antiretroviral toxic neuropathy (ATN), a complication associated with AIDS treatment. ATN can occur in AIDS patients in countries where the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) stavudine (d4T) or didanosine (ddI) are used. Concentrations between 0.1 and 100 uM of Ubisol-Aqua™: Coenzyme Q10 (H_QO™) were tested in this DRG model which measures neurite morphology and growth. All concentrations of H_QO™ tested were associated with improved neurite growth (p<0.0001 versus control). DRGs cultured with H_QO™ also remained viable for at least one week beyond those cultured under control conditions.

DRGs exposed to d4T demonstrated impaired neurite growth compared to controls (p = 0.01). When cells treated with d4T were exposed to H_QO™, greater neurite growth was observed than those with d4T alone (p = 0.01) and were not different than controls. Similarly, when DRGs were exposed to ddI, neurite growth was significantly reduced compared to controls (p<0.001), and neurites were dead by day 16. This toxicity was completely prevented by H_QO™ resulting in neurite morphology and growth that was the same as controls. These studies demonstrate that H_QO™ enhances the growth and survival of fetal rat DRGs and reduces the toxicity of d4T and ddI in this in vitro model of ATN. These data support the possibility that coenzyme H_QO™ may be useful for preventing ATN associated with ddI and d4T.

Lipshutz, B.H., Aguinaldo, G.T., Ghorai, S., and Voigtritter. K. “Olefin Cross-Metathesis Reactions at Room Temperature Using the Nonionic Amphiphile “PTS”: Just Add Water”, Organic Letters 2008, 10(7), 1325-1328.

This publication describes the first examples of unsymmetrical olefin cross-metathesis reactions in water as the only solvent. The reactions were conducted using water-insoluble substrates at room temperature, with commercially available catalysts, and small percentages of Zymes’ PTS. Nanometer micelles are formed in water that accommodate both substrates and Ru-based metathesis catalysts. The reactions proceed with high efficiency and very high E-selectivity, the products from which can be easily isolated.

Lipshutz, B.H. and Taft, B.R. “Heck Couplings at Room Temperature in Nanometer Aqueous Micelles”, Organic Letters 2008, 10(7), 1329-1332.

PTS, part of Zymes’ proprietary solubilization platform Ubisol-Aqua, has been shown to promote Heck cross-coupling between non-water-soluble reaction partners, in water, at room temperature. The formation of nanomicelles in water allows these first examples of Heck reactions in water (as the only solvent) at room temperature.

Lipshutz, BH, Petersen, TB, and Abela, AR , “Room Temperature Suzuki-Miyaura Couplings in Water Facilitated by Nonionic Amphiphiles”, Organic Letters 2008, 10(7), 1333-1336.

Small percentages of PTS in water can be used to promote Suzuki-Miyaura cross- couplings. A dilute aqueous solution containing an arylboronic acid and one of a wide variety of aryl halides or pseudo-halides, in the presence of a Pd catalyst and inexpensive base, has been shown to afford biaryl cross-coupling products in good yields. In most cases, the reactions proceed at ambient temperatures, even with sterically hindered and lipophilic substrates.

Page modified: 2008-07-17 16:29:53.

Science and Technology

Adipose - Fat tissue.

Aerobic - Without oxygen.

Adequate Intake (AI) - A recommended intake value based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of healthy people, that are assumed to be adequate- used when an RDA cannot be determined.

Aldosterone - A steroid hormone, synthesized from cholesterol by the adrenal gland regulates sodium and potassium levels in the blood.

Amyloid Plaques - An abnormal accumulation of beta-amyloid proteins in the brain that are seen in patients with Alzheimer’s disease.

Amino Acids - Small molecules that are the building blocks of proteins.

Analogue - Something that is similar to something else.

Antioxidant - A chemical compound or substance like a vitamin that inhibits the oxidation of other molecules.

Arteries - Blood vessels that carry oxygenated blood away from the heart, whereas veins carry deoxygenated blood to the heart.

Atherosclerosis - A disease of the arteries resulting from the formation of an atherosclerosis plaque, historically known as “hardening of the arteries”. The plaque consists of excess cholesterol and other lipids, inflammatory cells such as macrophages, with excess of proteins and calcium. The plaque eventually ruptures and causes narrowing of the artery leading to an insufficient blood supply to the organ it feeds.

ATP - Adenosine triphosphate. The cells of the body cannot use food directly for energy. The energy (calories) in food must be broken down into a form of energy small enough for the cells to use. That smallest form of energy is ATP.

Bias - To influence in an unfair way.

Beta Blocker - A medicine used to treat high blood pressure and some other heart conditions.

Bile Acids - Specific compounds produced by the liver and excreted in the bile to help in the digestion of fats.

Bioavailability - A term used by pharmacologists and pharmacists to describe the amount of a medication that reaches the blood stream.

Biological Membranes - All cells are surrounded by a cell membrane, sometimes called a plasma membrane or plasmalemma. It is a thin double layer of phospholipid and proteins that envelopes the cell, separating the cell’s interior from its surroundings and controlling what moves in and out.

Biosynthesis - A process where chemical compounds are made in the body from simpler compounds or smaller molecules, an important part of metabolism.

Blinded - Most clinical studies are “blinded” to assure accurate results. Double-blinded means that neither the patient nor the investigator know which group the patient is assigned to. Single-blinded means the investigator knows which group the patient is assigned to, but the patient does not.

Carbohydrates - Commonly known as sugars (monosaccharides and disaccharides) and starches (polysaccharides), their most important function is energy storage.

Cardiac Asthma - An asthmatic attack caused by heart disease.

Cell Membrane - Also called a plasma membrane or plasmalemma. It is the outermost layer of a cell composed of primarily phospholipids and proteins. It serves to separate and protect the cell interior from its surroundings and regulate the movement of molecules into and out of cell.

Centers for Disease Control (CDC) - A government agency that studies infectious diseases.

Chemical Bonds - The holding together of molecules by attraction of atoms to each other, commonly through sharing of electrons.

Chylomicrons - Small fat globule composed of protein and lipid (fat) created by the cells of the small intestine used to transport fat from the intestine to the liver and to fat tissue. After a fatty meal, the blood is so full of chylomicrons that it looks milky.

Cognition - The ability to think, reason, and remember.

Confidence Intervals - Describes the range within which the real effect is likely to occur. As with the 5% chance described for the p value, the confidence interval usually provided is the 95% confidence interval. For example if a new cholesterol drug lowered cholesterol by a mean of 20 mg/dL with a 95% CI of 4 to 35, there is a 95% probability that the true effect of the drug lies within this range. If the CI does not overlap 1.0, the result is said to be significant at p<0.05. In our example the CI (4, 35) does not overlap 1.0, therefore the treatment effect is considered to be statistically significant.

Cortisol - A steroid hormone, synthesized from cholesterol by the adrenal gland that is involved in the response to stress. Also used as a drug, synthetic cortisol also known as hydrocortisone, is used to teat allergic and inflammatory diseases.

Dementia - A progressive decline in mental functioning, over and above what’s expected from normal aging, due to damage or disease in the brain.

Double Blind - In clinical studies, double blind means that neither the patient nor the investigator know which treatment group the patient is assigned to.

Dietary Reference Intakes - Includes four measurements; Recommended Daily Allowance (RDA), Allowable Intake (AI), Tolerable Upper Intake Level (UL) and Estimated Average Requirement (EAR). DRI is generally used by nutrition professionals instead of RDAs.

Efficacy - The ability of a drug to produce an acceptable amount of the desired effect. In precise terms ‘efficacy’ refers to the effect of a drug in the controlled setting of a clinical trial. This is different from ‘effectiveness’ which refers to the effect of a drug in real world setting.

Electron - A negatively charged particle that orbits the nucleus of an atom. The flow of electrons produces electricity.

Electron Transport Chain - The energy currency of the body, ATP, is made in the mitochondria, from the food we eat, through a series of chemical reactions called the electron transport chain. Electrons are transported through a series of compounds in what is known as the electron transport chain. Each time electrons are transferred from one compound to another, the energy generates a proton gradient that provides the energy to produce ATP.

Eliminate - After drugs are metabolized, they are removes from the body by two main routes: in the urine through the kidneys and in the feces through the gastrointestinal tract.

Enterocyte - An intestinal cell that helps to break up food molecules and transports them into the tissues of the body.

Estimated Average Requirement (EAR) - A daily nutrient intake value that is estimated to meet the requirement of half of the healthy individuals in a life stage and gender group - used to assess dietary adequacy and as the basis for RDA.

Estrogen - A steroid hormone, synthesized from cholesterol that is the primary hormone involved in the development of female sex characteristics. Estrogen is also present at a significantly lower level in men.

Fermentation - A process that occurs in the absence of oxygen such as making alcohol (wine) from grapes with yeast.

Fibrate - A class of drugs used to lower cholesterol that work differently than the statins.

Folic Acid - One of the B vitamins.

Free Radicals - Atoms or molecules with highly reactive unpaired electrons that are generally pro-oxidants. Also referred to as reactive oxygen species such as superoxide, hydrogen peroxide, and hydroxyl radical and are associated with cell damage. Free radicals are neutralized in the body by anti-oxidants.

Free Radical Scavenger - Found in every living cell of the body and are potent antioxidants.

Gamma Rays - Electromagnetic radiation of high energy that is released by radioactive decay.

Genetic Material - Deoxyribonucleic acid (DNA), used to store the genetic information of an organism.

Glucose Toxicity - High blood glucose can lead to damage of organs and the complications of diabetes.

Gram - The standard measure of mass in the metric system indicated by the symbol g. 1 gram (g) = 1000 milligrams (mg). 1 gram = 1/1000 of a kilogram (kg). 1 ounce = 28.3 grams, 1 gram is about the mass of a paper clip.

GRAS - Generally Regarded As Safe is recognition by the FDA (Food and Drug Administration of the Department of Health and Human Services) of the safety of a substance that is added to food.

Heavy Metals - Common metals that are “heavy” include gold, cobalt, copper, manganese, molybdenum, vanadium, strontium, zinc, mercury, lead, and cadmium. Some like cobalt, copper, manganese, molybdenum, vanadium, strontium, zinc, are required in the diet in trace amounts, but high levels can be detrimental. Others such as mercury, lead, and cadmium are not essential to bodily functions and accumulation is associated with illness.

Hemoglobin A1C (HbA1C) - A measure of blood sugar control over 2 to 3 months.

High Energy Phosphates - Compounds like adenosine triphosphate (ATP) and adenosine diphosphate (ADP) that contain high energy phosphate bonds that when broken release energy for the body to use.

HMG-CoA Reductase - The rate-limiting enzyme, 3 - hydroxy - 3 - methyl - glutaryl - CoA reductase or HMGR, of the pathway that synthesizes cholesterol and other molecules. Drugs that inhibit HMG-CoA reductase are commonly called statins because of the commonality of the generic drug names: atorvastatin, pravastatin, and simvastatin. Statins are used to lower blood levels of LDL cholesterol, a risk factor for cardiovascular disease.

Hormone - From the Greek horman - “to set in motion”. A chemical substance that is secreted into body fluids and transported to another cell or organ, where it produces a specific effect.

Hypothesis - The explanation for certain facts or observations that can be tested through experimentation.

Ionizing Radiation - Produced by radioactive decay, nuclear reactions, and by extremely hot objects like the sun. X-rays are a use of ionizing radiation as is radiation to kill cancerous cells. However, overuse of ionizing radiation can be hazardous.

In Vitro - Refers to experiments performed in test tubes or cell cultures.

In Vivo - Refers to experiments performed in live animals.

Jugular Reflux - An elevation of venous pressure that can be seen in bulging jugular veins and in the veins of the arm and can be produced by congestive heart failure.

LDL - Low density lipoprotein, a fatty droplet composed of protein and cholesterol used to carry cholesterol throughout the body. Referred to as the “bad” cholesterol because it may accumulate on the walls of the arteries leading to atherosclerosis.

Left Ventricle - The largest lower chamber of the heart, it that receives oxygenated blood from the left atrium and pumps it out to the body through the aorta to the body.

Lymphatic System - A network of vessels carrying lymph (a colorless fluid) to and from lymph organs (lymph nodes, spleen, and thymus) that produce and store infection-fighting cells.

Lymphoma - Any of the many often malignant tumors of the lymph nodes or in other lymphoid tissue.

Lactate/Pyruvate Ratio - Elevation in this ratio may be used to estimate mitochondrial dysfunction. If the mitochondria (makes energy through aerobic pathways) are not functioning properly, the body may turn to anerobic pathways to generate energy which increase lactate compare to pyruvate.

Lipases - Enzymes in the digestive system that break down fats.

Lipids - A class of water insoluble compounds essential for the structure and function of living cells. Lipids make up cell membranes and are used for energy storage. They also can be hormones and vitamins. Lipids are often called ‘fats’, however, fats are only one type of lipid.

Metabolism - All of the processes of the body including those that build up (anabolism) and breakdown (catabolism) molecules in the body. Drug metabolism is the process the body uses to break down (deactivate) a drug for elimination form the body.

Mevalonic Acid - A compound used by the body to make cholesterol and other steroids.

Mitochondria - A cell structure often referred to as the “powerhouse of the cell” because that is where the food we eat is turned into energy. All cells, with the exception of red blood cells, have mitochondria. Mitochondria convert the energy found in the food we eat into a small energy rich molecule called ATP that all cells can use.

Mitochondrial Electron Transport Chain - The energy currency of the body, ATP, is made in the mitochondria, from the food we eat, through a series of chemical reactions called the electron transport chain. Electrons are transported through a series of compounds in what is known as the electron transport chain. Each time electrons are transferred from one compound to another, the energy generates a proton gradient that provides the energy to produce ATP.

Multicenter - In clinical studies, when the same study is performed in patient found in more than one study center.

Myeloma - A tumor of antibody-producing cells that are normally found in the bone marrow.

Neurodegenerative Diseases - Disease that results from the deterioration of nerve cells such as Alzheimer’s disease and Parkinson’s disease.

Neuron - The nerve cells which make up the central nervous system that communicate to each other by transmitting electrical signals to other neurons.

Neutrons - A subatomic particle found in the nucleus of every atom, except hydrogen, it has no electrical charge; it is neutral.

Nucleic Acids - Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), the molecules the body uses to store and transmit genetic information.

Open Label - In clinical studies, when the patient knows which drug treatment they are being given.

Oxidative Phosphorylation - The process during which nutrients are broken down into ATP using the oxygen we breathe.

Oxidative Stress - A term for damage to animal or plant cells, tissues and organs caused by free radicals and other pro-oxidant molecules. It is often defined as an imbalance between too many pro-oxidants and not enough antioxidants.

Oxidized - Oxidation is the loss of an electron. Molecules that have the ability to oxidize other molecules are also known as pro-oxidants, oxidizing agents, oxidants or oxidizers. When the oxidant removes electrons from the other molecule, it becomes reduced.

Ozone - A molecule of three oxygen atoms present in low concentrations throughout the Earth’s atmosphere. In the upper atmosphere it prevents harmful ultraviolet light form reaching the Earth’s surface. At ground level ozone is associated with respiratory problems, atherosclerosis and Alzheimer’s disease.

Pancreas - An organ located near the stomach that makes digestive enzymes that aid in digestion, and it produces several hormones, including insulin and glucagon.

Pantothenic Acid - Also called vitamin B5, is an antioxidant water-soluble vitamin needed to break down carbohydrates, proteins, and fats.

pH - A measurement of acidity or alkalinity of a solution like blood or water.

Placebo-Controlled - Refers to a clinical trial in which the effectiveness of an experimental drug is compared to that of placebo (contains no useful medicinal content) group.

Platelet - Cells involved in blood clotting.

Progesterone - a steroid hormone, synthesized from cholesterol, involved in the regulation of the processes of the female reproductive system.

Pro-Oxidant - A substance that can produce oxygen byproducts of metabolism that can cause damage to cells.

Prospective - A study that collects data after the study begins; unlike a retrospective study which analyzes data that has already been collected.

Proteins - Chains of amino acids used by the body for many things including: cell movement (muscles), structures (hair), enzymes (biological catalysts), hormones (insulin), energy storage (egg albumin), transport of oxygen (hemoglobin), and antibodies (immune system).

PTS™ - The lead compound in the family of Ubisol-Aqua™ solubilizers.

Pulmonary Edema - Swelling and/or fluid accumulation in the lungs.

P Value - A measure of significance. A p value that is deemed significant if it is p<0.05 (read, p is less than .05). If the p value is less than 0.05, the difference between the treatment groups is considered statistically significant. It means that there is less than a 5% chance that the difference between the two treatment groups occurred by chance and that the difference between the two groups is most likely attributable to a treatment effect rather than chance. If the p value is greater than .05 (p>0.05), then it is likely that the difference between the two treatment groups occurred by chance.

Randomized - A method of assignment in which individuals have a random chance of being assigned to one group or another.

Range- Describes the highest and lowest number in the data set.

Reactive Oxygen Species - Atoms or molecules with highly reactive unpaired electrons that are generally pro-oxidants. Also referred to as free radicals and are associated with cell damage. Free radicals are neutralized in the body by anti-oxidants.

Recommended Daily Allowance - The average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group. RDA is now incorporated into the DRI. For more information please refer to the International Food Information Council.

Reduced - Reduction is the gaining of an electron. Molecules that have the ability to reduce other molecules are also known as reducing agents, reductants or reducers. When the reducing agent gains electrons from the other molecule, it becomes oxidized.

Remacemide - A drug used treat Parkinson’s disease.

Reperfusion Injury - The damage to tissue that is caused when the blood supply returns to the tissue after a period of no or reduced blood flow.

Safety - Relates to the detection, evaluation, understanding, and prevention of adverse effects of drugs during short and long term use.

Statistically Significant - A mathematical measure to describe if there is a difference between groups. The difference is said to be “statistically significant” if it is greater than what might be expected to happen by chance alone.

Striatal Spiny Neurons - A type of medium sized neuron in the striatum that when destroyed, may cause problems with movement.

Standard Deviation (SD) and Standard Error (SE) - Mathematically complex calculations. What you need to know is that large SD and SE indicate a lot of variability in the data, and small SD and SE indicate that the data values are clustered closely around the mean.

Statin - A group of drugs that reduce the amount of cholesterol made by the body.

Substantia Nigra - Dark gray matter deep within the brain where cells make the neurotransmitter dopamine for movement control. Degeneration of cells in this region may lead to movement disorders such as Parkinson’s disease.

Subcutaneous - Under the skin.

Synthetic - A substance that is made a chemical process, it generally does not apply to substances created by naturally occurring biological processes.

Testosterone - A steroid hormone, synthesized from cholesterol that is the primary hormone involved in the development of male sex characteristics. Testosterone is also present at a significantly lower level in women.

Tolerable Upper Intake Level (UL) - The highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals in the general population. As intake increased above the UL, the potential risk of adverse effects increases.

Ultraviolet Light - Electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays.

United States Recommended Daily Allowances (USRDA) - Was devised by the Food and Drug Administration (FDA) for nutritional labeling of processed foods and vitamin products. The USRDA lists the percentage of each of 19 essential nutrients that are contained per serving of the labeled product. The Recommended Dietary Allowance (RDA) is the amount of nutrients and calories recommended for most healthy individuals (of any age) to consume in their daily diet to meet the requirements of the body.

Unsaturated Fats - A fat with one or more double bond in the fatty acid chain and liquid at room temperature. Unsaturated fats are commonly found in avocados, nuts, soybeans, canola oil and olive oil. Saturated fats have no double bonds in the fatty acid chain and are solid at room temperature such as butter and animal fat.

Ubiquinol - The reduced form of coenzyme Q₁₀.

Ubiquinone - The oxidized form of coenzyme Q₁₀.

Villus> - Hair-like protrusions into the intestine — emanating from the wall of the intestine. The purpose of the villi is to slow the passage of food, and to allow food particles to be captured in among these finger-like villi — so that the blood inside the villi can absorb the nutrients in the food.

Vitamin - A molecule required by the body in minute amounts for proper health. In general, vitamins cannot be made by the body.

X-Rays - A form of electromagnetic radiation primarily used in medicine to produce radiographic images. Is also a form of ionizing radiation which can be dangerous.