INTRODUCTION:

Physiological or biological stress is an organism's response to a stressor such as an environmental Condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation of which results in the fight to flight response. Because the body cannot keep this state for long periods of time, the parasympathetic system returns the body's physiological Conditions to normal (homeostasis). In humans, stress typically describes a negative Condition or a positive Condition that can have an impact on a person's mental and physical wellbeing.

Stress can increase the risk of strokes, heart attacks, ulcers, and mental disorders such as depression. Stress can be external and related to the environment, but may also be created by internal perceptions that cause an individual to experience anxiety or other negative emotions surrounding a situation, such as pressure, discomfort, etc., which they then deem stressful. Stress is usually caused by any kind of emotional or physical stimulus or situation. Most often, people speak of varied types of stress like relationship stress, work stress, or parenting stress. There are a few kinds of stress that are related to particular stages of life such as pregnancy, ageing, teen years, menopausal transition and the like. In fact, even children are affected by stress in the Contemporary world. Risk factors Contributing to uncontrollable stress include medical illness, lack of social support networks, social and financial problems and family history of family discord or stress. On top of this, our lifestyle and food habits make our nerves weak from both structural as well as functional point of view. The safest way of Coming out of such a situation is not the stress reducers but to nourish our nervous health so that it responds Constructively to otherwise difficult situation in life. Being able to recognize Common stress symptoms can give a jump on managing them. Stress that's left unchecked can Contribute to health problems, such as high blood pressure, heart disease, obesity and diabetes.

History of stress

Hans Selye began using the term stress after Completing his medical training at the University of Montreal in the 1920’s. He noticed that no matter what the hospitalized patients suffered from, they all had one thing in Common. They all looked sick. In his view, they all were under physical stress. He proposed that stress was a nonspecific strain on the body caused by irregularities in normal body functions. This stress resulted in the release of stress hormones. He called this the “General Adaptation Syndromes”.

Brief information about Coenzyme Q10

History: The Co Q10 was first discovered by Professor Fredrick L. Crane and Colleagues at the University of WisConsin–Madison Enzyme Institute in 1957. In 1958, it’s chemical structure was reported by Dr. Karl Folkers and Co workers at Merck. In 1961 Peter Mitchell proposed the electron transport chain (which includes the vital proton motive role of Co Q10) and he received a Nobel prize for the same in 1978. In 1972, Gian Paolo Littarru and Karl Folkers separately demonstrated a deficiency of Co Q10 in human heart disease. The 1980s witnessed a steep rise in the number of clinical trials due to the availability of large quantities of pure CoQ10 and methods to measure plasma and blood Co Q10 Concentrations. The redox functions of Co Q10 in cellular energy production and antioxidant protection are based on the ability to exchange two electrons in a redox cycle between ubiquinol (reduced Co Q10) and ubiquinone (oxidized Co Q10). The antioxidant role of the molecule as a free radical scavenger was widely studied by Lars Ernster. Numerous scientists around the globe started studies on this molecule since then in relation to various diseases including cardiovascular diseases and cancer¹.

Definition of Coenzyme:

A substance that enhances the action of an enzyme. Coenzymes are small molecules. They cannot by themselves catalyze a reaction but they can help enzymes to do so. In technical terms, Coenzymes are organic nonprotein molecules that bind with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). A number of the water-soluble vitamins such as vitamins B1, B2 and B6 serve as Coenzymes².

Scientific Names:

Ubiquinone, Ubidecarenone, Mitoquinone.

Common Names:

Co-Enzyme Q10, Coenzyme Q10, Co-enzyme Q-10, Co Enzyme Q 10, CoQ, CoQ10, Co Q 10, Co-Q-10, CoQ-10, CO Q10, Q10, Vitamin Q10.Coenzyme Q10, also known as ubiquinone, Coenzyme Q, and abbreviated at times to CoQ10 / CoQ, or Q10 is a 1,4benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.

Structure:

Figure no 1. Shows the structure of Ubiquinol

Biochemistry and Source:

Coenzyme Q10 is synthesized in intracellular region in the human body using tyrosine as the fundamental building block. This first step requires pyridoxal 5’-phosphate (vitamin B6) as a Cofactor, so adequate vitamin B6 nutriture is essential for Co Q10 biosynthesis. Certain situations can disrupt the body’s ability to produce enough Co Q10 to meet requirements. Cells and tissues that are metabolically active have the highest Co Q10 requirements (such as the heart, immune system, and gingiva) and as such are most susceptible to Co Q10 deficiency. This oil soluble, vitamin like substance is present in most eukaryotic cells, primarily in the mitochondria. It is a Component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. 95% of the human body’s energy is generated this way. Therefore, those organs with the highest energy requirements—such as the heart, liver and kidney have the highest Co Q10 Concentrations. There are two redox states of Co Q10: fully oxidized (ubiquinone), and fully reduced (ubiquinol).The capacity of this molecule to exist in a Completely oxidized form and a Completely reduced form enables it to perform its functions in the electron transport chain, and as an antioxidant, respectively³.

Role and Utility:

Coenzyme Q10 (Co Q10) is a Compound found naturally in virtually every cell in the human body. Because of its ubiquitous presence in nature and its quinone structur (similar to that of vitamin K), Co Q10 is also known as ubiquinone. Co Q10 is a fat-soluble substance whose primary role is as a vital intermediate of the electron transport system in the mitochondria. Adequate amounts of Co Q10 are necessary for cellular respiration and ATP production. Co Q10 also functions as an intercellular antioxidant. True deficiency states are rare but often present with severe health Consequences. Numerous disease processes, linked to low levels of Co Q10, can benefit from Co Q10 supplementation including Cardiovascular disease, Parkinson’s disease, muscular dystrophy, breast and other cancers, diabetes mellitus, male infertility, acquired immunodeficiency syndrome (AIDS), asthma, thyroid disorders, and periodontal disease⁴.

Formation of free radicals:

Free radicals may be formed through natural human physiological processes as well as from the environment. They may be the result of diet, stress, smoking, alCohol, exercise, inflammation, drugs or exposure to sunlight and air pollutants. While there are many types of free radicals that can be formed, the most Common in aerobic (oxygen breathing) organisms are oxygen free radicals, often referred to as Reactive Oxygen Species (ROS), which include superoxides, hydroxyl anions, hydrogen peroxide and singlet Oxygen. A free radical is an atom or group of atoms that has an unpaired electron and is therefore unstable and highly reactive. An atom’s chemical behavior is determined by the number of electrons in its outermost shell. When the outermost shell is full, the atom is stable and tends not to engage in chemical reactions. Free radicals may form spontaneously or they may be the result of exposure to heat, light or something in the environment. Sometimes the body’s immune system creates them on purpose to neutralize viruses and bacteria. In the human body, we have a vast array of molecules that are more susceptible to free radical attacks than others. These include fats, DNA, RNA, cellular membranes, proteins, vitamins and carbohydrates. Unfortunately, Oxygen is very susceptible to free radical formation, and with aerobic organisms, this can be lethal. Oxygen free radicals are implicated in the overall aging process and are responsible for photoaging, cancer and inflammation in the skin. Oxygen free radicals cause lipid peroxidation, which results in damage to cell membranes and this can cause premature aging, skin cancer and cell death.

Mechanism of action:

The primary role of Co Q10 is as a vital intermediate of the electron transport system in the Mitochondria. Adequate amounts of Co Q10 are necessary for cellular respiration and ATP production. Due to its involvement in ATP synthesis, Co Q10 affects the functions of all cells in the body, making it essential for the health of all tissues and organs. Co Q10 also functions as an intercellular antioxidant at the mitochondrial level, perhaps accounting for its benefit in neurodegenerative diseases, and periodontal disease.

Pharmacodynamics:

Coenzyme Q10 serves as the electron acceptor for Complexes I and II of the Mitochondrial electron transport chain and also acts as an antioxidant and is neuro protective. Water-soluble Coenzyme Q10 acts by stabilizing the Mitochondrial membrane when neuronal cells are subjected to oxidative stress (Somayajulu et al 2005). It would be an effective plasma antioxidant because it can regenerate plasma vitamin E. Coenzyme Q10 has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and excessive oxidative damage. The following are some of the effects that have been demonstrated in experimental studies: Coenzyme Q10 was shown to have neuroprotective effect in the 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine model of parkinsonism (Cleren et al 2008). In animal models of Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease, Coenzyme Q10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3 nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in Huntington disease. Coenzyme Q10 significantly extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. Coenzyme Q10 has a neuroprotective effect on the brain in infarction induced by ischemic injury in aged and susceptible transgenic mice (Li et al 2007). Coenzyme Q10 has been shown to ameliorate most of the biochemical changes induced by ischemia/reperfusion in irradiated rat brain⁵.

Pharmacokinetics:

Because of its hydrophobicity and large molecular weight, absorption of dietary Coenzyme Q10 is slow and limited. Solubilized Coenzyme Q10 formulations show enhanced bioavailability with T_max of approximately 6 hours and an elimination half life of approximately 33 hours (Bhagavan and Chopra 2006). Oral preparations of Coenzyme Q10 are used in human therapeutics. A randomized crossover study investigated the absorptive properties of 4 different Coenzyme Q10 preparations: Fast melting, Effervescent, Soft gelatin, and Powder filled hard shell (Joshi et al 2003). Area under the curve for various formulations were not significantly different. Maximum drug Concentration for the various formulations ranged between 0.70 and 0.86 μg/mL. T max for the fast melting and effervescent formulations was 1.3 and 2 hours, respectively. This was significantly shorter Compared with the T max of soft gel and powder filled forms which was 3.7 and 4.1 hours, respectively. Q Gel, a solubilized form of Coenzyme Q10, is superior to tablets and capsules regarding bioavailability^6-7.

Therefore, lower doses of Q Gel are required to rapidly reach and maintain adequate blood Coenzyme Q10 levels. A Colloidal Q10 preparation has been shown to improve the intestinal absorption and the bioavailability of Coenzyme Q10 in humans (Liu and Artmann 2009). Clinical laboratory monitoring is available for measurement of total Coenzyme Q10 in plasma and tissue and for measurement of redox status, i.e., the ratio of reduced and oxidized forms of Coenzyme Q10. It is recommended that laboratory monitoring should be Correlated with effects of treatment.

Dosing:

· For known Coenzyme Q10 deficiency: 150 mg daily.

· For Mitochondrial disorders (Mitochondrial encephalomyopathies): 150 to 160mg, or 2mg/kg/day. In some cases, doses may be gradually increased to 3000 mg per day.

· For Heart Failure in adults: 100 mg per day divided into 2 or 3 doses.

· For reducing the risk of future cardiac events in patients with recent myocardial infarction: 120 mg daily in 2 divided doses.

· For high blood pressure: 120 to 200 mg per day divided into 2 doses.

· For Isolated Systolic Hypertension: 60 mg twice daily.

· For preventing Migraine Headache: 100 mg three times daily. A dose of 13 mg/kg has also been used in paediatric and adolescent patients.

· For Parkinson’s disease: 300 mg, 600 mg, 1200 mg, and 2400 mg per day in 34 divided doses.

· For HIV/AIDS: 200 mg per day.

· For infertility in men: 200 to 300 mg per day.

The effects of free radicals:

Figure no 2. Shows the effects of free radicals in various parts of human body

Therapeutic Indications

Ø Congestive heart failure (CHF):

Some research suggests that heart failure might be linked with low Coenzyme Q10 levels. Although most evidence shows that taking Coenzyme Q10 alone does not help treat heart failure, there is some evidence that it might be helpful when taken in Combination with other heart failure medications and treatments⁸.

Ø Chest pain (Angina):

In case of chest pain this CO Q10 is also applied, In one clinical study, Coenzyme Q10 showed fewer incidents of angina pectoris Compared to placebo.

Ø High blood pressure (Hypertension):

55% of patients who take Coenzyme Q10 (doses of 75- 360mg/day) have shown to have a 25.9 mmHg reduction in systolic blood pressure with 12 weeks of therapy. Studies have also shown that when Coenzyme Q10 is added to other anti hypertensives seems to provide an additional blood pressure lowering effect and might allow dosage reduction or disContinuation of some anti hypertensives medications.One study showed a mean decrease in systolic blood pressure from 151mmHg to 139mmHg and a mean diastolic blood pressure decrease from 92mmHg to 84mmHg when adding Coenzyme Q10 to antihypertensive medication regimens^8-9.

Ø Parkinson’s disease:

In case of Parkinson’s Coenzyme Q10 at high doses (1200mg/day) appears to slow the progressive deterioration of function in early PD when Compared to placebo.

Ø Dental problem:

Coenzyme Q10 is also used in case of dental disease, in case of dental problem it should be applied directly to the teeth and gums.

Ø Improving the immune system:

Patients with HIV/AIDS have shown to have a decline in Coenzyme Q10. Taking Coenzyme Q10 supplement (doses of 200 mg/day) have shown to increase plasma levels therefore improve the immune system, which Coenzyme Q10 may have immune stimulatory activity.

Ø Migraine headache:

Taking Coenzyme Q10 by mouth seems to help prevent migraine headaches. Studies show it can decrease the frequency of headaches by about 30% and the number of days with headache related nausea by about 45% in adults. Taking Coenzyme Q10 also appears to reduce migraine frequency in children who have low levels of Coenzyme Q10. It can take up to 3 months for significant benefit. However, Coenzyme Q10 does not seem to be effective in treating migraines once they have developed.

Ø Heart failure:

Muscular dystrophy and periodontal disease. It is also said to boost energy and speed recovery from exercise. Some people take it to help reduce the effects certain medicines can have on the heart, muscles, and other organs. But you may still hear about CO Q10 supplements and heart failure. CO Q10 has not been shown definitely to relieve heart failure symptoms. Only some of the studies of Coenzyme Q10 showed that it helps heart failure symptoms.

Ø Age related vision loss (age related macular degeneration). Taking a specific product Containing Coenzyme Q10, acetyl carnitine, and omega 3 fatty acids(Phototropic) by mouth seems to improve vision in people with age related vision loss.

Side effects:

Taking 100 mg a day or more of CO Q10 has caused mild insomnia in some people. And research has detected elevated levels of liver enzymes in people taking doses of 300 mg per day for long periods of time. Liver toxicity has not been reported. Other reported side effects include rashes, nausea, upper abdominal pain, dizziness, sensitivity to light, irritability, headache, heart burn, and fatigue. Medicines for high cholesterol (statins) and medicines that lower blood sugar cause a decrease of CO Q10 levels and reduce the effects of CO Q10 supplements. CO Q10 can reduce the body's response to the blood thinner (anticoagulant) medicine Warfarin (Coumadin) and can decrease insulin requirements in people with diabetes. The U.S. Food and Drug Administration (FDA) does not regulate dietary supplements in the same way it regulates medicines. A dietary supplement can be sold with limited or no research on how well it works or on its safety. Always tell your doctor if you are using a dietary supplement or if you are thinking about Combining a dietary supplement with your Conventional medical treatment. It may not be safe to forgo your Conventional medical treatment and rely only on a dietary supplement. This is especially important for women who

are pregnant or breast feeding¹⁰.

Adverse effects:

No serious adverse events have been reported with Coenzyme Q10. Gastrointestinal disturbances have been reported after oral intake of large doses of Coenzyme Q10.

Current development

Coenzyme Q₁₀ production in plants:

Coenzyme Q10 (CO Q10) or Ubiquinone10 (UQ10), an isoprenylated benzoquinone, is well-known for its role as an electron carrier in aerobic respiration. It is a sole representative of lipid soluble antioxidant that is synthesized in our body. In recent years, it has been found to be associated with a range of pathophysiological Conditions and its oral administration has also reported to be of therapeutic value in a wide spectrum of chronic diseases. Additionally, as an antioxidant, it has been widely used as an ingredient in dietary supplements, neutraceuticals, and functional foods as well as in anti aging creams. Since its limited dietary uptake and decrease in its endogenous synthesis in the body with age and under various diseases states warrants its adequate supply from an external source. To meet its growing demand for pharmaceutical, Cosmetic and food industries, there is a great interest in the Commercial production of CO Q10. Various synthetic and fermentation of microbial natural producers and their mutated strains have been developed for its Commercial production. Although, microbial production is the major industrial source of CO Q10 but due to low yield and high production Cost, other Cost effective and alternative sources need to be explored. Plants, being photosynthetic, producing high biomass and the engineering of pathways for producing CO Q10 directly in food crops will eliminate the additional step for purification and thus Could be used as an ideal and Costeffective alternative to chemical synthesis and microbial production of CO Q10. A better understanding of CO Q10 biosynthetic enzymes and their regulation in model systems like E. Coli and yeast has led to the use of metabolic engineering to enhance CO Q10 production not only in microbes but also in plants. The plant based CO Q10 production has emerged as a Cost-effective and environment-friendly approach capable of supplying CO Q10 in ample amounts. The current strategies, progress and Constraints of CO Q10 production in plants are discussed in this review¹¹.

Batch production of Coenzyme Q10 by recombinant Escherichia coli containing the decaprenyl diphosphate synthase gene from Sphingomonas baekryungensis:

Coenzyme Q10 is an important antioxidant used in medicine, dietary supplements, and Cosmetic applications. In the present work, the production of CO Q10 using a recombinant Escherichia coli strain Containing the decaprenyl diphosphate synthase from Sphingomonas baekryungensis was investigated, wherein the effects of culture medium, temperature, and agitation rate on the production process were assessed. It was found that Luria Bertani (LB) medium was superior to M9 with glucose medium. Higher temperature (37 °C) and higher agitation rate (900 rpm) improved the specific CO Q10 Content significantly in LB medium, on the Contrary, the use of M9 medium with glucose showed similar values. Specifically, in LB medium, an increase from 300 to 900 rpm in the agitation rate resulted in increases of 55 and 197 % in the specific CO Q10 Content and CO Q10 productivity, respectively. Therefore, the results obtained in the present work are a valuable Contribution for the optimization of CO Q10 production processes using recombinant E. Coli strains¹².

Production of Coenzyme Q10 by metabolically engineered Escherichia Coli:

Coenzyme Q10 is a lipophilic antioxidant that improves human immunity, delays senility and enhances the vitality of the human body and has wide applications in pharmaceutical and Cosmetic industries. Microbial fermentation is a sustainable way to produce Co Q10, and attracts increased interest. In this work, the native CO Q8 synthetic pathway of Escherichia Coli was replaced by the Co Q10 synthetic pathway through integrating decaprenyl diphosphate synthase gene (dps) from Rhodobacter sphaeroides into chromosome of E. Coli ATCC 8739, followed by deletion of the native octaprenyl diphosphate synthase gene (ispB). The resulting strain GD14 produced 0.68 mg/L Co Q10with a yield of 0.54 mg/g DCW. Modulation of dxs and idi genes of the MEP pathway and ubiCA genes in Combination led to 2.46fold increase of CO Q10 production (from 0.54 to 1.87 mg/g DCW). Recruiting glucose facilitator protein of Zymomonas mobilis to replace the native phosphoenolpyruvate: carbohydrate phosphotransferase systems (PTS) further led to a 16% increase of CO Q10 yield. Finally, fedbatch fermentation of the best strain GD51was performed, which produced 433 mg/L CO Q10 with a yield of 11.7 mg/g DCW. To the best of our knowledge, this was the highest Co Q10 titer and yield obtained for engineered E.Coli¹³.

Coenzyme Q10 protects human endothelial cells from β-amyloid uptake and oxidative stress induced injury:

Neuropathological symptoms of Alzheimer's disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, ß-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant Coenzyme Q10 against ß amyloid induced damage on human endothelial cells. We analyzed the protective effect of CO Q against A β induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and Confocal microscopy, biochemical techniques and RMN based metabolomics. Our results show that CO Q pretreatment of HUVECs delayed A β incorporation into the plasma membrane and mitochondria¹⁴.

Marketed products of Coenzyme Q10

Some Marketed product of Coenzyme Q10 are Coenzyme Q10_, Co-Q10_, Elppa CoQ10_,LiQsorb, Liquid Co-Q10, Nutra Drops, Q-Sorb CO Q10, QuinZyme.

CONCLUSION:

After Completion the total survey it can be Concluded that Coenzyme Q10 plays a major role in human life. It helps to scavenge the free radicals. It has many important functions against the management of stress. In modern hectic life, stress is very much Common and this Coenzyme Q10 is helpful to prevent this. This Coenzyme Q10 is available in all over the world. The supplement tablets are very much used by people. Lots of research work is already going on this matter. In future if some research is needed on this Coenzyme Q10 then this survey will stand as an informative document to researcher.

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Received on 23.04.2016 Modified on 21.05.2016

Research J. Pharm. and Tech. 2016; 9(6):635-640

DOI: 10.5958/0974-360X.2016.00121.9