ANTIOXIDANTNarveer Shekhawat

We will discuss

ROS : Definition, Source, function and effect on human body

Antioxidants: Definition, Type and Examples Different disorders where Antioxidants is indicated Role of ROS in these disorders Treatment options Antioxidant USPs

ROS - FREE RADICALSDEFINITION

Free radicals are molecules with an unpaired electron in their outer atomic orbital, causing the molecule to be extremely reactive

Free radicals cause oxidative damage in biological systems, which includes damage to the cell membrane and other structures, DNA molecules, lipids, and proteins

This damage arises from exposure to free radicals

ROS - FREE RADICALSSOURCE

1.Byproduct of cellular respiration 2. Synthesized by enzyme systems – phagocytic cells, neutrophils and

macrophage3. Exposure to ionizing radiation 4. Smoking, herbicides, pesticides, fried foods, etc

ROS - FREE RADICALSFUNCTION

1. Necessary for production of some hormones (thyroxine).

2. Generated to kill some types of bacteria and engulfed pathogens.

3. Normal cell functions and cell signaling.

4. A balance:

a. Free radicals generated by normal processes do become harmful if inadequate anti-oxidant defenses are present. A balance between production and removal/inactivation is required.

b. When free radicals are present in excess of the defense mechanism’s ability to control them is when damage may occur.

c. Anti-oxidants – compounds which will provide electrons to free radicals to neutralize them. The compounds are able to accommodate

ROS - FREE RADICALSEFFECT ON HUMAN

Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging.

ROS have been implicated in more than 100 diseases

ROS IS IMPLICATED IN Diabetic complications CVD – Atherosclerosis Debility – Chronic fatigue Prostate cancer Infertility Pregnancy complications Breast Cancer Eye Disorders

HOW TO CONTROL ROS

Free radicals are formed when an electron has escaped from the outer orbit of molecule

Free radicals quench electron from nearby cell and inturn damage the cell

Free radicals can be neutralized by donating an electron and stabilizing the molecule

AN ANTIOXIDANT IS A MOLECULE CAPABLE OF INHIBITING THE OXIDATION OF OTHER MOLECULES. OXIDATION IS A CHEMICAL REACTION THAT TRANSFERS ELECTRONS OR HYDROGEN FROM A SUBSTANCE TO AN OXIDIZING AGENT.

OXIDATION REACTIONS CAN PRODUCE FREE RADICALS. IN TURN, THESE RADICALS CAN START CHAIN REACTIONS.

TYPES OF ANTIOXIDANTS:

Mainly Hydrophilic and Hydrophobic

Antioxidant enzymes: 

1. Catalase2. Glutathione peroxidase3. Glutathione reductase4. Super oxide dismutase (both Cu-Zn and Mn)

Metals binding proteins: 

1. Ceruloplasmin 2. Ferritin3. Lactoferrin 4. Metallotheinein5. Transferrin 6. Hemoglobin7. Myoglobin

Common antioxidants (scavengers) 

1. Bilirubin 2. Carotenoids

a. Beta-carotene b. Alpha-carotene c. Beta-cryptoxanthin d. Lutein e. Zeaxanthin f. Lycopene 

3. Flavonoidsa. Quercetinb. Rutin c. Catechin

4. Uric acids 5. Thiols (R-SH) 6. Coenzyme Q10 7. Vitamin A, C, E, D. Others antioxidants 

1. Copper 2. glutathione (GSH) 3. Alpha lipoic acid 4.Manganise5. Selenium 6. Zinc

Antioxidant compoundsFoods containing high levels of these antioxidants

Vitamin C (ascorbic acid) Fresh Fruits and vegetables

Vitamin E (tocopherols, tocotrienols)

Vegetable oils

Polyphenolic antioxidants (resveratrol, flavonoids)

Tea, coffee, soy, fruit, olive oil, chocolate, cinnamon, oregano and red wine

Carotenoids(lycopene, carotenes, lutein)

Fruit, vegetables and eggs.

Natural antioxidants

ANTIOXIDANT SYSTEM IN OUR BODY

Superoxide dismutase (SOD)

Catalase

Glutathione peroxidase

The enzymatic antioxidants

The nonenzymatic antioxidants

Vitamins E, C, A or Provitamin A(beta-carotene),

GSH

IDEAL ANTIOXIDANT THERAPY

Not one antioxidant alone can lead to health benefits but the combination, as found for example in fruits and vegetables, is the active principle, leads to synergistic effects.

Mol Nutr Food Res. 2007 Jul 18;

IDEAL ANTIOXIDANT THERAPY

The clinical studies have shown that the Antioxidant supplements which are high in ORAC contents are very potent in action against the Oxidative Stress and Free Radicals which are responsible for the complications of the various Diseases in the humans.

ANTIOXIDANT DEFENSES INHUMAN PLASMA AND LDL

Small Molecule Antioxidants Typical Plasma Conc.• Water-Soluble: μM

Uric Acid 300Ascorbic Acid (Vitamin C) 50Albumin-Bound Bilirubin 15Glutathione (GSH) < 2

• Lipid-Soluble (Lipoprotein): mol/mol LDLα-Tocopherol (Vitamin E) 25 10Ubiquinol-10 (Coenzyme Q10) 1.0 0.4β-Carotene (Pro-Vitamin A) 0.5 0.2Lycopene 0.5 0.2

DIABETES

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to insufficiency of secretion (Type 1)

or utilization of endogenous insulin (Type 2)

ROS & DIABETES

Increased oxidative stress is a widely accepted participant in the development and progression of diabetes and its complications

Free radicals are formed disproportionately in diabetes by glucose oxidation, on enzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins.

ROS & DIABETES

Abnormally high levels of free radicals and the simultaneous decline of antioxidant defence mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance.

These consequences of oxidative stress can promote the development of complications of diabetes mellitus

DIABETES: AFFECTS QUALITY OF LIFE

Diabetes complications affecting the vascular system, kidney, retina, lens, peripheral nerves, Skin

Complications are common and are extremely costly in terms of longevity and quality of life.

CARDIOVASCULAR DISEASE

Oxidative damage is believed to be the underlying mechanism in the etiology of cardiovascular disease (CVD)

More recently, the multifaceted role of oxidatively modified LDL has been proposed as being instrumental in atherogenesis

PREVALENCE OF CARDIOVASCULAR DISEASESAGE 20 AND OLDER BY AGE AND GENDER

Note: These data include CHD, CHF, stroke and hypertension.

Source: CDC/NCHS. : 1988-94

INDIAN DATA

CARDIOVASCULAR DISEASE

According to recent estimates, Cases of CVD may increase from about 2.9 crore in 2000 to as many as 6.4 crore in 2015

Deaths from CVD will also more than double. Most of this increase will occur on account of

coronary heart disease —AMI, angina, CHF and inflammatory heart disease

Source:—Burden of Disease in India (New Delhi, India), September 2005

RISING PREVALENCE AND MORTALITY

Forecasting the prevalence rate (%) of coronary heart disease (CHD) in India

Estimated mortality from coronary heart disease (CHD)

CHD ESTIMATES

Estimates and trends of coronary heart disease (CHD) cases in various age groups

ATHEROSCLEROSIS

Hardening, loss of elasticity, and thickening of arterial walls with narrowing of the lumen of the artery

Principal cause of myocardial infarction and stroke (heart and brain attack)

OXIDATIVE MODIFICATION HYPOTHESIS OF ATHEROSCLEROSIS

Diaz, Frei et al. New Engl. J. Med. 1997;337:408-416

MECHANISMS OF ANTIOXIDANT ACTION IN ATHEROSCLEROSIS

Diaz, Frei et al. New Engl. J. Med. 1997;337:408-416

WHY ANTIOXIDANTS IN ATHEROSCLEROSIS?

Inverse association between plasma levels of carotenoids and the risk of atherosclerosis in various vascular territories support the hypothesis that antioxidants protect against atherosclerosis and other arterial diseases

Atherosclerosis 153 (2000) 231-239

WHY ANTIOXIDANTS IN ATHEROSCLEROSIS?

Inverse association between plasma levels High serum levels of total carotene, comprising alpha- and beta-carotenes and lycopene, may reduce the risk for cardiovascular disease mortality

J Epidemiol. 2006 Jul;16(4):154-60.

CHRONIC FATIGUE

Intractable or chronic fatigue lasting more than 6 months that is not reversed by sleep is the most common complaint of patients seeking medical care

It is also an important secondary condition in many clinical diagnoses and occurs naturally during aging

CHRONIC FATIGUE

Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion.

Many medical conditions are associated with fatigue, including respiratory, coronary, musculoskeletal, and bowel conditions as well as infections and cancer

CHRONIC FATIGUE:ETIOLOGY

Fatigue is related to cellular energy systems found primarily in the cells' mitochondria.

Damage to mitochondrial components, mainly by ROS oxidation, can impair their ability to produce high-energy molecules such as ATP.

This occurs naturally with aging and during chronic illnesses, where the production of ROS can cause oxidative stress and cellular damage, resulting in oxidation of lipids, proteins and DNA

Mitochondria

CHRONIC FATIGUE : TREATMENT

Antioxidant

to Preserve mitochondrial function

Prevent oxidative membrane damage

Prevent oxidation of lipids and proteins

LRT to generate energy

prostate cancer prevention and therapy

Normal Prostate

Prostate Cancer

ANTIOXIDANTS IN PROSTATE CANCER

In prostate cancer, a study has demonstrated inhibition of cell line proliferation in the presence of physiological concentration of lycopene in combination with vit.E

pastori m,pfander H, Biophys Res Commun,

1998;250:582-585

PROSTATE CANCER

Intake of exogenous antioxidants (vitamins E, C, beta-carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS.

J Am Coll Nutr October 2001 vol. 20 no. suppl 5 464S-472S

Chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals (Mainly Vit C, Vit E, beta-carotene, selenium & Zinc)

Int J Cancer 2005

PREGNANCY & ROS

Pregnancy places increased demands on the mother to provide adequate nutrition to the growing conceptus. A number of micronutrients function as essential cofactors for or themselves acting as antioxidants.

Oxidative stress is generated during normal placental development; however, when supply of antioxidant micronutrients is limited, exaggerated oxidative stress within both the placenta and maternal circulation occurs, resulting in adverse pregnancy outcomes.

Oxidative Medicine and Cellular Longevity Volume 2011 (2011),

PLACENTA AND UMBILICAL CORD

PRE-ECLAMPSIA & IUGR

Pre-eclampsia is a human pregnancy specific

disorder that adversely affects the mother by vascular dysfunction the fetus by intrauterine growth

restriction

Etiology is unknown

PREECLAMPSIA & IUGR

Pregnancy induced hypertension (PIH) may be estimated to develop in 8–10% women

Preeclampsia in 2–3% Reduced gestation period (Preterm delivery) Underweight Baby

ANTIOXIDANTS IN PREGNANCY

Reduces pre-eclampsia Reduces incidence of PIH Reduces incidences of IUGR Facilitates full-term delivery

BREAST CANCER

Breast cancer is the most common cancer and the second leading cause of cancer-related death among women

BREAST CANCER

Excess production of free radicals and/or deficiency of the antioxidant defence system can result in oxidative stress, causing damage to DNA and other molecules

Over time, such damage may become irreversible and may lead to diseases such as cancer.

There is evidence showing that oxidative stress and lipid peroxidation are linked to the etiology of breast cancer

ANTIOXIDANTS & BREAST CANCER

Antioxidants “mopping up” free radicals decrease oxidative stress and oxidative DNA damage

Antioxidants may selectively induce apoptosis in cancer cells but spare normal cells, and inhibit cell proliferation

WHY ANTIOXIDANTS IN BREAST CANCER?

supplementation of certain antioxidants such as beta-carotene, vitamin C, vitamin E and zinc may reduce the risk of breast cancer

Pan et al. BMC Cancer 2011, 11:372

MALE INFERTILITY: OVERVIEW

1. Male Infertility2. Oxidative Stress and Male

Infertility3. Antioxidant Therapy for Male

Infertility

MALE INFERTILITY: PREVALENCE

15% of couples suffer from infertilityA male factor is responsible for the couple infertility in 30-50% of cases

~5-10% of males are infertile or sub-fertile

ETIOLOGY OF MALE INFERTILITY

Multi-factorial PrevalenceVaricocele 35%Idiopathic 25%Infection – genito-urinary tract 10%Genetic 10%Endocrine 1 - 5%Immunologic 1 - 5%Obstruction 1 - 5%Developmental 1 - 5%Lifestyle: smoking, diet, heat ???%

VARICOCELE

Dilated testicular veins

Mechanisms of Injury:

Increased Heat

Venous Stasis

OXIDATIVE STRESS IN MALE INFERTILITY

Multi-factorialVaricocele Idiopathic Infection Oxidative stress is due to the elaboration Genetic ofEndocrine ROS (reactive oxygen species)Immunologic Obstruction Developmental Lifestyle

de Lamirande et al, Fertil Steril, 1995 Wesse et al, J Urol, 1993 Hendin et al, J Urol, 1999 Mazzilli et al, Fertil Steril, 1994 Vicari et al, Hum Reprod, 1999

ROLE OF ANTIOXIDANTS IN SEMEN

FunctionProtect normal sperm from

ROS-producing spermProtect normal sperm from

WBC-derived ROSSuppress premature sperm maturation

Site of Action Male reproductive tract

ROS AND NORMAL SPERM FUNCTION

Low levels of oxidative stress in vitro enhance: sperm hyperactivation sperm capacitation acrosome reaction sperm-egg binding sperm-egg fusion Fertilization

Bize et al, Biol Reprod, 1991 de Lamirande et al, Int J Androl, 1993 Griveau et al, Int J Androl, 1994, 1995 Zini et al, J Androl, 1995 Kodama et al, J Androl, 1996 Aitken et al, Biol Reprod, 1998

MALE INFERTILITY:Oxidative stress is important in

Male Reproduction

25% of infertile men have high levels of semen

ROS

Spermatogenesis is very sensitive to oxidative

stress

Lipid & DNA oxidation/damage are key

pathologic events

ANTIOXIDANTS IN MALE INFERTILITY:ADDITIONAL EVIDENCE

Oral antioxidant (containing Vit C & E,

Zinc, Selenium, Carotenoids) improve

sperm quality and pregnancy rate . Biomed Online 2010

ANTIOXIDANTS IN MALE INFERTILITY

Reaches in high concentration Improves acrosome reaction Enhances

Sperm morphology Sperm motility Sperm count

EYE DISORDERS

Glaucoma – Restricts the vision angle Cataract – Blurred vision AMD – Degeneration of eye

AMD

Age-Related Macular Degeneration (AMD) is a degenerative disorder of the macula, the central part of the retina.

Late-stage AMD results in an inability to read, recognize faces, drive, or move freely.

AMD

The prevalence of late AMD steeply increases with age

AMD is expected to increase in the next 20 years by more than 50%

ANTIOXIDANTS IN AMD

A high dietary intake of beta carotene, vitamins C and E, and zinc was associated with a substantially reduced risk of AMD in elderly persons.

JAMA. 2005;294:3101-3107

USP’s of antioxidants:

•Destroy the free radicals that damage cells.

•Promote the growth of healthy cells.

•Protect cells against premature, abnormal aging.

•Help fight age-related macular degeneration.

•Provide excellent support for the body’s immune system, making it

an effective disease preventative.

No Matter What Your Age…You Need Antioxidants!