INTRODUCTION:

A multitude of normal biological activities in our bodies release free radicals, including breathing, digesting food, metabolising alcohol and medications, and converting lipids into energy. Our body's natural antioxidant system normally destroys free radicals¹. Oxidative stress is one of the unavoidable aspects of aerobic life. It is the result of an imbalance between the production of reactive oxygen species (ROS) andantioxidant defences in living organisms². Several metabolic, chronic, or cancer-related illnesses have been linked to oxidative stress^3,4,5. Free radicals play a role in a variety of biological processes. Many of these are necessary for survival, such as phagocytes' intracellular killing of microorganisms, particularly by granulocytes and macrophages. One of the most reactive oxygen radical was hydroxyl radical and it is consequently shot-term lived known radicalAccording to investigators Free radicals are also engaged in several biological signalling pathways known as redox signalling^3,4.

At low to moderate levels, ROS are advantageous in regulating processes involving themaintenance of homeostasis as well as a large number of cellular functions^3,4,6. The oxidants/free radicals are species with very short half-life, high reactivity and damaging activity towards macromolecules like proteins, DNA and lipids⁷.

Current researches have confirmed that Free radicals can cause damage, known as "oxidative stress".Oxidative stress is a large increase in the cellular reduction potential, or a large decrease in the reducing capacity of the cellular redox couples which is thought to play a role in the development of many diseases, including Alzheimer's disease, cancer, eye disease, heart disease, Parkinson's disease, and rheumatoid arthritis⁸. These defensive mechanisms rely heavily on antioxidants. Oxidative stress is one of the unavoidable aspects of aerobic life. It is the result of an imbalance between the production of reactive oxygen species (ROS) and antioxidant defences in living organisms⁹.

Antioxidants:

Antioxidants are chemicals that considerably delay or prevent the oxidation of an oxidisable substrate when present in low concentrations compared to those of the oxidisable substrate. Antioxidants play a vital role in preventing free radical mediated oxidation by suppressing free radical production and scavenging radicals. A chemical reaction in which electrons are transferred from a substance to an oxidizer is known as oxidation. Free radicals are produced during oxidation events, which start chain reactions that injure cells. Antioxidants inhibit chain reactions by eliminating free radical intermediates and becoming self-oxidized, therefore preventing further oxidation events. Antioxidants' redox capabilities are crucial for absorbing and neutralising free radicals, quenching singlet and triplet oxygen, and degrading peroxides¹⁰.

Sources and Antioxidant Types:

Recently there has been an increased interest in the food industry and in preventive medicine in the development of ‘natural antioxidants’ from plant material.Natural antioxidants are found in various vegetables such as carrot, beat, tomato, lotus, cauliflower, cabbage, capsicum etc; green tea leaves; grapes and wines; soya beans; citrus peel; sesame seed; cocoa seed; grapes and wines; willow tree; grape stems; orange and apple fruits; barley and maltgrains; olives; ashwagandha; rhubarb; Virginia skullcap;various spices such as cardamom, cinnamon, clove, coriander, ginger, dill, garlic etc; neem etc¹¹.

The better known antioxidants are some of the mineral elements e.g. selenium and vitamins A, C and E which play important cooperative roles, and polyphenols and carotenoids¹².

Types of antioxidants:

Antioxidants are divided into two categories:

A. Natural or Primary antioxidants

B. Synthetic or Secondary antioxidants

A. Natural or Primary antioxidants:

They're antioxidants that break lipid radical chains and convert them to molecules that are more stable. They are mostly phenolic in structureand contain the following¹³

1. Antioxidant minerals: Antioxidant minerals are cofactors for antioxidant enzymes. If carbs, for instance, are not present, many macromolecules will be impacted. Selenium, copper, iron, and other elements are examples.

2. Antioxidant vitamins: The majority of body metabolic functions require antioxidant vitamins. Vitamins C, E, and B are only a few of them.

3. Phytochemicals: These are non-vitamin and non-mineral phenolic substances. Diterpenes, rosmariquinone, thyme, nutmeg, clove, black pepper, ginger, garlic, curcumin, and derivatives, as well as flavonoids, catechins, carotenoids, carotene and lycopene, are some of the compounds.

Flavonoids:

The hues of vegetables, fruits, grains, seeds, leaves, flowers, and bark are phenolic chemicals. Green/black tea and sesamol, contain the most powerful antioxidants, catechins. Carotenoids are fat-soluble pigments that provide colour to fruits and vegetables. Spinach and other dark greens are high in zeaxanthin.

B. Synthetic or Secondary antioxidants:

Synthetic or secondary antioxidants are phenolic compounds that can catch free radicals and

interrupt chain reactions¹³:

1. Butylatedhydroxyanisole (BHA)

2. Butylatedhydroxytoluene (BHT)

3. Propyl gallate (PG) and metal chelating agent (EDTA)

4. Tertiary butylhydroquinone (TBHQ)

5. Nordihydroguaiaretic acid (NDGA).

Synthetic antioxidants, on the contrary, have certain potentially harmful side effects. As a result, ingesting natural antioxidants from foods is the first choice, because Natural antioxidants are beneficial not only in the prevention and treatment of illness, but also in the prevention of negative health impacts.

Flavonoids:

In 1930, Vitamin P, an unique molecule was discovered in oranges that belonged to a new class of vitamins. This substance was later identified as a flavonoid (rutin), and there are now over 4000 flavonoids to choose from¹⁴.

Flavonoids are a polyphenolic class of plant secondary metabolites which can be present in fruits, vegetables, and drinks. They have a variety of metabolic and antioxidant properties that have been linked to disorders like cancer, Alzheimer's disease (AD) and atherosclerosis^15,16,17. Flavonoids also exist as valuable antioxidants in plant foods. There is abundant evidence from in vitro biochemical studies that flavonoids defend cells from lipid peroxidation, and from human intervention studies that dietary supplements decrease incidence of cancer and atherosclerosis¹⁸. The flavonoids (flavones, flavonols, flavanols, and flavanones) all have the same fundamental 15-carbon flavan structure (C6C3C6). These carbon atoms are organised in three rings (A, B, and C)¹⁹. Aglycones, glycosides, and methylated derivatives are all examples of flavonoids. The aglycone molecule is the most basic flavonoid structure. The benzene ring is condensed with the six-membered dihydro derivative ring or pyrone (flavonols and flavanones). Flavonoids are divided into two types: flavonols and flavanones. The position of the benzenoid substituent distinguishes flavonoids (2-position) from isoflavonoids (3-position) (3-position). Flavonols have a hydroxyl group in the third position and a C2-C3 double bond, which distinguishes them from flavanones²⁰.

· Natural polyphenolic compounds' ability to scavenge free radicals appears to be influenced by the number and positioning of free OH groups on the flavonoid backbone.

· The B-ring substitution pattern is particularly crucial for flavonols' radical scavenging action.

· Flavonoids with numerous hydroxyl groups have more antioxidant activity than those with only one. The inclusion of the ortho3, 4-dihydroxy structure boosts antioxidative activity¹⁸.

Fig: 1 Basic Structure of Flavonoids

· Isoflavones are flavonoids with the B ring linked to the C ring at position 3.

· Neoflavonoids have the B ring linked in position 4; Based on the structural properties of the C ring, those with the B ring joined in position 2 can be divided into several subgroups. The subgroups are flavones, flavonols, flavanones, flavanonols, flavanols or catechins, anthocyanins, and chalcones.²¹.

Fig: 2 Different Types of Flavanoids and Their Structures

Subgroups of Flavonoids:

Flavones:

One of the most well-known flavonoid subclasses is flavones. Flavones are found as glucosides in leaves, flowers, and fruits. Parsley, chamomile, red peppers, celery, mint, and ginkgo biloba are all high in flavones. Lutein, apigenin, and tangeritin are flavonoids that belong to this category. In citrus fruit peels, the polymethoxylated flavones tageretin, nobiletin, and sinensetin are prevalent. They have a ketone at position 4 and a double bond between positions 2 and 3 in the C ring. The large percentage of flavones have a hydroxyl group in position 5 of the A ring, which is most usually in position 7 of the A ring or 3' and 4' of the B ring, according on the taxonomic classification of the individual vegetable or fruit²².

Flavonols:

Flavonols are flavonoids that include a ketone group. Proanthocyanins are made up of these basic units. Flavonols are plentiful in various fruits and vegetables. The flavonols that have been investigated the most are kaempferol, quercetin, myricetin, and fisetin. Lettuce, tomatoes, apples, onions grapes, kale and berries are high in flavonols. Flavonols can also be found in tea and red wine, in addition to fruits and vegetables. Consumption of flavonols has been linked to a variety of health advantages, including antioxidant activity and a lower risk of cardiovascular disease. Flavonols having a glycosylable -OH group at the 3 position of the C ring, unlike flavones. Flavonols, like flavones, have a variety of methylation and hydroxylation patterns, and because of their different glycosylation patterns, they are the most common and largest subclass of flavonoids found in fruits and vegetables. Many plant meals, for example, include quercetin²³.

Flavanones:

Flavanones are a chemical class that is found primarily in citrus fruits including oranges, lemons, and grapes. Hesperitin, naringenin, and eriodictyol are among the flavonoids in this category. Because of their ability to scavenge free radicals, flavonones have been linked to a variety of health advantages. Citrus fruit juice and peel contain these chemicals, which give them a bitter taste. Citrus flavonoids offer antioxidant, anti-inflammatory, blood lipid-lowering, and cholesterol-lowering activities, among other things. Flavanones, also known as dihydroflavones, have a saturated C ring; as a result, The major structural distinction between the two flavonoid subgroups is that, The double bond between positions 2 and 3 is saturated, unlike flavones In the last 15 years, the number of flavanones has increased considerably²³.

Isoflavonoids:

Flavonoids are divided into isoflavonoids, which are a vast and separate subset of flavonoids. Soybeans and other leguminous plants contain the most isoflavonoids, with a small distribution elsewhere in the plant kingdom. Certain isoflavonoids have also been discovered in microbes²⁴. They've also been found as essential predecessors in the production of phytoalexins during plant-microbe interactions^25,26. Isoflavonoids offer a lot of promise when it comes to fighting diseases. Due to their oestrogenic action in animal models, isoflavones like genistein and daidzein are frequently classified as phyto-oestrogens. Szkudelska and Nogowski reviewed the role of genistein in causing hormonal and metabolic alterations, which can affect a number of different illness paths²⁷.

Neoflavonoids:

Flavonoids possess a 2-phenylchromen-4-one backbone, while neoflavonoids have a 4-phenylchromen backbone without any hydroxyl group substitution at position 2. Calophyllolide, obtained from the seeds of Calophylluminophyllum, was the first natural neoflavone found in 1951. It's also seen in the bark and wood of the endemic Sri Lankan plant Mesua thwaitesii^28,29,30.

Flavanols or Catechins:

Catechins are a kind of flavanol. Flavanonols are the 3-hydroxy derivatives of flavanones, commonly known as dihydroflavonols or catechins. They are a multisubstituted and extremely diverse subclass. Because the hydroxyl group is always attached to position 3 of the C ring, flavanols are also known as flavan-3-ols. There is no double bond between positions 2 and 3 unlike many flavonoids. Bananas, apples, blueberries, peaches, and pears are high in flavanols²¹.

Anthocyanins:

Plants, flowers, and fruits contain pigments called anthocyanins, which give them their colour. Cyanidin, delphinidin, malvidin, pelargonidin, and peonidin are the most thoroughly investigated anthocyanins. Cranberries, black currants, red grapes, merlot grapes, raspberries, strawberries, blueberries, bilberries, and blackberries, among other fruits, have high levels of flavonoids. Because of their stability and health benefits, these chemicals can be employed in various food-related applications. The colour of anthocyanin is affected by pH, as well as methylation or acylation of the hydroxyl groups on the A and B rings³¹.

Clinical Effects:

The various clinical effects of flavonoids are described in depth below.

Antiatherosclerotic effects:

Flavonoids are anticipated to have a significant impact on the vascular system due to their antioxidative properties. LDL can be oxidised by oxygen radicals, which damages the endothelium wall and causes atherosclerotic alterations. In a few clinical studies, flavonoid ingestion has been proven to protect against CHF^43,44.

Antiinflammatory effects:

Inflammatory mediators like cyclooxygenase and lipoxygenase play an important part in the inflammation process. They aid in the production of arachidonic acid, an inflammatory precursor. The cyclooxygenase and 5-lipoxygenase pathways have been discovered to be inhibited by phenolic substances^45,46. Quercetin, in example, inhibits the activities of both cyclooxygenase and lipoxygenase, reducing the generation of inflammatory metabolites^47,48. A number of reports have been published which demonstrate that flavonoids can modulate arachidonic acid metabolism via inhibition of cyclo-oxygenase (COX) and lipooxygenase activity (LO)⁴⁹.

Antitumor effects:

A number of antioxidants have been shown to inhibit cancer induction by a broad range of chemical carcinogens and/or radiation in mice, rats and hamsters at many target locations. Epidemiological studies indicate that a diet wealthy in plant products with natural antioxidants can deter carcinogenicity. Damage from reactive oxygen species has been linked tocarcinogenesis, and antioxidant systems are frequently inadequate.^50,51. When cells divide with unrepaired or misrepaired damage, reactive oxygen species can damage DNA, causing mutations. If these mutations appear in important genes like oncogenes or tumour suppressor genes, cancer may start or progress. Directly disrupting cell signalling and proliferation is possible with reactive oxygen species. Flavonoids have been found to inhibit carcinogenesis as antioxidants⁵². Fisetin, apigenin, and luteolin, among other flavonoids, have been demonstrated to be potent cell growth inhibitors. Flavonoids may also suppress angiogenesis, according to certain theories⁵³. In the human body, angiogenesis is generally a tightly controlled process. In cancer, pathologic, uncontrolled angiogenesis ensues⁵⁴, Flavonoids appear to be one of the most potent inhibitors of angiogenesis⁵⁵.

Antithrombogenic effects:

Aggregation of platelets has a role in atherosclerosis and the formation of acute platelet thrombus, As a result, stenosed arteries become embolized. When active platelets adhere to the vascular endothelium, they produce lipid peroxides and oxygen free radicals, which block the endothelium from producing prostacyclin and nitrous oxide. Tea pigment has been found to reduce blood coagulability, enhance fibrinolysis, and inhibit platelet adhesion and aggregation in studies dating back to the 1960s⁵⁶. Flavonoids like quercetin, kaempferol, and myricetin have been demonstrated to be effective inhibitors of platelet aggregation in dogs and monkeys⁵⁷. Because flavonols directly scavenge free radicals and lower endothelial prostacyclin and nitric oxide levels, they are particularly antithrombotic⁵⁸.

Antiosteoporotic effects:

Bone mineral density was examined in an English study between elderly women who drank tea and those who did not. In the study, tea-drinking women had better bone mineral density than non-drinking women. Tea's flavonoids may play a role in osteoporosis prevention⁵⁹.

Antiviral effects:

Flavonoids were discovered to have antiviral properties in a study by Wang⁶⁰. Herpes simplex virus, respiratory syncytial virus, parainfluenza virus, and adenovirus have all been demonstrated to be influenced by flavonoids.Quercetin has been found to have anti-infective and anti-replicative properties. Many steps of the viral replication cycle have been shown to interact with flavonoids in the past⁶¹. According to certain research, flavonoids in their glycone form appear to be more inhibitory of rotavirus infectivity than flavonoids in their aglycone form⁶².

CONCLUSION:

Preventing oxidative stress may be as simple as living a balanced lifestyle. The best treatment for oxidative stress is antioxidants, and nutrition plays a crucial part in it. Oxidative stress has an impact on the development of potentially fatal diseases. In addition to metabolic products, some environmental Stressors have been found to have a prooxidant effect, leading to the conclusion that lifestyle and diet can play a significant role in oxidative stress regulation. Bioactive compounds originating from plants have received a lot of interest in recent years due to their therapeutic value in both sickness prevention and treatment. Flavonoids are phytochemicals that have biological effects on a large number of organisms that are beneficial to human health. Natural antioxidants are abundant in human diets. Flavonoids are important in the prevention of a wide range of disorders because they are good at neutralising the negative effects of free radicals. Antiviral, antimicrobial, hepatoprotective, anti-inflammatory, and anticancer properties have been discovered in flavonoids. New insights and, without a doubt, a new age of flavonoid-based pharmacological therapies for infectious and degenerative disorders will certainly result from further achievements. Cranberries, black currants, red grapes, merlot grapes, raspberries, strawberries, blueberries, bilberries, and blackberries, among other fruits, have high levels of flavonoids. Because of their stability and health benefits, these chemicals can be employed in various food-related applications.

CONFLICT OF INTEREST:

The authors declare that there are no conﬂicts of interest.

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Received on 17.06.2022 Modified on 19.11.2022

Research J. Pharm. and Tech 2023; 16(10):4952-4958.

DOI: 10.52711/0974-360X.2023.00802

S. No.	Flavonoid Subgroups	Constituents Present	Source	References
1.	Flavones	Rutin, Luteolin, Chrysin, Apigenin and Glucosidestangeretin.	Buckwheat, red pepper, fruit skins, red wine, tomato skin, Parsley, Thyme.	14, 35, 36, 37
2.	Flavonols	Quercetin, Kaempferol, Myricetin and Tamarixetin.	Broccoli, onion, red wine, kale, olive oil, apples, cherries, berries, and grapefruit and tea.	38
3.	Flavonones	Hesperidin, Taxifolin, Naringenin, and Naringin.	Oranges, Citrus fruits, lemons, and grapefruits.	39, 40
4.	Isoflavones	Genistein, Daidzein.	Legumes, Soya beans.	41, 42
5.	Flavanols	Catechin, Epigallocatechin, Glausan-3-Epicatechin, Epicatechin, and Proanthocyanidins.	Apple, tea.	38
6.	Anthocyanidins	Apigenidin, cyaniding, delphinidin, malvidin and pelargonidin.	Grapes, strawberry, easberry, and Cherries.	37, 38