Role of Plant Flavonoids In Mammalian Cell Inflammation

Dahiphale Hanumant Venkatrao

DEPARTMENT OF VETERINARY PHARMACOLOGY AND TOXICOLOGYCOVAS, PARBHANI

Flavonoids (or bioflavonoids) 1) Derived from the Latin word flavus meaning

yellow color in nature2) class of plant secondary metabolites.3) Also referred to as Vitamin P .

Flavonoids: source

Fruit and vegetables:(All classes)

Red wine:(Flavanol, Flavonols)

Cocoa:(Flavanolsand procyanidins)

Tea:(Flavanols)

Berries:(Anthocyanins)

Citrus:(Flavanone)

Dietary sources

Seperation techniques

1) Thin layer chromatography (TLC)2) High Performance Liquid Chromatography3) Paper Chromatography4) Column Chromatography

structures1) These are low molecular weight substances.

2) Are phenylbenzo- pyrones.

3) Structures are based on a common three-

ring nucleus.

Flavonoids: structure

Flavanol

Flavonol

Isoflavone

Flavanone

Anthocyanin

R2

HO O

R1

R3

OHOH

O

O

R1

R2 R4

R3

R5O +

OH

HO

OH

OHR1

R2

O

O

HO

OHOH

R1R2

R3OHO

OH O

R1

R2

R3

1) Antioxidativeactivities

2) Modulation of inflammatory related

cell functions

5) Modulation of proinflammatory gene expression

4) Modulation of the production of other

proinflammatory molecules

3) Modulation of proinflammatory enzyme activities

Proposed mechanisms underlying the inflammatory effects of flavonoids

Several mechanisms explaining the anti-inflammatoryactivity of flavonoids have been described, including

Antioxidative activities

Antioxidativeactivities

Inhibition of ROS

production

Free radical

Lipid peroxidation

Inhibition of pro-oxidant

enzyme

Radical scavanging

EFFECTMECHANISMACTIVITY

1) Body cells and tissues are continuously threatened by thedamage caused by free radicals and reactive oxygenspecies.

2) which are produced during normal oxygen metabolism.

3) The increased production of reactive oxygen species leadsto forms of tissue injury.

4) which have been implicated in a multitude of diseasestates ranging from inflammatory injury to myocardialinfarction and cancer.

5) The mechanisms and the sequence of events by which freeradicals interfere with cellular functions are not fullyunderstood

6) But some of the detrimental effects in biological systemsincludes.

a) Peroxidation of membrane lipids,b) Oxidative damage to nucleic acids or

carbohydrates andc) The oxidation of sulfhydryl and other susceptible

groups in proteins.7) In addition, free radicals can attract various inflammatory

mediators contributing to a generalized inflammatoryresponse and tissue damage

flavonoids are powerful in vitro antioxidants, beingable to scavenge a wide range of free radicals, as well as toinhibit their formation.

Modulation of inflammatory related cell functions

Modulation of inflammatory

related cell functions

Modulation of enzymatic

activity Inflammatory

cells activationModulation of

Secretory procesess

ACTIVITY MECHANISM EFFECT

1) The immune system is integrated by a highly complexregulated group of cells.

2) that may interact in a cellcell manner and may alsorespond to intercellular messages.

3) The immune response can be modified bya) Dietb) pharmacological agentsc) environmental pollutantsd) and naturally occurring food chemicals such as

vitamins and flavonoids.

4) Some flavonoids display a remarkable array ofbiochemical and pharmacological actions.

5) that affect the function of immune and inflammatory cellssuch as

a) T cells,b) B cells,c) macrophages,d) neutrophils,e) mast cells, or basophils.

6) Several flavonoids specifically affect enzyme systemscritically involved in the generation of inflammatoryprocesses.

7) especially tyrosine and serine-threonine protein kinases.8) These enzymes are involved in signaling transduction and

cell activation processes such asa) T cell proliferation,b) B lymphocyte activation orc) cytokine production by stimulated monocytes

Modulation of proinflammatory enzyme activities

Modulation of proinflammatory enzyme activities

inhibition of Arachidonicacid enzyme Inflammatory

mediators:NO, Leukotrienes,

prostaglandinsinhibition of NO synthase

EFFECTMECHANISMACTIVITY

1) Many investigations have shown that different flavonoidmolecules modulate the activity of arachidonic acidmetabolizing enzymes such as

a) phospholipase ,b) cyclooxygenase (COX) and lipoxygenase (LOX)c) And the nitric oxide (NO) producing enzyme,

nitric oxide synthase (NOS).2) The inhibition of these enzymes reduces the production of

AA, prostaglandins, leucotrienes, and NO. which aremediators of inflammation.

3) Thus, the inhibition of these enzymes by flavonoids may beone of the most important mechanisms of their anti-inflammatory activity.

Modulation of the production of other proinflammatory molecules

Modulation of the production of other

proinflammatory molecules

Modulation of cytokine production

InflammatoryCytokine:

TNF- ,Interleukines.

EFFECTMECHANISMACTIVITY

1) In addition to COX-2 several cytokines are deeplyassociated with inflammatory diseases

2) In particular, tumor necrosis factor-a (TNF-a) is prominentcontributors to chronic inflammatory responses.

3) The comparison of molecular structures from differentflavonoids shows that

a) That the presence of a double bond at position C2C3 of the C ring

b) With oxo function at position 4,c) Along with the presence of OH groups at positions

30 and 40 of the B ringare required for optimal inhibition of LPS

stimulated TNF-a release.

Modulation of proinflammatory gene expression

Modulation of proinflammatory gene expression

Modulation of single

transduction

proinflammatoryGene transcription

EFFECTMECHANISMACTIVITY

1) In recent years, several lines of evidence have supportedthe idea that certain flavonoids are modulators ofproinflammatory gene expression

2) thus leading to the attenuation of the inflammatoryresponse

3) It is not known to what extent these proinflammatory geneexpression changes contribute to the inflammatoryresponse

4) but is evident that flavonoids show anti-inflammatoryactivity, at least in part, by affecting mRNA levels.

5) The mechanisms by which flavonoids blockproinflammatory gene expression arecurrently being investigated6) but pioneer studies suggest an effect ontranscriptional activity suppression inresponse to inflammatory stimuli.

CONCLUSIONS

Excessive inflammation is considered as a criticalfactor in many human diseases, including twoof the most extended burdens in the world:cancer and cardiovascular diseases.Epidemiological studies have demonstrated aninverse relationship between dietary flavonoidintake and prevalence and risk of thesediseases.So that, flavonoids research have received muchattention over the past years.

References

Flavonoids as anti-inflammatory agents:implications in cancer and cardiovascular diseaseAna Garca-Lafuente ,Eva Guillamon.Ana Villares,Mauricio A. Rostagno.Jose Alfredo Martnez. The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, andCancerELLIOTT MIDDLETON, JR., CHITHAN KANDASWAMIAND THEOHARIS C. THEOHARIDES1

References

Organic Chemistry of Natural products Vol2- Gurdeep.R.Chatwal Organic Chemistry- Reactions and Reagents-O.P Aggarwal Chemistry of Natural Products- SV Bhat, BH Nagasampagi, M.Sivakumar