Widanga (Embelia ribes)



Widanga (Embelia ribes)
Introduction

Widanga (Embelia ribes Burm f) is one of the oldest herbs used as medicine world-wide. Sushruta the father of surgery identified many varieties of Widanga (species of Embelia) and described their stomachic, carminative, anthelmintic and alterative properties. Later Dr. Harris found in ancient Arabian writing, Widanga, (birang-I-kabauli in Arabic) being used as a remedy for tapeworm (The Lancet July 23, 1887). Tribal societies knew that Widanga (Embelia ribes) inhibits the process of implantation of embryo in the uterus. It was originally described in detail by Nicolas Laurens Burman in his publication: Flora Indica in 1768.  

Widanga (Embelia ribes) is described as a powerful anthelmintic (Krimighna) in classical Ayurvedic texts "Charaka Samhitaa" and “Sushruta Samhitaa'. Modern world has validated the medicinal properties of Widanga described in Aayurvedic scriptures.  

However, the dried fruit of Widanga (Embelia ribes) was officially declared and accepted as the botanical source of 'drug' by the Govt. of India in 1966 and was included in Indian Pharmacopoeia.

Widanga (Embelia ribes) is used in 75 Aayurvedic formulations. It is now an endangered, ‘Red listed’ species because of over-harvesting for medicinal purpose. Concerned about this Widanga (Embelia ribes) is listed in the ‘Priority Species List’   for cultivation by the National Medicinal Plant Board, India and the Maharashtra State Horticulture and Medicinal Plant Board, India. The Medicinal Board, Govt. of India, New Delhi has undertaken a project for large-scale cultivation of Widanga (Embelia ribes). Unfortunately, traditional methods of propagation are not successful in the large-scale production of this species and artificial regeneration of this species is difficult due to poor seed viability. Lack of knowledge about its distribution, poor natural regeneration and unknown propagation techniques have resulted in the lack of availability of ‘Quality Planting Material’ for promoting cultivation. Misidentification of the species Embelia ribes coupled with the use of adulterants and substitutes have   further worsened the problem. [1], [2], [3], [4], [5]

Other Names
Botanical: Embelia ribes Burm
Sanskrit: Tandula, Vella, Jantughna, Krimighna. Krimihara, Krimiripu
English: False Black Pepper
Assamese: Widanga
Bengali: Widanga
Gujarati : Waawadinga, Waayawadanga
Hindi: Waayawidanga
Kannada: Waayuwidanga, Waayuwilanga
Kashmiri: Baabadinga 
Malayalam: Wizalaari, Wizhalaari
Marathi: Waawadinga
Oriya: Widanga, Bidanga
Punjabi : Waawaringa, Baabrunga
Tamil : Waayuwidangam, Waayuwilangam
Telugu : Waayuwidangalu
 Urdu: Baobarang, Babrang [6]

Scientific Classification

Kingdom: Plantae
(Unranked): Angiosperm
(Unranked): Eudicots
(Unranked): Asterids
Order: Ericales
Family: Myrsinaceae  [7]

Geographical distribution

Widanga (Embelia ribes Burm), a climber, is an Indo-Malaysian species, reported from India, Sri Lanka, Singapore and South China.   It is found in places up to the height of 5000 feet (1500 meters). In India it occurs in Central and lower Himalayas, Arunachal Pradesh, Assam, Maharashtra, Andhra Pradesh, Karnataka, Kerala and Tamil Nadu. It is sparsely distributed in the evergreen to moist    deciduous forests of the Western Ghats. It is distributed globally up to an altitude of 5000 feet (1500 meters). The species Embelia ribes Burm grows in semi-evergreen and deciduous forests throughout India. It ranges from India to Southern China, South to Indonesia, East Africa and on Malayan estates [8], [9]

Plant Morphology
Macroscopic


Widanga (Embelia ribes) Plant


Widanga (Embelia ribes) Burm. f. plant is a large, scadent (climbing) flexible, dioecious, woody shrub; branches long, slender, terete with long internodes.  The bark is studded with lenticels.
(Note: dioecious = having the male and female reproductive organs in separate flowers on separate plants)
Root: brownish grey hairy; rootlets reddish, hairy

                                           Widanga (Embelia ribes) Stem
Stem: whitish grey, girth 45-72 cms when mature. The bark is studded with lenticels.



Widanga (Embelia ribes) Leaves

Leaves: simple, coriaceous (like leather in texture), 6-14 cm long and 2-4 cm broad, alternate, elliptic (ovate) or lanceolate, shortly and obtusely acuminate, entire, entire, perfectly glabrous on both sides, shining above, paler and somewhat silvery beneath, smooth; the whole surface covered with scattered minute reddish sunken gland (conspicuous in the young leaves), base rounded or acute; main nerves numerous, slender; petioles 0.8 to 1 cm long, more or less   margined (having a distinct margin or border) glabrous; midrib prominent. 


Widanga (Embelia ribes) Flower 
  
Flowers: numerous, small, pentamerous (having five parts), globular, greenish yellow to whitish pink, in lax panicled (a much-branched inflorescence) racemes which are terminal and form the upper axils (the upper angle between a branch and the stem or trunk);  branches of the panicle often 7.5-10 cm long with more or less glandular, pubescent; bracts (bract= a modified leaf) minute, setaceous (bristle like, having bristles), deciduous; Calyx is about 1.25 mm. long; sepals connate (united so as to form a single part), about  1/3rd of the way  up, the teeth 5, broadly triangular-ovate, ciliated  (having tiny hair-like projections); Petals 5, greenish yellow, free, 4 mm. long, elliptic, subobtuse (partially   obtuse), and pubescent (covered with soft small hair, downy) on both sides; Stamens 5, shorter than the petals, erect; filaments inserted a little below the middle of the petals.



Widanga (Embelia ribes) Fruits

Fruit: small, oval shaped drupaceous berry, smooth, succulent, 3-4 mm in diameter found in  bunches, varying in color from grey to red, reddish  brown to brown black when unripe, black  when ripe, like a peppercorn when dried, having a small beak-like projection, tipped with the  persistent remains of style at the apex, outer rind fragile, wrinkled or warty when dry. In some fruits the pedicel (a small stalk bearing an individual flower in an inflorescence) along with persistent calyx is present. The flowers are polygamous. The fruits have a faint spicy odor and a pungent and astringent taste.   



Widanga (Embelia ribes) Seeds     

Seeds: Each fruit possesses a single seed which occupies the major portion of the fruit. The seed is    enclosed by the stony endocarp. The seed is circular in shape, of reddish or brownish black in color speckled with yellowish brown or white spots; with a small beak at the apex. Most of the seeds are striate. The seeds are aromatic and slightly astringent pungent in taste. [10], [11], [12], [13]

Different Varieties: At present Embelia Tsjeriam -Cottom-R et S, Embelia robusta are supplied as Widanga (Embelia ribes) in India, but taxonomically they are not Widanga (Embelia ribes). P. V. Sharmaji reported that Myrsine africana Linn is sold as Widnga (Embelia ribes) but it is NOT Widanga (Embelia ribes), it is an adulterant. 

  

True Widanga (Embelia ribes)

 

Embelia Tsjerian- Cottom- R et S (Adulterant)



Embelia robusta (Adulterant)


   
Myrsine africana (Adulterant)

Microscopic Characteristics
Seed
Cross section of the seed measures about 1258.3 µm in length and 1167.9 µm in diameter, circular in outline, depression at the base exhibiting 3-4 inward intrusion of the perisperm. The seed is albuminous and trizonate, composed of seed coat, endosperm and embryo. The seed coat is distinctively multi-layered. Below the integument a few cell layers of nucellus (the central part of the ovule containing the embryo sac) are compressed and seeds with irregular tegmen (inner layer of seed coat) producing invagination inwards which protrudes into endosperm. The endosperm occupies the major portion of the seed and consists of several layers of cells with dense cytoplasm. The endosperm appears to be of labyrinthine type, composed of a network of lobules.  

Embryo: small lies at the center of the seed, 724.9 µm in diameter, somewhat straight and embedded by the nutritive tissues of endosperm.  

Root: 

The mature root in transverse section is circular in outline with single layered epidermis. The epidermis possesses multi-cellular and uni-cellular glandular trichomes (a small hair or other outgrowth from epidermis); cork having 15-17 layers and schizogenous cavities (an inter-cellular space formed by splitting of the walls of adjacent cells). The cork is followed by a wavy sclerenchymatous ring. Beneath this, are seen secondary vascular tissues.  Biseriate (having two layers) medullary rays with tannin cells are very conspicuous.   

Stem: 

Mature stem in transverse section appears somewhat circular in outline. The epidermis single layered with unicellular gladular trichomes; Periderm 5-6 layered followed by distinguishable cortical region of parenchymatous and sclerenchymatous tissue. Tannin cells are prominent in parenchymatous region (in phloem tissue). Schizogenous cavities are conspicuous. Schizogenous strand arches into the secondary phloem tissue. The secondary xylem and secondary phloem are produced by cambium. The vessels have large lumen. Medullary rays are thin walled and biseriate. Pith cells are parenchymatous.        
Leaf: 
The transverse section shows common dicotyledonous characters. The epidermis single layered without trichomes; Mesophyll consists of a single layered palisade, spongy tissue with abundant intercellular spaces. The cells of mesophyll are rich tannin and oil glands. The vascular bundle 'C' shaped, broad; phloem fibers very prominent; stomata of Ranunculaceous type.  

Petiole:
In transverse section the petiole appears shield shaped in outline; vascular bundle crescent shaped; epidermis single layered; cuticle thin, cortical region parenchymatous; schezogenous cavities few; tannin cells are very common.  

Fruit:

In mature fruits, the transverse section shows the pericarp possessed a thin epicarp, a more or less fleshy parenchymatous mesocarp and stony endocarp. The epidermis of the epicarp usually obliterated in surface view, consists of a single continuous layer of rectangular cells, covered by the thick wrinkled cuticle which is thinned towards the end of fruit development because of undergoing accentuated reduction in thickness which can in part be the result of rapidly expansion of pericarp. The mesocarp consists of a number of reddish-brown colored scattered patches of brachysclerides and numerous fibrovascular bundles and rarely a few prismatic crystals of calcium oxalate,   oil bodies and abundant starch grains may also be found. Inner part of mesocarp and endodermis composed of stone cells. Endocarp is composed of several internal layers of brachysclerides arranged in a pyramidal fashion. The cells are irregular shape, thick-walled. The thickness of stony endocarp is 99.9 µm to 100.2 µm. The cells contain fixed oil and proteinous masses. Extensive lignifications of the endocarp provide it as the main protective layer of pericarp. The typical drupes frequently possess sclerified endocarps. Such drupes considered to be highly specialized fruits, are provided with several secretory structures.  
   
Embryo:

Small when present otherwise most of the seeds are sterile. 
Powder
Reddish in color.The microscopic examination of the powder shows:
----Reddish brown parenchyma
----Stone cells and sclerides of the mesocarp
----Epicarp in the surface view with striated cuticle
----Dark brown-colored cells of perisperm
----Cells of endosperm filled with aleurone (a protein found in protein granules of maturing seeds) grains and fixed oil
----Dark brown-colored palisade like cells of the endocarp [17], [18], [19], [20], [21]

Phytochemistry:

Several chemicals found in berries of Widanga (Embelia ribes) are:
Christembine, potassium embelate, rapanone, embelic acid, caffeic acid, vanillic acid, chlorogenic acid, cinnamic acid, o-cumaric acid, volatile oil, resin, tannin, embelin, flavonoid quercetin, benzoquinone, fatty ingredients and vilangin, sitosterol and daucosterol.

Some new compounds identified in seeds are: embelinol, embeliaribyl ester, embeliol and a known compound embelin. [22]

Identity, Purity and Strength:

Identification

(1) To 20 ml of solvent ether, add 1 g of powdered seeds of Widanga (Embelia ribes), shake for 5 minutes, filter. To a portion (10 ml) of the filtrate add slowly 5% v/v solution of NaOH (sodium hydroxide), a deep violate color develops in the aqueous portion. To the other portion add 2 drops of dilute ammonia (NH4OH) solution, a bluish violate precipitate is obtained.

(2) To 25 ml of alcohol, add 5 g of powdered seeds of Widanga (Embelia ribes), boil, filter, a deep red colored filtrate is obtained. Divide into two portions. To one add lead acetate [Pb(CH3COO)2] solution, a dirty green precipitate is obtained. To the other portion, add ferric chloride (FeCl 3] solution, a reddish-brown precipitate is obtained.  [23]        

TLC Finger printing Profile of Stem:

Researchers observed prominent bands with anisaldehyde spray and sulphuric acid spray at the Rf values 0.13, o.33, 0.54, 0.97 and 0.37, 0.55 and 0.98 respectively 

TLC Finger printing profile of leaf:

Researchers observed several bands with anisaldehyde spray and long UV and Chlorophyll content is major contributor for the banding pattern.  


TLC Finger printing profile of Fruit:

Researchers observed prominent bands with anisaldehyde spray and sulphuric acid spray at the Rf values 0.27, 0.91 and 0.32, 0.51, 0.56 respectively. One band is visible under long UV and short UV.  

HPLC analysis:

In one study the fruits of Widanga (Embelia ribes) when extracted in 100 % methanol for 30 minutes yielded 14.9 mg/gm dry weight of Embelin, a new anticancer agent. [24], [25]

Assay:

Sift 10 g of Widanga (Embelia ribes) powder through 40 mesh sieve. Transfer to 500 ml stoppered glass conical flask. Shaking intermittently mix it with 150 ml of solvent ether, pack the whole mass in a percolator, allow to macerate for 30 minutes, extract the solvent ether till the ethereal solution ceases to give a pink color with a drop of dilute ammonia solution. Distil off the ether, treat the residue with small quantity of light petroleum, cool in ice, filter through a Buchner funnel under suction and reject the filtrate. Wash the   Wash the residue further with small quantities of cooled ether. Transfer the residue to a tared beaker (previously weighed beaker) with sufficient quantity of solvent ether, remove the petroleum, dry the residue of embelin. The residue contains not less than 2% w/w of embelin (limit 1.85 to 2.15)   [26]

Chromosome numbers:

For number of years there was controversy regarding the 'chromosomal identity' of Widanga (Embelia ribes). Now researchers are in agreement that number of chromosomes in Widanga (Embelia ribes) 2n=16. This number agrees with all previous chromosome numbers reported in the literature. [27]  

Genetic Identification:

By using RAPD-PCR and SCAR markers the researchers established an accurate genetic identity of Widanga (Embelia ribes). 28], [29]

Standards:

Foreign matter NOT more than 2 percent
Total ash NOT more than 6 percent
Acid-insoluble ash NOT more than 1.5 percent
Alcohol-soluble extractive NOT less than 10 percent
Water-soluble extractive NOT less than 9 percent
The ether extract of Widanga (Embelia ribes) contains not less than 2 percent w/w of embelin (range 1.85-2.15) [30]

Purity:

The international guidelines for acceptable microbial limits in herbal formulations are: 

Microbial Limits:

Total bacterial count:                                  Not more than 105cfu/g
Total yeast and mould count:                     Not more than 104cfu/g
Bile tolerant gram negative bacteria:          Not more than 104cfu/g

Specific Pathogens:

Salmonella spp:                          Absent in 25 g
Escherichia coli:                          Absent in 1g   
Staphylococcus aureus:              Absent in 1g          
Pseudomonas aeruginosa:          Absent in 1g

Heavy Metals:

Arsenic:          Not more than 5.0 mg/kg
Mercury:        Not more than 0.5mg/kg
Lead:              Not more than 10.0 mg/kg
Chromium:    Not more than 0.3 mg/kg


Physicochemical Parameters:

The determination of physicochemical parameters is important in determination of adulterants and improper handling of drugs. The   following table shows physicochemical parameters of powder of the fruit of Widanga (Embelia ribes)

Physicochemical
Parameters
Mean  (mg/kg)    
SD (Standard Deviation)
SE (Standard Error)  
% RSD (Relative Standard Deviation
Total Ash
48.6                  
0.07                              
0.085      
0.144

Acid insoluble ash        
12.49                        
0.546                            
0.355
4.37       
Ethanol Extractable  matter    
111.15                      
1.434                            
1.432                                  
1.29                                                  
Loss on drying      (100-1050C)
         
25.3                          
0.0036                          
0.004                                
1.42                                                  
Foaming Index              
<100 nbsp="" o:p="">
       0
      0
     0

Ash Values:

Ash values are used to determine quality and purity of crude drugs. Ash values indicate the presence of various impurities like carbonate,     oxalate, silicate etc. The acid insoluble ash consists mainly of silica that indicates contamination with earthy material. The water soluble     ash indicates the presence of inorganic elements in drugs. The following table indicates ash values for powder of the fruit of Widanga (Embelia ribes

Physicochemical Parameters
Mean  (mg/kg)    
SD(Standard Deviation)
SE ((Standard Error)  
% RSD (Relative Standard Deviation)
Water soluble ash                
13.88                        
0.151                                    
0.13                                  
1.09          
Water extractable matter        
91.45                        
0.94                                      
1.122                                
1.02
Swelling Index
2.95                      
0.0057                                  
0.0081                              
0.195
[31]

Properties and Pharmacology:
Ayurvedic properties:

Ganas:  (Classical Catagories)
Charaka+ Ganas- Warga: Krimighna, Kushthaghna
Sushruta+Ganas- Warga: Surasaadi, Pippalyaadi
Ashtaanga Sangraha+ Ganas-Warga:  Surasaadi, Pippalyaadi [32], [33]

Energetics:

Rasa (Taste): Katu (Acrid, Pungent, Piquant), Tikta (Bitter), Kashaya (Astringent)
Weerya/ Virya (Energy State): Ushna (Hot)
Wipaaka/ Vipak (End result, Post digestive effect): Katu (Acrid)
Prabhaawa/Prabhav (Special Effect, Prominent Effect): Krimighna (Anthelmintic)
Note: Here I wish to clarify the meaning of these technical words:
Virya (Weerya): Potency, power, vigor
Vipak (Wipaak): After digestion change of taste. The food we take is acted upon by jaatharagni (digestive activity, digestive juices) and the taste of the food changes. The original rasa (taste) changes to vipak (new or same taste.)
Prabhav (Prabhaawa): Effect, prominent, peculiar or special action of an herb. Innate and specific property
Gunas (Qualities): Laghu (light), Rooksha (dry), Teekshna (penetrating)

Effects on Doshas: Waata, Kapha
Actions on Dhaatus (Tissues): Rasa (lymph), Rakta (Blood), Meda (Fat), Shukra (Semen)
Actions on Srotas (Systems): Pureeshwaha (Colorectal region), Rasawaha (Lymphatic syatem), Raktawaha (Hematopoetic system) Mootrawaha (Urinary system), Shukrawaha (Genital system) [34]

Ayurvedic Actions (Karma):

Deepana/ Wahnikara/ Agnimaandyahara: Appetizer, relieves indigestion
Aruchihara: Relieves anorexia
Paachana: Digestive 
Shoolahara: Relieves abdominal pain
Aadhmaanahara: Relieves abdominal bloating
Waatahara: Useful in abdominal flatulence
Anulomana: Prokinetic, Carminative
Sara: Laxative
Wibandhanut: Relieves constipation
Udarahara: Relieves ascites
Kriminaashana/Krimihara: Anthelmintic
Krimikushtha: Useful in skin infections
Shleshma-krimihara: Useful for worm infestation of Kapha origin
Shirorogahara: Relieves headache
Aartinut: Analgesic
Wibhraatihara: Releaves gidiness, dizziness, vertigo 
Raktashodhaka: Purifies blood, Anti-anemia
Rasaayana: Rejuvenative, Adaptogenic
Warnya: Beneficial for complexion
Pramehahara: Antidabetic [35], [36], [37]

Important References from Ayurvedic Texts
Charak Samhitaa:
Widangam krimighnaanaam (shreshtham): Widanga is anthelmintic par excellencs (Charak Samhitaa; SootraSthaana 25)

Sushruta Samhitaa:

Katu: (Acrid, Pungent, Piquant)     
Sara: Laxative
Krimighna: Anthelmintic
Kushthaghna: Anti-leprotic and Anti-infective for skin disorders
Pramehahara: Anti-diabetic, Reduces polyuria
Shirorogahara: Alleviates headache (Sushrut Samhitaa; Sootrasthaana 45)

Bhaawaprakaasha/ Raja-Nighantu:

Wibhramahara: Alleviates dementia, confusion, Alleviates vertigo
Aadhmaanahara: Antiflatuent 
Shoolahara: Anti-colic
Udarahara: Relieves ascites
Wibandhahara: Relieves constipation [38]
Modern View:
Widanga (Embelia ribes) is anti-inflammatory, antibacterial, febrifuge, anthelmintic, carminative, astringent and hypotensive.
Pulp is purgative.
Fresh juice is laxative and diuretic.
The aqueous extract of the fruit is anthelmintic especially against tapeworms. The root acts as anti-diarrheal. The seeds are spermicidal, oxitocic and diuretic.
The whole plant shows blood purifying properties. The active principles found in the plant show estrogenic and progestogenic   activity. [39]

Widanga (Embelia ribes) shows anti-inflammatory, anti-oxidant, antibacterial, anthelmintic, hypoglycemic, cardioprotective, antifertility and anti-tumor activity.
Widanga-fruits are used for the treatment of bronchitis, mental disorders, cardiovascular disorders, diabetes and jaundice; roots for influenza; seeds for tuberculosis and leaves for leprosy and many skin disorders. [40], [41]

Embelin

Molecular formula: C17H26O4
Structural formula:













Other Names:  Embelin is also known as emberine, embelic acid, potassium embelate benzoquinone and many more.

Embelin is found to be located on the outer coat of seed beneath a thin membranous film, below the pericarp of the fruit.
  
Embelin occurs as golden yellow needles sparingly soluble in water but soluble in alcohol, chloroform and benzene. It is used to color silk and wool.
      
Sublimation and volatility are major characteristics of Embelin. It does not decompose under normal pressure after being heated. It can be distilled with water vapor which makes it easy to be extracted and purified.

Due to poor water solubility, bioavailability of embelin is erratic. That is why its clinical applications have limitations. On the other hand, its long alkyl chain (undecyl) provides it   with long lipophilic ability and high cell membrane permeability which make it more stable and allow it enter the cells easily.    

When irradiated with light of appropriate wave length, embelin can be activated to produce     anti-inflammatory, anti-oxidant and anti-tumor effects. [42], [43], [44], [45]

Recently embelin has been synthesized in the laboratory. It will be of great advantage for new drug development [46]


Phytopharmacology of Embelin:

Anti-inflammatory activity:

In an experimental study, embelin, a plant based benzoquinone derivative, shows an appreciable anti-inflammatory and analgesic activity [47]   

In a study embelin was condensed with various primary amines to yield ten new derivatives along with monomethyl embelin. All these compounds and embelin, at 10 and 20 mg/kg body weight showed anti-inflammatory and analgesic activities. Embelin and two of its derivatives almost completely abolished the acetic acid induced writhing. However p-Sulfonylamine phenylamino derivative of embelin showed better anti-inflammatory activity than embelin. [48]  

TNF- α is a pro-inflammatory chemical. TNF- α is synthesized as a membrane anchored protein (pro-TNF- α). A protease enzyme called TNF- α converting enzyme converts pro-TNF- α into a soluble form that is released into the extracellular space. This soluble form is responsible for the development of inflammation. By blocking this cascade, Embelin found in fruits of Widanga (Embelia ribes) acts as a natural anti-inflammatory agent. [49]

Antioxidant Activity:

In an experimental study embelin was found to scavenge DPPH (2, 2-diphenyl-1 picrylhydrazyl) radicals. It inhibited hydroxyl radical   induced lipid peroxidation and restored impaired manganese superoxide dismutase in mitochondria of the hepatocytes in rats. Using nanosecond pulse radiolysis technique suggests that embelin can act as a competitive antioxidant in physiological conditions.[ 50], [51]

Using different antioxidant tests, free radical scavenging activity and lipid peroxidation in albino rats, a group of researchers evaluated the       antioxidant activity of embelin. By this study they concluded that embelin has a very potent antioxidant property.  [52]

Antibacterial Activity:

The principal phytochemical in the ethanol extract of Widanga (Embelia ribes) is embelin. At concentration of 100 mg/disc embelin showed antibacterial activity against Staphylococcus aureus, Shigella flexneri and Shigella sonnei. This activity was superior to kanamycin at 39 mg/ disc. Same kind of response was observed when embelin was used at 100 mg/disc against Pseudomonas aeruginosa at which it was superior to ciprofloxacin at 5 mg/disc. Embelin also shows strong antibacterial activity against Streptococcus pyogenes, Salmonella typhi, Shiegella boydii, Proteus mirabilis and mild antibacterial activity against Streptococcuc fecalis and Vibrio cholera. Methanol and aqueous extracts of the plant show moderate activity against multi-drug resistant Salmonella typhi.

In summary it can be said that embelin show good antibacterial activity against gram +ve and gram -ve organisms depending on the dose.
[53], [54], [55], [56], [57].

In another study, researchers isolated embelin in pure form from Widanga (Embelia ribes). By using disc diffusion they found that pure embelin had strong antibacterial activity against Streptococcus mitis and Bacillus subtilis, weak antibacterial activity against Staphylococcus aureus and no antibacterial activity against Escherichia coli.
The researchers are of the opinion that embelin is not a very efficient antibacterial compound but could give rise to more potent bioactive molecules by biotransformation. [58]

In Ayurveda  Widanga (Embelia ribes Burm. f.) is famous for antimicrobial activity. However another species of Widanga is also used for antimicrobial activity. Taxonomically it is Embeliaro busta auct. Nonroxb. Therefore though this other species shows antimicrobial activity similar to that of Widanga (Embelia ribes Burm. f.); scientifically the other species is an adulterant. Researchers have proved Widanga (Embelia ribes Burm. f.) has more potent antimicrobial activity than the adulterant species Embeliaro busta auct. Nonroxb. 

Hence the importance of chromosomal and genetic identification of herbs for effective pharmacological actions. [59]     

The chemists developed semi-synthetic derivatives of embelin. The scientists compared the antibacterial and anti-fungal activities of these two compounds against 21 bacterial and 4 fungal pathogens. Both the compounds showed broad spectrum antibacterial activity against gram positive and gram negative bacteria at a concentration of 200 µg/ml. Among the tested bacteria some strains of Escherichia coli, Salmonella typhi, Staphylococcus aureus and Vibreo chloera were found to be highly susceptible to the tested compounds with activity ranging between 75 and 94% of that of that of ciprofloxacin. Similarly the tested compounds showed anti-fungal activity against four pathogenic fungi. Their antifungal activity was compared with that of griseofulvin.  [60]

Recently a series of dihydropyran and dihydropyridin derivatives of embelin were synthesized. The obtained compounds showed antibacterial activity against Gram positive and Gram negative bacteria; more significantly against multi-drug-resistant Staphylococcus   aureus.  [61]        

Antifungal Activity:

Using standard in vitro anti-fungal susceptibility methods, researchers found that embelin shows anti-fungal activity against Candida albicans, Candida tropicalis, Candida parapsilosis, Candida alidus and A. flavus [62]

By employing various concentrations of the extract of seeds of Widanga (Embelia ribes), a group of researchers evaluated the antifungal     activity of the plant. They found, the extract showed antifungal activity against eight different fungi. The inhibition zones observed were: Colletotricum crassipes (18mm), Cladosporium (17. 5 mm), Armillalria mellea (17mm), Oryzae (16.5 mm). Aspergillus niger (16.5),     Rhizopus, Aspergillus terreus ans Candida albicans less than 15.5-16.5. Of all concentrations high inhibition zone was observed at the concentration of 2mg. [63]

Antiparasitic Activity:

By definition, anthelmintics are drugs that expel / eradicate parasitic worms from the body, by either inhibiting or killing them. Accordingly     anthelmintics are called as vermifuges (inhibiting drugs) or vermicides (killing drugs). Honigberger reported Widanga, (Embelia ribes Burm.) as a vermifuge. After him almost all researchers described Widanga, (Embelia ribes Burm. f.) as 'vermifuge' anthelmintic. [64]  

Watt GA reported addition of powdered seeds of Widanga (Embelia ribes) in curdled milk in combination with castor oil for effective eradication of tape worms. [65]

Embelin a benzoquinone shows anthelmintic activity. It is also ovicidal. Its activity is comparable to livamisole. While the parasites develop genetic resistance to levamisole, albendazole, ivermectin and mebendazole, the researchers found that the parasites have not developed resistance to embelin and Widanga (Embelia ribes) extract or powder. [66]

A Herbal monograph reported, Embelin is effective against tape worm but not against round worm or hookworm. [67], [68]

Furthermore, embelin was found to active against Trypanosoma cruzi trypomastigotes. [69]

The aqueous extract of Widanga (Embelia ribes) containing embelin exhibited anthelmintic activity against a variety of worms. This activity   was comparable to piperazine citrate.  [70]   

The ethanolic extract of seeds of Widanga (Embelia ribes) was evaluated for anthelmintic activity against round worm. In vitro graded doses of the extract (10, 50, 100 and 200 µg/ml) showed a significant anthelmintic activity against round worm. Levamisol and Ivermectin were used as reference drugs.  [71], [72]

Antimalarial activity:

Benzoquinone derivatives have been reported to possess antiplasmodial activity. Embelin being a benzoquinone derivative was studied for its antimalarial activity. The study suggested that embelin is a useful antimalarial phytochemical. [73] 

Embelin is found to be useful in the treatment of Plasmodium falciparum malaria. [74]

According to a group of researchers, embelin is not ideal to be suggested as an anti-malarial agent to be used against Plasmodium falciparum malaria, but it has a potential to ameliorate chloroquin resistance. [75]    
                
Actions on the Skin:

A study was designed to investigate the effects of embelin on lipopolysachharide-induced TNF-α production in mice and in human keratocytes and also to study the effects of embelin on acute and chronic skin-inflammations in mice. By blocking the synthesis of TNF-α, embelin inhibited topical edema in the ear of mouse leading to reduction in the skin weight and thickness, reduction in inflammatory cytokine production, neutrophil-mediated myeloperoxidase activity. These observations were supported by histopathological studies. Embelin was also effective in reducing inflammatory damage induced by chronic exposure to TPA. Thus embelin has anti-inflammatory activities in both acute and chronic dermatitis. [76]


Wound Healing Activity:

In a study on Swiss Albino Rat model, the wound healing activity of embelin isolated from the ethanol extract of the leaves of Widanga (Embelia ribes) was evaluated. The ethanol extract at 30 mg/ml showed rapid epithelization of the incised wound and faster rate of wound contraction. In dead space wounds also formation of granulation tissue was rapid and increased strength of collagen tissue. Both the observations were supported by histological study. [77]

Actions on Musculoskeletal System:

It is well known that most malignant tumors metastasise in bones. Thereafter osteoclastic activity increases resulting in osteolysis or destruction of the bone. Embelin has been shown to bind and inhibit x-linked inhibitor of apoptosis protein and prevent the bone loss. Embelin also has been shown to induce the ostoblastic activity and the bone regeneration. [78]

Actions on Hematopoetic System:

Signal transducer and transcription activator-3 (STAT-3) mediates cellular responses to interleukins. Phosphatase and tensin (PTEN) homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers. [79]

By down-regulating the expression of STAT-3 regulated gene products, embelin suppresses the cell proliferation and survival of multiple myeloma via the protein tyrosine phosphatase PTEN [80]

Actions on the Eye:

Muller glia or Muller cells are a type of retinal glial cells. They maintain the stability of the retinal extravascular environment. [81]

Hyperglycemia induces alterations in the Muller cells such as cell proliferation and VEGF production. This is the precursor of development of diabetic retinopathy. Embelin counter acts these alterations and prevents the development of diabetic retinopathy. [82]  

Actions on the Breast:

MCF-7 is the acronym of Michigan Cancer Foundation-7. MCF-7 is a breast cancer cell line isolated in 1970 from a 69 year old Caucasian woman. This cell line is used in cancer research. 

A group of researchers found that embelin induced apoptosis of MCF-7 breast cancer cells in the G2/M phase via the mitochondrial   pathway in a dose-dependent manner. However the exact mechanism of action remains unclear. [83]

A study shows that embelin primes inflammatory breast cancer cells (IBC cells) for TNF-alpha-related-apoptosis-inducing-ligand (TRAIL) mediated apoptosis by its direct action on the anti-caspase activity of X-linked inhibitor of apoptosis protein (XIAP).  [84] 
    
Mortalin is a protein involved in multiple basic mitochondrial processes, including energy metabolism, free radical generation. p53 is a key tumor suppressor protein that eliminates genetically unstable cells. Targeting mortalin by embelin causes activation of tumor suppressor     p53 and deactivation of metastatic signaling in breast cancer. [85], [86]

Antipyretic activity:

By various chemical reactions and chemical processes disalts and diamines of embelin are developed. Embelin, its disalts and diamines exhibit anti-pyretic and anti-inflammatory activity. [87]  

Actions on CNS:

Action on traumatic brain injury:

Traumatic brain injury is a serious problem. Both in children it can be life threatening and even fatal. The survivors suffer from many complications. A study revealed that embelin can be useful in the treatment of some complications. [88]    

Effect on autoimmune encephalomyelitis:

A study showed that embelin suppressed human CD 14(+) monocyte-derived dendritic cells (DC) differentiation, maturation and endocytosis. Embelin also inhibited the stimulatory function of mature dendritic cells on allogenic T cell proliferation in vitro. Embelin also prevents the demyelination of nerves. Thus embelin has potent anti-inflammatory and immunosupressive properties. This makes it a potential therapeutic agent for the treatment of autoimmune encephalitis and inflammatory diseases of CNS. [89]      

Analgesic activity:

Embelin is a non-norcotic analgesic effective by oral, intramuscular and intravenous routes. Its action is not antagonized by naloxone indicating a different central site of action. Furthermore in vivo studies indicate that mu and kappa binding sites in the brain may be   involved in the analgesic action of embelin. Its analgesic action is as strong as morphine. Embelin is not habit forming and not addictogenic and is remarkably free from adverse effects. This makes it safe analgesic for long term use. [90], [01], [92]

Anxiolytic activity:
   
A study was aimed at evaluating anxiolytic activity of embelin isolated from Widanga (Embelia ribes). The study group found embelin to be a potent anxiolytic agent. Needless to say that the anxiolytic activity was dependent on the dose used.[93]

Antidepressant activity

To evaluate the antidepressant activity of embelin, intraperitonial injections of embelin were administered at 2.5 and 5 mg/kg body weight   30 minutes prior to induction of experimental depression in Swiss albino mice of both sexes. Embelin exhibited antidepressant activity. The effective dose was 5 mg/kg body weight which was as good as imipramine 15 mg/kg body weight.

Since, the anxiolytic effect of embelin was shown to be mediated through GABA system, similar mechanism of antidepressant action cannot be ruled out. [94]

Antipsychotic activity:

In Ayurveda Widanga (Embelia ribes) was claimed to be useful in the treatment of diseases of the nervous system. In a study on rodents, embelin was administered orally to the study animals at 5 and 10 mg/kg body weight once a day for 15 days before exposing them to apomorphine injections. The study showed that embelin restored the elevated levels of dopamine, noradrenaline and serotonin to normal. Embelin wast more effective at the dose of 10 mg/kg body weight than at the dose of 5 mg/kg body weight. Researchers concluded that embelin possesses antipsychotic activity. In the research paper researchers did not explain the exact pharmacological mechanism of anti-psychotic activity of embelin. Further research is needed in this regard. [95]

Anticonvulsant activity:

In experimental animals, embelin administered by intraperitonial injections at 2.5, 5 and 10 mg / kg body weight significantly inhibited seizures induced by phentylenetetrazole and electroshocks. The effect was dependent on the dose of embelin used. The anticonvulsant activity of embelin was comparable to phenytoin and diazepam. The observations suggest that embelin can be useful in the treatment of   grand mal and petit mal epilepsy. [96]  

Actions on Sickness behavior:

Sickness behavior is a coordinated set of adaptive behavioural changes that develop in illness especially during the course of infection. A study was undertaken to investigate actions of embelin on lipopolysaccharide (LPS)-induced sickness behavior in adult Swiss albino mice. The animals were pre-treated with 10 and 20 mg/kg body weight of embelin for 3 days and then challenged with LPS 400 µg/kg body weight. Anti-inflammatory, antioxidant, anxiolytic and neuroprotective actions of embelin attenuated the behavioral changes induced by LPS. Embelin reduced anorexia, prevented anhedonia (inability to feel pleasure) and ameliorated brain oxidative stress markers. The study demonstrated protective effects of embelin on LPS-induced sickness behaviour in mice.[97]
        
Effect on focal ischaemia:

In cerebral ischaemia the brain receives inadquately oxygenatd blood and in inadequate quantity too. This generates reactive oxygen species that inflict brain damage. Embelin is a potent antioxidant. Its chemical structure resembles that of co-enzyme Q 10. Patel and Gohil investigated the effect of embelin on focal cerebral ischaemia using middle cerebral artery occlusion model in male Wistar rats. The occlusion resulted in infarct in the middle cerebral artery territory. Male Wister rats were then treated with embelin at doses of 50, 75 and 100 mg/kg body weight. Embelin not only decreased the area of infarct but also increased super oxide dismutase (SOD) levels [98]

Effects on global ischaemia-reperfusion injury:

A study was designed to investigate the protective effect of embelin on global ischaemia-reperfusion brain injury in rats. Transient global ischaemia was induced by occluding both internal carotid arteries for 30 minutes followed by 24 hour reperfusion.  Physical, biochemical and histoppathological changes were recorded. The animals pretreated with emnelin at doses of 25 and 50 mg/kg body weight were protected from ill effects of ischaemia. Their locomotor activity was preserved. Pretreatment and treatment with embelin also reduced the lipid peroxidation and increased glutathione-S-transferase activity in the brain. The histopathological studies revealed decreased area of cerebral infarction. These findings suggest that embelin is a potent neuroprotective agent and may prove to be useful in prevention and treatment of stroke. [99]  

Ischaemic stroke:

Embelin has been shown to relieve some effects of ischaemic stroke. [100]

Effects on Huntington's disease:

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurones, which affects muscle coordination. It leads to decline in mental function and behavioural symptos. 3-Nitropropionic acid (3-NP) causes severe neurotoxicity in animals which resembles Huntington's disease in humans. A study was designed to study the protective effect of embelin in 3-NP induced neurotoxicity in adult Wistar rats. Neurotoxicity was induced in Wistar rats by administering of 3-NP at the dose of 15 mg/kg body weight for 7 days. From 8 th day onwards the animals were co-treated with embelin (10 and 20 mg/kg body weight) for   7 days. The animals treated with embelin showed improvement in neurological symptoms and behaviour.  [101]  
      
Effect on Multiple Sclerosis (MS):

A chronic progressive damage to the sheaths of nerve cells in the brain, spinal cord, optic nerve etc. is termed as multiple sclerosis (MS). It is an autoimmune disease due to chronic inflammation. Xue et al demonstrated that embelin possesses a strong therapeutic potential for autoimmune anti-inflammatory conditions in multiple sclerosis (MS).  [102]

Effect on malignant glioma:

A study was designed to investigate whether embelin could have a therapeutic effect in glioma. The study showed that   embeiln suppressed the proliferation of human glioma cells. In addition, embelin induced apoptosis in human glioma cells by inhibiting NF-κ B. The results indicate that embelin could be a potent novel therapeutic modality for glioma. [104]

Actions on CVS:

To investigate the cardioprotective effect of and possible mechanism of action of embelin on isproterenol-induced myocardial infarction in rats, rats were pretreated for three days with embelin at a dose of 50 mg/kg body weight. There after isoproterenol was injected subcutaneously at the dose of 85 mg/kg body weight at an interval of 24 hours for 2 consecutive days. Serum was analysed for cardiac specific injury biomarkers, lipids and lipoprotein contents. Heart tissues were isolated for histopathology, antioxidant and mitochondrial respiratory enzyme activity assays and westernblot analysis. Results showed that pretreatment with embelin significantly protected the myocardium from isoproterenol-induced cardiaca injury. This suggests that embelin may have a potential benefit in preventing ischaemic heart disease. [105]  

In another study on rabbits some researchers investigated the protective effects of embelin on myocardial ischaemia-reperfusion injury following cardiac arrest. Following cardiac arrest, hemodynamics, pro-inflammatory cytokines, cardiac troponins, necrosis ratio, apoptotic index, nuclear factor-kappa B p65 and histological damage were evaluated. They found that animals treated with embelin showed    improvement in myocardial morphology. These results were attributed to anti-inflammatory activity of embelin. [106]

Embelin has the ability to lower elevated systolic blood pressure. [107]

Actions on RS:

A study was aimed at investigating the effect of embelin on lipopolysachharide (LPS)-induced acute respiratory distress syndrome in rats. Embelin was administered orally to rats at 5, 10 and 20 mg/kg body weight for four days before lipopolysachharide (LPS) challenge. The results showed that embelin prevented pO2 down-regulation and pCO2 augmentation. Embelin also attenuated histopathological changes in the lung in acute respiratory distress syndrome. This was attributed to anti-inflammatory and protective effect of embelin against LPS-induced airway inflammation and obstruction. [108]    
Embelin induces apoptosis in lung cancer cells via activation of p38/JNK pathway. Reactive oxygen species play a crucial role in embelin- activity.  [109]    

Actions on GI System:

Administration of embelin orally at 75 mg/kg per day for 15 to 30 days to male rats caused significant elevation in the uptake of D-glucose, L-alanine, L-leucin and calcium in the small intestine. Embelin also produced significant increase in enzymes sucrase, maltase, lactase, alkaline phosphatase and leucine aminopeptidase. All these changes returned to control levels on withdrawal of the drug. [110]

In an experimental study, intra-rectal administration of 3% acetic acid for 7 days induced ulcerative colitis in rats. When treated with   embelin at doses of 25, 50 and 100 mg /kg body weight there was a significant remission in the colitis. The treatment also reduced significantly the colonic myeloperoxidase activity, lipid peroxides and serum lactose dehydrogenase. The treatment also increased the decreased glutathione. The histopathological also supported the remission of the disease. The protective effect of embelin was attributed to the anti-inflammatory and antioxidant activities of the phytochemical. [111]

In another experimental study, colitis was induced in BALB/c mice by feeding them with 5% dextran sodium sulfate (DDS) for 7 days in drinking water. Embelin was then administered orally for 7 days to these animals at 10, 30 and 50 mg/kg body weight doses. The treatment significantly suppressed weight loss, diarrhea, bleeding and infiltration of immune cells. The histopathological study showed that embelin reduced the mucosal edema and the loss of crypts induced by dextran sodium sulfate. Furthermore embelin inhibited the abnormal secretions and mRNA expressions of pro-inflammatory cytokines. [112]

Actions on Pancreas:

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide variety of cancer cells. TRAIL does not exert toxic effects on normal cells. Therefore TRAIL may be a suitable agent for anti cancer therapy. In various pancreatic cancer cell lines TRAIL induced apoptosis. However the cancer cells soon developed resistance. Embelin reduced the resistance to TRAIL by the pancreatic cancer cells. [113] 

Actions on the Liver:

Hepatoprotection:

The rat liver is susceptible to damage induced by carbon tetrachloride (CCl4) through production of reactive metabolites, namely trichlormethyl-free radicals. After the induction of liver damage by carbon tetrachloride the animals were treated with embelin by oral administration of 25 mg/kg body weight from day 1 to 15. With embelin treatment the peroxidative damage was minimal. The antioxidant activity of embelin was found to be useful to protect the liver against carbon chloride- induced hepatotoxicity in rats. The hepatoprotection by embelin was superior to that by silymarin. [114]                  

Another group of researchers use N-Nitrosodimethylamine and Carbon tetrachloride to induce hepatootxicity. They then treated the animals with embelin. Their results were similar as described above. [115]

Alcoholic and non alcoholic liver disease:

Anti-inflammatory, antioxidant and free radical scavenging activity of embelin is useful in protecting the liver against   alcoholic and non alcoholic liver disease. The effective dose of embelin is found to be 50 mg/kg body weight.   [116]          

Hepato-biliary malignancy:

Anti-inflammatory is useful in the treatment of certain hepatic malignancies and cancer cell metastasis. [117]

Embelin causes inhibition of cancer cell proliferation but does not induce cancer cell apoptosis. By this mechanism embelin   inhibits proliferation of cholangiocarcinoma. [118]   

Embelin 50 mg /kg body weight (in combination with curcumin 100 mg/ kg body weight) prevented the induction of hepatic hyperplastic nodules, body weight loss, hypoproteinemia and elevation of liver enzymes in adult male Wistar rats.[119] 

Actions on Metabolism:

To evaluate efficacy of embelin in the treatment of obesity, male Wistar rats were fed on high fat diet for 28 days. Obese rats were then treated with embelin, 50 mg/ kg body weight for 21 days. Embelin treatment reduced body weight, reduced BMI, normalized blood pressure, serum lipid levels as well as coronary artery risk and atherogenic index. Embelin reduced serum glucose levels by 24.77 %, insulin by 35 % and leptin by 43.39%. Furthermore, embelin treatment significantly decreased the byproduct or degradation products of fat metabolism (TBARS) in the liver. Embelin increased the levels of superoxide dismutase (SOD), glutathione (GSH). The effects of embelin were similar to 10 mg/ kg body weight of orlistat. Embelin could be valuable in the development of new drug therapies to prevent and treat obesity, hyperlipidemia, diabetes, some complications of diabetes and oxidative stress. [120]

Antidiabetic activity:

Streptozotocin-induced diabetic rats were treated with embelin at 25 and 50 mg/kg body weight per day for 3 weeks. They showed a significant reduction in plasma glucose, glycosylated haemoglobin and pro-inflammatory mediators. Embelin also improved altered architecture of β-islet cells of pancreas and hepatocytes. This activity is attributed to the anti-inflammatory activity of embelin. The study suggests that embelin can be a useful adjuvant for the treatment of type 2 diabetes. [121]
   
Another group of researchers induced diabetes in rats by using alloxan. They treated the animals with embelin. Their results   were similar to the results mentioned above [122]

Embelin 50 mg/kg body weight administered to type 2 diabetic rats not only controlled the blood sugar but also modulated   the altered lipid lipid profile. Embelin also reduced the weight, regulated insulin resistance, altered β cell dysfunction, inhibited adiponectin activity and regulated insulin mediated glucose uptake in epididymal adipose tissue. These effects were attributed to antioxidant activity of embelin.[123]  
Embelin increases the antioxidant status in the pancreas. This prevents the β cell apotosis and protects them. The histopathological study of pancreas of the diabetic rats shows degenerated pancreas with reduced β cell counts, while embelin treatment was shown to significantly protect the β cells.  [124]  

Actions on Urinary System:

A study was designed to evaluate the nephroprotective and anti-polyuric activity of embelin on lithium-induced nephrogenic diabetes  insipidus (NDI). Diabetes insipidus was induced in rats by administering lithium chloride 4 mg/kg body weight per day for 6 days. After induction embelin 50 and 100 mg/kg body weight was administered orally once a day for 21 days. At 0, 7, 14 and 21 days the body weight, protein in urine, creatinine in urine, blood urea nitrogen serum creatinine levels were assessed. The results showed that embelin 50   and 100 mg/kg body weight showed increase in body weight and decrease in protein and creatinine in urine and normalization of blood urea nitrogen and serum creatinine. Histopathological examination of the kidney showed reduced vascular degeneration of tubules and slight degeneration and dilatation of renal tubules. These effects of embelin were due to its antioxidant activity. The decreased urine excretion may be due to the blocking of sodium channels. [125]

Actions on Male Reproductive System

Embelin administered by subcutaneous route at 0.3, 0.4 and 0.5 mg /kg body weight for 35 days to experimental animal model reduced sperm count and altered the testicular histology. Embelin was found to possess anti-androgenic activity. Embelin was used by some couples as an oral contraceptive. This is very cheap and can be a useful oral contraceptive for village-couples. [126]  
    
Daily subcutaneous injection of embelin isolated from the seed extract of Widanga (Embelia ribes) at a dose of 20 mg/kg body weight to male albino rats for 15-30 days revealed the inhibition of: (1) motile sperm count in the epididymis (2) the enzyme activity of glycolysis (3) energy metabolism (4) fertility parameters. These changes were reversible.

Treatment with embelin causes both in vitro and in vivo morphological changes in spermatozoa: (1) decapitation of spermatozoal head (2) discontinuity of outer membranous sheath in the mid-piece and and the tail region and (3) alteration in the shape of the shape of the cytoplasmic droplet in the tail. Embelin also caused a significant reduction in the sperm count, motility of the sperms and weight of the  testes. All these contribute to antifertility activity of embelin in male albino rats. [127] 
Having confirmed the efficacy of embelin as an effective contraceptive or antifertility agent, the next challenge was to determine the effective therapeutic dose. After studying various biochemical, hormonal and histopathological parameters and different routs of administration the doses finalized were: (1) Intramuscular injection- 5.0 mg/kg body weight (2) Oral administration (suspension)-10 mg/kg body weight (3) Oral tablet of base 50 mg/kg body weight (4) Subcutaneous injection (minimum effective dose)-20 mg /kg body weight [128]    
      
Actions on the prostate:

Embelin ameliorates testosterone-induced hyperplasia in rats. [129]

Embelin induces apoptosis in PC3 cell line of the prostate cancer cells. But the exact mechanism is not known. [130]

Embelin enhances therapeutic efficacy of ionising radiation in prostate cancer [131]

Actions on Female Reproductive System:

In an experimental study on female Sprgue-Dawlee rats having regular estrous cycle, embelin at doses of 10 and 20 mg/kg body weight decreased the plasma levels of estrogen and progesterone. This anti-fertility effect in females is due to suppression of    ovarian function. [132], [133]    
                         
Treatment of female rats with embelin reduces the serum levels of estradiol and progesterone. Embelin also reduces the weight of ovaries     uterus. These effects of embelin interfere with the implantation of fertilized ovum in the uterus. [134]

That herbal therapy is safe and devoid of side effects is a myth. Administration of embelin at a dose of 120 mg/kg body weight to female rats for six weeks caused severe pathological changes in the liver and kidneys such as marked necrotic changes, perinuclear vacuolation, tubular damage. The adrenals showed marked hypertrophy. There was increase in acid and alkaline phosphatase. However the histological     features of spleen remained unchanged. [135]

Anticancer activity:

Embelin is reported to decrease tumor size and inhibit activity of serum enzymes viz. acid phosphatase, T-glutamyl transferase, lactate dehydrogenase, aldose etc. in rats with experimental fibrosarcoma. Embelin interferes with carbohydrate and aminoacid metabolism in tumor bearing animals.

The osteoclasts are responsible for the osteolysis in bone metastases of the tumor. RANKL (receptor activator for nuclear factor κB ligand), a member of the TNF superfamily and an activator of the NF- κB signaling pathway, has emerged as a major mediator of bone loss, commonly associated with cancer and other chronic inflammatory diseases.  [136], [137]  
  
Nuclear factor-kappa B (NF- κB) regulates several gene associated with inflammation, proliferation, carcinigenesis and apoptosis. Embelin inhibits tumor necrosis factor alpha (TNF-α) induced NF- κB activation. Thus embelin prevents carcinogenesis. Furthermore, embelin down-regulates gene products involved in cell survival, proliferation, invasion and metastasis of the tumor. [138] 

Mortalin is a protein involved in multiple basic mitochondrial processes, including energy metabolism, free radical generation. p53 is a key tumor suppressor protein that eliminates genetically unstable cells. Targeting mortalin by embelin causes activation of tumor suppressor p53 and deactivation of metastatic signaling. [139], [140]

TNF-α is synthesized as a membrane anchored protein, pro-TNF-α. The soluble component of pro-TNF-α is then released in the extra- cellular space by the action of a protease, TNF-α converting enzyme. This the first step in development of inflammation and cancer.  Embelin inhibits TNF-α converting enzyme and cancer cell metastasis. [141]

In the normal quiescent state of vasculature, only 0.01% of endothelial cells (ECs)  are proliferating. However during angiogenesis the endothelial cells proliferate markedly. This proliferation depends on mitochondrial oxidative phosphorylation. This neo-angiogenesis is the     key stage in tumor growth. The antooxidant activity of embelin inhibits endothelial mitochondrial respiration and impairs neo-angiogenesis and tumor growth.  [142]  

Safety and Toxicity:

Mice treated with embelin administered orally at doses of 50-100 mg/kg body weight did not show acute toxicity. The subcutaneous dose       of 10 mg/kg body weight for 10 weeks was also well tolerated by animals without any side effect. Embelin administered orally to rats from 10 mg to 3 g/kg body weight did not show any adverse effect on heart, liver, kidney and bone marrow.

The female rats of reproductive age having normal cycles however did show toxicity even on short term use. Administration of 120 mg/kg     body weight was a safe dose, however higher dose was unsafe. The dose also caused liver and kidney damage. Embelin can cause   hormonal disturbances in males and females. Embelin can cause morphological alterations in the adrenals, testes and ovaries. 

It can be said, embelin is safe to use even for long term use in therapeutic doses. [143]

Contraindications:

Embelin is cotraindicated during pregnancy, lactation.
Newly married couples should not use embelin as a contraceptive. 

Dosages:  
Intramuscular injection- 5.0 mg/kg body weight
Oral administration (suspension)-10 mg/kg body weight
Oral tablet of base 50 mg/kg body weight 
Subcutaneous injection (minimum effective dose)-20 mg /kg body weight      
      
Embelin Derivatives:

By the success in synthesis of embelin, researchers were inspired to develop derivatives of embelin. By combining embelin with various metals such as sodium, potassium, copper, cobalt, nickel, zinc etc. salts of embelin were synthesized. These derivatives showed better pharmacological actions than natural embelin. Natural embelin exhibited anticancer activity. The search for better and better anticancer drugs is incessant. This led to develop better anticancer derivatives of embelin.

I wish to present a short review of embelin derivatives and their pharmacology.

Anti-inflammatory, analgesic, antioxidant and free radical scavenging activities. 

Recently embelin was condensed with various aromatic substituted primary amines to yield ten new derivatives. At 10-20 mg/kg body   weight these componds show anti-inflammatory, analgesic, antioxidant and free radical scavenging activities. [144]

Antimicrobial activity:

Aromatic aldehyde derivatives of embelin show antibacterial activities against gram positive and gram negative bacteria including multidrug   resistant Staphylococcus aureus.  [145]

Cobalt [Co(II)], Nickel [Ni(II)] Copper [Cu (II)] and Zinc [Zn (II)] derivatives of embelin show antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. At higher concentrations these derivatives show antibacterial activity comparable to rifampicin. 
In a study various derivatives of mbelin showed antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa, Escherichia coli and Candida albicans. [147]

Antidiabetic activity:

Nanoparticles of embelin and its metal complexes exhibit potent antidiabetic activity. [148], [149]

Anticancer activity:

All derivatives of embelin exhibit anticancer activity against a variety of cancer. Many research papers are available for references on this subject. [150], [151], [152]

Rapanone:

Molecular formula: C19H30O4    [153]
Structural formula: 



Many pharmacological actions of rapanone are similar to those of embelin. Here I have selected those   that are different from those of embelin especially in their mechanism of action.

Anti-inflammatory and Analgesic activity 

Rapanone is a mild anti-inflammatory, anti-oxidant agent. Increased activity of phospholipid A2  (PLA 2) in synovial fluid is an important cause of inflammation of joints. Rapanone is a selective and potent human synovial PLA2 inhibitor. Rapanone showed a mild anti-lipoperoxidative profile in rat liver   microsomes and inhibited degranulation of human neutrophils. Rapanone decreases carageenan induced paw edema and inflammations in the synovial membranes of joints. Rapanone is very efficient in controlling inflammatory process by different routes of administration. Rapanone is a potent analgesic. [154], [155], [156]

Antioxidant activity:

Oxidative stress generates reactive oxygen species (ROS). They damage various tissues and organs. To stabilize health it is necessary to neutralize or deactivate them. In an experimental study rapanone was found to scavenge oxygen free radicals and act as antioxidant agent. [157] 

Antiparasitic activity:

In an in vitro experimental study rapanone at a concentartion of 200 µg/ml displayed anti-amoebic activity against Entamoeba histolytica. In weanling Wistar rats administration of rapanone 200 mg /kg body weight for 4 days cured intestinal amoebiasis and in golden hamsters at 100 mg/kg body weight for 4 days cured hepatic amoebiasis. [158]

Antifertility activity:

Oral administration of 60 and 120 mg/kg body weight of rapanone to female mice reduced the number of pregnancies suggesting anovulatory cycles. Rapanone also inhibited the implantation of trophoblast. Daily administration of rapanone to male mice showed antispermatogenic effect. There were no acute toxicity at the doses tested during research. [159]

Anticancer activity:
   
In experimental studies rapanone showed anticancer activity against adenocarcinoma of the breast, colorectal adenocarcinoma DLD-1 cells, small cell lung cancer A549 cells, hepatocarcinoma Hep G2 cells, mesothelioma SPC 212 cells. Antiproliferative activity of rapanone-induced apoptosis in these cancer cells.  [160]

Rapanone shows anthelmintic activity. Rapanone is also inhibitor of angiotensin converting enzyme, hence useful in lowering raised blood pressure. [161]

Vilangin:
  
Molecular formula: C35H52O8 [162]
Structural formula: 



Vilangin was synthesized by condensation of embelin with formaldehyde in acetic acid.
Vilangin is bright orange-yellow in color, insoluble or sparingly soluble in common organic solvents, but   easily soluble in dioxane and nitrobenzene. It is soluble in water-alcohol.
Many pharmacological actions of vilangin are similar to those of embelin. Here I have selected those that are different from those of embelin especially in their mechanism of action. [163], [164], [165]

Vilangin inhibits angiogenesis. This delays the process of wound healing. Suppression of angiogenesis also reduces the vascularity of malignant tumors, exerting antimalignant effect of vilangin. [166]

Vilangin relieves itching of the skin, purifies blood and lymph. Vilangin is anthelmintic. [167]
At the concentration of 62.5 µg/mL vilangin showed antibacterial activity against Staphylococcus epidermidis and Salmonella typhimuricum. The free radical scavenging activity of vilangin was maximum at a concentration 100062.5 µg/mL. Antioxidant power of vilangin was two-fold higher than the standard antioxidants used in experimental studies. Vilangin showed a potent cytotoxic activity in vitro against A549 lung adenocarcinoma cell line at a dose of 500 µg/mL. Vilangin can thus be useful as a new anticancer drug. [168]    
  
In diabetic rats, vilangin reduced the body weight, elevated plasma glucose and plasma insulin. Vilangin also altered the lipid profile. 

This study suggests that vilangin may be useful in the prevention and treatment of obesity and type 2 diabees. [169] 

Pharmacological actions of vilangin are similar to the actions of estrogen. In male albino rats vilangin shows antispermatogenic and antifertility activity. [170]

Embelic acid:

Embelic acid is same as embelin (See above)

Potassium embelate:
Molecular formula: C17H25KO4 [171] 
Structural formula: 



Potassium embelate is a potassium salt of embelic acid.

Potassium embelate was administered orally and intravenously at a dose of 20 mg/kg body weight to rats to study the pharmacokinetics. The results showed that the absorption of potassium embelate was complete and fast (bioavailability 97%). The disposition half life on intravenous administration was 9.7 hours and 11 hours on oral administration. High concentrations of the drug were found in the brain between 0.25 and 2 hours. The kidney plays a major role in the excretion of the drug.  [172], [173] 

Potassium embelate shows antibacterial activity against Enterobacter aerugenes and antifungal activity against Candida species and some other fungi. [174]

Potassium embelate with copper-bound Streptomyces castaneoglobisporus tyrosinase is a potent tyrosinase inhibitor. This information   could contribute for further development of tyrosinase inhibitors for the prevention of hyperpigmentation. [175]

Potassium embelate is a non-narcotic analgesic. It is effective by oral, subcutaneous, intramuscular routes of administrations. It acts centrally to produce analgesia. Its effect is not antagonized by nalaxone. This suggests that it has a different central site of action. It is as powerful analgesic as morphine but is not habit forming. It increases the threshold to pain sensation or perception. It is said to inhibit COX-2. But its exact mechanism of action is unclear. Potassium embelate is not a potent anti-inflammatory agent. But its analgesic activity relieves joint pains. [176], [177]

Certain analgesics affect the metabolic status of the brain and other parts of the nervous system. Following administration 30 mg/kg body weight of potassium embelate to albino rats, there occurs alteration in the energy status of the brain, glycogenesis, glycogenolysis and cerebral turnover of noradrenalin. The antinociception begins within 15 minutes, reaches maximum in 30 minutes and diminishes by 90 minutes. Further studies would clarify the relationship between the brain metabolism and nociception. [178]

A study was carried out on the rat brain to clarify the characterization of binding sites for potassium embelate, a potent centrally acting analgesic compound. The results indicate that mixed mu and kappa binding sites in the brain may be involved in the analgesic action of of potassium embelate. [179]

Ammonium embelate:

Molecular formula:

Structural formula:

Embelic acid is contained in the fruit of Widanga (Embelia ribes). Ammonium embelate is ammonium salt of embelic acid. It is grayish violate powder. It is irritant to mucous membranes causing violent sneezing. Jt is used as anthemintic (in children 200 mg and in adults 350-400 mg). In children ammonium embelate is administered with honey for three consecutive days preceded by milk diet and followed by a dose of castor oil. Similar is the regimen for adults. [180]     

Caffeic acid:

Molecula formula: C9H8O4 
Srtuctural formula: 

2D diagram of caffeic acid


Caffeic acid is a yellow solid organic compound found in all plants. It is susceptible to autooxidation. Glutathione, ascorbic acid have protective effect on oxidation. 

Caffeic acid has antioxidant, anti-inflammatory and immunomodulatory activity.
Antioxidant activity of caffeic acid makes it a natural fungicide against Aspergillus flavus.

Caffeic acid shows anticancer activity against human fibrosarcoma cell line in experimental studies. Oral administration of high doses of caffeic acid in rats caused stomach papillomas, but in the same study when high doses of caffeic acid were combined with other antioxidants showed a significant decrease in growth of colonic cancers. These effects of caffeic acid were attributed to alterations in formation of metabolites of caffeic acid by bacteria in the gut of rats.

Caffeic acid is thiamine antagonist. No other untoward effects of caffeic acid are recorded in humans.  [181] 

Ikeda et al reported that caffeic acid has valuable properties such as antioxidant, antiinflammatory, antiviral, antidepressant, antidiabetic and anticancer. They also reported that caffeic acid inhibits multiplication of herpes simplex virus. [182]

Oxidative stress and vascular endothelial growth factor (VEGF) are implicated in retinal angiogenesis and retinopathy in diabetics. Caffeic acid was reported to show anti-angiogenetic effect on retinal neovascularization. This activity is attributed to inhibition of aldose reductase by caffeic acid. [183]

In an in vitro study caffeic acid was found to lower the raised LDL. It also prevented the oxidation and metabolic modification of LDL. This effect was dependent on the dose of caffeic acid used. [184]

Caffeic acid is a mild stimulant and reduces fatigue. It can cause and worsen insomnia.
Caffeic acid is said to be safe during pregnancy however it should be avoided during breast feeding. [185]

Caffeic acid is a natural product containing catechol with α, β- unsaturated carboxylic acid chain that has hepatoprotective properties. [186]

Vanillic acid: 

Molecular formula: C8H8O4 
Structural formula:



Vanillic acid is a phenolic acid found in many plants and in plant extracts in some form of vanilla.   It is a flavouring and scent agent that produces a pleasant odor. Vanillic acidia is a metabolic byproduct of caffeic acid and is often found in the urine of humans who have consumed tea, coffee, chocolate and vanilla-flavoured confectionery.  
  
Vanillic acid selectively and specifically inhibits 5' nucleotidase activity. [187] 

Vanillic acid shows anti-inflammatory, immununomodulatory and hepatoprotective activity. [188] 

In experimental studies on animal models Vanillic acid was found exert a good anti-inflammatory and analgesic activity in a wide range of murine inflammation models. Its mechanisms of action involve antioxidant effects and NFκB-related inhibition of pro-inflammatory cytokine production. [189]

Vanillic acid attenuates oxidative stress and improves cognitive function. [190]

A study was undertaken to compare the antioxidant and free radical scavenging properties of vanillin, vanillic acid and other 13 phenolic compounds. The results showed that antioxidant and free radical scavenging activities of vanillic acid were poor. [191]

At 200 mg /L vanillic acid shows maximal antimicrobial activity. [192]                            
By inhibiting 5'nucleotidase and platelet aggregation Naja naja venom inhibits blood coagulation.Thus Naja naja venom poisoning induces bleeding. By inhibiting Naja naja venom activity, vanillic acid acts as an antidote for Naja naja venom poisoning. [193]
In male Wistar rats vanillic acid at 5 mg and 10 mg/kg body weight showed cardioprotective effect against isoprenalin (100 mg/kg body weight) induced cardiotoxicity. These effects of vanillic acid were attributed to anti-inflammatory and antioxidant activities of vanillic acid. The cardioprotective activity was supported   by ECG recordings, studies of troponins and histopathology of myocardium. [194] 
Vanillic acid counter acts the ill effects of carbon dioxide excess or carbon dioxide poisoning as was observed in controlled experiments in healthy young adult male volunteers. [195]    
     
In experimental studies on animal models, dextran sulpfate sodium is used to induce ulcerative colitis. Vanillic acid significantly suppresses the expression of cyclooxigenase-2 and the activation of NFκB p65 in colon tissue. Thus vanillic acid may be useful for the treatment of ulcerative colitis. [196] 
                  
Via improving hepatic insulin signalling and alleviating inflammation vanillic acid ameliorates insulin resistance in rats fed on high fat diet. These findings suggest that vanillic acid may be used to prevent type 2 diabetes. [197]

Vanillic acid by preventing glycation can prevent diabetic neuropathy. It also prevents apoptosis of nerve cells. [198]

In vitro direct exposure of spermatozoa to vanillic acid a doses 25-100 mg % did not significantly affect their motility or fertilizing effect. Vanillic acid does not interfere with enhancement of fertilization by other chemicals such as piperine as was shown by studies in hamsters. [199]

Chlorogenic acid:  
Molecular formula: C16H18O9 
Structural formula: 


Chlorogenic acid is the ester of caffeic acid. The term "chlorogenic acids" refers to a related polyphenol family of esters. Despite the word "chloro", chlorogenic acid does not contain chlorine. Instead the name comes from the Greek, pertaining to the green color produced when chlorogenic acids are oxidized. Chlorogenic acid is freely soluble in ethanol and acetone. Chlorogenic acid is found in coffee and many plants.  [200]   

Anti-inflammatory activity:

Anti-inflammatory activity of chlorogenic acid was examined in lipopolysaccharide (LPS)-stimulated mice. The results showed that chlorogenic acid exerted anti-inflammatory activity as was evident by lower levels of inflammatory markers. [201] 

In rats chlorogenic acid at doses 50 and 100 mg/kg body weight exhibited anti-inflammatory, antinociceptive and antipyretic action within two hours of experimental procedure. Chlorogenic acid did not inhibit febrile response induced by lipopolysaccharide (LPS). The highest tested dose was 200 mg/ kg body weight which neither produce any untoward side effects nor any toxic effects. [202] 

Anti-inflammatory and antioxidant activity:

Chlorogenic acid controls oxidative stress and shows anti-inflammatory activity. [203]
Although chlorogenic acid is a good antioxidative agent it is unstable when exposed to light and heat. However recently it has been made stable by encapsulating it with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin). [204]

To evaluate effect of topical application of 1 % ointment of chlorogenic acid, excision wounds were inflicted in Wistar rats. The wounds were dressed with 1% ointment of chlorogenic acid. The anti-inflammatory and antioxidant properties of chlorogenic acid accelerated the process of wound healing.  [205]  

As physiological importance of an orally administered drug depends on its absorption in the intestine and action on target tissues, an in vivo intestinal ischemia-reperfusion model was used to evaluate antioxidant activity of chlorogenic acid. The study showed that chlorogenic acid protected the intestinal tissues from ischemia-reperfusion injury. [206]     
     
Immunomodulatory activity:

Bronchial asthma is a chronic inflammatory disease characterized by hypersensitivity response, reversible airway obstruction and remodeling of the airways. Immunomodulatory activity of chlorogenic acid was investigated in ovalbumin (OVA)-induced allergic bronchial asthma in mice. The results showed that suppressed the hypersensitivity response, eosinophilia, expression of interleukin-4 (IL-4), interleukin-5, tumor necrosis factor-α (TNF-α) as well as total and ovalbumin-specific immunoglobulin E (Ig E). [207]

Using in vitro and in vivo models researchers proved that chlorogenic acid inhibied compound 48/80-induced systemic anaphylactic shock in mice and skin vascular permeability in rats. Chlorogenic acid also inhibited anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-         mediated passive cutaneous anaphylaxix (PCA). Moreover, depending on the dose, chlorogenic acid reduced histamine and (TNF-α) release from rat basophilic leukemia 2H3 (RBL2H3) cells. These results suggest that chlorogenic acid can be used in mast cell dependent allergic and anaphylactic reactions. [208] 
    
Currently the popliteal lymphnode is considered a very promising tool for assessing immunosensitizing potential of low molecular weight compounds (LMWCs). In a study it was found that chlorogenic acid failed to induce immunoreactivity to some antigens. The study also showed that chlorogenic acid lacks the intrinsic capacity to stimulate or dysregulate immune responses to some antigens. [209]    

In response to the controversies of published studies on the potential sensitization of chlorogenic acid, Mingbao Lin et al, analyzed 108 articles published from January 1979 to October 2012. They feel much of the data was not of high quality. More high quality research is necessary to declare the final conclusion regarding the use of chlorogenic acid in allergic disorders. [210]     
                                                                  
Sepsis is a complex, multifactorial, rapidly progressive disease characterized by an overwhelming activation of immune system and the countervailing anti-inflammatory response. In a study chlorogenic acid suppressed progression of the sepsis. [211]  

Antibacterial activity:

Chlorogenic acid increases the outer and plasma membrane permeability, resulting in the loss of barrier function, disruption of outer membrane leading to death of many microorganisms. Chlorogenic acid shows bacteriostatic activity. Chlorogenic acid has antibacterial activity against Escherichia coli.   

In an in vitro study chlorogenic acid showed antibacterial activity against Bacillus cereus, Clostridium sporogenes, Micrococcus luteus, Escherichia coli, Staphylococcus aureus, Pseudomonas flourescens and Salmonella enterica.  [212], [213]

Antiviral activity:  
                             
Viral neuraminidases are implicated in viral replication. By blocking viral neuraminidases chlorogenic acid exerts antiviral activity against influenza and parainfluenza viruses. Therefore chlorogenic acid is used for the treatment viral infections of the upper respiratory tract and influenza. Recently intravenous injection of 100 mg/kg body weight of chlorogenic acid was found to alleviate influenza infection caused by H 1 N 1 and H 3 N 2 viruses. [214]

In a study chlorogenic acid and its compounds were shown to inhibit HepG2.2.15 cells and duck hepatitis virus. [215]

In China, 20 mg/kg body weight of chlorogenic acid was found to be effective for the treatment of Enterovirus 71 (EV 71) infection. In laboratory, human rhabdomysarcoma (RD) cells are used to diagnose enterovirus infection. In experimental study chlorogenic acid inhibited EV 71 2A transcription and translation in EV 71-infected RD cells. Chlorogenic acid inhibited secretions of IL-6, TNF- α, interferon (IFN-γ) and monocyte chemotactic protein (MCP-1) in EV 71-infected RD cells. [216] 

Antifungal activity:

Chlorogenic acid, by disrupting the structure of cell membrane of many pathological fungi, showed antifungal activity in vitro. The antifungal activity of chlorogenic acid did not show any hemolytic effect on human erythrocytes. Thus chlorogenic acid can be a future candidate for the development of new antifungal agent. [217]                                   
Chlorogenic acid showed antifungal and anti-mycotoxigenic activities against Aspergillus flavus and Aspergillus ochraceus. [218]

Actions on Hematopoetic System:

4-tert-octylphenol (OP) is a chemical compound from the group of alkylphenols. The substance is estrogenic and belongs to the chemicals known as 'endocrine disruptors'. In animal studies, 4-tert-octylphenol (OP) induced significant pnacytopenia, decreased   serum levels of sodium, potassium, chloride, calcium and phosphorus. OP reduces glutathione-S-transferase, glutathione peroxidase, glutathione reductase, catalase and superoxide dismutase. More over OP increased serum hepcidin, ferritin, transferrin, erythropoietin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatae, urea, creatinine, selenium, zinc, manganese, copper, iron,  malondialdehyde and protein carbonyl levels. Treatment with chlorogenic acid corrected anemia, pancytopenia, mineral disturbances and restored all the disturbed levels to normal values. [219]

Chlorogenic acid promotes expression of caspase-3,-7,-8,-9 in U 937 cells. Chlorogenic acid induces cell death in U 937 leukemia cells through caspase dependent and mitochondria-dependent pathways. [220] 

Actions on the Skin:

TPA (12-O-tetradecanoylphorbol-13-acetate) is used in cancer research to stimulate division of B-cells during cytogenic diagnosis of B-cell cancers such as chronic lymphocytic leukemia. Topical application of chlorogenic acid inhibits epidermal ornithine decarboxylase activity. Thus chlorogenic acid inhibits TPA (12-O-tetradecanoylphorbol-13-acetate) induced tumors. [221]  

Actions on Musculo-skeletal System:

In female Sprague-Dawley rats at 27 and 45 mg/kg body weight per day chlorogenic acid inhibited the decrease of bone density caused by estrogen deficiency. Furthermore chlorogenic acid was found to promote proliferation of osteoblast precursors and subsequently differentiation of osteoblasts by inhibiting Shp-2 gene, phospho-Akt and cyclin D1. Thus chlorogenic acid can prevent osteoporosis. [222]   

Actions on Endocrine System:

Chlorogenic acid modifies gastrointestinal (GI) hormone secretion and glucose tolerance. [223]

Actions on the Breast:

Chlorogenic acid belongs to phenolic acid group. It does exhibit group action. Its antiproliferative and apoptotic effects show anti-breast cancer activity. This effect is attributed to the antioxidant property of this compound on T47D human breast cancer cells. Chlorogenic acid does not interfere with steroid and adrenergic receptors.  [224]     
Action on Nervous system:

Chlorogenic acid is said to be present in human nervous tissue. Chlorogenic acid from decaffeinated green coffee is highly absorbed and metabolized in humans. Chlorogenic acid is used as a nutritional supplement. [225]

Chlorogenic acid has protective effect against cerebral ischemia. Depending upon the dose, Chlorogenic acid reduces the volume of infarct, sensory-motor functional deficit, reduces brain edema, reduces lipid peroxidation (LPO) and inhibits matrix metalloproteinase (MMP) expressions and activities. These effects of chlorogenic acid were due to its antioxidant and free radical scavenging activities. These results suggest that chlorogenic acid has protective effect against cerebral ischemia. [226] 

Recent evidence suggests that consumption of chlorogenic acid in the diet protects the brain from neuro-degenerative changes. [227]

The activated microglia release pro-inflammatory factors in the brain. They contribute to the progression of neurodegenerative diseases. The anti-inflammatory activity of chlorogenic acid, by mediating microglial activation protects the brain from neuro-        degenerative diseases. [228]

In mice chlorogenic acid exerted neuro-protective effect against scopolamine induced amnesia via improving antioxidant defense mechanism and by decreasing the activity of acetylcholine esterase. [229]

Chlorogenic acid and its metabolites evoke neurotrophic respone in hippocampal cells. [230]

Cadmium induces brain damage due to oxidative stress. Cadmium treated rats displayed numerous pathological changes in the brain such as inhibition of acetylcholinesterase, elevated lipid peroxidation, depletion of enzymatic and non-enzymatic antioxidants, reduction of membrane-bound ATPase activity, mitochondrial dysfunction and DNA fragmentation. Pretreatment of the rats with chlorogenic acid attenuated these ill effects induced by cadmium. This study suggests that chlorogenic acid is beneficial in the prevention of brain damage and neuropathy due to heavy metal poisoning.  [231]  

The most detrimental effects of alcohol (ethanol) exposure are the loss of neurones in the hippocampus and neocortex which may be related to the apoptosis and necrosis due to oxidative stress. By counteracting against oxidative stress chlorogenic acid prevents alcohol induced neurotoxicity.  [232]
    
The activated microglia release pro-inflammatory factors in the brain. They might be responsible for tumorigenesis in the brain. Chlorogenic acid is potent inhibitor of microsomal glucose 6-phosphate translocase (G6PT). This process is thought possess cancer chemopreventive properties. A study showed that chlorogenic acid has the potential to regulate invasive brain tumor-derived glioma cells. [233]                        
                                                                                         
Actions on CVS:

Chlorogenic acid increases the homocysteine level in the blood even in healthy persons which is detrimental to the heart. Homocysteine is a biomarker for cardiovascular disease. It is yet unclear whether chlorogenic acid merely increases the biomarker or it actually increases the cardiovascular risk. [234], [235]

Chlorogenic acid and its metabolites exert a potent anti-hypertensive effect. This effect is attributed to ferulic acid a metabolite of chlorogenic acid. Ferulic acid is vasodilator. [236], [237], [238]

Chlorogenic acid is vasodilator, reduces elevated blood pressure, attenuates endothelial dysfunction and improves endothelial function. Chlorogenic acid reduces oxidative stress and improves the bioavailability of nitric oxide in hypertensive subjects. [239]  

Anti-inflammatory and antioxidant activities of chlorogenic acid protect endothelial cells of the human umbilical vein from the toxic damage induced by Perfluorooctane Sulphonate. [240]

Several research papers reported anti-hypertensive activity of chloroenic acid. To arrive at a definite scientific conclusion on this issue Onakpoya I J et al undertook a meta-analytical review. Five eligible studies including 364 patients were included. The meta-analysis also showed that chloroenic acid significantly reduced systolic and diastolic blood pressure. [241] 
                            
Antioxidant activity, better bioavailability of nitric oxide in arterial vasculature and improvement in endothelial function are the key factors for lowering of blood pressure by chlorogenic acid. Inclusion of chlorogenic acid in the diet may hold a promise for providing a non-pharmacological approach for the prevention and treatment of hypertension. [242]

Actions on RS:

A study was designed to evaluate protective effects of chlorogenic acid against lipopolysaccharide (LPS)-induced acute lung injury. The study group treated mice with chlorogenic acid at doses of 5, 20 and 50 mg/kg body weight 30 minutes or 3 hours after intra-tracheal administration of lipopolysaccharide (LPS). The histological study after the treatment with chlorogenic acid displayed reduction in edema, hemorrhage, vascularity and alveolar structural damage caused by lipopolysaccharide (LPS). At the dose of 50 mg/kg body weight chlorogenic acid protected mice from acute lung injury caused by lipopolysaccharide (LPS). [243]    

Actions on the Pancreas:

Chlorogenic acid in decaffeinated coffee (green coffee) inhibited porcine pancreatic lipase. [244]

Actions on Liver:

Anti-inflammatory and antioxidant properties of chlorogenic acid protected the liver from carbontetrachloride (CCl4) induced hepato-toxicity in male Sprague-Dawley rats. Chlorogenic acid significantly attenuated the symptoms of liver inflammation and fibrosis induced by carbontetrachloride (CCl4). Chlorogenic acid also significantly reduced the elevated liver enzymes. The histological study also revealed improvement in the structure of the liver. This is attributed to inhibition of the activation of toll-like receptor 4 (TLR4/NF-κB) signaling pathway in the liver by chlorogenic acid.  [245]  

Methamphetamine intoxication can cause acute hepatic failure. If treated with chlorogenic acid before administration of methamphetamine chlorogenic acid can prevent hepatic injury. [246]

Hepatic ischemia-reperfusion is accompanied by excessive reactive oxygen species and hepatic inflammation. Chlorogenic acid has been shown to exert potent anti-inflammatory, antioxidant and antimicrobial activities. Thus chlorogenic acid might have potential as an agent for the treatment of hepatic ischemia-reperfusion injury. [247] 

Chlorogenic acid suppresses the invasion of AH109A, a rat ascites hepatoma cell line at concentrations of 5-40 µM without altering the cell proliferation. Thus in future chlorogenic acid can be an important chemical for the treatment of hepatoma. [248]      

5-fluorouracil (5-FU) inhibits proliferation of heptocellular carcinoma cells. Chlorogenic acid enhances the effects of 5-fluorouracil.  Chlorogenic acid acts as a chemosensitizer of 5-fluorouracil in the treatment of hepatocellular carcinoma. This activity is attributed to inhibition of extracellular signal-regulated kinases by chlorogenic acid [249]

Actions in Diabetes:

Chlorogenic acid lowered blood sugar in streptozotocin-induced diabetic rats. Chlorogenic acid also improved memory, prevented neuropathy and improved acetylcholine esterase (AChE) activity in streptozotocin-induced diabetic rats. [250]

Diabetic rats treated with chlorogenic acid showed an increase in adenosine monophosphate hydrolysis in cerebral cortex. Furthermore chlorogenic acid also reduced the platelet aggregation in the brain. [251]

AMPK (5' adenosine monophosphate-activated protein kinase) is an enzyme that plays an important role in cellular energy homeostasis.   The net effect of AMPK activation is stimulation of activation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle  fatty acid oxidation and glucose uptake; inhibition of cholesterol synthesis, triglyceride synthesis, lipogenesis, inhibition of adepocyte- lipolysis and modulation of insulin secretion by pancreatic beta-cells. Chlorogenic acid stimulates glucose uptake in skeletal muscle through activation of 5' adenosine monophosphate-activated protein kinase (AMPK). [252], [253], [254]

On Metabolism/Obesity:

Disorders of glucose metabolism and lipid metabolism are closely related. They may result into diabetes, obesity, hypertension, hepatic steatisis, cardiovascular disease, neuropathies and cancer. Chlorogenic acid can prevent these events. [255]  

Chlorogenic acid has a significant effect on the absorption and utilization of glucose. Use of chlorogenic acid for an extended time may reduce body fat and body mass.
A study on high fat-fed mice showed that, chlorogenic acid improved body weight, lipid metabolism and levels of obesity-related hormones in high-fat fed mice. Chlorogenic acid seemed to be more potent for body weight reduction and regulation of lipid metabolism than caffeic acid. [256], [257], [258]

To assess the effects of chlorogenic acid on lipid metabolism in male golden hamsters, the animals were fed on 15% high fat diet. The animals were treated with chlorogenic acid 80 mg/kg body weight for eight weeks. The results of the treatment showed that the levels of fasting serum triglyceride (TG), free fatty acid (FFA), total cholesterol (TC), low density lipoprotein cholesterol (LDL) glucose and insulin were significantly lower. Chlorogenic acid also led to higher activity of hepatic lipase (HL), lower contents of TG (triglyceride) and FFA (free fatty acid) in the liver. Thus chlorogenic acid can modify lipid and glucose metabolism [259], [260] 

Actions on Reproductive System:

In the only reported rat study, chlorogenic acid at 5-500 mg/kg body weight per day induced rib defects in fetuses of 5-12 weeks of gestation. No CNS defects and fetal or maternal mortality was reported. [261]      

Antitumor Activity:

Chlorogenic acid can prevent lung cancer. Chlorogenic acid induces high levels of topoisimerase I- and topoisomerase II-DNA complexes in cells. This is responsible for anticancer activity of chlorogenic acid. The lung cancer cells (A549) are more sensitive than normal lung fibroblasts (MRC5) to chlorogenic acid. This and the findings from some other studies suggest that the cytotoxic activity of chlorogenic acid may be selective in killing cancer cells.  [262]  

In a study, treatment of adenocarcinoma cells of colon with chlorogenic acid and neochlorogenic acid at concentrations of 150-500 µmol significantly reduced cell proliferation. The cell morphology of treated cells changed: the surface of cells became uneven, more rough and irregular in shape. These changes were dependent on the concentrations used. [263]

Chlorogenic acid is able to change gene expression involved in immunepathways. Chlorogenic acid promotes the activation and proliferation of T cells,macrophages and natural killer cells. Thus by enhancing killing abilities of these cells, chlorogenic acid can suppress the growth rate of tumor cells. [264]
   
Chlorogenic acid upregulates glycogen synthase kinase 3 (GSK-3β) and antigen-presenting cell (APC) genes which could inhibit free β-catenin into the nucleus. This disrupts the cell proliferation and causes apoptosis of cancer cells. [265]    
  
Toxicity of Chlorogenic acid:

High intake of chlorogenic acid could be responsible for the higher homocysteine concentration in the blood. This can be a risk for  cardiovascular diseases. [266]  
         
Dose: 120-300 mg for oral intake [267]

Cinnamic acid:

Molecular formula: C9H8O2 (C6H5CHCHCO2H)
Structural formula:


Cinnamic acid is a white crystalline organic compound, slightly soluble in water, and freely soluble in many organic solvents. It is classified as an unsaturated carboxylic acid. It occurs naturally in a number of plants.

Cinnamic acid is obtained from oil of cinnamon or from balsams such as storax. Cinnamic acid has a honey like odor. In pharmaceuticals it is a popular flavoring agent.

Cinnamic acid in its pure form is a precursor of famous sweetener aspartame.
[Note: Aspartame is widely used as an artificial sweetener. Upon ingestion it produces methanol as a metabolite which is subsequently converted into formaldehyde and formate. Both are hepatotoxic and carcinogenic. Terefore Cinnamic acid should be used with caution] [268], [269] 

Pharmacokinetics:

After oral administration cinnamic acid is quickly absorbed in stomach and intestine. It is completely metabolized in the liver before it is absorbed in the blood and is excreted in urine. [270]

Anti-inflammatory activity:

Cinnamic acid is not used as a medicine or a drug. Derivatives and esters of cinnamic acid have anti-inflammatory, antioxidant and cytotoxic properties. They are lipooxigenase inhibitors. Some derivatives and esters are tested for anticancer activities. [271]

Cinnamic acid derivatives especially those with phenolic hydroxyl group are strong antioxidants. They have several health benefits. They show anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal properties. [272]

Like cinnamic acid, its derivative 7-O-Cinnamoylmorroniside exhibits a strong anti-inflammatory activity. E-selectin, also known as CD62 antigen-like family member E (CD 62 E) is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. E-selectin plays an important role in inflammations. Cinnamoylmorroniside is a potent inhibitor of tumor necrosis factor alpha (TNF-α)-     induced expression. [273] 

Antioxidant activity:

Derivatives of cinnamic acid show higher antioxidant activity than that of cinnamic acid. This is due to the presence of vinyl fragments. This property of the derivatives attracts attention of pharma industry for the development of new drugs especially for the treatment of pathologies related to lipid peroxidation in cellular membranes. [274]
Cinnamic acid derivatives especially those with phenolic hydroxyl group are strong antioxidants. They have several health benefits. They show anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal properties. [275]

Antimicrobial activity:

Most of the cinnamic acids, their esters, amides, aldehydes and alcohols show significant inhibition of growth of several bacterial and fungal species. The data of antimicrobial species is however inadequate. The search is on to develop antitubercular drug with hybrids between cinnamic acids and biologically active other antimicrobial compounds. [276]

Recently a series of esters, substituted derivatives and amides of cinnamic acid were synthesized. They showed antibacterial activity against Gram negative organisms. They were especially effective against Escherichia coli and the fungus Candida albicans. [277]   

Antiviral activity:

Cinnamic acid, trans-cinnamic acid and derivatives of cinnamic acid exhibit antiviral activity against many viruses. They are not virucidal but inhibit the replication cycle of viruses [278]

Antifungal Activity:
                       
In a study Kim JH et al found antifungal activity of cinnamic acid and its derivatives. Of these 4-chloro cinnamate showed highest antifungal activity against C. rolfsii. [279]    
Antimalarial activity:

Cinnamic acid and its derivatives inhibit the transport of monocarboxylate across erythrocyte and mitochondrial membranes. They also inhibit parasite growth and are effective at ring and trophozoite stages of the malarial parasite. Antimalarial activity of cinnamic acid could be due to inhibition of lactate transport or of mitochondrial respiration. Since cinnamic acid and its derivatives are also noxious to host cells they cannot be used to develop novel anti-malarial drugs. However they are useful tools in research. [280] 

Actions on the skin:

By causing irreversible damage to DNA leading to cell death, cinnamic acid and its derivatives induce apoptosis in human melanoma cells. In a study, human melanocyte cell line (HT-144) and human melanocyte cell line derived from blue nevus (NGM) were exposed to cinnamic acid. HT-144 cells were sensitive to cinnamic acid treatment while NGM cells were less sensitive. The cell death was due to aberrations caused in DNA leading to non-viability of cells. This study showsthat cinnamic acid has effective antiproliferative activity against melanoma cells. Further study is necessary to develop anticancer drugs from cinnamic acid. [281]

Actions on CNS:

Fourteen derivatives of cinnamic acid were tested for their effects on central nervous system. All of them prolonged the sleep induced by phenobarbitone. This shows that cinnamic acid derivatives are central nervous system depressants. [282]

To evaluate effects of cinnamic acid and its derivatives, experiments were performed on slices of rat brains of either sexes. Increase in the concentration of potassium ions results in the increases in the oxygen uptake by respiring slices of cerebral cortex. Cinnamic acid and its derivatives suppressed the potassium activated oxygen uptake in brain slices. [283]

Halogenated cinnamic acid derivativives show highest CNS depressant activity. [284]

Actions on CVS:

Cinnamic acid and its derivatives viz. 3, 4-dihydrocinnamate i.e. L-serine methyl ester and L-aspartic acid show lipid lowering property. By using clofibrate as a positive control Kim and co-workers reported that cinnamic acid derivatives lowered atherogenic index and increased serum HDL. The derivatives also lowered hepatic cholesterol.

By inhibiting human acetyl-Co A, cellular cholesterol storage and LDL-oxidation these derivatives prevent atherosclerosis. [285]  
                     
Actions on RS:

A series of novel cinnamic acid derivatives was synthesized. They suppress the growth of A 549 lung cancer cells effectively. [286]

Actions on GI System:

Trans-cinnamic acid (tCA) was observed to inhibit the proliferation of colon carcinoma cells. No toxic changes were found in the heart, lung, colon, liver, kidney or bone marrow following histopathological examination. [287]

Recently cinnamyl sulphonamide hydroxamate, a novel derivative of cinnamic acid has been synthesized. Histone deacetylases (HDAC) are a group of enzymes that regulate DNA expression. The hydroxamate derivatives of cinnamic acid are inhibitors of HDAC enzyme. By acting through HDAC enzyme inhibition hydroxamate derivatives of cinnamic acid act against adenocarcinoma of the colon. [288]
                 
Actions on the Liver:

Trichlorfon is hepatotoxic, mutagenic pesticide. Cinnamic acid at 30 and 60 mg/kg body weight protects the liver against toxicity caused by trichlorfon. Cinnamic acid can cure trichlorfon-induced hepatotoxicity. [289]

Pre-treatment with cinnamic acid at 2.8 mg/kg body weight was found to protect the liver against mutagenic effects of cyclophosphamide.   Cinnamic acid also reversed the hepatocyte damage caused by cyclophosphamide treatment. [290]

At 20 mg/kg body weight, cinnamic acid protects the liver from cisplatin-induced hepatotoxicity. Therefore cinnamic acid can be     considered to be considered to be a potential candidate for hepato-renal protection against cisplatin-induced toxicity. [291]

At 28 and 56 mg/kg body weight cinnamic acid protects the liver from acute hepatocyte damage caused by endoxan. This activity is much superior to protection offered by vitamin C. Cinnamic acid even prevents the necrosis of hepatocytes caused by endoxan. [292]

Actions on Metabolism/ Obesity:

Obesity is a chronic metabolic and proinflammatory disorder associated with hyperlipidemia (dyslipidemia), diabetes mellitus, hypertension, atherosclerosis, ccardiovascular disease, non alcoholic fatty liver disease, nephropathy and cancer. In experimental studies on animal models, cinnamic acid at 30 mg/kg body weight for 7days, normalized the body weight in high fat diet fed animals, lipid profile reverted back to normal levels the activities of lipase and angiotensin converting enzyme. Cinnamic acid also prevented the vasoconstriction of aorta as evidenced on echocardiography. Cinnamic acid also prevented the steatosis of the liver. [293]                   
Cinnamates and various other derivatives of cinnamic acid such as compound b and c also lower the raised lipid levels in plasma as does cinnamic acid. Whereas cinnamic acid lowered hepatic-HMG-CoA reductase activity, its synthetic derivatives (a and b) do not affect hepatic-HMG-CoA reductase activity [294]

Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors are much sought after drugs for the treatment of type 2 diabetes and obesity. Cinnamic acid and its derivatives (o-Hydroxycinnamic acid 25 µM and p-Hydroxycinnamic acid 25 µM) being PTP1B inhibitors are useful for the treatment of type 2 diabetes and obesity. [295]

A series of cinnamic acid derivatives were synthesized. They inhibit LDL-oxidation, acyl-Co A cholesterol acyltransferase-1 and-2 activities. Thus cinnamic acid derivatives are useful as anti-atherosclerotic agents [296]

Antidiabetic Activity:

Cinnamic acid derivatives show strong hypoglycemic activity. [297]

At doses of 40-100 mg/kg body weight, by stimulating insulin secretion from the β cells of the pancreas p-methoxycinnamic acid lowers blood sugar in normal and streptozotocin-induced diabetic rats. [298]

Cinnamic acid derivatives show insulin releasing properties. [299]

By increasing calcium influx via L-type calcium channels p-methoxycinnamic acid stimulates insulin secretion from the β cells of the pancreas but not through the closure of ATP-sensivive K-channels. 

Furthermore based on several in vitro studies researchers found that cinnamic acid and its derivatives act on different mechanism of  actions including stimulation of beta cells to secrete insulin, improving the function of beta cells of the pancreas, increased insulin signaling pathway, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, delay of carbohydrate digestion and glucose absorption and inhibition of protein glycation. However bioavailability of cinnamic acid and its derivatives is low and not much study has been done on human subjects. Therefore these useful agents have limited use in clinical practice. [300], [301]                      

Hydrocinnamic acid derivatives act as supplements to other conventional oral hypoglycemic agents and may reduce the secondary complications caused by oral hypoglycemic agents. [302] 

Actions on Male Reproductive system:

Cinnamic acid and its derivatives have higher affinity for α 1 A-adrenoceptors. Researchers are investigating their role and importance in benign hyperplasia of prostate.  [303] 

Antitumor Activity:

Products derived from cinnamic acid such as cinnamoyl acid, esters, amides, hydrazides and related derivatives show cytotoxic and antitumor activity. [304]

Cinnamic acid and its derivatives have inspired researcher to design inhibitors of oncogenic protein kinases. The mode of inhibition may vary from ATP-competitive to non-competitive one. [305]

Analogues of cinnamic acid benzyle amide exhibit pleiotropic effects on cancer cells. [306]
Cynnamic acid and its derivatives induce cell cycle arrest in cancer cell lines [307]

Cinnamyl sulphonamide hydroxamate derivatives (HDAC) inhibitors show anti-angiogenic, anti-cancer and anti-metastatic activities in human cancer cells. [308]

Toxicity of cinnamic acid:

Cinnamic acid is a compound of low toxicity. Its compounds aldehyde, alcohol, esters and those containing cyano and fluoro moieties are more toxic. [309]

O-Cumaric acid: 
Molecular formula: C9H8O3  
Structural formula:


O-Coumaric acid is a hydroxycinnamic acid. There are three isomers of coumaric acid: o-coumaric acid, m-oumaric acid and p-coumaric acid. p-coumaric acid is the most abundant isomer of the three in the nature. They are slightly soluble in water but well soluble in ethanol and diethyl ether.  

O-Coumaric acid can be found in vinegar. [310]

O-coumaric acid is antioxidant and is useful in the treatment of obesity and diabetes.

Christembine:

Christambine are crystalline compounds of embolic acid with soda, potash and ammonia. They are alkaloids and pharmacologically act as     alkaloids. [311]

Daucosterol  
Molecular formula: C35H60O6
Structural formula:



Daucosterol aka Elutheroside A is a natural phytosterol-like compound. It is the glucoside of β-sitosterol.       

Daucosterol exhibits many properties similar to β-sitosterol.

Daucosterol promotes the proliferation of neural stem cells.

Daucosterol is used by athletes to build up stamina. 

A study shows that daucosterol is an efficient and inexpensive growth factor that could be used in clinical medicine and research applications. [312], [313]

Some testimonials from modern research
Pharmacology, toxicity, dosages etc of each phytochemical contained in Widanga (Embelia ribes) have been discussed in detail above. The pharmacological actions of  Widanga (Embelia ribes) therefore are a collective action of all the phytochemicals contained in it.  




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