Pharmacology of Embelin found in Widanga (Embelia ribes)

Pharmacology of Embelin found in Widanga (Embelia ribes)


Introduction
Widanga (Embelia ribes) was an important medicine in the chest of grandmothers. It shows pleotropic pharmacological activities. Almost all of its pharmacological actions are due to a phytochemical “Embelin” found in it. I take an opportunity to describe the pharmacology of “Embelin”.

Embelin is also known as emberine, embelic acid, potassium embelate benzoquinone etc.

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. [1], [2], [3], [4]

Recently embelin has been synthesized in the laboratory. It will be of great advantage for new drug development [5]

Anti-inflammatory activity

In an experimental study, embelin, a plant based benzoquinone derivative, shows an appreciable anti-inflammatory and analgesic activity. [6]   
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.  [7] 

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. [8]

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 nano second pulse radiolysis technique suggests that embelin can act as a competitive antioxidant in physiological conditions. [9], [10]

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. [11]   

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. [12], [13], [14], [15]

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. [16]
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.  [17]    

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. [18] 

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.  [19]     

Antifungal Activity

Using standard in vitro anti-fungal susceptibility methods, researchers found that embelin shows anti-fungal activity against Candida lbicans, Candida tropicalis, Candida parapsilosis, Candida alidus and A. flavus [20]
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.  [21] 

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. [22]

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.  [23]

A Herbal monograph reported, Embelin is effective against tape worm but not against round worm or hookworm. [24], [25]

Furthermore, embelin was found to active against Trypanosoma cruzi trypomastigotes. [26] 
The aqueous extract of Widanga (Embelia ribes) containing embelin exhibited anthelmintic activity against a variety of worms. This activity   was comparable to piperazine citrate.  [27]   

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.  [28]

Mojumdar V and Mishra SD reported nematidicidal activity of embelin. [29]

Antimalarial activity

Benzoquinone derivatives have been reported to possess antiplasmdial activity. Embelin being a benzoquinone derivative was studied for its   antimalarial activity. The study suggested that embelin is a useful antimalarial phytochemical. [30]

Embelin is found to be useful in the treatment of Plasmodium falciparum malaria. [31]
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.  [32]      
              
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. [33]

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. [33]

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. [34]

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. [35]
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 [36]

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. [37]

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.   [38]

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. [39]

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).  [40] 

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. [41], [42]

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.   [43]

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. [44] 

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. [45]      

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. [46], [47], [48]

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. [49]

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. [50]

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. [51]

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.  [52] 

Actions on Sickness behavior

Sickness behaviour 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 behaviour 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 behavioural changes induced by LPS. Embelin reduced anorexia, prevented anhedonia (inability to feel pleasure), ameliorated brain oxidative stress markers. The study demonstrated protective effects of embelin on LPS-induced sickness behaviour in mice. [53]




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 [54]

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.  [55] 

Ischaemic stroke

Embelin has been shown to relieve some effects of ischaemic stroke. [56]

Effects in 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.  [57]        
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). [58] 

Effect on malignant glioma

Embelin has been reported to exhibit therapeutic activity against cancers. In a study embelin induced apoptosis in glioblastoma and  astrocytes.[59]

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. [60]

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.  [61] 

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. [62]

Embelin has the ability to lower elevated systolic blood pressure. [63]

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. [64]    
Embelin induces apoptosis in lung cancer cells via activation of p38/JNK pathway. Reactive oxygen species play a crucial role in embelin- activity.  [65]  
  
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.[66]

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. [67]

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 of immune cells. The histopathological  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. [68]

Actions on the 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. [69]

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. [70]    
           
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. [71]

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. [72]  

Hepato-biliary malignancy

Anti-inflammatory is useful in the treatment of certain hepatic malignancies and cancer cell metastasis. [73]

Embelin causes inhibition of cancer cell proliferation but does not induce cancer cell apoptosis. By this mechanism embelin   inhibits proliferation of cholangiocarcinoma. [74] 
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. [75]
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. [76]

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.  [77] 

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 [78]

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. [79] 

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.  [80]  




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. [81]

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.  [82]  
     
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 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. [83]

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  [84]          

Actions on the prostate

Embelin ameliorates testosterone-induced hyperplasia in rats. [85]

Embelin induces apoptosis in PC3 cell line of the prostate cancer cells. But the exact mechanism is not known. [86]

Embelin enhances therapeutic efficacy of ionising radiation in prostate cancer [87]

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. [88], [89]

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. [90]

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. [91]

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. [92], [93]    
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. [94] 

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. [95], [96]  

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. [97]

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.   [98]

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. [99]



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

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 a 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.

Antiinflammatory, 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 compounds show anti-inflammatory, analgesic, antioxidant and free radical scavenging activities. [100]

Antibacterial activity

Aromatic aldehyde derivatives of embelin show antibacterial activities against gram positive and gram negative bacteria including multidrug   resistant Staphylococcus aureus.  [101]

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. [102]

In a study various derivatives of mbelin showed antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa, Escherichia coli and Candida albicans.[103]

Antidiabetic activity

Nanoparticles of embelin and its metal complexes exhibit potent antidiabetic activity.
[104], [105]

Anticancer activity

All derivatives of embelin exhibit anticancer activity against a variety of cancer. Many research papers are available for references on this subject. [106], [107]

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