Of Chlorogenic Acid in Widanga (Embelia ribes)


Of Chlorogenic Acid in Widanga (Embelia ribes)

Introduction

Widanga (Embelia ribes) contains many pharmacologically active phytochemicals. One of them is Chlorogenic acid.







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.  

Chlorogenic acid exhibits a pleiotropic pharmacological activity. [1]  

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. [2] 

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 did not produce any untoward side effects nor any toxic effects. [3]

Anti-inflammatory and antioxidant

Chlorogenic acid controls oxidative stress and shows anti-inflammatory activity. [4]

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). [5]


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. [6]
   
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. [7]  
                   
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 (IgE). [8]

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. [9]  

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. [10] 

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. [11]

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. [12] 

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. [13], [14] 

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. [15]

In a study chlorogenic acid and its compounds were shown to inhibit HepG2.2.15 cells and duck hepatitis virus. [16]

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. [17]

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. [18]  
                               
Chlorogenic acid showed antifungal and anti-mycotoxigenic activities against Aspergillus flavus and Aspergillus ochraceus. [19]
   
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. [20]
  
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. [21]

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. [22]  

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. [23] 

Actions on Endocrine System

Chlorogenic acid modifies gastrointestinal (GI) hormone secretion and glucose tolerance. [24]

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. [25]
       
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. [26]

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. [27]

Recent evidence suggests that consumption of chlorogenic acid in the diet protects the brain from neuro-degenerative changes. [28]

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. [29] 

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. [30]
Chlorogenic acid and its metabolites evoke neurotrophic respone in hippocampal cells. [31]

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. [32]   

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. [33]
      
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 thepotential to regulate invasive brain tumor-derived glioma cells. [34] 
     
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. [35], [36]

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. [37], [38], [39]

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. [40] 
  
Anti-inflammatory and antioxidant activities of chlorogenic acid protect endothelial cells of the human umbilical vein from the toxic     damage induced by Perfluorooctane Sulphonate. [41]

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. [42] 

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. [43]

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  intratracheal 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). [44] 

Actions on the Pancreas

Chlorogenic acid in decaffeinated coffee (green coffee) inhibited porcine pancreatic lipase. [45]
        
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. [46]   

Methamphetamine intoxication can cause acute hepatic failure. If treated with chlorogenic acid before administration of  methamphetamine chlorogenic acid can prevent hepatic injury. [47]

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. [48]  

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. [49]

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 [50]

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. [51]

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. [52]

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). [53], [54], [55]
  
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. [56]  

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. [57], [58], [59]

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 [60], [61] 

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. [62]

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. [63] 
      
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. [64]

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.[66]

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. [67]

Toxicity of Cclorogenic acid

High intake of chlorogenic acid could be responsible for the higher homocysteine concentration in the blood. This can be a risk for cardiiovascular diseases. [68]
   
             
Dose: 120-300 mg for oral intake [69]

References:

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