Daniele Citta
Arianna Savi
Introduction
Tumeric or Curcuma longa is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia but is now widely cultivated in the tropical and subtropical regions of the world. The deep orange-yellow powder known as turmeric is prepared from boiled and dried rhizomes of the plant. It has been commonly used as spice and medicine (Rhizome Curcumae Longae), particularly in Asia.
Curcumin keto form 
Curcumin enol form 
The most important chemical components of turmeric are a group of compounds called curcuminoids, which include curcumin (diferuloylmethane or
1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl ), demethoxycurcumin , and bisdemethoxycurcumin .The best studied compound is curcumin, which constitutes 3.14% (on average) of powdered turmeric. In addition there are other important volatile oils such as turmerone, atlantone, and zingiberene. Some general constituents are sugars, proteins, and resins.
A curcuminoid is a linear diarylheptanoid, with molecules such as curcumin or derivatives of curcumin with different chemical groups that have been formed to increase solubility of curcumins and make them suitable for drug formulation. These compounds are natural phenols and produce a pronounced yellow color.
Many curcumin characters are unsuitable for use as drugs by themselves. They have poor solubility in water at acidic and physiological pH, and also hydrolyze rapidly in alkaline solutions. Therefore, curcumin derivatives are synthezised to increase their solubility and hence bioavailability. Curcuminoids are soluble in dimethyl sulfoxide, acetone and ethanol, but are poorly soluble in lipids. It is possible to increase curcuminoid solubility in aqueous phase with surfactants or co-surfactants. Cucurmin derivatives were synthesized in order to be more powerful than cucurmin itself Most common derivatives have different substituents on the phenyl groups.
Curcuma longa Extract Protects against Gastric Ulcers
The gastroprotective and antiulcerogenic effects of C. longa extract may be related with the histamine receptor (H2R) signaling pathway.This extract selectively inhibited the activation of H2R and protected the stomach from gastric acid induced ulcers.
The H2R is a seven transmembrane G protein-coupled receptor (GPCR) coupled to the enzyme adenylyl cyclase, which produces the intracellular second messenger, cyclicAMP.H2R, which is expressed by various tissues, including the brain, stomach, heart, and lung, is involved in histamine-induced gastric acid secretion.
In gastric parietal cells especially,H2R triggers the secretion of acid (HCl) into the stomach lumen through cAMP/protein kinase A/proton pump pathway.Hence,H2R blockers may be useful for treating diseases that involve gastric acid hyper-secretion, such as stomach ulcers and reflux esophagitis.
Therefore H2R is the primary target of anti-ulcer drugs, and HR antagonists have been shown to inhibit gastric acid secretion in many animal model systems.
Administration per os of C. longa extract significantly inhibited gastric acid, gastric juice secretion, and ulcer formation, comparable to the effects of ranitidine.
Ranitidine has been shown to have a marked anti-ulcer effect and has been used in the treatment and prevention of a variety of gastrointestinal disorders associated with gastric acid secretion.
Application of various concentrations of dimaprit (a selective H2R agonist,on the generation of cAMP) triggered cAMP production in a concentration-dependent manner, and with an EC50 of 5.5 0.9m M. The effect of 10m M dimaprit was inhibited by 10m M of the specific H2 receptor antagonist, ranitidine (10m M), and by C. longa extract in a concentration-dependent manner. In addition, C. longa extract also suppressed histamine-induced cAMP production in a concentration-dependent manner.
C. longa extract may block Gsα -protein activity rather than H2R, while it did not affect isoproterenol-induced cAMP production on β2-adrenoceptor.
The inability of C. longa extract to inhibit β2-adrenoceptor mediated cAMP production indicates that the active component of C. longa extract are highly selective, inhibiting only the binding of histamine (or dimaprit) to H2R.
The most important C.longa extracts with H2R antagonistic effect are the ethyl acetate (EA) and the n-buthanol (n-Buta).
The ethyl acetate (EA) extract showed the most potent H2R antagonistic effect against dimaprit-induced cAMP production. However, curcumin, a major component of C. longa extract, shows no H2R blocking effect.
The EA and n-buthanol (n-Buta) extracts significantly inhibited dimaprit-induced cAMP production, the effect of EA extract was more pronounced, but both extracts significantly inhibited H2R in a concentration-dependent manner
These findings indicate that substance in C. longa that acts H2R is probably contained in the EA extract.
C. longa and H. pylori infections
Helicobacter pylori infection of the lining of the stomach induces an array of inflammatory cytokine production leading to gastritis and peptic ulcer disease. The infection is also associated with mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. Infection of epithelial cells by the microbial pathogen Helicobacter pylori leads to activation of the transcription factor nuclear factor kB (NF-kB), the induction of pro-inflammatory cytokine/chemokine genes and the motogenic response (cell scattering).
Curcuma longa seems to have anti-inflammatory, antitumoral and bactericidal effects on H. pilori gastric infections.
H. pylori-induced NF-kB activation and the subsequent release of interleukin 8 (IL-8) are inhibited by curcumin (diferuloylmethane), a yellow pigment in C. longa. Curcumin inhibits IkBa degradation, the activity of IkB kinases a and b (IKKa and b), and NF-kB DNA-binding. Importantly, these effects are dose-dependent.
Anomalous expression of activation-induced cytidine deaminase (AID) in Helicobacter pylori-infected gastric epithelial cells has been postulated as one of the key mechanisms in the development of gastric cancer. AID has been identified as a key enzyme for CSR (Class Switch Recombination) and SHM (Somatic Hyper Mutation) leading to chromosomal translocations and genetic mutations. AID is overexpressed in the cells through nuclear factor NF-kB activation by H. pylori and hence, inhibition of NF-kB pathway can downregulate the expression of AID. Nonbactericidal concentrations of curcumin downregulated H. pylori-induced AID expression in gastric epithelial cells, probably via the inhibition of NF-kB pathway. Instead, the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2) and p38, which are also activated by H. pylori infection, do not seems to be inhibited by curcumin.
The H. pylori-induced motogenic response was blocked by curcumin. One mechanism of curcumin-mediated inhibition of cell motility could be the blocking of Src kinase activity. It has been shown that c-Src is the critical kinase necessary for CagA phosphorylation. Curcumin can inhibit Src activity and, as a consequence, blocks critical signalling components necessary for the enhanced cellular motility characteristic for v-Src transformed fibroblasts. On the basis of these two observations, one might speculate that curcumin-mediated inhibition of Src subsequently blocks CagA phosphorylation, which is a prerequisite for the induction of cell scattering. This is particularly important for the neoplastic aspects: gastric tumor development and progression are dependent upon the enhanced motility of tumor cells.
Curcumin blocks H. pylori-induced motogenic response in ep- ithelial cells. AGS cells were infected with wild-type H. pylori strain P1 at MOI 50. Phase-contrast microscopy was performed before and 3 h after infection. (A and C) uninfected AGS cells. (B) AGS cells infected with H. pylori for 3 h. (D) cells pretreated with curcumin 30 min prior to infection (3 h).
Another extract from the radix of curcuma, diterpenoid C, can block NF-kB signal pathway, effectively reducing the secretion of H. pylori-induced proinflammatory cytokines and increasing the secretion of anti-inflammatory cytokines. Its chemical properties and constitution are different from curcumin (diterpenoid C has a better bioavailability). In gastric epithelium cell lines infected with Helicobacter pylori, diterpenoid C can reduce cell proliferation (in association with Amoxicillin) and the activation of pro-inflammatory pathways (IL-8, NF-kB), stimulating other cytokines (IL-4). In gastric epithelial cell lines infected with H. pylori cells became round, adherent cells are decreased and floating cells increased, fragments occur around cells, cell junction is reduced, the boundaries between cell nucleus and cytoplasm are obscure and we can see nucleus-cytoplasm fusion. If treated with diterpenoid C, adherent cells increase and cell morphology gradually recovers at 24 h.
Nevertheless, the mechanism of anti-inflammatory effect of curcumin in vivo is not clear, particularly whether it affects cytokine production in gastric tissue of patients with H. pylori infection. A study didn’t find an inhibitory effect of curcumin on the expression of inflammatory cytokine mRNA in the gastric biopsies of H. pylori-infected patients, differently from in vitro studies. It is conceivable that the amounts of active ingredients in curcumin extracts used in the in vitro studies are more than that contained in the in vivo’s and the effects of curcumin on cytokine production in vitro may be different from in vivo. Additionally it is known that the bioavailability of curcumin in vivo is generally low, so further investigation to enhance its distribution and bioavailability are needed. It should also be noted that a single dose of curcumin was investigated in this study. Whether a higher dose of curcumin would have an effect on the production of inflammatory cytokines in vivo remains to be determined. A relief of symptoms after curcumin use has been reported previously. It is, therefore, conceivable that curcumin relieves symptoms through other mechanisms such as inhibition of gastric acid secretion by blocking H2 histamine receptor. Further investigation for a better understanding of its mechanisms should be carried out. The use of curcumin in combination with therapeutic regimen may benefit patients in terms of better compliance or may be used as an alternative treatment in drug resistant H. pylori-infected cases.
The antibacterial activity of C. longa is debated. Studies in vitro are controversial. In mice curcumin seems to be highly effective in eradicating H. pylori, although the MIC is relatively high (this may be due to the poor bioavailability). We must report that studies on high doses of curcumin in animals and humans have confirmed a lack of any toxic side effects. In humans curcumin alone may have limited anti-bactericidal effect on H. pylori.
Bibliography
- Curcuma longa Extract Protects against Gastric Ulcers by Blocking H2 Histamine Receptors
- Chemical Composition and Product Quality Control of Turmeric
- Investigation of the anti-inflammatory effect of Curcuma longa in Helicobacter pylori-infected patients
- Modulation of Activation-Induced Cytidine Deaminase by Curcumin in Helicobacter pylori-Infected Gastric Epithelial Cells
- Antimicrobial Activity of Curcumin against Helicobacter pylori Isolates from India and during Infections in Mice
- Effects of radix curcumae-derived diterpenoid C on Helicobacter pylori-induced inflammation and nuclear factor kappa B signal pathways
- Curcumin blocks NF-jB and the motogenic response in Helicobacter pylori-infected epithelial cells
Key words
Curcuma longa; H2 histamine receptor; gastric ulcer; curcuminoids; curcumin; H. pylori
