On October 23rd, 2014, we updated our
By continuing to use LinkedIn’s SlideShare service, you agree to the revised terms, so please take a few minutes to review them.
Review Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease Angélica M. González Sánchez – University of Puerto Rico at Cayey __________________________________________________________________ Abstract Inflammatory bowel disease (IBD) is one of the most serious diseases of the gastrointestinal tract. Although its causes are not well known, it has been linked to a deregulation on the molecules that control stress response in the intestinal tissue. These uncontrolled molecules cause severe inflammation in the intestine as an immune response to stress. Curcumin is a natural herb-derived compound commonly used for cooking and as an organic remedy for common illnesses. Recent researches have shown a relationship between curcumin and IBD. It has been concluded that curcumin has a direct effect on regulating the molecules that are decontrolled in IBD intestinal tissue. The reasons why curcumin does this are not thoroughly understood by the scientific community, but they have been linked to its antioxidant properties, as well as to its capacity to bind to several proteins and enzymes. More research needs to be done in order to fully comprehend curcumin’s behavior, to establish its safe dosage, to increase its bioavailability and to prove it as a viable therapeutic alternative for IBD. ____________________________________________________________________________ Keywords: Inflammatory Bowel Disease (IBD) / curcumin / stress-response pathways / NF-κB / cytokines / chemokines / white blood cells / p38 MAPK / MPO / antioxidant / bioavailability. Introduction Inflammatory bowel disease (IBD) is an causes a stress response and leads to IBD, it isacute syndrome on which the gastrointestinal thought that it arises from uncontrolledwall suffers severe inflammation. Its causes pathways of molecules related to the immuneremain unknown, although recent investigations system (Salh et al., 2003).have linked it to genetic, environmental and Intestinal mucosa has several functions,immunological factors, which are the most mostly on absorbing nutrients and on protectingprominent ones (Pithadia and Jain, 2011). Even the organism from infections. When swollen,though it is a rare condition statistically (Jian et this mucosal doesn’t work as it’s supposed to,al., 2005), its implications on people’s quality of leading to mayor complications. Some of theselife make it a huge and relevant field for complications can be reflected as severeinvestigations. symptoms such as abdominal pain, ulcers, Despite origins of IBD are uncertain, its bleeding diarrhea, weight loss due to themain source is the inflammation of the intestinal diarrhea, anemia, between others. Othermucosa. Because inflammation is almost always conditions have also been associated to sidelinked to an immune response, analysis of IBD effects of IBD, such as osteoporosis, arthritis,has focused on stress-response causes. Since skin rashes, liver disease and colon cancer. IBDthere haven’t been found any pathogen that rarely causes death on its own, but some of its November 2011
Curcumin’s Therapeutic Effects on Inflammatory Bowel Diseasecomplications, such as extreme diarrhea and the herb Curcuma longa. It can take manyanemia can cause weakness of the organism, chemical structures, called curcuminoidswhich can make it susceptible to other illnesses. (Anand et al., 2008), but its main constituents IBD can be divided into two main types: always are several hydroxyl radicals (HO),Ulcerative colitis and Crohn’s disease. Both of hydroxide ions (OH-), oxides (O2), methylthese share the characteristic inflammation of (CH3) and methoxides (CH3O-) groups whichthe intestinal mucosa but they differ on the join together forming rings which make thespecific areas of the intestinal tract that they compound a hydrophobic polyphenol. It hasaffect. While Ulcerative colitis affects only the been traditionally used in foods as a componentcolon, Crohn’s disease can affect any area from of the spice turmeric and as an herbal remedythe gastrointestinal tract, especially the lowest for several illnesses because polyphenols arepart of the small intestine, called the ileum. known to be natural antioxidants (Rajasekaran, Actual treatments for IBD focus on 2011). Since its first documented use as alessening and delaying the symptoms of the medical treatment in 1937 (Srivastava et al.,condition, but not necessarily on effectively 2011), curcumin has revealed antioxidant, anti-transposing the causes of the inflammation, inflammatory, antimicrobial and anti-which will be described further on. Most of carcinogenic activities (Anand et al., 2008).them consist on anti-inflammatory medicines Exactly how curcumin accomplishes theseand immune-suppressors, such as duties is not well known. However, it has beenaminosalicylates, monoclonal antibodies, linked to its ability to bind to several proteinscorticosteroids, antibiotics, between others. and regulatory enzymes and to inhibit oxidationThese treatments have been improving in the chain reactions which can cause damage orlast decades by the development of targeted death to the cell by activating multiplebiologic therapies, the optimization of older intracellular signaling pathways (Srivastava ettherapies, and a better understanding of the al., 2011). That way, curcumin regulates themucosal immune system involved in the presence of several molecules, which in turnpathogenesis of IBD (Pithadia and Jain, 2011). control a great number of cellular processesHowever, these therapies are still very especially stress response. The regulation ofunspecific, meaning that they would treat some these molecules, which are mostly transcriptionof the symptoms but others might remain factors, enzymes and proteins, is directly relateduntreated. They also cause lots of side effects, as to immunity and inflammation. That’s whyfor example steroid dependence, anaphylaxis curcumin has been linked to the treatment ofand pancreatitis. These treatments are vastly immune and inflammatory diseases, such asexpensive too. That’s why new, more accessible IBD.and natural therapies for IBD are needed This paper is intended to present thecurrently. relationship between curcumin and IBD and A new therapeutic approach for IBD that why it is considered a potential treatment forhas been studied since decades ago is the use of this condition. It will do so by presenting studiescurcumin. This compound, also called that have proved its benefits and its limitationsdiferuloylmethane, is obtained from the roots of as a therapeutic alternative.November 2011 2
Curcumin’s Therapeutic Effects on Inflammatory Bowel DiseaseMacroscopic effects of curcumin on IBD inflammation and eventual elimination of As shown by several studies of rat disease-causing agents. They are mostly presentmodels with induced IBD, curcumin effectively in T helper cells, which are a type of whitecounteracts many of the effects of IBD in many blood cell. When well regulated, cytokines andways. On the rat colitis models, it showed chemokines contribute to the health of thetangible effects out of the intestine were an organism and help to maintain a balance onincrease in the rate of survival and weight gain inflammation. As for example, for cytokineswere noticeable (Jian et al., 2005) (Salh et al., there are both inflammatory and anti-2003). Curcumin also caused a decrease in the inflammatory ones. The inflammatory ones,inflammation of the intestinal tissues. The such as interleukin-1 beta (IL-1β), activate atstudies concluded that all of these macroscopic any threatening signal, but when the attack iseffects are directly related to microscopic counteracted, the anti-inflammatory ones, suchprocesses of the cell (see Figure 2). as interleukin-10 (IL-10), activate and make the tissue go back to normal. Chemokines areDeregulated molecules in IBD responsible for sending signals to alert on the There are several proteins and presence of foreign agents, therefore inducingtranscription factors that are responsible of the production of leucocytes (white blood cells),regulating immunity in the intestines and, especially macrophages to engulf them. Aftertherefore, they are in charge of protecting it the pathogen is eliminated, the signaling stops.from external damaging agents or pathogens. On IBD, NF-κB binding activity isWhen appropriately regulated, these proteins increased, which leads to a rise in the immuneand transcription factors help on the well- and inflammatory response by thefunctioning of the intestinal tract and normal overproduction of cytokines and chemokines.protection given by the intestinal mucosa. Therefore, in inflammatory bowel diseaseHowever, when deregulated they can cause an chemokines are up-regulated and provide auncontrollable inflammation in the tissue with continuous signal for the production of whiteno apparent cause. This happens because the blood cells, which results on inflammation (Jianoverproduction or underproduction of these et al., 2005). Equally, pro-inflammatoryagents alters normal cell pathways, as those cytokines are highly expressed in IBD, whilerelated to immunity, which are stress-response anti-inflammatory cytokines are at low ratespathways. This occurs on IBD (see Figure 1). (Salh et al., 2003). One of the transcription factors whose There are other deregulated proteins inpresence is not normal in the intestinal tissue IBD that alter pathways related to intrusion, alsoand mucosa of IBD patients is the nuclear factor called stress-responsive signaling pathways.kappa-light-chain-enhancer of activated B cells One of them is the mitogen-activated protein(NF-κB). This factor binds to the DNA to kinase 38 (p38 MAPK) which, under stress,produce proteins such as cytokines and helps to produce lymphocytes (a type of whitechemokines. These proteins are responsible of blood cell), cyclooxygenases and lipoxygenases.detecting foreign cells and pathogens, creating These lasts ones are enzymes responsible ofan immune response which can result in modulating inflammation by the production of aNovember 2011 3
Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease hormone called prostaglandin. This p38 MAPK Microscopic effects of curcumin on IBD also secretes chemokines, as does NF-κB. In the case of IBD, p38 MAPK is over-activated, which leads to an overproduction of lymphocytes, chemokines, cyclooxygenases and lipoxygenases (Srivastava et al., 2011), consequently causing extreme inflammation. Because of the huge presence of white blood cells in the intestinal tissues of IBD patients, there’s also an over-expression of myeloperoxidase (MPO) in IBD (Salh et al., 2003). MPO is a peroxidase enzyme present in neutrophil granulocytes, a type of white blood cells. This enzyme produces hypoclorous acid radical and the amino acid tyrosyl radical upon oxidation. In other words, the oxidation of MPO Figure 2: Summary causes the formation of highly reactive of the macroscopic molecules with negative charge which are used and microscopic by the neutrophils to kill bacteria and other effects of curcumin pathogens when they are well-regulated. When on IBD. they are not well-regulated, they can run free in the body and cause many reactions that might lead to aging, degenerative diseases, and cancer. Most of the recent researches on curcumin have concluded that it displaysFigure 1: Summary of immunomodulatory activity upon thethe deregulated deregulation of molecules on IBD (Srivastava etmolecules responsible for al., 2011). It has shown to regulate the NF-κBinflammation on IBD. pathway and to suppress its binding activity. Therefore, it has functioned to reduce IL-1β expression and to increase IL-10 expression (Rajasekaran, 2011). As a consequence it inhibits the proliferation of macrophages and other types of white blood cells. Curcumin is also useful on diminishing the activation of p38 MAPK, therefore controlling the production of lymphocytes, cyclooxygenases and lipoxygenases. The ways by which curcumin achieves all these activities are still not well known, but there are being studies conducted about it (Srivastava et al., 2011). It has been November 2011 4
Curcumin’s Therapeutic Effects on Inflammatory Bowel Diseasepreliminarily linked to curcumin’s ability on suitable environment for curcumin’sbinding to several proteins and enzymes. transference. By adding itself to curcumin it can Finally, curcumin has presented an effect therefore promote its absorbance because of itson the offsetting of myeloperoxidase activity lipophilic-hydrophobic inside and hydrophilicbecause of its antioxidant properties (Salh et al., outside (Yadav et al., 2009). Other2003). As an antioxidant, curcumin functions to investigations have proposed to blockinhibit the oxidation of MPO by oxidizing itself, curcumin’s metabolic pathways, to improve itstherefore preventing free radicals from running effective transportation through the body withfreely in the body and reducing the oxidation the use of new nanoparticle systems and tochain reactions. encapsulate the compound (Rajasekaran, 2011). More development still has to be done to reachCurcumin’s usage and limitations curcumin’s enhancement. Actual reviews on curcumin’s effective Figure 3:concentration dose reveal some ambiguity. Curcumin’sWhile ones say that it has shown to be safe at limitationsvery high doses (Anand et al., 2008), other as astudies imply that it’s effective and safe dosages therapeuticcan vary upon the type of cell treated. For some alternativecells it might be toxic at high concentrations, for IBD.and for others not (Srivastava et al., 2011).Further investigations need to be done to defineat which concentration curcumin’s functionalityincreases and is secure enough for humanconsumption. That might be one of the reasonswhy curcumin isn’t commonly used fortherapeutic purposes. Conclusion Another limitation of curcumin has been Although not so many researches haveproved to be its low oral bioavailability due to been accomplished on relating curcumin to IBD,its poor solubility and rapid metabolism most of them have shown similar conclusions(Rajasekaran, 2011). Bioavailability is the on its proactivity on this disease. Not all of themamount of substance that is really absorbed and have concluded curcumin’s effects in all theused by an organism when the substance, mostly same molecules and pathways, but all of thema drug, is introduced into the body. Recent have related its outcomes on its regulatoryresearch has shown that curcumin’s low properties. Moreover, it can be concluded thatbioavailability is compensable by making curcumin is a good modulator of the appropriatecertain modifications to the compound. One of quantities of molecules needed for stressthose modifications can be making an inclusion response. Since IBD has been linked to acomplex between curcumin and a soluble deregulation on the stress response pathways,compound, such as cyclodextrin (CD). This curcumin’s therapeutic effects on IBD havecomplex is very soluble and can create a been observable. However, we can determineNovember 2011 5
Curcumin’s Therapeutic Effects on Inflammatory Bowel Diseasethat there are still many aspects about curcumin Pithadia A, Jain S. 2011. Treatment of inflammatorythat aren’t well comprehended (see Figure 3). bowel disease (IBD). Pharmacological Reports.We conclude that additional research is 63(1):629-642.necessary. Eventually, as more research on this Rajasekaran S. 2011. Therapeutic potential of curcumin in gastrointestinal diseases. Worldtopic is promoted, curcumin’s use would be Journal of Gastrointestinal Pathophysiology. 2(1):better understood and it will probably be able to 1-14.function as an alternative treatment for IBD. Salh B, Assi K, Templeman V, Parhar K, Owen D, Gómez A, Jacobson K. 2003. Curcumin attenuatesReferences DNB-induced murine colitis. American Journal ofAnand P, Thomas S, Kunnumakkara A, Sundaram Physiology Gastrointestinal and Liver Physiology. C, Harikumar K, Sung B, Tharakan S, Misra K, 285:G235-G243. Priyadarsini I, Rajasekharan K, Aggarwal B. 2008. Biological activities of curcumin and its analogues Srivastava R, Singh S, Dubey S, Misra K, Khar A. (Congeners) made by man and Mother Nature. 2011. Immunomodulatory and therapeutic activity Biochemical Pharmacology Journal. 76(1):1590- of curcumin. International Immunopharmacology 1611. Journal. 11(1):331-341.Jian Y, Mai G, Wang J, Zhang Y, Luo R, Fang Y. Yadav V, Suresh S, Devi K, Seema Y. 2009. Effect 2005. Preventive and therapeutic effects of NF- of Cyclodextrin Complexation of Curcumin on its kappaB inhibitor curcumin in rats colitis induced Solubility and Antiangiogenic and Anti- by trinitrobenzene sulfonic acid. World Journal of inflammatory Activity in Rat Colitis Model. Gastroenterology. 11(12):1747-1752. AAPS PharmSciTech. 10(3):752-762.November 2011 6