TY - JOUR
AU - MS(Pharm), Priyanka P. Trivedi,
AB - Abstract Ulcerative colitis (UC), an inflammatory bowel disease, affects many people across the globe, and its prevalence is increasing steadily. Inflammation and oxidative stress play a vital role in the perpetuation of inflammatory process and the subsequent DNA damage associated with the development of UC. UC induces not only local but also systemic damage, which involves the perturbation of multiple molecular pathways. Furthermore, UC leads to an increased risk of colorectal cancer, the third most common malignancy in humans. Most of the drugs used for the treatment of UC are unsatisfactory because they are generally mono-targeted, relatively ineffective and unaffordable for many people. Thus, agents that can target multiple molecular pathways and are less expensive have enormous potential to treat UC. Melatonin has beneficial effects against UC in experimental and clinical studies because of its ability to modulate several molecular pathways of inflammation, oxidative stress, fibrosis, and cellular injury. However, many novel targets are yet to be explored on which melatonin may act to exert its favorable effects in UC. It is time to explore improved intervention strategies with melatonin in UC on the basis of studies investigating different molecular targets using proteomic and genomic approaches. This review identifies various molecular targets for melatonin with the intent of providing novel strategies for combating UC and the associated extraintestinal manifestations of this debilitating disease. ulcerative colitis, melatonin, inflammation, oxidative stress, DNA damage, novel targets Melatonin (N-acetyl-5-methoxytryptamine), a pineal gland secretory product and an evolutionarily conserved molecule,1,2 was discovered in 1958 in bovine pineal tissue.3 Evidence regarding the presence of melatonin in the gastrointestinal tract (GIT) was obtained in 1974, when Raikhlin and Kvetnoi4 identified it in the human appendix. Finally, its presence in the GIT was confirmed in 1977, when the indole was found in the mucosal lining of the intestine.5 The content of melatonin is calculated to be 400 to 500 times more than in the pineal gland.6 This suggests that melatonin synthesized in the GIT may have some vital role in the GIT physiology and pathophysiology. In the intestine, melatonin influences physiological effects such as regeneration of the epithelium and regulation of its function, modulation of the immune response and reduction in the tone of GI muscles through specific membrane receptors such as melatonin-1 receptor (MT-1), MT-2, and possibly through MT-3.7,–9 Melatonin is also reported to act as a potent antioxidant, anti-inflammatory and antigenotoxic agent in all organs.10,–16 Because of its lipophilic nature, it enters all cells, and it is considered an important molecule because of its multifactorial role and myriad of beneficial effects. It helps in inducing sleep, treating jet lag, boosting the immune system, preventing free radical damage, and possibly influencing longevity.17,–19 It has an ability to target multiple molecules involved in the pathophysiology of various diseases, which justifies its use for the treatment of a range of disorders such as cataracts, cardiovascular, neurodegenerative, pulmonary, renal, and gastrointestinal (GI) disorders, rheumatoid arthritis, diabetes, and cancer.20,–29 Among the GIT disorders, it is used to treat irritable bowel syndrome, gastroesophageal reflux disease, Crohn's disease, and ulcerative colitis (UC).30,–33 UC is a chronic GI disorder affecting a part of the colon or the entire colon, based on its severity. Inflammation, along with oxidative stress, plays a vital role in the pathogenesis of UC.34 UC causes an elevation in various inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2).35,–37 Furthermore, the oxidant/antioxidant balance has been reported to play an important role in the recurrence and progression of UC.38 UC is associated with an elevated production of free oxygen radicals accompanied by an increased oxidative damage.39 Moreover, inflammation-associated oxidative stress leads to DNA damage, which may further contribute to the process of carcinogenesis. UC leads to an increased risk of developing colorectal cancer, which is the third most common malignancy observed in humans.40 Apart from colorectal cancer, UC is associated with the development of several extraintestinal manifestations.37,41,42 This involves several molecular processes and global damage. Current treatments for UC are not always effective and often accompanied by serious side effects, and hence, there is considerable interest in finding an alternative treatment for this debilitating disease. Melatonin, with its ability to modulate the multiple molecular pathways involved in the pathogenesis of UC, may have a better therapeutic potential and may be useful in the preventive and therapeutic armamentarium for UC and the associated local and global damage. However, conflicting results have been obtained regarding the use of melatonin for the treatment of experimental colitis.43,44 Hence, well-designed experimental and clinical studies are required before its better clinical application. The present review reveals various molecular targets of melatonin and its subsequent role in potentially diminishing the severity of UC and the associated extraintestinal manifestations. Inflammation: A Roadway to DNA Damage The word “inflammation” is derived from the Latin word “inflammatio”, i.e, to set on fire, which was characterized by a Roman physician, Cornelius Celsus, as the one which consists of heat (calor), redness (rubor), pain (dolor), and swelling (tumor). Inflammation is a short-term friend and a long-term foe, because acute inflammation is the body's most primitive arsenal developed to fight infection; in contrast, chronic inflammation causes several diseases such as GI, cardiovascular, pulmonary, and neurological diseases, diabetes, obesity, and cancer.45,46 One of the means by which inflammation paves the way toward DNA damage is the production of reactive oxygen species (ROS) and reactive nitrogen species by activated neutrophils and macrophages leading to lethal cancer-causing mutations in the epithelial cells.47 Chronic inflammation induces oxidative damage in the DNA of cells of the inflamed tissue. ROS and reactive nitrogen species thus generated can damage both nuclear and mitochondrial DNA, RNA, lipids, and proteins.48,49 Inflammation and DNA damage are associated with UC in mice.50 Oxidative DNA damage in the mucosa of UC increases with disease duration and dysplasia.51 Several reports document that the risk of colorectal cancer is greater in the patients suffering from UC because of inappropriate inflammatory response to a luminal pathogen, abnormal immune response to intestinal bacterial flora, role of cytokines, and oxidative DNA damage at the local site of inflammation in the colon.35,52 Earlier, we reported that UC in mice was associated with not only the local, but also the global damage such as systemic toxicity and hepatotoxicity.37,41,53,54 Moreover, intestinal inflammation also causes DNA damage in extraintestinal tissues and in the spleen, mesenteric and peripheral lymph nodes, and hepatocytes.42 Because, in UC, inflammation and oxidative stress are mainly responsible for the DNA damage in the colon and other tissues, agents combating inflammation and oxidative stress may possess beneficial effects in ameliorating the severity of UC and the associated global damage in patients. Multiple Targets of Melatonin in UC Melatonin is useful in several pathological conditions because of its effect on multiple targets. Melatonin can be classified as a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin.55 It acts with overall homeostatic functions, and its pleiotropic nature controls the detoxification and stress response genes, thus conferring protection against a number of xenobiotics produced by acute and chronic lethal stimuli.56 It is present in high concentration in the GIT and is known to be synthesized in the enterochromaffin cells of the intestine, where it plays a vital role in maintaining the GIT physiology.57 Hence, it is likely that melatonin influences inflammation-related GI disorders including UC. UC is a chronic GI disorder associated with elevated levels of various proinflammatory cytokines and ROS, which in turn, activate NF-κB, a proinflammatory transcription factor that has emerged as an important player in the development and progression of UC.58 NF-κB is a transcription factor that resides in the cytoplasm as a heterotrimer consisting of p50, p65, and IκBα in its resting stage. IκBα kinases cause the phosphorylation of IκBα, which results in the release and translocation of NF-κB to the nucleus, where it activates the transcription of target genes that regulate the inflammatory response by the production of cytokines, chemokines, and cell adhesion molecules.59,60 NF-κB is implicated in the development and progression of chronic inflammatory diseases partly through the elevated production of various cytokines such as TNF-α, IL-6, and IL-1β.61 In UC, NF-κB activation occurs both in macrophages and in epithelial cells.62,63 Activation of NF-κB has been reported in the colonic mucosa of patients with collagenous colitis and UC.64 Melatonin ameliorates the severity of colitis by targeting NF-κB. It decreases inflammation-associated injury through the inhibition of NF-κB activation, regulation of macrophages activity, and reduction in the expression of chemokines, bacterial translocation, and apoptosis in rat with trinitrobenzene sulfonic acid (TNBS)-induced colitis.65,–68 It inhibits NF-κB activation and decreases serum levels of pentraxin-3, lipid peroxides, and total thiols in rat with acetic acid–induced colitis.69 By virtue of its powerful anti-inflammatory and antioxidant activities, melatonin treatment resulted in significant improvement of acetic acid–induced colitis in rat by reducing the elevated levels of proinflammatory cytokines (TNF-α, IL- 1β, and IL-6), myeloperoxidase, malondialdehyde, and by increasing the levels of reduced glutathione and superoxide dismutase.34,57 Furthermore, melatonin lowered the immunohistochemical expression of NF-κB in azoxymethane/dextran sodium sulfate (DSS)-induced large bowel oncogenesis in rat.70 Thus, melatonin reduces the levels of various stimuli responsible for the activation of NF-κB and thereby plays a vital role in protecting the gut mucosa by decreasing the expression of NF-κB in UC. In UC, increased expression of NF-κB is accompanied with an elevated expression of inflammation-induced COX-2 enzyme.37 Melatonin has a protective effect on colonic injury induced by both acetic acid and 2,4,6-trinitrobenzene sulfonic acid enemas by reducing inducible nitric oxide synthase (iNOS) and COX-2 expression in the colonic mucosa.43 Melatonin, in combination with erythropoietin, protected pinealectomized rats against dinitrobenzene sulfonic acid–induced colitis by reducing inflammation, cellular damage, and apoptosis.71 Protective effects of melatonin against dinitrobenzene sulfonic acid–induced colitis in rats were due to its ability to decrease the levels of TNF-α, myeloperoxidase, malondialdehyde, nitrotyrosine, poly (ADP-ribose) synthetase, intercellular adhesion molecule 1, P-selectin, COX-2, iNOS, activation of NF-κB, phosphorylation of c-Jun, Fas ligand expression, and apoptosis in the colon.72,73 UC is associated with an increased oxidative stress along with inflammation.37,74 Melatonin and its metabolites have been shown to be highly effective as free radical scavengers and thereby reduce the oxidative stress under a variety of experimental settings, where the free radical generation is elevated.75,76 Interestingly, one report showed that exposure to continuous darkness ameliorates gastric and colonic inflammation in the rat due to excess amount of melatonin synthesized in darkness that reduces the oxidative stress.77 Recently, high levels of melatonin have been found in mitochondria, which are a major source of free radical generation in living organisms, and hence, melatonin has been described as a mitochondrial-targeted antioxidant.78,79 The mitochondrial antioxidant property of melatonin may prove beneficial in the treatment of various inflammatory disorders including UC. Mucosal inflammation in UC leads to collagen deposition, which in turn, results in the induction of matrix metalloproteinases (MMPs). MMPs are implicated in the pathogenesis of colitis because of their influence on the function and migration of inflammatory cells, mucosal ulceration, matrix deposition, and degradation.80,–83 Various clinical and experimental studies have demonstrated an increase in the abundance of these matrix-degrading proteases in inflammatory bowel diseases, and the inhibition of MMP activation has been shown to ameliorate experimental colitis.80,84,–86 Melatonin, an inhibitor of MMP,87,88 prevents experimental colitis in rats by regulating MMP-9 and MMP-2 activity and expression.89 It also alleviates MMP-9 and MMP-3 expression in mice with gastric ulcers through the reduction of activator protein-1 activity.90 Furthermore, it has been reported that reduced MMP-9 and MMP-2 activities are associated with lower expression of TNF-α.89 Moreover, TNF-α is a potent endogenous mutagen, and TNF-α–generated ROS have DNA-damaging effects comparable to those of ionizing radiation.91 Melatonin, because of its anti-inflammatory property, decreases TNF-α level, and may, at least in part, play a role in diminishing TNF-α–induced DNA damage in UC. Recently, we reported that melatonin reduced the local and systemic damage in mice with DSS-induced colitis by reducing the markers of inflammation, oxidative stress, fibrosis, and DNA damage. It also ameliorated the colonic mucosal damage, decreased bacterial translocation to the systemic circulation, and reduced the associated systemic inflammation and DNA damage.92 The protective effect of melatonin against DSS-induced colitis has been reported because of its effect on the smooth muscle of the colon, the blood supply in the mucosa, its capability as an antioxidant and scavenger of free radicals, and its effect on the immune system of the gut.93 Mucosal healing property of melatonin94 may help in ameliorating the severity of UC. Surprisingly enough, few experimental studies reported aggravation of UC symptoms with melatonin treatment. Acutely administered melatonin ameliorated, whereas its chronic administration aggravated the progression of TNBS-induced colitis in rat.44 Melatonin was effective in the prevention and short-term treatment of inflammatory process in acetic acid–induced colitis in rat, whereas the benefit of long-term treatment was ambiguous.69 Similar conflicting results for the use of melatonin in inflammatory bowel diseases exist in clinical conditions. One study reported that the use of melatonin in combined therapy for inflammatory bowel diseases (Crohn's disease and UC) considerably improved the results of treatment and promoted a more complete ultrastructural recovery of the colonic mucosa.32 However, a case report depicted that melatonin triggered Crohn's disease symptoms. A 35-year-old woman diagnosed with Crohn's disease decided by herself to take melatonin capsules before going to sleep during the remission period. After 4 days, symptoms of the disease emerged again. When she stopped taking melatonin, 24 hours later, there was a complete remission of symptoms.95 Furthermore, melatonin used to treat sleep abnormalities in children with neurodevelopmental disabilities surprisingly improved their GI conditions including UC.96,97 A case report showed that self-administration of melatonin as a cure for jet leg on international flights by a 47-year-old man suffering from UC reduced the disease symptoms, and the symptoms recurred within 1 week of running out of the medication.98 Yet in another case report, the symptoms of UC were aggravated in a 56-year-old man on self-administering melatonin.99 The only available pilot randomized, double-blind, placebo-controlled phase 2 clinical trial on the Web site “clinicaltrials.gov” was designed in the year 2009 and sponsored by Emroy University, Atlanta, Georgia, to elucidate the effect of melatonin against UC. However, the status is still incomplete.100 Melatonin in UC: The Possible Reasons for Conflicting Results Conflicting results for melatonin usage in UC could be due to (1) variation in the experimental models used, (2) chemically induced UC in animals versus UC in humans with unknown etiology (genetic, epigenetic, environmental, immunological, microbiological, or lifestyle), (3) variation in the duration of disease onset, (4) difference in the daily time of administration of melatonin, (5) variation in its dose and duration for the treatment, (6) diurnal variations of melatonin and its binding sites in different organs including the GIT, (7) differences in individual sensitivity and their pharmacodynamic and pharmacokinetic profiles, (8) endogenous melatonin level at different stages of the disease (mild, moderate, severe), (9) endogenous melatonin level during different (a) seasons and (b) age. Melatonin level in the GIT peaked at birth and then declined to stable level at the age of 21 days in a postnatal rat.101 Difference in the circadian rhythm and sleeping pattern among individuals may also affect the endogenous melatonin levels, and thereby the disease status and the effect of exogenous melatonin on the disease onset or progression. Sleep deprivation worsens inflammation and delays recovery in experimental models and patients with UC, which might be due to reduced endogenous melatonin level.102,103 Effect of UC on the endogenous melatonin level is also variable among individuals as reported by different studies.93,104 It might be possible that during the initial stage of the disease, GIT may produce more melatonin to overcome the stress. However, as the disease progresses, GI cells might not be efficient enough to produce sufficient melatonin to ameliorate the disease-associated stress, and ultimately its level decreases. Variations in the endogenous melatonin level may further affect the outcome of exogenously administered melatonin in experimental models and patients with UC. Moreover, melatonin level in the lower gut is supposed to be influenced by the luminal contents,8 and therefore, variation in the luminal contents among individuals may affect the role of melatonin in UC. In vitro autoradiography depicted tremendous diversity in the distribution of binding sites of 2-[125I]-iodomelatonin in the GIT of different species substantiating that melatonin may elicit different functions in the gut of diverse species.105 Furthermore, melatonin receptors (MT1, MT2, and MT3) exhibit differences in the regional distribution in the GIT.8 MT1 and MT2 are the G protein-coupled receptors that can couple to different signaling cascades, whose activation can lead to unique cellular responses. MT3 is an enzyme, quinone reductase 2, with potent antioxidant properties.106 Single nucleotide polymorphisms in the genes coding for critical enzymes and receptors involved in the melatonin pathway are known to be associated with several pathological conditions such as multiple sclerosis and type 2 diabetes.107,108 Differences in the susceptibility among individuals toward such single nucleotide polymorphisms due to genetic and epigenetic variations may be one of the causes of variability in their response to melatonin treatment for UC. The concept of personalized melatonin treatment may be beneficial for the management of UC under such conditions. Studies in UC revealed that chronic inflammatory states are accompanied by marked increases in CpG island methylation in normal-appearing tissues, affirming that proinflammatory exposures could account for part of the epigenetic variation in human populations, which in turn, occurs because of difference in age, environment, lifestyle, or genetic factors.109 Melatonin-mediated protection against UC might be due to its anti-inflammatory and antioxidant properties, whereas melatonin-mediated aggravation of UC might be due to its immunostimulatory and proinflammatory properties. Further experimental and clinical studies are needed to elucidate the exact role of various factors on the effect of melatonin against UC and to explore the reasons for contradictory effects in UC. Novel Targets of Melatonin in UC Nrf2 A plethora of evidence points to nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a key regulator of the cellular response to inflammatory cytokines and oxidative stress in multiple tissue and cell types. Nrf2 is a redox-sensitive transcription factor, which is sequestered in the cytoplasm by the cytoskeleton-associated protein, Kelch-like ECH-associated protein 1 (Keap1), under basal resting conditions.110 In response to oxidative stress, Nrf2 is liberated from its repressor Keap1 and translocates into the nucleus, where it forms a heterodimer with a small musculoaponeurotic fibrosarcoma (sMaf) protein.111 The Nrf2–sMaf dimer then binds to antioxidant response elements (ARE) resulting in an activation of various phase II detoxifying or antioxidant enzymes such as NAD(P)H:quinone oxidoreductase (NQO-1), glutathione S-transferase (GST), heme oxygenase-1 (HO-1), glutathione peroxidase (GPx), glutamate cysteine ligase (GCL), and peroxiredoxin I (Prx I) all of which play key roles in cellular defense by removing the cytotoxic electrophiles or ROS.112,113 In this manner, Nrf2 responds to proinflammatory stimuli and rescues cells and tissues from inflammatory injuries.114,–119 UC involves chronic inflammation, wherein various inflammatory cells become activated, and their activation is accompanied by a rise in the release of ROS at the site of inflammation. Nrf2 deficiency leads to elevated inflammation-induced and oxidative stress–induced tissue damage. This notion is substantiated by the fact that in a DSS-mediated mouse colitis model, Nrf2-knockout mice depict an increased production of COX-2, iNOS, IL-1β, IL-6, and TNF-α as compared to the wild-type mice suggesting a beneficial role of Nrf2 in UC. Increased severity of colitis in Nrf2-deficient mice is associated with decreased expression of antioxidant/phase II detoxifying enzymes including HO-1, NQO-1, UDP-glucuronosyltransferase 1A1, and GST Mu-1.120 Furthermore, Nrf2-activated HO-1 mediates protection against TNBS-induced colitis in mice presumably by blocking the TNF-α–induced nuclear translocation of NF-κB.121 Based on this evidence, it can be inferred that Nrf2 plays an important role in the defense against inflammation and oxidative stress possibly by suppression of NF-κB–mediated proinflammatory signaling pathways and activation of cellular antioxidant machinery. Furthermore, Nrf2 genotype plays a major role in modulating inflammation-promoted colorectal tumorigenesis. Increased colonic inflammatory injury and formation of aberrant crypt foci were found in Nrf2-deficient mice on azoxymethane and DSS treatment.122 Nrf2/ARE signaling is involved in attenuating inflammation-associated pathogenesis in UC by increasing gene expression of various cytoprotective enzymes that extinguish the “fires within” (inflammation). Therefore, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat inflammation and oxidative stress–related diseases and the associated DNA damage. Interestingly, melatonin targets Nrf2 and thereby protects against tissue damage in experimental and clinical conditions.123,–126 The cell protection signaling of melatonin involves redox-sensitive components, and it regulates the cross talk between NF-κB and Nrf2 pathways.76 By regulating these pathways, melatonin stimulates the expression of antioxidant and detoxification genes and thereby enhances the glutathione system, which is a potent endogenous antioxidant system. Studies demonstrating the protective role of melatonin in UC through an activation of Nrf2-mediated signaling pathway are required to prove its better therapeutic role in UC. Nrf2 could be considered as a novel target for melatonin to ameliorate the severity of UC. Signal Transducer and Activator of Transcription 3 (STAT3) and IL-17 STAT3 belongs to the family of proteins that are intracellular signal transduction molecules involved in the expression of numerous proinflammatory genes in inflammatory cells. It is an important mediator in both human inflammatory bowel diseases and in animal models of colitis. Under resting condition, STAT3 is present in the cytoplasm of most cells. It undergoes sequential tyrosine phosphorylation, dimerization, nuclear translocation, DNA binding, and gene transcription in response to certain inflammatory stimuli and growth factors.45 UC is associated with an elevated level of IL-6, which in turn, induces the transcription factor STAT3 through IL-6/STAT-3 trans-signaling pathway.127,–129 In addition, the expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel diseases.130 Furthermore, inhibition of STAT3 by antisense oligonucleotide in TNBS-induced murine colitis had a beneficial effect in the amelioration of colitis.131 STAT3 is upregulated in the colonic mucosa of patients with UC, and it should be explored as a potential therapeutic target.132 Moreover, STAT3, activated by both IL-6 and IL-23, plays a critical role in T helper 17 (Th17) development.133 Th17, also known as inflammatory Th17, is responsible for the synthesis of various cytokines such as IL-17A, IL-17F, IL-21, IL-22, and IL-26.134,–136 IL-17A, IL-17F, IL-22, and IL-26 are excessively produced in the inflamed gut of patients with UC.137,–140 It has been reported that IL-17 functions as a proinflammatory cytokine and acts synergistically with TNF-α and IL-1.141 Moreover, IL-1β and TNF-α may also be involved in promoting Th17 development or in regulating the expression of IL-17.142,143 Both STAT3 and Th-17 cytokines play a role in the perpetuation of the inflammatory process and the subsequent DNA damage associated with the development of UC. Blocking such signaling pathways can open new avenues for the development of therapeutic strategies to ameliorate the severity of UC. Melatonin alleviates high levels of IL-1β, IL-6, and TNF-α, which are involved in regulating the expression of STAT3 and IL-17.144 Another possible target of melatonin against UC could be IL-21, which leads to the expansion of both Th1 and Th17 cell responses in the gut.145,146 Like human inflammatory bowel diseases, mice with acute DSS-colitis and TNBS-relapsing colitis produce elevated levels of IL-21, which in turn, increase the production of Th17-related cytokines.145 Hence, these may serve as potential targets for melatonin to combat inflammation and the associated DNA damage, and thereby reduce the severity of UC. Sirtuins Sirtuins, with either histone deacetylase or mono-ribosyl transferase activity, play a critical role in the regulation of inflammation and the associated pathogenesis. The sirtuin family consists of 7 members (SIRT1 to SIRT7) that localize to the nucleus (SIRT1, 6, and 7), the cytoplasm (SIRT2), and the mitochondria (SIRT3, 4, and 5); however, some of them can shuttle between these compartments.147 The deacetylase activity of these proteins leads to the removal of the lysine-linked acetyl group of the target protein.148 SIRT1 acts as a negative regulator of NF-κB activity through the deacetylation of the p65 lysine 310.149 This NF-κB-SIRT1–negative loop has been established in several experimental models, confirming its biological relevance. Several studies have shown that systemic SIRT1 activation decreases inflammation by reducing NF-κB activity.150,151 Lack of SIRT1 activity results in activation of NF-κB and contributes to the development of cellular inflammation. DSS-induced colitis in mice has been found to be associated with a decrease in SIRT1 gene expression and an increase in NF-κB expression. Colitis was abrogated with the treatment of resveratrol, which led to an induction of SIRT1 and reduction in NF-κB activation.152 This suggests that reduced SIRT1 expression and elevated NF-κB activation are implicated in the development of UC. Several studies have reported the upregulation of SIRT1 and an increased deacetylation of various SIRT1 substrates such as PGC-1a, Foxo1, NF-κB, and p53 by melatonin.153,–155 Recently, melatonin was found to modulate sirtuin activity, which is associated with several pathological conditions, including chronic intestinal inflammation and colon cancer.9 Hence, SIRT1 may be one of the potential targets of melatonin for the treatment of UC. Poly (ADP-ribose) Polymerase 1 (PARP1) PARP1 is a major intracellular NAD-consuming enzyme that competes with SIRT1 for its substrate, and both of their activities depend on the availability of NAD.156 Overactivation of PARP1 depletes NAD and increases the level of nicotinamide, which further inhibits SIRT1 activity.157 PARP1 inhibitors contribute in maintaining high intracellular NAD levels resulting in increased SIRT1 activity.158 Thus, PARP1 inhibitors offer new pharmacological opportunities to activate sirtuins by inhibiting competing NAD-consuming enzymes. PARP1 plays an important role in the colon injury associated with colitis. In UC, the colonic mucosa is infiltrated with neutrophils suggesting the presence of activated T cells and macrophages.159 In macrophages, an ADP-ribosylation reaction mediated by PARP leads to the activation of NF-κB and precedes the upregulation of iNOS activity and the release of proinflammatory cytokines.160 Inhibition of PARP attenuates NF-κB activation in macrophages and prevents the release of cytokines.161 Moreover, inhibition of PARP activation reduced intracellular adhesion molecule-1 and P-selectin expression, leading to an inhibition of neutrophil recruitment and decreased oxidant generation in the lamina propria of mice.162,163 Furthermore, lack of sufficient ATP, which is caused by PARP, results in a damaged cell undergoing necrosis rather than apoptosis.164 PARP inhibition may improve barrier function and suppress inflammation by preventing the necrosis of colonic epithelial cells after oxidant-mediated injury.165 Several studies depict the potential of melatonin to attenuate PARP activation.166,–168 Inflammation and oxidative stress lead to DNA damage, and PARP gets activated in response to DNA damage.169 Thus, an ability of melatonin to reduce PARP activation might be attributed to its anti-inflammatory, antioxidant, and antigenotoxic effects. Because UC is associated with inflammation, oxidative stress, and DNA damage, which in turn, leads to PARP activation; melatonin may decrease PARP activation by modulating inflammation, oxidative stress, and genotoxicity. Therefore, PARP may be another potential target for melatonin to combat inflammation, oxidative stress, and the subsequent DNA damage associated with UC. Death Proteins Death proteins are the cytosolic enzymes that spill out of the cell when the plasma membrane gets ruptured during necrosis and become activated in the presence of high extracellular calcium concentration.170 In the case of fulminating UC, there occurs colonic wall necrosis, which in turn, may result into the leakage of these hydrolytic enzymes from the necrotic cells.171 These death proteins hydrolyze their respective substrates in the plasma membrane of neighboring cells, thereby leading to self-perpetuating tissue injury.170 The evidence for a role of death proteins in the pathogenesis of UC was obtained from a study in which TNBS-induced UC led to an elevation in the level of calpain, a cytosolic enzyme, in the colon mucosa of rat, and calpain inhibitor had been known to reduce the colon injury caused by dinitrobenzene sulfonic acid in rat.172,173 Another cytosolic enzyme, secretory phospholipase A2, increases in the colonic epithelial cells and in serum of the patients with UC.174,175 Melatonin reduces the levels of various proteases such as calpain and caspase-3 in an experimental model of spinal cord injury.176,177 Melatonin, because of its anti-inflammatory and antioxidant properties, reduces UC-associated mucosal damage in experimental models of colitis.34,72 Furthermore, melatonin plays a vital role in the regeneration of mucosal epithelium in the GIT.9 Because of its mucosal healing property, it can ameliorate the colonic mucosal necrosis in UC and lower the levels of hydrolytic enzymes, thereby alleviating the progression of self-perpetuated tissue injury. Hence, elucidating the potential role of melatonin in the reduction of UC-associated elevated death proteins may unravel its prospective as a better interventional agent to ameliorate the severity of UC. Telomere Dysfunction Telomerase enzyme is a key regulator of telomere length that signals cell death. The process of accelerated colon aging has been observed in patients with UC, which is further associated with telomere shortening in the colon mucosa.178,179 In UC, there is a reduction in the level of telomerase and alteration in telomere-binding proteins such as telomere repeat–binding factor 2 (TRF2) and repressor activator protein-1 (RAP1). TRF2 and RAP1 mRNA expression decreases in activated T lymphocytes in the patients with UC, suggesting a possible telomeric deficiency of these proteins, which could lead to telomeric dysfunction.180,181 Chronic inflammation and oxidative stress are associated with shorter leukocyte telomere lengths in the patients with periodontitis and antioxidants have been reported to prevent telomere shortening in women consuming a multivitamin supplement.182,183 Shorter telomeres associated with UC may be due to persistent inflammation and oxidative stress. Melatonin, being a potent anti-inflammatory and antioxidant agent, might play some role in preventing UC-associated telomere shortening by modulating inflammation and oxidative stress. Strategies can be explored to use melatonin alone or in combination with other enteroprotective agents to mitigate the severity of this debilitating disease. Epigenetic Alterations UC is associated not only with genetic, but also with epigenetic alterations, in the colonic mucosa.184,185 UC is characterized by an increased expression of various inflammatory genes in the colonic mucosa.37 Histone acetylation modulates the function of various cytokine receptors, nuclear hormone receptors, intracellular signaling molecules, and transcription factors.186 Increased expression of HDAC9 is associated with colitis in mice, and HDAC9-knockout mice are resistant to developing colitis.187 Apart from alterations in histone acetylation, UC is linked to modifications in DNA methylation.185,188 Studies reported that patients with UC exhibit DNA hypermethylation of tumor suppressor genes such as estrogen receptor gene (ESR-1) and tumor suppressor gene candidate-3 (TUSC3, N-33).189 Furthermore, epigenetic changes such as DNA methylation and histone modification are thought to play an essential role in inflammation-induced carcinogenesis. Histone hyperacetylation ameliorates experimental colitis in mice.190 Melatonin induces histone hyperacetylation and inhibits DNA methyltransferase in experimental studies.191,192 Thus, melatonin may play an important role in the epigenetic regulation and alter UC-associated epigenetic modifications, thereby ameliorating the disease severity. The detailed molecular pathways that can be targeted by melatonin for its better therapeutic intervention in UC have been depicted in Figure 1. Figure 1. View largeDownload slide Diagrammatic representation of the molecular targets, both cytoplasmic and nuclear (genetic and epigenetic), of melatonin for possible protection against UC. “M” represents melatonin. “?” depicts that the targets have not yet been explored for possible protection with melatonin in UC. Figure 1. View largeDownload slide Diagrammatic representation of the molecular targets, both cytoplasmic and nuclear (genetic and epigenetic), of melatonin for possible protection against UC. “M” represents melatonin. “?” depicts that the targets have not yet been explored for possible protection with melatonin in UC. Missing Links and Future Prospects Melatonin has been explored as an interventional agent for ameliorating the severity of UC, both in experimental and clinical conditions, because it acts on various molecular targets. However, there are several other unexplored molecular targets on which melatonin can act to exert its possible beneficial effects in UC. Uncovering previously unexplored targets of melatonin in UC using cutting-edge science with well-designed experimental and clinical trials can provide better opportunity for future research. The effects of melatonin on UC-associated genetic and epigenetic alterations require detailed examination for the design of better clinical strategies. The use of genomic and proteomic techniques could make a substantial contribution in identifying the novel targets for melatonin at the early stages of disease initiation and for more reliable intervention. Interestingly, melatonin-loaded nanomedicines have shown better efficacy in an experimental model of sepsis.193 This approach of therapy should be explored in preclinical and clinical trials for the treatment of UC. Recently, it has been shown that higher accumulation of liposomal drug in inflammatory area and specific release of liposomes by enteric coated capsules provide better option for the treatment of colonic disease.194 Similar concept can be used for the targeted delivery of melatonin-loaded liposomes to the colon in patients with UC. Targeted delivery of hormones such as methylprednisolone and budesonide has already depicted better efficacy in UC.195,196 Melatonin, being a hormone, can also be targeted to colon in a similar manner. Topical melatonin such as melatonin suppositories and enemas could provide better efficacy in colitis. Furthermore, targeted delivery of melatonin to colon could enhance its effectiveness and could be the key for its ability to impact a desired pathway involved in the pathogenesis of UC. For better efficacy, attention must be given to both receptor-mediated and receptor-independent actions of melatonin in UC and its dose and time of administration. This would form the basis for further studies to understand the mechanisms involved in melatonin-mediated protection against UC and the associated extra-intestinal manifestations. It will also provide a clue on how to best take advantage of the potential therapeutic targets of melatonin for the treatment of UC. The targets mentioned in this review need critical validation at both preclinical and clinical situation for better translation. Conclusions UC is a debilitating disease with severe health consequences having considerable impact on the quality of patients' life. Thus, a better understanding of ways to treat UC would be of potential relevance to a great number of people. It has been postulated that inflammation, oxidative stress, and the subsequent DNA damage are hallmarks in the development and progression of UC. Melatonin has the potential to interact with multiple molecular targets and can provide an exciting avenue to explore various novel strategies to reduce the occurrence and to mitigate the severity of UC. However, this cannot be solely based on administering the compound under investigation to the patients with UC. 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TI - A Review of the Use of Melatonin in Ulcerative Colitis: Experimental Evidence and New Approaches
JO - Inflammatory Bowel Diseases
DO - 10.1097/01.MIB.0000436962.32164.6e
DA - 2014-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-review-of-the-use-of-melatonin-in-ulcerative-colitis-experimental-NZmUOp49m0
SP - 553
EP - 563
VL - 20
IS - 3
DP - DeepDyve
ER -